US20090192122A2 - Inflammatory cytokine release inhibitor - Google Patents

Inflammatory cytokine release inhibitor Download PDF

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Publication number
US20090192122A2
US20090192122A2 US11/835,997 US83599707A US2009192122A2 US 20090192122 A2 US20090192122 A2 US 20090192122A2 US 83599707 A US83599707 A US 83599707A US 2009192122 A2 US2009192122 A2 US 2009192122A2
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United States
Prior art keywords
group
substituted
trifluoromethyl
phenyl
phenyl group
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Abandoned
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US11/835,997
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US20080249071A1 (en
Inventor
Susumu Muto
Tatsuo Nagano
Tomomi Sotome
Akiko Itai
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Institute of Medicinal Molecular Design Inc IMMD
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Institute of Medicinal Molecular Design Inc IMMD
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Priority to US11/835,997 priority Critical patent/US20090192122A2/en
Publication of US20080249071A1 publication Critical patent/US20080249071A1/en
Publication of US20090192122A2 publication Critical patent/US20090192122A2/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the present invention relates to pharmaceutical compositions having inhibitory activity against the production and release of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF- ⁇ ), and having inhibitory activity against the activation of NF- ⁇ B.
  • IL interleukin
  • IL-6 interleukin-6
  • IL-8 tumor necrosis factor
  • TNF- ⁇ tumor necrosis factor
  • Inflammation is a basic defense mechanism to various infestations, where inflammatory cytokine such as interleukin (IL)-1 and TNF- ⁇ (tumor necrosis factor) are known to play important roles.
  • IL interleukin
  • TNF- ⁇ tumor necrosis factor
  • This NF- ⁇ B is a hetero dimer(also called as complex) of p65 (also called as Rel A) and p50 (also called as NF- ⁇ B ⁇ 1), usually binds to I- ⁇ B when external stimulation does not exist, and exists in cytoplasm as an inactive type.
  • I- ⁇ B is phosphorated by various external stimulations such as oxidative stress, cytokine, lipopolysaccharide, virus, UV, free radical, protein kinase C to become ubiquitin, and then decomposed by proteasome (Verma I. M., Stevenson J. K., et al., Genes Dev., 9, 2723-2735 (1995)).
  • NF- ⁇ B separated from I- ⁇ B immediately move into nucleus, and plays a role as a transcription factor by binding to promoter region which has recognition sequence of NF- ⁇ B.
  • IKK I ⁇ B kinase abbreviated as “IKK”
  • IKK- ⁇ a also called as IKK1
  • IKK- ⁇ also called as IKK2
  • aspirin which is a widely used anti-inflammatory agent, which is known to be based on inhibition of NF- ⁇ B activation (Kopp E., et al., Science, 265, 956-959 (1994)). Moreover, it was revealed that aspirin regulates release and activation of NF- ⁇ B by binding reversibly to IKK- ⁇ which is I ⁇ I; B kinase competing with ATP and by inhibiting phosphorylation of I- ⁇ B (Yin M. J., et al., Nature, 396, 77-80 (1998)).
  • Glucocorticoids steroid hormones
  • dexamethasone suppress NF- ⁇ B activation by binding to their receptors (called as glucocorticoid receptor, Scheinman R. I., et al., Science, 270, 283 (1995)).
  • glucocorticoid receptor a receptor for NF- ⁇ n B activation
  • Leflunomide as an immunosuppressive agent, as an isoxazole-type agent, also has NF- ⁇ B inhibitory action (Manna S., et al., J.
  • IKK- ⁇ Compounds having specific inhibitory action against IKK- ⁇ , found by using IKK- ⁇ as a target which directly induces phosphorylation of IKK- ⁇ , are expected to have inhibitory action against production and release of the target inflammatory cytokine and inhibitory action against production of inflammatory cell adhesion molecules, without affecting other signal transfer pathway, that is, without serious side effects.
  • NF- ⁇ B activation is induced by the aforementioned external stimulation, and as a result, proteins such as inflammatory cytokine are expressed.
  • TNF- ⁇ and interleukine (IL)-1 whose gene expression itself is considered to be regulated positively by NF- ⁇ B to form positive feedback loop (TNF- ⁇ NF- ⁇ B ⁇ TNF- ⁇ ) and is considered to participate in chronicity of inflammation (18 th Meeting of The Japanese Inflammatory Society, Symposium “Mechanism of Antirheumatic Pharmaceutical composition and New Development” Tokyo, 2000). Accordingly, the compounds which specifically inhibit IKK- ⁇ as a target are expected to be useful drugs for inflammatory diseases advanced in a chronic stage and diseases caused by TNF- ⁇ and IL-1.
  • an object of the present invention is to provide medicaments useful for preventive and/or therapeutic treatment of inflammatory disorders, autoimmune disease such as chronic arthrorheumatism, and bone disease such as osteoporosis, in which inflammatory cytokine is participated.
  • Another object of the present invention is to provide an inhibitor against release of an inflammatory cytokine which avoids side effects by specifically inhibiting IKK- ⁇ , and has inhibitory activity against N F- ⁇ B activation.
  • the inventors of the present invention carried out search for compounds having inhibitory action against NF- ⁇ B activation by selective inhibition of IKK- ⁇ by using computerized molecular design technology to solve the aforementioned object.
  • Appropriate protein kinases with high homology with IKK- ⁇ were selected from the kinases whose structures are registered in PDB (Protein Data Bank), and three-dimensional structure model of IKK- ⁇ was constructed by applying the homology modeling technique employing the chosen kinase as a template, and then binding mode of aspirin to the ATP binding region of IKK- ⁇ and characteristic intermolecular interactions were analyzed by using automatic search program for binding modes of a drug molecule to a protein.
  • an automatic search program of a ligand from a three-dimensional compound database based on the tree-dimensional structure of the protein was carried out, and compounds potentially be specific inhibitors against IKK- ⁇ were selected by a virtual screening out of compounds registered in a database of commercial compounds. Further, inhibitory activity of those compounds against NF- ⁇ B activation was confirmed by a reporter assay method under TNF- ⁇ stimulation. Among them, the compounds with potent activities were further studied on the binding mode to IKK- ⁇ and interactions. On the basis of these results, the present invention was achieved by further carrying out search from compound databases of analogous compounds and syntheses
  • the medicament of the present invention is: (1) that having inhibitory action against NF- ⁇ B activation which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in the main chain is 2 to 4 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a hetero arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as
  • preferred medicaments include:
  • [Substituent group ⁇ -6e] a halogen atom, cyano group, a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 6 halogenated allyl group which may be substituted, a C 6 to C 10 aryl group which may be substituted, a C 7 to C 16 aralkyl group which may be substituted, a 6 membered nonaromatic heteroring group, a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 6 to C 10 aryl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted;
  • the medicament having inhibitory action against NF- ⁇ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1-dimethyl)-ethyl]thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-ethylthiazol-2-yl group, 5-methyl-4-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-yl group, 4-benz
  • the medicament having inhibitory action against NF- ⁇ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 4-(1,1-dimethyl)ethyl-5[(2,2-dimethyl)propionyl]thiazol-2-yl group.
  • the medicament of the present invention may be used as gene expression inhibitor of one or more substances selected from the following substance group ⁇ : [Substance group ⁇ ] tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony-stimulating factor, interferon 6, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class ⁇ , B2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C 4 , c-myc, transcript derived from HIV gene, transcript derived from HTLV gene, transcript derived from simian virus 40 gene, transcript derived from cytomegalovirus gene, and transcript derived from adenovirus gene.
  • TNF tumor necrosis factor
  • interleukin-1 interleukin-2,
  • the medicament of the present invention may be used as an inhibitor against production and release of an inflammatory cytokine or as an immunosuppressive agent.
  • the medicament of the present invention may be used for preventive and/or therapeutic treatment of one or more diseases selected from the following disease group ⁇ -1:
  • Disease group ⁇ -1 an inflammatory disease, an autoimmune disease, an allergic disease, a cancers such as carcinoma and sarcoma, a metabolic disease, a cardiovascular disease, an angioproliferation disease, a septic disease, a viral disease, or from the following disease group ⁇ -2 which is resulted from NF- ⁇ B activation or overproduction of an inflammatory cytokine:
  • the present invention provides use of each of the substances for manufacture of the medicament according to the aforementioned (1) to (38).
  • the present invention provides: a method for inhibiting activation of NF- ⁇ B in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for inhibiting expression of one or more substances selected from the aforementioned substance group 6 in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for inhibiting production and release of an inflammatory cytokine in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for immune inhibition in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for preventive and/or therapeutic treatment of one or more diseases selected from aforementioned disease group ⁇ -1, which comprises the step of administering the aforementioned disease
  • the present invention further provides (1) a compound represented by the general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof: wherein Z 1 represents 2-hydroxyphenyl group which may have a substituent in the 5-position or 2-acetoxyphenyl group which may have a substituent in the 5-position, E 1 represents a phenyl group substituted with two C 1 to C 6 halogenated alkyl groups wherein said phenyl group may further have one or more substituents in addition to the two C 1 to C 6 halogenated alkyl groups, provided that the following compounds are excluded:
  • Preferred examples include:
  • E 1 is a phenyl group substituted with two C 1 to C 6 alkyl groups each of which is substituted with one or more fluorine atoms wherein said phenyl group may further have one or more substituents in addition to the two C 1 to C 6 alkyl groups which are substituted with one or more fluorine atoms;
  • E 1 is a phenyl group substituted with two C 1 to C 6 alkyl groups each of which is substituted with three or more fluorine atoms wherein said phenyl group may further have one or more substituents in addition to the two C 1 to C 6 alkyl groups each of which is substituted with three or more fluorine atoms;
  • E 1 is a group represented by the following formula wherein one of R 1e2 and R 1e3 represents hydrogen atom and the other represents a C 1 to C 6 alkyl group substituted with three or more fluorine atoms, and R 1e5 represents a C 1 to C 6 alkyl group substituted with three or more fluorine atoms; (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E 1 is 3,5-bis(trifluoromethyl)phenyl group, or 2,5-bis(trifluoromethyl)phenyl group; (7) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E 1 is 2,5-bis(trifluoromethyl)phenyl group; (8) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof wherein E 1 is 2,5-bis(trifluoromethyl)phenyl group; (8) the compound or a pharma
  • the present invention further provides the compound represented by the following general formula (I-2) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof: wherein Z 2 represents 2-hydroxyphenyl group which may be substituted in the 5-position, or 2-acetoxyphenyl group which may be substituted in the 5-position, E 2 represents a phenyl group whose 3-position or 5-position is substituted with a C 1 to C 6 halogenated alkyl group wherein said phenyl group may further have one or more substituents (except when the substituent is a C 1 to Cr, halogenated alkyl group) in addition to the C 1 to C 6 halogenated alkyl group in the 3-position or 5-position, provided that the following compounds are excluded:
  • Preferred examples include:
  • E 2 is a phenyl group whose 3-position or 5-position is substituted with a C 1 to C 6 alkyl group which is substituted with one or more fluorine atoms wherein said phenyl group may have one or more substituents (except when the substituent is a C 1 to C 6 halogenated alkyl group) in addition to the C 1 to C 6 alkyl group in the 3-position or the 5-position which is substituted with one or more fluorine atoms:
  • E 2 is a phenyl group whose 3-position or 5-position is substituted with a C 1 to C 6 allyl group which is substituted with three or more fluorine atoms wherein said phenyl group may have one or more substituents (except when the substituent is a C 1 to C 6 halogenated alkyl group) in addition to the C 1 to C 6 alkyl group in the 3-position or the 5-position which is substituted with three or more fluorine atoms;
  • E 2 is a phenyl group whose 3-position or 5-position is substituted with a C 1 to C 6 alkyl group which is substituted with three or more fluorine atoms wherein said phenyl group may have one or more substituents selected from the following substituent group ⁇ -7e in addition to the C 1 to C 6 alkyl group in the 3-position or 5-position which is substituted with three or more fluorine atoms: [substituent group ⁇ -7e] a halogen atom, nitro group, cyano group, a C 1 to C 6 alkyl group which may be substituted, a 5 to 6 membered nonaromatic heteroring group which may be substituted, a C 1 to C 6 alkoxy group which may be substituted, a C 1 to C 6 alkyl-sulfanyl group which may be substituted;
  • E 2 is 3-(trifluoromethyl)phenyl group, 9-fluoro-3-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 4-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-6-(trifluoromethyl)phenyl group,
  • the present invention provides (1) the compound represented by the following general formula (I-3) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
  • Z 3 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position
  • E 3 represents a group represented by the following formula wherein R 3e2 and R 3e3 may be the same or different and each represents hydrogen atom, a hydrocarbon group which may be substituted, or hydroxy group which may be substituted, except that where both of R 3e2 and R 3e3 are hydrogen atoms is excluded
  • R 3e5 represents a C 2 to C 6 hydrocarbon group which may be substituted.
  • Preferred examples include:
  • R 3e2 and R 3e3 may be the same or different and each represents hydrogen atom, a C 1 to C 6 alkyl group which may be substituted, or a C 1 to C 6 alkoxy group which may be substituted, provided that where both of R 3e2 and R 3e3 are hydrogen atoms is excluded, R 3e5 is a C 2 to C 6 alkyl group which may be substituted;
  • the present invention further provides (1) the compound represented by the following general formula (I-4) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof: wherein Z 4 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E 4 is a group represented by the following formula: wherein R 4e4 represents a hydrocarbon group which may be substituted, R 4e5 represents a halogen atom, cyano group, acyl group which may be substituted, or a heteroring group which may be substituted.
  • Preferred examples include:
  • R 4e4 represents a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 6 halogenated alkyl group which may be substituted, or a C 6 to C 10 aryl group which may be substituted
  • R 4e5 represents a halogen atom, cyano group, a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 6 to C 10 aryl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted, or a 6-membered nonaromatic heteroring group which may be substituted;
  • E 4 is 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5 bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-pheny
  • Z 4 is a group represented by the following formula: wherein A 4 represents hydrogen atom or acetyl group, R 4z represents a halogen atom, a C 6 to C 10 aryl group which may be substituted, or a 5-membered heteroaryl group; (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein A 4 is hydrogen atom; and (7) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R 4z is a halogen atoms.
  • any of fluorine atom, chlorine atom, bromine atom, or iodine atom may be used unless otherwise specifically referred to.
  • hydrocarbon group examples include, for example, an aliphatic hydrocarbon group, an aryl group, an arylene group, an aralkyl group, a bridged cyclic hydrocarbon group, a spiro cyclic hydrocarbon group, and a terpene hydrocarbon.
  • aliphatic hydrocarbon group examples include, for example, alkyl group, alkenyl group, alkynyl group, alkylene group, alkenylene group, alkylidene group and the like which are straight chain or branched chain monovalent or bivalent acyclic hydrocarbon groups; cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group, cycloalkyl-alkyl group, cycloalkylene group, and cycloalkenylene group, which are saturated or unsaturated monovalent or bivalent alicyclic hydrocarbon groups.
  • alkyl group examples include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyL 2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n
  • alkenyl group examples include, for example, vinyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-2-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en
  • alkynyl group examples include, for example, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl, dec-1-yn-1-yl, dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl, dodec-1-yn-1-yl, dodec-11-yn-1-y
  • alkylene group examples include, for example, methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, and 1,1,4,4-tetramethylbutane-1,4-diyl group, which are C 1 to C 8 straight chain or branched chain alkylene groups.
  • alkenylene group examples include, for example, ethene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl, but-2-ene-1,4-diyl, 2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl, and hex-3-ene-1,6-diyl group, which are C 1 to C 6 straight chain or branched chain allylene groups.
  • alkylidene group examples include, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, and hexylidene, which are C 1 to C 6 straight chain or branched chain alkylidene groups.
  • cycloalkyl group examples include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, which are C 3 to C 8 cycloalkyl groups.
  • the aforementioned cycloalkyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl group.
  • Examples of the cycloalkenyl group includes, for example, 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, and 1-cyclopenten-1-yl group, which are C 3 to C 6 cycloalkenyl groups.
  • the aforementioned cycloalkenyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4,-tetrahydronaphthalen-2-yl,
  • cycloalkanedienyl group examples include, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and 2,5-cyclohexanedien-1-yl group, which are C 5 to C 6 cycloalkanedienyl groups.
  • the aforementioned cycloalkanedienyl group may be fused with benzene ring, naphthalene ring and the like, and examples of the group include, for example, 1-indenyl and 2-indenyl group.
  • cycloalkyl-alkyl group examples include the group in which one hydrogen atom of alkyl group is substituted with cycloalkyl group, and include, for example, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, cyclooctylmethyl, and 6-cyclooctylhexyl group, which are C 4 to C 14 cycloalkyl-alkyl groups.
  • cycloalkylene group examples include, for example, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, and cyclooctane-1,2-
  • cycloalkenylene group examples include, for example, 2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl, 2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl, 2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl, 3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl, and 1-cyclohexene-1,2-diyl group, which are C 3 to CG cycloalkenylene groups.
  • aryl group examples include a monocyclic or a fused polycyclic aromatic hydrocarbon group, and include, for example, phenyl, 1-naphtyl, 2-naphtyl, anthryl, phenanthryl, and acenaphthylenyl group, which are C 6 to C 14 aryl groups.
  • the aforementioned aryl group may be fused with aforementioned C 3 to C 8 cycloalkyl group, C 3 to C 6 cycloalkenyl group, C 5 to C 6 cycloalkanedienyl group or the like, and the example of the group include, for example, 4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl, 5-phenalenyl, 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and 9-phenalenyl group.
  • arylene group examples include, for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, and anthracene-1,4-diyl, which are C 6 to C 14 arylene groups.
  • aralkyl group examples include the group in which one hydrogen atom of alkyl group is substituted with aryl group, and include, for example, benzyl, 1-naphtylmethyl, 2-naphtylmethyl, anthracenylmethyl, phenanthrenyl methyl, acenaphthylenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 4-phenylbutyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)buty
  • bridged cyclic hydrocarbon group examples include, for example, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]octyl, and adamanty group.
  • spiro cyclic hydrocarbon group examples include, for example, spiro[3.4]octyl, and spiro[4.5]decane-1,6-dienyl group.
  • terpene hydrocarbon examples include, for example, geranyl, neryl, linalyl, phytyl, menthyl, and bornyl group.
  • halogenated allyl group examples include the group in which one hydrogen atom of alkyl group is substituted with a halo-en atom, and include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, and perfluorohexyl group, which are C 1 to C 6 straight chain or branched chain halogenated alkyl groups substituted with 1 to 13 halogen atoms.
  • heterocyclic group examples include, for example, a monocyclic or a fused polycyclic hetero aryl group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic nonaromatic heterocyclic group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms).
  • Examples of the monocyclic heteroaryl group include, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazol)-4-yl, (1,2,3-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl,
  • fused polycyclic heteroaryl group examples include, for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b] thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl, 1-indolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol)
  • Examples of the monocyclic nonaromatic heterocyclic group include, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl, 1-imidazolidinyl, 9-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl), 2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl), piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl, 2-tetrahydropyranyl, morpholino, (thiomorpholin)-4-yl, 1-piperazinyl
  • fused polycyclic nonaromatic heterocyclic group examples include, for example, 9-quinuclidinyl, 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7′-isochromanyl, 8-isochromanyl, 2-thiochromanyl, 3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl, 7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl, 3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl, 6-isothiochromanyl, 7-isothiochromanyl, 8-thi
  • heterocyclic groups a monocyclic or a fused polycyclic hetero aryl groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic nonaromatic heterocyclic groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms) are referred to as “cyclic amino groups”.
  • Examples include, for example, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino, morpholino, 1-piperazinyl, thiomorpholin-4-yl, 1-homopiperidinyl, 1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazolin-1-yl, 2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl,
  • hydrocarbon-oxy group examples include the group in which hydrogen atom of hydroxy, group is substituted with hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon.
  • hydrocarbon-oxy group examples include, for example, alkoxy group (alkyl-oxy group), alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group, cycloalkyl-alkyl-oxy group and the like which are aliphatic hydrocarbon-oxy groups, aryl-oxy group, aralkyl-oxy group, and alkylene-dioxy group.
  • alkoxy(alkyl-oxy group) examples include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-
  • alkenyl-oxy group examples include, for example, vinyloxy, (prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl)oxy, (but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, (2-methylprop-2-en-1-yl)oxy, (1-methylprop-2-en-1-yl)oxy, (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy, (pent-3-en-1-yl)oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy, (3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy, (hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy, (4-methyl
  • alkynyl-oxy group examples include, for example, ethynyloxy, (prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but-1-yn-1-yl)oxy, (but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy, (pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy, (hept-1-n ⁇ 1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy, (oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy, (dec-1-yn-1-yl)oxy, (dec-9-yny
  • cycloalkyl-oxy group examples include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy group, which are C 3 to C 8 cycloalkyl-oxy groups.
  • cycloalkyl-alkyl-oxy group examples include, for example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy, 6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy, cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctylhexyloxy group, which are C 4 to C 14 cycloalkyl-alkyl-oxy groups.
  • aryl-oxy group examples include, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, and acenaphthylenyloxy group, which are C 6 to C 14 aryl-oxy groups.
  • aralkyl-oxy group examples include, for example, benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy, phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-(1-naphthyl)ethoxy, 1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, 3-phenylpropoxy, 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy, 4-phenylbutoxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy, 5-phenylpentyloxy, 5-(1-n-
  • alkylenedioxy group examples include, for example, methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and 1,1-dimethylmethylenedioxy group.
  • halogenated alkoxy group(halogenated alkyl-oxy group) examples include the group in which hydrogen atom of hydroxy group is substituted with halogenated alkyl group, and include, for example, fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy group, which are C 1 to C 6 straight chain or branched chain halogenated alkoxy groups substituted with 1 to 13 halogen atoms.
  • heterocyclic-oxy group examples include the group in which hydrogen atom of hydroxy group is substituted with the heterocyclic group, and examples of the heteroring include similar groups to the aforementioned heterocyclic group.
  • heteroring-oxy group examples include, for example, a monocyclic heteroaryl-oxy group, a fused polycyclic heteroaryl-oxy group, a monocyclic nonaromatic heteroring-oxy group, a fused polycyclic nonaromatic heteroring-oxy group and the like.
  • Examples of the monocyclic heteroaryl-oxy group include, for example, 3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, and (pyrimidin-4-yl)oxy group.
  • fused polycyclic heteroaryl-oxy group examples include, 5-indolyloxy, (benzimidazol-2-yl)oxy, 2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy group.
  • Examples of the monocyclic nonaromatic heteroring-oxy group include, for example, 3-pyrrolidinyloxy, and 4-piperidinyloxy group.
  • fused polycyclic nonaromatic heteroring-oxy group examples include, for example, 3-indolynyloxy, and 4-chromanyloxy group.
  • hydrocarbon-sulfanyl group examples include the group in which hydrogen atom of sulfanyl group is substituted with a hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon.
  • hydrocarbon-sulfanyl group examples include, for example, alkyl-sulfanyl group, alkenyl-sulfanyl group, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group, cycloalkyl-alkyl-sulfanyl group and the like which are aliphatic hydrocarbon-sulfanyl groups, aryl-sulfanyl group, and aralkyl-sulfanyl group.
  • alkyl-sulfanyl group examples include, for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, (2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl, neopentylsulfanyl, (1,2-dimethylpropyl)sulfanyl, (1-ethylpropyl)sulfanyl, n-hexylsulfanyl, (4-methylpentyl)sulfanyl, (3-methylpentyl)sulfanyl, (2-methylpentyl)sulfanyl
  • alkenyl-sulfanyl group examples include, for example, vinylsulfonyl, (prop-1-en-1-yl)sulfanyl, alkylsulfanyl, isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl, (but-2-en-1-yl)sulfanyl, (but-3-en-1-yl)sulfanyl, (2-methylprop-2-en-1-yl)sulfanyl, (1-methylprop-2-en-1-yl)sulfanyl, (pent-1-en-1-yl)sulfanyl, (pent-2-en-1-yl)sulfanyl, (pent-3-en-1-yl)sulfanyl, (pent-4-en-1-yl)sulfanyl, (3-methylbut-2-en-1-yl)sulfanyl, (3-methylbut-3-en-1-yl)sulfanyl, (hex
  • alkynyl-sulfanyl group examples include, for example, ethynylsulfanyl, (prop 1-yn-1-yl)sulfanyl, (prop-2-yn-1-yl)sulfanyl, (but-1-yn-1-yl)sulfanyl, (but-3-yn-1-yl)sulfanyl, (1-methylprop-2-yn-1-yl)sulfanyl, (pent-1-yn-1-yl)sulfanyl.
  • cycloalkyl-sulfanyl group examples include, for example, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, and cyclooctylsulfanyl group, which are C 3 to C 8 cycloalkyl-sulfanyl groups.
  • cycloalkyl-alkyl-sulfanyl group examples include, for example, (cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl, (2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl, (4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl, (6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl, (cyclopentyl)methyl)sulfanyl, (2-cyclobutylmethyl)sulfanyl, (cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl, (2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl, (4-cyclo
  • aryl-sulfanyl group examples include, for example, phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl, fenanthrylsulfanyl, and acenaphthylenylsulfanyl group, which are C 6 to C 11 aryl-sulfanyl groups.
  • aralkyl-sulfanyl group examples include, for example, benzylsulfanyl, (1-naphthylmethyl)sulfanyl, (2-naphthylmethyl)sulfanyl, (anthracenylmethyl)sulfanyl, (phenanthrenylmethyl)sulfanyl, (acenaphthylenylmethyl)sulfanyl, (diphenylmethyl)sulfanyl, (1-phenethyl)sulfanyl, (2-phenethyl)sulfanyl, (1-(1-naphthyl)ethyl)sulfanyl, (1-(2-naphthyl)ethyl)sulfanyl, (9′ (1-naphthyl)ethyl)sulfanyl, (2-(2-naphthyl)ethyl)sulfanyl, (3-phenylpropyl
  • halogenated alkyl-sulfanyl group examples include the group in which hydrogen atom of sulfanyl group is substituted with a halogenated alkyl group, and include, for example, (fluoromethyl)sulfanyl, (chloromethyl)sulfanyl, (bromomethyl)sulfanyl, (iodomethyl)sulfanyl, (difluoromethyl)sulfanyl, (trifluoromethyl)sulfanyl, (trichloromethyl)sulfanyl, (9,2,2-trifluoroethyl)sulfanyl, (pentafluoroethyl)sulfanyl, (3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl)sulfanyl, (heptafluoroisopropyl)sulfanyl, (nonafluorobutyl)sulfanyl, and (perflu
  • heterocyclic-sulfanyl group examples include the group in which hydrogen atom of sulfanyl group is substituted with the heterocyclic group, and examples of the heteroring include similar groups to the aforementioned heterocyclic group.
  • heteroring-sulfanyl group examples include, for example, monocyclic heteroaryl-sulfanyl group, fused polycyclic heteroaryl-sulfanyl group, monocyclic nonaromatic heteroring-sulfanyl group, and fused polycyclic nonaromatic heteroring-sulfanyl group.
  • Examples of the monocyclic heteroaryl-sulfanyl group include, for example, (imidazol-2-yl)sulfanyl, (1,2,4-triazol-2-yl)sulfanyl, (pyridin-2-yl)sulfanyl, (pyridin-4-yl)sulfanyl, and (pyrimidin-2-yl)sulfanyl group.
  • fused polycyclic heteroaryl-sulfanyl group examples include, for example, (benzimidazol-2-yl)sulfanyl, (quinolin-2-yl)sulfanyl, and (quinolin-4-yl)sulfanyl group.
  • Examples of the monocyclic non-aromatic heteroring-sulfanyl group include, for example, (3-pyrrolidinyl)sulfanyl group and (4-piperidinyl)sulfanyl group.
  • fused polycyclic nonaromatic heteroring-sulfanyl group examples include, for example, (3-indolinyl)sulfanyl and (4-chromanyl)sulfanyl group.
  • acyl group examples include, for example, formyl group, glyoxyloyl group, and thioformyl group, and the group represented by the following formulas: wherein R a1 and R b1 may be the same or different and each represents a hydrocarbon group or heterocyclic group, or R a1 and R b1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.
  • hydrocarbon-carbonyl groups whose examples include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2 naphthoyl, and phenylacetyl group.
  • heterocyclic groups Those groups in which R a1 is a heterocyclic group are referred to as “heteroring-carbonyl” groups whose examples include, for example, 2-thenoyl, 3-furoyl, nicotinoyl, and isonicotinoyl group.
  • hydrocarbon-oxy-carbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl groups” whose examples include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl) groups” whose example includes, for example, 3-pyridyloxycarbonyl group.
  • hydrocarbon-carbonyl-carbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl groups” whose example includes, for example, pyruvoyl group, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-carbonyl-carbonyl groups”.
  • hydrocarbon-oxy-carbonyl-carbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl groups” whose examples include, for example, methoxalyl and ethoxalyl groups, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-carbonyl groups”.
  • hydrocarbon-sulfanyl-carbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-sulfanyl-carbonyl groups”.
  • hydrocarbon-thiocarbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-thiocarbonyl groups”.
  • hydrocarbon-oxy-thiocarbonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-oxy-thiocarbonyl groups”.
  • N-hydrocarbon-carbamoyl groups those groups in which R a1 is a hydrocarbon group are referred to as referred to as “N-hydrocarbon-carbamoyl groups” whose example includes, for example, N-methylcarbamoyl group, and those groups in which R a1 is a heterocyclic group are referred to as “N-heteroring-carbamoyl groups”.
  • N,N-dihydrocarbon-carbamoyl groups those groups in which both R a1 and R b1 are hydrocarbon groups are referred to as “N,N-dihydrocarbon-carbamoyl groups” whose example includes, for example, N,N-dimethylcarbamoyl group
  • those groups in which both R a1 and R b1 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl groups”
  • those groups in which R a1 is a hydrocarbon group and R b1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring substituted carbamoyl groups”
  • those groups in which R a1 and R b1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-carbonyl groups” whose example includes, for example, morpholino-carbon
  • N-hydrocarbon-thiocarbamoyl groups those groups in which R a1 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “N-heteroring-thiocarbamoyl groups”.
  • those groups in which both R a1 and R b1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl groups”
  • those groups in which both R a1 and R b1 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl groups”
  • those groups in which R a1 is a hydrocarbon group and R b1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl groups”
  • those groups in which R a1 and R b1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-thiocarbonyl groups”.
  • N-hydrocarbon-sulfamoyl groups those groups in which R a1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl groups”.
  • N,N-di(hydrocarbon)-sulfamoyl groups those groups in which both R a1 and R b1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl groups” whose example includes, for example, N,N-dimethylsulfamoyl group
  • those groups in which both R a1 and R b1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl groups”
  • those groups in which R a1 is a hydrocarbon group and R b1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl groups”
  • those groups in which R a1 and R b1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl groups” which include
  • N-hydrocarbon-sulfinamoyl groups those groups in which R a1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl groups”.
  • those groups in which both R a1 and R b1 , are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl groups”
  • those groups in which both R a1 and R b1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl groups”
  • those groups in which R a1 is a hydrocarbon group and R b1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl groups”
  • those groups in which R a1 and R b1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl groups”.
  • hydrocarbon-oxy-sulfonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-oxy-sulfonyl groups”.
  • hydrocarbon-oxy-sulfinyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl groups”, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl groups”.
  • hydrocarbon-sulfonyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl groups” whose examples include, for example, methanesulfonyl and benzenesulfonyl, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-sulfonyl groups”.
  • hydrocarbon-sulfinyl groups those groups in which R a1 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl groups” whose examples include, for example, methylsulfinyl and benzenesulfinyl, and those groups in which R a1 is a heterocyclic group are referred to as “heteroring-sulfinyl groups”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas ( ⁇ -1A) through ( ⁇ -21A) include the similar groups to the aforementioned hydrocarbon group.
  • Examples of the hydrocarbon-carbonyl groups represented by the formula ( ⁇ -1A) include, for example, an alkyl-carbonyl group, an alkenyl-carbonyl group, an alkynyl-carbonyl group, a cycloalkyl-carbonyl group, a cycloalkenyl-carbonyl group, a cycloalkanedienyl-carbonyl group, a cycloalkyl-alkyl-carbonyl group which is an aliphatic hydrocarbon-carbonyl group, an aryl-carbonyl group, an aralkyl-carbonyl group, a bridged cyclic hydrocarbon-carbonyl group, a spirocyclic hydrocarbon-carbonyl group, and a terpene family hydrocarbon-carbonyl.
  • Examples of the heteroring in the groups represented by the aforementioned formulas ( ⁇ -1A) through ( ⁇ -21A) include similar groups to the aforementioned heterocyclic group.
  • Examples of the heteroring-carbonyl group represented by the formula ( ⁇ -1A) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic nonaromatic heteroring-carbonyl group, and a fused polycyclic nonaromatic heteroring-carbonyl.
  • groups represented by the formulas ( ⁇ -2A) through ( ⁇ -21A) are similar to those explained above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas ( ⁇ -10A) through ( ⁇ -16A) include similar groups to the aforementioned cyclic amino group.
  • acyl groups which may be substituted.
  • substituent existing in the functional group examples include, for example, halogen atoms, oxo group, thioxo group, nitro group, nitroso group, cyano group, isocyano group, cyanato group, thiocyanato group, isocyanato group, isothiocyanato group, hydroxy group, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalo group, methooxalo group, thiocarboxy group, dithiocarboxy group, carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfinamoyl group, phosphono group, hydroxy-phosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heteroring-oxy group, hydro
  • substituents When two or more substituents exist according to the above-mentioned definition of “which may be substituted”, said two or more substituents may combine to each other, together with atom(s) to which they bind, to form a ring.
  • substituents for these cyclic groups, as ring-constituting atoms (ring forming atoms), one to three kinds of one or more hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like may be included, and one or more substituents may exist on the ring.
  • the ring may be monocyclic or fused polycyclic, and aromatic or nonaromatic.
  • substituents according to the abovementioned definition of “which may be substituted” may further be substituted with the aforementioned substituents at the chemically substitutable positions on the substituent.
  • Kind of substituents, number of substituents, and positions of substituents are not particularly limited, and when the substituents are substituted with two or more substituents, they may be the same or different.
  • substituents include, for example, a halogenated alkyl-carbonyl group (trifluoroacetyl group as an example), a halogenated alkyl-sulfonyl group (trifluoromethanesulfonyl group as an example), an acyl-oxy group, an acyl-sulfanyl group, an N-hydrocarbon-amino group, an N,N-di(hydrocarbon)-amino group, an N-heteroring-amino group, an N-hydrocarbon-N-heteroring-amino group, an acyl-amino group, and a di(acyl)-amino group.
  • substitution on the aforementioned substituents may be repeated multiple orders.
  • acyl-oxy group examples include the group in which hydrogen atom of hydroxy group is substituted with acyl group, and include, for example, formyloxy group, glyoxyloyloxy group, and thioformyloxy group, and the group represented by the following formulas: wherein R a2 and R b2 may be the same or different and represent a hydrocarbon group or a heterocyclic group, or R a2 and R b2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.
  • acyl-oxy group among the groups represented by the formula ( ⁇ -1B), those groups in which R a2 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-oxy group” whose examples include, for example, acetoxy and benzoyloxy group, and those groups in which R a2 is a heterocyclic group are referred to as “heteroring-carbonyl-oxy group”.
  • N-hydrocarbon-carbamoyl-oxy group groups in which R a2 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-oxy group”, and groups in which R a2 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-oxy group”.
  • those groups in which both R a2 and R b2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-oxy group”
  • those groups in which both R a2 and R b2 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl-oxy group”
  • those groups in which R a2 is a hydrocarbon group and R b2 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-carbamoyl-oxy group”
  • those groups in which R a2 and R b2 combine each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-oxy group”.
  • those groups in which both R a2 and R b2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-oxy group”
  • those groups in which both R a2 and R b2 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-oxy group”
  • those groups wherein R a2 is a hydrocarbon group and R b2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl-oxy group”
  • those groups in which R a2 and R h2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-oxy group”.
  • N-hydrocarbon-sulfamoyl-oxy groups those groups in which R a2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-oxy groups”, and those groups in which R a2 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl-oxy groups”.
  • those groups in which both R a2 and R b2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-oxy groups”
  • those groups in which both R a2 and R b2 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-oxy groups”
  • those groups in which R a2 is a hydrocarbon group and R b2 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-sulfamoyl-oxy groups”
  • those groups in which R a2 and R b2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl-oxy groups”.
  • N-hydrocarbon-sulfinamoyl-oxy groups those groups in which R b2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-oxy groups”, and those groups where R a2 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl-oxy groups”.
  • those groups in which both R a2 and R b2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-oxy groups”
  • those groups in which both R a2 and R b2 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl-oxy groups”
  • those groups in which R a2 is a hydrocarbon group and R b2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl-oxy groups”
  • those groups in which R a2 and R b2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl-oxy group”.
  • hydrocarbon-oxy-sulfinyl-oxy groups those groups in which R a2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-oxy groups”, those groups in which R a2 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl-oxy groups”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas ( ⁇ -1B) through ( ⁇ -21B) include the similar groups to the aforementioned hydrocarbon group.
  • Examples of the hydrocarbon-carbonyl-oxy groups represented by the formula ( ⁇ -1B) include, for example, an alkyl-carbonyl-oxy group, an alkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, a cycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, a cycloalkanedienyl-carbonyl-oxy group, and a cycloalkyl-alkyl-carbonyl-oxy group, which are aliphatic hydrocarbon-carbonyl-oxy groups, an aryl-carbonyl-oxy group, an aralkyl-carbonyl-oxy group, a bridged cyclic hydrocarbon-carbonyl-oxy group, a spirocyclic hydrocarbon-carbonyl
  • Examples of the heteroring in the groups represented by the aforementioned formulas ( ⁇ -1B) through ( ⁇ -21B) include similar groups to the aforementioned heterocyclic group.
  • Examples of the heteroring-carbonyl group represented by the formula ( ⁇ -1B) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic nonaromatic heteroring-carbonyl group, and a fused polycyclic nonaromatic heteroring-carbonyl group.
  • groups represented by the formulas ( ⁇ -2B) through ( ⁇ -21B) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas ( ⁇ -10B) through ( ⁇ -16B) include similar groups to the aforementioned cyclic amino group.
  • acyl-oxy group hydrocarbon-oxy group, and heterocyclic-oxy group are generically referred to as “substituted oxy group”.
  • substituted oxy group hydrocarbon-oxy group, and heterocyclic-oxy group are generically referred to as “substituted oxy group”.
  • substituted oxy group and hydroxy group are generically referred to as “hydroxy group” which may be substituted.
  • acyl-sulfanyl examples include the group in which hydrogen atom of sulfanyl group is substituted with acyl group, and include, for example, formylsulfanyl group, glyoxylsulfanyl group, and thioformylsulfanyl group, and groups represented by the following formulas: wherein R a3 and R b3 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or R a3 and R b3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • acyl-sulfanyl group among the groups represented by the formula ( ⁇ -1C), those groups in which R a3 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl sulfanyl group”, and those groups in which R a3 is a heterocyclic group are referred to as “heteroring-carbonyl-sulfanyl group”.
  • N-hydrocarbon-carbamoyl-sulfanyl group those groups in which R a3 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-sulfanyl group”, and those groups in which R a3 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-sulfanyl group”.
  • those groups in which both R a3 and R b3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group”
  • those groups in which and R a3 and R b3 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-sulfanyl group”
  • those groups in which R a3 is a hydrocarbon group and R b3 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-thiocarbomoyl-sulfanyl group”
  • those groups in which R a1 and R b3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-sulfamoyl group”.
  • N-hydrocarbon-sulfamoyl-sulfanyl group those groups in which R a3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-sulfanyl group”, and those groups in which R a3 is a heteroring group are referred to as “N-heterocyclic-sulfamoyl-sulfanyl group”.
  • those groups in which both R a3 and R b3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-sulfanyl group”
  • those groups in which both R a3 and R b3 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-sulfinyl group”
  • those groups in which R a3 is a hydrocarbon group and R b3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl-sulfanyl group”
  • those groups in which R a3 and R b3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfonyl-sulfanyl group”.
  • N-hydrocarbon-sulfinamoyl-sulfanyl group those groups in which R a3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-sulfanyl group”, and those groups in which R a3 is a heteroring group are referred to as “N-heterocyclic-sulfinamoyl-sulfanyl group”.
  • those groups in which both R a3 and R b3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl group”
  • those groups in which both R a3 and R b3 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl-sulfanyl group”
  • those groups in which R a3 is a hydrocarbon group and R b3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl-sulfanyl group”
  • those groups in which R a3 and R b3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfanyl-sulfanyl group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas ( ⁇ -1C) through ( ⁇ -21C) include similar groups to the aforementioned hydrocarbon group.
  • Examples of the hydrocarbon-carbonyl-sulfanyl groups represented by the formula ( ⁇ -1C) include, for example, an alkyl-carbonyl-sulfanyl group, an alkenyl-carbonyl-sulfanyl group, an alkynyl-carbonyl-sulfanyl group, a cycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbonyl-sulfanyl group, a cycloalkanedienyl-carbonyl-sulfanyl group, a cycloalkyl-alkyl-carbonyl-sulfanyl group which is an aliphatic hydrocarbon-carbonyl-sulfanyl groups, an aryl-carbonyl-sulfanyl group, an aralkyl-
  • Examples of the heteroring in the groups represented by the aforementioned formulas ( ⁇ -1C) through ( ⁇ -21C) include similar groups to the aforementioned heterocyclic group.
  • Examples of the heteroring-carbonyl-sulfanyl group represented by the formula ( ⁇ -1C) include, for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a fused polycyclic heteroaryl-carbonyl-sulfanyl group, a monocyclic nonaromatic heteroring-carbonyl-sulfanyl group, and a fused polycyclic nonaromatic heteroring-carbonyl-sulfanyl group.
  • groups represented by the formula ( ⁇ -2C) through ( -21C) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas ( ⁇ -10C) through ( ⁇ -16C) include similar groups to the aforementioned cyclic amino group.
  • acyl-sulfanyl group hydrocarbon-sulfanyl group, and heterocyclic-sulfanyl group are generically referred to as “substituted sulfanyl group”.
  • substituted sulfanyl group and sulfanyl group are generically referred to as “sulfanyl groups” which may be substituted.
  • N-hydrocarbon-amino group examples include the group in which one hydrogen atom of amino group is substituted with a hydrocarbon group, and include, for example, an N-alkyl-amino group, an N-alkenyl-amino group, an N-alkynyl-amino group, an N-cycloalkyl-amino group, an N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, and an N-aralkyl-amino group.
  • N-alkyl-amino group examples include, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, (2-methylbutyl)amino, (1-methylbutyl)amino, neopentylamino, (1,2-dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexylamino, (4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino, (1-methylpentyl)amino, (3,3-dimethylbutyl)amino, (2,2-dimethylbutyl)amino, (1,1-di
  • N-alkenyl-amino group examples include, for example, vinyl amino, (prop-1-en-1-yl)amino, alkylamino, isopropenylamino, (but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino, (2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino, (pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino, (pent-3-en-1-yl)amino, (pent-4-en-1-yl)amino, (3-methylbut-2-en-1-yl)amino, (3-methylbut-3-en-1-yl)amino, (hex-1-en-1-yl)amino, (hex-2-en-1-yl)amino, (hex-3-en-1-y
  • N-alkynyl-amino group examples include, for example, ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino, (but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino, (1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino, (pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino, (hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino, (oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (n
  • N-cycloalkyl-amino group examples include, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, and cyclooctylamino group, which are C 3 to C 8 N-cycloalkyl-amino groups.
  • N-cycloalkyl-alkyl-amino group examples include, for example, (cyclopropylmethyl)amino, (1-cyclopropylethyl)amino, (2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino, (4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino, (6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino, (2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino, (4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino, (cyclooc
  • N-aryl-amino group examples include, for example, phenylamino, 1-naphthylamino, 2-naphtylamino, anthrylamino, phenanthrylamino, and acenaphthylenylamino, which are C 6 to C 14 N-mono-arylamino groups.
  • N-aralkyl-amino group examples include, for example, benzylamino, (1-naphthylmethyl)amino, (2-naphthylmethyl)amino, (anthracenylmethyl)amino, (phenanthrenylmethyl)amino, (acenaphthylenylmethyl)amino, (diphenylmethyl)amino, (1-phenethyl)amino, (2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino, (1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino, (2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino, (3-(1-naphthyl)propyl)amino, (3-
  • N,N-di(hydrocarbon)-amino group examples include the group in which 2 hydrogen atoms of amino group are substituted with hydrocarbon group, and include, for example, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N,N-di-n-propylamino, N,N-diisopropylamino, N-allyl-N-methylamino, N-(prop-2-yn-1-yl)-N-methylamino, N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino, N-cyclohexylmethylamino-N-methylamino, N,N-diphenylamino, N-methyl-N-phenylamino, N,N-dibenzylamino, and N-benzyl-N-methylamino group.
  • N-heteroring-amino group examples include the group in which one hydrogen atom of amino group is substituted with heterocyclic group, and include, for example, (3-pyrrolizinyl)amino, (4-piperidinyl)amino, (2-tetrahydropyranyl)amino, (3-indolinyl)amino, (4-chromanyl)amino, (3-thienyl)amino, (3-pyridyl)amino, (3-quinolyl)amino, and (5-indolyl)amino.
  • N-hydrocarbon-N-heteroring-amino group examples include the group in which 2 hydrogen atoms of amino group are substituted with hydrocarbon group and heterocyclic group respectively, and include, for example, N-methyl-N-(4-piperidinyl)amino, N-(4-chromanyl)-N-methylamino, N-methyl-N-(3-thienyl)amino, N-methyl-N-(3-pyridyl)amino, N-methyl-N-(3-quinolyl)amino and the like.
  • acyl-amino group examples include the group in which one hydrogen atom of the amino group is substituted with an acyl group, and include, for example, formylamino group, glyoxyloylamino group, and thioformylamino group, and groups represented by the following formulas: wherein R a4 and R b4 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or R a4 and R b4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • acyl-amino group among the groups represented by the formula ( ⁇ -1D), those groups in which R a4 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-amino group”, and those groups in which R a4 is a heterocyclic group are referred to as “heteroring-carbonyl-amino group”.
  • N-hydrocarbon-carbamoyl group those groups in which R a4 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl group”, and those groups in which R a4 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-amino group”.
  • those groups in which both R a4 and R b4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-amino group”
  • those groups in which both R a4 and R b4 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl-amino group”
  • those groups in which R a4 is a hydrocarbon group and R b4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-carbamoyl-amino group”
  • those groups in which R a4 and R b4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-amino group”.
  • those groups in which both R a4 and R b1 are hydrocarbon groups are referred to as “N,N′-di(hydrocarbon)-thiocarbamoyl-amino group”
  • those groups in which both R a4 and R b4 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-amino group”
  • those groups in which R a4 is a hydrocarbon group and R b4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl-amino group”
  • those groups in which R a4 and R b4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-amino group”.
  • N-hydrocarbon-sulfamoyl-amino group those groups in which R u4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-amino group”, and those groups in which R a4 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl-amino group”.
  • those groups in which both R a4 and R b -1 are hydrocarbon groups are referred to as “di(hydrocarbon)-sulfamoyl-amino group”
  • those groups in which both R a4 and R b1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-amino group”
  • those groups in which R a4 is a hydrocarbon group and R b4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl-amino group”
  • those groups in which R a4 and R b4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfonyl-amino group”.
  • N-hydrocarbon-sulfinamoyl-amino group those groups in which R a4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-amino group”, and those groups in which R a4 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl-amino group”.
  • those groups in which both R a4 and R b4 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-amino group”
  • those groups in which both R a4 and R b4 are heterocyclic groups are referred to as “O,O′-di(heteroring)-phosphono-amino group”
  • those groups in which R a4 is a hydrocarbon group and R b4 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heteroring-phosphono-amino group”.
  • hydrocarbon-carbonyl-amino groups represented by the formula ( ⁇ -1D) include, for example, an alkyl-carbonyl-amino group, an alkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, a cycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl-amino group, a cycloalkanedienyl-carbonyl-amino group, a cycloalkyl-alkyl-carbonyl-amino group which is an aliphatic hydrocarbon-carbonyl-amino groups, an aryl-carbonyl-amino group, an aralkyl-carbonyl-amino group, a bridged cyclic hydrocarbon-carbonyl-a
  • Examples of the heteroring in the groups represented by the aforementioned formulas ( ⁇ -1D) through ( ⁇ -21D) include similar groups to the aforementioned heterocyclic group.
  • Examples of the heteroring-carbonyl-amino group represented by the formula ( ⁇ -1D) include, for example, a monocyclic heteroaryl-carbonyl-amino group, a fused polycyclic heteroaryl-carbonyl-amino group, a monocyclic nonaromatic heterocyclic-carbonyl-amino group, and a fused polycyclic nonaromatic heterocyclic-carbonyl-amino group.
  • groups represented by the formulas ( ⁇ -2D) through ( ⁇ -21D) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas ( ⁇ -10D) through ( ⁇ -16D) include similar groups to the aforementioned cyclic amino group.
  • the aforementioned di(acyl)-amino group include the group in which 2 hydrogen atoms of amino group are substituted with acyl groups in the definitions of the aforementioned substituents according to “which may be substituted”.
  • Examples include, for example, di(formyl)-amino group, di(glyoxyloyl)-amino group, and di(thioformyl)-amino group, and groups represented by the following formulas wherein R a5 and R b5 may be the same or different and represent hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or R a5 and R b5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • those groups in which both R a5 and R b5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group”
  • those groups in which both R a S and R b5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-thiocarbamoyl]-amino group”
  • those groups in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-thiocarbamoyl)-amino group”
  • those groups in which R a5 and R b5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-thiocarbonyl)-amino group”.
  • those groups in which both R a5 and R b5 are hydrocarbon groups are referred to as “bis[N,N;-di(hydrocarbon)-sulfamoyl]-amino group”
  • those groups in which both R a5 and R b5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-sulfamoyl]-amino group”
  • those groups in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-sulfamoyl)-amino group”
  • those groups in which R a5 and R b5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfonyl)amino group”.
  • those groups in which R a5 and R b5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino group”
  • those groups in which R a5 and R b5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-sulfinamoyl]amino group”
  • those groups in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-sulfinamoyl)-amino group”
  • those groups in which R a5 and R b5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfinyl)amino group”.
  • those groups in which both R a5 and R b5 are hydrocarbon groups are referred to as “bis[O,O′-di(hydrocarbon)-phosphono]-amino group”
  • those groups in which both R a5 and R b5 are heterocyclic groups are referred to as “bis[O,O′-di(heteroring)-phosphono]-amino group”
  • those groups in which R a5 is a hydrocarbon group and R a5 is a heterocyclic group are referred to as “bis(O-hydrocarbon—O′-heteroring-phosphono)-amino group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas ( ⁇ -1E) through ( ⁇ -21E) include similar groups to the aforementioned hydrocarbon group.
  • Examples of the bis(hydrocarbon-carbonyl)-amino groups represented by the formula ( ⁇ -1E) include, a bis(alkyl-carbonyl)-amino group, a bis(alkenyl-carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino group, a bis(cycloalkyl-carbonyl)-amino group, a bis(cycloalkenyl-carbonyl)-amino group, a bis(cycloalkanedienyl-carbonyl)-amino group, a bis(cycloalkyl-allyl-carbonyl)-amino group which is a bis(aliphatic hydrocarbon-carbonyl)-amino group, a bis(aryl-carbonyl)-amino group,
  • Examples of the heteroring in the groups represented by the aforementioned formulas ( ⁇ -1E) through ( ⁇ -21E) include similar groups to the aforementioned heterocyclic group.
  • Examples of the bis(heteroring-carbonyl)-amino group represented by the formula ( ⁇ -1E) include, for example, bis(monocyclic heteroaryl-carbonyl)-amino group, bis(fused polycyclic heteroaryl-carbonyl)-amino group, bis(monocyclic nonaromatic heterocyclic-carbonyl)-amino group, and bis(fused polycyclic nonaromatic heterocyclic-carbonyl)-amino group.
  • groups represented by the formulas ( ⁇ -2E) through ( ⁇ -21E) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas ( ⁇ -10E) through ( ⁇ -16E) include similar groups to the aforementioned cyclic amino group.
  • acyl-amino group and di(acyl)-amino group are generically referred to as “acyl substituted amino group”.
  • acyl substituted amino group N-hydrocarbon-amino group, N,N-di(hydrocarbon)-amino group, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-amino group, cyclic amino group, acyl-amino group, and di(acyl)-amino group.
  • substituted amino group and amino group are generically referred to as “amino groups which may be substituted”.
  • Connecting group whose number of atoms of main chain is 2 to 4” in the definition of X means connecting groups wherein 2 to 4 atoms in a main chain link together between rings Z and E.
  • the aforementioned “number of atoms of the main chain” is counted so as to minimize the number of connecting atoms existing between the rings Z and E, regardless of the presence or absence of hetero atom(s). For example, the number of atoms of 1,2-cyclopentylene is counted as 2, the number of atoms of 1,3-cyclopentylene is counted as 3, the number of atoms of 1,4-phenylene is counted as 4, the number of atoms of 2,6-pyridine-diyl is counted as 3.
  • the aforementioned “connecting group whose number of atoms of main chain is 2 to 4” is formed by one functional group selected from the following group of divalent group ⁇ -1, or formed by combining 2 to 4 functional groups of 1 to 4 kinds selected from the following divalent group ⁇ -2.
  • connection group whose number of atoms of a main chain is 2 to 4 is preferably a group selected from the following “connecting group ⁇ ”.
  • Connecting group a the following formulas: wherein the bond at the left end binds to ring Z and the bond at the right end binds to to E.
  • Examples of the substituent according to “connecting group which may be substituted” in the definition of “a connecting group whose number of atoms of the main chain is 2 to 4”, include similar groups to the substituents in the definition of the aforementioned “which may be substituted”.
  • a C 1 to C 6 alkyl group is preferred, and a methyl group is more preferred.
  • the substituent may combine with a substituent of the ring E or Z, together with atoms to which they bind, to form a cyclic group which may be substituted. Examples include the compounds represented by the general formula (I) being those represented by the following formulas:
  • examples of A include hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of the “arene” in “an arene which may be substituted” in the definition of ring Z include a monocyclic or fused heterocyclic aromatic hydrocarbon, and include, for example, benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, and acenaphylene ring.
  • C 6 to C 10 arenes such as benzene ring, naphthalene ring and the like are preferred, benzene ring and naphthalene ring are more preferred, and benzene ring is most preferred.
  • hetero arene examples include a monocyclic or a fused polycyclic aromatic heterocyclic rings containing at least one of 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and include, for example, furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring, 1,2,3-thiadiazole ring, 1,2,3-triazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, 1,2,3-triazine ring, 1,2,4-triazine
  • substituents include halogen atoms, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, acyl group which may be substituted, ureido group which may be substituted, thioureido group which may be substituted, and diazenyl group which may be substituted, which are defined as those of substituent group ⁇ -1z.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group ⁇ -1z, and the “hydroxy group which may be substituted” in the definition of R z include similar groups to the “hydroxy group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituents in the definition of the aforementioned “which may be substituted”.
  • Hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”, a C 1 to C 6 on alkoxy group which may be substituted is more preferred, and methoxy group is further preferred.
  • Examples of the “amino group which may be substituted” in the definition of the substituent group ⁇ -1z, and the “amino group which may be substituted” in the definition of R z include similar group to the “amino group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent according to the definition of the aforementioned “which may be substituted”.
  • Di(hydrocarbon)-amino group and hydrocarbon-carbonyl-amino group are preferred as the “amino group which may be substituted”, di(C 1 to C 6 alkyl)-amino group and C 6 to C 10 aryl-carbonyl-amino group are more preferred, and dimethylamino group and benzoylamino group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group ⁇ -1z, and the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R z include similar groups to the substituents according to the definition of the aforementioned “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 6 halogenated allyl group which may be substituted, a C 2 to C 6 alkenyl group which may be substituted, a C 1 to C 6 alkynyl group which may be substituted, a C 6 to C 10 aryl group which may be substituted, and a C 1 to C 16 aralkyl group which may be substituted are preferred as the “hydrocarbon group which may be substituted”, and methyl group, tert-butyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1[(benzyloxy)aminoethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethylphenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenylethen-1-yl group, 9,2-dicyan
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of the substituent group ⁇ -1z, and the substituent in the definition of “heterocyclic group which may be substituted” in the definition of R z include similar groups to the substituents according to the definition of the aforementioned “which may be substituted”.
  • a heteroaryl group which may be substituted is preferred as the “heterocyclic group which may be substituted”, a 5 to 6-membered heteroaryl group which may be substituted is more preferred, and 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, and 2-pyridyl group are further preferred.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group ⁇ -1z, and the “acyl group which may be substituted” in the definition of R z include similar groups exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • Carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a hydrocarbon-carbonyl group which may be substituted, a hydrocarbon-oxy-carbonyl group which may be substituted, a heteroring-carbonyl group which may be substituted, and a heteroring-sulfonyl group which may be substituted are preferred as the “acyl group which may be substituted”, carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, and a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted are more preferred, and [3,5-bis(trifluoromethyl)phenyl]carbamoyl group
  • Examples of the substituent in the definition of “ureido group which malt be substituted” in the definition of the substituent group ⁇ -1z, and the substituent in the definition of “ureido group which may be substituted” in the definition of R z include similar groups to the substituent explained for the definition “which may be substituted”. 3-Phenylureido group is preferred as the “ureido group which may be substituted”.
  • Examples of the substituent in the definition of “thioureido group which may be substituted” in the definition of the substituent group ⁇ -1z, and the substituent in the definition of “thioureido group which may be substituted” in the definition of R z include similar groups to the substituent explained for the definition “which may be substituted”. (3-Phenylthio)ureido group is preferred as the “thioureido group which may be substituted”.
  • Examples of the substituent in the definition of “diazenyl group which may be substituted” in the definition of the substituent group ⁇ -1z, and the substituent in the definition of “diazenyl group which may be substituted” in the definition of R z include similar groups to the substituent explained for the definition “which may be substituted”.
  • (4-Nitrophenyl)diazenyl group and ⁇ [(4-pyridin-9-yl)sulfamoyl]pheny ⁇ diazenyl group are preferred as the “diazenyl group which may be substituted”.
  • R z examples include halogen atom, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, acyl group which may be substituted, ureido group which may be substituted, thioureido group which may be substituted, and diazenyl group which may be substituted, and halogen atom is most preferred.
  • Examples of the aryl group of “an aryl group which may be substituted” in the definition of E include similar groups to the aryl group in the definition of the aforementioned “hydrocarbon group”, and C 6 to C 10 aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group and the like are preferred, and phenyl group is most preferred.
  • Examples of the substituent in the definition of “an aryl group which may be substituted” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted”.
  • Preferred embodiments of the phenyl group according to “an aryl group which may be substituted” in the definition of E are:
  • Examples of the “C 1 to C 6 halogenated alkyl group” in “phenyl group substituted with two C 1 to C 6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C 1 to Cr, halogenated allyl groups” in the definition of E include similar groups to those exemplified in the aforementioned definition of “C 1 to C 6 halogenated alkyl group”, and examples of the substituent in the definition of “said phenyl group may be substituted in addition to the two C 1 to C 6 halogenated alkyl groups” include similar groups to the substituent explained for the definition “which may be substituted”.
  • Phenyl group substituted with two C 1 to Cu; halogenated alkyl groups is preferred as the “phenyl group substituted with two C 1 to C 6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C 1 to CG halogenated alkyl groups”.
  • 3,5-Bis(trifluoromethyl)phenyl group and 2,5-bis(trifluoromethyl)phenyl group are preferred, and 3,5-bis(trifluoromethyl)phenyl group is most preferred.
  • Examples of the substituent in the definition of “phenyl group substituted with one C 1 to C 6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C 1 to C 6 halogenated alkyl group) in addition to one C 1 to C 6 halogenated alkyl group” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted” (a C 1 to C 6 halogenated alkyl group is excluded).
  • Halogen atoms, nitro group, cyano group, hydroxy group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, sulfanyl group which may be substituted which are defined in substituent group ⁇ -1e are preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group ⁇ -1e include similar groups to the “hydroxy group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • Hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”
  • C 1 to C 6 alkoxy group which may be substituted which is defined as substituent group ⁇ -2e is more preferred, and methoxy group is further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group ⁇ -1e, and the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R z include similar groups to the substituent explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted which is defined in substituent group ⁇ -2e is preferred as the “hydrocarbon group which may be substituted”, and methyl group is more preferred.
  • heterocyclic group which may be substituted examples include similar groups to the substituents explained for the definition “which may be substituted”.
  • a 5 to 6-membered nonaromatic heterocyclic group which may be substituted which is defined in substituent group ⁇ -2e is preferred as the “heterocyclic group which may be substituted”, and 1-pyrrolidinyl group and morpholino group are more preferred.
  • Examples of the “sulfanyl group which may be substituted” in the definition of the substituent group ⁇ -1e include similar groups to the “sulfanyl group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • a hydrocarbon-sulfanyl group which may be substituted is preferred as the “sulfanyl group which may be substituted”, and a C 1 to C 6 alkyl-sulfanyl group which may be substituted, which is defined in substituent group ⁇ -2e, is more preferred, and methylsulfanyl group is further preferred.
  • C 1 to C 6 halogenated alkyl group in “phenyl group substituted with one C 1 to C 6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C 1 to C 6 halogenated alkyl group) in addition to the C 1 to C 6 halogenated alkyl group” in the definition of E include similar groups to the aforementioned “C 1 to C 6 halogenated alkyl group”.
  • C 1 to C 6 alkyl groups substituted with one or more fluorine atoms are preferred, C 1 to C 6 alkyl groups substituted with three or more fluorine atoms are more preferred, and trifluoromethyl group is most preferred.
  • Examples of the “phenyl group substituted with one C 1 to C 6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C 1 to C 6 halogenated alkyl group) in addition to the C 1 to C 6 halogenated alkyl group” in the definition of E include 29(trifluoromethyl)phenyl group, 3-(trifluoromethyl)phenyl group, 4-(trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 2-chloro-4-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 4-fluoro-3-(triflu
  • 2-Chloro-5-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, and 3-methoxy-5-(trifluoromethyl)phenyl group are more preferred, and 2-chloro-5-(trifluoromethyl)phenyl group is most preferred.
  • Examples of the substituent in the definition of “phenyl group which may be substituted (except with a C 1 to C 6 halogenated alkyl group)” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted”. Halogen atoms, nitro group, hydroxy group which may be substituted, hydrocarbon group which may be substituted, and acyl group which may be substituted which are defined in substituent group ⁇ -3e are preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group ⁇ -3e include similar groups to the “hydroxy group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • Unsubstituted hydroxy group and a hydrocarbon-oxy group which may be substituted are preferred as the “hydroxy group which may be substituted”, and unsubstituted hydroxy group and C 1 to C 6 alkoxy group which may be substituted which are defined in substituent group ⁇ -4e are more preferred, and unsubstituted hydroxy group and methoxy group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group ⁇ -3e include similar groups to the substituent explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted, a C 6 to C 10 aryl group which may be substituted, and a C 1 to C 8 alkylene group which may be substituted which are defined in substituent group ⁇ -4e are preferred as the “hydrocarbon group which may be substituted”, and methyl group, tert-butyl group and 1,1,4,4-tetramethylbutane-1,4-diyl group are more preferred.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group ⁇ -3e include the similar group to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”.
  • a hydrocarbon-carbonyl group which may be substituted and a hydrocarbon-oxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”.
  • a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted which are defined in substituent group ⁇ -4e are more preferred, and acetyl group and methoxycarbonyl group are further preferred.
  • heteroaryl group examples include similar groups to the “monocyclic heteroaryl group” and “fused polycyclic heteroaryl group” in the definition of the aforementioned “heteroaryl group”.
  • a 5 to 13-membered heteroaryl group is preferred, and thienyl group, pyrazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group, pyrimidinyl group, indolyl group, and carbazolyl group are more preferred, and thiazolyl group is most preferred.
  • Examples of the substituent in the definition of “thiazolyl group which may be substituted” in the above definition of E include similar groups to the substituent explained for the definition “which may be substituted”. Halogen atoms, cyano group, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, and acyl group which may be substituted which are defined as substituent group ⁇ -5e are preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group ⁇ -5e include similar groups to the substituents explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 6 halogenated alkyl group which may be substituted, a C 6 to C 10 aryl group which may be substituted, and a C 1 to C 6 aralkyl group which may be substituted which are defined in substituent group ⁇ -6e are preferred as the “hydrocarbon group which may be substituted”.
  • Methyl group, ethyl group, isopropyl group, n-butyl group, tert-butyl group, carboxymethyl group, trifluoromethyl group, phenyl group, 4-fluorophenyl group, 3-(trifluoromethyl)phenyl group, pentafluorophenyl group, and benzyl group are preferred.
  • heterocyclic group which may be substituted examples include similar groups to the substituent explained for the definition “which may be substituted”.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group ⁇ -5e include similar groups to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”.
  • a hydrocarbon-carbonyl group which may be substituted, a carbamoyl group which may be substituted, and a hydrocarbon-oxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”.
  • Carbamoyl group which may be substituted a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 6 to C 10 aryl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted which are defined in substituent group ⁇ -6e are more preferred, and N-methylcarbamoyl group, N-ethylcarbamoyl group, N-isopropylcarbamoyl group, N-(2-phenethyl)carbamoyl group, acetyl group, pivaloyl group, benzoyl group, and ethoxycarbonyl group are further preferred.
  • Z 1 is 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position.
  • halogenated alkyl group in the “phenyl group substituted with two C 1 to C 6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C 1 to C 6 halogenated all-yl groups” in the definition of E 1 include similar group to those exemplified in the aforementioned definition of “halogenated alkyl group”.
  • substituents according to the definition of “said phenyl group may be substituted in addition to the two C 1 to C 6 halogenated alkyl groups” include similar groups to the substituents explained for the definition “which may be substituted”.
  • phenyl group substituted with two C 1 to CG halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C 1 to C 6 halogenated alkyl groups an example is a phenyl group substituted with two C 1 to C 6 alkyl groups which is substituted with one or more fluorine atoms in which said phenyl group may further have substituents in addition to the two C 1 to C 6 alkyl groups substituted with one or more fluorine atoms.
  • More preferred example is a phenyl group substituted with two C 1 to C 6 alkyl groups which is substituted with three or more fluorine atoms in which said phenyl group may further have substituents in addition to the two C 1 to C 6 halogenated alkyl groups which are substituted with one or more fluorine atoms, and a phenyl group substituted with the two C 1 to C 6 alkyl groups which are substituted with three or more fluorine atoms is further preferred. It is preferred that these two substituents are substituted in the 2-position and 5-position, or 3-position and 5-position on the phenyl group.
  • Trifluoromethyl group is most preferred as “C 1 to C 6 alkyl group which is substituted with three or more fluorine atoms” in the definition of R 1e2 , R 1e3 , and R 1e5 .
  • a 1 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of R 1z include similar groups to the “hydroxy group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • a hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”.
  • a C 1 to C 6 alkoxy group which may be substituted is more preferred, and methoxy group is further preferred.
  • Examples of the “amino group which may be substituted” in the definition of R 1z include similar groups to the “amino group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”.
  • Di(hydrocarbon)-amino group and hydrocarbon-carbonyl-amino group are preferred as the “amino group which may be substituted”, and di(C 1 to C 6 alkyl)-amino group and Cc, to C 10 aryl-amino group are more preferred, and dimethylamino group and benzoylamino group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R 1z include similar groups to the substituent explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 6 halogenated alkyl group which may be substituted, a C 2 to Cc, alkenyl group which may be substituted, a C 2 to C 6 alkynyl group which may be substituted, a C 6 to C 10 aryl group which may be substituted, and a C 7 to C 16 aralkyl group which may be substituted are preferred as the hydrocarbon group which may be substituted”, and methyl group, tert-butyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(tri
  • heterocyclic group which may be substituted examples include similar groups to the substituent explained for the definition “which may be substituted”.
  • a heteroaryl group which may be substituted is preferred as the “heterocyclic group which may be substituted”, and a 5 to 6-membered heteroaryl group which may be substituted is more preferred, and 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, and 2-pyridyl group are further preferred.
  • Examples of the “acyl group which may be substituted” in the definition of R 1z include similar groups to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”.
  • Carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a hydrocarbon-carbonyl group which may be substituted, a hydrocarbon-oxy-carbonyl group which may be substituted, a heterocyclic-carbonyl group which may be substituted, and a heterocyclic-sulfonyl group which may be substituted are preferred as the “acyl group which may be substituted”, and carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 1 to C 6 alkoxy-carbonyl group which may be substituted, a 5-member heteroaryl-sulfonyl group which may be substituted, and a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted are more preferred.
  • 3,5-Bis(trifluoromethyl)phenyl]carbamoyl group dimethylcarbamoyl group, dimethylsulfamoyl group, acetyl group, isobutyryl group, methoxycarbonyl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, and (pyrrol-1-yl)sulfonyl group are further preferred.
  • Examples of the substituent in the definition of “ureido group which may be substituted” in the definition R 1z include similar groups to the substituents explained for the definition “which may be substituted”. 3-Phenylureido group is preferred as the “ureido group which may be substituted”.
  • Examples of the substituent in the definition of “thioureido group which may be substituted” in the definition of R 1z include similar groups to the substituents explained for the definition “which may be substituted”. (3-Phenylthio)ureido group is preferred as the “thioureido group which may be substituted”.
  • Examples of the substituent in the definition of “diazenyl group which may be substituted” in the definition of R 1z include similar groups to the substituents explained for the definition “which may be substituted”. (4-Nitrophenyl)diazenyl group and ⁇ 1(4-pyridin-2-yl)sulfamoyl]phenyl ⁇ diazenyl group are preferred as the “diazenyl group which may be substituted”.
  • R 1z examples include a halogen atom, nitro group cyano group, hydroxy group which may be substituted, amino group which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, a diazenyl group which may be substituted, a halogen atom, a C 1 to C 6 alkyl group which may be substituted, and a C 1 to C 6 halogenated alkyl group which may be substituted are preferred, and a halogen atom is most preferred.
  • Each compound defined by the aforementioned general formula (I-1) or a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, except the following 6 compounds, is novel compound, and uses of the compounds according to the present invention relating to the chemical substances are not limited.
  • Z 2 is 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted at the 5-position.
  • halogenated alkyl group in “phenyl group wherein a C 1 to C 6 halogenated alkyl group is substituted in the 3-position or 5-position” in the definition of E 2 (wherein said phenyl group may further have one or more substituents (except when the substituent is C 1 to C 6 halogenated alkyl group) in addition to the C 1 to C 6 halogenated alkyl group in the 3-position or 5-position) include similar groups to those exemplified in the aforementioned definition of “halogenated alkyl group”.
  • a C 1 to C 6 alkyl group substituted with one or more fluorine atoms is preferred, and a C 1 to C 6 alkyl group substituted with three or more fluorine atoms is more preferred, and trifluoromethyl group is most preferred.
  • substituents in the definition of “phenyl group wherein a C 1 to C 6 halogenated alkyl group is substituted in the 3-position or 5-position” include similar groups to the substituents explained for the definition “which may be substituted”.
  • Preferred examples of the “phenyl group wherein a C 1 to C 6 halogenated alkyl groups is substituted in the 3-position or 5-position (wherein said phenyl group may further have one or more substituents (except when the substituent is a C 1 to C 6 halogenated alkyl) in addition to the C 1 to C 6 halogenated alkyl group in the 3-position or 5-position))” in the definition of E 2 include 3-(Trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro
  • a 2 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • R 2a examples include a halogen atom, a C 1 to C 6 alkyl group which may be substituted, and a C 1 to C 6 halogenated alkyl group which may be substituted, and preferred examples include a halogen atom, methyl group, tert-butyl group, trifluoromethyl group, and pentafluoroethyl group.
  • Each compound defined by the aforementioned general formula ( ⁇ -2) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof, except the following 15 compounds, is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
  • Z 3 is 2-hydroxyphenyl group which may be substituted in the 5-position and 2-acetoxyphenyl group which may be substituted in the 5-position.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R 3e2 and R 3e3 include similar groups to the substituents explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group is preferred as the “hydrocarbon group which may be substituted”, and tert-butyl group is most preferred.
  • Examples of the substituent in the definition of “hydroxy group which may be substituted” in the definition of R 3e2 and R 3e3 include similar groups to the substituents explained for the definition “which may be substituted”.
  • a C 1 to Cc, alkoxy group is preferred as the “hydroxy group which may be substituted”, and methoxy group is most preferred.
  • Examples of the substituent in the definition of “C 2 to C 6 hydrocarbon group which may be substituted” in the definition of R 3e5 include similar groups to the substituents explained for the definition “which may be substituted”.
  • a C 2 to C 6 alkyl group is preferred as the “C 2 to C 6 alkyl group which may be substituted”, and tert-butyl group is most preferred.
  • a 2 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • R 3z examples include halogen atom, C 1 to C 6 alkyl group and C 1 to C 6 halogenated alkyl group, and halogen atom, methyl group, tert-butyl group, trifluoromethyl group, and pentafluoroethyl group are preferred.
  • Each compound defined by the aforementioned general formula (I-3) or a pharmacologically acceptable salt thereof, or a hydrate thereof and a solvate thereof is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
  • Z 4 includes 2-hydroxyphenyl group which may be substituted in the 5-position and 2-acetoxyphenyl group which may be substituted in the 5-position.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R 4e4 include similar groups to the substituent explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl group which may be substituted, a C 1 to C 10 halogenated alkyl group which may be substituted, and a C 6 to C 10 aryl group which may be substituted are preferred as the “hydrocarbon group which may be substituted”, and methyl group, isopropyl group, tert-butyl group, phenyl group, and pentafluorophenyl are more preferred.
  • Examples of the substituent in the definition of “acyl group which may be substituted” in the definition of R 4e5 include similar groups to the substituents explained for the definition “which may be substituted”.
  • a C 1 to C 6 alkyl-carbonyl group which may be substituted, a C 6 to C 10 aryl-carbonyl group which may be substituted, and a C 1 to C 6 alkoxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”, and acetyl group, pivaloyl group and benzoyl group are more preferred.
  • heterocyclic group which may be substituted examples include similar groups to the substituents explained for the definition “which may be substituted”.
  • a 6-membered nonaromatic heterocyclic group which may be substituted is preferred as the “heterocyclic group which may be substituted”, and piperidino group, morpholino group, 4-methylpiperazin-1-yl group, 4-phenylpiperazin-1-yl group are more preferred.
  • a 4 includes hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • R 4z examples include a halogen atom, a C 6 to C 10 aryl group, and a 5-membered heteroaryl group, and a halogen atom, phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 4-(trifluoromethyl)phenyl group, 1-pyrrolyl group, and 2-thienyl group are preferred.
  • Each compound defined by the aforementioned general formula (I-4) or a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
  • the compounds represented by the aforementioned general formulas (I) (I-1), (I-2), (I-3), and (I-4) may form salts.
  • pharmacologically acceptable salts include, when acidic groups exist, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salts, or ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, dicyclohexylammonium salt, and when basic groups exist, mineral acid salts such as hydrochloride, oxalate, hydrosulfate, nitrate, phosphate, or organic acid salts such as methane sulfonate, benzene sulfonate, para-toluene sulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate. Salts may
  • the compounds or salts thereof represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3), and (I-4) may exist as hydrates or solvates.
  • any of the aforementioned substances may be used.
  • the compounds represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3), and (I-4) may sometimes have one or more asymmetric carbons, and may exist as steric isomers such as optically active substance and diastereomer.
  • active ingredients of the medicament of the present invention pure forms of stereoisomers, arbitrary mixture of enantiomers or diastereomers, and racemates may be used.
  • the configuration may be in either E or Z, and as active ingredients of the medicament of the present invention, geometrical isomer in either of the configurations or a mixture thereof may be used.
  • the compounds represented by the general formula (I) can be prepared, for example, by methods shown bellow.
  • a 101 represents a hydrogen atom or protecting groups of hydroxy group (preferably, an alkyl group such as methyl group and the like; an aralkyl group such as benzyl group and the like; an acetyl group, an alkoxyalkyl group such as methoxymethyl group and the like; a substituted silyl group such as trimethylsilyl group or the like),
  • R 101 represents a hydrogen atom, a C 1 to C 6 alkyl group or the like
  • E 101 represents E or precursor of E in the definition of the general formula (I)
  • G represents a hydroxy group, halogen atoms (preferably, a chlorine atom), a hydrocarbon-oxy group (preferably, an aryl-oxy group which may be substituted by halogen atom), an acyl-oxy group, an imido
  • the amide (3) can be prepared by dehydrocondensation of the carboxylic acid derivative (1) and the amine (2). This reaction is carried out at a reaction temperature of from 0° C. to 180° C., without solvent or in an aprotic solvent, in the existence of an acid halogenating agent or a dehydrocondensating agent, and in the existence of or nonexistence of a base.
  • halogenating agent reagent examples include, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or the like, when A 101 is hydrogen atom, phosphorus trichloride is preferable, and when A 101 is acetyl group or the like, phosphorus oxychloride is preferable.
  • examples include, for example, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphorylazide or the like.
  • examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrocarbonate or the like, or organic bases such as pyridine, triethylamine, N,N′-diethylaniline or the like.
  • examples include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene, o-dichlorobenzene, N,N′-dimethylformamide, N-methylpyrrolidone or the like, when the reaction is carried out in the presence of the acid halogenating agent, particularly, toluene, monochlorobenzene, o-dichlorobenzene are preferable.
  • a target compound can be prepared, for example, by a method or similar method described in J. Med. Chem., 1998, 41, 2939, that the acid chloride is prepared and isolated from carboxylic acid in advance, then it is made to react with an amine having E 101 .
  • the final target compound (4) can be prepared by a reaction for deprotection and/or functional group modification in this step.
  • a reaction for deprotection and/or functional group modification for example, an amino group and its protector or precursor; a carboxy group and its protector or precursor; a hydroxy group and its protector or precursor
  • the final target compound (4) can be prepared by a reaction for deprotection and/or functional group modification in this step.
  • Various well-known methods can be used for the reaction.
  • Aforementioned methods are applicable by combining raw materials properly even in the case where X is other connecting group, for example, —SO 2 NH—, —NHCO—, —NHSO 2 —, —CONHCH 2 -, —CONHCH 2 CH 2 —; wherein the hydrogen atom on the said connecting group may be substituted.
  • X is other connecting group, for example, —SO 2 NH—, —NHCO—, —NHSO 2 —, —CONHCH 2 -, —CONHCH 2 CH 2 —; wherein the hydrogen atom on the said connecting group may be substituted.
  • the imine derivative of the formula (7) (wherein the definition of R 1 ⁇ R 4 and B the same as those in the general formula (I)) can be prepared by dehydrocondensation of the aldehyde(5) and the amine (6). This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in a solvent, in the existence of or nonexistence of a dehydrating agent.
  • a dehydrating agent examples include anhydrous magnesium sulfate, molecular sieves or the like.
  • the solvent examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • Aforementioned methods are applicable by combining raw materials properly even in the case where X is other connecting group, for example, —CONHN ⁇ C—; the hydrogen atom on the said connecting group may be substituted.
  • the target compound (8) can be prepared by reduction of the imine derivative (7).
  • This reaction is carried out at the reaction temperature of from 0° C. to 100° C. in a solvent, in the existence of a reducing agent.
  • a reducing agent examples include sodium borohydride, lithium borohydride or the like.
  • the solvent examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • this reaction can be carried out by a method of catalytic hydrogenation also.
  • the catalyst examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like.
  • solvent examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • the reaction is carried out at the reaction temperature of from 0° C. to 200° C., and the hydrogen pressure is at normal pressure or applied pressure.
  • the compounds represented by the general formula (I), wherein X is —CH—CH— (the hydrogen atom on the said connecting group may be substituted), can be prepared by a method described in the reaction scheme 3. wherein each of A and E has the same meaning as that defined in the general formula (I), W represents O,O′-di-hydrocarbon-phosphono group or triarylphosphonium group.
  • the target compound (11) can be prepared by dehydrocondensation of the aldehyde (9) and the phosphorus compound (10). This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the existence of a base.
  • a base examples include inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N′-diethylaniline or the like. Examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxan, methanol, ethanol, water or the like are preferable.
  • the compounds represented by the general formula (I), wherein X is —COCH ⁇ CH— and —COCH 2 CH 2 — (the hydrogen atom on the said connecting group may be substituted), can be prepared by the method, for example, described in the reaction scheme 4.
  • the target compound enone (14) can be prepared by dehydrocondensation of the ketone (12) and the aldehyde (13). This reaction is carried out in a solvent at the a reaction temperature of from 0° C. to the boiling point of the solvent in the existence of a base.
  • a base examples include inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N′-diethylaniline or the like. Examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxan, methanol, ethanol, water or the like are preferable.
  • the target compound (15) can be prepared by reduction of the enone (14).
  • This reaction is carried out at the reaction temperature of from 0° C. to 100° C. in solvent, in the existence of a reducing agent.
  • a reducing agent examples include sodium borohydride, lithium borohydride or the like.
  • the solvent examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • this reaction is carried out by a method of catalytic hydrogenation also.
  • the catalyst examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like.
  • solvent examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • the reaction is carried out at the reaction temperature of from 0° C. to 200° C., and the hydrogen pressure is at normal pressure or applied pressure
  • the compounds represented by the general formula (I) have inhibitory action against NF- ⁇ B activation and inhibitory action against the production and release of inflammatory cytokines, and are useful as active ingredients of pharmaceutical compositions such as NF- ⁇ B inhibitor and inflammatory cytokine release inhibitor.
  • the aforementioned medicament can be suitably used as an expression inhibitor of genes of one or more substances selected from a group comprising tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony-stimulating factor, interferon ⁇ , cell adhesion factor ICAM-1, VCAM-1, and ELAM-1, nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class II, ⁇ 2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, transcript derived from HIV gene, transcript derived from HTLV gene, transcript derived from simian virus 40 gene, transcript derived from cytomegalovirus gene, and transcript derived from adenovirus gene.
  • the medicament of the present invention is useful for preventive and/or therapeutic treatment of diseases caused by NF- ⁇ B
  • the medicament of the present invention may be used for preventive and/or therapeutic treatment of the following diseases wherein NF- ⁇ B activation and/or inflammatory cytokine is believed to be involved, for example, autoimmune diseases such as chronic rheumatism, osteoarthritis, systematic lupus erythematosus, systematic scleroderma, polymyositis, Sjoegren's syndrome, vasculitis syndrome, antiphospholipid syndrome, Still's disease, Behcet's disease, periarteritis nodosa, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerulonephritis, and chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, endothelial hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, allergic disease such as pollinosis, asthma, bronchi
  • the medicament of the present invention is also useful for preventive and/or therapeutic treatment of metabolic bone diseases or the like such as osteoporosis and osteocarcinomic pain or the like.
  • the medicament may also be used for prevention of deterioration of an organ during organ conservation before transplantation.
  • the active ingredient of the medicament on the present invention 1 or more kinds of substances selected from the group consisting of the compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof may be used.
  • the aforementioned substance, per se, may be administered as the medicament of the present invention, however, preferably, the medicament of the present invention is provided in the form of a pharmaceutical composition comprising the aforementioned substance which is an active ingredient together with one or more pharmacologically acceptable pharmaceutical additives.
  • a ratio of the active ingredient to the pharmaceutical additives is 1 weight % to 90 weight %.
  • compositions of the present invention may be administered as pharmaceutical compositions for oral administration, for example, granules, subtilized granules, powders, hard capsules, soft capsules, syrup, emulsion, suspension, or solution, or may be administered as pharmaceutical compositions for parenteral administration, for example, injections for intravenous administration, intramuscular administration, or subcutaneous administration, drops, suppositories, percutaneous absorbent, transmucosal absorption preparations, nasal drops, ear drops, instillation, and inhalants. Preparations made as pharmaceutical compositions in a form of powder may be dissolved when necessary and used as injections or drip infusions.
  • solid or liquid pharmaceutical additives may be used.
  • Pharmaceutical additives may either be organic or inorganic.
  • an excipient is added to the active ingredient, and further binders, disintegrator, lubricant, colorant, corrigent are added, if necessary, preparations in the forms of tablets, coating tablets, granules, powders, capsules and the like may be manufactured by common procedures.
  • the excipient include lactose, sucrose, saccharose, glucose, corn starch, starch, talc, sorbit, crystal cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide.
  • binder examples include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum Arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, dextrin, and pectin.
  • lubricant examples include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.
  • the coloring agent any material can be used which are approved to be added to ordinary pharmaceuticals.
  • corrigent cocoa powder, menthol, aromatic acid, peppermint oil, d-borneol, cinnamon powder and the like can be used. These tables and granules may be applied with sugarcoating, gelatine coating, or an appropriate coating, if necessary. Preservatives, antioxidant and the like may be added, if required.
  • liquid preparations for oral administration such as emulsions, syrups, suspensions, and solutions
  • ordinary used inactive diluents for example, water or vegetable oil may be used.
  • adjuvants such as wetting agents, suspending aids, sweating agents, flavoring agents, coloring agents or preservatives may be blended.
  • the preparation may be filled in capsules made of a absorbable substance such as gelatin.
  • solvents or suspending agents used for the preparations of parenteral administration such as injections or suppositories include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin.
  • base materials used for preparation of suppositories include, for example, cacao butter, emulsified cacao butter, lauric fat, and witepsol. Methods for preparation of the aforementioned preparations are not limited, and any method ordinarily used in the art may be used.
  • carriers such as, for example, diluents including water, ethanol, macrogol, propyleneglycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide, pH modifiers and buffer solutions including sodium citrate, sodium acetate and sodium phosphate, stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate may be used.
  • diluents including water, ethanol, macrogol, propyleneglycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide
  • pH modifiers and buffer solutions including sodium citrate, sodium acetate and sodium phosphate
  • stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate
  • a sufficient amount of a salt; glucose, mannitol or glycerin may be blended in the preparation to manufacture an isotonic solution, and an ordinary solubilizer, a soothing agent, or a topical anesthetic may be used.
  • an ordinarily used base material, a stabilizer, a wetting agent, and a preservative may be blended, if necessary, and may be prepared by mixing the components by a common method.
  • the base material for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, and bentonite may be used.
  • the preservative paraoxy methyl benzoate, paraoxy ethyl benzoate, paraoxy propyl benzoate and the like may be used.
  • the aforementioned ointment, cream gel, or paste and the like may be applied by a common method to an ordinary support.
  • the support fabric made of cotton, span rayon, and synthetic fibersor or nonwoven fabric, and a film or a foam sheet such as made of soft vinyl chloride, polyethylene, and polyurethane and the like may be preferably used.
  • a dose of the medicament of the present invention is not particularly limited.
  • a dose may generally be 0.01 to 5,000 mg per day for an adult as the weight of the compound of the present invention. It is preferred to increase or decrease the above dose appropriately depending on the age, pathological conditions, and symptoms of a patient.
  • the above dose may be administered once a day or 2 to 3 times a day as divided portions with proper intervals, or intermittent administration for every several days may be acceptable.
  • the dose When the medicament is used as an injection, the dose may be 0.001 to 100 mg per day for an adult as the weight of the compound of the present invention.
  • o-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was dissolved in benzene (8 mL). Phenethylamine (0.12 g, 1.00 mmol) and pyridine(0.3 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate.
  • Carbon tetrachloride (5 mL), iron powder (0.03 g) and bromine(25 ⁇ l, 0.45 mmol) were added to 2-hydroxy-N-(2-phenethyl)benzamide (79.6 mg, 0.33 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydrogen sulfite and extracted with ethyl acetate.
  • WSC.HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-56(morpholino)carbonylindane(refer to Chem. Pharm. Bull., 2000, 48, 131; 141 mg, 0.5 mmol) and triethylamine(70 ⁇ L, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • the obtained residue was dissolved in ethanol (5 mL), added dropwise 2 N sodium hydroxide (0.1 mL, 0.2 mmol), and stirred at room temperature for 30 minutes.
  • the reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
  • the solid was crystallized from n-hexane-ethyl acetate to give the title compound (445 mg, 63.1%) as a slight dark brown crystal.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • This compound is a commercially available compound.
  • Triethylamine (0.2 mL) was added to a mixture of 5-formylsalicylic acid (332 mg, 2 mmol). Cyanoacetic acid methyl ester (198 mg, 2 mmol) and acetic acid (6 mL), and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into water, and the separated crystal was Filtered and recrystallized (n-hexane) to give the title compound (327.7 mg, 66.3%) as a light yellow solid.
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide 950 mg, 2 mmol
  • trimethylsilylacetylene 246 mg, 2.5 mmol
  • Tetrakis(triphenylphosphine)palladium 23 mg, 0.02 mmol
  • cuprous iodide 4 mg, 0.02 mmol
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide (233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2 N sodium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-water to give the title compound (67 mg, 35.9%) as a light gray crystal.
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide 200 mg, 0.42 mmol was dissolved in 1,2-dimethoxyethane (3 mL). Tetrakis(triphenylphosphine)palladium (16 mg, 0.0014 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1M sodium carbonate (1.3 mL) were added and refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate.
  • N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (2.85 g, 7 mmol) was suspended in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL). 2 N aqueous sodium hydroxide (14 mL) was added, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was added 2 N hydrochloric acid (20 ml) and the separated solid was filtered, washed with water, dried to give the title compound (2.68 g, 97.4%) as a white crystal.
  • WSC.HCl (95 mg, 0.50 mmol) was added to a solution of 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242 mg, 0.56 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) and triethylamine (311 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate.

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Abstract

A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient:
Figure US20090192122A2-20090730-C00001
 wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application is a Divisional of U.S. application Ser. No. 10/433,619, which is a National Stage of PCT/JP2001/011084, filed Dec. 18, 2001, which was not published in English under PCT Article 21(2), and which claims priority of Japanese Application No. 2000-383202, filed Dec. 18, 2000. The entire disclosure of application Ser. No. 10/433,619 is considered as being part of this application, and the entire disclosure of application Ser. No. 10/433,619 is expressly incorporated by reference herein in its entirety.
    • FIELD OF INVENTION
  • The present invention relates to pharmaceutical compositions having inhibitory activity against the production and release of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF-α), and having inhibitory activity against the activation of NF-κ B.
    • BACKGROUND ART
  • Inflammation is a basic defense mechanism to various infestations, where inflammatory cytokine such as interleukin (IL)-1 and TNF-α (tumor necrosis factor) are known to play important roles. Due to the progress of gene analysis of inflammatory cytokines and inflammatory cell adhesion factors, it has been revealed that these cytokines are controlled by a common transcription factor (also called as transcription regulatory factor). This transcription factor is a protein called as NF-κ B (also described as NF κ B, Clark B. D., et al., Nucl. Acids Res., 14, 7898 (1984); Nedospasov S. A., et al., Cold Spring Harb. Symp. Quant. Biol., 51, 611 (1986)).
  • This NF-κ B is a hetero dimer(also called as complex) of p65 (also called as Rel A) and p50 (also called as NF-κ B−1), usually binds to I-κ B when external stimulation does not exist, and exists in cytoplasm as an inactive type. I-κ B is phosphorated by various external stimulations such as oxidative stress, cytokine, lipopolysaccharide, virus, UV, free radical, protein kinase C to become ubiquitin, and then decomposed by proteasome (Verma I. M., Stevenson J. K., et al., Genes Dev., 9, 2723-2735 (1995)). NF-κ B separated from I-κ B immediately move into nucleus, and plays a role as a transcription factor by binding to promoter region which has recognition sequence of NF-κ B.
  • In 1997, phosphoenzyme (called as Iκ B kinase abbreviated as “IKK”), which participates in phosphorylation of I-κ B, was identified (DiDonation J., Hayakawa M., et al., Nature, 388, 548-554 (1997); Regnier C. H., Song H. Y., et al., Cell, 90, 373-383 (1997)). IKK-α a (also called as IKK1) and IKK-β (also called as IKK2) which resemble each other and exist among a class of IKK, and they are known to form a complex to bind directly to Iκ B and phosphorize Iκ B (Woronicz J. D., et al., Science, 2978, 866-869 (1997); Zandi, E., et al., Cell, 91, 243-252 (1997)).
  • Recently, a mechanism except cyclooxygenase inhibition is suggested for aspirin which is a widely used anti-inflammatory agent, which is known to be based on inhibition of NF-κ B activation (Kopp E., et al., Science, 265, 956-959 (1994)). Moreover, it was revealed that aspirin regulates release and activation of NF-κ B by binding reversibly to IKK-β which is Iκ I; B kinase competing with ATP and by inhibiting phosphorylation of I-κ B (Yin M. J., et al., Nature, 396, 77-80 (1998)). However, since huge amount of aspirin needs to be administered to sufficiently suppress NF-κ B activation, and as a result, since possibility of side effects such as gastrointestinal disorders by prostaglandin synthesis inhibition and increase of bleeding tendency by anticoagulation is expected with high probability, aspirin is not suitable for long term application.
  • Besides aspirin, some pharmaceuticals are known to have inhibitory action against NF-κ n B activation. Glucocorticoids (steroid hormones) such as dexamethasone suppress NF-κ B activation by binding to their receptors (called as glucocorticoid receptor, Scheinman R. I., et al., Science, 270, 283 (1995)). However, long term use is not suitable, because they have serious side effects such as aggravation of an infectious disease, generation of peptic ulcer, degradation of bone density, and central action. Leflunomide as an immunosuppressive agent, as an isoxazole-type agent, also has NF-κ B inhibitory action (Manna S., et al., J. Immunol., 164, 2095-2102 (1999)), however, the drug is also not suitable for long term use due to serious side effects. Furthermore, substituted pyrimidine derivatives (Japanese Patent Publication of International Application (Kohyo) (Hei) 1-512399, J. Med. Chem., 41, 413 (1998)), xanthine derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei)9-227561), isoquinoline derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei)10-87491), indan derivatives (WO00/05234), epoxyquinomycin C, D, and their derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei)10-45738, Bioorg. Med. Chem. Lett., 10, 865-869 (2000)) are known as inhibitors against NF-κ B activation. However, mechanism of inhibition against NF-κ B activation and participating receptors or proteins have not been revealed.
    • DISCLOSURE OF THE INVENTION
  • Compounds having specific inhibitory action against IKK-β, found by using IKK-β as a target which directly induces phosphorylation of IKK-β, are expected to have inhibitory action against production and release of the target inflammatory cytokine and inhibitory action against production of inflammatory cell adhesion molecules, without affecting other signal transfer pathway, that is, without serious side effects. NF-κ B activation is induced by the aforementioned external stimulation, and as a result, proteins such as inflammatory cytokine are expressed. Among the inflammatory cytokines, TNF-α and interleukine (IL)-1 whose gene expression itself is considered to be regulated positively by NF-κ B to form positive feedback loop (TNF-α→NF-κ B→TNF-α) and is considered to participate in chronicity of inflammation (18th Meeting of The Japanese Inflammatory Society, Symposium “Mechanism of Antirheumatic Pharmaceutical composition and New Development” Tokyo, 2000). Accordingly, the compounds which specifically inhibit IKK-β as a target are expected to be useful drugs for inflammatory diseases advanced in a chronic stage and diseases caused by TNF-α and IL-1.
  • Therefore, an object of the present invention is to provide medicaments useful for preventive and/or therapeutic treatment of inflammatory disorders, autoimmune disease such as chronic arthrorheumatism, and bone disease such as osteoporosis, in which inflammatory cytokine is participated. Another object of the present invention is to provide an inhibitor against release of an inflammatory cytokine which avoids side effects by specifically inhibiting IKK-β, and has inhibitory activity against N F-κ B activation.
  • The inventors of the present invention carried out search for compounds having inhibitory action against NF-κ B activation by selective inhibition of IKK-β by using computerized molecular design technology to solve the aforementioned object. Appropriate protein kinases with high homology with IKK-β were selected from the kinases whose structures are registered in PDB (Protein Data Bank), and three-dimensional structure model of IKK-β was constructed by applying the homology modeling technique employing the chosen kinase as a template, and then binding mode of aspirin to the ATP binding region of IKK-β and characteristic intermolecular interactions were analyzed by using automatic search program for binding modes of a drug molecule to a protein. On the basis of the results obtained, an automatic search program of a ligand from a three-dimensional compound database based on the tree-dimensional structure of the protein was carried out, and compounds potentially be specific inhibitors against IKK-β were selected by a virtual screening out of compounds registered in a database of commercial compounds. Further, inhibitory activity of those compounds against NF-κ B activation was confirmed by a reporter assay method under TNF-α stimulation. Among them, the compounds with potent activities were further studied on the binding mode to IKK-β and interactions. On the basis of these results, the present invention was achieved by further carrying out search from compound databases of analogous compounds and syntheses
  • The medicament of the present invention is:
    (1) that having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:
    Figure US20090192122A2-20090730-C00002
    wherein X represents a connecting group whose number of atoms in the main chain is 2 to 4 (said connecting group may be substituted),
    A represents hydrogen atom or acetyl group,
    E represents an aryl group which may be substituted or a hetero aryl group which may be substituted,
    ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a hetero arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.
  • Among them, preferred medicaments include:
  • (2) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group selected from the following connecting group a which may be substituted:
    [Connecting groups α] The groups of the following formulas:
    Figure US20090192122A2-20090730-C00003
    wherein the bond at the left end binds to ring Z and the bond at the right end binds to E;
    (3) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group which may be substituted and represented by the following formula:
    Figure US20090192122A2-20090730-C00004
    wherein the bond at the left end binds to ring Z and the bond at the right end binds to E;
    (4) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group represented by the following formula:
    Figure US20090192122A2-20090730-C00005
    wherein the bond at the left end binds to ring Z and the bond at the right end binds to E;
    (5) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein A is a hydrogen atom;
    (6) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a C6 to C10 arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I), or a 6 to 13-membered hetero arene which may have one or more substituents in addition to the group represented by formula O— A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (7) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is selected from the following ring group β which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I):
    [Ring Group β] benzene ring, naphthalene ring, pyridine ring, indole ring, quinoxaline ring, carbazole ring;
    (8) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a benzene ring which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I);
    (9) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a benzene ring which may further have one or more substituents selected from the following substituent group γ-1z in addition to the group represented by formula —O— A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I):
  • [substituent group γ-1z] a halogen atom, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, acyl group which may be substituted, ureido group which may be substituted, thioureido group which may be substituted, diazenyl group which may be substituted;
    (10) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein the following partial structural formula (Iz-1) including ring Z in the general formula (I):
    Figure US20090192122A2-20090730-C00006
    is a group represented by the following formula (Iz-2)
    Figure US20090192122A2-20090730-C00007
    wherein Rz represents hydrogen atom, a halogen atom, nitro group, cyano group, hydroxy group which may be substituted, an amino group which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted;
    (11) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein Rz is hydrogen atom, a halogen atom, nitro group, cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C6 to C10 aryl-carbonyl-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbamoyl group which may be substituted, a C1 to C6 alkoxy-carbamoyl group which may be substituted, a 5 membered heteroaryl-sulfonyl group which may be substituted, a 6 membered nonaromatic heterocylic-sulfonyl group which may be substituted, or a diazenyl group which may be substituted;
    (12) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein Rz is hydrogen atom, a halogen atom, nitro group, cyano group, methoxy group, dimethylamino group, benzoylamino group, methyl group, tert-butyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, phenyl group, 2-phenethyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, 2-pyridyl group, N-[3,5-bis(trifluoromethyl)-phenyl]carbamoyl group, dimethylcarbamoyl group, dimethylsulfamoyl group, acetyl group, isobutyryl group, methoxycarbonyl group, piperidinocarbonyl group, 4-benzylpiperidino group, (pyrrol-1-yl)sulfonyl group, 3-phenylureido group, (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, or {[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl group;
    (13) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein R— is a halogen atom;
    (14) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a C6 to C10 aril group which may be substituted or a 5 to 13 membered heteroaryl group which may be substituted;
    (15) the medicament having inhibitory action against NF r B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a C6 to C10 aryl group which may be substituted;
    (16) the medicament having inhibitory action against NF r B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group which may be substituted:
    (17) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group substituted with two C1 to C6 halogenated alkyl groups and said phenyl group may further have one or more substituents in addition to the two C1 to C6 halogenated alkyl groups;
    (18) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group substituted with two C1 to C6 halogenated alkyl groups;
    (19) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 3,5-bis(trifluoromethyl)phenyl group or 2,5-bis(trifluoromethyl)phenyl group;
    (20) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 3,5-bis(trifluoromethyl)phenyl group;
    (21) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group substituted with one C1 to C6 halogenated alkyl group and said phenyl group may further have one or more substituents, except a C1 to C6 halogenated alkyl group, in addition to the C1 to C6 halogenated alkyl group;
    (22) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group substituted with one C1 to C6 halogenated alkyl group and said phenyl group mast further have one or more substituents selected from the following substituent group γ-1e in addition to the C1 to C6 halogenated alkyl group:
    [Substituent group γ-1e] a halogen atom, nitro group, cyano group, hydroxy group which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, sulfanyl group which may be substituted;
    (23) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group substituted with one C1 to C6 halogenated allyl group and said phenyl group may further have one or more substituents selected from the following substituent group γ-2e in addition to the C1 to C6 halogenated alkyl group:
    [Substituent group γ-2e] a halogen atom, nitro group, cyano group, a C1 to C6 alkyl group which may be substituted, a 5 to 6 membered nonaromatic heterocyclic group which may be substituted, a C1 to C6 alkoxyl group which may be substituted, a C1 to C6 alkyl-sulfanyl group which may be substituted;
    (24) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 2-(trifluoromethyl)phenyl group, 3-(trifluoromethyl)phenyl group, 4(trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 9-chloro-4(trifluoromethyl)phenyl group, 2 fluoro-5-(trifluoromethyl)phenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 4-nitro-3(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group, or 2-morpholino-5-(trifluoromethyl)phenyl group;
    (25) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 2-chloro-5-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethylphenyl group, or 3-methoxy-5-(trifluoromethyl)phenyl group;
    (26) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein is 2-chloro-5-(trifluoromethyl)phenyl group;
    (27) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group which may have one or more substituent except a C1 to C6 halogenated alkyl group;
    (28) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof wherein E is a phenyl group which may have one or more substituents selected from the following substituent group γ-3e:
    [Substituent group γ-3e] a halogen atom, nitro group, hydroxy group which may be substituted, hydrocarbon group which may be substituted, acyl group which may be substituted;
    (29) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a phenyl group which is substituted with one or more substituents selected from the following substituent group γ-4-e; [Substituent group γ-4e] a halogen atom, nitro group, hydroxy group, a C1 to C6 alkyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C1 to C6 alkylene group which may be substituted, a C1 to C6 alkoxy group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxycarbonyl group which may be substituted;
    (30) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 3,4,5-trichlorophenyl group, pentafluorophenyl group, 3,5-dinitrophenyl group, 3,5-dichloro-4-hydroxyphenyl group, 2,5-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-dimethylphenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group, biphenyl-3-yl group, 4-methoxybiphenyl-3-yl group, 3-acetylphenyl group, or 3,5-bis (methoxycarbonyl)phenyl group;
    (31) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3, 5-bis[(1,1-dimethyl)ethyl]phenyl group, or 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group;
    (32) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a 5 to 13 membered heteroaryl group which may be substituted;
    (33) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a thienyl group which may be substituted, a pyrazolyl group which may be substituted, an oxazolyl group which may be substituted, a thiazolyl group which may be substituted, a thiadiazolyl group which may be substituted, a pyridyl group which may be substituted, a pyrimidinyl group which may be substituted, an indolyl group which may be substituted, a quinolyl group which may be substituted, or a carbazolyl group which may be substituted;
    (34) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a thiazolyl group which may be substituted;
    (35) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a thiazolyl group which may have one or more substituents selected from the following substituent group γ-5e:
    [Substituent group γ-5e] a halogen atom, cyano group, a hydrocarbon group which may be substituted, a heteroring group which may be substituted, an acyl group which may be substituted;
    (36) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is a thiazolyl group which may have one or more substituents selected from the following substituent group γ-6e:
  • [Substituent group γ-6e] a halogen atom, cyano group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated allyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 6 membered nonaromatic heteroring group, a C1 to C6 alkyl-carbonyl group which may be substituted, a C6 to C10 aryl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted;
  • (37) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1-dimethyl)-ethyl]thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-ethylthiazol-2-yl group, 5-methyl-4-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)-propionyl]thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)-thiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, 4,5-diphenylthiazol-2-yl group, 4-phenylthiazol-2-yl group, 4,5-dimethyl thiazol-2-yl group, 2-thiazolyl group, 5-methylthiazol-2-yl group, 4-ethyl-1-phenylthiazol-2-yl group, 5-carboxymethyl-4-phenylthiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group, 5-ethyl carbamoyl-4-phenylthiazol-2-yl group, 5-isopropylcarbamoyl-4-phenyl thiazol-2-yl group, 5-(2-phenethyl)carbamoyl-4-phenylthiazol-2-yl group, 4-(n-butyl)-5-phenylthiazol-2-yl group, 4-methyl-1-[(3-trifluoromethyl)phenyl]thiazol-2-yl group, or 5-(4-fluorophenyl)-4-methylthiazol-2-yl group; and
  • (38) the medicament having inhibitory action against NF-κ B activation which comprises as an active ingredient a substance selected from the group consisting of the compound and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, wherein E is 4-(1,1-dimethyl)ethyl-5[(2,2-dimethyl)propionyl]thiazol-2-yl group.
  • The medicament of the present invention may be used as gene expression inhibitor of one or more substances selected from the following substance group δ: [Substance group δ] tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony-stimulating factor, interferon 6, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class □, B2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, transcript derived from HIV gene, transcript derived from HTLV gene, transcript derived from simian virus 40 gene, transcript derived from cytomegalovirus gene, and transcript derived from adenovirus gene.
  • The medicament of the present invention may be used as an inhibitor against production and release of an inflammatory cytokine or as an immunosuppressive agent. The medicament of the present invention may be used for preventive and/or therapeutic treatment of one or more diseases selected from the following disease group ε-1:
  • [Disease group ε-1] an inflammatory disease, an autoimmune disease, an allergic disease, a cancers such as carcinoma and sarcoma, a metabolic disease, a cardiovascular disease, an angioproliferation disease, a septic disease, a viral disease, or from the following disease group ε-2 which is resulted from NF-κ B activation or overproduction of an inflammatory cytokine:
  • [Disease group ε-2] an autoimmune diseases such as chronic rheumatism, osteoarthritis, systematic lupus erythematosus, systematic scleroderma, polymyositis, Sjoegren's syndrome, vasculitis syndrome, antiphospholipid syndrome, Still's disease, Behcet's disease, periarteritis nodosa, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerulonephritis, and chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, endothelial hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, allergic disease such as pollinosis, asthma, bronchitis, interstitial pneumonia, lung disease involving granuloma, chronic obstructive pulmonary disease, chronic pulmonary thromboembolism, inflammatory colitis, insulin resistance, obesity, diabetes and its complications (nephropathy, retinopathy, neurosis, hyperinsulinemia, arteriosclerosis, hypertension, peripheral vessel obstruction and the like) a disease with abnormal vascular proliferation such as hyperlipemia, retinopathy, pneumonia, Alzheimer's disease, encephalomyelitis, acute hepatitis, chronic hepatitis, pharmaceutical composition induced toxic hepatopathy, alcoholic hepatitis, viral hepatitis, icterus, cirrhosis, hepatic insufficiency, atrial myxoma, Caslemann's syndrome, mesangial nephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, pancreatic cancer, other solid cancer, sarcoma, osteosarcoma, metastatic invasion of cancer, carceration of inflammatory focus, cancerous cachexia, metastasis of cancer, leukemia such as acute myeloblastic leukemia, multiple myeloma, Lennert's lymphoma, malignant lymphoma, development of carcinostatic resistance of cancer, carciration of foci such as viral hepatitis and cirrhosis, carciration from polyp of colon, brain tumor, nervous tumor, endotoxic shock, sepsis, cytomegaloviral pneumonia, cytomegaloviral retinopathy, adenoviral cold, adenoviral pool fever, adenoviral ophthalmia, conjunctivitis, AIDS, uveitis, diseases or complications provoked by infections of other bacteria, viruses, and mycete, complications after surgery such as generalized inflammatory symptoms, restenosis after percutaneous tubal coronary artery plastic surgery, reperfusion disorders after vascular occlusion opening such as ischemia reperfusion disorders, organ transplantation rejection and reperfusion disorders of heart, liver, or kidney, etc., itch, anorexia, malaise, chronic fatigue syndrome, osteoporosis, metabolic bone disease such as osteocarcinomic pain, deterioration of organ during organ conservation before transplantation.
  • From another aspect, the present invention provides use of each of the substances for manufacture of the medicament according to the aforementioned (1) to (38).
  • Furthermore, the present invention provides: a method for inhibiting activation of NF-κ B in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for inhibiting expression of one or more substances selected from the aforementioned substance group 6 in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for inhibiting production and release of an inflammatory cytokine in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for immune inhibition in a mammal including a human, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; a method for preventive and/or therapeutic treatment of one or more diseases selected from aforementioned disease group ε-1, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human; and a method for preventive and/or therapeutic treatment of one or more diseases selected from aforementioned disease group ε-2 caused by NF-κ B activation or inflammatory cytokine overproduction, which comprises the step of administering the aforementioned medicament (1) to (38) to a mammal including a human.
  • The present invention further provides (1) a compound represented by the general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof:
    Figure US20090192122A2-20090730-C00008
    wherein Z1 represents 2-hydroxyphenyl group which may have a substituent in the 5-position or 2-acetoxyphenyl group which may have a substituent in the 5-position, E1 represents a phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may further have one or more substituents in addition to the two C1 to C6 halogenated alkyl groups, provided that the following compounds are excluded:
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-hydroxy-5-iodobenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide, and
    • 2-hydroxy-N-[2,3,5-tris(trifluoromethyl)phenyl]benzamide).
  • Preferred examples include:
  • (2) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is a phenyl group substituted with two C1 to C6 alkyl groups each of which is substituted with one or more fluorine atoms wherein said phenyl group may further have one or more substituents in addition to the two C1 to C6 alkyl groups which are substituted with one or more fluorine atoms;
  • (3) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is a phenyl group substituted with two C1 to C6 alkyl groups each of which is substituted with three or more fluorine atoms wherein said phenyl group may further have one or more substituents in addition to the two C1 to C6 alkyl groups each of which is substituted with three or more fluorine atoms;
  • (4) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is a phenyl group substituted with two C1 to C6 allyl groups each of which is substituted with three or more fluorine atoms;
  • (5) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is a group represented by the following formula
    Figure US20090192122A2-20090730-C00009
    wherein one of R1e2 and R1e3 represents hydrogen atom and the other represents a C1 to C6 alkyl group substituted with three or more fluorine atoms, and R1e5 represents a C1 to C6 alkyl group substituted with three or more fluorine atoms;
    (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is 3,5-bis(trifluoromethyl)phenyl group, or 2,5-bis(trifluoromethyl)phenyl group;
    (7) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E1 is 2,5-bis(trifluoromethyl)phenyl group;
    (8) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein Z1 is a group represented by the following formula:
    Figure US20090192122A2-20090730-C00010
    wherein A1 represents hydrogen atom or acetyl group, R1z represents hydrogen atom, a halogen atom, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, a hydrocarbon group which may be substituted, a heteroring group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, a diazenyl group which may be substituted;
    (9) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein A1 is hydrogen atom;
    (10) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R1z is hydrogen atom, a halogen atom, nitro group, cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C0 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxyl-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, or diazenyl group which may be substituted;
    (11) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R1z is a halogen atom, a C1 to C6 alkyl groups which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted; and
    (12) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R1z is a halogen atom.
  • Most preferably, the following compounds or pharmacologically acceptable salts thereof, or hydrates thereof or solvates thereof are provided. N-[3,5-bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-cyano-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-(1,1-dimethylethyl-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(trifluoromethyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(1,1,2,2,2-pentafluoroethyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(9-phenylethen-1 yl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide,
    • 3-({3-[3,5-bis(trifluoromethyl)phenyl]carbamoyl-}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester,
    • 3-({3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-ethynyl-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(phenylethynyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxybiphenyl-3-carboxamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-phenylethyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(3-thienyl)benzamide,
    • N-[3,7-bis(trifluoromethyl)phenyl]-2-hydroxy-6-(1 pyrrolyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-pyridyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylamino-2-hydroxybenzamide,
    • 5-benzoylamino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • N3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N1,N1-dimethylisophthalamide,
    • N1,N3-bis[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-carbonyl)-benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl] 5-dimethylsulfamoyl-9-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyl-5-(pyrrole-1-sulfonyl)benzamide,
    • 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methylester,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(4-nitrophenyl)diazenyl]benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}-diazenyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(3-phenyl)ureido]benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(3-phenyl)thioureido]benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(1-hydroxyethyl)benzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-methoxybenzamide,
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[1-(methoxyimino)ethyl]benzamide,
    • 5-{1-[(benzyloxy)imino]ethyl}-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-9-hydroxybenzamide,
    • N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
    • 2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide,
    • 2-acetoxy-N-[2,5-bis(trifluoromethyl)phenyl]-5-chlorobenzamide, and
    • 2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-chlorobenzamide.
  • The present invention further provides the compound represented by the following general formula (I-2) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
    Figure US20090192122A2-20090730-C00011
    wherein Z2 represents 2-hydroxyphenyl group which may be substituted in the 5-position, or 2-acetoxyphenyl group which may be substituted in the 5-position, E2 represents a phenyl group whose 3-position or 5-position is substituted with a C1 to C6 halogenated alkyl group wherein said phenyl group may further have one or more substituents (except when the substituent is a C1 to Cr, halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group in the 3-position or 5-position, provided that the following compounds are excluded:
    • 5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,
    • 5-bromo-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,
    • 2-hydroxy-5-iodo-N-[3-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide,
    • 5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,
    • 5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]-benzamide
    • 5-chloro-2-hydroxy-—N-(3-trifluoromethyl-4-{[4-(trifluoromethyl)sulfanyl]phenoxy}-phenyl)benzamide
    • N-[4-(benzothiazol-2-yl)sulfanyl-3-(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
    • 5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl] benzamide,
    • 5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • 5-chloro-2-hydroxy-N-[1-naphthyloxy)-5-(1-naphthyloxy)-(trifluoromethyl)phenyl]benzamide, and
    • 5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.
  • Preferred examples include:
  • (2) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E2 is a phenyl group whose 3-position or 5-position is substituted with a C1 to C6 alkyl group which is substituted with one or more fluorine atoms wherein said phenyl group may have one or more substituents (except when the substituent is a C1 to C6 halogenated alkyl group) in addition to the C1 to C6 alkyl group in the 3-position or the 5-position which is substituted with one or more fluorine atoms:
  • (3) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E2 is a phenyl group whose 3-position or 5-position is substituted with a C1 to C6 allyl group which is substituted with three or more fluorine atoms wherein said phenyl group may have one or more substituents (except when the substituent is a C1 to C6 halogenated alkyl group) in addition to the C1 to C6 alkyl group in the 3-position or the 5-position which is substituted with three or more fluorine atoms;
  • (4) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E2 is a phenyl group whose 3-position or 5-position is substituted with a C1 to C6 alkyl group which is substituted with three or more fluorine atoms wherein said phenyl group may have one or more substituents selected from the following substituent group γ-7e in addition to the C1 to C6 alkyl group in the 3-position or 5-position which is substituted with three or more fluorine atoms: [substituent group γ-7e] a halogen atom, nitro group, cyano group, a C1 to C6 alkyl group which may be substituted, a 5 to 6 membered nonaromatic heteroring group which may be substituted, a C1 to C6 alkoxy group which may be substituted, a C1 to C6 alkyl-sulfanyl group which may be substituted;
  • (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E2 is 3-(trifluoromethyl)phenyl group, 9-fluoro-3-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 4-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-6-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidino)-5-(trifluoromethyl)phenyl group, or 2-morpholino-5-(trifluoromethyl)phenyl group;
    (7) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein Z2 is a group represented by the following formula
    Figure US20090192122A2-20090730-C00012
    wherein A2 represents hydrogen atom or acetyl group, R2z represents a halogen atom, a C1 to C6 alkyl group or a C1 to C6 halogenated alkyl group;
    (8) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein A2 is hydrogen atom; and
    (9) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R2z is halogen atom.
  • Most preferably, the following compounds or pharmacologically acceptable salts thereof, or hydrates thereof or solvates thereof are provided:
    • 5-chloro-N-[2-fluoro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-bromo-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 2-acetoxy-5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]benzamide,
    • N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide,
    • 5-chloro N′-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-bromo-N-[3-bromo-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-N-[3-fluoro-6-(trifluoromethyl)phenyl]-9-hydroxybenzamide,
    • 5-chloro-N-N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-bromo-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide,
    • 5-chloro-2-hydroxy-N-[2-nitro-5-(trifluoromethyl)phenyl]benzamide,
    • 5-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
    • 5-chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-2-hydroxy-N-[2-methyl-5-(trifluoromethyl)phenyl]benzamide,
    • 2-hydroxy-5-methyl-N-[2-methyl-5-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-2-hydroxy-N-[4-methyl-3-(trifluoromethyl)phenyl]benzamide,
    • 2-hydroxy-5-methyl-N-[4-methyl-3-(trifluoromethyl)phenyl]benzamide,
    • 5-bromo-2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]benzamide,
    • 2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl-5-methyl]benzamide.
    • 5-bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]benzamide,
    • 2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]-5-methylbenzamide,
    • 5-chloro-2-hydroxy-N-[2-methylsulfanyl-5-(trifluoromethyl)phenyl]benzamide,
    • 5-chloro-2-hydroxy-N-[2-(1-pyrrolidino)-5-(trifluoromethyl)phenyl]benzamide, and
    • 5-chloro-2-hydroxy-N-[2-morpholino-5-(trifluoromethyl)phenyl]benzamide.
  • Furthermore, the present invention provides (1) the compound represented by the following general formula (I-3) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
    Figure US20090192122A2-20090730-C00013
    wherein Z3 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E3 represents a group represented by the following formula
    Figure US20090192122A2-20090730-C00014
    wherein R3e2 and R3e3 may be the same or different and each represents hydrogen atom, a hydrocarbon group which may be substituted, or hydroxy group which may be substituted, except that where both of R3e2 and R3e3 are hydrogen atoms is excluded, R3e5 represents a C2 to C6 hydrocarbon group which may be substituted.
  • Preferred examples include:
  • (2) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R3e2 and R3e3 may be the same or different and each represents hydrogen atom, a C1 to C6 alkyl group which may be substituted, or a C1 to C6 alkoxy group which may be substituted, provided that where both of R3e2 and R3e3 are hydrogen atoms is excluded, R3e5 is a C2 to C6 alkyl group which may be substituted;
  • (3) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E3 is 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, or 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group;
    (4) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein Z3 is a group represented by the following formula:
    Figure US20090192122A2-20090730-C00015
    wherein A3 represents hydrogen atom or acetyl group, R3z represents a halogen atom, a C1 to C6 allyl group, or a C1 to C6 halogenated alkyl group;
    (5) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein A3 is hydrogen atom;
    (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R3z is halogen atom.
  • Most preferably, the following compounds or pharmacologically acceptable salts thereof, or hydrates thereof or solvates thereof are provided:
    • N-{2,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide,
    • N-{-2,5-bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-methylbenzamide,
    • N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide,
    • N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-bromo-2-hydroxybenzamide,
    • N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-methylbenzamide,
    • 2-acetoxy-N-{3,5-bis-[(1,1-dimethyl)ethyl]phenyl}-5-chlorobenzamide,
    • 5-chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-2-hydroxybenzamide,
    • N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-2-hydroxy-5-benzamide, and
    • 2-acetoxy-5-chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]benzamide.
  • The present invention further provides (1) the compound represented by the following general formula (I-4) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
    Figure US20090192122A2-20090730-C00016
    wherein Z4 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E4 is a group represented by the following formula:
    Figure US20090192122A2-20090730-C00017
    wherein R4e4 represents a hydrocarbon group which may be substituted, R4e5 represents a halogen atom, cyano group, acyl group which may be substituted, or a heteroring group which may be substituted.
  • Preferred examples include:
  • (2) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R4e4 represents a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, or a C6 to C10 aryl group which may be substituted, R4e5 represents a halogen atom, cyano group, a C1 to C6 alkyl-carbonyl group which may be substituted, a C6 to C10 aryl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, or a 6-membered nonaromatic heteroring group which may be substituted;
  • (3) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E4 is 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5 bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, or 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group;
  • (4) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein E4 is 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group;
  • (5) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein Z4 is a group represented by the following formula:
    Figure US20090192122A2-20090730-C00018
    wherein A4 represents hydrogen atom or acetyl group, R4z represents a halogen atom, a C6 to C10 aryl group which may be substituted, or a 5-membered heteroaryl group;
    (6) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein A4 is hydrogen atom; and
    (7) the compound or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof wherein R4z is a halogen atoms.
  • Most preferably, the following compounds or pharmacologically acceptable salts thereof, or hydrates thereof or solvates thereof are provided.
    • 5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide,
    • 5-bromo N[5-bromo-4-(trifluoromethyl)thiazol-2-yl]-2-hydroxybenzamide,
    • 5-chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl] thiazol-2-yl}-2-hydroxybenzamide,
    • 5-bromo-N-{6-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide,
    • 5-chloro-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide,
    • 5-bromo-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide,
    • N-(5-acetyl-4-phenylthiazol-2-yl)-5-bromo-2-hydroxybenzamide,
    • N-(5-benzoyl-4-phenylthiazol-2-yl)-5-bromo-2-hydroxybenzamide,
    • 2-(5-bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazol-5-carboxylic acid ethylester,
    • 2-(5-bromo-2-hydroxybenzoyl)amino-4-(trifluoromethyl)thiazol-5-carboxylic acid ethylester,
    • 2-(6-chloro-9-hydroxybenzoyl)amino-4-phenylthiazol-6-carboxylic acid ethylester,
    • 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-[(4-hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-[(4-fluoro-4-hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-[(2′,4′-difluoro-4-hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-{4-hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthizol-5-carboxylic acid ethylester,
    • 2-[4-hydroxy-4-(1-pyrrolyl)benzoyl]amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-[2-hydroxy-5-(1-thienyl)benzoyl]amino-4-phenylthiazol-5-carboxylic acid ethylester,
    • 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-carboxylic acid ethylester,
    • 5-bromo-N-[4-(1,1-dimethyl)ethyl-6-piperidinothiazol-2-yl]-2-hydroxybenzamide,
    • 5-bromo-N-[4-(1,1-dimethyl)ethyl-6-morpholinothiazol-2-yl]-2-hydroxybenzamide,
    • 5-bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl]-2-hydroxybenzamide, and
    • 5-bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl]thiazol-2-yl)-2-hydroxybenzamide.
    BEST MODE FOR CARRYING OUT THE INVENTION
  • The terms used in the present specification have the following meanings.
  • As the halogen atom, any of fluorine atom, chlorine atom, bromine atom, or iodine atom may be used unless otherwise specifically referred to.
  • Examples of the hydrocarbon group include, for example, an aliphatic hydrocarbon group, an aryl group, an arylene group, an aralkyl group, a bridged cyclic hydrocarbon group, a spiro cyclic hydrocarbon group, and a terpene hydrocarbon.
  • Examples of the aliphatic hydrocarbon group include, for example, alkyl group, alkenyl group, alkynyl group, alkylene group, alkenylene group, alkylidene group and the like which are straight chain or branched chain monovalent or bivalent acyclic hydrocarbon groups; cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group, cycloalkyl-alkyl group, cycloalkylene group, and cycloalkenylene group, which are saturated or unsaturated monovalent or bivalent alicyclic hydrocarbon groups.
  • Examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyL 2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, and n-pentadecyl group, which are C1 to C15 straight chain or branched chain alkyl groups.
  • Examples of the alkenyl group include, for example, vinyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-2-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, hept-1-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl, non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl, undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl, tridec-1-en-1-yl, tridec-12-en-1-yl, tetradec-1-en-1-yl, tetradec-13-en-1-yl, pentadec-1-en-1-yl, and pentadec-14-en-1-yl group, which are C2 to C15 straight chain or branched chain alkenyl groups.
  • Examples of the alkynyl group include, for example, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl, dec-1-yn-1-yl, dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl, dodec-1-yn-1-yl, dodec-11-yn-1-yl, tridec-1-yn-1-yl, tridec-12-yn-1-yl, tetradec-1-yn-1-yl, tetradec-13-yn-1-yl, pentadec-1-yn-1-yl, and pentadec-14-yn-1-yl group, which are C2 to C15 straight chain or branched chain alkyvnl groups.
  • Examples of the alkylene group include, for example, methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, and 1,1,4,4-tetramethylbutane-1,4-diyl group, which are C1 to C8 straight chain or branched chain alkylene groups.
  • Examples of the alkenylene group include, for example, ethene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl, but-2-ene-1,4-diyl, 2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl, and hex-3-ene-1,6-diyl group, which are C1 to C6 straight chain or branched chain allylene groups.
  • Examples of the alkylidene group include, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, and hexylidene, which are C1 to C6 straight chain or branched chain alkylidene groups.
  • Examples of the cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, which are C3 to C8 cycloalkyl groups.
  • The aforementioned cycloalkyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl group.
  • Examples of the cycloalkenyl group includes, for example, 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, and 1-cyclopenten-1-yl group, which are C3 to C6 cycloalkenyl groups.
  • The aforementioned cycloalkenyl group may be fused with benzene ring, naphthalene ring and the like, and examples include, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4,-tetrahydronaphthalen-2-yl,
    • 1-indenyl, and 2-indenyl group.
  • Examples of the cycloalkanedienyl group include, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and 2,5-cyclohexanedien-1-yl group, which are C5 to C6 cycloalkanedienyl groups.
  • The aforementioned cycloalkanedienyl group may be fused with benzene ring, naphthalene ring and the like, and examples of the group include, for example, 1-indenyl and 2-indenyl group.
  • Examples of the cycloalkyl-alkyl group include the group in which one hydrogen atom of alkyl group is substituted with cycloalkyl group, and include, for example, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, cyclooctylmethyl, and 6-cyclooctylhexyl group, which are C4 to C14 cycloalkyl-alkyl groups.
  • Examples of the cycloalkylene group include, for example, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, and cyclooctane-1,2-diyl group, which are C3 to C8 cycloalkylene groups.
  • Examples of the cycloalkenylene group include, for example, 2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl, 2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl, 2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl, 3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl, and 1-cyclohexene-1,2-diyl group, which are C3 to CG cycloalkenylene groups.
  • Examples of the aryl group include a monocyclic or a fused polycyclic aromatic hydrocarbon group, and include, for example, phenyl, 1-naphtyl, 2-naphtyl, anthryl, phenanthryl, and acenaphthylenyl group, which are C6 to C14 aryl groups.
  • The aforementioned aryl group may be fused with aforementioned C3 to C8 cycloalkyl group, C3 to C6 cycloalkenyl group, C5 to C6 cycloalkanedienyl group or the like, and the example of the group include, for example, 4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl, 5-phenalenyl, 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and 9-phenalenyl group.
  • Examples of the arylene group include, for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, and anthracene-1,4-diyl, which are C6 to C14 arylene groups.
  • Examples of the aralkyl group include the group in which one hydrogen atom of alkyl group is substituted with aryl group, and include, for example, benzyl, 1-naphtylmethyl, 2-naphtylmethyl, anthracenylmethyl, phenanthrenyl methyl, acenaphthylenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 4-phenylbutyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, 5-phenylpentyl, 5-(1-naphthyl)pentyl, 5-(2-naphthyl)pentyl, 6-phenylhexyl, 6-(1-naphthyl)hexyl, and 6-(2-naphthyl)hexyl group, which are C7 to C16 aralkyl groups.
  • Examples of the bridged cyclic hydrocarbon group include, for example, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]octyl, and adamanty group.
  • Examples of the spiro cyclic hydrocarbon group include, for example, spiro[3.4]octyl, and spiro[4.5]decane-1,6-dienyl group.
  • Examples of the terpene hydrocarbon include, for example, geranyl, neryl, linalyl, phytyl, menthyl, and bornyl group.
  • Examples of the halogenated allyl group include the group in which one hydrogen atom of alkyl group is substituted with a halo-en atom, and include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, and perfluorohexyl group, which are C1 to C6 straight chain or branched chain halogenated alkyl groups substituted with 1 to 13 halogen atoms.
  • Examples of the heterocyclic group include, for example, a monocyclic or a fused polycyclic hetero aryl group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic nonaromatic heterocyclic group which comprises at least one atom of 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as ring-constituting atoms (ring forming atoms).
  • Examples of the monocyclic heteroaryl group include, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazol)-4-yl, (1,2,3-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, (1,2,5-oxadiazol)-3-yl, (1,2,5-oxadiazol)-4-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, furazanyl, (1,2,3-thiadiazol)-4-yl, (1,2,3-thiadiazol)-5-yl, (1,2,4-thiadiazol)-3-yl, (1,2,4-thiadiazol)-5-31, (1,2,5-thiadiazol)-3-yl, (1,2,5-thiadiazol)-4-yl, (1,3,4-thiadiazolyl)-2-yl, (1,3,4-thiadiazolyl)-5-yl, (1H-1,2,3-triazol)-1-yl, (1H-1,2,3-triazol)-4-yl, (1H-1,2,3-triazol)-5-yl, (2H-1,2,3-triazol)-2-yl, (2H-1,2,3-triazol)-4-yl, (1H-1,2,4-triazol)-1-yl, (1H-1,2,4-triazol)-3-yl, (1H-1,2,4-triazol)-5-yl, (4H-1,2,4-triazol)-3-yl, (4H-1,2,4-triazol)-4-yl, (1H-tetrazol)-1-yl, (1H-tetrazol)-5-yl, (2H-tetrazol)-2-yl, (2H-tetrazol)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, (1,2,3-triazin)-4-yl, (1,2,3-triazin)-5-yl, (1,2,4-triazin)-3-yl, (1,2,4-triazin)-5-yl, (1,2,4-triazin)-6-yl, (1,3,5-triazin)-2-yl, 1-azepinyl, 2-azepinyl, 3-azepinyl, 4-azepinyl, (1,4-oxazepin)-2-yl, (1,4-oxazepin)-3-yl, (1,4-oxazepin)-5-yl, (1,4-oxazepin)-6-yl, (1,4-oxazepin)-7-yl, (1,4-thiazepin)-2-yl, (1,4-thiazepin)-3-yl, (1,4-thiazepin)-5-yl, (1,4-thiazepin)-6-yl, and (1,4-thiazepin)-7-yl group, which are 5- to 7-membered monocyclic heteroaryl groups.
  • Examples of the fused polycyclic heteroaryl group include, for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b] thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl, 1-indolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol)-1-yl, (2H-isoindol)-2-yl, (2H-isoindol)-4-yl, H-isoindol)-5-yl, (1H-indazol)-1-yl, (1H-indazol)-3-yl, (1H-indazol)-4-yl, (1H-indazol)-5-yl, (1H-indazol)-6-yl, (1H-indazol)-7-yl, (2H-indazol)-1-yl, (2H-indazol)-2-yl, (2H-indazol)-4-yl, (2H-indazol)-5-yl, 2-benzoxazolyl, (1,2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1,2-benzisoxazol)-3-yl, (1,2-benzisoxazol)-4-yl, (1,2-benzisoxazol)-5-yl, (1,2-benzisoxazol)-6-yl, (1,2-benzisoxazol)-7-yl, (2,1-benzisoxazol)-3-yl, (2,1-benzisoxazol)-4-yl, (2,1-benzisoxazol)-5-yl, (2,1-benzisoxazol)-6-yl, (2,1-benzisoxazol)-7-yl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, (1,2-benzisothiazol)-3-yl, (1,2-benzisothiazol)-4-yl, (1,2-benzisothiazol)-5-yl, (1,2-benzisothiazol)-6-yl, (1,2-benzisothiazol)-7-yl; (2,1-benzisothiazol)-3-yl, (2,1-benzisothiazol)-4-yl, (2,1-benzisothiazol)-5-yl, (2,1-benzisothiazol)-6-yl, (2,1-benzisothiazol)-7-yl, (1,2,3-benzoxadiazol)-4-yl, (1,2,3-benzoxadiazol)-5-yl, (1,2,3-benzoxadiazol)-6-yl, (1,2,3-benzoxadiazol)-7-yl, (2,1,3-benzoxadiazol)-4-yl, (2,1,3-benzoxadiazol)-56-yl, (1,2,3-benzothiadiazol)-4-yl, (1,2,3-benzothiadiazol)-5-yl, (1,2,3-benzothiadiazol)-6-yl, (1,2,3-benzothiadiazol)-7-yl, (2,1,3-benzothiadiazol)-4-yl, (2,1,3-benzothiadiazol)-5-yl, (1H-benzotriazol)-1-yl, (1H-benzotriazol)-4-yl, (1H-benzotriazol)-5-yl, (1H-benzotriazol)-6-yl, (1H-benzotriazol)-7-yl, (2H-benzotriazol)-2-yl, (2H-benzotriazol)-4-yl, (2H-benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl, 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 2-(α-carbolinyl), 3-(α-carbolinyl), 4-(α-carbolinyl), 5-(α-carbolinyl), 6-(α-carbolinyl), 7(α-carbolinyl), 8-(α-carbolinyl), 9-(α-carbolinyl), 1-(β-carbolinyl), 3-(β-carbolinyl), 4-(β-carbolinyl), 5-(β-carbolinyl), 5-(β-carbolinyl), 7-(β-carbolinyl), 8-(β-carbolinyl), 9-(β-carbolinyl), 1-(γ-carbolinyl), 2-(γ-carbolinyl), 4-(γ-carbolinyl), 5-(γ-carbolinyl), 6-(γ-carbolinyl), 7-(γ-carbolinyl), 8(γ-carbolinyl), 9-(γ-carbolinyl), 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl, 1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, 10-phenoxazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl, 2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl, 4-phenoxathiinyl, thieno[2,3,-b]furyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-a]pyridazinyl group, which are 8- to 14-membered fused polycyclic heteroaryl groups.
  • Examples of the monocyclic nonaromatic heterocyclic group include, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl, 1-imidazolidinyl, 9-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl), 2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl), piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl, 2-tetrahydropyranyl, morpholino, (thiomorpholin)-4-yl, 1-piperazinyl, and 1-homopiperazinyl group, which are 3- to 7-membered saturated or unsaturated monocyclic nonaromatic heterocyclic groups.
  • Examples of the fused polycyclic nonaromatic heterocyclic group include, for example, 9-quinuclidinyl, 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7′-isochromanyl, 8-isochromanyl, 2-thiochromanyl, 3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl, 7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl, 3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl, 6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochromanyl, 1-indolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 2-(4H-chromenyl), 3-(4H-chromenyl), 4-(4H-chromenyl), 5-(4H-chromenyl), 6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl), 1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl, 6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1-(1H-pyrrolidinyl), 2-(1H-pyrrolidinyl), 3-(1H-pyrrolidinyl), 5-(1H-pyrrolidinyl), 6-(1H-pyrrolidinyl), and 7-(1H-pyrrolidinyl) group, which are 8- to 10-membered saturated or unsaturated fused polycyclic nonaromatic heterocyclic groups.
  • Among the aforementioned heterocyclic groups, a monocyclic or a fused polycyclic hetero aryl groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms), and a monocyclic or a fused polycyclic nonaromatic heterocyclic groups which may have 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, in addition to the nitrogen atom that has the bond, as ring-constituting atoms (ring forming atoms) are referred to as “cyclic amino groups”. Examples include, for example, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino, morpholino, 1-piperazinyl, thiomorpholin-4-yl, 1-homopiperidinyl, 1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazolin-1-yl, 2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl,
    • 1,2,3,4-tetrahydroisoquinolin-2-yl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-indolyl, 1-indazolyl, and 2-isoindolyl group.
  • Examples of the hydrocarbon-oxy group include the group in which hydrogen atom of hydroxy, group is substituted with hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon. Examples of the hydrocarbon-oxy group include, for example, alkoxy group (alkyl-oxy group), alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group, cycloalkyl-alkyl-oxy group and the like which are aliphatic hydrocarbon-oxy groups, aryl-oxy group, aralkyl-oxy group, and alkylene-dioxy group.
  • Examples of the alkoxy(alkyl-oxy group) include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy, 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy, and n-pentadecyloxy group, which are C1 to C15 straight chain or branched chain alkoxy groups.
  • Examples of the alkenyl-oxy group include, for example, vinyloxy, (prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl)oxy, (but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, (2-methylprop-2-en-1-yl)oxy, (1-methylprop-2-en-1-yl)oxy, (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy, (pent-3-en-1-yl)oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy, (3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy, (hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy, (hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1-en-1-yl)oxy, (oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8-en-1-yl)oxy, (dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec-1-en-1-yl)oxy, (undec-10-en-1-yl)oxy, (dodec-1-en-1-yl)oxy, (dodec-11-en-1-yl)oxy, (tridec-1-en-1-yl)oxy, (tridec-12-en-1-yl)oxy, (tetradec-1-en-1-yl)oxy, (tetradec-13-en-1-yl)oxy, (pentadec-1-en-1-yl)oxy, and (pentadec-14-en-1-yl)oxy group, which are C2 to C15 straight chain or branched chain alkenyl-oxy groups.
  • Examples of the alkynyl-oxy group include, for example, ethynyloxy, (prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but-1-yn-1-yl)oxy, (but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy, (pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy, (hept-1-n−1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy, (oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy, (dec-1-yn-1-yl)oxy, (dec-9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy, (undec-10-yn-1-yl)oxy, (dodec-1-yn-1-yl)oxy, (dodec-11-yn-1-yl)oxy, (tridec-1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy, (tetradec-1-yn-1-yl)oxy, (tetradec-13-yn-1-yl)oxy, (pentadec-1-yn-1-yl)oxy, and (pentadec-14-yn-1-yl)oxy group, which are C2 to C15 straight chain or branched chain alkynyl-oxy groups.
  • Examples of the cycloalkyl-oxy group include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy group, which are C3 to C8 cycloalkyl-oxy groups.
  • Examples of the cycloalkyl-alkyl-oxy group include, for example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy, 6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy, cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctylhexyloxy group, which are C4 to C14 cycloalkyl-alkyl-oxy groups.
  • Examples of the aryl-oxy group include, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, and acenaphthylenyloxy group, which are C6 to C14 aryl-oxy groups.
  • Examples of the aralkyl-oxy group include, for example, benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy, phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-(1-naphthyl)ethoxy, 1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, 3-phenylpropoxy, 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy, 4-phenylbutoxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy, 5-phenylpentyloxy, 5-(1-naphthyl)pentyloxy, 5-(2-naphthyl)pentyloxy, 6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy, and 6-(2-naphthyl)hexyloxy group, which are C7 to C16 aralkyl-oxy groups.
  • Examples of the alkylenedioxy group include, for example, methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and 1,1-dimethylmethylenedioxy group.
  • Examples of the halogenated alkoxy group(halogenated alkyl-oxy group) include the group in which hydrogen atom of hydroxy group is substituted with halogenated alkyl group, and include, for example, fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy group, which are C1 to C6 straight chain or branched chain halogenated alkoxy groups substituted with 1 to 13 halogen atoms.
  • Examples of the heterocyclic-oxy group include the group in which hydrogen atom of hydroxy group is substituted with the heterocyclic group, and examples of the heteroring include similar groups to the aforementioned heterocyclic group.
  • Examples of the heteroring-oxy group include, for example, a monocyclic heteroaryl-oxy group, a fused polycyclic heteroaryl-oxy group, a monocyclic nonaromatic heteroring-oxy group, a fused polycyclic nonaromatic heteroring-oxy group and the like.
  • Examples of the monocyclic heteroaryl-oxy group include, for example, 3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, and (pyrimidin-4-yl)oxy group.
  • Examples of the fused polycyclic heteroaryl-oxy group include, 5-indolyloxy, (benzimidazol-2-yl)oxy, 2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy group.
  • Examples of the monocyclic nonaromatic heteroring-oxy group include, for example, 3-pyrrolidinyloxy, and 4-piperidinyloxy group.
  • Examples of the fused polycyclic nonaromatic heteroring-oxy group include, for example, 3-indolynyloxy, and 4-chromanyloxy group.
  • Examples of the hydrocarbon-sulfanyl group include the group in which hydrogen atom of sulfanyl group is substituted with a hydrocarbon group, and examples of the hydrocarbon include similar groups to the aforementioned hydrocarbon. Examples of the hydrocarbon-sulfanyl group include, for example, alkyl-sulfanyl group, alkenyl-sulfanyl group, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group, cycloalkyl-alkyl-sulfanyl group and the like which are aliphatic hydrocarbon-sulfanyl groups, aryl-sulfanyl group, and aralkyl-sulfanyl group.
  • Examples of the alkyl-sulfanyl group include, for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, (2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl, neopentylsulfanyl, (1,2-dimethylpropyl)sulfanyl, (1-ethylpropyl)sulfanyl, n-hexylsulfanyl, (4-methylpentyl)sulfanyl, (3-methylpentyl)sulfanyl, (2-methylpentyl)sulfanyl, (1-methylpentyl)sulfanyl, (3,3-dimethylbutyl)sulfanyl, (2,2-dimethylbutyl)sulfanyl, (1,1-dimethylbutyl)sulfanyl, (1,2-dimethylbutyl)sulfanyl, (1,3-dimethylbutyl)sulfanyl, (2,3-dimethylbutyl)sulfanyl, (2-ethylbutyl)sulfanyl, (1-ethylbutyl)sulfanyl, (1-ethyl-1-methylpropyl)sulfanyl, n-heptylsulfanyl, n-octylsulfanyl, n-nonylsulfanyl, n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl, n-tridecylsulfanyl, n-tetradecylsulfanyl, and n-pentadecylsulfanyl group, which are C1 to C15 straight chain or branched chain alkyl-sulfanyl groups.
  • Examples of the alkenyl-sulfanyl group include, for example, vinylsulfonyl, (prop-1-en-1-yl)sulfanyl, alkylsulfanyl, isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl, (but-2-en-1-yl)sulfanyl, (but-3-en-1-yl)sulfanyl, (2-methylprop-2-en-1-yl)sulfanyl, (1-methylprop-2-en-1-yl)sulfanyl, (pent-1-en-1-yl)sulfanyl, (pent-2-en-1-yl)sulfanyl, (pent-3-en-1-yl)sulfanyl, (pent-4-en-1-yl)sulfanyl, (3-methylbut-2-en-1-yl)sulfanyl, (3-methylbut-3-en-1-yl)sulfanyl, (hex-1-en-1-yl)sulfanyl, (hex-2-en-1-yl)sulfanyl, (hex-3-en-1-yl)sulfanyl, (hex-4-en-1-yl)sulfanyl, (hex-5-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl, (hept-1-en-1-yl)sulfanyl, (hept-6-en-1-yl)sulfanyl, (oct-1-en-1-yl)sulfanyl, (oct-7-en-1-yl)sulfanyl, (non-1-en-1-yl)sulfanyl, (non-8-en-1-yl)sulfanyl, (dec-1-en-1-yl)sulfanyl, (dec-9-en-1-yl)sulfanyl, (undec-1-en-1-yl)sulfanyl, (undec-10-en-1-yl)sulfanyl, (dodec-1-en-1-yl)sulfanyl, (dodec-11-en-1-yl)sulfanyl, (tridec-1-en-1-yl)sulfanyl, (tridec-12-en-1-yl)sulfanyl, (tetradec-1-en-1-yl)sulfanyl, (tetradec-13-en-1-yl)sulfanyl, (pentadec-1-en-1-yl)sulfanyl, and (pentadec-14-en-1-yl)sulfanyl, which are C2 to C15 straight chain or branched chain alkenyl-sulfanyl groups.
  • Examples of the alkynyl-sulfanyl group include, for example, ethynylsulfanyl, (prop 1-yn-1-yl)sulfanyl, (prop-2-yn-1-yl)sulfanyl, (but-1-yn-1-yl)sulfanyl, (but-3-yn-1-yl)sulfanyl, (1-methylprop-2-yn-1-yl)sulfanyl, (pent-1-yn-1-yl)sulfanyl. (pent-4-yn-1-yl)sulfanyl, (hex-1-yn-1-yl)sulfanyl, (hex-5-yn-1-yl)sulfanyl, (hept-yn-1-yl)sulfanyl, (hept-6-yn-1-yl)sulfanyl, (oct-1-yn-1-yl)sulfanyl, (oct-7-yn-1-yl)sulfanyl, (non-1-yn-1-yl)sulfanyl, (non-8-yn-1-yl)sulfanyl, (dec-1-yn-1-yl)sulfanyl, (dec-9-yn-1-yl)sulfanyl, (undec-1-yn-1-yl)sulfanyl, (undec-10-yn-1-yl)sulfanyl, (dodec-1-yn-1-yl)sulfanyl, (dodec-11-yn-1-yl)sulfanyl, (tridec-1-yn-1-yl)sulfanyl, (tridec-12-yn-1-yl)sulfanyl, (tetradec-1-yn-1-yl)sulfanyl, (tetradec-13-yn-1-yl)sulfanyl, (pentadec-1-yn-1-yl)sulfanyl, and (pentadec-14-yn-1-yl)sulfanyl, which are C2 to C15 straight chain or branched chain alkynyl-sulfanyl groups.
  • Examples of the cycloalkyl-sulfanyl group include, for example, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, and cyclooctylsulfanyl group, which are C3 to C8 cycloalkyl-sulfanyl groups.
  • Examples of the cycloalkyl-alkyl-sulfanyl group include, for example, (cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl, (2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl, (4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl, (6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl, (cyclopentyl)methyl)sulfanyl, (2-cyclobutylmethyl)sulfanyl, (cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl, (2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl, (4-cyclohexylbutyl)sulfanyl, (cycloheptylmethyl)sulfanyl, (cyclooctylmethyl)sulfanyl, and (6-cyclooctylhexyl)sulfanyl group, which are C4 to C14 cycloalkyl-alkyl-sulfanyl groups.
  • Examples of the aryl-sulfanyl group include, for example, phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl, fenanthrylsulfanyl, and acenaphthylenylsulfanyl group, which are C6 to C11 aryl-sulfanyl groups.
  • Examples of the aralkyl-sulfanyl group include, for example, benzylsulfanyl, (1-naphthylmethyl)sulfanyl, (2-naphthylmethyl)sulfanyl, (anthracenylmethyl)sulfanyl, (phenanthrenylmethyl)sulfanyl, (acenaphthylenylmethyl)sulfanyl, (diphenylmethyl)sulfanyl, (1-phenethyl)sulfanyl, (2-phenethyl)sulfanyl, (1-(1-naphthyl)ethyl)sulfanyl, (1-(2-naphthyl)ethyl)sulfanyl, (9′ (1-naphthyl)ethyl)sulfanyl, (2-(2-naphthyl)ethyl)sulfanyl, (3-phenylpropyl)sulfanyl, (3-(1-naphthyl)propyl)sulfanyl, (3-(2-naphthyl)propyl)sulfanyl, (4-phenylbutyl)sulfanyl, (4-(1-naphthyl)butyl)sulfanyl, (4-(2-naphthyl)butyl)sulfanyl, (1-phenylpentyl)sulfanyl, (5-(1-naphthyl)pentyl)sulfanyl, (5-(2-naphthyl)pentyl)sulfanyl, (6-phenylhexyl)sulfanyl, (6-(1-naphthyl)hexyl)sulfanyl, and (6-(2-naphthyl)hexyl)sulfanyl group, which are C7 to C16 aralkyl-sulfanyl groups.
  • Examples of the halogenated alkyl-sulfanyl group include the group in which hydrogen atom of sulfanyl group is substituted with a halogenated alkyl group, and include, for example, (fluoromethyl)sulfanyl, (chloromethyl)sulfanyl, (bromomethyl)sulfanyl, (iodomethyl)sulfanyl, (difluoromethyl)sulfanyl, (trifluoromethyl)sulfanyl, (trichloromethyl)sulfanyl, (9,2,2-trifluoroethyl)sulfanyl, (pentafluoroethyl)sulfanyl, (3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl)sulfanyl, (heptafluoroisopropyl)sulfanyl, (nonafluorobutyl)sulfanyl, and (perfluorohexyl)sulfanyl group, which are C1 to C6 straight chain or branched chain halogenated alkyl-sulfanyl groups substituted with 1 to 13 halogen atoms.
  • Examples of the heterocyclic-sulfanyl group include the group in which hydrogen atom of sulfanyl group is substituted with the heterocyclic group, and examples of the heteroring include similar groups to the aforementioned heterocyclic group. Examples of the heteroring-sulfanyl group include, for example, monocyclic heteroaryl-sulfanyl group, fused polycyclic heteroaryl-sulfanyl group, monocyclic nonaromatic heteroring-sulfanyl group, and fused polycyclic nonaromatic heteroring-sulfanyl group.
  • Examples of the monocyclic heteroaryl-sulfanyl group include, for example, (imidazol-2-yl)sulfanyl, (1,2,4-triazol-2-yl)sulfanyl, (pyridin-2-yl)sulfanyl, (pyridin-4-yl)sulfanyl, and (pyrimidin-2-yl)sulfanyl group.
  • Examples of the fused polycyclic heteroaryl-sulfanyl group include, for example, (benzimidazol-2-yl)sulfanyl, (quinolin-2-yl)sulfanyl, and (quinolin-4-yl)sulfanyl group.
  • Examples of the monocyclic non-aromatic heteroring-sulfanyl group include, for example, (3-pyrrolidinyl)sulfanyl group and (4-piperidinyl)sulfanyl group.
  • Examples of the fused polycyclic nonaromatic heteroring-sulfanyl group include, for example, (3-indolinyl)sulfanyl and (4-chromanyl)sulfanyl group.
  • Examples of the acyl group include, for example, formyl group, glyoxyloyl group, and thioformyl group, and the group represented by the following formulas:
    Figure US20090192122A2-20090730-C00019
    Figure US20090192122A2-20090730-C00020
    wherein Ra1 and Rb1 may be the same or different and each represents a hydrocarbon group or heterocyclic group, or Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.
  • In the definition of the aforementioned acyl group, among the groups represented by the formula (ω-1A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl groups” whose examples include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2 naphthoyl, and phenylacetyl group. Those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-carbonyl” groups whose examples include, for example, 2-thenoyl, 3-furoyl, nicotinoyl, and isonicotinoyl group.
  • Among the groups represented by the formula (ω-2A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl groups” whose examples include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl) groups” whose example includes, for example, 3-pyridyloxycarbonyl group.
  • Among the groups represented by the formula (ω-3A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl groups” whose example includes, for example, pyruvoyl group, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-carbonyl-carbonyl groups”.
  • Among the groups represented by the formula (ω-4A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl groups” whose examples include, for example, methoxalyl and ethoxalyl groups, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-carbonyl groups”.
  • Among the groups represented by the formula (ω-5A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-sulfanyl-carbonyl groups”.
  • Among the groups represented by the formula (ω-6A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-thiocarbonyl groups”.
  • Among the groups represented by the formula (ω-7A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-oxy-thiocarbonyl groups”.
  • Among the groups represented by the formula (ω-8A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-sulfanyl-thiocarbonyl groups”.
  • Among the groups represented by the formula (ω-9A), those groups in which Ra1 is a hydrocarbon group are referred to as referred to as “N-hydrocarbon-carbamoyl groups” whose example includes, for example, N-methylcarbamoyl group, and those groups in which Ra1 is a heterocyclic group are referred to as “N-heteroring-carbamoyl groups”.
  • Among the groups represented by the formula (ω-110A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-dihydrocarbon-carbamoyl groups” whose example includes, for example, N,N-dimethylcarbamoyl group, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl groups”, those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring substituted carbamoyl groups”, and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-carbonyl groups” whose example includes, for example, morpholino-carbonyl.
  • Among the groups represented by the formula (ω-11A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “N-heteroring-thiocarbamoyl groups”.
  • Among the groups represented by the formula (ω-12A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl groups”, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl groups”, those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl groups”, and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-thiocarbonyl groups”.
  • Among the groups represented by the formula (ω-13A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl groups”.
  • Among the groups represented by the formula (ω-14A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl groups” whose example includes, for example, N,N-dimethylsulfamoyl group, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl groups”, those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl groups”, and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl groups” which include, for example 1-pyrrolylsulfonyl group.
  • Among the groups represented by the formula (ω-15A), those groups in which Ra1 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl groups”.
  • Among the groups represented by the formula (ω-16A), those groups in which both Ra1 and Rb1, are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl groups”, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl groups”, those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl groups”, and those groups in which Ra1 and Rb1 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl groups”.
  • Among the groups represented by the formula (ω-17A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-oxy-sulfonyl groups”.
  • Among the groups represented by the formula (ω-18A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl groups”, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl groups”.
  • Among the groups represented by the formula (ω-19A), those groups in which both Ra1 and Rb1 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono groups”, those groups in which both Ra1 and Rb1 are heterocyclic groups are referred to as “O,O′-di(heteroring)-phosphono groups”, and those groups in which Ra1 is a hydrocarbon group and Rb1 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heteroring-phosphono groups”.
  • Among the groups represented by the formula (ω-20A), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl groups” whose examples include, for example, methanesulfonyl and benzenesulfonyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-sulfonyl groups”.
  • Among the groups represented by the formula (ω-21L), those groups in which Ra1 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl groups” whose examples include, for example, methylsulfinyl and benzenesulfinyl, and those groups in which Ra1 is a heterocyclic group are referred to as “heteroring-sulfinyl groups”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1A) through (ω-21A) include the similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl groups represented by the formula (ω-1A) include, for example, an alkyl-carbonyl group, an alkenyl-carbonyl group, an alkynyl-carbonyl group, a cycloalkyl-carbonyl group, a cycloalkenyl-carbonyl group, a cycloalkanedienyl-carbonyl group, a cycloalkyl-alkyl-carbonyl group which is an aliphatic hydrocarbon-carbonyl group, an aryl-carbonyl group, an aralkyl-carbonyl group, a bridged cyclic hydrocarbon-carbonyl group, a spirocyclic hydrocarbon-carbonyl group, and a terpene family hydrocarbon-carbonyl. In the following, groups represented by the formulas (ω-2A) through (ω-21A) are similar to those explained above.
  • Examples of the heteroring in the groups represented by the aforementioned formulas (ω-1A) through (ω-21A) include similar groups to the aforementioned heterocyclic group. Examples of the heteroring-carbonyl group represented by the formula (ω-1A) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic nonaromatic heteroring-carbonyl group, and a fused polycyclic nonaromatic heteroring-carbonyl. In the following, groups represented by the formulas (ω-2A) through (ω-21A) are similar to those explained above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10A) through (ω-16A) include similar groups to the aforementioned cyclic amino group.
  • The aforementioned acyl group, carbamoyl group, thiocarbamoyl group, sulfamoyl group, and sulfinamoyl group are generically referred to as “acyl groups” which may be substituted.
  • In the present specification, when a certain functional group is defined as “which may be substituted”, the definition means that the functional group may sometimes have one or more substituents at chemically substitutable positions, unless otherwise specifically mentioned. Kind of substituents, number of substituents, and the position of substituents existing in the functional groups are not particularly limited, and when two or more substituents exist, they may be the same or different. Examples of the substituent existing in the functional group include, for example, halogen atoms, oxo group, thioxo group, nitro group, nitroso group, cyano group, isocyano group, cyanato group, thiocyanato group, isocyanato group, isothiocyanato group, hydroxy group, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalo group, methooxalo group, thiocarboxy group, dithiocarboxy group, carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfinamoyl group, phosphono group, hydroxy-phosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heteroring-oxy group, hydrocarbon-sulfanyl group, heteroring-sulfanyl group, acyl group, amino group, hydrazino group, hydrazono group, diazenyl group, ureido group, thioureido group, guanidino group, carbamimidoyl group (amidino group), azido group, imino group, hydroxyamino group, hydroxyimino group, aminooxy group, diazo group, semicarbazino group, semicarbazono group, allophanyl group, hydantoyl group, phosphano group, phosphoroso group, phospho group, boryl group, silyl group, stannyl group, selanyl group, oxido group and the like.
  • When two or more substituents exist according to the above-mentioned definition of “which may be substituted”, said two or more substituents may combine to each other, together with atom(s) to which they bind, to form a ring. For these cyclic groups, as ring-constituting atoms (ring forming atoms), one to three kinds of one or more hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like may be included, and one or more substituents may exist on the ring. The ring may be monocyclic or fused polycyclic, and aromatic or nonaromatic.
  • The above substituents according to the abovementioned definition of “which may be substituted” may further be substituted with the aforementioned substituents at the chemically substitutable positions on the substituent. Kind of substituents, number of substituents, and positions of substituents are not particularly limited, and when the substituents are substituted with two or more substituents, they may be the same or different. Examples of the substituent include, for example, a halogenated alkyl-carbonyl group (trifluoroacetyl group as an example), a halogenated alkyl-sulfonyl group (trifluoromethanesulfonyl group as an example), an acyl-oxy group, an acyl-sulfanyl group, an N-hydrocarbon-amino group, an N,N-di(hydrocarbon)-amino group, an N-heteroring-amino group, an N-hydrocarbon-N-heteroring-amino group, an acyl-amino group, and a di(acyl)-amino group. Moreover, substitution on the aforementioned substituents may be repeated multiple orders.
  • Examples of the acyl-oxy group include the group in which hydrogen atom of hydroxy group is substituted with acyl group, and include, for example, formyloxy group, glyoxyloyloxy group, and thioformyloxy group, and the group represented by the following formulas:
    Figure US20090192122A2-20090730-C00021
    Figure US20090192122A2-20090730-C00022
    wherein Ra2 and Rb2 may be the same or different and represent a hydrocarbon group or a heterocyclic group, or Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group.
  • In the definition of aforementioned acyl-oxy group, among the groups represented by the formula (ω-1B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-oxy group” whose examples include, for example, acetoxy and benzoyloxy group, and those groups in which Ra2 is a heterocyclic group are referred to as “heteroring-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-2B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-oxy group”, and those groups in which Ra2 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-3B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-oxy group”, and groups in which Ra2 is a heterocyclic group are referred to as “heteroring-carbonyl-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-4B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-oxy group”, and groups in which Ra2 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-5B), those groups in which Ran is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-oxy group”, and groups where Ra2 is a heterocyclic group are referred to as “heteroring-sulfanyl-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-6B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-oxy group”, and groups where Ra2 is a heterocyclic group are referred to as “heteroring-thiocarbonyl-oxy group”.
  • Among the groups represented by the formula (ω-7B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-oxy group”, and groups in which Ra2 is a heterocyclic group are referred to as “heteroring-oxy-thiocarbonyl-oxy group”.
  • Among the groups represented by the formula (ω-8B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-oxy group”, and groups wherein Ra1 is a heterocyclic group are referred to as “heteroring-sulfanyl-thiocarbonyl-oxy group”.
  • Among the groups represented by the formula (ω-9B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-oxy group”, and groups in which Ra2 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-oxy group”.
  • Among the groups represented by the formula (ω-10B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-oxy group”, those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl-oxy group”, those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-carbamoyl-oxy group”, and those groups in which Ra2 and Rb2 combine each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-oxy group”.
  • Among the groups represented by the formula (ω-11B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-oxy group”, and those groups in which Ra2 is a heterocyclic group are referred to as “N-heteroring-thiocarbonyl-oxy group”.
  • Among the groups represented by the formula (ω-12B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-oxy group”, those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-oxy group”, those groups wherein Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl-oxy group”, and those groups in which Ra2 and Rh2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-oxy group”.
  • Among the groups represented by the formula (ω-13B), those groups in which Ra2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-oxy groups”, and those groups in which Ra2 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl-oxy groups”.
  • Among the groups represented by the formula (ω-14B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-oxy groups”, those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-oxy groups”, those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-sulfamoyl-oxy groups”, and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfonyl-oxy groups”.
  • Among the groups represented by the formula (ω-15B), those groups in which Rb2 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-oxy groups”, and those groups where Ra2 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl-oxy groups”.
  • Among the groups represented by the formula (ω-16B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-oxy groups”, those groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl-oxy groups”, those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl-oxy groups”, and those groups in which Ra2 and Rb2 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclic amino-sulfinyl-oxy group”.
  • Among the groups represented by the formula (ω-17B), those groups in which Rb2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-oxy group”, and those groups in which Ra2 is a heterocyclic group are referred to as “heteroring-oxy-sulfonyl-oxy group”.
  • Among the groups represented by the formula (ω-18B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-oxy groups”, those groups in which Ra2 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl-oxy groups”.
  • Among the groups represented by the formula (ω-19B), those groups in which both Ra2 and Rb2 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-oxy group”, groups in which both Ra2 and Rb2 are heterocyclic groups are referred to as “O,O′-di(heteroring)-phosphono-oxy group”, and those groups in which Ra2 is a hydrocarbon group and Rb2 is a heterocyclic group are referred to as “O-hydrocarbon substituted-O′-heteroring substituted phosphono-oxy group”.
  • Among the groups represented by the formula (ω-20B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-oxy group”, and those groups in which Ra2 is a heterocyclic group referred to as “heteroring-sulfonyl-oxy group”.
  • Among the groups represented by the formula (ω-21B), those groups in which Ra2 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-oxy group”, and those groups in which Ra2 is a heterocyclic group are referred to as “heteroring-sulfinyl-oxy group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1B) through (ω-21B) include the similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-oxy groups represented by the formula (ω-1B) include, for example, an alkyl-carbonyl-oxy group, an alkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, a cycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, a cycloalkanedienyl-carbonyl-oxy group, and a cycloalkyl-alkyl-carbonyl-oxy group, which are aliphatic hydrocarbon-carbonyl-oxy groups, an aryl-carbonyl-oxy group, an aralkyl-carbonyl-oxy group, a bridged cyclic hydrocarbon-carbonyl-oxy group, a spirocyclic hydrocarbon-carbonyl-oxy group, and a terpene family hydrocarbon-carbonyl-oxy group. In the following, groups represented by the formulas (ω-2B) through (ω-21B) are similar to those explained above.
  • Examples of the heteroring in the groups represented by the aforementioned formulas (ω-1B) through (ω-21B) include similar groups to the aforementioned heterocyclic group. Examples of the heteroring-carbonyl group represented by the formula (ω-1B) include, for example, a monocyclic heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl group, a monocyclic nonaromatic heteroring-carbonyl group, and a fused polycyclic nonaromatic heteroring-carbonyl group. In the following, groups represented by the formulas (ω-2B) through (ω-21B) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10B) through (ω-16B) include similar groups to the aforementioned cyclic amino group.
  • The aforementioned acyl-oxy group, hydrocarbon-oxy group, and heterocyclic-oxy group are generically referred to as “substituted oxy group”. Moreover, these substituted oxy group and hydroxy group are generically referred to as “hydroxy group” which may be substituted.
  • Examples of the acyl-sulfanyl include the group in which hydrogen atom of sulfanyl group is substituted with acyl group, and include, for example, formylsulfanyl group, glyoxylsulfanyl group, and thioformylsulfanyl group, and groups represented by the following formulas:
    Figure US20090192122A2-20090730-C00023
    Figure US20090192122A2-20090730-C00024
    wherein Ra3 and Rb3 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • In the definition of aforementioned acyl-sulfanyl group, among the groups represented by the formula (ω-1C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-carbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-2C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-5C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-carbonyl-carbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-6C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-carbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-5C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-sulfanyl-carbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-6C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-thiocarbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-7C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-oxy-thiocarbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-8C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-sulfanyl-thiocarbonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-9C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-10C), those groups in which both Ra3 and Rb3 are a hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-sulfanyl group”, those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl-sulfanyl group”, groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-carbonyl-sulfanyl group”, and those groups in which Ra3 as and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-sulfamoyl group”.
  • Among the groups represented by the formula (ω-11C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “N-heteroring-thiocarbamoyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-12C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group”, those groups in which and Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-sulfanyl group”, those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon N-heteroring-thiocarbomoyl-sulfanyl group”, and those groups in which Ra1 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-sulfamoyl group”.
  • Among the groups represented by the formula (ω-13C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-sulfanyl group”, and those groups in which Ra3 is a heteroring group are referred to as “N-heterocyclic-sulfamoyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-14C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl-sulfanyl group”, those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-sulfinyl group”, those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl-sulfanyl group”, and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-15C), those groups in which Ra3 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-sulfanyl group”, and those groups in which Ra3 is a heteroring group are referred to as “N-heterocyclic-sulfinamoyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-16C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl group”, those groups in which both Ra3 and Rb3 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl-sulfanyl group”, those groups in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl-sulfanyl group”, and those groups in which Ra3 and Rb3 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfanyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-17C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-sulfanyl group”, and those groups in which Ra3 is a heteroring group are referred to as “heterocyclic-oxy-sulfonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-18C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-sulfanyl group”, and those groups in which Ra3 is a heteroring group are referred to as “heterocyclic-oxy-sulfinyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-19C), those groups in which both Ra3 and Rb3 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-sulfanyl group”, those groups in which both Ra3 and Rb3, are heterocyclic groups are referred to as “O,O′-di(heteroring)-phosphono-sulfanyl group”, and those groups in which Ra3 is a hydrocarbon group and Rb3 is a heteroring group are referred to as “O-hydrocarbon-O′-heterocyclic-phosphono-sulfanyl group”. Among the groups represented by the formula (ω-20C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-sulfanyl group”, and those groups in which Ra3 is a heterocyclic group are referred to as “heteroring-sulfonyl-sulfanyl group”.
  • Among the groups represented by the formula (ω-21C), those groups in which Ra3 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-sulfanyl group”, and those groups in which Ra3 is a heteroring group are referred to as “heterocyclic-sulfinyl-sulfanyl group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1C) through (ω-21C) include similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-sulfanyl groups represented by the formula (ω-1C) include, for example, an alkyl-carbonyl-sulfanyl group, an alkenyl-carbonyl-sulfanyl group, an alkynyl-carbonyl-sulfanyl group, a cycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbonyl-sulfanyl group, a cycloalkanedienyl-carbonyl-sulfanyl group, a cycloalkyl-alkyl-carbonyl-sulfanyl group which is an aliphatic hydrocarbon-carbonyl-sulfanyl groups, an aryl-carbonyl-sulfanyl group, an aralkyl-carbonyl-sulfanyl group, a bridged cyclic hydrocarbon-carbonyl-sulfanyl group, a spiro cyclic hydrocarbon-carbonyl-sulfanyl group, and a terpene family hydrocarbon-carbonyl-sulfanyl group. In the following, groups represented by the formulas (ω-2C) through (ω-21C) are similar to those mentioned above.
  • Examples of the heteroring in the groups represented by the aforementioned formulas (ω-1C) through (ω-21C) include similar groups to the aforementioned heterocyclic group. Examples of the heteroring-carbonyl-sulfanyl group represented by the formula (ω-1C) include, for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a fused polycyclic heteroaryl-carbonyl-sulfanyl group, a monocyclic nonaromatic heteroring-carbonyl-sulfanyl group, and a fused polycyclic nonaromatic heteroring-carbonyl-sulfanyl group. In the following, groups represented by the formula (ω-2C) through ( -21C) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10C) through (ω-16C) include similar groups to the aforementioned cyclic amino group.
  • The aforementioned acyl-sulfanyl group, hydrocarbon-sulfanyl group, and heterocyclic-sulfanyl group are generically referred to as “substituted sulfanyl group”. These substituted sulfanyl group and sulfanyl group are generically referred to as “sulfanyl groups” which may be substituted.
  • Examples of the N-hydrocarbon-amino group include the group in which one hydrogen atom of amino group is substituted with a hydrocarbon group, and include, for example, an N-alkyl-amino group, an N-alkenyl-amino group, an N-alkynyl-amino group, an N-cycloalkyl-amino group, an N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, and an N-aralkyl-amino group.
  • Examples of the N-alkyl-amino group include, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, (2-methylbutyl)amino, (1-methylbutyl)amino, neopentylamino, (1,2-dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexylamino, (4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino, (1-methylpentyl)amino, (3,3-dimethylbutyl)amino, (2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino, (1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino, (2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, (1-ethylbutyl)amino, (1-ethyl-1-methylpropyl)amino, n-heptylamino, n-octylamino, n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino, n-tridecylamino, n-tetradecylamino, and n-pentadecylamino group, which are C1 to C15 straight chain or branched chain N-alkyl amino groups.
  • Examples of the N-alkenyl-amino group include, for example, vinyl amino, (prop-1-en-1-yl)amino, alkylamino, isopropenylamino, (but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino, (2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino, (pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino, (pent-3-en-1-yl)amino, (pent-4-en-1-yl)amino, (3-methylbut-2-en-1-yl)amino, (3-methylbut-3-en-1-yl)amino, (hex-1-en-1-yl)amino, (hex-2-en-1-yl)amino, (hex-3-en-1-yl)amino, (hex-4-en-1-yl)amino, (hex-5-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino, (hept-1-en-1-yl)amino, (hept-6-en-1-yl)amino, (oct-1-en-1-yl)amino, (oct-7-en-1-yl)amino, (non-1-en-1-yl)amino, (non-8-en-1-yl)amino, (dec-1-en-1-yl)amino, (dec-9-en-1-yl)amino, (undec-1-en-1-yl)amino, (undec-10-en-1-yl)amino, (dodec-1-en-1-yl)amino, (dodec-11-en-1-yl)amino, (tridec-1-en-1-yl)amino, (tridec-12-en-1-yl)amino, (tetradec-1-en-1-yl)amino, (tetradec-13-en-1-yl)amino, (pentadec-1-en-1-yl)amino, and (pentadec-14-en-1-yl)amino group, which are C2 to C15 straight chain or branched chain N-alkenyl amino groups.
  • Examples of the N-alkynyl-amino group include, for example, ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino, (but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino, (1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino, (pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino, (hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino, (oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (non-8-yn-1-yl)amino, (dec-1-yn-1-yl)amino, (dec-9-yn-1-yl)amino, (undec-1-yn-1-yl)amino, (undec-10-yn-1-yl)amino, (dodec-1-yn-1-yl)amino, (dodec-11-yn-1-yl)amino, (tridec-1-yn-1-yl)amino, (tridec-12-yn-1-yl)amino, (tetradec-1-yn-1-yl)amino, (tetradec-13-yn-1-yl)amino, (pentadec-1-yn-1-yl)amino, and (pentadec-14-yn-1-yl)amino group, which are C2 to C15 straight chain or branched chain N-alkynyl-amino groups.
  • Examples of the N-cycloalkyl-amino group include, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, and cyclooctylamino group, which are C3 to C8 N-cycloalkyl-amino groups.
  • Examples of the N-cycloalkyl-alkyl-amino group include, for example, (cyclopropylmethyl)amino, (1-cyclopropylethyl)amino, (2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino, (4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino, (6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino, (2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino, (4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino, (cyclooctylmethyl)amino, and (6-cyclooctylhexyl)amino, which are C4 to C14 N-cycloalkyl-alkyl-amino groups.
  • Examples of the N-aryl-amino group include, for example, phenylamino, 1-naphthylamino, 2-naphtylamino, anthrylamino, phenanthrylamino, and acenaphthylenylamino, which are C6 to C14 N-mono-arylamino groups.
  • Examples of the N-aralkyl-amino group include, for example, benzylamino, (1-naphthylmethyl)amino, (2-naphthylmethyl)amino, (anthracenylmethyl)amino, (phenanthrenylmethyl)amino, (acenaphthylenylmethyl)amino, (diphenylmethyl)amino, (1-phenethyl)amino, (2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino, (1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino, (2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino, (3-(1-naphthyl)propyl)amino, (3-(2-naphthyl)propyl)amino, (4-phenylbutyl)amino, (4-(1-naphthyl)butyl)amino, (4-(2-naphthyl)butyl)amino, (5-phenylpentyl)amino, (5-(1-naphthyl)pentyl)amino, (5-(2-naphthyl)pentyl)amino, (6-phenylhexyl)amino, (6-(1-naphthyl)hexyl)amino, and (6-(2-naphthyl)hexyl)amino, which are C7 to C16 N-aralkyl-amino groups.
  • Examples of the N,N-di(hydrocarbon)-amino group include the group in which 2 hydrogen atoms of amino group are substituted with hydrocarbon group, and include, for example, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N,N-di-n-propylamino, N,N-diisopropylamino, N-allyl-N-methylamino, N-(prop-2-yn-1-yl)-N-methylamino, N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino, N-cyclohexylmethylamino-N-methylamino, N,N-diphenylamino, N-methyl-N-phenylamino, N,N-dibenzylamino, and N-benzyl-N-methylamino group.
  • Examples of the N-heteroring-amino group include the group in which one hydrogen atom of amino group is substituted with heterocyclic group, and include, for example, (3-pyrrolizinyl)amino, (4-piperidinyl)amino, (2-tetrahydropyranyl)amino, (3-indolinyl)amino, (4-chromanyl)amino, (3-thienyl)amino, (3-pyridyl)amino, (3-quinolyl)amino, and (5-indolyl)amino.
  • Examples of the N-hydrocarbon-N-heteroring-amino group include the group in which 2 hydrogen atoms of amino group are substituted with hydrocarbon group and heterocyclic group respectively, and include, for example, N-methyl-N-(4-piperidinyl)amino, N-(4-chromanyl)-N-methylamino, N-methyl-N-(3-thienyl)amino, N-methyl-N-(3-pyridyl)amino, N-methyl-N-(3-quinolyl)amino and the like.
  • Examples of the acyl-amino group include the group in which one hydrogen atom of the amino group is substituted with an acyl group, and include, for example, formylamino group, glyoxyloylamino group, and thioformylamino group, and groups represented by the following formulas:
    Figure US20090192122A2-20090730-C00025
    Figure US20090192122A2-20090730-C00026
    wherein Ra4 and Rb4 may be the same or different and represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • In the definition of the aforementioned acyl-amino group, among the groups represented by the formula (ω-1D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-carbonyl-amino group”.
  • Among the groups represented by the formula (ω-2D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-amino group”, and those groups in which Ra4 is a heteroring group are referred to as “heterocyclic-oxy-carbonyl-amino group”.
  • Among the groups represented by the formula (ω-3D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-carbonyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-carbonyl-carbonyl-amino group”.
  • Among the groups represented by the formula (ω-4D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-carbonyl-carbonyl-amino group”, and those groups in which R-4 is a heterocyclic group are referred to as “heteroring-oxy-carbonyl-carbonyl-amino group”
  • Among the groups represented by the formula (ω-5D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-carbonyl-amino group”, and those groups in which Rat is a heterocyclic group are referred to as “heteroring-sulfanyl-carbonyl-amino group”.
  • Among the groups represented by the formula (ω-6D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-thiocarbonyl amino group”.
  • Among the groups represented by the formula (ω-7D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-amino group”, and those groups in which Reel is a heterocyclic group are referred to as “heteroring-oxy-thiocarbonyl-amino group”. Among the groups represented by the formula (ω-8D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfanyl-thiocarbonyl-amino group”, and those groups in which R-14 is a heterocyclic group are referred to as “heteroring-sulfanyl-thiocarbonyl-amino group”.
  • Among the groups represented by the formula (ω-9D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-carbamoyl group”, and those groups in which Ra4 is a heterocyclic group are referred to as “N-heteroring-carbamoyl-amino group”.
  • Among the groups represented by the formula (ω-10D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl-amino group”, those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heteroring)-carbamoyl-amino group”, those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-carbamoyl-amino group”, and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-amino group”.
  • Among the groups represented by the formula (ω-11D), those groups in which Rat is a hydrocarbon group are referred to as “N-hydrocarbon-thiocarbamoyl-amino group”, and those groups in which Ra4 is a heteroring group are referred to as “N-heterocyclic-thiocarbamoyl-amino group”.
  • Among the groups represented by the formula (ω-12D), those groups in which both Ra4 and Rb1 are hydrocarbon groups are referred to as “N,N′-di(hydrocarbon)-thiocarbamoyl-amino group”, those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heteroring)-thiocarbamoyl-amino group”, those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-thiocarbamoyl-amino group”, and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-amino group”.
  • Among the groups represented by the formula (ω-13D), those groups in which Ru4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfamoyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “N-heteroring-sulfamoyl-amino group”.
  • Among the groups represented by the formula (ω-14D), those groups in which both Ra4 and Rb-1 are hydrocarbon groups are referred to as “di(hydrocarbon)-sulfamoyl-amino group”, those groups in which both Ra4 and Rb1 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfamoyl-amino group”, those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfamoyl-amino group”, and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfonyl-amino group”.
  • Among the groups represented by the formula (ω-15D), those groups in which Ra4 is a hydrocarbon group are referred to as “N-hydrocarbon-sulfinamoyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “N-heteroring-sulfinamoyl-amino group”.
  • Among the groups represented by the formula (ω-16D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl-amino group”, those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “N,N-di(heteroring)-sulfinamoyl-amino group”, groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “N-hydrocarbon-N-heteroring-sulfinamoyl-amino group”, and those groups in which Ra4 and Rb4 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-sulfinyl-amino group”.
  • Among the groups represented by the formula (ω-17D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfonyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl-amino group”.
  • Among the groups represented by the formula (ω-18D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-oxy-sulfinyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-oxy-sulfinyl-amino group”.
  • Among the groups represented by the formula (ω-19D), those groups in which both Ra4 and Rb4 are hydrocarbon groups are referred to as “O,O′-di(hydrocarbon)-phosphono-amino group”, those groups in which both Ra4 and Rb4 are heterocyclic groups are referred to as “O,O′-di(heteroring)-phosphono-amino group”, and those groups in which Ra4 is a hydrocarbon group and Rb4 is a heterocyclic group are referred to as “O-hydrocarbon-O′-heteroring-phosphono-amino group”.
  • Among the groups represented by the formula (ω-20D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfonyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-sulfonyl-amino group”.
  • Among the groups represented by the formula (ω-21D), those groups in which Ra4 is a hydrocarbon group are referred to as “hydrocarbon-sulfinyl-amino group”, and those groups in which Ra4 is a heterocyclic group are referred to as “heteroring-sulfinyl-amino group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1D) through (ω-21D), similar groups to the aforementioned hydrocarbon group. Examples of the hydrocarbon-carbonyl-amino groups represented by the formula (ω-1D) include, for example, an alkyl-carbonyl-amino group, an alkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, a cycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl-amino group, a cycloalkanedienyl-carbonyl-amino group, a cycloalkyl-alkyl-carbonyl-amino group which is an aliphatic hydrocarbon-carbonyl-amino groups, an aryl-carbonyl-amino group, an aralkyl-carbonyl-amino group, a bridged cyclic hydrocarbon-carbonyl-amino group, a spiro cyclic hydrocarbon-carbonyl-amino group, and a terpene family hydrocarbon-carbonyl-amino group. In the following, groups represented by the formulas (ω-2D) through (ω-21D) are similar to those explained above.
  • Examples of the heteroring in the groups represented by the aforementioned formulas (ω-1D) through (ω-21D) include similar groups to the aforementioned heterocyclic group. Examples of the heteroring-carbonyl-amino group represented by the formula (ω-1D) include, for example, a monocyclic heteroaryl-carbonyl-amino group, a fused polycyclic heteroaryl-carbonyl-amino group, a monocyclic nonaromatic heterocyclic-carbonyl-amino group, and a fused polycyclic nonaromatic heterocyclic-carbonyl-amino group. In the following, groups represented by the formulas (ω-2D) through (ω-21D) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10D) through (ω-16D) include similar groups to the aforementioned cyclic amino group.
  • The aforementioned di(acyl)-amino group include the group in which 2 hydrogen atoms of amino group are substituted with acyl groups in the definitions of the aforementioned substituents according to “which may be substituted”. Examples include, for example, di(formyl)-amino group, di(glyoxyloyl)-amino group, and di(thioformyl)-amino group, and groups represented by the following formulas
    Figure US20090192122A2-20090730-C00027
    Figure US20090192122A2-20090730-C00028
    wherein Ra5 and Rb5 may be the same or different and represent hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted.
  • In the definition of aforementioned di(acyl)-amino group, among the groups represented by the formula (ω-1E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl)-amino group”, and those groups in which Ra5 is a heteroring group are referred to as “bis(heterocyclic-carbonyl)-amino group”.
  • Among the groups represented by the formula (ω-2E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-carbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-oxy-carbonyl)-amino group”.
  • Among the groups represented by the formula (ω-3E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl-carbonyl)-amino group”, and those groups in which Ra15 is a heterocyclic group are referred to as “bis(heteroring-carbonyl-carbonyl)-amino group”. Among the groups represented by the formula (ω-4E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-oxy-carbonyl-carbonyl)-amino group”.
  • Among the groups represented by the formula (ω-5E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfanyl-carbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-sulfanyl-carbonyl)-amino group”.
  • Among the groups represented by the formula (ω-6E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-thiocarbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-thiocarbonyl)-amino group”.
  • Among the groups represented by the formula (ω-7E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-thiocarbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(ringoxy-thiocarbonyl)-amino group”.
  • Among the groups represented by the formula (ω-8E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-sulfanyl-thiocarbonyl)-amino group”.
  • Among the groups represented by the formula (ω-9E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-carbamoyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heteroring-carbamoyl)-amino group”.
  • Among the groups represented by the formula (ω-110E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-carbamoyl]-amino group”, those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-carbamoyl]-amino group”, groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-carbamoyl)-amino group”, and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino groups are referred to as “bis(cyclicamino-carbonyl)amino group”.
  • Among the groups represented by the formula (ω-11E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-thiocarbamoyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heteroring-thiocarbamoyl)-amino group”.
  • Among the groups represented by the formula (ω-12E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group”, those groups in which both RaS and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-thiocarbamoyl]-amino group”, those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-thiocarbamoyl)-amino group”, and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-thiocarbonyl)-amino group”.
  • Among the groups represented by the formula (ω-13E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-sulfamoyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heteroring-sulfamoyl)-amino group”.
  • Among the groups represented by the formula (ω-14), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N;-di(hydrocarbon)-sulfamoyl]-amino group”, those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-sulfamoyl]-amino group”, those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-sulfamoyl)-amino group”, and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfonyl)amino group”.
  • Among the groups represented by the formula (ω-15E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(N-hydrocarbon-sulfinamoyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(N-heteroring-sulfinamoyl)-amino group”.
  • Among the groups represented by the formula (ω-16E), those groups in which Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino group”, those groups in which Ra5 and Rb5 are heterocyclic groups are referred to as “bis[N,N-di(heteroring)-sulfinamoyl]amino group”, those groups in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group are referred to as “bis(N-hydrocarbon-N-heteroring-sulfinamoyl)-amino group”, and those groups in which Ra5 and Rb5 combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfinyl)amino group”.
  • Among the groups represented by the formula (ω-17E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-sulfonyl)-amino group”, and those groups in which R-15 is a heterocyclic group are referred to as “bis(heteroring-oxy-sulfonyl)-amino group”.
  • Among the groups represented by the formula (ω-1SE), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-sulfinyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-oxy-sulfinyl)-amino group”.
  • Among the groups represented by the formula (ω-19E), those groups in which both Ra5 and Rb5 are hydrocarbon groups are referred to as “bis[O,O′-di(hydrocarbon)-phosphono]-amino group”, those groups in which both Ra5 and Rb5 are heterocyclic groups are referred to as “bis[O,O′-di(heteroring)-phosphono]-amino group”, and those groups in which Ra5 is a hydrocarbon group and Ra5 is a heterocyclic group are referred to as “bis(O-hydrocarbon—O′-heteroring-phosphono)-amino group”.
  • Among the groups represented by the formula (ω-20E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfonyl)-amino group”, and those groups in which Ra5 is a heterocyclic group are referred to as “bis(heteroring-sulfonyl)-amino group”.
  • Among the groups represented by the formula (ω-21E), those groups in which Ra5 is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfinyl)-amino group”, and those groups in which R-15 is a heterocyclic group are referred to as “bis(heteroring-sulfinyl)-amino group”.
  • Examples of the hydrocarbon in the groups represented by the aforementioned formulas (ω-1E) through (ω-21E) include similar groups to the aforementioned hydrocarbon group. Examples of the bis(hydrocarbon-carbonyl)-amino groups represented by the formula (ω-1E) include, a bis(alkyl-carbonyl)-amino group, a bis(alkenyl-carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino group, a bis(cycloalkyl-carbonyl)-amino group, a bis(cycloalkenyl-carbonyl)-amino group, a bis(cycloalkanedienyl-carbonyl)-amino group, a bis(cycloalkyl-allyl-carbonyl)-amino group which is a bis(aliphatic hydrocarbon-carbonyl)-amino group, a bis(aryl-carbonyl)-amino group, a bis(aralkyl-carbonyl)-amino group, a bis(bridged cyclic hydrocarbon-carbonyl)-amino group, a bis(spiro cyclic hydrocarbon-carbonyl)-amino group, and a bis(terpene family hydrocarbon-carbonyl)-amino group. In the following, groups represented by the formulas (ω-2E) through (ω-21E) are similar to those explained above.
  • Examples of the heteroring in the groups represented by the aforementioned formulas (ω-1E) through (ω-21E) include similar groups to the aforementioned heterocyclic group. Examples of the bis(heteroring-carbonyl)-amino group represented by the formula (ω-1E) include, for example, bis(monocyclic heteroaryl-carbonyl)-amino group, bis(fused polycyclic heteroaryl-carbonyl)-amino group, bis(monocyclic nonaromatic heterocyclic-carbonyl)-amino group, and bis(fused polycyclic nonaromatic heterocyclic-carbonyl)-amino group. In the following, groups represented by the formulas (ω-2E) through (ω-21E) are similar to those groups mentioned above.
  • Examples of the cyclic amino in the groups represented by the aforementioned formulas (ω-10E) through (ω-16E) include similar groups to the aforementioned cyclic amino group.
  • The aforementioned acyl-amino group and di(acyl)-amino group are generically referred to as “acyl substituted amino group”. Furthermore, the aforementioned N-hydrocarbon-amino group, N,N-di(hydrocarbon)-amino group, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-amino group, cyclic amino group, acyl-amino group, and di(acyl)-amino group are generically referred to as “substituted amino group”. These substituted amino group and amino group are generically referred to as “amino groups which may be substituted”.
  • In the following, compounds represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3), (I-4) are explained in details.
  • “Connecting group whose number of atoms of main chain is 2 to 4” in the definition of X means connecting groups wherein 2 to 4 atoms in a main chain link together between rings Z and E. The aforementioned “number of atoms of the main chain” is counted so as to minimize the number of connecting atoms existing between the rings Z and E, regardless of the presence or absence of hetero atom(s). For example, the number of atoms of 1,2-cyclopentylene is counted as 2, the number of atoms of 1,3-cyclopentylene is counted as 3, the number of atoms of 1,4-phenylene is counted as 4, the number of atoms of 2,6-pyridine-diyl is counted as 3.
  • The aforementioned “connecting group whose number of atoms of main chain is 2 to 4” is formed by one functional group selected from the following group of divalent group ζ-1, or formed by combining 2 to 4 functional groups of 1 to 4 kinds selected from the following divalent group ζ-2.
    [Divalent group ζ-1] the groups of the following formulas
    Figure US20090192122A2-20090730-C00029
    [Divalent group ζ-2] the groups of the following formulas
    Figure US20090192122A2-20090730-C00030
    When 2 or more divalent groups combine, each group may be the same or different.
  • The aforementioned “connecting group whose number of atoms of a main chain is 2 to 4” is preferably a group selected from the following “connecting group α”. [Connecting group a] the following formulas:
    Figure US20090192122A2-20090730-C00031
    wherein the bond at the left end binds to ring Z and the bond at the right end binds to to E.
  • The group represented by the following formula is most preferred:
    Figure US20090192122A2-20090730-C00032
    wherein, the bond at the left end binds to ring Z and the bond at the right end binds to E.
  • Examples of the substituent, according to “connecting group which may be substituted” in the definition of “a connecting group whose number of atoms of the main chain is 2 to 4”, include similar groups to the substituents in the definition of the aforementioned “which may be substituted”. A C1 to C6 alkyl group is preferred, and a methyl group is more preferred. The substituent may combine with a substituent of the ring E or Z, together with atoms to which they bind, to form a cyclic group which may be substituted. Examples include the compounds represented by the general formula (I) being those represented by the following formulas:
    Figure US20090192122A2-20090730-C00033
  • In the aforementioned general formula (I), examples of A include hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of the “arene” in “an arene which may be substituted” in the definition of ring Z include a monocyclic or fused heterocyclic aromatic hydrocarbon, and include, for example, benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, and acenaphylene ring. C6 to C10 arenes such as benzene ring, naphthalene ring and the like are preferred, benzene ring and naphthalene ring are more preferred, and benzene ring is most preferred.
  • When ring Z is a benzene ring, substituents according to the definition of “which may be substituted in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I)” are preferred to locate on the position of Rz when the following partial formula (Iz-1) in the general formula containing ring Z
    Figure US20090192122A2-20090730-C00034
    is a group represented by the following formula (Iz-2).
    Figure US20090192122A2-20090730-C00035
  • Examples of the “hetero arene” in “a hetero arene which may be substituted” in the definition of ring Z include a monocyclic or a fused polycyclic aromatic heterocyclic rings containing at least one of 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom and the like as ring-constituting atoms (ring forming atoms), and include, for example, furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring, 1,2,3-thiadiazole ring, 1,2,3-triazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, 1,2,3-triazine ring, 1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepine ring, 1,4-thiazepine ring, benzofuran ring, isobenzofuran ring, benzo[b]thiophene ring, benzo[c]thiophene ring, indole ring, 2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzooxazole ring, 1,2-benzoisooxazole ring, 2,1-benzoisooxazole ring, benzothiazole ring, 1,2-benzoisothiazole ring, 2,1-benzoisothiazole ring, 1,2,3-benzooxadiazole ring, 2,1,3-benzooxadiazole ring, 1,2,3-benzothiadiazole ring, 2,1,3-benzothiadiazole ring, 1H-benzotriazole ring, 2H-benzotriazole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, phthalazine ring, naphthyridine ring, 1H-1,5-benzodiazepine ring, carbazole ring, α-carboline ring, β-carboline ring, γ-carboline ring, acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenanthridine ring, phenanthroline ring, thianthrene ring, indolizine ring, and phenoxathiin ring, which are 5 to 14 membered monocyclic or fused polycyclic aromatic heterocyclic rings. 6 to 13 membered monocyclic or fused polycyclic aromatic heterocyclic rings are preferred, and pyridine ring, indole ring, quinoxaline ring, and carbazole ring are more preferred.
  • Examples of the substituent in the definition of “which may be substituted in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I)” in the definition of ring Z include similar groups to the substituent explained for the definition “which may be substituted”. When ring Z is “a benzene ring which may be substituted in addition to the group represented by formula —O-A wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined in the general formula (I)”, preferred examples of the substituents include halogen atoms, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, acyl group which may be substituted, ureido group which may be substituted, thioureido group which may be substituted, and diazenyl group which may be substituted, which are defined as those of substituent group γ-1z.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group γ-1z, and the “hydroxy group which may be substituted” in the definition of Rz include similar groups to the “hydroxy group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituents in the definition of the aforementioned “which may be substituted”. Hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”, a C1 to C6 on alkoxy group which may be substituted is more preferred, and methoxy group is further preferred.
  • Examples of the “amino group which may be substituted” in the definition of the substituent group γ-1z, and the “amino group which may be substituted” in the definition of Rz include similar group to the “amino group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent according to the definition of the aforementioned “which may be substituted”. Di(hydrocarbon)-amino group and hydrocarbon-carbonyl-amino group are preferred as the “amino group which may be substituted”, di(C1 to C6 alkyl)-amino group and C6 to C10 aryl-carbonyl-amino group are more preferred, and dimethylamino group and benzoylamino group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group γ-1z, and the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of Rz include similar groups to the substituents according to the definition of the aforementioned “which may be substituted”. A C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated allyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C1 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, and a C1 to C16 aralkyl group which may be substituted are preferred as the “hydrocarbon group which may be substituted”, and methyl group, tert-butyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1[(benzyloxy)aminoethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethylphenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenylethen-1-yl group, 9,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, phenyl group, and 2-phenethyl group are more preferred.
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of the substituent group γ-1z, and the substituent in the definition of “heterocyclic group which may be substituted” in the definition of Rz include similar groups to the substituents according to the definition of the aforementioned “which may be substituted”. A heteroaryl group which may be substituted is preferred as the “heterocyclic group which may be substituted”, a 5 to 6-membered heteroaryl group which may be substituted is more preferred, and 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, and 2-pyridyl group are further preferred.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group γ-1z, and the “acyl group which may be substituted” in the definition of Rz include similar groups exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. Carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a hydrocarbon-carbonyl group which may be substituted, a hydrocarbon-oxy-carbonyl group which may be substituted, a heteroring-carbonyl group which may be substituted, and a heteroring-sulfonyl group which may be substituted are preferred as the “acyl group which may be substituted”, carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, and a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted are more preferred, and [3,5-bis(trifluoromethyl)phenyl]carbamoyl group, dimethylcarbamoyl group, dimethylsulfamoyl group, acetyl group, isobutyryl group, methoxycarbonyl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, and (pyrrol-1-yl)sulfonyl group are further preferred.
  • Examples of the substituent in the definition of “ureido group which malt be substituted” in the definition of the substituent group γ-1z, and the substituent in the definition of “ureido group which may be substituted” in the definition of Rz include similar groups to the substituent explained for the definition “which may be substituted”. 3-Phenylureido group is preferred as the “ureido group which may be substituted”.
  • Examples of the substituent in the definition of “thioureido group which may be substituted” in the definition of the substituent group γ-1z, and the substituent in the definition of “thioureido group which may be substituted” in the definition of Rz include similar groups to the substituent explained for the definition “which may be substituted”. (3-Phenylthio)ureido group is preferred as the “thioureido group which may be substituted”.
  • Examples of the substituent in the definition of “diazenyl group which may be substituted” in the definition of the substituent group γ-1z, and the substituent in the definition of “diazenyl group which may be substituted” in the definition of Rz include similar groups to the substituent explained for the definition “which may be substituted”. (4-Nitrophenyl)diazenyl group and {[(4-pyridin-9-yl)sulfamoyl]pheny}diazenyl group are preferred as the “diazenyl group which may be substituted”.
  • Examples of Rz include halogen atom, nitro group, cyano group, hydroxy group which may be substituted, amino group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, acyl group which may be substituted, ureido group which may be substituted, thioureido group which may be substituted, and diazenyl group which may be substituted, and halogen atom is most preferred.
  • Examples of the aryl group of “an aryl group which may be substituted” in the definition of E include similar groups to the aryl group in the definition of the aforementioned “hydrocarbon group”, and C6 to C10 aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group and the like are preferred, and phenyl group is most preferred.
  • Examples of the substituent in the definition of “an aryl group which may be substituted” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted”.
  • Preferred embodiments of the phenyl group according to “an aryl group which may be substituted” in the definition of E are:
  • (1) phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups;
  • (2) phenyl group substituted with one C1 to C6 halogenated allyl group wherein said phenyl group may be substituted (except with a C1 to C6 halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group; and
  • (3) phenyl group which may be substituted (except with a C1 to C6 halogenated alkyl group).
  • Examples of the “C1 to C6 halogenated alkyl group” in “phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to Cr, halogenated allyl groups” in the definition of E include similar groups to those exemplified in the aforementioned definition of “C1 to C6 halogenated alkyl group”, and examples of the substituent in the definition of “said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups” include similar groups to the substituent explained for the definition “which may be substituted”.
  • “Phenyl group substituted with two C1 to Cu; halogenated alkyl groups” is preferred as the “phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to CG halogenated alkyl groups”. 3,5-Bis(trifluoromethyl)phenyl group and 2,5-bis(trifluoromethyl)phenyl group are preferred, and 3,5-bis(trifluoromethyl)phenyl group is most preferred.
  • Examples of the substituent in the definition of “phenyl group substituted with one C1 to C6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C1 to C6 halogenated alkyl group) in addition to one C1 to C6 halogenated alkyl group” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted” (a C1 to C6 halogenated alkyl group is excluded). Halogen atoms, nitro group, cyano group, hydroxy group which may be substituted, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, sulfanyl group which may be substituted which are defined in substituent group γ-1e are preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group γ-1e include similar groups to the “hydroxy group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. Hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”, C1 to C6 alkoxy group which may be substituted which is defined as substituent group γ-2e is more preferred, and methoxy group is further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group γ-1e, and the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of Rz include similar groups to the substituent explained for the definition “which may be substituted”. A C1 to C6 alkyl group which may be substituted which is defined in substituent group γ-2e is preferred as the “hydrocarbon group which may be substituted”, and methyl group is more preferred.
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of the substituent group γ-1e include similar groups to the substituents explained for the definition “which may be substituted”. A 5 to 6-membered nonaromatic heterocyclic group which may be substituted which is defined in substituent group γ-2e is preferred as the “heterocyclic group which may be substituted”, and 1-pyrrolidinyl group and morpholino group are more preferred.
  • Examples of the “sulfanyl group which may be substituted” in the definition of the substituent group γ-1e include similar groups to the “sulfanyl group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. A hydrocarbon-sulfanyl group which may be substituted is preferred as the “sulfanyl group which may be substituted”, and a C1 to C6 alkyl-sulfanyl group which may be substituted, which is defined in substituent group γ-2e, is more preferred, and methylsulfanyl group is further preferred.
  • Examples of the “C1 to C6 halogenated alkyl group” in “phenyl group substituted with one C1 to C6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C1 to C6 halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group” in the definition of E include similar groups to the aforementioned “C1 to C6 halogenated alkyl group”. C1 to C6 alkyl groups substituted with one or more fluorine atoms are preferred, C1 to C6 alkyl groups substituted with three or more fluorine atoms are more preferred, and trifluoromethyl group is most preferred.
  • Examples of the “phenyl group substituted with one C1 to C6 halogenated alkyl group wherein said phenyl group may be substituted (except with a C1 to C6 halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group” in the definition of E include 29(trifluoromethyl)phenyl group, 3-(trifluoromethyl)phenyl group, 4-(trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 2-chloro-4-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2 nitro-5-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 9-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidino)-5-(trifluoromethyl)phenyl group, and 2-morpholino-5-(trifluoromethyl)phenyl group. 2-Chloro-5-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-methoxy-5-(trifluoromethyl)phenyl group, and 3-methoxy-5-(trifluoromethyl)phenyl group are more preferred, and 2-chloro-5-(trifluoromethyl)phenyl group is most preferred.
  • Examples of the substituent in the definition of “phenyl group which may be substituted (except with a C1 to C6 halogenated alkyl group)” in the definition of E include similar groups to the substituent explained for the definition “which may be substituted”. Halogen atoms, nitro group, hydroxy group which may be substituted, hydrocarbon group which may be substituted, and acyl group which may be substituted which are defined in substituent group γ-3e are preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of the substituent group γ-3e include similar groups to the “hydroxy group which may be substituted” according to the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. Unsubstituted hydroxy group and a hydrocarbon-oxy group which may be substituted are preferred as the “hydroxy group which may be substituted”, and unsubstituted hydroxy group and C1 to C6 alkoxy group which may be substituted which are defined in substituent group γ-4e are more preferred, and unsubstituted hydroxy group and methoxy group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group γ-3e include similar groups to the substituent explained for the definition “which may be substituted”. A C1 to C6 alkyl group which may be substituted, a C6 to C10 aryl group which may be substituted, and a C1 to C8 alkylene group which may be substituted which are defined in substituent group γ-4e are preferred as the “hydrocarbon group which may be substituted”, and methyl group, tert-butyl group and 1,1,4,4-tetramethylbutane-1,4-diyl group are more preferred.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group γ-3e include the similar group to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”. A hydrocarbon-carbonyl group which may be substituted and a hydrocarbon-oxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”. A C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted which are defined in substituent group γ-4e are more preferred, and acetyl group and methoxycarbonyl group are further preferred.
  • Phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 3,4,5-trichlorophenyl group, pentafluorophenyl group, 3,5-dinitrophenyl group, 3,5-dichloro-4 hydroxyphenyl group, 2,5-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-dimethylphenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group, biphenyl-3-yl group, 4-methoxybiphenyl-3-yl group, 3-acetylphenyl group, and 3,5-bis(methoxycarbonyl)phenyl group are preferred as “phenyl group which may be substituted (except with a C1 to C6 halogenated alkyl group)” in the definition of E. 2,5-Bis[(1,1-dimethyl)ethyl]phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group, and 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group are more preferred, and 2-chloro-5-(trifluoromethyl)phenyl group is most preferred.
  • Examples of the “heteroaryl group” in “heteroaryl group which may be substituted” in the definition of E include similar groups to the “monocyclic heteroaryl group” and “fused polycyclic heteroaryl group” in the definition of the aforementioned “heteroaryl group”. A 5 to 13-membered heteroaryl group is preferred, and thienyl group, pyrazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group, pyrimidinyl group, indolyl group, and carbazolyl group are more preferred, and thiazolyl group is most preferred.
  • Examples of the substituent in the definition of “heteroaryl group which may be substituted” in the above definition of E include similar groups to the substituent explained for the definition “which may be substituted”.
  • Examples of the substituent in the definition of “thiazolyl group which may be substituted” in the above definition of E include similar groups to the substituent explained for the definition “which may be substituted”. Halogen atoms, cyano group, hydrocarbon group which may be substituted, heterocyclic group which may be substituted, and acyl group which may be substituted which are defined as substituent group γ-5e are preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of the substituent group γ-5e include similar groups to the substituents explained for the definition “which may be substituted”. A C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C6 to C10 aryl group which may be substituted, and a C1 to C6 aralkyl group which may be substituted which are defined in substituent group γ-6e are preferred as the “hydrocarbon group which may be substituted”. Methyl group, ethyl group, isopropyl group, n-butyl group, tert-butyl group, carboxymethyl group, trifluoromethyl group, phenyl group, 4-fluorophenyl group, 3-(trifluoromethyl)phenyl group, pentafluorophenyl group, and benzyl group are preferred.
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of the substituent group γ-5e include similar groups to the substituent explained for the definition “which may be substituted”. A 6-membered nonaromatic heterocyclic group which may be substituted, which is defined in substituent group γ-6e, is preferred as the “heterocyclic group which may be substituted”, and piperidino group, morpholino group, 4-methylpiperidin-1-yl group, and 4-phenylpiperidin-1-yl group are more preferred.
  • Examples of the “acyl group which may be substituted” in the definition of the substituent group γ-5e include similar groups to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”. A hydrocarbon-carbonyl group which may be substituted, a carbamoyl group which may be substituted, and a hydrocarbon-oxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”. Carbamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C6 to C10 aryl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted which are defined in substituent group γ-6e are more preferred, and N-methylcarbamoyl group, N-ethylcarbamoyl group, N-isopropylcarbamoyl group, N-(2-phenethyl)carbamoyl group, acetyl group, pivaloyl group, benzoyl group, and ethoxycarbonyl group are further preferred.
  • 5-Bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]-thiazol-2-yl group, 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-ethylthiazol-2-yl group, 5-methyl-4-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl)-5-(ethoxycarbonyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl)-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, 4,5-diphenylthiazol-2-yl group, 4-phenylthiazol-2-yl group, 4,5-dimethylthiazol-2-yl group, 2-thiazolyl group, 5-methylthiazol-2-yl group, 4-ethyl-5-phenylthiazol-2-yl group, 5-carboxymethyl-4-phenylthiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group, 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl group, 5-(2-phenetyl)carbamoyl-4-phenylthiazol-2-yl group, 4-(n-butyl)-5-phenylthiazol-2-yl group, 4-methyl-5-[(3-trifluoromethyl)phenyl]thiazol-2-yl group, and 5-(4-fluorophenyl)-4-methylthiazol-2-yl group are preferred as “thiazolyl group which may be substituted” in the definition of E, and 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group is more preferred.
  • In the aforementioned general formula (ω-1), Z1 is 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position.
  • Examples of the “halogenated alkyl group” in the “phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to C6 halogenated all-yl groups” in the definition of E1 include similar group to those exemplified in the aforementioned definition of “halogenated alkyl group”. Examples of substituents according to the definition of “said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups” include similar groups to the substituents explained for the definition “which may be substituted”. As the “phenyl group substituted with two C1 to CG halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups”, an example is a phenyl group substituted with two C1 to C6 alkyl groups which is substituted with one or more fluorine atoms in which said phenyl group may further have substituents in addition to the two C1 to C6 alkyl groups substituted with one or more fluorine atoms. More preferred example is a phenyl group substituted with two C1 to C6 alkyl groups which is substituted with three or more fluorine atoms in which said phenyl group may further have substituents in addition to the two C1 to C6 halogenated alkyl groups which are substituted with one or more fluorine atoms, and a phenyl group substituted with the two C1 to C6 alkyl groups which are substituted with three or more fluorine atoms is further preferred. It is preferred that these two substituents are substituted in the 2-position and 5-position, or 3-position and 5-position on the phenyl group.
  • Trifluoromethyl group is most preferred as “C1 to C6 alkyl group which is substituted with three or more fluorine atoms” in the definition of R1e2, R1e3, and R1e5.
  • As E1, 3,5-bis(trifluoromethyl)phenyl group or 2,5-bis(trifluoromethyl)phenyl group is preferred, and 2,5-bis(trifluoromethyl)phenyl group is most preferred.
  • A1 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of the “hydroxy group which may be substituted” in the definition of R1z include similar groups to the “hydroxy group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. A hydrocarbon-oxy group which may be substituted is preferred as the “hydroxy group which may be substituted”. A C1 to C6 alkoxy group which may be substituted is more preferred, and methoxy group is further preferred.
  • Examples of the “amino group which may be substituted” in the definition of R1z include similar groups to the “amino group which may be substituted” in the definition of the aforementioned “which may be substituted”, and examples of the substituent include similar groups to the substituent explained for the definition “which may be substituted”. Di(hydrocarbon)-amino group and hydrocarbon-carbonyl-amino group are preferred as the “amino group which may be substituted”, and di(C1 to C6 alkyl)-amino group and Cc, to C10 aryl-amino group are more preferred, and dimethylamino group and benzoylamino group are further preferred.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R1z include similar groups to the substituent explained for the definition “which may be substituted”. A C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to Cc, alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, and a C7 to C16 aralkyl group which may be substituted are preferred as the hydrocarbon group which may be substituted”, and methyl group, tert-butyl group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynyl group, and 2-phenethyl group are more preferred.
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of R1z include similar groups to the substituent explained for the definition “which may be substituted”. A heteroaryl group which may be substituted is preferred as the “heterocyclic group which may be substituted”, and a 5 to 6-membered heteroaryl group which may be substituted is more preferred, and 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group, and 2-pyridyl group are further preferred.
  • Examples of the “acyl group which may be substituted” in the definition of R1z include similar groups to those exemplified in the aforementioned definition of “acyl group which may be substituted”, and examples of the substituent include similar groups to the substituents explained for the definition “which may be substituted”. Carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a hydrocarbon-carbonyl group which may be substituted, a hydrocarbon-oxy-carbonyl group which may be substituted, a heterocyclic-carbonyl group which may be substituted, and a heterocyclic-sulfonyl group which may be substituted are preferred as the “acyl group which may be substituted”, and carbamoyl group which may be substituted, sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-member heteroaryl-sulfonyl group which may be substituted, and a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted are more preferred. 3,5-Bis(trifluoromethyl)phenyl]carbamoyl group, dimethylcarbamoyl group, dimethylsulfamoyl group, acetyl group, isobutyryl group, methoxycarbonyl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, and (pyrrol-1-yl)sulfonyl group are further preferred.
  • Examples of the substituent in the definition of “ureido group which may be substituted” in the definition R1z include similar groups to the substituents explained for the definition “which may be substituted”. 3-Phenylureido group is preferred as the “ureido group which may be substituted”.
  • Examples of the substituent in the definition of “thioureido group which may be substituted” in the definition of R1z include similar groups to the substituents explained for the definition “which may be substituted”. (3-Phenylthio)ureido group is preferred as the “thioureido group which may be substituted”.
  • Examples of the substituent in the definition of “diazenyl group which may be substituted” in the definition of R1z include similar groups to the substituents explained for the definition “which may be substituted”. (4-Nitrophenyl)diazenyl group and {1(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl group are preferred as the “diazenyl group which may be substituted”.
  • Examples of R1z include a halogen atom, nitro group cyano group, hydroxy group which may be substituted, amino group which may be substituted, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, a diazenyl group which may be substituted, a halogen atom, a C1 to C6 alkyl group which may be substituted, and a C1 to C6 halogenated alkyl group which may be substituted are preferred, and a halogen atom is most preferred.
  • Each compound defined by the aforementioned general formula (I-1) or a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, except the following 6 compounds, is novel compound, and uses of the compounds according to the present invention relating to the chemical substances are not limited.
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
    • N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
    • N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide
    • 2-Hydroxy-N-[2,3,5-tris(trifluoromethyl)phenyl] benzamide
  • In the aforementioned general formula (I-2), Z2 is 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted at the 5-position.
  • Examples of the “halogenated alkyl group” in “phenyl group wherein a C1 to C6 halogenated alkyl group is substituted in the 3-position or 5-position” in the definition of E2 (wherein said phenyl group may further have one or more substituents (except when the substituent is C1 to C6 halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group in the 3-position or 5-position) include similar groups to those exemplified in the aforementioned definition of “halogenated alkyl group”. A C1 to C6 alkyl group substituted with one or more fluorine atoms is preferred, and a C1 to C6 alkyl group substituted with three or more fluorine atoms is more preferred, and trifluoromethyl group is most preferred. Examples of the substituent in the definition of “phenyl group wherein a C1 to C6 halogenated alkyl group is substituted in the 3-position or 5-position” (wherein said phenyl group may further have one or more substituents (except when the substituent is C1 to C6 halogenated alkyl group) in addition to the C1 to C6 halogenated alkyl group in the 3-position or 5-position) include similar groups to the substituents explained for the definition “which may be substituted”. A halogen atom, nitro group, cyano group, a C1 to C6 alkyl group which may be substituted, a 5 to 6 membered nonaromatic heterocyclic group which may be substituted, a C1 to C6 alkoxy group which may be substituted, a C1 to C6 alkyl-sulfanyl group which may be substituted, which are defined in substituent group γ-7e, are preferred, and a halogen atom, nitro group, cyano group, methoxy group, methyl group, 1-pyrrolidinyl group, morpholino group, and methyl sulfanyl group are more preferred.
  • Preferred examples of the “phenyl group wherein a C1 to C6 halogenated alkyl groups is substituted in the 3-position or 5-position (wherein said phenyl group may further have one or more substituents (except when the substituent is a C1 to C6 halogenated alkyl) in addition to the C1 to C6 halogenated alkyl group in the 3-position or 5-position))” in the definition of E2 include 3-(Trifluoromethyl)phenyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl group, 2-chloro-5-(trifluoromethyl)phenyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo-5-(trifluoromethyl)phenyl group, 4-chloro-2-(trifluoromethyl)phenyl group, 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phenyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-methyl-3-(trifluoromethyl)phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl)phenyl group, 2-methoxy-6-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluoromethyl)phenyl group, 4-methoxy-3-(trifluoromethyl)phenyl group, 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidino)-5-(trifluoromethyl)phenyl group, and 2-morpholino-5-(trifluoromethyl)phenyl group
  • A2 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of R2a include a halogen atom, a C1 to C6 alkyl group which may be substituted, and a C1 to C6 halogenated alkyl group which may be substituted, and preferred examples include a halogen atom, methyl group, tert-butyl group, trifluoromethyl group, and pentafluoroethyl group.
  • Each compound defined by the aforementioned general formula (ω-2) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof, except the following 15 compounds, is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
    • 5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide
    • 6-bromo-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide
    • 2-hydroxy-5-iodo-N-[3-(trifluoromethyl)phenyl]benzamide
    • 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • 5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • 5-chloro-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide
    • 5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl] benzamide
    • 5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]-benzamide
    • 5-chloro-2-hydroxy-N-(3-trifluoromethyl)-4-{[4-(trifluoromethyl)sulfanyl]-phenoxy}phenyl)benzamide
    • N-[4-(benzothiazol-2-yl)sulfanyl-3-(trifluoromethyl)phenyl]-5-chloro-9-hydroxybenzamide
    • 5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • 5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide
    • 5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide
    • 5-chloro-2-hydroxy-N′-[2-(1 naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide
    • 5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl] benzamide
  • In the aforementioned general formula (I-3), Z3 is 2-hydroxyphenyl group which may be substituted in the 5-position and 2-acetoxyphenyl group which may be substituted in the 5-position.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R3e2 and R3e3 include similar groups to the substituents explained for the definition “which may be substituted”. A C1 to C6 alkyl group is preferred as the “hydrocarbon group which may be substituted”, and tert-butyl group is most preferred.
  • Examples of the substituent in the definition of “hydroxy group which may be substituted” in the definition of R3e2 and R3e3 include similar groups to the substituents explained for the definition “which may be substituted”. A C1 to Cc, alkoxy group is preferred as the “hydroxy group which may be substituted”, and methoxy group is most preferred.
  • Examples of the substituent in the definition of “C2 to C6 hydrocarbon group which may be substituted” in the definition of R3e5 include similar groups to the substituents explained for the definition “which may be substituted”. A C2 to C6 alkyl group is preferred as the “C2 to C6 alkyl group which may be substituted”, and tert-butyl group is most preferred.
  • As E3, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group, 3,5-bis[(1,1-dimethyl)ethyl]-phenyl group and 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group are preferred.
  • A2 is hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of R3z include halogen atom, C1 to C6 alkyl group and C1 to C6 halogenated alkyl group, and halogen atom, methyl group, tert-butyl group, trifluoromethyl group, and pentafluoroethyl group are preferred.
  • Each compound defined by the aforementioned general formula (I-3) or a pharmacologically acceptable salt thereof, or a hydrate thereof and a solvate thereof is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
  • In the aforementioned general formula (I-4), Z4 includes 2-hydroxyphenyl group which may be substituted in the 5-position and 2-acetoxyphenyl group which may be substituted in the 5-position.
  • Examples of the substituent in the definition of “hydrocarbon group which may be substituted” in the definition of R4e4 include similar groups to the substituent explained for the definition “which may be substituted”. A C1 to C6 alkyl group which may be substituted, a C1 to C10 halogenated alkyl group which may be substituted, and a C6 to C10 aryl group which may be substituted are preferred as the “hydrocarbon group which may be substituted”, and methyl group, isopropyl group, tert-butyl group, phenyl group, and pentafluorophenyl are more preferred.
  • Examples of the substituent in the definition of “acyl group which may be substituted” in the definition of R4e5 include similar groups to the substituents explained for the definition “which may be substituted”. A C1 to C6 alkyl-carbonyl group which may be substituted, a C6 to C10 aryl-carbonyl group which may be substituted, and a C1 to C6 alkoxy-carbonyl group which may be substituted are preferred as the “acyl group which may be substituted”, and acetyl group, pivaloyl group and benzoyl group are more preferred.
  • Examples of the substituent in the definition of “heterocyclic group which may be substituted” in the definition of R4e5 include similar groups to the substituents explained for the definition “which may be substituted”. A 6-membered nonaromatic heterocyclic group which may be substituted is preferred as the “heterocyclic group which may be substituted”, and piperidino group, morpholino group, 4-methylpiperazin-1-yl group, 4-phenylpiperazin-1-yl group are more preferred.
  • As E4,5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl] thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,9-dimethyl)propionyl]thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, and 4-(1,1-dimethyl)ethyl-5-(4 phenylpiperidin-1-yl)thiazol-2-yl group are preferred, and 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group is most preferred.
  • A4 includes hydrogen atom and an acetyl group, and hydrogen atom is preferred.
  • Examples of R4z include a halogen atom, a C6 to C10 aryl group, and a 5-membered heteroaryl group, and a halogen atom, phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 4-(trifluoromethyl)phenyl group, 1-pyrrolyl group, and 2-thienyl group are preferred.
  • Each compound defined by the aforementioned general formula (I-4) or a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is novel, and uses of the compounds according to the present invention relating to chemical substances are not limited.
  • The compounds represented by the aforementioned general formulas (I) (I-1), (I-2), (I-3), and (I-4) may form salts. Examples of pharmacologically acceptable salts include, when acidic groups exist, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salts, or ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, dicyclohexylammonium salt, and when basic groups exist, mineral acid salts such as hydrochloride, oxalate, hydrosulfate, nitrate, phosphate, or organic acid salts such as methane sulfonate, benzene sulfonate, para-toluene sulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate. Salts may sometimes be formed with amino acids such as glycine. As active ingredients of the medicament of the present invention, pharmacologically acceptable salts may also be suitably used.
  • The compounds or salts thereof represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3), and (I-4) may exist as hydrates or solvates. As active ingredients of the medicament of the present invention, any of the aforementioned substances may be used. Furthermore, the compounds represented by the aforementioned general formulas (I), (I-1), (I-2), (I-3), and (I-4) may sometimes have one or more asymmetric carbons, and may exist as steric isomers such as optically active substance and diastereomer. As active ingredients of the medicament of the present invention, pure forms of stereoisomers, arbitrary mixture of enantiomers or diastereomers, and racemates may be used. When the compounds represented by the general formulas (I), (I-1), (I-2), (I-3), and (I-4) have olefinic double bonds, the configuration may be in either E or Z, and as active ingredients of the medicament of the present invention, geometrical isomer in either of the configurations or a mixture thereof may be used.
  • Examples of the compounds as preferred active ingredients of the medicaments of the present invention are shown below. However, the active ingredients of the medicaments of the present invention are not limited to the compound set out below. In the table, Me represents methyl group, and Et represents ethyl group.
    Figure US20090192122A2-20090730-C00036
    Compound Number
    Figure US20090192122A2-20090730-C00037
         		X E
    1
    Figure US20090192122A2-20090730-C00038
    Figure US20090192122A2-20090730-C00039
    Figure US20090192122A2-20090730-C00040
    2
    Figure US20090192122A2-20090730-C00041
    Figure US20090192122A2-20090730-C00042
    Figure US20090192122A2-20090730-C00043
    3
    Figure US20090192122A2-20090730-C00044
    Figure US20090192122A2-20090730-C00045
    4
    Figure US20090192122A2-20090730-C00046
    Figure US20090192122A2-20090730-C00047
    Figure US20090192122A2-20090730-C00048
    5
    Figure US20090192122A2-20090730-C00049
    Figure US20090192122A2-20090730-C00050
    Figure US20090192122A2-20090730-C00051
    6
    Figure US20090192122A2-20090730-C00052
    Figure US20090192122A2-20090730-C00053
    Figure US20090192122A2-20090730-C00054
    7
    Figure US20090192122A2-20090730-C00055
    Figure US20090192122A2-20090730-C00056
    Figure US20090192122A2-20090730-C00057
    8
    Figure US20090192122A2-20090730-C00058
    Figure US20090192122A2-20090730-C00059
    Figure US20090192122A2-20090730-C00060
    9
    Figure US20090192122A2-20090730-C00061
    Figure US20090192122A2-20090730-C00062
    Figure US20090192122A2-20090730-C00063
    10
    Figure US20090192122A2-20090730-C00064
    Figure US20090192122A2-20090730-C00065
    Figure US20090192122A2-20090730-C00066
    11
    Figure US20090192122A2-20090730-C00067
    Figure US20090192122A2-20090730-C00068
    Figure US20090192122A2-20090730-C00069
    12
    Figure US20090192122A2-20090730-C00070
    Figure US20090192122A2-20090730-C00071
    Figure US20090192122A2-20090730-C00072
    13
    Figure US20090192122A2-20090730-C00073
    Figure US20090192122A2-20090730-C00074
    Figure US20090192122A2-20090730-C00075
    14
    Figure US20090192122A2-20090730-C00076
    Figure US20090192122A2-20090730-C00077
    Figure US20090192122A2-20090730-C00078
    15
    Figure US20090192122A2-20090730-C00079
    Figure US20090192122A2-20090730-C00080
    Figure US20090192122A2-20090730-C00081
    16
    Figure US20090192122A2-20090730-C00082
    Figure US20090192122A2-20090730-C00083
    Figure US20090192122A2-20090730-C00084
    17
    Figure US20090192122A2-20090730-C00085
    Figure US20090192122A2-20090730-C00086
  • Figure US20090192122A2-20090730-C00087
    Compound Number
    Figure US20090192122A2-20090730-C00088
         		E
    18
    Figure US20090192122A2-20090730-C00089
    Figure US20090192122A2-20090730-C00090
    19
    Figure US20090192122A2-20090730-C00091
    Figure US20090192122A2-20090730-C00092
    20
    Figure US20090192122A2-20090730-C00093
    Figure US20090192122A2-20090730-C00094
    21
    Figure US20090192122A2-20090730-C00095
    Figure US20090192122A2-20090730-C00096
    22
    Figure US20090192122A2-20090730-C00097
    Figure US20090192122A2-20090730-C00098
    23
    Figure US20090192122A2-20090730-C00099
    Figure US20090192122A2-20090730-C00100
    24
    Figure US20090192122A2-20090730-C00101
    Figure US20090192122A2-20090730-C00102
    25
    Figure US20090192122A2-20090730-C00103
    Figure US20090192122A2-20090730-C00104
    26
    Figure US20090192122A2-20090730-C00105
    Figure US20090192122A2-20090730-C00106
    27
    Figure US20090192122A2-20090730-C00107
    Figure US20090192122A2-20090730-C00108
    28
    Figure US20090192122A2-20090730-C00109
    Figure US20090192122A2-20090730-C00110
    29
    Figure US20090192122A2-20090730-C00111
    Figure US20090192122A2-20090730-C00112
    30
    Figure US20090192122A2-20090730-C00113
    Figure US20090192122A2-20090730-C00114
  • Figure US20090192122A2-20090730-C00115
    Compound Number
    Figure US20090192122A2-20090730-C00116
         		E
    31
    Figure US20090192122A2-20090730-C00117
    Figure US20090192122A2-20090730-C00118
    32
    Figure US20090192122A2-20090730-C00119
    Figure US20090192122A2-20090730-C00120
    33
    Figure US20090192122A2-20090730-C00121
    Figure US20090192122A2-20090730-C00122
    34
    Figure US20090192122A2-20090730-C00123
    Figure US20090192122A2-20090730-C00124
  • Figure US20090192122A2-20090730-C00125
    Compound Number
    Figure US20090192122A2-20090730-C00126
         		E
    35
    Figure US20090192122A2-20090730-C00127
    Figure US20090192122A2-20090730-C00128
    36
    Figure US20090192122A2-20090730-C00129
    Figure US20090192122A2-20090730-C00130
    37
    Figure US20090192122A2-20090730-C00131
    Figure US20090192122A2-20090730-C00132
    38
    Figure US20090192122A2-20090730-C00133
    Figure US20090192122A2-20090730-C00134
    39
    Figure US20090192122A2-20090730-C00135
    Figure US20090192122A2-20090730-C00136
    40
    Figure US20090192122A2-20090730-C00137
    Figure US20090192122A2-20090730-C00138
    41
    Figure US20090192122A2-20090730-C00139
    Figure US20090192122A2-20090730-C00140
    42
    Figure US20090192122A2-20090730-C00141
    Figure US20090192122A2-20090730-C00142
    43
    Figure US20090192122A2-20090730-C00143
    Figure US20090192122A2-20090730-C00144
    44
    Figure US20090192122A2-20090730-C00145
    Figure US20090192122A2-20090730-C00146
    45
    Figure US20090192122A2-20090730-C00147
    Figure US20090192122A2-20090730-C00148
    46
    Figure US20090192122A2-20090730-C00149
    Figure US20090192122A2-20090730-C00150
    47
    Figure US20090192122A2-20090730-C00151
    Figure US20090192122A2-20090730-C00152
  • Figure US20090192122A2-20090730-C00153
    Compound Number
    Figure US20090192122A2-20090730-C00154
         		E
    48
    Figure US20090192122A2-20090730-C00155
    Figure US20090192122A2-20090730-C00156
    39
    Figure US20090192122A2-20090730-C00157
    Figure US20090192122A2-20090730-C00158
    50
    Figure US20090192122A2-20090730-C00159
    Figure US20090192122A2-20090730-C00160
    51
    Figure US20090192122A2-20090730-C00161
    Figure US20090192122A2-20090730-C00162
    52
    Figure US20090192122A2-20090730-C00163
    Figure US20090192122A2-20090730-C00164
    53
    Figure US20090192122A2-20090730-C00165
    Figure US20090192122A2-20090730-C00166
    54
    Figure US20090192122A2-20090730-C00167
    Figure US20090192122A2-20090730-C00168
    55
    Figure US20090192122A2-20090730-C00169
    Figure US20090192122A2-20090730-C00170
    56
    Figure US20090192122A2-20090730-C00171
    Figure US20090192122A2-20090730-C00172
    57
    Figure US20090192122A2-20090730-C00173
    Figure US20090192122A2-20090730-C00174
    58
    Figure US20090192122A2-20090730-C00175
    Figure US20090192122A2-20090730-C00176
    59
    Figure US20090192122A2-20090730-C00177
    Figure US20090192122A2-20090730-C00178
    60
    Figure US20090192122A2-20090730-C00179
    Figure US20090192122A2-20090730-C00180
    61
    Figure US20090192122A2-20090730-C00181
    Figure US20090192122A2-20090730-C00182
    62
    Figure US20090192122A2-20090730-C00183
    Figure US20090192122A2-20090730-C00184
    63
    Figure US20090192122A2-20090730-C00185
    Figure US20090192122A2-20090730-C00186
    64
    Figure US20090192122A2-20090730-C00187
    Figure US20090192122A2-20090730-C00188
    65
    Figure US20090192122A2-20090730-C00189
    Figure US20090192122A2-20090730-C00190
    66
    Figure US20090192122A2-20090730-C00191
    Figure US20090192122A2-20090730-C00192
    67
    Figure US20090192122A2-20090730-C00193
    Figure US20090192122A2-20090730-C00194
    68
    Figure US20090192122A2-20090730-C00195
    Figure US20090192122A2-20090730-C00196
    69
    Figure US20090192122A2-20090730-C00197
    Figure US20090192122A2-20090730-C00198
    70
    Figure US20090192122A2-20090730-C00199
    Figure US20090192122A2-20090730-C00200
    71
    Figure US20090192122A2-20090730-C00201
    Figure US20090192122A2-20090730-C00202
    72
    Figure US20090192122A2-20090730-C00203
    Figure US20090192122A2-20090730-C00204
    73
    Figure US20090192122A2-20090730-C00205
    Figure US20090192122A2-20090730-C00206
    74
    Figure US20090192122A2-20090730-C00207
    Figure US20090192122A2-20090730-C00208
    75
    Figure US20090192122A2-20090730-C00209
    Figure US20090192122A2-20090730-C00210
    76
    Figure US20090192122A2-20090730-C00211
    Figure US20090192122A2-20090730-C00212
    77
    Figure US20090192122A2-20090730-C00213
    Figure US20090192122A2-20090730-C00214
    78
    Figure US20090192122A2-20090730-C00215
    Figure US20090192122A2-20090730-C00216
    79
    Figure US20090192122A2-20090730-C00217
    Figure US20090192122A2-20090730-C00218
    80
    Figure US20090192122A2-20090730-C00219
    Figure US20090192122A2-20090730-C00220
    81
    Figure US20090192122A2-20090730-C00221
    Figure US20090192122A2-20090730-C00222
    82
    Figure US20090192122A2-20090730-C00223
    Figure US20090192122A2-20090730-C00224
    83
    Figure US20090192122A2-20090730-C00225
    Figure US20090192122A2-20090730-C00226
    84
    Figure US20090192122A2-20090730-C00227
    Figure US20090192122A2-20090730-C00228
    85
    Figure US20090192122A2-20090730-C00229
    Figure US20090192122A2-20090730-C00230
    86
    Figure US20090192122A2-20090730-C00231
    Figure US20090192122A2-20090730-C00232
    87
    Figure US20090192122A2-20090730-C00233
    Figure US20090192122A2-20090730-C00234
    88
    Figure US20090192122A2-20090730-C00235
    Figure US20090192122A2-20090730-C00236
    89
    Figure US20090192122A2-20090730-C00237
    Figure US20090192122A2-20090730-C00238
    90
    Figure US20090192122A2-20090730-C00239
    Figure US20090192122A2-20090730-C00240
    91
    Figure US20090192122A2-20090730-C00241
    Figure US20090192122A2-20090730-C00242
    92
    Figure US20090192122A2-20090730-C00243
    Figure US20090192122A2-20090730-C00244
    93
    Figure US20090192122A2-20090730-C00245
    Figure US20090192122A2-20090730-C00246
    94
    Figure US20090192122A2-20090730-C00247
    Figure US20090192122A2-20090730-C00248
    95
    Figure US20090192122A2-20090730-C00249
    Figure US20090192122A2-20090730-C00250
    96
    Figure US20090192122A2-20090730-C00251
    Figure US20090192122A2-20090730-C00252
    97
    Figure US20090192122A2-20090730-C00253
    Figure US20090192122A2-20090730-C00254
    98
    Figure US20090192122A2-20090730-C00255
    Figure US20090192122A2-20090730-C00256
    99
    Figure US20090192122A2-20090730-C00257
    Figure US20090192122A2-20090730-C00258
    100
    Figure US20090192122A2-20090730-C00259
    Figure US20090192122A2-20090730-C00260
    101
    Figure US20090192122A2-20090730-C00261
    Figure US20090192122A2-20090730-C00262
    102
    Figure US20090192122A2-20090730-C00263
    Figure US20090192122A2-20090730-C00264
    103
    Figure US20090192122A2-20090730-C00265
    Figure US20090192122A2-20090730-C00266
  • Figure US20090192122A2-20090730-C00267
    Compound Number
    Figure US20090192122A2-20090730-C00268
         		E
    104
    Figure US20090192122A2-20090730-C00269
    Figure US20090192122A2-20090730-C00270
    105
    Figure US20090192122A2-20090730-C00271
    Figure US20090192122A2-20090730-C00272
    106
    Figure US20090192122A2-20090730-C00273
    Figure US20090192122A2-20090730-C00274
    107
    Figure US20090192122A2-20090730-C00275
    Figure US20090192122A2-20090730-C00276
    108
    Figure US20090192122A2-20090730-C00277
    Figure US20090192122A2-20090730-C00278
    109
    Figure US20090192122A2-20090730-C00279
    Figure US20090192122A2-20090730-C00280
    110
    Figure US20090192122A2-20090730-C00281
    Figure US20090192122A2-20090730-C00282
    111
    Figure US20090192122A2-20090730-C00283
    Figure US20090192122A2-20090730-C00284
    112
    Figure US20090192122A2-20090730-C00285
    Figure US20090192122A2-20090730-C00286
    113
    Figure US20090192122A2-20090730-C00287
    Figure US20090192122A2-20090730-C00288
    114
    Figure US20090192122A2-20090730-C00289
    Figure US20090192122A2-20090730-C00290
    115
    Figure US20090192122A2-20090730-C00291
    Figure US20090192122A2-20090730-C00292
    116
    Figure US20090192122A2-20090730-C00293
    Figure US20090192122A2-20090730-C00294
    117
    Figure US20090192122A2-20090730-C00295
    Figure US20090192122A2-20090730-C00296
    118
    Figure US20090192122A2-20090730-C00297
    Figure US20090192122A2-20090730-C00298
    119
    Figure US20090192122A2-20090730-C00299
    Figure US20090192122A2-20090730-C00300
    120
    Figure US20090192122A2-20090730-C00301
    Figure US20090192122A2-20090730-C00302
    121
    Figure US20090192122A2-20090730-C00303
    Figure US20090192122A2-20090730-C00304
    122
    Figure US20090192122A2-20090730-C00305
    Figure US20090192122A2-20090730-C00306
    123
    Figure US20090192122A2-20090730-C00307
    Figure US20090192122A2-20090730-C00308
    124
    Figure US20090192122A2-20090730-C00309
    Figure US20090192122A2-20090730-C00310
    125
    Figure US20090192122A2-20090730-C00311
    Figure US20090192122A2-20090730-C00312
    126
    Figure US20090192122A2-20090730-C00313
    Figure US20090192122A2-20090730-C00314
    127
    Figure US20090192122A2-20090730-C00315
    Figure US20090192122A2-20090730-C00316
    128
    Figure US20090192122A2-20090730-C00317
    Figure US20090192122A2-20090730-C00318
    129
    Figure US20090192122A2-20090730-C00319
    Figure US20090192122A2-20090730-C00320
    130
    Figure US20090192122A2-20090730-C00321
    Figure US20090192122A2-20090730-C00322
    131
    Figure US20090192122A2-20090730-C00323
    Figure US20090192122A2-20090730-C00324
    132
    Figure US20090192122A2-20090730-C00325
    Figure US20090192122A2-20090730-C00326
    133
    Figure US20090192122A2-20090730-C00327
    Figure US20090192122A2-20090730-C00328
    134
    Figure US20090192122A2-20090730-C00329
    Figure US20090192122A2-20090730-C00330
    135
    Figure US20090192122A2-20090730-C00331
    Figure US20090192122A2-20090730-C00332
    136
    Figure US20090192122A2-20090730-C00333
    Figure US20090192122A2-20090730-C00334
    137
    Figure US20090192122A2-20090730-C00335
    Figure US20090192122A2-20090730-C00336
    138
    Figure US20090192122A2-20090730-C00337
    Figure US20090192122A2-20090730-C00338
  • Figure US20090192122A2-20090730-C00339
    Compound Number
    Figure US20090192122A2-20090730-C00340
         		E
    139
    Figure US20090192122A2-20090730-C00341
    Figure US20090192122A2-20090730-C00342
    140
    Figure US20090192122A2-20090730-C00343
    Figure US20090192122A2-20090730-C00344
    141
    Figure US20090192122A2-20090730-C00345
    Figure US20090192122A2-20090730-C00346
    142
    Figure US20090192122A2-20090730-C00347
    Figure US20090192122A2-20090730-C00348
    143
    Figure US20090192122A2-20090730-C00349
    Figure US20090192122A2-20090730-C00350
    144
    Figure US20090192122A2-20090730-C00351
    Figure US20090192122A2-20090730-C00352
    145
    Figure US20090192122A2-20090730-C00353
    Figure US20090192122A2-20090730-C00354
    146
    Figure US20090192122A2-20090730-C00355
    Figure US20090192122A2-20090730-C00356
    147
    Figure US20090192122A2-20090730-C00357
    Figure US20090192122A2-20090730-C00358
    148
    Figure US20090192122A2-20090730-C00359
    Figure US20090192122A2-20090730-C00360
    149
    Figure US20090192122A2-20090730-C00361
    Figure US20090192122A2-20090730-C00362
    150
    Figure US20090192122A2-20090730-C00363
    Figure US20090192122A2-20090730-C00364
    151
    Figure US20090192122A2-20090730-C00365
    Figure US20090192122A2-20090730-C00366
    152
    Figure US20090192122A2-20090730-C00367
    Figure US20090192122A2-20090730-C00368
    153
    Figure US20090192122A2-20090730-C00369
    Figure US20090192122A2-20090730-C00370
    154
    Figure US20090192122A2-20090730-C00371
    Figure US20090192122A2-20090730-C00372
    155
    Figure US20090192122A2-20090730-C00373
    Figure US20090192122A2-20090730-C00374
    156
    Figure US20090192122A2-20090730-C00375
    Figure US20090192122A2-20090730-C00376
    157
    Figure US20090192122A2-20090730-C00377
    Figure US20090192122A2-20090730-C00378
    158
    Figure US20090192122A2-20090730-C00379
    Figure US20090192122A2-20090730-C00380
    159
    Figure US20090192122A2-20090730-C00381
    Figure US20090192122A2-20090730-C00382
    160
    Figure US20090192122A2-20090730-C00383
    Figure US20090192122A2-20090730-C00384
    161
    Figure US20090192122A2-20090730-C00385
    Figure US20090192122A2-20090730-C00386
    162
    Figure US20090192122A2-20090730-C00387
    Figure US20090192122A2-20090730-C00388
    163
    Figure US20090192122A2-20090730-C00389
    Figure US20090192122A2-20090730-C00390
    164
    Figure US20090192122A2-20090730-C00391
    Figure US20090192122A2-20090730-C00392
    165
    Figure US20090192122A2-20090730-C00393
    Figure US20090192122A2-20090730-C00394
    166
    Figure US20090192122A2-20090730-C00395
    Figure US20090192122A2-20090730-C00396
    167
    Figure US20090192122A2-20090730-C00397
    Figure US20090192122A2-20090730-C00398
    168
    Figure US20090192122A2-20090730-C00399
    Figure US20090192122A2-20090730-C00400
    169
    Figure US20090192122A2-20090730-C00401
    Figure US20090192122A2-20090730-C00402
    170
    Figure US20090192122A2-20090730-C00403
    Figure US20090192122A2-20090730-C00404
    171
    Figure US20090192122A2-20090730-C00405
    Figure US20090192122A2-20090730-C00406
    172
    Figure US20090192122A2-20090730-C00407
    Figure US20090192122A2-20090730-C00408
    173
    Figure US20090192122A2-20090730-C00409
    Figure US20090192122A2-20090730-C00410
    174
    Figure US20090192122A2-20090730-C00411
    Figure US20090192122A2-20090730-C00412
    175
    Figure US20090192122A2-20090730-C00413
    Figure US20090192122A2-20090730-C00414
    176
    Figure US20090192122A2-20090730-C00415
    Figure US20090192122A2-20090730-C00416
    177
    Figure US20090192122A2-20090730-C00417
    Figure US20090192122A2-20090730-C00418
    178
    Figure US20090192122A2-20090730-C00419
    Figure US20090192122A2-20090730-C00420
    179
    Figure US20090192122A2-20090730-C00421
    Figure US20090192122A2-20090730-C00422
  • Figure US20090192122A2-20090730-C00423
    Compound Number
    Figure US20090192122A2-20090730-C00424
         		E
    180
    Figure US20090192122A2-20090730-C00425
    Figure US20090192122A2-20090730-C00426
    181
    Figure US20090192122A2-20090730-C00427
    Figure US20090192122A2-20090730-C00428
    182
    Figure US20090192122A2-20090730-C00429
    Figure US20090192122A2-20090730-C00430
    183
    Figure US20090192122A2-20090730-C00431
    Figure US20090192122A2-20090730-C00432
    184
    Figure US20090192122A2-20090730-C00433
    Figure US20090192122A2-20090730-C00434
    185
    Figure US20090192122A2-20090730-C00435
    Figure US20090192122A2-20090730-C00436
    186
    Figure US20090192122A2-20090730-C00437
    Figure US20090192122A2-20090730-C00438
    187
    Figure US20090192122A2-20090730-C00439
    Figure US20090192122A2-20090730-C00440
    188
    Figure US20090192122A2-20090730-C00441
    Figure US20090192122A2-20090730-C00442
    189
    Figure US20090192122A2-20090730-C00443
    Figure US20090192122A2-20090730-C00444
    190
    Figure US20090192122A2-20090730-C00445
    Figure US20090192122A2-20090730-C00446
    191
    Figure US20090192122A2-20090730-C00447
    Figure US20090192122A2-20090730-C00448
    192
    Figure US20090192122A2-20090730-C00449
    Figure US20090192122A2-20090730-C00450
    193
    Figure US20090192122A2-20090730-C00451
    Figure US20090192122A2-20090730-C00452
    194
    Figure US20090192122A2-20090730-C00453
    Figure US20090192122A2-20090730-C00454
    195
    Figure US20090192122A2-20090730-C00455
    Figure US20090192122A2-20090730-C00456
    196
    Figure US20090192122A2-20090730-C00457
    Figure US20090192122A2-20090730-C00458
    197
    Figure US20090192122A2-20090730-C00459
    Figure US20090192122A2-20090730-C00460
    198
    Figure US20090192122A2-20090730-C00461
    Figure US20090192122A2-20090730-C00462
    199
    Figure US20090192122A2-20090730-C00463
    Figure US20090192122A2-20090730-C00464
    200
    Figure US20090192122A2-20090730-C00465
    Figure US20090192122A2-20090730-C00466
    201
    Figure US20090192122A2-20090730-C00467
    Figure US20090192122A2-20090730-C00468
    202
    Figure US20090192122A2-20090730-C00469
    Figure US20090192122A2-20090730-C00470
    203
    Figure US20090192122A2-20090730-C00471
    Figure US20090192122A2-20090730-C00472
    204
    Figure US20090192122A2-20090730-C00473
    Figure US20090192122A2-20090730-C00474
    205
    Figure US20090192122A2-20090730-C00475
    Figure US20090192122A2-20090730-C00476
    206
    Figure US20090192122A2-20090730-C00477
    Figure US20090192122A2-20090730-C00478
    207
    Figure US20090192122A2-20090730-C00479
    Figure US20090192122A2-20090730-C00480
    208
    Figure US20090192122A2-20090730-C00481
    Figure US20090192122A2-20090730-C00482
    209
    Figure US20090192122A2-20090730-C00483
    Figure US20090192122A2-20090730-C00484
    210
    Figure US20090192122A2-20090730-C00485
    Figure US20090192122A2-20090730-C00486
    211
    Figure US20090192122A2-20090730-C00487
    Figure US20090192122A2-20090730-C00488
    212
    Figure US20090192122A2-20090730-C00489
    Figure US20090192122A2-20090730-C00490
    213
    Figure US20090192122A2-20090730-C00491
    Figure US20090192122A2-20090730-C00492
    214
    Figure US20090192122A2-20090730-C00493
    Figure US20090192122A2-20090730-C00494
    215
    Figure US20090192122A2-20090730-C00495
    Figure US20090192122A2-20090730-C00496
    216
    Figure US20090192122A2-20090730-C00497
    Figure US20090192122A2-20090730-C00498
    217
    Figure US20090192122A2-20090730-C00499
    Figure US20090192122A2-20090730-C00500
    218
    Figure US20090192122A2-20090730-C00501
    Figure US20090192122A2-20090730-C00502
    219
    Figure US20090192122A2-20090730-C00503
    Figure US20090192122A2-20090730-C00504
    220
    Figure US20090192122A2-20090730-C00505
    Figure US20090192122A2-20090730-C00506
    221
    Figure US20090192122A2-20090730-C00507
    Figure US20090192122A2-20090730-C00508
    222
    Figure US20090192122A2-20090730-C00509
    Figure US20090192122A2-20090730-C00510
    223
    Figure US20090192122A2-20090730-C00511
    Figure US20090192122A2-20090730-C00512
  • The compounds represented by the general formula (I) can be prepared, for example, by methods shown bellow.
  • <Method 1>
  • The compounds represented by the general formula (I), wherein X is —CONH—(the hydrogen atom on the nitrogen may be substituted) can be prepared, for example, by a method described in the reaction scheme 1.
    Figure US20090192122A2-20090730-C00513
    wherein A101 represents a hydrogen atom or protecting groups of hydroxy group (preferably, an alkyl group such as methyl group and the like; an aralkyl group such as benzyl group and the like; an acetyl group, an alkoxyalkyl group such as methoxymethyl group and the like; a substituted silyl group such as trimethylsilyl group or the like), R101 represents a hydrogen atom, a C1 to C6 alkyl group or the like, E101 represents E or precursor of E in the definition of the general formula (I), G represents a hydroxy group, halogen atoms (preferably, a chlorine atom), a hydrocarbon-oxy group (preferably, an aryl-oxy group which may be substituted by halogen atom), an acyl-oxy group, an imido-oxy group or the like.
    (First Step)
  • The amide (3) can be prepared by dehydrocondensation of the carboxylic acid derivative (1) and the amine (2). This reaction is carried out at a reaction temperature of from 0° C. to 180° C., without solvent or in an aprotic solvent, in the existence of an acid halogenating agent or a dehydrocondensating agent, and in the existence of or nonexistence of a base.
  • As the halogenating agent reagent, examples include, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or the like, when A101 is hydrogen atom, phosphorus trichloride is preferable, and when A101 is acetyl group or the like, phosphorus oxychloride is preferable. As the dehydrocondensating agent, examples include, for example, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphorylazide or the like. As the base, examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrocarbonate or the like, or organic bases such as pyridine, triethylamine, N,N′-diethylaniline or the like. As the aprotic solvent, examples include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene, o-dichlorobenzene, N,N′-dimethylformamide, N-methylpyrrolidone or the like, when the reaction is carried out in the presence of the acid halogenating agent, particularly, toluene, monochlorobenzene, o-dichlorobenzene are preferable.
  • Furthermore, a target compound can be prepared, for example, by a method or similar method described in J. Med. Chem., 1998, 41, 2939, that the acid chloride is prepared and isolated from carboxylic acid in advance, then it is made to react with an amine having E101.
  • (Second Process)
  • When the amide (3) has a protecting group and/or has a favorable substituent for functional group modification, for example, an amino group and its protector or precursor; a carboxy group and its protector or precursor; a hydroxy group and its protector or precursor, the final target compound (4) can be prepared by a reaction for deprotection and/or functional group modification in this step. Various well-known methods can be used for the reaction. For the reaction of deprotection and functional group modification, for example, methods described in “Protective Groups in Organic Syntheses” P. G. M. Wuts, T. Green, Eds., Third version, 1999, Wiley, John & Sons, “Handbook of Reagents for Organic Synthesis” L. A. Paquette, Ed., 4 Volumes, 1999, Wiley, John & Sons can be used, and for reaction of functional group modification, for example, methods described in “Palladium Reagents in Organic Syntheses” R. F. Heck, 1985, Academic Press, “Palladium Reagents and Catalysts: Innovations in Organic Synthesis” J. Tsuji, 1999, Wiley, John & Sons, or the like can be used.
  • Aforementioned methods are applicable by combining raw materials properly even in the case where X is other connecting group, for example, —SO2NH—, —NHCO—, —NHSO2—, —CONHCH2-, —CONHCH2CH2—; wherein the hydrogen atom on the said connecting group may be substituted.
  • <Method 2>
  • The compounds represented by the general formula (I), wherein X is —CH2NH—, for example, can be prepared by a method described in the reaction scheme 2.
    Figure US20090192122A2-20090730-C00514
    (wherein each of A and E has the same meaning as that defined in the general formula (I))
  • First, the imine derivative of the formula (7) (wherein the definition of R1˜R4 and B the same as those in the general formula (I)) can be prepared by dehydrocondensation of the aldehyde(5) and the amine (6). This reaction is carried out at a reaction temperature of from 0° C. to 100° C. in a solvent, in the existence of or nonexistence of a dehydrating agent. As the dehydrating agent, examples include anhydrous magnesium sulfate, molecular sieves or the like. As the solvent, examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable.
  • Aforementioned methods are applicable by combining raw materials properly even in the case where X is other connecting group, for example, —CONHN═C—; the hydrogen atom on the said connecting group may be substituted.
  • Next, the target compound (8) can be prepared by reduction of the imine derivative (7). This reaction is carried out at the reaction temperature of from 0° C. to 100° C. in a solvent, in the existence of a reducing agent. As the reducing agent, examples include sodium borohydride, lithium borohydride or the like. As the solvent, examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. Moreover, this reaction can be carried out by a method of catalytic hydrogenation also. As the catalyst, examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like. As solvent, examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. The reaction is carried out at the reaction temperature of from 0° C. to 200° C., and the hydrogen pressure is at normal pressure or applied pressure.
  • <Method 3>
  • The compounds represented by the general formula (I), wherein X is —CH—CH— (the hydrogen atom on the said connecting group may be substituted), can be prepared by a method described in the reaction scheme 3.
    Figure US20090192122A2-20090730-C00515
    wherein each of A and E has the same meaning as that defined in the general formula (I), W represents O,O′-di-hydrocarbon-phosphono group or triarylphosphonium group.
  • The target compound (11) can be prepared by dehydrocondensation of the aldehyde (9) and the phosphorus compound (10). This reaction is carried out in a solvent at a reaction temperature of from 0° C. to the boiling point of the solvent, in the existence of a base. As the base, examples include inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N′-diethylaniline or the like. Examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxan, methanol, ethanol, water or the like are preferable.
  • <Method 4>
  • The compounds represented by the general formula (I), wherein X is —COCH ═CH— and —COCH2CH2— (the hydrogen atom on the said connecting group may be substituted), can be prepared by the method, for example, described in the reaction scheme 4.
    Figure US20090192122A2-20090730-C00516
  • First, the target compound enone (14) can be prepared by dehydrocondensation of the ketone (12) and the aldehyde (13). This reaction is carried out in a solvent at the a reaction temperature of from 0° C. to the boiling point of the solvent in the existence of a base. As the base, examples include inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, or organic base such as pyridine, triethylamine, N,N′-diethylaniline or the like. Examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxan, methanol, ethanol, water or the like are preferable.
  • Next, the target compound (15) can be prepared by reduction of the enone (14). This reaction is carried out at the reaction temperature of from 0° C. to 100° C. in solvent, in the existence of a reducing agent. As the reducing agent, examples include sodium borohydride, lithium borohydride or the like. As the solvent, examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. Moreover, this reaction is carried out by a method of catalytic hydrogenation also. As the catalyst, examples include palladium carbon, platinum carbon, palladium hydroxide, palladium black or the like. As solvent, examples include nonreactive solvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are preferable. The reaction is carried out at the reaction temperature of from 0° C. to 200° C., and the hydrogen pressure is at normal pressure or applied pressure
  • In the examples of the specification, preparation methods of typical compounds included in the general formula (I) are explained in details. Therefore, those skilled in the art can prepare any compound included in the general formula (I) by referring to the explanations of the aforementioned general preparation methods and of specific preparation methods of the examples, selecting appropriate reaction raw materials, reaction reagents, and reaction conditions, and by adding appropriate modification and alteration of these methods, if necessary.
  • The compounds represented by the general formula (I) have inhibitory action against NF-κ B activation and inhibitory action against the production and release of inflammatory cytokines, and are useful as active ingredients of pharmaceutical compositions such as NF-κ B inhibitor and inflammatory cytokine release inhibitor. The aforementioned medicament can be suitably used as an expression inhibitor of genes of one or more substances selected from a group comprising tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony-stimulating factor, interferon β, cell adhesion factor ICAM-1, VCAM-1, and ELAM-1, nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class II, β 2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, transcript derived from HIV gene, transcript derived from HTLV gene, transcript derived from simian virus 40 gene, transcript derived from cytomegalovirus gene, and transcript derived from adenovirus gene. Moreover, the medicament of the present invention is useful for preventive and/or therapeutic treatment of diseases caused by NF-κ B activation and inflammatory cytokine overproduction.
  • More specifically, the medicament of the present invention may be used for preventive and/or therapeutic treatment of the following diseases wherein NF-κB activation and/or inflammatory cytokine is believed to be involved, for example, autoimmune diseases such as chronic rheumatism, osteoarthritis, systematic lupus erythematosus, systematic scleroderma, polymyositis, Sjoegren's syndrome, vasculitis syndrome, antiphospholipid syndrome, Still's disease, Behcet's disease, periarteritis nodosa, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerulonephritis, and chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, endothelial hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, allergic disease such as pollinosis, asthma, bronchitis, interstitial pneumonia, lung disease involving granuloma, chronic obstructive lung disease, chronic pulmonary thromboembolism, inflammatory colitis, insulin resistance, obesity, diabetes and its complications (nephropathy, retinopathy, neurosis, hyperinsulinemia, arteriosclerosis, hypertension, peripheral vessel obstruction, etc.) diseases involving abnormal vascular proliferation such as hyperlipemia, retinopathy, and pneumonia, Alzheimer's disease, encephalomyelitis, acute hepatitis, chronic hepatitis, drug induced toxic hepatopathy, alcoholic hepatitis, viral hepatitis, icterus, cirrhosis hepatic insufficiency, atrial myxoma, Caslemann's syndrome, mesangial nephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, pancreatic cancer, other solid cancer, sarcoma, osteosarcoma, metastatic invasion of cancer, carceration of inflammatory focus, cancerous cachexia, metastasis of cancer, leukemia such as acute myeloblastic leukemia, multiple myeloma, Lennert's lymphoma, malignant lymphoma, development of carcinostatic resistance of cancer, carciration of foci such as viral hepatitis and cirrhosis, carciration from polyp of colon, brain tumor, nervous tumor, endotoxic shock, sepsis, cytomegaloviral pneumonia, cytomegaloviral retinopathy, adenoviral cold, adenoviral pool fever, adenoviral ophthalmia, conjunctivitis, AIDS, uveitis, diseases or complications provoked by infections of other bacteria, viruses, and mycetes, complications after surgery such as generalized inflammatory symptoms, restenosis after percutaneous tubal coronary artery plastic surgery, reperfusion disorders after vascular occlusion opening such as ischemia reperfusion disorders, organ transplantation rejection and reperfusion disorders of heart, liver, kidney or the like, itch, anorexia, malaise, chronic fatigue syndrome or the like. Furthermore, inflammatory cytokine and NF-κ B are involved in differentiation and activation of osteoclast, and consequently, the medicament of the present invention is also useful for preventive and/or therapeutic treatment of metabolic bone diseases or the like such as osteoporosis and osteocarcinomic pain or the like. The medicament may also be used for prevention of deterioration of an organ during organ conservation before transplantation.
  • As the active ingredient of the medicament on the present invention, 1 or more kinds of substances selected from the group consisting of the compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof may be used. The aforementioned substance, per se, may be administered as the medicament of the present invention, however, preferably, the medicament of the present invention is provided in the form of a pharmaceutical composition comprising the aforementioned substance which is an active ingredient together with one or more pharmacologically acceptable pharmaceutical additives. In the aforementioned pharmaceutical compositions, a ratio of the active ingredient to the pharmaceutical additives is 1 weight % to 90 weight %.
  • The pharmaceutical compositions of the present invention may be administered as pharmaceutical compositions for oral administration, for example, granules, subtilized granules, powders, hard capsules, soft capsules, syrup, emulsion, suspension, or solution, or may be administered as pharmaceutical compositions for parenteral administration, for example, injections for intravenous administration, intramuscular administration, or subcutaneous administration, drops, suppositories, percutaneous absorbent, transmucosal absorption preparations, nasal drops, ear drops, instillation, and inhalants. Preparations made as pharmaceutical compositions in a form of powder may be dissolved when necessary and used as injections or drip infusions.
  • For preparation of pharmaceutical compositions, solid or liquid pharmaceutical additives may be used. Pharmaceutical additives may either be organic or inorganic. When an oral solid preparation is prepared, an excipient is added to the active ingredient, and further binders, disintegrator, lubricant, colorant, corrigent are added, if necessary, preparations in the forms of tablets, coating tablets, granules, powders, capsules and the like may be manufactured by common procedures. Examples of the excipient include lactose, sucrose, saccharose, glucose, corn starch, starch, talc, sorbit, crystal cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide. Examples of the binder include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum Arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, dextrin, and pectin. Examples of the lubricant include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. As the coloring agent, any material can be used which are approved to be added to ordinary pharmaceuticals. As the corrigent, cocoa powder, menthol, aromatic acid, peppermint oil, d-borneol, cinnamon powder and the like can be used. These tables and granules may be applied with sugarcoating, gelatine coating, or an appropriate coating, if necessary. Preservatives, antioxidant and the like may be added, if required.
  • For liquid preparations for oral administration such as emulsions, syrups, suspensions, and solutions, ordinary used inactive diluents, for example, water or vegetable oil may be used. For these preparations, besides inactive diluents, adjuvants such as wetting agents, suspending aids, sweating agents, flavoring agents, coloring agents or preservatives may be blended. After a liquid preparation is manufactured, the preparation may be filled in capsules made of a absorbable substance such as gelatin. Examples of solvents or suspending agents used for the preparations of parenteral administration such as injections or suppositories include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin. Examples of base materials used for preparation of suppositories include, for example, cacao butter, emulsified cacao butter, lauric fat, and witepsol. Methods for preparation of the aforementioned preparations are not limited, and any method ordinarily used in the art may be used.
  • When the composition are prepared in the form of injections, carriers such as, for example, diluents including water, ethanol, macrogol, propyleneglycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide, pH modifiers and buffer solutions including sodium citrate, sodium acetate and sodium phosphate, stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate may be used. For the preparation, a sufficient amount of a salt; glucose, mannitol or glycerin may be blended in the preparation to manufacture an isotonic solution, and an ordinary solubilizer, a soothing agent, or a topical anesthetic may be used.
  • When the preparation in the form of an ointment such as a paste, a cream, and a gel is manufactured, an ordinarily used base material, a stabilizer, a wetting agent, and a preservative may be blended, if necessary, and may be prepared by mixing the components by a common method. As the base material, for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, and bentonite may be used. As the preservative, paraoxy methyl benzoate, paraoxy ethyl benzoate, paraoxy propyl benzoate and the like may be used. When the preparation in the form of a patch is manufactured, the aforementioned ointment, cream gel, or paste and the like may be applied by a common method to an ordinary support. As the support, fabric made of cotton, span rayon, and synthetic fibersor or nonwoven fabric, and a film or a foam sheet such as made of soft vinyl chloride, polyethylene, and polyurethane and the like may be preferably used.
  • A dose of the medicament of the present invention is not particularly limited. For oral administration, a dose may generally be 0.01 to 5,000 mg per day for an adult as the weight of the compound of the present invention. It is preferred to increase or decrease the above dose appropriately depending on the age, pathological conditions, and symptoms of a patient. The above dose may be administered once a day or 2 to 3 times a day as divided portions with proper intervals, or intermittent administration for every several days may be acceptable. When the medicament is used as an injection, the dose may be 0.001 to 100 mg per day for an adult as the weight of the compound of the present invention.
    • EXAMPLES
  • The present invention will be explained more specifically with reference to the following examples. However the scope of the present invention is not limited to the following examples. And the commercially available compounds, which were purchased and used for the examinations, are contained in these examples. As for such compounds, the suppliers of the reagents and the catalog code numbers are show n.
    • Example 1 Preparation of N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-5-bromo-2-hydroxybenzamide Compound No. 1
  • Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC.HCl hereafter.; 192 mg, 1 mmol) was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol), 3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol), 4-dimethylaminopyridine(12 mg, 0.1 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8 mg, 55.4%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 4.69 (2H, d, J=5.7 Hz), 6.93 (1H, d, J=8.7 Hz), 7.56 (1H, dd, J=8.7, 2.4 Hz), 8.02 (1H, d, J=2.4 Hz), 8.06 (3H, s), 9.41 (1H, t, J=6.7 Hz), 12.13 (1H, s).
    • Example 9 5-Bromo-2 hydroxy-N-(2-phenethyl)benzamide Compound No. 2 (1) 2-Acetoxy-N-(2-phenethyl)benzamide
  • o-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was dissolved in benzene (8 mL). Phenethylamine (0.12 g, 1.00 mmol) and pyridine(0.3 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=2:1→1:1) to give the title compound (155.5 mg, 54.9%) as a white crystal.
  • 1H-NMR (CDCl3): δ 2.09 (3H, s), 2.92 (2H, t, J=6.8 Hz), 3.71 (2H, q, J=6.8 Hz), 6.32 (1H, brs), 7.07 (1H, dd, J=8.4, 1.2 Hz), 7.23-7.35 (6H, m), 7.44 (1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.73 (1H, dd, J=7.6, 1.6 Hz).
    • (2) 9-Hydroxy-N-(2-phenethyl)benzamide
  • Methanol (5 mL) and 2 N sodium hydroxide (0.1 mL) were added to 2-acetoxy-N-(2-phenethyl)benzamide (155.5 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized(dichloromethane/hexane) to give the title compound (106.9 mg, 80.7%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 2.86 (2H, t, J=7.6 Hz), 3.52 (1H, q, J=7.6 Hz), 6.84-6.88 (2H, m), 7.18-7.31 (5H, m), 7.37 (1H, ddd, J=8.4, 7.2, 1.6 Hz), 7.80 (1H, dd, J=8.4, 1.6 Hz), 8.84 (1H, s), 1.51 (1H, s).
    • (3) 5-Bromo-2-hydroxy-N-(2-phenethyl)benzamide
  • Carbon tetrachloride (5 mL), iron powder (0.03 g) and bromine(25 μl, 0.45 mmol) were added to 2-hydroxy-N-(2-phenethyl)benzamide (79.6 mg, 0.33 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydrogen sulfite and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give the title compound (62 mg, 58.7%) as white powder.
  • 1H-NMR (DMSO-d6s): δ 2.85 (2H, t, J=7.6 Hz), 3.52 (1H, q, J=7.6 Hz), 6.37 (1H, d, J=8.8 Hz), 7.18-7.31 (5H, m), 7.52 (1H, dd, J=8.8, 2.4 Hz), 8.01 (1H, d, J=2.4 Hz), 8.90 (1H, s), 12.51 (1H, s).
    • Example 3 5-Bromo-2-hydroxy-N [5-(morpholinocarbonyl)indan-2-yl]benzamide Compound No. 3
  • WSC.HCl(96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-56(morpholino)carbonylindane(refer to Chem. Pharm. Bull., 2000, 48, 131; 141 mg, 0.5 mmol) and triethylamine(70 μL, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2 N hydrochloric acid, water and brine one after another, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography on silica gel(dichloromethane:methanol=19:1) to give the title compound (26 mg, 11.9%) as a white crystal.
  • 1H-NMR (CDCl3): δ 2.66 (1H, dd, J=16.2, 7.2 Hz), 2.82 (1H, dd, J=16.2, 7.2 Hz), 3.16-3.25 (2H, m), 3.43-3.86 (8H, m), 4.79-4.92 (1H, m), 6.88 (1H, d, J=8.7 Hz), 7.14-7.15 (3H, m), 7.46 (1H, dd, J=8.7, 2.4 Hz), 7.74 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=2.4 Hz).
    • Example 4 3-(1-Chlorophenyl)-1-(2,6-dihydroxyphenyl)-3-(4-hydroxyphenyl)propan-1-one Compound No. 4
  • This compound is a commercially available compound.
  • Supplier: Apin Chemicals.
  • Catalog code number: N 0100D.
    • Example 5 1-(5-Chloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)propan-1-one Compound No. 5
  • This compound is a commercially available compound.
  • Supplier: Specs.
  • Catalog code number: AI-233/31581024.
    • Example 6 1-(9-Hydroxy-4-methoxyphenyl)-3-(2-methoxyphenyl)propen-1-one Compound No. 6
  • This compound is a commercially available compound.
  • Supplier: Maybridge.
  • Catalog code number: RJC 00106.
    • Example 7 3-(3,4-Dihydro-9H-benzo[b][1,4]dioxepin-7-yl)-1-(2-hydroxy-5-methylphenyl)propen-1-one Compound No. 7
  • This compound is a commercially available compound.
  • Supplier: Maybridge.
  • Catalog code number: BTB 13230.
    • Example 8 3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-[2-hydroxy-4-(methoxymethyl)phenyl]propen-1-one Compound No. 8
  • This compound is a commercially available compound.
  • Supplier: Maybridge.
  • Catalog code number: BTB 114482.
    • Example 9 4-Chloro-2-[(4-chlorophenyl)ethen-2-yl]phenol Compound No. 9
  • 5-Chlorosalicylaldehyde(313 mg, 2 mmol) and 4-chlorobenzyltriphenyl-phosphonium chloride (847 mg, 2 mmol) were dissolved in N,N-dimethylfomamide (20 mL). Potassium carbonate (1.382 g, 10 mmol) dissolved in water (10 mL) was added, and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound (44.6 mg, 8.4%) as a light gray solid.
  • 1H-NMR (CDCl3): δ 5.04 (1H, s), 6.74 (1H, d, J=9.0 Hz), 7.05 (1H, d, J=16.5 Hz), 7.10 (1H, dd, J=8.4, 2.4 Hz), 7.26 (1H, d, J=16.5 Hz), 7.33 (2H, d, J=8.4 Hz), 7.45 (2)H, d, J=8.4 Hz), 7.49 (1H, d, J=2.4 Hz).
    • Example 10 5 Bromo-N-(3,5-dichloro)phenyl-2-hydroxybenzenesulfonamide Compound No. 10 (1) 5-Bromo-N-(3,5-dichloro)phenyl-2-methoxybenzenesulfonamide
  • 5-Bromo-2-methoxybenzenesulfonyl chloride (857 mg, 3 mmol) was dissolved in dichloromethane (6 mL). A solution of 3,5-dichloroaniline (510 mg, 3.15 mmol) and pyridine(261 mg, 3.3 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 6 hours. After the reaction mixture was diluted with dichloromethane, washed with 2 N-hydrochloric acid, water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to give 5-bromo-2-methoxy-N-(3,5-dichloro)benzenesulfonamide (900 mg, 73.0%) as a white crystal.
  • 1H-NMR(DMSO-d6): δ 4.03 (3H, s), 6.92 (1H, d, J=9.0 Hz), 7.01 (2H, d, J=1.5 Hz), 7.07-7.08 (1H, m), 7.24 (1H, brs), 7.63 (1H, dd, J=8.7, 2.4 Hz), 7.99 (1H, d, J=2.4 Hz).
    • (2) 5-Bromo-N-(3,5-dichloro)phenyl-2-hydroxybenzenesulfonamide
  • A mixture of the white crystal of 5-Bromo-N-(3,5-dichloro)phenyl-2-methoxybenzenesulfonamide(206 mg, 0.5 mmol), lithium iodide (134 mg, 1 mmol) and 2,4,6-collidine(5 mL) was refluxed for 30 minutes under argon atmosphere. After cooling to room temperature, the reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. Ater the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to give the title compound (90 mg, 45.3%) as a white crystal.
  • mp 158-159° C.
  • 1H-NMR (DMSO-d6, δ): 6.92 (1H, d, J=8.7 Hz), 7.11 (2H, d, J=2.1 Hz), 7.21-7.22 (1H, m), 7.62 (1H, dd, J=8.7, 2.7 Hz), 7.80 (1H, d, J=2.4 Hz), 10.70 (1H, br), 11.37 (1H, br).
    • Example 11 3,5-Bis(trifluoromethyl)-N-(2-hydroxyphenyl)benzamide Compound No. 11
  • 2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in dichloromethane (3 mL) and pyridine(0.5 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (5 mL), added dropwise 2 N sodium hydroxide (0.1 mL, 0.2 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound (288 mg, 73.6%) as a light pink crystal.
  • mp 183° C. (dec.).
  • 1H-NMR (DMSO-d6, δ): 6.83 (1H, td, J=8.0, 1.2 Hz), 6.93 (1H, dd, J=8.0, 1.2 Hz), 7.08 (1H, td, J=8.0, 1.6 Hz), 7.50 (1H, d, J=8.0 Hz), 8.35 (2H, s), 9.61 (1H, s), 10.15 (1H, 5).
    • Example 12 N-(5-Chloro-2-hydroxyphenyl)-3,5-dichlorobenzamide Compound No. 12
  • 2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine (243 mg, 2.4 mmol) were dissolved in dichloromethane (5 mL). A solution of 3,5-dichlorobenzoyl chloride(419 mg, 2 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was diluted with ethyl acetate, washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give a light brown solid. The solid was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (205 mg, 32.4%) as a white crystal.
  • mp 251-252° C.
  • 1H-NMR(DMSO-d6): δ (6.93 (1H, d, J=9.0 Hz), 7.11 (1H, dd, J=8.7, 2.7 Hz), 7.67 (2H, d, J=2.7 Hz), 7.86-7.68 (1H, m), 7.97 (1H, d, J=1.8 Hz), 9.85 (1H, s), 10.03 (1H, s).
    • Example 13 N-(5-Chloro-2-hydroxyphenyl)-3,5-dichlorobenesulfonamide Compound No. 13
  • 2-Amino-4-chlorophenol (287 mg, 2 mmol) and 3,5-dichlorobenzenesulfonyl chloride (540 mg, 2.2 mmol) were dissolved in dichloromethane (4 mL). Pyridine(1 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1→1:1) to give a reddish brown solid. The solid was crystallized from n-hexane-ethyl acetate to give the title compound (445 mg, 63.1%) as a slight dark brown crystal.
  • mp 190-191° C.
  • 1H-NMR(DMSO-d6): δ 7.68 (1H, d, J=9.0 Hz), 7.08 (1H, dd, J=8.7, 2.7 Hz), 7.17 (1H, d, J=2.4 Hz), 7.70 (2H, d, J=1.8 Hz), 7.95-7.96 (1H, m), 10.00 (1H, s), 10.06 (1H, s).
    • Example 14 N-[(5-Bromo-2-hydroxyphenyl)methyl]-3,5-dichloroaniline Compound No. 14 (1) 4-Bromo-2[(3,5-diphenylimino)methyl]phenol
  • A mixture of 5-bromosalicylaldehyde (1.01 g, 5 mmol), 3,5-dichloroaniline(810 mg, 5 mmol) and ethanol (25 mL) was refluxed for 1 hour under argon atmosphere. After the reaction mixture was cooled to room temperature, the separated crystal was filtered to give 3,5-dichloro-N-(5-bromo-2-hydroxybenzylidene)aniline (1.52 g, 88.2%) as an orange crystal.
  • mp 161-163° C. 1H-NMR(CDCl3, δ): 6.94 (1H, d, J=9.0 Hz), 7.16 (2H, d, J=1.8 Hz), 7.30-7.31 (1H, m), 7.47-7.53 (2H, m), 8.51 (1H, s).
    • (2) N-[(5-Bromo-2-hydroxyphenyl)methyl]-3,5-dichloroaniline
  • 3,5-Dichloro-N-(5-bromo-2-hydroxybenzylidene)aniline (1.04 g, 3 mmol) was dissolved in tetrahydrofuran (12 mL) and ethanol (6 mL). Sodium borohydride (113 mg, 3 mmol) was added under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 12 hours. Acetone (10 mL) was added to the reaction mixture, and the residue obtained by concentration under reduced pressure was added water and extracted with dichloromethane. After the dichloromethane layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give a light yellow viscous material. This was crystallized by n-hexane to give the title compound (971 mg, 93.3%) as a white crystal.
  • mp 125-126° C. 1H-NMR (CDCl3, δ): δ 4.31 (2H, s), 6.64 (2H, d, J=1.8 Hz), 6.74-6.77 (1H, m), 6.84-6.85 (1H, m), 7.30-7.34 (2H, m).
    • Example 15 5-Chloro 2-hydroxybenzoic acid (2,4-dihydroxybenzylidene)hydrazide Compound No. 15
  • This compound is a commercially available compound.
  • Supplier: Sigma-Aldrich.
  • Catalog code number: S3203-5.
    • Example 16 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxy-N-methylbenzamide Compound No. 16
  • A mixture of 5-chlorosalicylic acid(173 mg, 1 mmol), 3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol), phosphorus trichloride(44 μl, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, n-hexane (50 mL) was added, and the separated crude crystal was filtered and dissolved in ethyl acetate (50 mL). After the ethyl acetate solution was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (75 mg, 18.9%) as a white crystal.
  • 1H-NMR (CDCl3): δ 6.59 (1H, d, J=2.4 Hz), 6.94 (1H, d, J=9.0 Hz), 7.21 (1H, dd, J=9.0, 2.7 Hz), 7.58 (2H, s), 7.80 (1H, s), 10.00 (1H, brs).
    • Example 17 1-(5-Bromo-2-hydroxy)benzoyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline Compound No. 17
  • Using 5-bromosalicylic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 42.0%.
  • 1H-NMR (CDCl3): δ 2.08 (2H, m), 2.92 (2H, t, J=6.6 Hz), 3.95 (2H, t, J=6.6 Hz), 6.91-6.94 (2H, m), 7.14 (1H, s), 7.32-7.35 (2H, m), 7.40 (1H, dd, J=8.7, 2.4 Hz), 10.06 (1H, s).
    • Example 18 N-(3,5-Dichlorophenyl)-2-hydroxy-1-naphthamide Compound No. 18
  • Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 51.29°.
  • mp 246-248° C.
  • 1H-NMR (DMSO-d6): 7.26 (1H, d, J=9.3 Hz), 7.31-7.3 (2H, m), 7.44-7.50 (1H, m), 7.65-0.68 (1H, m), 7.8, 7.90 (1H, m), 10.23 (1H, s), 10.74 (1H, s).
    • Example 19 N-(3,5-Dichlorophenyl)-3-hydroxy-2-naphthalide Compound No. 19
  • Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • mp 254-255° C.
  • 1H-NMR(DMSO-d6): 7.34-7.39 (3H, m), 7.49-7.54 (1H, m), 7.76-7.79 (1H, m), 7.89 (2H, d, J=1.8 Hz), 7.92 (1H, m), 8.39 (1H, s), 10.75 (1H, s), 11.01 (1H, s).
    • Example 20 N-(3,5-Dimethoxyphenyl)-3-hydroxy-2-naphthamide Compound No. 20
  • This compound is a commercially available compound.
  • Supplier: Sigma-Aldrich.
  • Catalog code number: S01361-8.
    • Example 21 N-[3,5-Bis(trifluoromethyl)phenyl]-1-hydroxy-2-naphthamide Compound No. 21
  • Using 1-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 6.5.5%.
  • 1H-NMR (DMSO-d6): δ 7.51 (1H, d, J=9.0 Hz), 7.60 (1H, td, J=7.8, 0.9 Hz), 7.70 (1H, d, J=7.8, 0.9 Hz), 7.89 (1H, s), 7.93 (1H, d, J=8.4 Hz), 8.09 (1H, d, J=9.0 Hz), 8.33 (1H, d, J=8.7 Hz), 8.51 (2H, s), 10.92 (1H, s), 13.36 (1H, s).
    • Example 22 {[(1-Hydroxynaphthalen-2-yl)carbonyl]amino}benzenesulfonyl fluoride Compound No. 22
  • This compound is a commercially available compound.
  • Supplier: Sigma-Aldrich.
  • Catalog code number: S58026-0.
    • Example 23 4-({[4-(2,5-Dichlorophenyl)azo-1-hydroxynaphthalen-2-yl]-carbonyl}amino)benzenesulfonyl fluoride Compound No. 23
  • This compound is a commercially available compound.
  • Supplier: Sigma-Aldrich.
  • Catalog code number: S63263-5.
    • Example 24 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxypyridine-3-carboxamide Compound No. 94
  • 5-Chloro-2-hydroxynicotinic acid(174 mg, 1 mmol), 3,5-bis(trifluoromethyl)aniline (273 mg, 1.2 mmol) and pyridine(316 mg, 4 mmol) were dissolved in tetrahydrofuran (20 mL) and dichloromethane (10 mL). Phosphorus oxychloride (0.112 ml, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (100 mL) and 0.2 N-hydrochloric acid (100 mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1-1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound (183 mg, 47.6%) as a white crystal.
  • mp >270° C.
  • 1H-NMR(DMSO-d6): δ 7.83 (1H, s), 8.15 (1H, d, J=3.3 Hz), 8.36 (1H, d, J=3.0 Hz), 8.40 (2H, s), 12.43 (1H, s).
    • Example 25 N-[2-Chloro-5-(trifluoromethyl)phenyl]-5-chloro-2-hydroxynicotinamide Compound No. 25
  • Using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 42.9%.
  • 1H-NMR (DMSO-d6): δ 7.52 (1H, dd, J=8.4, 2.1 Hz), 7.81 (1H, d, J=8.4 Hz), 8.16 (1H, s), 8.39 (1H, d, J=2.7 Hz), 8.96 (1H, d, J=2.1 Hz), 12.76 (1H, s), 13.23 (1H, s).
    • Example 26 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxynicotinamide Compound No. 26
  • Using 5-chloro-2-hydroxynicotinic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 59.1%.
  • 1H-NMR(DMSO-d6): δ 1.29 (18H, s), 7.18 (1H, t, J=1.8 Hz), 7.52 (2H, d, J=1.8 Hz), 8.07 (1H, d, J=2.4 Hz), 8.35 (1H, d, J=3.3 Hz), 11.92 (1H, s), 13.10 (1H, s).
    • Example 27 N-[3,5-Bis(trifluoromethyl)phenyl]-3-hydroxypyridine-2-carboxamide Compound No. 27
  • Using 3-hydroxypyridine-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 4.5.0%.
  • 1H-NMR (CDCl3): δ 7.40 (1H, dd, J=8.4, 1.8 Hz), 7.46 (1H, dd, J=8.4, 4.2 Hz), 7.68 (1H, s), 8.16 (1H, dd, J=4.2, 1.2 Hz), 8.25 (2H, s), 10.24 (1H, s), 11.42 (1H, s).
    • Example 28 N-[3,5-Bis(trifluoromethyl)phenyl]-6-chloro-2-hydroxyindole-3-carboxamide Compound No. 28
  • Under argon atmosphere, 3,5-bis(trifluoromethyl)isocyanate(255 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution 6-chloro-oxindole(184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane-ethyl acetate=4:1) to give the title compound (172.2 mg, 40.7%) as a pink solid.
  • 1H-NMR (DMSO-d6): δ 3.97 (2H, s), 7.29 (1H, dd, J=8.1, 2.1 Hz), 7.41 (1H, d, J=8.1 Hz), 7.88 (1H, s), 8.04 (1H, d, J=2.1 Hz), 8.38 (2H, s), 10.93 (1H, s).
    • Example 29 N-[3,5-Bis(trifluoromethyl)phenyl]-3-hydroxyquinoxaline-2-carboxamide Compound No. 29
  • Using 3-hydroxyquinoxaline-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 2.7%.
  • 1H-NMR(DMSO-d6): δ 7.40-7.45 (2H, m), 7.69 (1H, td, J=8.4, 1.5 Hz), 7.90-7.93 (12H, m), 8.41 (2H, s), 11.64 (1H, s), 13.02 (1H, s).
    • Example 30 N-(4-Chlorophenyl)-2-hydroxy-9H-carbazole-3-carboxamide Compound No. 30
  • This compound is a commercially available compound.
  • Supplier: Sigma-Aldrich.
  • Catalog code number: S83846-2.
    • Example 31 2-1Hydroxy-N-(1-naphthyl)benzamide Compound No. 31
  • This compound is a commercially available compound.
  • Supplier: Maybridge.
  • Catalog code number: RDR 01818.
    • Example 32 5-Chloro-2-hydroxy-N-(1-naphthyl)benzamide Compound No. 32
  • Using 5-chlorosalicylic acid and 1-naphthylamine as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 65.0%.
  • 1H-NMR (DMSO-d6): δ 7.09 (1H, d, J=8.7 Hz), 7.51-7.61 (4H, m), 7.85 (1H, d, J=8.4 Hz), 7.96 (1H, d, J=7.5 Hz), 7.99-8.05 (2-H, m), 8.13 (1H, d, J=2.7 Hz), 10.88 (1H, s), 12.31 (1H, s).
    • Example 33 5-Chloro-2-hydroxy-N-(4-methoxynaphthalen-2-yl)benzamide Compound No. 33
  • Using 5-chlorosalicylic acid and 4-methoxy-1-naphthylamine as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 84.3%.
  • 1H-NMR (DMSO-d6): δ 3.99 (3H, s), 7.05 (1H, d, J=9.0 Hz), 7.30 (1H, d, J=1.5 Hz), 7.39-7.4.5 (1H, m), 7.48-7.54 (2H, m), 7.83 (1H, d, J=7.8 Hz), 8.00 (1H, s), 8.02 (1H, d, J=2.4 Hz), 8.09 (1H, d, J=7.8 Hz), 10.54 (1H, s), 11.88 (1H, s).
    • Example 34 2-Acetoxy-5-Chloro-N-(4-methoxynaphthalen-2-yl)benzamide Compound No. 34
  • Using 2-acetoxy-5-chlorobenzoic acid and 4-methoxy-1-naphthylamine as the raw materials, the same operation as the example 24 gave the title compound. (2-Acetoxy-5-chlorobenzoic acid: refer to Eur. J. Med. Chem., 1996, 31, 861.)
  • Yield: 39.9% red solid.
  • 1H-NMR(DMSO-d6): δ 2.23 (3H, s), 3.96 (3H, s), 7.23 (1H, d, J=1.2 Hz), 7.34 (1H, d, J=8.7 Hz), 7.40 (1H, dt, J=8.1, 1.2 Hz), 7.50 (1H, dt, J=8.1, 1.5 Hz), 7.67 (1H, dd, J=8.7, 2.7 Hz), 7.81 (1H, d, J=8.7 Hz), 8.72 (1H, d, J=3.0 Hz), 8.02 (1H, s), 8.08 (1H, d, J=8.71 Hz), 10.58 (1H, s).
    • Example 35 2-(5-Chloro-9-hydroxybenzoyl)amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester Compound No. 35
  • Using 5-chlorosalicylic acid and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 49.6%.
  • 1H-NMR (DMSO-d6): δ 1.32 (3H, t, J=7.2 Hz), 1.74 (4H, br), 2.63 (2H, br), 2.7.5 (2H, br), 4.30 (2H, q, J=7.2 Hz), 7.05 (1H, d, J=9.0 Hz), 7.50 (1H, dd, J=8.7, 3.0 Hz), 7.92 (1H d, J=3.0 Hz), 12.23 (1H, s), 13.07 (1H, s).
    • Example 36 5-Bromo-2 hydroxy-N-(5-phenylpyrazol-3-yl)benzamide Compound No. 36
  • Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 9.2%.
  • 1H-NMR (DMSO-d6): δ 6.98 (1H, d, J=8.8 Hz), 7.01 (1H, s), 7.35 (1H, t, J=7.6 Hz), 7.46 (2H, t, J=7.6 Hz), 7.58 (1H, dd, J=8.8, 2.8 Hz), 7.74-7.76 (2H, m), 8.19 (1H, s), 10.86 (1H, s), 12.09 (1H, s), 13.00 (1H, brs).
    • Example 37 5-Bromo-N-(4,6-diethyloxazol-2-yl)-2-hydroxybenzamide Compound No. 37 (1) 2-Amino-4,5-diethyloxazol
  • Propioin(1.03 g, 8.87 mmol) was dissolved in ethanol (15 mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(dichloromethane:methanol=9:1) to give the title compound (369.2 mg, 29.7%) as a yellow amorphous.
  • 1H-NMR(DMSO-d6): δ 1.04 (3H, t, J=7.5 Hz), 1.06 (3H, t, J=7.5 Hz), 2.20 (2H, q, J=7.5 Hz), 2.43 (2H, q, J=7.5 Hz), 6.15 (2H, s).
    • (2) 2-Acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide
  • Using 2-acetoxy-6-bromobenzoic acid and 2-amino-4,5-diethyloxazol as the raw materials, the same operation as the example 24 gave the title compound. (2-Acetoxy-5-bromobenzoic acid: refer to Eur. J. Med. Chem., 1996, 31, 861.)
  • Yield: 22.0%.
  • 1H-NMR (CDCl1): δ 1.22 (3H, t, J=7.5 Hz), 1.23 (3H, t, J=7.5 Hz), 2.438 (2H, q, J=7.5 Hz), 2.57 (2H, q, J=7.5 Hz), 6.96 (1H, d, J=8.7 Hz), 7.58 (1H, dd, J=8.7, 2.7 Hz), 8.32 (1H, s), 11.40 (1H, br).
    • (3) 5-Bromo-N (4,5-diethyloxazol-2-yl)-2-hydroxybenzamide
  • Using 2-acetoxy-5-bromo-N-(4,5-diethyloxazol-9-yl)benzamide as the raw material, the same operation as the example 2(2) gave the title compound.
  • Yield: 70.2%.
  • 1H-NMR (CDCl3): δ 1.25 (3H, t, J=−7.5 Hz), 1.26 (3H, t, J=7.5 Hz), 2.52 (2H, q, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 6.84 (1H, d, J=8.7 Hz), 7.43 (1H, dd, J=8.7, 3.0 Hz), 8.17 (1H, d, J=3.0 Hz), 11.35 (1H, br), 12.83 (1H, br).
    • Example 38 5-Bromo-N-(4,5-diphenyloxazole-2-yl)-2-hydroxybenzamide Compound No. 38
  • Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the raw materials, the same operation as the example 16 gave the title compound. (2° Amino-4,5-diphenyloxazole: refer to Zh. Org. Khim., 1980, 16, 218-5.)
  • Yield: 32.6%.
  • mp 188-189° C.
  • 1H-NMR (DMSO-d6, δ): 6.98 (1H, d, J=8.7 Hz), 7.40-7.-19 (6H, m), 7.53-7.56 (2H, m), 7.59-7.63 (3H, m), 8.01 (1H, d, J=2.4 Hz), 11.80 (2H, brs).
    • Example 39 5-Bromo-N-[4,5-bis(furan-2-yl)oxazol-2-yl]-2-hydroxybenzamide Compound No. 39 (1) 2-Amino-4,5-bis(furan-2-yl)oxazole
  • Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a dark brown crystal.
  • 1H-NMR (DMSO-d6): δ 6.59 (1H, dd, J=3.3, 2.1 Hz), 6.62 (1H, dd, J=3.3, 2.1 Hz), 6.73 (1H, dd, J=3.3, 0.6 Hz), 6.80 (1H, dd, J=3.3, 0.9 Hz), 7.05 (2H, s), 7.75-7.76 (2H, m).
    • (2) 5-Bromo-N-[4,5-bis(furan-9-yl)oxazol-2-yl] 2-hydroxybenzamide
  • Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 12.9%.
  • 1H-NMR (DMSO-d6): δ 6.65 (1H, dd, J=3.6, 1.3 Hz), 6.68 (1H, dd, J=3.6, 1.8 Hz), 6.75 (1H, d, J=8.7 Hz), 6.92 (1H, dd, J=3.6, 0.9 Hz), 6.93 (1H, d, J=3.3 Hz), 7.37 (1H, dd, J=8.7, 2.7 Hz), 7.80 (1H, dd, J=1.8, 0.9 Hz), 7.84 (1H, dd, J=1.8, 0.9 Hz), 7.92 (1H, d, J=3.0 Hz), 14.88 (2H, br).
    • Example 40 2-Hydroxy-N-5[(trifluoromethyl)-1,3,4-thiadiazol-2-yl]benzamide Compound No. 40 (1) 2-Acetoxy-N-[(trifluoromethyl) 1,3,4-thiadiazol-2-yl]benzamide
  • Using o-acetylsalicyloyl chloride and 2-amino-5(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the example 2 (1) gave the title compound.
  • Yield: 51.1%.
  • 1H-NMR(DMSO-d6): 2.23 (3H, s), 7.32 (1H, dd, J=8.0, 1.2 Hz), 7.45 (1H, td, J=7.6, 1.2 Hz), 7.69 (1H, td, J=8.0, 2.0 Hz), 7.87 (1H, dd, J=8.0, 2.0 Hz), 13.75 (1H, brs).
    • (2) 2-Hydroxy-N-5-[(trifluoro methyl)-1,3,4-thiadiazol-2-yl]benzamide
  • Using 2-acetoxy-N-5-[(trifluoromethyl)-1,3,4-thiadiazol-2-yl]benzamide as the raw material, the same operation as the example 2 (2) gave the title compound.
  • Yield: 99.9%.
  • 1H-NMR(DMSO-d6): δ 7.00 (1H, td, J=8.0, 0.8 Hz), 7.06 (1H, d, J=8.4 Hz), 7.51 (1H, ddd, J=3.4, 7.6, 2.0 Hz), 7.92 (1H, dd, J=8.0, 1.6 Hz), 12.16 (1H, br).
    • Example 41 5-Bromo-2-hydroxy-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-9-yl]benzamide (Compound No. 41).
  • Using 5-bromosalicylic acid and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 80.2%
  • 1H-NMR (DMSO-d6): δ 7.01 (1H, d, J=9.0 Hz), 7.63 (1H, dd, J=8.7, 2.7 Hz), 7.97 (1H, d, J=2.4 Hz).
    • Example 42 5-Chloro-N-(2-chloropyridin-4-yl)-2-hydroxybenzamide Compound No. 42
  • Using 5-chlorosalicylic acid and 4-amino-2-chloropyridine as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 12.2%.
  • 1H-NMR (DMSO-d6): δ 7.04 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=9.0, 3.0 Hz), 7.54 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=2.7 Hz), 8.21 (1H, dd, J=8.7, 2.7 Hz), 8.74 (1H, d, J=2.7 Hz), 10.6 (1H, s), 11.57 (1H, s).
    • Example 43 5-Chloro N (6-chloro-4-methoxypyrimidin-2-yl)-2-hydroxybenzamide Compound No. 43
  • Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 2.2%, white solid.
  • 1H-NMR (DMSO-d6): δ 3.86 (3H, s), 6.85 (1H, s), 7.01 (1H, d, J=9.0 Hz), 7.47 (1H, dd, J=9.0, 3.0 Hz), 7.81 (1H, d, J=3.0 Hz), 11.08 (1H, s), 11.65 (1H, s).
    • Example 44 2-Aceoxy-5-chloro-N-(indol-2-yl)benzamide Compound No. 44
  • Using 2-acetoxy-5-chlorosalicylic acid and 2-aminoindole as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 13.3%.
  • 1H-NMR (DMSO-d6): δ 2.90 (3H, s), 6.41 (1H, t, J=2.1 Hz), 7.27-7.36 (4H, m), 7.63 (1H, dd, J=8.7, 2.7 Hz), 7.74 (1H, d, J=2.7 Hz), 7.93 (1H, s), 10.21 (1H, s), 11.04 (1H, s).
    • Example 45 7-[(2-Acetoxybenzoyl)amino]indole-3-carboxylic acid ethyl ester Compound No. 45
  • This compound is a commercially available compound.
  • Supplier: Peakdale.
  • Catalog code number: PFC-0448.
    • Example 46 5-Chloro-2-hydroxy-N-(quinolin-3-yl)benzamide Compound No. 46
  • Using 5-chlorosalicylic acid and 2-aminoquinoline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 4.3%.
  • 1H-NMR (DMSO-d6): δ 7.07 (1H, d, J=8.7 Hz), 7.51 (1H, dd, J=9.0, 3.0 Hz), 7.61 (1H, dt, J=7.8, 1.2 Hz), 7.70 (1H, dt, J=7.8, 1.5 Hz), 7.98 (2H, d, J=3.0 Hz), 8.01 (1H, s), 8.82 (1H, d, J=2.4 Hz), 10.80 (1H, s), 11.74 (1H, s).
    • Example 47 N-(9-Ethylcarbazol-3-yl)-5-chloro-2-hydroxybenzamide Compound No. 47
  • Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 64.6%.
  • 1H-NMR (DMSO-d6): δ 1.33 (3H, t, J=7.0 Hz), 4.46 (2H, q, J=7.0 Hz), 7.04 (1H, d, J=9.0 Hz), 7.21 (1H, t, J=7.3 Hz), 7.45-7.52 (2H, m), 7.64-7.65 (2H, m), 7.70 (1H, d, J=8.4, 1.9 Hz), 8.11-8.15 (2H, m), 8.49 (1H, d, J=1.9 Hz), 10.55 (1H, s), 19.22 (1H, s).
    • Example 48 2-Acetoxy-[3,5-bis(trifluoromethyl)phenyl]benzamide Compound No. 95
  • Using o-acetylsalicyloyl chloride and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 2 (1) gave the title compound.
  • Yield: 84.2%.
  • 1H-NMR (DMSO-d6): δ 2.36 (3H, s), 7.19 (1H, dd, J=8.0, 1.2 Hz), 7.39 (1H, td, J=7.6, 1.2 Hz), 7.57 (1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.65 (1H, s), 7.83 (1H, dd, J=8.0, 1.6 Hz), 8.11 (2H, s), 8.31 (1H, s).
    • Example 49 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 48
  • Using 2-acetoxy-[3,5-bis(trifluoromethyl)phenyl]benzamide as the raw material, the same operation as the example 2 (2) gave the title compound.
  • Yield: 45.1%.
  • 1H-NMR(DMSO-d6): δ 6.96-7.02 (2H, m), 7.45 (1H, ddd, J=9.0, 7.2, 1.6 Hz), 7.81 (1H, s), 7.87 (1H, dd, J=8.0, 1.6 Hz), 8.46 (2H, s), 10.80 (1H, s), 11.26 (1H, s).
    • Example 50 N-[3,5-Bis(trifluoromethyl)phenyl]5-fluoro-2-hydroxybenzamide Compound No. 49
  • Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 58.7%.
  • 1H-NMR(DMSO-d6): δ 7.04 (1H, ddd, J=9.0, 4.5, 1.2 Hz), 7.30-7.37 (1H, m), 7.66 (1H, ddd, J=9.0, 3.3, 1.2 Hz), 7.84 (1H, s), 8.46 (2H, s), 10.85 (1H, s), 11.21 (1H, brs).
    • Example 51 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-9-hydroxybenzamide Compound No. 50)
  • Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 85.5%.
  • 1H-NMR (DMSO-d6): δ 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.8.5 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).
    • Example 52 N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Compound No. 51
  • Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 88.5%.
  • 1H-NMR(DMSO-d6): δ 6.98 (1H, d, J=8.8 Hz), 7.59 (1H, dd, J=8.8, 2.8 Hz), 7.83 (1H, s), 7.98 (1H, d, J=2.8 Hz), 8.43 (2H, s), 10.82 (1H, s), 11.37 (1H, s).
    • Example 63 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide Compound No. 52
  • Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 62.2%.
  • 1H-NMR (DMSO-d6): δ 6.86 (1H, d, J=8.4 Hz), 7.74 (1H, dd, J=8.7, 2.4 Hz), 7.84 (1H, s), 8.13 (1H, d, J=2.1 Hz), 8.84 (2H, s), 10.82 (1H, s), 11.41 (1H, s).
    • Example 54 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide Compound No. 53
  • Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 57.2%.
  • 1H-NMR (DMSO-d6): δ 7.18 (1H, d, J=9.0 Hz), 7.86 (1H, s), 8.31 (1H, dd, J=9.0, 3.0 Hz), 8.45 (2H, s), 8.70 (1H, d, J=3.0 Hz), 11.12 (1H, s).
    • Example 55 N-[3,5-Bis(trifluoromethyl)phenyl]-5-cyano-9-hydroxybenzamide Compound No. 54
  • Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 16.6%.
  • 1H-NMR(DMSO-d6): δ 7.15 (1H, d, J=8.7 Hz), 7.85 (1H, s), 7.86 (1H, dd, J=8.7, 2.1 Hz), 8.22 (1H, d, J=2.4 Hz), 8.43 (2H, s), 10.93 (1H, s), 12.00 (1H, brs).
    • Example 56 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide Compound No. 55
  • Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 54.9%.
  • 1H-NMR (DMSO-d6): δ 6.92 (1H, d, J=8.7 Hz), 7.28 (1H, dd, J=8.7, 1.8 Hz), 7.71 (1H, d, J=1.8 Hz), 7.82 (1H, s), 8.47 (2H, s), 10.80 (1H, s), 11.14 (1H, s).
    • Example 57 N-[3,5-Bis(trifluoromethyl)phenyl]-5-(1,1-dimethyl)ethyl-2-hydroxybenzamide Compound No. 56
  • Using 5-[(1,1-dimethyl)ethyl]salicylic acid and 3,5-bis(trifluoro methyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 53.8%.
  • 1H-NMR (DMSO-d6): δ 1.30 (9H, s), 6.96 (1H, d, J=8.7 Hz), 7.50 (1H, dd, J=8.7, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz), 7.83 (1H, s), 8.46 (2H, s), 10.80 (1H, s), 11.12 (1H, s).
    • Example 58 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 78 (1) 5-Acetyl-2-benzyloxybenzoic acid methyl ester
  • A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 106 mmol), potassium carbonate (19.35 g, 140 mmol) and methylethylketone (360 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2 N-hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from isopropyl ether to give the title compound (14.20 g, 71.4%) as a white solid.
  • 1H-NMR(CDCl3): δ 2.58 (3H, s), 3.93 (3H, s), 5.27 (2H, s), 7.07 (1H, d, J=8.7 Hz), 7.26-7.43 (3H, m), 7.4-7.50 (2H, m), 8.07 (1H, dd, J=8.7, 2.4 Hz), 8.44 (1H, d, J=2.4 Hz).
    • (2) 5-Acetyl-2-benzyloxybenzoic acid
  • 5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (20 mL). 2 N sodium hydroxide (11 mL) was added dropwise, and the mixture was stirred for 8 hours. The solvent was evaporated under reduced pressure. 2 N-hydrochloric acid was added to the residue, and it was extracted with dichloromethane. After the dichloromethane layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was washed with isopropyl ether to give the title compound (4.92 g, 91.0%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 2.65 (3H, s), 5.32 (2H, s), 7.30-7.43 (4H, m), 7.49-7.52 (2H, m), 8.09 (1H, dd, J=9.0, 2.7 Hz), 8.22 (1H, d, J=2.4 Hz).
    • (3) 5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
  • Using 5-acetyl-2-benzyloxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24, gave the title compound (5.47 g, 63.1%) as a slight yellowish green solid.
  • 1H-NMR (DMSO-d6): δ 2.57 (3H, s), 7.11 (1H, d, J=8.7 Hz), 7.86 (1H, s), 8.05 (1H, dd, J=8.4, 2.1 Hz), 8.44 (1H, d, J=2.1 Hz), 8.47 (2H, 5), 10.96 (1H, s), 11.97 (1H, brs).
    • (4) Preparation of 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
  • Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to 5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602 mg, 1.25 mmol) and 5% palladium-carbon (60 mg), and the mixture was hydrogenated at room temperature for 30 minutes. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure and the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (230 mg, 47.0%) as a white solid.
  • 1H-NMR (DMSO-d6): δ d 2.59 (3H, s), 5.35 (2H, s), 7.32-7.36 (3H, m), 7.43 (1H, d, J=8.7 Hz), 7.52-7.55 (2H, m), 7.82 (1H, s), 8.16 (1H, dd, J=8.7, 2.4 Hz), 8.25 (1H, d, J=2.4 Hz), 8.31 (2H, s), 10.89 (1H, s).
    • Example 59 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(1-hydroxyethyl)benzamide Compound No. 57
  • 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(50.5 mg, 0.13 mmol) was suspended in ethanol (2 mL). Sodium borohydride (23.6 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound (39.7 mg, 78.3%) as white powder.
  • 1H-NMR (DMSO-d6): δ 1.34 (3H, d, J=6.3 Hz), 4.71 (1H, q, J=6.3 Hz), 5.18 (1H, brs), 6.97 (1H, d, J=8.4 Hz), 7.44 (1H, dd, d=8.4, 2.1 Hz), 7.84 (1H, s), 7.86 (1H, d, J=2.1 Hz), 8.48 (2H, s), 10.85 (1H, s), 11.32 (1H, s).
    • Example 60 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(1-methoxyimino)ethyl]benzamide Compound No. 58
  • 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (100.0 mg, 0.26 mmol) was dissolved in ethanol (3 mL). Pyridine(45 μg 1, 0.56 mmol) and O-methylhydroxylamine hydrochloride (25.8 mg, 0.31 mmol) were added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=4:1) to give the title compound (102.1 mg, 95.3%) as a white crystal.
  • 1H-NMR (DMSO-d6): δ 2.19 (3H, s), 3.91 (3H, s), 7.06 (1H, d, J=8.7 Hz), 7.77 (1H, dd, J=8.7, 2.4 Hz), 7.85 (1H, s), 8.09 (1H, d, J=2.4 Hz), 8.47 (2H, s), 10.87 (1H, s), 11.48 (1H, s).
    • Example 61 5-[(1-Benzyloxyimino)ethyl]-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 59
  • Using 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide and O-benzylhydroxylamine hydrochloride as the raw materials, the same operation as the example 60 gave the title compound.
  • Yield: 79.9%.
  • 1H-NMR(DMSO-d6): δ 2.24 (3H, s), 5.20 (2H, s), 7.04 (1H, d, J=8.71 Hz), 7.29-7.47 (5H, m), 7.76 (1H, dd, J=8.7, 2.4 Hz), 7.85 (1H, s), 8.07 (1H, d, J=2.1 Hz), 8.46 (2H, s), 10.87 (1H, s), 11.47 (1H, s).
    • Example 62 N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide Compound No. 60 (1) 5-(2,2-Dicyanoethen-1-yl)-2-hydroxybenzoic acid
  • Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling with ice bath, benzylamine (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The separated yellow crystal was filtered and recrystallized (ethanol) to give the title compound (139.9 mg, 32.7%) as a light yellow solid.
  • 1H-NMR(DMSO-d6): δ 7.12 (1H, d, J=8.7 Hz), 8.09 (1H, dd, J=8.7, 2.4 Hz), 8.41 (1H, s), 8.50 (1H, d, J=2.4 Hz).
    • (2) N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide
  • Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 9.1%.
  • 1H-NMR (DMSO-d6): δ 7.13 (1H, d, J=9.0 Hz), 7.83 (1H, s), 8.04 (1H, dd, J=9.0, 2.4 Hz), 8.36 (1H, s), 8.38 (1H, d, J=2.4 Hz), 8.43 (2H, s), 11.43 (1H, s).
    • Example 63 3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester Compound No. 62 (1) 5-[(2-Cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid
  • Triethylamine (0.2 mL) was added to a mixture of 5-formylsalicylic acid (332 mg, 2 mmol). Cyanoacetic acid methyl ester (198 mg, 2 mmol) and acetic acid (6 mL), and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into water, and the separated crystal was Filtered and recrystallized (n-hexane) to give the title compound (327.7 mg, 66.3%) as a light yellow solid.
  • 1H-NMR (DMSO-d6): δ 3.85 (3H, s), 7.15 (1H, d, J=8.7 Hz), 8.20 (1H, dd, J=8.7, 2.4 Hz), 8.37 (1H, s), 8.66 (1H, d, J=2.4 Hz).
    • (2) 3-({N-[3,5-Bis(trifluoromethyl)phenyl] carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester
  • Using 5-[(2-cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 66.3%.
  • 1H-NMR(DMSO-d6): δ 3.85 (3H, s), 7.15 (1H, d, J=8.7 Hz), 8.20 (1H, dd, J=8.7, 2.4 Hz), 8.37 (1H, s), 8.66 (1H, d, 2.4 Hz).
    • Example 64 3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid Compound No. 61
  • 3 ({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester (30 mg, 0.11 mmol) was dissolved in ethanol (5 mL). 2 N sodium hydroxide (0.11 ml, 0.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate) to give the title compound(13.5 mg, 30.4%) as a light yellow solid.
  • 1H-NMR(DMSO-d6): δ 7.12 (1H, d, J=8.4 Hz), 7.84 (1H, s), 7.94 (1H, dd, J=8.4, 2.1 Hz), 3.38 (1H, d, J=2.1 Hz), 8.45 (2H, s), 9.87 (1H, s), 11.41 (1H, s).
    • Example 65 N-[3,5-Bis(trifluoromethyl)phenyl]-9-hydroxy-5-(2-phenylethen-1-yl)benzamide Compound No. 63
  • A mixture of N-[3,5-bis(trifluoro methyl)phenyl]-2-hydroxy-5-iodobenzamide(475 mg, 1 mmol), styrene(130 mg, 1.25 mmol), palladium acetate (4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine (12.2 mg, 0.04 mmol), diisopropylamine (388 mg, 3 mmol) and N,N-dimethylformamide (2 mL) was refluxed for 8 hours. After cooling, water was added to the reaction mixture, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was purified by column chromatography on silica gel(hexane-isopropyl ether:2/1→1/1) to give the title compound (173 mg, 38.3%) as a pale yellow solid.
  • 1H-NMR (DMSO-d6): δ 7.04 (1H, d, J=8.4 Hz), 7.20-7.29 (3H, m), 7.38 (2H, t, J=7.5 Hz), 7.59 (2H, d, J=7.5 Hz), 7.72 (1H, dd, J=8.4, 2.1 Hz), 7.86 (1H, s), 8.07 (1H, d, J=2.1 Hz), 8.49 (2H, s), 10.89 (1H, s), 11.33 (1H, brs).
    • Example 66 N-[3,5-Bis(trifluoro methyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)-ethynyl]benzamide Compound No. 66
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (950 mg, 2 mmol) and trimethylsilylacetylene (246 mg, 2.5 mmol) were dissolved in triethylamine(2mL) and N,N-dimethylformamide (4 mL). Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprous iodide (4 mg, 0.02 mmol) were added under argon atmosphere, and the mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (100 mL) and 1 N citric acid (100 mL), stirred, and filtered through celite. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=19:1) to give a light orange solid. This was crystallized by n-hexane to give the title compound (286 mg, 32.1%) as a white crystal.
  • 1H-NMR (DMSO-d6): δ 0.23 (9H, s), 7.00 (1H, d, J=8.7 Hz), 7.54 (1H, dd, J=8.7, 2.4 Hz), 7.85 (1H, s), 7.98 (1H, d, J=2.1 Hz), 8.46 (2H, s), 10.86 (1H, s), 11.69 (1H, s).
    • Example 67 N-[3,5-Bis(trifluoromethyl)phenyl]-5-ethynyl-2-hydroxybenzamide Compound No. 64
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide (233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2 N sodium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-water to give the title compound (67 mg, 35.9%) as a light gray crystal.
  • 1H-NMR (DMSO-d6): δ 4.11 (1H, s), 7.02 (1H, d, J=8.4 Hz), 7.55 (1H, dd, J=8.4, 2.1 Hz), 7.85 (1H, s), 7.983 (1J, d, J=2.1 Hz), 8.46 (2H, s), 8.46 (2H, s), 10.86 (1H, s), 11.62 (1H, s).
    • Example 68 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5(phenylethynyl)-benzamide Compound No. 65
  • Using N-[3,5-b is(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide and phenylacetylene as the raw materials, the same operation as the example 66 gave the title compound.
  • 1H-NMR(DMSO-d6): δ 7.06 (1H, d, J=8.4 Hz), 7.42-7.46 (3H, m), 7.53-7.57 (2H, m), 7.64 (1H, dd, J=8.7, 2.1 Hz), 7.86 (1H, s), 8.06 (1H, d, J=2.1 Hz), 8.48 (2H, s), 10.94 (1H, s), 11.64 (1H, brs).
    • Example 69 N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxybiphenyl-3-carboxamide Compound No. 67
  • N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (200 mg, 0.42 mmol) was dissolved in 1,2-dimethoxyethane (3 mL). Tetrakis(triphenylphosphine)palladium (16 mg, 0.0014 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1M sodium carbonate (1.3 mL) were added and refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1→3:1) to give the title compound(109 mg, 61.1%) as a white crystal.
  • 1H-NMR (DMSO-d6): δ 7.12 (1H, d, J=8.7 Hz), 7.33-7.38 (1H, m), 7.48 (2H, t, J=7.5 Hz), 7.67-7.70 (2H, m), 7.79 (1H, dd, J=8.4, 2.4 Hz), 7.87 (1H, s), 8.17 (1H, d, J=2.4 Hz), 8.49 (2H, s), 10.92 (1H, s), 11.41 (1H, s).
    • Example 70 N-[3,5-Bis(trifluoromethyl)phenyl]-9-hydroxy-5 (2-phenethyl)benzamide Compound No. 68
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-29-hydroxy-5-(phenylethynyl)benzamide as the raw material, the same operation as the example 58 (4) gave the title compound.
  • Yield: 86.2%.
  • 1H-NMR(DMSO-d6): δ 2.88 (4H, s), 6.93 (1H, d, J=8.1 Hz), 7.15-7.341 (6H, m), 7.76 (1H, d, J=2.4 Hz), 7.84 (1H, s), 8.47 (2H, s), 10.79 (1H, s), 11.15 (1H, s).
    • Example 71 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(trifluoromethyl)-benzamide Compound No. 69
  • Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(trifluoromethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
  • Yield: 44.7%.
  • 1H-NMR (CDCl3, δ): 7.17 (1H, d, J=9.0 Hz), 7.72-7.75 (2H, m), 7.86 (1H, s), 8.17 (2H, s), 8.35 (1H, s), 11.88 (1H, s).
    • Example 72 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pentafluoroethyl)-benzamide Compound No. 70
  • Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(pentafluoroethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
  • Yield: 65.7%.
  • 1H-NMR(CDCl3, δ): 7.19 (1H, d, J=90 Hz), 7.70 (1H, dd, J=8.7, 2.1 Hz), 7.81 (1H, d, J=2.1 Hz), 8.17 (2H, s), 8.37 (1H, s), 11.92 (1H, s).
    • Example 73 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrol-1-yl)benzamide Compound No. 71
  • Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 57.8%.
  • 1H-NMR (DMSO-d6): δ 6.2 (2H, dd, J=2.4, 1.8 Hz), 7.10 (1H, d, J=9.0 Hz), 7.29 (2H, dd, J=2.4, 1.8 Hz), 7.66 (1H, dd, J=9.0, 2.7 Hz), 7.86 (1H, s), 7.98 (1H, d, J=2.4 Hz), 8.47 (2H, s), 10.39 (1H, s), 11.24 (1H, s).
    • Example 74′. N-[3,5-Bis(trifluoromethyl)phenyl]2-hydroxy-5-(thiophen-2-yl)-benzamide Compound No. 72
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide and 2-thipheneboronic acid as the raw materials, the same operation as the example 69 gave the title compound.
  • 1H-NMR (DMSO-d6): δ 7.08 (1H, d, J=8.4 Hz), 7.14 (1H, dd, J=5.4, 3.6 Hz), 7.45 (1H, dd, J=3.6, 1.2 Hz), 7.51 (1H, dd, J=5.1, 0.9 Hz), 7.75 (1H, dd, J=8.4, 2.4 Hz), 7.59 (1H, s), 8.08 (1H, d, J=2.4 Hz), 8.48 (2H, s), 10.91 (1H, s), 11.38 (1H, s).
    • Example 75 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(thiophen-3-yl)-benzamide Compound No. 73
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide and 3-thipheneboronic acid as the raw materials, the same operation as the example 69 gave the title compound.
  • Yield: 38.7%.
  • 1H-NMR (DMSO-d6): δ 7.06 (1H, d, J=8.7 Hz), 7.5 (1H, dd, J=4.8, 1.5 Hz), 7.66 (1H, dd, J=4.8, 3.0 Hz), 7.81-7.84 (2H, m), 7.86 (1H, s), 8.18 (1H, d, J=2.1 Hz), 8.49 (2H, s), 10.90 (1H, s), 11.3.3 (1H, s).
    • Example 76 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide Compound No. 75 (1) 2-Benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
  • 5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (4.81 g. 10 mmol) was dissolved in THF (30 ml). Phenyltrimethylammonium bromide (3.75 g, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with aqueous sodium hydrogen sulfite, water, and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=4:1), and recrystallized(ethyl acetate/hexane) to give the title compound (2.39 g, 42.7%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 4.91 (2H, s), 5.36 (2H, s), 7.32-7.35 (3H, m), 7.47 (1H, d, J=9.0 Hz), 7.52-7.56 (2H, m), 7.82 (1H, s), 8.21 (1H, dd, J=8.7, 2.4 Hz), 8.29 (1H, d, J=2.4 Hz), 8.31 (2H, s), 10.91 (1H, s).
    • (2) 2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide
  • A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.5 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and saturated brin, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 2.72 (3H, s), 5.29 (2H, s), 7.33-7.36 (3H, m), 7.40 (1H, d, J=9.0 Hz), 7.54-7.57 (2H, m), 7.81 (1H, s), 7.94 (1H, s), 8.12 (1H, dd, J=8.7, 2.1 Hz), 8.27 (1H, d, J=2.1 Hz), 8.31 (2H, s), 10.86 (1H, s).
    • (3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide
  • 2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2 methylthiazol-4-yl)benzamide (160 mg, 0.3 mmol) and 10% Pd—C (240 mg) were dissolved in ethanol (10 ml) and stirred for 3.5 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (103.4 mg, 79.2%) as a white solid.
  • 1H-NMR (DMSO-d6): 2.92 (3H, s), 7.08 (1H, d, J=8.7 Hz), 7.83 (1H, s), 7.85 (1H, s), 8.01 (1H, dd, J=8.7, 2.4 Hz), 8.42 (1H, d, J=2.1 Hz), 8.50 (2H, s), 10.96 (1H, s), 11.40 (1H, s).
    • Example 77 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-3-(imidazo[1,2-a]pyridin-9-yl)benzamide Compound No. 75
  • A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), 2-aminopyridine(51.8 mg, 0.5.5 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=1:2) to give the title compound (130.3 mg, 45.9%) as a white solid. Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=1:3) to give the title compound(18.3 mg, 20.2%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 6.90 (1H, dt, J=6.6, 0.9 Hz), 7.10 (1H, d, J=8.71 Hz), 7.25 (1H, m), 7.57 (1H, d, J=9.0 Hz), 7.86 (1H, s), 8.04 (1H, dd, J=8.7, 2.1 Hz), 8.3-5 (1H, s), 8.48-5.56 (4H, m), 11.00 (1H, s), 11.41 (1H, s).
    • Example 78 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)-benzamide Compound No. 76 (1) N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide
  • A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (4.75 g, 10 mmol), chloromethyl methyl ether (1.14 ml, 15 ml), potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was refluxed for 8 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=3:1), and recrystallized(n-hexane/ethyl acetate) to give the title compound (3.96 g, 76.3%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 3.38 (3H, s), 5.28 (2H, s), 7.12 (1H, d, J=9.0 Hz), 7.81 (1H, s), 7.82 (1H, dd, J=8.7, 2.4 Hz), 7.88 (1H, d, J=2.4 Hz), 8.40 (2H, s), 10.87 (1H, s).
    • (2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide
  • N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml). Tri-n-butyl(9-pyridyl)tin (0.13 ml, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate-2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a white powder.
  • 1H-NMR(CDCl3): δ 3.64 (3H, s), 5.53 (2H, s), 7.23-7.28 (1H, m), 7.36 (1H, d, J=8.7 Hz), 7.65 (1H, s), 7.77-7.84 (2H, m), 8.20 (2H, s), 8.31 (1H, dd, J=8.7, 2.4 Hz), 8.68-8.70 (1H, m), 8.83 (1H, d, J=2.4 Hz), 10.12 (1H, s).
    • (3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)benzamide
  • Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml) were added to N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide (37.9 mg, 0.08 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (16.2 mg, 47.2%) as a white powder,
  • 1H-NMR(DMSO-d6): δ 7.13 (1H, d, J=8.4 Hz), 7.73 (1H, ddd, J=7.5, 6.3, 1.2 Hz), 7.86-7.91 (2H, m), 7.97 (1H, d, J=7.8 Hz), 8.20 (1H, dd, J=8.7, 2.1 Hz), 8.50 (2H, s), 8.59 (1H, d, J=2.4 Hz), 8.64-8.66 (1H, m), 10.97 (1H, s), 11.53 (1H, s).
    • Example 719 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-methoxybenzamide Compound No. 77
  • Using 5-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 56.8%.
  • 1H-NMR(DMSO-d6): δ 3.77 (3H, s), 6.97 (1H, d, J=9.0 Hz), 7.10 (1H, dd, J=9.0, 3.0 Hz), 7.43 (1H, d, J=3.0 Hz), 7.84 (1H, s), 8.47 (2H, s), 10.84 (1H, s), 10.91 (1H, s).
    • Example 80 N-[3,5-Bis(trifluoro methyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide Compound No. 79 (1) 5-Acetyl-2-methoxybenzoic acid methyl ester
  • A mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), sodium carbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL) was cooled with ice bath. Methyl iodide (2.5 mL, 40.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed under suspension(isopropyl ether/n-hexane) to give the title compound(5.17 g, 96.5%) as a white crystal.
  • 1H-NMR(CDCl3): δ 2.59 (3H, s), 3.92 (3H, s), 3.99 (3H, s), 7.04 (1H, d, J=8.7 Hz), 8.12 (1H, dd, J=8.7, 2.4 Hz), 8.41 (1H, d, J=2.4 Hz).
    • (2) 5-Isobutyryl-2-methoxybenzoic acid methyl ester
  • A mixture of 5-acetyl-2-methoxybenzoic acid methyl ester (0.50 g, 2.40 mmol), potassium tert-butoxide (0.81 g, 7.22 mmol) and tetrahydrofuran (10 mL) was cooled with ice bath. Methyl iodide (0.5 mL, 8.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:1→2:1) to give the title compound (143.1 mg, 25.2%) as a light yellow oil.
  • 1H-NMR(CDCl3): δ 1.22 (6H, d, J=6.9 Hz), 3.52 (1H, m), 3.92 (3H, s), 3.98 (3H, s), 7.05 (1H, d, J=8.7 Hz), 8.13 (1H, dd, J=8.7, 2.4 Hz), 8.42 (1H, d, J=2.4 Hz).
    • (3) 5-Isobutyryl-2-methoxybenzoic acid
  • 5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) was dissolved in methanol (5 mL). 2 N aqueous sodium hydroxide (1 ml) was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (134 mg, yield:quantitative) as a white crystal.
  • 1H-NMR (CDCl3): δ 1.22 (6H, d, J=6.9 Hz), 3.59 (1H, m), 4.15 (3H, s), 7.16 (1H, d, J=8.7 Hz), 8.24 (1H, dd, J=8.7, 2.4 Hz), 8.73 (1H, d, J=2.1 Hz).
    • (4) 5-Butyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide
  • Using 5-isobutyryl-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • 1H-NMR(CDCl3): δ 1.23 (6H, d, J=6.9 Hz), 3.64 (1H, m), 4.20 (3H, s), 7.18 (1H, d, J=8.7 Hz), 7.65 (1H, s), 8.19 (2H, s), 8.22 (1H, dd, J=8.7, 2.1 Hz), 8.88 (1H, d, J=2.1 Hz), 9.98 (1H, s).
    • (5) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide
  • A mixture of 5-butyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine(3 ml) and lithium iodide (53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N-hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:1) and crystallized(ethyl acetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) as a white crystal.
  • 1H-NMR (DMSO-d6): δ 1.12 (6H, d, J=6.9 Hz), 3.66 (1H, m), 7.12 (1H, d, J=8.4 Hz), 7.85 (1H, s), 8.07 (1H, dd, J=8.4, 2.4 Hz), 8.4 (1H, d, J=2.4 Hz), 8.47 (2H, s), 10.93 (1H, s), 11.9 (1H, brs).
    • Example 81 N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester Compound No. 81
  • Using 4-hydroxyisophthalic acid 1-methyl ester and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 91.5%.
  • 1H-NMR (DMSO-d6): δ 3.85 (3H, s), 7.12 (1H, d, J=8.4 Hz), 7.86 (1H, s), 8.02 (1H, dd, J=8.7, 2.4 Hz), 8.46-8.47 (3H, m), 10.96 (1H, s), 12.03 (1H, brs).
    • Example 82 N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid Compound No. 80)
  • N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (2.85 g, 7 mmol) was suspended in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL). 2 N aqueous sodium hydroxide (14 mL) was added, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was added 2 N hydrochloric acid (20 ml) and the separated solid was filtered, washed with water, dried to give the title compound (2.68 g, 97.4%) as a white crystal.
  • 1H-NMR(DMSO-d6): δ 7.10 (1H, d, J=8.7 Hz), 7.82 (1H, s), 7.86 (1H, s), 8.01 (1H, dd, J=8.7, 2.4 Hz), 8.47 (2H, s), 8.48 (1H, d, J=2.4 Hz), 10.97 (1H, s), 11.98 (1H, brs).
    • Example 83 N1,N3-Bis[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamide Compound No. 82
  • Using 4-hydroxyisophthalic acid (182 mg, 1 mmol), 3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorus trichloride(87 μl; 1 mmol) and toluene (10 mL), the same operation as the example 16 gave the title compound (151 mg, 25.0%) as a white crystal.
  • 1H-NMR(DMSO-d6): d 7.18 (1H, d, J=8.7 Hz), 7.82 (1H, s), 7.86 (1H, s), 8.11 (1H, dd, J=8.7, 2.4 Hz), 8.50 (21H, s), 8.54 (2H, s), 8.56 (1H, d, J=2.4 Hz), 10.79 (1H, s), 10.99 (1H, s), 11.84 (1H, brs).
    • Example 84 N3-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxy-N1, N1-dimethylisophthalamide Compound No. 83 (1) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methyl ester
  • Sodium hydride(60%; 1.04 g, 26 mmol) was washed with n-hexane, suspended in N,N-dimethylformamide (100 mL). A solution of N-[3,5-bis(trifluoromethyl)-phenyl]-4-hydroxyisophthalamic acid methyl ester (8.15 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added dropwise under cooling with ice bath. After the addition was finished, the mixture was stirred at room temperature for 1 hour. A solution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice and water, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized(ethyl acetate/n-hexane) to give the title compound (5.38 g, 54.1%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 3.87 (3H, s), 5.33 (2H, s), 7.33-7.36 (3H, m), 7.46 (1H, d, J=8.71 Hz), 7.53-7.56 (2H, m), 7.82 (1H, s), 8.15 (1H, dd, J=8.7, 2.1 Hz), 8.25 (1H, d, J=2.1 Hz), 8.28 (2H, s), 10.87 (1H, s).
    • (2) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
  • Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methyl ester as the raw material, the same operation as the example 82 gave the title compound.
  • Yield: 79.7-1%.
  • 1H-NMR(DMSO-d6): δ 5.32 (2H, s), 7.32-7.34 (3H, m), 7.43 (1H, d, J=8.7 Hz), 7.52-7.56 (2H, m), 7.81 (1H, s), 8.12 (1H, dd, J=8.7, 2.1 Hz), 8.22 (1H, d, J=2.1 Hz), 8.28 (2H, s), 10.85 (1H, s), 13.81 (1H, brs).
    • (3) 4-Benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethylisophthalamide
  • WSC.HCl(95 mg, 0.50 mmol) was added to a solution of 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242 mg, 0.56 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) and triethylamine (311 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with diluted hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=1:4) to give the title compound (165 mg, 64.9%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 2.99 (6H, s), 5.29 (2H, s), 7.32-7.38 (4H, m), 7.52-7.56 (2H, m), 7.64 (1H, dd, J=8.7, 2.1 Hz), 7.73 (1H, d, J=2.1 Hz), 7.80 (1H, s), 8.28 (2H, s), 10.83 (1H, s).
    • (4) N3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N1,N1-dimethylisophthalamide
  • A solution of 4-benzyloxy-N3-[3,5-bis (trifluoromethyl)phenyl]-N1,N1-dimethylisophthalamide (141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in the mixture of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid. 1H-NMR (DMSO-d6): δ 2.98 (6H, s), 7.02 (1H, d, J=8.7 Hz), 7.52 (1H, dd, J=3.7, 2.1 Hz), 7.84 (1H, s), 7.95 (1H, d, J=2.1 Hz), 8.46 (2H, s), 11.10 (1H, brs), 11.63 (1H, brs).
    • Example 85 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide (1) 2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl](piperidine-1-carbonyl)benzamide
  • Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and piperidine as the raw materials, the same operation as the example 84 (3) gave the title compound.
  • Yield: 56.4%.
  • 1H-NMR (CDCl3): δ 1.53-1.70 (6H, m), 3.44 (2H, brs), 3.70 (2H, brs), 5.26 (2H, s), 7.24 (1H, d, J=8.7 Hz), 7.26 (1H, s), 7.52-7.58 (5H, m), 7.66 (2H, s), 7.74 (1H, dd, J=8.7, 2.4 Hz), 8.37 (1H, d, J=2.1 Hz), 10.27 (1H, s).
    • (2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide
  • Using 2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)benzamide as the raw material, the same operation as the example 84 (4) gave the title compound.
  • Yield: 96.3%, white solid.
  • 1H-NMR (DMSO-d6): δ 1.51 (4H, brs), 1.60-1.65 (2H, m), 3.47 (4H, brs), 7.04 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=82.4, 2.1 Hz), 7.83 (1H, s), 7.92 (1H, d, J=2.1 Hz), 8.46 (2H, s), 10.99 (1H, s), 11.64 (1H, brs).
    • Example 86 5-(4-Benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (1) 2-Benzyl-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide
  • Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and 4-benzylpiperidine as the raw materials, the same operation as the example 84 (3) gave the title compound.
  • Yield: 76.7%.
  • 1H-NMR (CD3OD): δ 1.18-1.33 (2H, m), 1.67 (1H, brs), 1.74 (1H, brs), 1.84-1.93 (1H, ma), 2.60 (2H, d, J=7.2 Hz), 2.83 (1H, brs), 3.10 (1H, brs), 3.78 (1H, brs), 4.59 (1H, brs), 5.34 (2H, s), 7.15-7.18 (3H, m), 7.24-7.28 (2H, m), 7.40-7.46 (4H, m), 7.57-7.63 (3H, m), 7.65 (1H, dd, J=8.7, 2.4 Hz), 7.96 (2H, s), 8.05 (1H, d, J=2.1 Hz).
    • (2) N-[3,5Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-carbonyl)benzamide
  • Using 2-benzyl-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide as the raw material, the same operation as the example 84 (4) gave the title compound.
  • Yield: 54.3%, white solid.
  • 1H-NMR(DMSO-d6): δ 1.08-1.22 (2H, m), 1.59-1.62 (2H, m), 1.77-1.50 (1H, m), 2.50-2.55 (2H, m), 2.87 (2H, brs), 3.75 (1H, br), 4.39 (1H, br), 7.06 (1H, d, J=8.4 Hz), 7.17-7.20 (3H, m), 7.28 (2H, t, J=7.2 Hz), 7.49 (1H, dd, J=8.4, 2.1 Hz), 7.84 (1H, s), 7.93 (1H, d, J=2.1 Hz), 8.47 (2H, s), 10.89 (1H, s), 11.65 (1H, s).
    • Example 87 N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-hydroxybenzamide (1) 2-Methoxy-5-sulfamoylbenzoic acid
  • Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was dissolved in methanol (30 mL). 2 N aqueous sodium hydroxide (30 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid, and the separated solid was filtered to give the title compound (4.56 g, 98.3%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 3.89 (3H, s), 7.30 (1H, d, J=8.7 Hz), 7.32 (2H, s), 7.92 (1H, dd, J=8.7, 2.7 Hz), 8.09 (1H, d, J=2.7 Hz), 13.03 (1H, br).
    • (2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide
  • Using 2-methoxy-56-sulfamoylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 24.2%.
  • 1H-NMR(DMSO-d6): δ 3.97 (3H, s), 7.38 (2H, s), 7.39 (1H, d, J=8.7 Hz), 7.85 (1H, s), 7.96 (1H, dd, J=8.7, 2.4 Hz), 8.06 (1H, d, J=2.4 Hz), 8.43 (2H, s), 10.87 (1H, s).
    • (3) N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-9-methoxybenzamide
  • A suspension of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide (442 mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol) and sodium carbonate (415 mg, 3.0 mmol) in acetonitrile (10 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was recrystallized from a mixed solvent of n-hexane and ethyl acetate(2:1) to give the title compound (207 mg, 44.1%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 2.62 (6H, s), 3.99 (3H, s), 7.45 (1H, d, J=9.0 Hz), 7.85 (1H, s), 7.91 (1H, dd, J=8.7, 2.4 Hz), 7.95 (1H, d, J=2.4 Hz), 8.413 (1′H, s), 10.90 (1H, s).
    • (4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-hydroxybenzamide
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-methoxybenzamide as the raw material, the same operation as the example 80(5) gave the title compound.
  • 1H-NMR(DMSO-d6): δ 2.77 (3H, d, J=4.5 Hz), 4.37 (1H, brs), 6.70 (1H, d, J=3.6 Hz), 7.04 (2H, s).
    • Example 88 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)benzamide Compound No. 87 (1) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamide
  • A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (442 mg, 1 mmol), 2,5-dimethoxytetrahydrofuran(159 mg, 1.2 mmol) and acetic acid (5 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg, 88.6%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 3.96 (3H, s), 6.36 (2H, d, J=2.4, 2.1 Hz), 7.37 (2H, dd, J=2.4, 2.1 Hz), 7.42 (1H, d, J=9.0 Hz), 7.85 (1H, s), 8.80 (1H, dd, J=9.0, 2.4 Hz), 8.18 (1H, d, J=2.7 Hz), 8.38 (2H, s), 10.92 (1H, s).
    • (2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)benzamide
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5(pyrrole 1-sulfonyl)benzamide as the raw material, the same operation as the example 80(5) gave the title compound.
  • Yield: 79.4%.
  • 1H-NMR (DMSO-d6, δ): 6.36 (2H, dd, J=2.4, 2.1 Hz), 7.18 (1H, d, J=9.0 Hz), 7.34 (2H, d, J=2.4, 2.1 Hz), 7.86 (1H, s), 7.99 (1H, dd, J=9.0, 2.7 Hz), 8.31 (1H, d, J=2.7 Hz), 8.42 (2H, s), 10.98 (1H, s).
    • Example 3 85-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 88
  • Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide as the raw material, the same operation as the example 84 (4) gave the title compound.
  • Yield: 98.0%.
  • 1H-NMR(DMSO-d6): δ 4.79 (2H, brs), 6.76 (1H, d, J=2.1 Hz), 6.76 (1H, s), 7.09 (1H, dd, J=2.1, 1.2 Hz), 7.80 (1H, s), 8.45 (2H, 5), 10.30 (1H, br), 10.84 (1H, s).
    • Example 90 N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylamino-2-hydroxybenzamide
  • Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 28.8%.
  • 1H-NMR (DMSO-d6): δ 2.85 (6H, s), 6.92 (1H, d, J=9.0 Hz), 7.01 (1H, dd, J=8.7, 3.0 Hz), 7.22 (1H, d, J=3.0 Hz), 7.84 (1H, s), 3.47 (2H, s), 10.62 (1H, s), 10.83 (1H, s).
    • Example 91 5-Benzoylamino-N-[3,5-bis(trifluoromethyl)phenyl]-2 hydroxybenzamide Compound No. 90
  • Under argon atmosphere, a mixture of 5 amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide (364 mg, 1 mmol), pyridine(90 mg, 1.2 mmol) and tetrahydrofuran (10 mL) was cooled on ice. Benzoyl chloride (155 mg, 1.1 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound (121 mg, 25.7%) as a white solid.
  • 1H-NMR(DMSO-d6): δ 7.04 (1H, d, J=8.7 Hz), 7.51-7.62 (3H, m), 7.81 (1H, dd, J=3.7, 2.4 Hz), 7.83 (1H, s), 7.98 (2H, d, J=7.2 Hz), 8.22 (1H, d, J=2.4 Hz), 8.49 (2H, s), 10.27 (1H, s), 10.89 (1H, s), 11.07 (1H, s).
    • Example 92 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(3-phenyl)ureido]benzamide Compound No. 91
  • 5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (100.2 mg, 0.28 mmol) was dissolved in acetonitrile (4 ml). 4-Dimethylaminopyridine(3 mg) and phenylisocyanate(30 μl 0.28 mmol) were added, and the mixture was stirred at 60° C. for 5 minutes. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel(hexane:ethyl acetate=1:1) to give the title compound (54.8 mg, 41.2%) as a light brown solid.
  • 1H-NMR (DMSO-d6): δ 6.93-6.98 (1H, m), 6.91 (1H, d, J=9.3 Hz), 7.27 (2H, t, J=7.8 Hz), 7.34-7.46 (2H, m), 7.60 (1H, dd, J=9.0, 9.4 Hz), 7.83 (1H, s), 7.88 (1H, s), 8.47 (2H, s), 8.56 (1H, s), 8.63 (1H, s), 10.87 (1H, s), 10.89 (1H, s).
    • Example 93 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(3-phenyl)-thioureido]benzamide compound No. 92
  • Using 5-amino-N-[3,5-b is(trifluoromethyl)phenyl]-2-hydroxybenzamide and phenylisothiocyanate as the raw materials, the same operation as the example 92 gave the title compound.
  • Yield: 66.3%.
  • 1H-NMR (DMSO-d6): δ 7.00 (1H, d, J=8.4 Hz), 7.13 (1H, tt, J=7.5, 1.2 Hz), 7.34 (2H, t, J=7.8 Hz), 7.45-7.51 (3H, m), 7.84 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.47 (2H, s), 9.65 (1H, s), 9.74 (1H, s), 10.84 (1H, s), 11.32 (1H, s).
    • Example 94 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(4-nitrophenyl)-diazenyl]benzamide Compound No. 93
  • Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 11.3%.
  • 1H-NMR (DMSO-d6): δ 4.23 (1H, d, J=9.0 Hz), 7.87 (1H, s), 8.06 (2H, d, J=9.0 Hz), 8.10 (1H, d, J=9.0, 2.4 Hz), 8.44 (1H, d, J=9.0 Hz), 8.50 (2H, s), 8.53 (1H, d, J=2.4 Hz), 11.13 (1H, s), 12.14 (1H, br).
    • Example 95 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)benzamide Compound No. 94
  • Using 5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 7.9%.
  • 1H-NMR(DMSO-d6): δ 6.87 (1H, t, J=6.0 Hz), 7.22 (1H, d, J=8.7 Hz), 7.21-7.23 (1H, m), 7.77 (1H, t, J=8.4 Hz), 7.87 (1H, s), 7.95-7.98 (3H, m), 8.03-8.07 (4H, m), 8.47 (1H, d, J=2.4 Hz), 8.49 (2H, s), 11.14 (1H, s), 12.03 (1H, br).
    • Example 96 2-Acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-chlorobenzamide Compound No. 96
  • N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(1.51 g, 3 mmol) and pyridine(285 mg, 3.6 mmol) were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N-hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (1.06 g, 83.0%) as a white solid.
  • 1H-NMR (DMSO-d6): δ 2.22 (3H, s), 7.35 (1H, d, J=9.0 Hz), 7.71 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.88 (1H, d, J=2.7 Hz), 8.37 (2H, s), 11.05 (1H, brs).
    • Example 97 4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5 chloro-2-hydroxybenzamide Compound No. 97 (1) 4-Acetylamino-5-chloro-2-methoxybenzoic acid
  • Using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester as the raw material, the same operation as the example 321 gave the title compound.
  • Yield: 88.0%.
  • 1H-NMR(DMSO-d6): δ 2.16 (3H, s), 3.78 (3H, s), 7.72 (1H, s), 7.77 (1H, s), 9.57 (1H, s), 12.74 (1H, s).
    • (2) 4-Acetylamino-N-[3,6-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide
  • Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 23.8%.
  • 1H-NMR (DMSO-d6): δ 2.17 (3H, s), 3.89 (3H, s), 7.77-7.82 (3H, m), 8.45-8.49 (2H, m), 9.66 (1H, s), 10.68 (1H, s).
    • (3) 4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
  • Using 4-acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide as the raw material, the same operation as the example 80 gave the title compound.
  • Yield: 72.8%.
  • 1H-NMR (DMSO-d6): δ 2.17 (3H, s), 7.75 (1H, s), 7.82 (1H, a), 7.95 (1H, s), 8.44 (2H, s), 9.45 (1H, s), 11.16 (1H, brs), 11.63 (1H, brs).
    • Example 98 N-[3,5-Bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide Compound No. 98
  • Using 4 chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 55.8%.
  • 1H-NMR (DMSO-d6): δ 7.05-7.08 (2H, m), 7.84-7.87 (2H, m), 8.45 (2H, s), 10.84 (1H, s), 11.64 (1H, brs).
    • Example 99 N-[3,5-Bis(trifluoromethyl)-2-bromophenyl]-5-chloro-2-hydroxybenzamide Compound No. 99
  • Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)-2-bromoaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 14.5%.
  • 1H-NMR (DMSO-d6): δ 7.11 (1H, d, J=9.0 Hz), 7.53 (1H, dd, J=9.0, 2.7 Hz), 7.91 (1H, d, J=1.8 Hz), 7.98 (1H, d, J=2.7 Hz), 9.03 (1H, d, J=1.8 Hz), 11.26 (1H, brs).
    • Example 100 N-[2,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide Compound No. 100
  • Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 3.6%.
  • 1H-NMR (CDCl3): δ 7.03 (1H, d, J=8.7 Hz), 7 0.43-7.48 (2H, m), 6.61 (1H, d, J=8.1 Hz), 7.85 (1H, d, J=8.4 Hz), 8.36 (1H, brs), 8.60 (1H, s), 11.31 (1H, s).
    • Example 101 N-[2,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Compound No. 101
  • Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 24.0%.
  • 1H-NMR (DMSO-d6): δ 7.03 (1H, d, J=8.7 Hz), 7.65 (1H, dd, J=9.7, 2.7 Hz), 7.76 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=8.1 Hz), 8.11 (1H, d, J=2.7 Hz), 8.74 (1H, s), 11.02 (1H, s), 12.34 (1H, s).
    • Example 102 N-[2,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide Compound No. 102
  • Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 1.5%.
  • 1H-NMR(CDCl3): δ 2.36 (3H, m) 6.97 (1H, d, J=8.4 Hz), 7.23 (1H, s), 7.32 (1H, dd, J=8.4, 1.5 Hz), 7.57 (1H, d, J=8.4 Hz), 7.83 (1H, d, J=8.46 Hz), 8.46 (1H, s), 8.69 (1H, s), 11.19 (1H, s).
    • Example 103 2-Acetoxy-N-[2,5-bis(trifluoromethyl)phenyl]-5-chlorobenzamide Compound No. 103
  • Using N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
  • Yield: 6.6%.
  • 1H-NMR (CDCl3): δ 2.35 (1H, s), 7.11 (1H, d, J=8.7 Hz), 7.54 (1H, dd, J=8.7, 2.4 Hz), 7.55 (1H, d, J=8.1 Hz), 7.80 (1H, d, J=8.1 Hz), 7.95 (1H, d, J=2.4 Hz), 8.60 (1H, s), 8.73 (1H, s).
    • Example 104 5-Chloro-2-hydroxy-N-[2-(trifluoromethyl)phenyl]benzamide Compound No. 104
  • Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 58.0%.
  • 1H-NMR(DMSO-d6): δ 7.07 (1H, d, J=8.7 Hz), 7.42 (1H, t, J=7.5 Hz), 7.52 (1H, d, J=8.7, 2.7 Hz), 7.74 (1H, t, J=8.1 Hz), 7.77 (1H, t, J=8.1 Hz), 7.99 (1H, d, J=2.7 Hz), 8.18 (1H, d, J=8.1 Hz), 10.76 (1H, s), 12.22 (1H, s).
    • Example 105 5-Chloro-N-[4-chloro-2-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 105
  • Using 5-chlorosalicylic acid and 4-chloro-2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 21.5%.
  • 1H-NMR(DMSO-d6): δ 7.07 (1H, d, J=8.7 Hz), 71.52 (1H, dd, J=8.7, 2.7 Hz), 7.80-7.85 (2H, m), 7.97 (1H, d, J=2.7 Hz), 8.26 (1H, d, J=8.4 Hz), 10.80 (1H, s), 12.26 (1H, s).
    • Example 106 5-Bromo-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide Compound No. 106
  • Using 5-bromosalicylic acid and 3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 50.31,%.
  • 1H-NMR(DMSO-d6, δ): 6.98 (1H, d, J=8.7 Hz), 7.48-7.52 (1H, m), 7.59 (1H, dd, J=8.7, 2.7 Hz), 7.62 (1H, t, J=8.1 Hz), 7.92-7.96 (1H, m), 8.02 (1H, d, J=2.4 Hz), 8.20 (1H, s), 10.64 (1H, s), 11.60 (1H, s).
    • Example 107 5-Chloro-N-[2 fluoro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide, Compound No. 107
  • Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 71.7%, white solid.
  • 1H-NMR (DMSO-d6): δ 7.07 (1H, d, J=9.0 Hz), 7.46 (1H, t, J=7.8 Hz), 7.52 (1H, dd, J=9.0, 2.7 Hz), 7.58 (1H, t, J=−7.2 Hz), 7.96 (1H, d, J=2.7 Hz), 8.49 (1H, t, J=7.2 Hz), 10.82 (1H, s), 12.13 (1H, brs).
    • Example 108 5-Chloro-N-[4 fluoro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 108
  • Using 5-chlorosalicylic acid and 4-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 72.1%, white solid.
  • 1H-NMR (DMSO-d6): δ 7.03 (1H, d, J=9.0 Hz), 7.48 (1H, dd, J=8.7, 2.7 Hz), 7.56 (1H, d, J=9.9 Hz), 7.90 (1H, d, J=2.7 Hz), 7.99-8.03 (1H, m), 8.21 (1H, dd, J=6.6, 2.4 Hz), 10.63 (1H, s), 11.58 (1H, s).
    • Example 109 5-Bromo-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 109
  • Using 5-bromosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 37.4%.
  • 1H-NMR (DMSO-d6): δ 6.98 (1H, d, J=8.7 Hz), 7.59 (1H, dd, J=8.7, 9.4 Hz), 7.73 (1H, d, J=8.7 Hz), 7.98 (1H, d, J=2.4 Hz), 8.00 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.4 Hz), 10.68 (1H, s), 11.52 (1H, brs).
    • Example 110 5-Chloro-N-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 110
  • Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 62.0%.
  • 1H-NMR(DMSO-d6): δ 7.04 (1H, d, J=3.7 Hz), 7.42 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz), 7.85 (1H, d, J=2.4 Hz), 7.94 (1H, dd, J=11.4, 2.1 Hz), 7.99 (1H, s), 10.73 (1H, s), 11.46 (1H, s).
    • Example 111 5-Bromo-N-[3-bromo-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 111
  • Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 73.3%.
  • 1H-NMR(DMSO-d6): δ 6.99 (1H, d, J=9.0 Hz), 7.60 (1H, dd, J=9.0, 2.4 Hz), 7.72 (1H, s), 7.97 (1H, d, J=2.7 Hz), 8.16 (1H, s), 8.28 (1H, s), 10.69 (1H, s), 11.45 (1H, s).
    • Example 112 5-Chloro-N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 112
  • Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 77.9%.
  • 1H-NMR (DMSO-d6): δ 7.07 (1H, d, J=9.0 Hz), 7.52 (1H, dd, J=9.0, 2.7 Hz), 7.58-7.61 (2H, m), 7.95 (1H, d, J=2.7 Hz), 8.71 (1H, d, J=7.5 Hz), 10.90 (1H, s), 12.23 (1H, s).
    • Example 113 5-Chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 113
  • Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 49.1%. 1H-NMR (DMSO-d6): δ 7.09 (1H, d, J=9.0 Hz), 7.53 (1H, dd, J=9.0, 3.0 Hz), 7.55 (1H, dd, J=8.4, 2.7 Hz), 7.83 (1H, d, J=8.4 Hz), 7.98 (1H, d, J=3.0 Hz), 8.88 (1H, d, J=−2.7 Hz), 11.14 (1H, s), 12.39 (1H, s).
    • Example 114 5-Bromo-N-[2-chloro-5-(trifluoromethyl)phenyl]2-hydroxybenzamide Compound No. 114
  • Using-5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 34.2%.
  • 1H-NMR(DMSO-d6): δ 7.04 (1H, d, J=8.7 Hz), 7.56 (1H, ddd, J=8.1, 2.4, 1.2 Hz), 7.64 (1H, dd, J=8.7, 2.7 Hz), 7.83 (1H, dd, J=8.1, 1.2 Hz), 8.11 (1H, d, J=2.7 Hz), 8.87 (1H, d, J=2.4 Hz), 11.12 (1H, s), 12.42 (1H, s).
    • Example 115 5-Chloro-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide Compound No. 115
  • Using 5-chlorosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 44.8%.
  • 1H-NMR (DMSO-d6): δ 7.04 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=9.0, 2.7 Hz), 7.81 (1H, d, J=2.7 Hz), 8.23-8.24 (2H, m), 8.43 (1H, d, J=1.2 Hz), 11.02 (1H, s), 11.30 (1H, br).
    • Example 116 5-Chloro-2-hydroxy-N-[9-nitro-5-(trifluoromethyl)phenyl]benzamide Compound No. 116
  • Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 8.1%.
  • 1H-NMR (DMSO-d6): δ 7.08 (1H, d, J=9.0 Hz), 7.53 (1H, dd, J=8.7, 2.7 Hz), 7.73 (1H, dd, J=8.4, 1.8 Hz), 7.95 (1H, d, J=3.0 Hz), 8.36 (1H, d, J=8.7 Hz), 9.01 (1H, d, J=1.8 Hz), 12.04 (1H, s), 12.20 (1H, s).
    • Example 117 5-Bromo-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide Compound No. 117
  • Using 5-bromosalicylic acid and 4-nitro-3 (trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 49.7%.
  • 1H-NMR(DMSO-d6): δ 6.99 (1H, d, J=8.7 Hz), 7.60 (1H, dd, J=8.7, 2.4 Hz), 7.92 (1H, d, J=2.7 Hz), 8.16 (2H, s), 8.42 (1H, s), 10.93 (1H, s), 11.36 (1H, s).
    • Example 118 5-Chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide Compound No. 118
  • Using 5-chlorosalicylic acid and 2-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 14.5%.
  • 1H-NMR(DMSO-d6): δ 2.36 (3H, d, J=1.2 Hz), 7.0.5 (1H, d, J=5.7 Hz), 7.46 (1H, t, J=8.1 Hz), 7.50 (1H, dd, J=8.7, 2.7 Hz), 7.60 (1H, d, J=7.2 Hz), 7.99 (1H, d, J=7.2 Hz), 8.00 (1H, d, J=2.4 Hz), 10.43 (1H, s), 12.08 (1H, s).
    • Example 119 5-Chloro-2-hydroxy-N-[4-methyl-3-(trifluoromethyl)phenyl]benzamide Compound No. 119
  • Using 5-chlorosalicylic acid and 4-methyl-3-(trifluoromethyl) aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 80.2%.
  • 1H-NMR(DMSO-d6): δ 7.01 (1H, d, J=8.7 Hz), 7.44 (1H, d, J=8.4 Hz), 7.47 (1H, dd, J=9.0, 2.7 Hz), 7.84 (1H, dd, J=8.4, 2.1 Hz), 7.92 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=2.1 Hz), 10.65 (1H, s), 11.68 (1H, br).
    • Example 120 5-Chloro-2-hydroxy-N-[2-methyl-5-(trifluoromethyl)phenyl]benzamide Compound No. 120
  • Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 73.3%.
  • 1H-NMR (DMSO-d6): δ 2.39 (3H, s), 7.07 (1H, d, J=8.7 Hz), 7.44-7.54 (3H, m), 7.99 (1H, d, J=3.0 Hz), 8.43 (1H, s), 10.52 (1H, s), 12.17 (1H, brs).
    • Example 121 5-Chloro-2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]benzamide Compound No. 121
  • Using 5-chlorosalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 79.1%.
  • 1H-NMR (DMSO-d6): δ 7.02 (1H, d, J=9.0 Hz), 7.30 (1H, d, J=9.0 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz), 7.92 (1H, dd, J=9.0, 2.4 Hz), 7.96 (1H, d, J=2.7 Hz), 8.04 (1H, d, J=2.4 Hz), 10.47 (1H, s), 11.78 (1H, s).
    • Example 122 5-Bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide Compound No 190
  • Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 68.8%.
  • 1H-NMR (DMSO-d6): δ 3.85 (3H, s), 6.98 (1H, d, J=8.7 Hz), 7.03 (1H, s), 7.57-7.61 (2H, m), 7.77 (1H, s), 8.00 (1H, d, J=2.4 Hz), 10.57 (1H, s), 11.56 (1H, s).
    • Example 123 5-Bromo-2-hydroxy-N [2-methoxy-5-(trifluoromethyl)phenyl]benzamide Compound No. 123
  • Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 71.3%.
  • 1H-NMR(DMSO-d6): δ 3.99 (3H, s), 7.03 (1H, d, J=9.0Hz), 7.30 (1H, d, J=8.7 Hz), 7.47-7.51 (1H, m), 7.61 (1H, dd, J=9.0, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz), 8.82 (1H, d, J=2.1 Hz), 11.03 (1H, s), 12.19 (1H, s).
    • Example 124 5-Chloro-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]-2-benzamide Compound No. 124
  • Using 5-chlorosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 83.4%.
  • 1H-NMR (DMSO-d6): δ 4.00 (3H, s), 7.08 (1H, d, J=9.0 Hz), 7.30 (1H, d, J=8.7 Hz), 7.47-7.52 (2H, m), 7.97 (1H, d, J=2.7 Hz), 8.83 (1H, d, J=2.4 Hz), 11.05 (1H, s), 12.17 (1H,
    • Example 123 5-Chloro-2-hydroxy-N-[2-methylsulfanyl-5-(trifluoromethyl)-phenyl]benzamide Compound No. 125
  • Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 79.2%.
  • 1H-NMR(DMSO-d6): δ 2.57 (3H, s), 7.0 (1H, d, J=8.7 Hz), 7.52 (1H, dd, J=8.7, 2.4 Hz), 7.55 (1H, dd, J=8.4, 1.5 Hz), 7.63 (1H, d, J=8.1 Hz), 8.00 (1H, d, J=2.4 Hz), 8.48 (1H, d, J=1.5 Hz), 10.79 (1H, s), 12.26 (1H, s).
    • Example 126 5-Bromo-2-hydroxy-N-[2-(1-pyrrolidinyl)-5(trifluoromethyl)-phenyl]benzamide Compound No. 126
  • Using 5-bromosalicylic acid and 2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 44.5%.
  • 1H-NMR (DMSO-d6): δ 1.86-1.91 (4H, m), 3.20-3.26 (4H, m), 6.99 (1H, d, J=8.7 Hz), 7.07 (1H, d, J=8.7 Hz), 7.43 (1H, dd, J=8.7, 2.1 Hz), 7.62 (1H, dd, J=8.7, 2.4 Hz), 7.94 (1H, d, J=2.1 Hz), 8.17 (1H, d, J=2.4 Hz), 10.54 (1H, s), 12.21 (1H, s).
    • Example 127 5-Bromo-2-hydroxy-N-[2-morpholino-5-(trifluoromethyl)phenyl]-benzamide Compound No. 127
  • Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 65.9%.
  • 1H-NMR (DMSO-d6): δ 2.90 (4H, dd, J=4.5, 4.2 Hz), 3.84 (4H, dd, J=4.8, 4.2 Hz), 7.09 (1H, d, J=8.4 Hz), 7.48 (2H, s), 7.61 (1H, dd, J=8.4, 2.7 Hz), 8.13 (1H, d, J=2.7 Hz), 8.90 (1H, s), 11.21 (1H, s), 12.04 (1H, s).
    • Example 128 5-Chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide Compound No. 123
  • Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 75.0%, white solid.
  • 1H-NMR (DMSO-d6): δ 7.04 (1H, d, J=9.0 Hz), 7.48 (1H, dd, J=8.7, 2.7 Hz), 7.74 (2H, d, J=8.7 Hz), 7.90 (1H, d, J=2.7 Hz), 7.95 (2H, d, J=9.0 Hz), 10.65 (1H, s), 11.59 (1H, s).
    • Example 199 5-Bromo-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-hydroxybenzamide Compound No. 129
  • Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 34.9%.
  • 1H-NMR(DMSO-d6): δ 7.04 (1H, d, J=8.7 Hz), 7.64 (1H, dd, J=8.7, 2.7 Hz), 7.99 (1H, dd, J=9.0, 2.1 Hz), 7.99 (1H, d, J=2.1 Hz), 8.11 (1H, d, J=2.4 Hz), 8.73 (1H, d, J=9.0 Hz), 11.13 (1H, s), 12.42 (1H, s).
    • Example 130 2-Acetoxy-5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]benzamide Compound No. 130
  • Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
  • Yield: 34.0%.
  • 1H-NMR (CDCl3): δ 2.39 (3H, s), 7.16 (1H, d, J=8.7 Hz), 7.37 (1H, ddd, J=8.7, 2.4, 0.6 Hz), 7.51-7.56 (2H, m), 7.97 (1H, d, J=3.0 Hz), 8.8S5 (1H, s), 8.94 (1H, d, J=1.8 Hz).
    • Example 131 N-[2-Chloro-5-(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide Compound No. 131
  • Using 5-nitrosalicylic acid and 2-chloro-6-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 31.1%.
  • 1H-NMR (DMSO-d6): δ 6.98 (1H, d, J=9.3 Hz), 7.52 (1H, dd, J=8.4, 2.1 Hz), 7.81 (1H, d, J=8.4 Hz), 8.21 (1H, dd, J=9.0, 3.3 Hz), 8.82 (1H, d, J=3.0 Hz), 8.93 (1H, d, J=2.4 Hz), 12.18 (1H, s).
    • Example 132 N-[2-Chloro-5-(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide Compound No. 132
  • Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 15.8%.
  • 1H-NMR (CDCl3): δ 2.36 (3H, s), 6.95 (1H, d, J=8.1 Hz), 7.26-7.31 (2H, m), 7.37 (1H, dd, J=8.4, 1.8 Hz), 7.56 (1H, d, J=8.4 Hz), 8.65 (1H, brs), 8.80 (1H, d, J=1.8 Hz), 11.33 (1H, brs).
    • Example 133 N-[2-Chloro-5-(trifluoromethyl)phenyl]-2-hydroxy-5-methoxybenzamide Compound No. 133
  • Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 56.4%.
  • 1H-NMR (DMSO-d6): δ 3.77 (3H, s), 6.91 (1H, d, J=9.0Hz), 7.07 (1H, dd, J=8.7, 3.0 Hz), 7.20 (1H, t, J=1.8 Hz), 7.52-7.54 (3H, m), 10.33 (1H, s), 11.44 (1H, s).
    • Example 134 N-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide Compound No. 134
  • Using 5-methylsalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 70.4%.
  • 1H-NMR (DMSO-d6): δ 2.29 (3H, s), 6.91 (1H, d, J=8.3 Hz), 7.27 (1H, ddd, J=8.3, 2.2, 0.6 Hz), 7.71 (1H, d, J=2.2 Hz), 7.72 (1H, d, J=8.5 Hz), 8.02 (1H, dd, J=8.5, 2.5 Hz), 8.33 (1H, d, J=2.5 Hz), 10.64 (1H, s), 11.25 (1H, s).
    • Example 135 2-Hydroxy-5-methyl-N-[4-methyl-3-(trifluoromethyl)phenyl]benzamide Compound No. 135
  • Using 5-methylsalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 63.7%.
  • 1H-NMR (DMSO-d6): δ 2.29 (3H, s), 2.42 (3H, s), 6.89 (1H, d, J=8.4 Hz), 7.26 (1H, ddd, J=8.4, 2.1, 0.6 Hz), 7.44 (1H, d, J=8.1 Hz), 7.75 (1H, d, J=2.1 Hz), 7.86 (1H, dd, J=8.4, 1.8 Hz), 8.13 (1H, d, J=2.1 Hz), 10.50 (1H, s), 11.42 (1H, s).
    • Example 136 2-Hydroxy-5-methyl-N-[2-methyl-5-(trifluoromethyl)phenyl]benzamide Compound No. 136
  • Using 5-methylsalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 14.2%, white solid.
  • 1H-NMR (DMSO-d6): δ 2.29 (3H, s), 2.38 (3H, s), 6.94 (1H, d, J=8.4 Hz), 7.27 (1H, ddd, J=8.4, 2.4, 0.6 Hz), 7.44 (1H, dd, J=8.1, 1.5 Hz), 7.52 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=2.4Hz), 8.46 (1H, d, J=1.5 Hz), 10.55 (1H, s), 11.72 (1H, s).
    • Example 137 2-Hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]-5-methylbenzamide Compound No. 137
  • Using 5-methylsalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 65.1%, slight yellow solid.
  • 1H-NMR (DMSO-d6): δ 2.35 (3H, s), 3.89 (3H, s), 6.88 (1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.1, 1.8 Hz), 7.30 (1H, d, J=8.4 Hz), 7.7 (1H, d, J=2.1 Hz), 7.92 (1H, dd, J=9.0, 2.1 Hz), 8.04 (1H, d, J=2.7 Hz), 10.42 (1H, s), 11.54 (1H, s).
    • Example 138 2-Hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylbenzamide Compound No. 138
  • Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 77.9%.
  • 1H-NMR (CDCl3): δ 2.35 (3H, s), 4.02 (3H, s), 6.93 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.4 Hz), 7.25-7.28 (2H, m), 7.36 (1H, ddd, J=8.4, 2.1, 0.9 Hz), 8.65 (1H, brs), 8.73 (1H, d, J=2.1 Hz), 11.69 (1H, s).
    • Example 139 5-Bromo-2-hydroxy-N-phenylbenzamide Compound No. 139
  • Using 5-bromosalicylic acid and aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 63.8%.
  • mp 229-230° C.
  • 1H-NMR(DMSO-d6): δ 6.96 (1H, d, J=9.0 Hz), 7.12-7.18 (1H, m), 7.35-7.41 (2H, m), 7.58 (1H, dd, J=8.7, 2.7 Hz), 7.67-7.71 (2H, m), 8.08 (1H, d, J=2.7 Hz), 10.43 (1H, s), 11.87 (1H, s).
    • Example 140 5-Bromo-N-(3-chlorophenyl)-2-hydroxybenzamide Compound No. 140
  • Using 5-bromosalicylic acid and 3-chloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 63.1%.
  • mp 231-232° C.
  • 1H-NMR (DMSO-d6): δ 6.97 (1H, d, J=8.7 Hz), 7.19-7.22 (1H, m), 7.38-7.43 (1H, m), 7.57-7.63 (2H, m), 7.91-7.92 (1H, m), 8.01 (1H, d, J=2.7 Hz), 10.49 (1H, s), 11.64 (1H, s).
    • Example 141 5-Bromo-N-(4-chlorophenyl)-2-hydroxybenzamide Compound No. 141
  • This compound is a commercially available compound.
  • Supplier: Tokyo Kasei.
  • Catalog code number: B0897.
    • Example 142 5-Chloro-N-(2,5-dichlorophenyl)-2-hydroxybenzamide Compound No. 142
  • Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 10.8%.
  • 1H-NMR (DMSO-d6): δ 7.08 (1H, d, J=9.0 Hz), 7.24-7.23 (1H, m), 7.50-7.54 (1H, m), 7.61 (1H, dd, J=9.0, 3.0 Hz), 7.97 (1H, d, J=2.7 Hz), 8.58 (1H, d, J=2.4 Hz), 11.02 (1H, s), 12.35 (1H, brs).
    • Example 143 5-Bromo-N-(3,4-dichlorophenyl)-2-hydroxybenzamide Compound No. 143
  • Using 5-bromosalicylic acid and 3,4-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 58.2%.
  • mp 249-251° C.
  • 1H-NMR (DMSO-d6): δ 6.97 (1H, d, J=8.7 Hz), 7.57-7.70 (3H, m), 7.98 (1H, d, J=2.7 Hz), 8.10 (1H, d, J=2.4 Hz), 10.54 (1H, s), 11.55 (1H, s).
    • Example 144 5-Bromo-N-(3,5-difluorophenyl)-2-hydroxybenzamide Compound No. 144
  • Using-5-bromosalicylic acid and 3,5-difluoroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 36.3%
  • mp 259-261° C.
  • 1H-NMR(DMSO-d6): δ 6.96-7.04 (2H, m), 7.45-7.54 (2H, m), 7.58 (1H, dd, J=8.7, 2.7 Hz), 7.94 (1H, d, J=2.7 Hz), 10.60 (1H, s), 11.4 (1H, s).
    • Example 145 2-Acetoxy-N-(3,5-dichlorophenyl)benzamide Compound No. 172
  • Using o-acetylsalicyloyl chloride and 3,5-dichloroaniline as the raw materials, the same operation as the example 2 (1) gave the title compound.
  • Yield: 73.5%.
  • mp 167-168° C.
  • 1H-NMR(CDCl3): δ 2.35 (3H, s), 7.14-7.18 (2H, m), 7.35-7.40 (1H, m), 7.52-7.5 (3H, m), 7.81 (1H, dd, J=7.8, 1.8 Hz), 8.05 (1H, brs).
    • Example 146 N-(3,5-Dichlorophenyl)-2-hydroxybenzamide Compound No. 145
  • Using 2-acetoxy-N-(3,5-dichlorophenyl)benzamide as the raw material, the same operation as the example 2 (2) gave the title compound.
  • Yield: 60.3%.
  • mp 218-219° C.
  • 1H-NMR(DMSO-d6): δ 6.95-7.02 (2H, m), 7.35-7.36 (1H, m), 7.42-7.47 (1H, m), 7.83-7.87 (3H, m), 10.54 (1H, s), 11.35 (1H, s).
    • Example 147 N-(3,5-Dichlorophenyl)-6-fluoro-9-hydroxybenzamide Compound No. 146
  • Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 33.3%.
  • mp 258-260° C.
  • 1H-NMR(DMSO-d6): δ 7.00-7.05 (1H, m), 7.28 7.37 (2H, m), 7.63 (1H, dd, J=9.3, 3.3 Hz), 7.84 (2H, d, J=2.1 Hz), 10.56 (1H, s), 11.23 (1H, s).
    • Example 148 5-Chloro N-(3,5-dichlorophenyl)-2-hydroxybenzamide Compound No. 147
  • Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 41.2%.
  • 1H-NMR (DMSO-d6): δ 7.03 (1H, d, J=9.0 Hz), 7.36-7.37 (1H, m), 7.48 (1H, dd, J=8.7, 2.7 Hz), 7.83-7.84 (3H, m), 10.56 (1H, s), 11.44 (1H, s).
    • Example 149 5-Bromo-N-(3,5-dichlorophenyl)-2-hydroxybenzamide Compound No. 148
  • Using 5-bromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 61.6%.
  • mp 24.3-244° C.
  • 1H-NMR (DMSO-d6): δ 6.98 (1H, d, J=8.7 Hz), 7.36-7.37 (1H, m), 7.59 (1H, dd, J=9.0, 2.4 Hz), 7.83 (2H, d, J=1.5 Hz), 7.95 (1H, d, J=2.4 Hz), 10.56 (1H, s), 11.46 (1H, s).
    • Example 150 N-(3,5-Dichlorophenyl)-2-hydroxy-5-iodobenzamide Compound No. 149
  • Using 5-iodosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 65.4%.
  • mp 244-245° C.
  • 1H-NMR(DMSO-d6): δ6.84 (1H, d, J=9.0 Hz), 7.35-7.37 (1H, m), 7.72 (1H, dd, J=9.0, 2.1 Hz), 7.83 (2H, d, J=1.8 Hz), 8.09 (1H, d, J=2.1 Hz), 10.56 (1H, s), 11.45 (1H, s).
    • Example 151 3,5-Dibromo-N-(3,5-dichlorophenyl)-2-hydroxybenzamide Compound No. 150
  • Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 44.2%.
  • mp 181-182° C.
  • 1H-NMR (DMSO-d6): δ 7.42-7.43 (1H, m), 7.80 (2H, d, J=1.8 Hz), 8.03 (1H, d, J=2.1 Hz), 8.17 (1H, d, J=2.1 Hz), 10.82 (1H, s).
    • Example 152 4-Chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide Compound No. 151
  • Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 57.2%
  • mp 255-256° C.
  • 1H-NMR (DMSO-d6): δ 7.03-7.06 (2H, m), 7.34-7.36 (1H, m), 7.82-7.85 (3H, m), 10.51 (1H, s), 11.70 (1H, brs).
    • Example 153 N-(3,5-Dichlorophenyl)-2-hydroxy-5-nitrobenzamide Compound No. 152
  • Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 83.1%.
  • mp 232-233.
  • 1H-NMR (DMSO-d6): δ 7.16 (1H, d, J=9.6 Hz), 7.37-7.39 (1H, m), 7.84 (1H, d, J=2.1 Hz), 8.29 (1H, dd, J=9.0, 3.0 Hz), 8.65 (1H, d, J=3.0 Hz), 10.83 (1H, s).
    • Example 154 N-(3,5-Dichlorophenyl)-2 hydroxy-5-methylbenzamide Compound No. 153
  • Using 5-methylsalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 71.0%.
  • mp 216-217° C.
  • 1H-NMR (DMSO-d6): δ 2.28 (3H, s), 6.90 (1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.7, 1.8 Hz), 7.34-7.36 (1H, m), 7.67 (1H, d, J=1.5 Hz), 7.85 (2H, d, J=1.3 Hz), 10.52 (1H, s), 11.15 (1H, s).
    • Example 155 N-(3,5-Dichlorophenyl)-2-hydroxy-5-methoxybenzamide Compound No. 154
  • Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 29.8%.
  • mp 230-232° C.
  • 1H-NMR (DMSO-d6): δ 3.76 (3H, s), 6.95 (1H, d, J=8.7 Hz), 7.08 (1H, dd, J=9.0, 3.0 Hz), 7.35-7.36 (1H, m), 7.40 (1H, d, J=3.0 Hz), 7.8S5 (2H, d, J=1.5 Hz), 10.55 (1H, s), 10.95 (1H, s).
    • Example 136 5-Bromo-2-hydroxy-N-(3,4,5-trichlorophenyl)benzamide Compound No. 155
  • Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 78.6%.
  • mp 297-299° C.
  • 1H-NMR (DMSO-d6): δ 6.98 (1H, d, J=9.0 Hz), 7.58 (1H, dd, J=8.4, 2.4 Hz), 7.95 (1H, d, J=2.4 Hz), 8.03 (1H, s), 10.58 (1H, s), 11.49 (1H, s).
    • Example 157 5-Bromo-2-hydroxy-N-(3,5-dichloro-4-hydroxyphenyl)benzamide Compound No. 156
  • Using 5-bromosalicylic acid and 3,5-dichloro-4-hydroxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • 1H-NMR(DMSO-d6): δ 6.96 (1H, d, J=8.7 Hz), 7.58 (1H, dd, J=8.7, 2.4 Hz), 7.76 (2H, s), 8.01 (1H, d, J=2.4 Hz), 10.03 (1H, s), 10.36 (1H, s), 11.67 (1H, brs).
    • Example 158 5-Chloro-2-hydroxy-N-(2,3,4,5,6-pentafluorophenyl)benzamide Compound No. 157
  • Using 5-chlorosalicylic acid and 2,3,4,5,6-pentafluoroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 58.6%.
  • 1H-NMR(DMSO-d6): δ 7.07 (1H, d. J=8.7 Hz), 7.53 (1H, dd, J=8.7, 2.7 Hz), 7.91 (1H, d, J=2.7 Hz), 10.38 (1H, brs), 11.74 (1H, brs).
    • Example 159 5-Bromo-N-(3,5-dinitrophenyl)-2-hydroxybenzamide Compound No. 158
  • Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 32.2%.
  • mp 258-260° C.
  • 1H-NMR(DMSO-d6): δ 6.98-7.02 (1H, m), 7.59-7.63 (1H, m), 7.96-7.97 (1H, m), 8.56-8.58 (1H, m), 9.03-9.05 (2H, m), 11.04 (1H, s), 11.39 (1H, brs).
    • Example 160 N-{2,5-Bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide Compound No. 159
  • Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 75.7%.
  • 1H-NMR (DMSO-d(−): δ 1.27 (9H, s), 1.33 (9H, s), 7.04 (1H, d, J=9.0 Hz), 7.26 (1H, dd, J=8.4, 2.1 Hz), 7.35-7.38 (2H, m), 7.49 (1H, dd, J=8.7, 2.7 Hz), 8.07 (1H, d, J=2.4 Hz), 10.22 (1H, s), 12.38 (1H, brs).
    • Example 161 5-Chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-2-hydroxybenzamide Compound No. 160
  • Using 5-chlorosalicylic acid and 5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 89.5%.
  • 1H-NMR (DMSO-d6): δ 1.28 (9H, s), 3.33 (3H, s), 7.01 (1H, d, J=8.7 Hz), 7.05 (1H, d, J=9.0 Hz), 7.11 (1H, dd, J=8.7, 2.4 Hz), 7.47 (1H, dd, J=9.0, 3.0 Hz), 7.99 (1H, d, J=3.0 Hz), 8.49 (1H, d, J=2.4 Hz), 10.78 (1H, s), 12.03 (1H, s).
    • Example 162 5-Bromo-N-(3,5-dimethylphenyl)-2-hydroxybenzamide Compound No. 161
  • Using 5-bromosalicylic acid and 3,5-dimethylaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 58.1%.
  • mp 18-190° C.
  • 1H-NMR (DMSO-d6): δ 2.28 (6H, s), 6.30 (1H, s), 6.96 (1H, d, J=8.7 Hz), 7.33 (2H, s), 7.58 (1H, dd, J=9.0, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz), 10.29 (1H, s), 11.93 (1H, brs).
    • Example 163 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide Compound No. 162
  • Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 34.1%.
  • 1H-NMR(CDCl3): δ 1.26 (18H, s), 6.99 (1H, d, J=8.7 Hz), 7.29 (1H, t, J=1.8 Hz), 7.39 (1H, dd, J=9.0, 2.4 Hz), 7.41 (2H, d, J=1.5 Hz), 7.51 (1H, d, J=2.1 Hz), 7.81 (1H, brs), 12.01 (1H, s).
    • Example 164 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-5-bromo-2-hydroxybenzamide Compound No. 163
  • Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 45.2%.
  • 1H-NMR(DMSO-d6, δ): 1.30 (1H, s), 6.95 (1H, d, J=8.7 Hz), 7.20 (1H, t, J=1.5 Hz), 7.56 (2H, d, J=1.5 Hz), 7.53 (1H, dd, J=8.7, 2.4 Hz), 8.12 (1H, d, J=2.7 Hz), 10.39 (1H, s), 11.98 (1H, s).
    • Example 165 5-Chloro-2 hydroxy-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide Compound No. 164
  • Using 5-chlorosalicylic acid and 2-amino-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 77.5%.
  • 1H-NMR(DMSO-d6): 1.93 (6H, s), 1.24 (6H, s), 1.64 (4H, s), 2.19 (3H, s), 7.13 (1H, d, J=9.0 Hz), 7.20 (1H, s), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.67 (1H, s), 8.04 (1H, d, J=2.7 Hz), 10.23 (1H, s), 12.26 (1H, s).
    • Example 166 N-(Biphenyl-3-yl)-5-chloro-2-hydroxybenzamide Compound No. 165
  • Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 75.6%.
  • 1H-NMR (DMSO-d6): δ 7.04 (1H, d, J=8.7 Hz), 7.35-7.44 (1H, m), 7.45-7.54 (5H, m), 7.65-7.63 (2H, m), 7.72 (1H, dt, J=7.2, 2.1 Hz), 7.99 (1H, d, J=3.0 Hz), 8.03 (1H, m), 10.50 (1H, s), 11.83 (1H, brs).
    • Example 167 5-Chloro-9-hydroxy-N-(4-methoxybiphenyl-3-yl)benzamide Compound No. 166
  • Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 37.0%.
  • 1H-NMR (DMSO-d6): δ 3.95 (3H, s), 7.08 (1H, d, J=8.7 Hz), 7.20 (1H, d, J=8.4 Hz), 7.34 (1H, t, J=7.2 Hz), 7.40-7.50 (4H, m), 7.62 (1H, d, J=8.7 Hz), 8.00 (1H, d, J=3.0 Hz), 8.77 (1H, d, J=2.1 Hz), 10.92 (1H, s), 12.09 (1H, s).
    • Example 168 5-Bromo-N-(2,5-dimethoxyphenyl)-2-hydroxybenzamide Compound No. 167
  • Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: δ 39.7%.
  • 1H-NMR (DMSO-d6): δ 3.72 (3H, s), 3.84 (3H, s), 6.66 (1H, ddd, J=9.0, 3.0, 0.6 Hz), 6.99-7.03 (2H, m), 7.58 (1H, ddd, J=9.0, 2.7, 0.6 Hz), 8.10 (1H, dd, J=2.4, 0.6 Hz), 8.12 (1H, d, J=3.0 Hz), 10.87 (1H, s), 12.08 (1H, s).
    • Example 169 5-Bromo-N-(3,5-dimethoxyphenyl)-2-hydroxybenzamide Compound No. 168
  • Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 40.3%.
  • mp 207-209° C.
  • 1H-NMR (DMSO-d6): δ 3.75 (6H, s), 6.30-6.32 (1H, m), 6.94-6.97 (3H, m), 7.57 (1H, dd, J=8.7, 2.4 Hz), 8.04 (1H, d, J=2.4 Hz), 10.32 (1H, s), 11.78 (1H, s).
    • Example 170 5-Chloro-N-(3-acetylphenyl)-2-hydroxybenzamide Compound No. 169
  • Using 5-chlorosalicylic acid and 3-acetylaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 80.0%.
  • 1H-NMR(DMSO-d6): δ 2.60 (:3H, s), 7.03 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=9.0, 3.0 Hz), 7.54 (1H, t, J=8.1 Hz), 7.76 (1H, dq, J=7.8, 0.9 Hz), 7.96-8.00 (2H, m), 8.30 (1H, t, J=1.8 Hz), 10.56 (1H, s), 11.75 (1H, s).
    • Example 171 5-{[(5-Bromo-2-hydroxy)benzoyl]amino}isophthalic acid dimethyl ester Compound No. 170
  • Using 5-bromosalicylic acid and 5-aminoisophthalic acid dimethyl ester as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 74.1%.
  • mp 254-256° C.
  • 1H-NMR(DMSO-d6): δ 3.92 (6H, s), 6.97 (1H, d, J=9.0 Hz), 7.60 (1H, dd, J=9.0, 2.4 Hz), 8.06 (1H, d, J=2.4 Hz), 8.24-8.25 (1H, m), 8.62 (2H, m), 10.71 (1H, s), 11.57 (1H, s).
    • Example 172 N-{4-[3-(2,3-Dichlorophenyl)thioureido]phenyl}-2-hydroxybenzamide Compound No. 171
  • This compound is a commercially available compound.
  • Seller: Maybridge.
  • Catalog code number: RDR 01434
    • Example 173 N-{2,5-Bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-methylbenzamide Compound No. 173
  • Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 61.1%.
  • 1H-NMR (DMSO-d6): δ 1.27 (9H, s), 1.33 (9H, s), 2.28 (3H, s), 6.89 (1H, d, J=8.1 Hz), 7.24 (1H, d, J=2.1 Hz), 7.27 (1H, d, J=2.1 Hz), 7.32 (1H, d, J=2.4 Hz), 7.37 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=1.5 Hz), 10.1.5 (1H, s), 11.98 (1H, brs).
    • Example 174 2-Acetoxy-N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chlorobenzamide Compound No. 174
  • Using N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
  • Yield: 66.1%.
  • 1H-NMR(CDCl3): δ 1.34 (18H, s), 2.36 (3H, s), 7.12 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=1.5 Hz), 7.44 (2H, d, J=1.2 Hz), 7.47 (1H, dd, J=8.7, 2.7 Hz), 7.87 (1H, d, J=2.4 Hz), 7.98 (1H, s).
    • Example 175 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-nitrobenzamide Compound No. 175
  • Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 46.7%.
  • 1H-NMR (CDCl3): δ 1.37 (18H, s), 7.13 (1H, d, J=9.3 Hz), 7.32 (1H, t, J=1.8 Hz), 7.46 (2H, d, J=1.8 Hz), 8.07 (1H, s), 8.33 (1H, dd, J=9.3, 2.1 Hz), 8.59 (1H, d, J=2.4 Hz), 13.14 (1H, s).
    • Example 176 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-methylbenzamide Compound No. 176
  • Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 16.3%.
  • 1H-NMR (CDCl3): 1.35 (18H, s), 2.35 (3H, s), 6.94 (1H, d, J=8.4 Hz), 7.23-7.28 (2H, m), 7.31 (1H, s), 7.42 (1H, d, J=1.8 Hz), 7.88 (1H, s), 11.86 (1H, s).
    • Example 177 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxy-5-methoxybenzamide Compound No. 177
  • Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 12.7%.
  • 1H-NMR (DMSO-d6): δ 3.56 (3H, s), 7.01 (1H, d, J=9.0 Hz), 7.11 (1H, dd, J=9.0, 3.0 Hz), 7.52-7.56 (2H, m), 7.83 (1H, d, J=8.1 Hz), 8.95 (1H, d, J=1.5 Hz), 11.29 (1H, s), 11.63 (1H, s).
    • Example 178 2-Acetoxy-5-chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-benzamide Compound No. 178
  • Using 6-chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]ethyl-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
  • Yield: 87.5%.
  • 1H-NMR(CDCl3): δ 1.35 (9H, s), 2.37 (3H, s), 3.91 (3H, s), 6.86 (1H, d, 8.7 Hz), 7.12 (1H, dd, J=8.7, 2.4 Hz), 7.13 (1H, d, J=9.0 Hz), 7.47 (1H, dd, J=9.0, 2.4 Hz), 8.02 (1H, d, J=2.7 Hz), 8.66 (1H, d, J=2.4 Hz), 8.93 (1H, s).
    • Example 179 N-[5 (1,1-Dimethyl)ethyl-2-methoxyphenyl]-2-hydroxy-5-methylbenzamide Compound No. 178
  • Using 5-methylsalicylic acid and 5-(1,1-dimethyl)ethyl-2-methoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 84.7%.
  • 1H-NMR(CDCl3): δ 1.35 (9H, s), 2.34 (3H, s), 3.93 (3H, s), 6.86 (1H, d, J=8.7 Hz), 6.93 (1H, d, J=8.4 Hz), 7.12 (1H, dd, J=8.7, 2.4 Hz), 7.24 (1H, dd, J=8.4, 1.8 Hz), 7.27 (1H, brs), 8.48 (1H, d, J=2.4 Hz), 8.61 (1H, brs), 11.95 (1H, s).
    • Example 180 5-Bromo-2° hydroxy-N-(thiazol-2-yl)benzamide Compound No. 180
  • Using 5-bromosalicylic acid and 2-aminothiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 12.0%.
  • mp 212° C. (dec.).
  • 1H-NMR (DMSO-d6): δ 6.94 (1H, brd, J=8.0 Hz), 7.25 (1H, brd, J=3.2 Hz), 7.56 (2H, m), 8.05 (1H, d, J=2.8 Hz).
    • Example 181 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide Compound No. 186 (1) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole
  • A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g, 90.9%) as a yellowish white powder.
  • 1H-NMR(CDCl3): δ 1.26 (9H, s), 4.96 (2H, brs), 6.09 (1H, s).
    • (2) 2 Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide
  • Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4-[(1,1-dimethyl)-ethyl]thiazole as the raw materials, the same operation as the example 24 gave the title compound.
  • Yield: 59.4%.
  • 1H-NMR(CDCl3): δ 1.31 (9H, s), 2.44 (3H, s), 6.60 (1H, s), 7.13 (1H, d, J=8.4 Hz), 7.68 (1H, dd, J=8.7, 2.4 Hz), 8.17 (1H, d, J=2.4 Hz), 9.72 (1H, brs).
    • (3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide
  • 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide(100.1 mg, 0.95 mmol) was dissolved in tetrahydrofuran (3 mL). 2 N sodium hydroxide (0.2 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized(isopropyl ether/n-hexane) to give the title compound (70.1 mg, 78.9%) as a light gray solid.
  • 1H-NMR(DMSO-d6): δ 1.30 (9H, s), 6.80 (1H, brs), 6.95 (1H, brs), 7.57 (1H, brs), 8.06 (1H, d, J=2.4 Hz), 11.82 (1H, brs), 13.27 (1H, brs).
    • Example 182 5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide Compound No. 181 (1) 2-Acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide
  • 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]imidazol-2-yl}benzamide (0.20 g, 0.50 mmol) was dissolved in acetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.56 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound as a crude product.
    • (2) 5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide
  • Using 2-acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide as the raw material, the same operation as the example 2 (2) gave the title compound.
  • Yield: 90.9% (2 steps).
  • mp 212° C. (dec.).
  • 1H-NMR (DMSO-d6): δ 1.42 (9H, s), 6.99 (1H, d, J=8.7 Hz), 7.61 (1H, dd, J=8.7, 2.7 Hz), 8.02 (1H, d, J=2.4 Hz), 11.79 (1H, brs), 12.00 (1H, brs).
    • Example 183 5-Bromo-N-[5-bromo-4-(trifluoromethyl)thiazol-2-yl]-2-hydroxybenzamide Compound No. 182
  • Using h-bromosalicylic acid and 2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-bromo-4-(trifluoromethyl)thiazole: refer to J. Heterocycl. Chem., 1991, 28, 1017.)
  • Yield: 22.4%.
  • mp 215° C. (dec.).
  • 1H-NMR (DMSO-d6): δ 7.0o(1H, d, J=8.8 Hz), 7.61 (1H, dd, J=8.8, 2.8 Hz), 7.97 (1H, d, J=2.4 Hz).
    • Example 184 5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol 2-yl}-2-hydroxybenzamide (1) α-Bromo-pivaloylacetonitrile
  • Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbon tetrachloride(1-5 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g, 87.9%) as a yellowish brown oil.
  • 1H-NMR (CDCl3): δ 1.33 (9H, s), 5.10 (1H, s).
    • (2) 2-Amino-5-cyano-{4-[(1,1-dimethyl)ethyl]thiazole
  • Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials, the same operation as the example 181(1) gave the title compound.
  • Yield: 66.3%.
  • 1H-NMR (CDCl3): δ 1.41 (9H, s), 5.32 (2H, s).
    • (3) 5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide
  • Using 5-chlorosalicylic acid and 2-amino-5-cyano-14-[(1,1-dimethyl)ethyl]-thiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 63.4%.
  • 1H-NMR (DMSO-d6): δ 1.43 (9H, s), 7.06 (1H, d, J=8.7 Hz), 7.51 (1H, dd, J=8.7, 3.0 Hz), 7.85 (1H, d, J=2.7 Hz), 12.31 (2H, br).
    • Example 135 α-Bromo-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide Compound No. 184
  • Using 5-bromosalicylic acid and 2-amino-5-cyano-{4-[(1,1-dimethyl)ethyl]-thiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 61.3%.
  • 1H-NMR (DMSO-d6): δ 1.43 (9H, s), 7.00 (1H, d, J=8.7 Hz), 7.62 (1H, dd, J=8.7, 2.7 Hz), 7.97 (1H, d, J=2.7 Hz), 11.75 (1H, br), 12.43 (1H, br).
    • Example 186 5-Bromo-2-hydroxy-N-(5-methylthiazol-2-yl)benzamide Compound No. 185
  • Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 12.9%.
  • 1H-NMR(DMSO-d6): δ 2.33 (3H, s), 6.91 (H, d, J=7.6 Hz), 7.26 (1H, s), 7.54 (1H, d, J=9.6 Hz), 8.03 (1H, d, J=2.8 Hz).
    • Example 187 5-Bromo-N-(4,5-dimethylthiazol-2-yl)-2-hydroxybenzamide Compound No. 187
  • Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 14.4%.
  • 1H-NMR (DMSO-d6): δ 2.18 (3H, s), 2.22 (3H, s), 6.89 (1H, d, J=8.8 Hz), 7.51 (1H, d, J=6.8 Hz), 8.02 (1H, d, J=2.8 Hz), 13.23 (1H, brs).
    • Example 188 5-Bromo-N-(5-methyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide Compound No. 188)
  • Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-methyl-4-phenylthiazole: refer to Yakugaku Zasshi, 1961, 81, 1456.)
  • Yield: 27.7%.
  • mp 243-244° C.
  • 1H-NMR(CD3OD): δ 2.47 (3H, s), 6.92 (1H, d, J=8.7 Hz), 7.36-7.41 (1H, m), 7.44-7.50 (2H, m), 7.53 (1H, dd, d=9.0, 2.7 Hz), 7.57-7.61 (2H, m), 8.16 (1H, d, J=2.7 Hz).
    • Example 189 5-Bromo-N [4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide Compound No. 189
  • Using (4-fluorophenyl)acetone as the raw material, the same operation as the examples 184 (1)-(3) gave the title compound.
  • Yield: 28.8% (3 steps).
    • (1) α-Bromo-(4-fluorophenyl)acetone
  • 1H-NMR(CDCl3): δ 2.33 (3H, s), 5.41 (1H, s), 7.07 (2H, t, J=8.7 Hz), 7.43 (2H, dd, J=8.7, 5.1 Hz).
    • (2) 2-Amino-4-methyl-5-(4-fluorophenyl)thiazole
  • 1H-NMR (CDCl3): δ 2.27 (3H, s), 4.83 (2H, s), 7.07 (2H, t, J=8.7 Hz), 7.32 (2H, dd, J=8.7, 5.4 Hz).
    • (3) 5-Bromo-N-[4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide
  • 1H-NMR (DMSO-d6): δ 2.36 (3H, s), 6.95 (1H, d, J=8.4 Hz), 7.33 (2H, t, J=8.7 Hz), 7.52-7.59 (3H, m), 8.06 (1H, d, J=3.0 Hz), 12.01-13.65 (2H, br).
    • Example 190 5-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl}-2-hydroxybenzamide Compound No. 190
  • Using 3-(trifluoromethyl)phenylacetone as the raw material, the same operation as the examples 184 (1)-(3) gave the title compound.
  • Yield: 39.8% (3 steps).
    • (1) α-Bromo-3-(trifluoromethyl)phenylacetone
  • 1H-NMR (CDCl3): δ 2.38 (3H, s), 5.43 (1H, s), 7.52 (1H, t, J=7.8 Hz), 7.61-7.66 (2H, m), 7.69-7.70 (1H, m).
    • (2) 2-Amino-4-methyl-5-[3-(trifluoromethyl)phenyl]thiazole
  • 1H-NMR(CDCl3): δ 2.32 (3H, s), 4.95 (2H, s), 7.46-7.56 (3H, m), 7.59-7.61 (1H, m).
    • (3) α-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl}-2-hydroxybenzamide
  • 1H-NMR (DMSO-d6): δ 2.40 (3H, s), 6.97 (1H, d, J=8.7 Hz), 7.59 (1H, dd, J=8.7, 2.4 Hz), 7.71-7.84 (4H, m), (2H, m), 8.06 (1H, d, J=2.4 Hz), 12.09 (1H, br), 12.91-1:3.63 (1H, br).
    • Example 191 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-9-yl}-2-hydroxybenzamide Compound No. 191
  • Using 2,2-dimethyl-3-hexanone as the raw material, the same operation as the examples 184 (1)-(3) gave the title compound.
  • Yield: 17.0% (3 steps).
    • (2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-ethylthiazole
  • 1H-NMR(CDCl3): δ 1.32 (3H, t, J=7.5 Hz), 1.32 (9H, s), 2.79 (2H, q, J=7.5 Hz), 4.63 (2H, brs).
    • (3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl}-2-hydroxybenzamide
  • 1H-NMR (CDCl3): δ 1.32 (3H, t, J=6 Hz), 1.41 (9H, s), 2.88 (2H, q, J=7.5 Hz), 6.84 (1H, d, J=9.0 Hz), 7.44 (1H, dd, J=8.7, 2.4 Hz), 8.05 (1H, d, J=2.7 Hz), 11.46 (2H, br).
    • Example 192 5-Bromo-N-(4-ethyl-6-phenylthiazol-2-yl)-2-hydroxybenzamide Compound No. 192
  • Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
  • Yield: 17.4%.
  • mp 224-295° C.
  • 1H-NMR (DMSO-d): δ 1.24 (3H, t, J=7.6 Hz), 2.70 (2H, q, J=7.6 Hz), 6.95 (1H, brd, J=7.6 Hz), 7.39-7.42 (1H, m), 7.45-7.51 (4H, m), 7.56 (1H, brd, J=8.0 Hz), 8.06 (1H, d, J=2.8 Hz), 11.98 (1H, brs).
    • Example 193 5-Bromo-N-(4-ethyl-5-isopropylthiazol-2-yl)-2-hydroxybenzamide Compound No. 193
  • Using benzyl isopropyl ketone as the raw material, the same operation as the examples 184 (1)-(3) gave the title compound.
  • Yield: 4.4% (3 steps).
    • (2) 2-Amino-4-ethyl-5-isopropylthiazole
  • 1H-NMR (CDCl3): δ 1.23 (6H, d, J=6.6 Hz), 3.05 (1H, m), 4.94 (1H, s), 7.28-7.41 (5H, m).
    • (3) 5-Bromo-N-(4-ethyl-5-isopropylthiazol-2-yl)-2-hydroxybenzamide
  • 1H-NMR (DMSO-d6): δ 1.26 (6H, d, J=6.0 Hz), 3.15 (1H, m), 6.98 (1H, brs), 7.43-7.53 (5H, m), 7.59 (1H, brs), 8.0 (1H, d, J=2.7 Hz), 11.90 (1H, brs), 13.33 (1H, brs).
    • Example 194 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide Compound No. 194
  • Using 1-phenyl-2-hexanone as the raw material, the same operation as the examples 184 (1)-(3) gave the title compound.
  • Yield: 52.6% (3 steps).
    • (1) α-Bromo-1-phenyl-2-hexanone
  • 1H-NMR (CDCl3): δ 0.35 (3H, t, J=7.2 Hz), 1.19-1.32 (2H, m), 1.50-1.60 (2H, m), 2.59 (2H, td, J=7.5, 3.9 Hz), 5.44 (1H, s), 7.34-7.45 (5H, m).
    • (2) 2-Amino-4-butyl-5-phenylthiazole
  • 1H-NMR(CDCl3, δ): 0.89 (3H, t, J=7.5 Hz), 1.28-1.41 (2H, m), 1.61-1.71 (2H, m), 2.56-2.61 (2H, m), 4.87 (2H, s), 7.25-7.40 (5H, m).
    • (3) 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide
  • 1H-NMR (DMSO-d6): δ 0.85 (3H, t, J=7.2 Hz), 1.23-1.35 (2H, m), 1.59-1.69 (2H, m), 2.70 (211, t, J=7.2 Hz), 6.96 (1H, d, J=6.9 Hz), 7.39-7.59 (6H, m) 8.07 (1H, d, J=2.4 Hz), 11.93 (1H, br), 13.18-13.59 (1H, br).
    • Example 195 5-Chloro-N-{-4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)-propionyl]thiazol-2-yl}-2-hydroxybenzamide Compound No. 195 (1) α-Bromo-dipivaloylmethane
  • Dipivaloylmethane (1.00 g, 5.42 mmol) was dissolved in carbon tetrachloride (10 mL). N-Bromosuccinimide(965.8 mg, 5.42 mmol) was added, and the mixture was refluxed for 2 hours. After cooling, the insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound (1.42 g, quant.) as a white crystal.
  • 1H-NMR(CDCl3, δ): 1.27 (18H, s), 5.67 (1H, s).
    • (2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole
  • A mixture of α-bromo-dipivaloylmethane(1.42 g), thiourea (451.8 mg) and ethanol(15 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized(dichloromethane/hexane) to give the title compound (1.23 g, 94.5%) as a white crystal.
  • 1H-NMR (CDCl3, δ): 1.26 (9H, s), 1.29 (9H, s), 5.03 (2H, s).
  • (3) 5 Chloro-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide.
  • A mixture of 5-bromosalicylic acid (0.20 g, 0.92 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-3-[(2,9-dimethyl)propionyl]thiazole(221.5 m, 0.92 mmol), phosphorus trichloride(40 μl, 0.46 mmol) and chlorobenzene (5 mL) was refluxed for 3 hours. The residue obtained by concentration of the reaction mixture under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (96.2 mg, 23.8%) as a white powder.
  • 1H-NMR (CDCl1, δ): 1.33 (9H, s), 1.35 (9H, s), 6.94 (1H, d, J=8.7 Hz), 7.55 (1H, dd, J=8.7, 2.1 Hz), 7.85 (1H, d, J=2.1 Hz), 10.51 (2H, br).
    • Example 196 5-Bromo-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]-thiazol-2-yl}-2-hydroxybenzamide Compound No. 196
  • Using 5-bromosalicylic acid and 2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole as the raw material, the same operation as the example 19.5 (3) gave the title compound.
  • Yield: 23.8%.
  • 1H-NMR(CDCl3): δ 1.33 (9H, s), 1.35 (9H, s), 6.94 (1H, d, J=8.7 Hz), 7.55 (1H, dd, J=8.7, 2.1 Hz), 7.85 (1H, d, J=2.1 Hz), 10.51 (2H, br).
    • Example 197 2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester Compound No. 197
  • Using pivaloyl acetic acid ethyl ester as the raw material, the same operation as the examples 195 (1)-(3) gave the title compound.
  • Yield: 45.7% (3 steps).
  • (1) α-Bromo-pivaloyl acetic acid ethyl ester.
  • 1H-NMR (CDCl3): δ 1.28 (9H, s), 1.29 (3H, t, J=7.2 Hz), 4.26 (2H, q, J=7.9 Hz), 5.24 (1H, s).
    • (2) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester
  • 1H-NMR(CDCl3, δ): 1.32 (3H, t, J=7.2 Hz), 1.43 (9H, s), 4.24 (2H, q, J=7.2 Hz), 5.18 (2H, s).
    • (3) 2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl ester
  • 1H-NMR(DMSO-d6): δ 1.30 (3H, t, J=7.2 Hz), 1.44 (9H, s), 4.27 (2H, q, J=6.9 Hz), 7.00 (1H, d, J=8.7 Hz), 7.63 (1H, dd, J=8.7, 2.7 Hz), 8.02 (1H, d, J=2.4 Hz), 11.80 (1H, br), 12.12 (1H, br).
    • Example 198 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl]-2-hydroxybenzamide (Compound No. 198). (1) 2-Amino-3-bromo-4-[(1,1-dimethyl)ethyl]thiazole
  • 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9 mL). N-Bromosuccinimide(1.00 g, 5.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=2:1) to give the title compound(1.23 g, 93.7%) as a yellowish gray powder.
  • 1H-NMR (CDCl3): δ 1.39 (9H, 3), 4.81 (2H, brs).
    • (2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole
  • A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g, 0.42 mmol), piperidine(0.1 mL), potassium carbonate (0.20 g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%) as a yellow crystal.
  • 1H-NMR (CDCl3): δ 1.32 (9H, s), 1.64 (4H, t, J=5.7 Hz), 1.71-1.77 (2H, m), 2.35 (2H, brs), 2.99 (2H, brs), 4.68 (2H, s).
    • (3) 2-Acetoxy-5-bromo-N-[4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl]benzamide
  • Under argon atmosphere, phosphorus oxychloride(46 μl, 0.50 mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid(J. Med. Chem. 31, 861-874 1996)(90.3 mg, 0.35 mmol), the thiazole (80.7 mg, 0.34 mmol), pyridine(0.1 mL) and THF (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N-hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) as a crude product.
    • (4) 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl]-2-hydroxybenzamide
  • 2-Acetoxy-5-bromo-N-[4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl]benzamide(crude product, 84.3 mg) was dissolved in ethanol (3 mL). 2 N aqueous sodium hydroxide (0.1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound (54.1 mg, 36.3%; 2 steps) as a white powder.
  • 1H-NMR(CDCl3): δ 1.41 (9H, s), 1.56 (2H, brs), 1.6-1.74 (4H, m), 2.79 (4H, brs), 6.85 (1H, d, J=9.0 Hz), 7.45 (1H, dd, J=9.0, 2.4 Hz), 8.06 (1H, d, J=2.4 Hz), 11.70 (2H, br).
    • Example 199 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-morpholinothiazol-9-yl]-2-hydroxybenzamide Compound No. 199
  • Using morpholine as the raw material, the same operation as the examples 198 (2)-(4) gave the title compound.
  • Yield. 17.1%.
    • (2) 2-Amino-4-[(1,1-dimethyl)ethyl]-3-morpholinothiazole
  • 1H-NMR(CDCl3): δ 1.33 (9H, s), 2.76 (4H, brs), 3.79 (4E1, brs), 4.66 (2H, s).
    • (3) 2-Acetoxy-5-bromo-N [4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl]benzamide
  • The product was used for the next reaction as a crude product.
    • (4) 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl]-9 hydroxybenzamide
  • 1H-NMR(CDCl3): δ 1.24 (9H, s), 2.89 (4H, dd, J=4.8, 4.2 Hz), 3.83 (4H, dd, J=4.5, 4.2 Hz), 6.89 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=9.0, 2.4 Hz), 7.98 (1H, d, J=2.1 Hz), 11.20 (2H, br).
    • Example 200 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-methylpiperazin-1-yl)thiazol-2-yl]-2-hydroxybenzamide Compound No. 200
  • Using 4-methylpiperazine as the raw material, the same operation as the examples 198 (2)-(4) gave the title compound.
  • Yield: 6.9%.
    • (2) 2-Amino-4-(1,1-dimethyl)ethyl-5-(4-methylpiperazin-1-yl)thiazole. 1H-NMR(DMSO-d6): δ 1.25 (9H, s), 2.12 (2H, brs), 2.19 (3H, s), 2.57 (2H, brs), 2.72 (4H, brs), 6.51 (2H, s). (3) 2-Acetoxy-N-[4 (1,1-dimethyl)ethyl-5-(4-methylpiperazin-1-yl)thiazol-2-yl]benzamide
  • The product was used for the next reaction as a crude product.
    • (4) 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-methylpiperazin-1-yl]thiazol-2-yl-2-hydroxybenzamide
  • 1H-NMR(CD3OD): δ 1.41 (9H, s), 2.55 (3H, s), 2.87 (4H, brs), 3.03 (4H, brs), 6.88 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 8.11 (1H, d, J=2.7 Hz).
    • Example 201 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-phenylpiperazin-1-yl)thiazol-2-yl]-2-hydroxybenzamide Compound No. 201
  • Using 4-phenylpiperazine as the raw material, the same operation as the examples 198 (2)-(4) gave the title compound.
  • Yield: 6.9%.
    • (2) 2° Amino-4 (1,1-dimethyl)ethyl 5-(4-phenylpiperazin-1-yl)thiazole
  • 1H-NMR (CDCl3): δ 1.34 (9H, s), 2.80 (2H, brs), 3.03 (4H, brs), 3.55 (2H, brs), 4.69 (2H, s), 6.88 (1H, tt, J=7.2, 1.2 Hz), 6.95 (2H, dd, J=9.0, 1.2 Hz), 7.28 (2H, dd, J=8.7, 7.2 Hz).
    • (3) 2-Acetoxy-5-bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-phenylpiperazin-1-yl)thiazol-2-yl]benzamide
  • The product was used for the next reaction as a crude product.
    • (4) 5-Bromo-N-[4-(1,1-dimethyl)ethyl-5-(4-phenylpiperazin-1-yl)thiazol 2-yl]-2-hydroxybenzamide
  • 1H-NMR(DMSO-d6): δ 1.39 (9H, s), 2.97 (4H, s), 3.30 (4H, s), 6.82 (1H, t, J=7.5 Hz), 6.97 (2H, brs), 6.99 (2H, t, J=7.5 Hz), 7.58 (1H, brs), 8.05 (1H, d, J=2.4 Hz), 11.69 (1H, brs), 11.82 (1H, brs).
    • Example 202 5-Bromo-N-(4-phenylthiazol-2-yl)-2-hydroxybenzamide Compound No. 202
  • Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the raw materials, the same operation as the example 19.5 (3) gave the title compound.
  • Yield: 16.0%.
  • mp 239° C. (dec.).
  • 1H-NMR(DMSO-d6): δ 7.02 (1H, d, J=8.4 Hz), 7.34 (1H, t, J=7.6 Hz), 7.44 (2H, t, J=7.6 Hz), 7.62 (1H, dd, J=3.4, 2.3 Hz), 7.67 (1H, s), 7.92 (2H, d, J=7.2 Hz), 8.08 (1H, d, J=2.8 Hz), 11.88 (1H, brs), 12.05 (1H, brs).
    • Example 203 {2-[(5 Bromo-9-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid Compound No. 203 (1) {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester
  • Using 5-bromosalicylic acid and 2 amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 32.1%.
  • mp 283.5-229.5° C.
  • 1H-NMR(DMSO-d6): δ 3.66 (3H, s), 3.95 (2H, s), 6.99 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=6.0 Hz), 7.48 (2H, brt, J=7.6 Hz), 7.56-7.61 (3H, m), 8.07 (1H, d, J=2.4 Hz), 11.85 (1H, brs), 11.98 (1H, brs).
    • (2) {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid
  • {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5 mL). 2 N sodium hydroxide (0.5 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 2 N-hydrochloric acid and extracted wish ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound(56 mg, 77.3%) as a light yellow white crystal.
  • mp 284-286° C.
  • 1H-NMR (DMSO-d6): δ 3.84 (2H, s), 6.98 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=6.8 Hz), 7.49 (2H, t, J=7.6 Hz), 7.58-7.61 (3H, m), 8.07 (1H, d, J=2.8 Hz), 12.25 (H, brs).
    • Example 204 5-Bromo-N-(4,5-diphenylthiazol-2-yl)-O-hydroxybenzamide Compound No. 204
  • Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the raw materials, the same operation as the example 195 (3) gave the title compound. (2-Amino-4,5-diphenylthiazole: refer to Nihon Kagaku Zasshi, 1962, 83, 209.)
  • Yield: 25.9%.
  • mp 262-263° C.
  • 1H-NMR(DMSO-d6): δ 7.02 (1H, d, J=8.1 Hz), 7.34-7.47 (10H, m), 7.63 (1H, d, J=6.9 Hz), 8.08 (1H, d, J=2.4 Hz), 11.88 (1H, brs), 12.08 (1H, brs).
    • Example 205 5-Bromo-N-(4-benzyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide Compound No. 205
  • Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as the raw materials, the same operation as the example 195 (3) gave the title compound. (2-Amino-4-benzyl-5-phenylthiazole: refer to Chem. Pharm. Bull., 1962, 10, 376.)
  • Yield: 28.1%.
  • mp 198-200° C.
  • 1H-NMR (DMSO-d6): δ 4.08 (2H, s), 6.95 (1H, d, J=8.8 Hz), 7.15-7.22 (3H, m), 7.30 (2H, t, J=7.6 Hz), 7.38-7.43 (1H, m), 7.47 (4H, d, J=4.4 Hz), 7.57 (1H, brd, J=8.8 Hz), 8.05 (1H, d, J=2.4 Hz), 11.98 (1H, brs).
    • Example 206 5Bromo-N-[5-phenyl-4-(trifluoro methyl)thiazol-2-yl]-2-hydroxybenzamide Compound No. 206
  • Using 5-bromosalicylic acid and 2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 19.5 (3) gave the title compound.
  • Yield: 33.2%.
  • mp 250-C(dec.).
  • 1H-NMR (DMSO-d6): 7.02 (1H, d, J=8.8 Hz), 7.51 (5H, s), 7.63 (1H, dd, J=8.8, 2.4 Hz), 8.02 (1H, d, J=2.8 Hz), 12.38 (1H, brs).
    • Example 207 5-Bromo-N-[5-acetyl-4-phenylthiazol-2-yl]-2-hydroxybenzamide Compound No. 209
  • Using 1-phenyl-1,3-butanedione as the raw material, the same operation as the examples 195 (1)-(3) gave the title compound.
  • Yield: 8.9% (3 steps).
    • (1) α-Bromo-1-phenyl-1,3-butanedione
  • 1H-NMR (CDCl3): δ 2.46 (3H, s), 5.62 (1H, s), 7.48-7.54 (2H, m), 7.64 (1H, tt, J=7.5, 2.1 Hz), 7.97-8.01 (2H, m).
    • (2) 2-Amino-5-acetyl-4-phenylthiazole
  • 1H-NMR(DMSO-d6): δ 2.18 (3H, s), 7.50-7.5.5 (2H, m), 7.59-7.68 (3H, m), 8.69 (2H, brs).
    • (3) 5-Bromo-N-[5-acetyl-4-phenylthiazol-2-yl]-2-hydroxybenzamide
  • 1H-NMR (DMSO-d6): 2.44 (3H, s), 6.99 (1H, d, J=9.0 Hz), 7.55-7.71 (4H, m), 7.76-7.80 (2H, m), 8.01 (1H, d, J=2.4 Hz), 12.36 (2H, br).
    • Example 208 5-Bromo-N [5-benzoyl-4-phenylthiazol-2-yl]-2-hydroxybenzamide Compound No. 208
  • Using 1,3-diphenyl-1,3-propanedione as the raw material, the same operation as the examples 195 (1)-(3) gave the title compound.
  • Yield: 49.7%.
    • (1) α-Bromo-1,3-diphenyl-1,3-propanedione
  • 1H-NMR(DMSO-d6): 6.55 (1H, s), 7.45-7.50 (4H, m), 7.61 (2H, tt, J=7.2, 2.1 Hz), 7.98-8.01 (4H, m).
    • (2) 2-Amino-5-benzoyl-4-phenylthiazole,
  • 1H-NMR(DMSO-d6): δ 7.04-7.18 (5H, m), 7.22-7.32 (3H, m), 7.35-7.38 (2° H, m), 8.02 (2H, s).
    • (3) 5-Bromo-N-[5 benzoyl-4-phenylthiazol-2-yl]-2-hydroxybenzamide
  • 1H-NMR(DMSO-d6): δ 7.03 (1H, d, J=8.7 Hz), 7.17-7.30 (5H, m), 7.39-7.47 (3H, m), 7.57-7.60 (2H, m), 7 0.64 (1H, dd, J=8.7, 2.7 Hz), 8.05 (1H, d, J=2.4 Hz), 11.82 (1H, brs), 12.35 (1H, brs).
    • Example 209 2-(5-Chloro-9-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 209
  • Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 69.4%.
  • 1H-NMR (DMSO-d6): δ 1.22 (3H, t, J=71.5 Hz), 4.21 (2H, q, J=7.5 Hz), 7.07 (1H, d, J=8.7 Hz), 7.43-7.47 (3H, m), 7.53 (1H, dd, J=8.7, 2.4 Hz), 7.70-7.74 (2H, m), 7.92 (1H, d, J=3.0 Hz), 11.88 (1H, br), 12.29 (1H, brs).
    • Example 210 2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 210
  • Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 28.6%.
  • mp 197-199° C.
  • 1H-NMR (DMSO-d6): δ 1.21 (3H, t, J=6.8 Hz), 4.20 (2H, q, J=6.8 Hz), 7.01 (1H, d, J=8.8 Hz), 7.43-7.48 (3H, m), 7.63 (1H, dd, J=8.8, 2.4 Hz), 7.70-7.72 (2H, m), 8.04 (1H, d, J=2.4 Hz), 12.33 (1H, brs).
    • Example 211 2-(5-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester Compound No. 211
  • Using pentafluorobenzoylacetic acid as the raw material, the same operation as the examples 195 (1)-(3) gave the title compound.
  • Yield: 40.0% (3 steps).
    • (1) α-Bromo-pentafluorobenzoylacetic acid ethyl ester
  • It was used for the next reaction as a crude product.
    • (2) 2-Amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester
  • 1H-NMR(CDCl3): δ 1.23 (3H, t, J=7.2 Hz), 4.21 (2H, q, J=7.2 Hz), 4.21 (2H, s).
    • (3) 2-(5-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester
  • 1H-NMR(DMSO-d6): δ 1.20 (3H, t, J=7.2 Hz), 2.51 (2H, q, J=7.2 Hz), 7.02 (1H, d, J=8.7 Hz), 7.64 (1H, dd, J=8.7, 2.7 Hz), 7.90 (1H, d, J=3.0 Hz), 11.92 (1H, br), 12.58 (1H, br).
    • Example 212 [2-(5-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-yl]-N-methylcarboxamide Compound No. 212 (1) 29(o-Bromo-9-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-carboxylic acid
  • Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid ethyl ester as the raw material, the same operation as the example 82 gave the title compound.
    • (2) [9-(6-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-yl]-N-methylcarboxamide
  • A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5 carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=1:2), and crystallized(dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
  • 1H-NMR (DMSO-d6): δ 2.70 (3H, d, J=4.5 Hz), 7.02 (1H, d, J=9.0 Hz), 7.40-7.48 (3H, m), 7.63 (1H, dd, J=9.0, 2.4 Hz), 7.68-7.71 (2H, m), 8.06 (1H, d, J=2.4 Hz), 8.16 (1H, t, J=4.5 Hz), 11.88 (1H, br), 12.1.5 (1H, brs).
    • Example 213 [2-(5-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-yl]-N-ethylcarboxamide Compound No. 213
  • Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid and 70% aqueous ethylamine solution as the raw materials, the same operation as the example 212 (2) gave the title compound.
  • Yield: 62.5%.
  • 1H-NMR(DMSO-d6): δ 1.05 (3H, t, J=6.9 Hz), 3.15-3.24 (2H, m), 7.02 (1H, d, J=8.7 Hz), 7.40-7.47 (3H, m), 7.63 (1H, dd, J=3.7, 3.0 Hz), 7.69-7.72 (2H, m), 8.06 (1H, d, J=2.4 Hz), 8.20 (1H, t, J=5.4 Hz), 11.84 (1H, br), 12.14 (1H, brs).
    • Example 214 [2-(5-Bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazol-5-yl]-N-isopropylcarboxamide Compound No. 214
  • Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid and isopropylamine as the raw materials, the same operation as the example 212 (2) gave the title compound.
  • Yield: 23.9%.
  • 1H-NMR(DMSO-d6): δ 1.07 (6H, d, J=6.3 Hz), 4.02 (1H, m), 7.02 (1H, d, J=9.0 Hz), 7.40-7.52 (3H, m), 7.64 (1H, dd, J=8.7, 2.7 Hz), 7.69-7.73 (2H, m), 8.06 (1H, d, J=2.7 Hz), 11.89 (1H, br), 12.14 (1H, brs).
    • Example 215 [2-(5-Bromo-9-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazol-5-yl]-N-(2-phenethyl)carboxamide Compound No. 215
  • Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid and 2-phenethylamine as the raw materials, the same operation as the example 212 gave the title compound.
  • Yield: 62.2%.
  • 1H-NMR(DMSO-d6): δ 2.78 (2H, t, J=7.5 Hz), 3.43 (2H, q, J=7.5 Hz), 7.02 (1H, d, J=9.0 Hz), 7.19-7.24 (3H, m), 7.27-7.33 (2H, m), 7.39-7.41 (3H, m), 7.61-7.65 (3H, m), 8.06 (1H, d, J=2.4 Hz), 8.25 (1H, t, J=6.0 Hz), 11.85 (1H, brs), 12.15 (1, brs).
    • Example 216 2(5-Bromo-2 hydroxybenzoyl)amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester Compound No. 216
  • Using 5-bromosalicylic acid and 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 88.7%.
  • 1H-NMR (DMSO-d6): S1.32 (3H, t, J=−7.2 Hz), 4.33 (2H, q, J=7.2 Hz), 7.01 (1H, d, J=8.7 Hz), 7.63 (1H, dd, J=8.7, 2.7 Hz), 7.98 (1H, d, J=2.4 Hz), 12.64 (1H, br).
    • Example 217 2-Acetoxy-5-chloro-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}benzamide
  • Using 5-chloro-N-{4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
  • Yield: 65.3%.
  • 1H-NMR(CDCl3): 1.32 (9H, s), 1.33 (9H, s), 2.46 (3H, s), 7.22 (1H, d, J=8.4 Hz), 7.56 (1H, dd, J=8.7, 2.4 Hz), 8.0o(1H, d, J=2.7 Hz), 9.82 (1H, brs).
    • Example 218 2-[(4-Hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 218
  • Using 4-hydroxybiphenyl-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound. (4-Hydroxybiphenyl-3-carboxylic acid: refer to Tetrahedron, 1997, 53, 11437.)
  • Yield: 61.7%.
  • mp 207-208° C.
  • 1H-NMR (DMSO-d6): δ 1.23 (3H, t, J=7.2 Hz), 4.22 (2H, q, J=7.2 Hz), 7.16 (1H, d, J=8.7 Hz), 7.36 (1H, t, J=7.5 Hz), 7.45-7.50 (5H, m), 7.69-7.76 (4H, m), 7.85 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.4 Hz), 11.73 (1H, brs), 12.60 (1H, brs).
    • Example 219 2-[(4′-Fluoro-4-hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 219
  • Using (4′-fluoro-4-hydroxybiphenyl)-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound. ((4′-Fluoro-4-hydroxybiphenyl)-3-carboxylic acid: refer to Tetrahedron, 1997, 53, 11437.)
  • Yield: 62.7%.
  • mp 237-238° C.
  • 1H-NMR(DMSO-d6): δ 1.22 (3H, t, J=7.2 Hz), 4.21 (2H, q, J=7.2 Hz), 7.13 (1H, d, J=8.4 Hz), 7.28 (2H, t, J=8.8 Hz), 7.44-7.45 (3H, m), 7.71-7.75 (4H, m), 7.81 (1H, dd, J=8.8, 2.4 Hz), 8.27 (1H, d, J=2.4 Hz), 11.67 (1H, brs), 12.58 (1H, brs).
    • Example 220 2-[(2′,4′-Difluoro-4-hydroxybiphenyl)-3-carbonyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 220
  • Using (2′,4′-difluoro-4-hydroxybiphenyl)-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 45.6%.
  • mp 206-207° C.
  • 1H-NMR(DMSO-d6): δ 1.22 (3H, t, J=7.2 Hz), 4.22 (29E, q, J=7.2 Hz), 7.17 (1H, d, J=9.0 Hz), 7.21 (1H, td, J=8.7, 2.4 Hz), 7.38 (1H, ddd, J=11.7, 9.3, 2.4 Hz), 7.44-7.46 (3H, m), 7.60-7.75 (4H, m), 8.13-8.14 (1H, m), 11.86 (1H, brs), 12.46 (1H, brs).
    • Example 221 2-{[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 221 (1) [4′-(Trifluoromethyl)-4-hydroxybiphenyl]-3-carboxylic acid
  • A mixture of 5-bromosalicylic acid (500 mg, 2.30 mmol), dihydroxy-4-(trifluoromethyl)phenylborane (488 mg, 2.97 mmol), palladium acetate (10 mg, 0.040 mmol) and 1M sodium carbonate (7 mL) was stirred at 80° C. for 1 hour. The reaction mixture was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563 mg). This liquid was dissolved in methanol (10 mL). 2 N sodium hydroxide (3 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and saturated brine one after another, dried over MgSO4, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound (458 mg, 70.4%) as a white crystal.
  • mp 185° C. (dec).
  • 1H-NMR(DMSO-d6): δ 7.09 (1H, d, J=8.8 Hz), 7.77 (2H, d, J=8.0 Hz), 7.85 (2H, d, J=8.0Hz), 7.90 (1H, dd, J=8.8, 2.0 Hz), 8.10 (1H, d, J=2.4 Hz), 11.80 (brs).
    • (2) 2-{[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthiazole-5-carboxylic acid ethyl ester
  • Using [4′-(trifluoromethyl)-4-hydroxybiphenyl]-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 41.7%.
  • mp 236-237° C.
  • 1H-NMR (DMSO-d6): δ 1.22 (3H, t, J=7.2 Hz), 4.21 (2H, q, J=7.2 Hz), 7.18 (1H, d, J=8.8 Hz), 7.44-7.45 (3H, m), 7.72-7.74 (2H, m), 7.81 (2H, d, J=8.4 Hz), 7.91 (1H, dd, J=8.8, 2.4 Hz), 7.93 (2H, d, J=8.4 Hz), 8.36 (1H, d, J=2.4 Hz), 11.78 (1H, brs), 12.62 (1H, brs).
    • Example 222 2-[2-Hydroxy-5-(1-pyrrolyl)benzoyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 222
  • Using 2-hydroxy-5 (1-pyrrolyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 55.0%.
  • 1H-NMR(DMSO-d6): δ 1.22 (3H, t, J=7.2 Hz), 4.22 (2-H, q, J=7.2 Hz), 6.26 (2H, t. J=2.1 Hz), 7.13 (1H, d, J=8.71 Hz), 7.32 (2H, t, J=2.1 Hz), 7.43-7.47 (3H, m), 7.70-7.75 (3H, m), 8.09 (1H, d, J=2.7 Hz), 11.58 (1H, brs), 12.55 (1H, brs).
    • Example 223 2-[2-Hydroxy-3 (2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester Compound No. 223 (1) 2-Hydroxy-5-(2-thienyl)benzoic acid
  • 5-Bromosaticylic acid (500 mg, 2.30 mmol) was dissolved in 1,2-dimethoxyethane (5 mL). Tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then dihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1M sodium carbonate (7 mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a yellow liquid (277 mg). This was dissolved in methanol(5 mL). 2 N sodium hydroxide (1.5 ml) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2 N-hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was crystallized from n-hexane-dichloromethane to give the title compound (58 mg, 11.5%) as a white crystal.
  • 1H-NMR(DMSO-d6): δ 6.95 (1H, d, J=8.8 Hz), 7.09 (1H, dd, J=4.8, 3.6 Hz), 7.37 (1H, dd, J=4.0, 1.2 Hz), 7.45 (1H, dd, J=5.2, 1.2 Hz), 7.74 (1H, dd, J=8.8, 2.8 Hz), 7.96 (1H, d, J=2.8 Hz).
    • (2) [2-Hydroxy-5 (2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester
  • Using 2-hydroxy-5-(2-thienyl)benzoic acid and 2-amino-4-phenylthiazole-1-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195 (3) gave the title compound.
  • Yield: 58.2%.
  • mp 213-2149° C.
  • 1H-NMR (DMSO-d6): δ 1.22 (3H, t, J=7.2 Hz), 4.21 (2H, q, J=7.2 Hz), 7.10 (1H, d, J=9.2 Hz), 7.12 (1H, dd, J=4.8, 3.6 Hz), 7.44-7.46 (4H, m), 7.50 (1H, dd, J=4.8, 1.2 Hz), 7.71-7.74 (2H, m), 7.79 (1H, dd, J=8.8, 2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 11.78 (1H, brs), 12.44 (1H, brs).
    • Test Example Measurement of Inhibitory Activity of NF-κ B Activation
  • Inhibitory activity of NF-κ B activation was measured referring to the method of Hill et al. (Hill C. S., et al., Cell, 73, 395-406 (1993).). Using a transfection reagent(Effectene; QIAGEN), the human hepatoma cell strain HepG2 or the human hysterocarcinoma cell strain HeLa was transfected with the firefly luciferase gene(Luc) contained plasmid(pNF κ B-Luc Reporter Plasmid; STRATAGENE) which contained oligonucleotide having five tandem copies of NF-κ B binding sequences(TGGGGACTTTCCGC) on a upstream region of Luc, according to the QUAGEN's protocol and it was incuvated for 6-24 hours. After addition of TNF-α (40 ng/ml) with or without the test compound, the cells were incuvated for 4 hours, and intracellular luciferase activity was measured with PicaGene LT (TOYO INK MFG Co., Ltd.) and chemical luminescence measurement device (SPECTRAFluor Plus; TECAN). The inhibition ratio was measured as a ratio to the value of the luciferase activity without the test compound. The inhibition ratio of NF-κ B activity with the test compound 10 μg/ml or 1 μg/ml were shown in the following table.
    The rate of inhibitory activity
    against NF-κ B activation (%)
    Concentration of the Concentration of the
    agent: agent:
    Compound Number 10 μg/mL 1 μg/mL
    1 54.4 −33.6
    2 83.2 18.6
    3 68.4 54.2
    4 94.1 42.9
    5 98.0 33.3
    6 61.9 27.8
    7 68.7 30.4
    8 59.9 35.3
    9 99.2 21.9
    10 78.6 7.1
    11 44.1 28.4
    12 87.3 68.6
    13 63.8 −7.1
    14 98.9 21.7
    15 70.4 15.2
    16 91.6 36.4
    17 96.5 19.9
    18 90.2 85.3
    19 95.1 −55.4
    20 86.8 −12.1
    21 95.0 89.6
    22 92.9 37.0
    23 96.6 75.7
    24 82.2 58.1
    25 86.9 85.4
    27 47.3 68.5
    28 41.7 16.3
    29 73.0 46.3
    30 98.1 76.5
    31 93.2 13.3
    32 96.3 89.3
    33 99.5 95.1
    34 98.5 90.5
    35 85.4 88.2
    36 84.7 26.6
    37 63.1 29.1
    38 81.8 −10.1
    39 56.0 21.4
    40 81.9 3.9
    41 90.3 26.1
    42 92.3 14.3
    43 78.9 25.5
    44 65.8 36.7
    45 91.3 61.7
    46 85.7 −43.7
    47 99.4 91.3
    48 95.6 93.3
    49 94.3 81.5
    50 99.5 96.3
    51 98.6 94.9
    52 85.4 86.6
    53 99.2 92.0
    54 99.6 92.2
    55 99.4 95.8
    56 98.3 92.9
    57 96.0 76.8
    58 98.3 94.7
    59 99.2 94.5
    60 99.4 42.7
    61 98.5 59.7
    62 99.1 74.9
    63 96.9 95.5
    64 90.1 53.3
    65 97.1 83.9
    66 94.9 91.1
    67 96.8 91.8
    68 98.3 92.3
    69 99.6 96.4
    70 95.4 93.3
    71 97.9 93.8
    72 97.8 79.5
    73 92.9 81.7
    74 95.3 82.1
    76 99.0 90.4
    77 97.0 30.7
    78 99.2 86.3
    79 98.7 90.7
    81 96.4 88.2
    82 94.5 −8.7
    83 87.1 16.0
    84 82.2 23.7
    85 96.0 44.9
    86 95.9 42.2
    87 98.1 84.4
    89 67.5 −21.6
    90 63.4 1.0
    91 88.4 20.5
    92 97.2 51.8
    93 98.7 96.2
    94 89.1 19.4
    95 97.1 90.9
    96 99.2 96.5
    97 96.0 69.9
    98 98.2 90.5
    101 98.3 95.7
    104 96.9 76.2
    105 93.9 89.6
    106 93.3 80.7
    107 95.0 92.3
    108 97.6 94.7
    109 88.8 83.0
    110 98.9 94.7
    111 98.7 96.7
    112 95.9 93.1
    113 97.1 94.8
    114 94.1 88.9
    115 94.3 89.0
    116 96.7 86.3
    117 93.0 89.2
    118 96.3 94.1
    119 91.7 88.1
    120 97.9 93.8
    121 96.5 85.5
    122 97.2 84.5
    123 93.4 76.6
    125 99.1 94.6
    126 97.8 95.8
    127 86.4 81.8
    128 95.0 87.2
    129 85.8 75.4
    139 60.2 −48.2
    140 96.7 94.2
    141 96.4 83.3
    142 96.9 95.1
    143 93.8 91.6
    144 96.8 91.8
    145 95.5 92.9
    146 97.0 94.2
    147 96.8 84.5
    148 92.8 77.1
    149 97.1 85.4
    150 95.1 91.4
    151 71.8 −42.8
    152 70.6 −56.8
    153 88.7 49.1
    154 48.2 −31.0
    155 94.1 85.6
    156 74.9 7.3
    157 98.1 86.2
    158 95.6 91.0
    159 96.3 89.1
    160 99.2 86.2
    161 92.6 86.3
    163 82.0 70.9
    164 98.6 94.9
    165 95.1 88.2
    166 97.9 82.4
    167 95.7 32.4
    168 96.8 38.3
    169 88.1 14.5
    170 56.4 −40.0
    171 95.8 33.7
    172 97.5 88.6
    180 42.8 −23.1
    181 98.7 96.5
    182 94.4 85.3
    183 92.4 92.6
    184 93.8 20.0
    185 69.7 −1.5
    186 95.2 88.4
    187 67.2 4.6
    188 94.4 83.6
    189 82.0 −8.4
    190 71.7 −32.4
    191 98.1 90.5
    192 87.6 28.8
    193 96.1 70.1
    194 88.7 46.1
    195 98.3 95.7
    196 97.5 86.8
    197 92.4 84.5
    198 97.8 93.6
    199 96.8 87.8
    200 89.6 36.3
    201 95.9 92.5
    202 78.8 −41.8
    203 72.1 2.4
    204 67.0 −5.8
    205 95.0 79.7
    206 89.4 85.1
    207 95.9 70.2
    208 97.3 90.7
    209 82.8 55.8
    210 94.2 80.7
    211 96.0 82.2
    212 58.6 50.8
    213 84.0 51.9
    214 91.3 49.6
    215 60.4 33.3
    216 96.5 87.6
    217 97.7 95.0
    218 78.6 34.6
    219 85.8 45.0
    220 90.3 31.8
    221 90.0 66.9
    222 90.1 74.0
    223 84.8 40.8
    • INDUSTRIAL APPLICABILITY
  • The medicaments of the present invention have inhibitory activity against the activation of transcription factor NF-κ B, furthermore they have suppressing activity against the production and release of inflammatory cytokines. Therefore, the medicaments of the present invention are useful as preventive and/or therapeutic agent for treatment of diseases caused by activation of NF-κ B and for diseases caused by overproduction of inflammatory cytokines.

Claims (37)

What is claimed is:
1. A method for inhibiting activation of NF-κB, for inhibiting production and release of an inflammatory cytokine or of immune inhibition which comprises administering to a mammal an effective amount for inhibiting activation of NF-κB, for inhibiting production and release of an inflammatory cytokine or for immuno suppression of at least one compound represented by the following formula (I), a pharmacologically acceptable salt, a hydrate, and a solvate thereof:
Figure US20090192122A2-20090730-C00517
wherein X represents a group represented by the following formula:
Figure US20090192122A2-20090730-C00518
wherein a bond at the left end binds to ring Z and a bond at the right end binds to E,
A represents a hydrogen atom or an acetyl group,
E represents an aryl group which may be substituted or a heteroaryl group which may be substituted, ring Z represents an arene which may be substituted in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above, or ring Z represents a heteroarene which may be substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above, provided that the compounds represented by the following (1) and (2) are excluded:
(1) the compounds represented by the aforementioned formula (I) wherein
X is a group represented by the following formula:
Figure US20090192122A2-20090730-C00519
wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,
A is a hydrogen atom,
E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group, ring Z represents a benzene ring which may further have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above; and
(2) the compounds represented by the aforementioned formula (I), wherein
X is a group represented by the following formula:
Figure US20090192122A2-20090730-C00520
wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,
A is a hydrogen atom or an acetyl group,
E is a 2,5-bis(trifluoromethyl)phenyl group, a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group, ring Z represents a benzene ring which may further have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above.
2. The method according to claim 1, wherein
A is a hydrogen atom or an acetyl group, ring Z is a C6 to C10 arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a phenyl group substituted with two C1 to C6 halogenated alkyl groups, wherein said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups or a phenyl group substituted with one C1 to C6 halogenated alkyl group wherein said phenyl group may be substituted except with a C1 to C6 halogenated alkyl group in addition to the C1 to C6 halogenated alkyl group.
3. The method according to claim 2, wherein
A is a hydrogen atom or an acetyl group, ring Z is a C6 to C10 arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a 3,5-bis(trifluoromethyl)phenyl group, a 2,5-bis(trifluoromethyl)phenyl group, a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 3-methoxy-5-(trifluoromethyl)phenyl group, a 4-methoxy-3-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group, or a 2-morpholino-5-(trifluoromethyl)phenyl group.
4. The method according to claim 3, wherein A is a hydrogen atom or an acetyl group, ring Z is a C6 to C10 arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as defined in the general formula (I), E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.
5. The method according to claim 4, wherein A is an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):
Figure US20090192122A2-20090730-C00521
represents a group represented by the following formula (Iz-2):
Figure US20090192122A2-20090730-C00522
wherein
Rz represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C6 to C10 aryl-carbonyl-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted,
E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.
6. The method according to claim 5, wherein A is an acetyl group, Rz is a halogen atom,
E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.
7. The method according to claim 6, wherein A is an acetyl group, Rz is a halogen atom,
E is a 3,5-bis(trifluoromethyl)phenyl group.
8. The method according to claim 3, wherein A is a hydrogen atom or an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):
Figure US20090192122A2-20090730-C00523
represents a group represented by the following formula (Iz-2):
Figure US20090192122A2-20090730-C00524
wherein
Rz represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C6 to C10 aryl-carbonyl-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted,
E is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.
9. The method according to claim 8, wherein A is a hydrogen atom, Rz is a halogen atom,
E is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.
10. The method according to claim 2, wherein A is a hydrogen atom or an acetyl group, ring Z is a C6 to C10 arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a heteroaryl group which may be substituted.
11. The method according to claim 10, wherein A is a hydrogen atom or an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):
Figure US20090192122A2-20090730-C00525
represents a group represented by the following formula (Iz-2):
Figure US20090192122A2-20090730-C00526
wherein
Rz represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C6 to C10 aryl-carbonyl-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 l to C 6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted, E is a thiazolyl group which may be substituted.
12. The method according to claim 11, wherein A is a hydrogen atom, Rz is a halogen atom, E is a 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-ethylthiazol-2-yl group, a 5-methyl-4-phenylthiazol-2-yl group, a 4-isopropyl-5-phenylthiazol-2-yl group, a 4-benzyl-5-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, a 5-acetyl-4-phenylthiazol-2-yl group, a 5-benzoyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, a 4,5-diphenylthiazol-2-yl group, a 4-phenylthiazol-2-yl group, a 4,5-dimethyl thiazol-2-yl group, a 2-thiazolyl group, a 5-methylthiazol-2-yl group, a 4-ethyl-5-phenylthiazol-2-yl group, a 5-carboxymethyl-4-phenylthiazol-2-yl group, a 5-methylcarbamoyl-4-phenylthiazol-2-yl group, a 5-ethyl carbamoyl-4-phenylthiazol-2-yl group, a 5-isopropylcarbamoyl-4-phenyl thiazol-2-yl group, a 5-(2-phenethyl)carbamoyl-4-phenylthiazol-2-yl group, a 4-(n-butyl)-5-phenylthiazol-2-yl group, a 4-methyl-5-[(3-trifluoromethyl)phenyl]thiazol-2-yl group, or a 5-(4-fluorophenyl)-4-methylthiazol-2-yl group.
13. The method according to claim 12, wherein A is a hydrogen atom, Rz is a halogen atom, E is a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group.
14. The method according to claim 1, which is an inhibitor against expression of a gene for one or more substances selected from the following substance group 6 comprising a tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, a granulocyte colony-stimulating factor, interferon β, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, a nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class II, P2-microglobulin, a immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, a transcript derived from a HIV gene, a transcript derived from a HTLV gene, a transcript derived from a simian virus 40 gene, a transcript derived from a cytomegalovirus gene, and a transcript derived from a adenovirus gene.
15. The method according to claim 1, wherein the inhibiting activation of NF-κB, inhibiting production and release of an inflammatory cytokine or of immune inhibition comprises inhibiting activation of NF-κB and administering to the mammal an effective amount of the at least one compound for inhibiting activation of NF-κB.
16. The method according to claim 15, wherein the mammal is a human.
17. The method according to claim 1, wherein the inhibiting activation of NF-κB or inhibiting production and release of an inflammatory cytokine comprises inhibiting production and release of an inflammatory cytokine and administering to the mammal an effective amount of the at least one compound for inhibiting production and release of an inflammatory cytokine.
18. The method according to claim 17, wherein the mammal is a human.
19. The method according to claim 1, wherein the inhibiting activation of NF-κB, inhibiting production and release of an inflammatory cytokine or of immune inhibition comprises immune inhibition and administering to the mammal an effective amount of the at least one compound for immuno suppression.
20. The method according to claim 19, wherein the mammal is a human.
21. A compound represented by the following general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof:
Figure US20090192122A2-20090730-C00527
wherein
Z1 represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E1 represents a phenyl group substituted with two C1 to C6 halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C1 to C6 halogenated alkyl groups,
provided that the compounds represented by the following (1) and (2) are excluded:
(1) the compounds represented by the aforementioned formula (I-1), wherein E1 is a 2,5-bis(trifluoromethyl)phenyl group; and
(2) the following compounds:
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide, and
2-hydroxy-N-[2,3,5-tris(trifluoromethyl)phenyl]benzamide.
22. The compound according to claim 21 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z1 represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E1 is a 3,5-bis(trifluoromethyl)phenyl group.
23. The compound according to claim 22 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z1 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00528
wherein A1 represents a hydrogen atom or an acetyl group, R1z represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group which may be substituted, an amino group which may be substituted, a hydrocarbon group which may be substituted, a heteroring group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, a diazenyl group which may be substituted, E1 is a 3,5-bis(trifluoromethyl)phenyl group.
24. The compound according to claim 23 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A1 is a hydrogen atom or an acetyl group, R1z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1 to C6 alkoxy group which may be substituted, a di(C1 to C6 alkyl)-amino group, a C6 to C10 aryl-carbonyl-amino group, a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, a C2 to C6 alkenyl group which may be substituted, a C2 to C6 alkynyl group which may be substituted, a C6 to C10 aryl group which may be substituted, a C7 to C16 aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C1 to C6 alkyl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted, E1 is a 3,5-bis(trifluoromethyl)phenyl group.
25. The compound according to claim 24 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A1 is a hydrogen atom or an acetyl group, R1z is a halogen atom, E1 is a 3,5-bis(trifluoromethyl)phenyl group.
26. A compound represented by the following general formula (I-2) or a salt thereof, or a hydrate thereof or a solvate thereof:
Figure US20090192122A2-20090730-C00529
wherein
Z2 represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position,
E2 represents a phenyl group whose 3-position or 5-position is substituted with a C1 to C6 halogenated alkyl group wherein said phenyl group may be substituted except when a substituent is a C1 to C6 halogenated alkyl group in addition to the C1 to C6 halogenated alkyl group in the 3-position or 5-position,
provided that the compounds represented by the following (1) and (2) are excluded:
(1) the compounds represented by the aforementioned formula (I-2), wherein E2 is a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group; and
(2) the following compounds:
5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,
5-bromo-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,
5-hydroxy-5-iodo-N-[3-(trifluoromethyl)phenyl]benzamide,
5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
5-chloro-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide,
5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,
5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]benzamide,
5-chloro-2-hydroxy-N-(3-trifluoromethyl-4-{[4-(trifluoromethyl)sulfanyl]phenoxy}phenyl)-benzamide,
N-[4-(benzothiazole-2-yl)sulfanyl-3-(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide,
5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
5-chloro-2-hydroxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide, and
5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.
27. The compound according to claim 26 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z2 is a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E2 is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.
28. The compound according to claim 27 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z2 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00530
wherein A2 represents a hydrogen atom or an acetyl group, R2z represents a halogen atom, a C1 to C6 alkyl group or a C1 to C6 halogenated alkyl group, E2 is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.
29. The compound according to claim 28 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A2 is a hydrogen atom, R2z is a halogen atom, E2 is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.
30. The compound according to claim 26 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z2 is a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E2 is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.
31. The compound according to claim 30 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z2 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00531
wherein A2 represents a hydrogen atom or an acetyl group, R2z represents a halogen atom, a C1 to C6 alkyl group or a C1 to C6 halogenated alkyl group, E2 is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.
32. The compound according to claim 31 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A2 is a hydrogen atom, R2z is a halogen atom, E2 is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.
33. A compound represented by the following general formula (I-3) or a salt thereof, or a hydrate thereof or a solvate thereof:
Figure US20090192122A2-20090730-C00532
wherein
Z3 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E3 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00533
wherein
R3e2 and R3e3 may be the same or different and each represents a hydrogen atom, a hydrocarbon group which may be substituted, or a hydroxyl group which may be substituted, provided that both of R3e2 and R3e3 are not simultaneously hydrogen atoms, R3e5 represents a C2 to C6 hydrocarbon group which may be substituted.
34. A compound represented by the following general formula (I-4) or a salt thereof, or a hydrate thereof or a solvate thereof:
Figure US20090192122A2-20090730-C00534
wherein
Z4 represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E4 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00535
wherein
R4e4 represents a hydrocarbon group which may be substituted, R4e5 represents a halogen atom, cyano group, an acyl group which may be substituted, or a heterocyclic group which may be substituted.
35. The compound according to claim 34 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein
Z4 is a group represented by the following formula:
Figure US20090192122A2-20090730-C00536
wherein A4 represents hydrogen atom or acetyl group,
R4z represents a halogen atom, a C6 to C10C aryl group which may be substituted, or a 5-membered heteroaryl group, R4e4 is a C1 to C6 alkyl group which may be substituted, a C1 to C6 halogenated alkyl group which may be substituted, or a C6 to C10 aryl group which may be substituted, R4e5 is a halogen atom, a cyano group, a C1 to C6 alkyl-carbonyl group which may be substituted, a C6 to C10 aryl-carbonyl group which may be substituted, a C1 to C6 alkoxy-carbonyl group which may be substituted, or a 6-membered nonaromatic heteroring group which may be substituted.
36. The compound according to claim 35 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A4 is a hydrogen atom, R4z is a halogen atom, E is a 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, a 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, a 5-acetyl-4-phenylthiazol-2-yl group, a 5-benzoyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, a 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, or a 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group.
37. The compound according to claim 36 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A4 is a hydrogen atom, R4z is a halogen atom, E4 is a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group.
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