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WO1997024325A1 - DERIVES DE DIPHENYLMETHANE UTILISES COMME ANTAGONISTES DU RECEPTEUR MIP-1α/RANTES - Google Patents

DERIVES DE DIPHENYLMETHANE UTILISES COMME ANTAGONISTES DU RECEPTEUR MIP-1α/RANTES Download PDF

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WO1997024325A1
WO1997024325A1 PCT/JP1996/003820 JP9603820W WO9724325A1 WO 1997024325 A1 WO1997024325 A1 WO 1997024325A1 JP 9603820 W JP9603820 W JP 9603820W WO 9724325 A1 WO9724325 A1 WO 9724325A1
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group
alkyl
optionally
carbamoyl
carbonyl
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PCT/JP1996/003820
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English (en)
Inventor
Kaneyoshi Kato
Mitsuo Yamamoto
Susumu Honda
Tomoyuki Fujisawa
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Takeda Chemical Industries, Ltd.
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Priority to AU12083/97A priority Critical patent/AU1208397A/en
Publication of WO1997024325A1 publication Critical patent/WO1997024325A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • TECHNICAL FIELD This invention relates to a compound which has a MIP-l ⁇ /RANTES receptor antagonism and is useful for preventing or treating allergic diseases (e.g. bronchial asthma, atopic dermaritis, etc.), inflammatory diseases (e.g. arteriosclerosis, rheumatoid arthritis, etc.) and multiple sclerosis.
  • allergic diseases e.g. bronchial asthma, atopic dermaritis, etc.
  • inflammatory diseases e.g. arteriosclerosis, rheumatoid arthritis, etc.
  • multiple sclerosis e.g. arteriosclerosis, rheumatoid arthritis, etc.
  • Chemokines are a group of cytokines regulating cheinotaxis of leukocytes and it has recently been becoming clear that chemokines and other cytokines have relevance to the progression and exacerbation of conditions of diseases in the acute and chronic periods of inflam atories .
  • RANTES regulated on activation, normal T expressed and secreted
  • MlP-l ⁇ macrophage inflammatory protein-lo.
  • MIP-l ⁇ /RANTES receptor described in this specification means a mutual receptor among chemokines, for example, MlP-l ⁇ , RANTES or MCP-3 (monocyte chemoattractant protein-3), etc., which is called CCR1 (Nature Medicine, page 1174, 1996).
  • bronchial asthma, atopic dermatis, arteriosclerosis, articular rheumatism, etc. may be prevented or treated by inhibiting the action of the above chemokines (Clinical Immunotherapy Vol. 4, pages 1-8, 1995).
  • chemokines Clinical Immunotherapy Vol. 4, pages 1-8, 1995.
  • Ar and Ar independently represent an optionally substituted aromatic group
  • Q and Q independently represent an optionally substituted divalent C__ 6 aliphatic hydrocarbon group which may have oxygen or sulfur within the carbon chain
  • R is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkyl-carbonyl group;
  • R is an optionally substituted hydrocarbon group or an acyl group, or R and R , taken together with the adjacent nitrogen atom, may form an optionally substituted nitrogen-containing heterocyclic ring; and a group of the formula: ⁇
  • This invention is, therefore, directed to: (1) A MIP-l ⁇ /RANTES receptor antagonist comprising a compound [I] or a salt thereof, (2) A composition as described in the above item (1), wherein
  • Ar 1 and Ar2 independently represent (A) a monocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, or (B) a 5- to 11- membered monocyclic or fused heteroaromatic group having at least one of 1 or 2 kinds of hetero atoms selected from nitrogen, sulfur and oxygen in addition to carbon atoms, said heterocyclic group being optionally fused with the monocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, each of which may have a substituent selected from the group consisting of
  • aralkyl group each of a group shown by above items (1) to (6) optionally having 1 to 5 substituents selected from the group consisting of (a) a halogen atom, (b) a C__ 3 alkylenedioxy group, (c) a nitro group, (d) a cyano group, (e) a C,_ 6 alkyl group optionally having 1 to 3 halogen atoms, (f) a C 3 _ 6 cycloalkyl group, (g) a C ⁇ alkoxy group optionally having 1 to 3 halogen atoms, (h) a C ⁇ g alkylthio group optionally having 1 to 3 halogen atoms, (i) a hydroxyl group, (j) an amino group, (k) a mono-C__ 6 alkylamino group, (1) a di-C ⁇ _ 6 alkylamino group, (m) a C,_ 6 alkyl- carbonyl group, (n) a carboxy
  • aryl-carbamoyl group (t) a sulfo group, (u) a C ⁇ alkylsulfonyl group, (v) a C 6 _ 10 aryl group, (w) a C 6 . 10 aryloxy group and (x) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (XVII) a C__ 6 alkyl-carbonyl group,
  • each of a group shown by the above items (I) to (III) may have oxygen or optionally oxydized sulfur within the carbon chain;
  • R 1 is (I) a hydrogen atom, (II) a C__ 6 alkyl group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen atom, (b) a C j _ 3 alkylenedioxy group, (c) a nitro group, (d) a cyano group, (e) a C__ 6 alkyl group optionally having 1 to 3 halogen atoms, (f) a C 3 _ 6 cycloalkyl group, (g) a C x .
  • a 5- to 11-membered heterocyclic group having at least one hetero atom selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring,
  • aryl-carbamoyl group (e-19) a sulfo group, (e-20) a C__ 6 alkylsulfonyl group, (e-21) a C 6 _ ln aryl group, (e-22) a C 6 _ 10 aryloxy group or (e-23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (f) a C 3 .
  • n-16 a mono-C j _ 6 alkyl-carbamoyl group, (n-17) a di-C,. 6 alkyl-carbamoyl group, (n-18) a C 6 . 10 aryl-carbamoyl group, (n-19) a sulfo group, (n-20) a Cj.
  • aryl-carbamoyl group (s-19) a sulfo group, (s-20) a C j .g alkylsulfonyl group, (s-21) a C 6 _ 10 aryl group, (s-22) a C 6 _ 10 aryloxy group or (s-23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (t) a di- Ci.
  • aryl-carbamoyl group (t-19) a sulfo group, (t-20) a C ⁇ alkylsulfonyl group, (t-21) a C 6 - ⁇ o aryl group, (t-22) a C 6 _ ⁇ 0 aryloxy group or (t-23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (u) an optionally halogenated C 6 .
  • aryloxy group (aa) a C 2 - 6 alkenylamino group, (bb) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (cc) a 5- to 7-membered cyclic amino group which may have an oxo group or which may be substituted with a hydroxyl group, (dd) a C ⁇ .
  • aryl- carbamoyl group (t) a sulfo group, (u) a C ⁇ _ 6 alkylsulfonyl group, (v) a C 6 _ 10 aryl group, (w) a C 6 _ 10 aryloxy group and (x) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (iv) a hydroxyl group,
  • R is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl-carbonyl group, a carboxyl group, an optionally substituted lower alkoxy-carbonyl group, an optionally substituted mono-lower alkylaminocarbonyl group, an optionally substituted di- lower alkylaminocarbonyl group, an optionally substituted 5- or 7-membered cyclic amino group or an optionally substituted aryloxy group; and R is a hydrogen atom or a lower alkyl group,
  • R 4 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl-carbonyl group, a carboxyl group, an optionally substituted lower alkoxy-carbonyl group, an optionally substituted mono-lower alkylaminocarbonyl group, an optionally substituted di- lower alkylaminocarbonyl group, an optionally substituted 5- or 7-membered cyclic amino group or an optionally substituted aryloxy group; and R is a hydrogen atom or a lower alkyl group,
  • R and R independently represent (a) a hydrogen atom, (b) a Ci_ 6 alkyl group optionally substituted with (b-1) a halogen atom, (b-2) a Cj_ 3 alkylenedioxy group, (b-3) a nitro group, (b-4) a cyano group, (b-5) a C 3 _ 6 cycloalkyl group, (b-6) a Cj_ 6 alkoxy group optionally having 1 to 3 halogen atoms, (b-7) a C__ 6 alkylthio group optionally having 1 to 3 halogen atoms, (b-8) a hydroxyl group, (b-9) an amino group, (b-10) a mono-C,_ ⁇ alkylamino group, (b-11) a di-C 6 alkylamino group, (b- 12) a Ci.s alkyl-carbonyl group, (b-13) a carboxyl group, (b-14) a C ⁇ _ 6
  • alkylenedioxy group (q-3) a nitro group, (q-4) a cyano group, (q-5) a C 3 . 6 cycloalkyl group, (q-6) a C ⁇ alkoxy group optionally having 1 to 3 halogen atoms, (q-7) a Cj.e alkylthio group optionally having 1 to 3 halogen atoms, (q-8) a hydroxyl group, (q-9) an amino group, (q-10) a ono-C j .g alkylamino group, (q-11) a di-C]_ 6 alkylamino group, (q-12) a C ⁇ alkyl-carbonyl group, (q-13) a carboxyl group, (q-14) a alkoxy-carbonyl group, (q-15) a carbamoyl group, (q-16) a mono-C ⁇ alkyl-carbamoyl group, (q-17) a di-Cj_
  • R 6 and R independently represent (a) a hydrogen atom, (b) a Ci_ 6 alkyl group optionally substituted with
  • (b-1) a hydroxyl group, (b-2) a di-Cj_ 6 alkylamino group, (b-3) a C j _ 6 alkoxy-carbonyl group, or (b-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (c) a C 7 .
  • aralkyl group (d) a C ⁇ alkyl-carbonyl group whose alkyl portion may be substituted with (d-1) a halogen atom, (d-2) a mono-C j .g alkylamino group, (d-3) a Cj_ 6 alkoxy-carbonyl group, or (d-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (e) a C__ 6 alkoxy-carbonyl group, (f) a formyl group which may be substituted with a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (g) a mono-Cj_ 6 alkyl-carbamo
  • Y is (i) a hydrogen atom, (ii) an optionally halogenated lower alkyl group, (iii) an optionally halogenated lower alkoxy group, (iv) an optionally halogenated lower alkylthio group, (v) a hydroxyl group, (vi) a cyano group, (vii) an alkyl- carbonyl group, (viii) a lower alkyl-carbonyloxy group, (ix) a formylamino group, (x) an amino group, (xi) a mono-lower alklylamino group, (xii) a di-lower alkylamino group, (xiii) a carboxyl group, (xiv) a lower alkoxy-carbonyl group or (xv) a lower alkyl- carbonylamino group, or (D) a group of the formula:
  • Ar is an optionally substituted aromatic group
  • n is an integer of 0 to 3
  • Y is a hydrogen atom or a hydroxyl group
  • Ar 1 and Ar 2 independently represent a 6 . aryl group or a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms of 1 or 2 kinds selected from nitrogen, oxygen and sulfur in addition to a carbon atom, each of which may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1-6 alkyl group, and an optionally halogenated Cj_ 6 alkoxy group,
  • Ar is a phenyl group optionally substituted with a halogen atom, n is an integer of 0 to 3, and Y is a hydrogen atom or a hydroxyl group;
  • R is a hydrogen atom or methyl;
  • R is (I) an C ⁇ alkyl group which may be substituted with a C__ 6 alkoxy-carbonyl group, a carboxyl group, a Cj_ 6 alkyl-carbonyl group or a formyl group or (II) an acyl group represented by the formula: wherein R is (i) a hydrogen atom,
  • a C 6 alkyl group which may have 1 to 5 substituents selected from (a) a hydroxyl group, (b) an amino group which may be substituted with a C__ 6 alkyl- carbonyl group, (c) a mono-C_.
  • a C j _ 6 alkyl group optionally substituted with (a-l) a hydroxyl group, (a-2) a di-C,_ 6 alkylamino group, (a- 3) a Ci . g alkoxy-carbonyl group or (a-4) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon or fused with benzene ring, (b) a C 7 . 16 aralkyl group, (c) a Ci_ 6 alkyl-carbonyl group whose alkyl portion may be substituted with (c-1) a halogen atom, (c-2) a mono-Ci.
  • a C__ 6 alkoxy-carbonyl group (d) a C__ 6 alkoxy-carbonyl group, (e) a formyl group which may be substituted with a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to a carbon atoms, said heterocyclic group being optionally fused with a benzene ring,
  • Ar , Ar 2 and Ar independently represent an optionally substituted aromatic group
  • Q and Q independently represent a divalent C ⁇ _ 6 aliphatic hydrocarbon group, which may have oxygen or sulfur within the carbon chain;
  • R is an optionally substituted hydrocarbon group or an acyl group or a salt thereof (except N-[5-[4-(4- chlorophenyl-4-hydroxypiperidino-2,2-diphenyIpentyl]-1- methanesulfonamide hydrochloride, N-[5-[4- chlorophenyl)-4-hydroxypiperidino-2,2-diphenyIpentyl]- l-(p-toluene)sulfonamide hydrochloride and N-[5-(4-(4- chlorophenyl)-4-hydroxypiperidino-2,2-diphenylpentyl]- l-(2-thiophene)sulfonamide hydrochloride) , (28) The compound as described in the above item (27)
  • R 2 is the formula wherein R A is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl-carbonyl group, a carboxyl group, an optionally substituted lower alkoxylcarbonyl group, an optionally substituted mono-lower alkylaminocarbonyl group, an optionally substituted di-lower alkylaminocarbonyl group or an optionally substituted 5- or 7-membered cyclic amino group,
  • R and R independently represent (a) a hydrogen atom, (b) a C 6 alkyl group optionally substituted with
  • _ 6 alkylthio group optionally having 1 to 3 halogen atoms, (p-8) a hydroxyl group, (p-9) an amino group, (p-10) a mono-C a . 6 alkylamino group, (p-11) a di-C__ 6 alkylamino group, (p-12) a C ⁇ g alkyl-carbonyl group, (p-13) a carboxyl group, (p-14) a C ⁇ alkoxy-carbonyl group, (p-15) a carbamoyl group, (p-16) a mono-C ⁇ alkyl-carbamoyl group, (p-17) a di-C__ 6 alkyl-carbamoyl group, (p-18) a C 6 _ 10 aryl-carbamoyl group, (p-19) a sulfo group, (p-20) a C ⁇ _ 6 alkylsulfonyl group, (p-21) a C ⁇ -io
  • aryloxy group or (p-23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (q) a di- Cj.e alkyl-carbamoyl group whose alkyl portion may be substituted with (q-1) a halogen atom, (q-2) a Cj_ 3 alkylenedioxy group, (q-3) a nitro group, (q-4) a cyano group, (q-5) a C 3 .
  • Ar and Ar independently represent a C 6 . lt , aryl group or a 5- to 7-membered heterocyclic groups having 1 to 3 hetero atoms of 1 or 2 kinds selected from nitrogen, oxygen and sulfur in addition to a carbon atom, each of which may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated
  • C__ 6 alkyl group and an optionally halogenated C x _ 6 alkoxy group, (35)
  • Ar and Ar independently represent phenyl, 4- chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl, or
  • Q is a C alkylene group; Q is a methylene group;
  • R 2 is (I) a C 1-6 alkyl group which may be substituted with a C__ 6 alkoxy-carbonyl group, a carboxyl group, a
  • a 5- to 7-membered cyclic amino group which may be substituted with (a) a C ⁇ _ 6 alkyl group optionally substituted with (a-l) a hydroxyl group, (a-2) a di-C,_ 6 alkylamino group, (a- 3) a Cj. 6 alkoxy-carbonyl group or (a-4) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (b) a C 7 . 16 aralkyl group, (c) a C_.
  • R is a hydrogen atom or a C__ 6 alkyl group
  • Ar is a phenyl group optionally substituted with a halogen atom
  • R ,2 is an acyl group, and the other symbols have the same meanings as described in the above item (27) or a salt thereof, which comprises subjecting a compound of the formula: wherein the all symbols have the same meanings as described in the above item (27) or a salt thereof to the acylation reaction, (38)
  • R represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl-carbonyl group, a carboxyl group, an optionally substituted lower alkoxy-carbonyl group, an optionally substituted mono-lower alkylaminocarbonyl group, an optionally substituted di-lower alkylaminocarbonyl group or an optionally substituted 5- or 6-membered cyclic amino group; and R is a hydrogen atom or a lower alkyl group, and the other symbols have the same meanings as defined in Claim 27 or a salt thereof, which comprises reacting a compound of the formula:
  • Ph is a phenyl group, and the other symbols have the same meanings as defined above or a salt thereof with a compound of the formula:
  • composition as described in the above item (1) which is a prophylactic or therapeutic agent for inflammatory diseases (40) A composition as described in the above item (1) which is a prophylatic or therapeutic agent for allergic diseases,
  • composition as described in the above item (1) which is a prophylactic or therapeutic agent for arteriosclerosis, bronchial asthma, atopy, multiple sclerosis or rheumatoid arthritis,
  • a MIP-l ⁇ /RANTES receptor antagonist comprising the compound as described in the above item (27),
  • a method of treating or preventing inflammatory diseases or allergic diseases which comprises administering to a mammal in need an effective amount of a compound of the formula:
  • Ar 1 and Ar 2 independently represent an optionally substituted aromatic group
  • Q and Q independently represent an optionally substituted divalent C 6 aliphatic hydrocarbon group which may have oxygen or sulfur within the carbon chain;
  • R is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkyl-carbonyl group; R is an optionally substituted hydrocarbon group or an acyl group, or R and R , taken together with the adjacent nitrogen atom, may form an optionally substituted nitrogen-containing heterocyclic ring; and a group of the formula:
  • Ar 1 and Ar 2 independently represent an optionally substituted aromatic group
  • Q 1 and Q independently represent an optionally substituted divalent C__ 6 aliphatic hydrocarbon group which may have oxygen or sulfur within the carbon chain;
  • R is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkyl-carbonyl group;
  • R is an optionally substituted hydrocarbon group or an acyl group, or R 1 and R , taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen-containing heterocyclic ring; and a group of the formula:
  • aromatic group of the "optionally substituted aromatic group" for Ar , Ar and Ar includes, for example, “aromatic hydrocarbon groups” and
  • heteromatic groups and these groups may have any number (preferably 1 to 5, more preferably 1 to 3, further more preferably 1 or 2) of substituents in any substitutable position.
  • aromatic hydrocarbon group includes, for example, monocyclic or fused polycyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms . Specific examples thereof include C 6 _ ⁇ _, aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl , anthryl, etc. Among them, phenyl, 1-naphthyl and
  • 2-naphthyl are preferred, and phenyl is particularly preferred.
  • heteromatic group includes, for example, 5- to 11-membered monocyclic or fused heteroaromatic groups having at least one (e.g. 1 to 4, preferably 1 to 3, more preferably 1 or 2 ) of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • aromatic heterocyclic group such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, thianthrene, furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indol, isoindol, lH-indazole, purine,
  • aromatic heterocyclic group such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, thianthrene, furan, isoind
  • 4H-quinolizine isoquinoline, quinoline, phtharazine, naphthyridine, quinoxaline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, isochroman, etc., or a monovalent group obtained by eliminating any hydrogen from a ring formed by condensing these rings (preferably monocyclic heterocycle mentioned above) with one or a plurality (preferably 1 or 2 , more preferably 1) of aromatic rings (e.g. aromatic hydrocarbon group, preferably benzene ring, etc.).
  • aromatic rings e.g. aromatic hydrocarbon group, preferably benzene ring, etc.
  • the preferred "aromatic heterocyclic group” include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2-thienyl, 3-thienyl, etc.
  • the more preferred one include, for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl, 2-benzothiazolyl, etc.
  • 2-pyridyl is commonly used.
  • the substituent that may be present on the "optionally substituted aromatic ring in any position" for Ar 1 , Ar 2 and Ar 3 includes, for example, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (e.g. C ⁇ alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), a nitro group, a cyano group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkenyl group, an optionally halogenated lower alkynyl group, a lower cycloalkyl group (e.g.
  • a halogen atom e.g. fluorine, chlorine, bromine, iodine, etc.
  • a lower alkylenedioxy group e.g. C ⁇ alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • C 3 _ 6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • a di-lower alkylamino group e.g.
  • di-Cj.g alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- to 7-membered cyclic amino group e.g. morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.
  • an acylamino group e.g. a lower alkyl-carbonyl group (e.g. Cj.g alkyl-carbonyl such as acetyl, propionyl, etc.), a carboxyl group, a lower alkoxy-carbonyl group (e.g.
  • C ⁇ alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • alkyl-carbamoyl such as dimethylcarbamoyl , diethylcarbamoyl, etc.
  • an aryl-carbamoyl group e.g. C 6 _ 10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • a sulfo group e.g. C j _ 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.
  • an aryl group e.g. C 6 .
  • aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 . 10 aryloxy such as phenyloxy, naphthyloxy, etc .
  • the "optionally halogenated lower alkyl group" mentioned above includes, for example, a lower alkyl group optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) (e.g.
  • c__ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • Specific examples thereof include methyl, chloromethyl , difluoromethyl, tric'hloromethyl, trifluoromethyl , ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3, 3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6, 6 ,6-trifluorohexyl , etc .
  • the "optionally halogenated lower alkenyl group” and “optionally halogenated lower alkynyl group” include, for example, a lower alkenyl group optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) (e.g. C 2 _ 6 alkenyl such as vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl , 5-hexen-l-yl, etc.) or a lower alkynyl group optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) (e.g. C 2 - 6 alkynyl such as 2-butyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl, etc.).
  • halogen atoms e.g. fluorine
  • the "optionally halogenated lower alkoxy group” include, for example, a lower alkoxy group optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) (e.g. Cj. 6 alkoxy such as methoxy, ethoxy, butoxy, propoxy, isoprpoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) .
  • halogen atoms e.g. fluorine, chlorine, bromine, iodine, etc.
  • Cj. 6 alkoxy such as methoxy, ethoxy, butoxy, propoxy, isoprpoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • the "optionally halogenated lower alkylthio group” include, for example, a lower alkylthio group optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) (e.g. C, . _ 6 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.).
  • halogen atoms e.g. fluorine, chlorine, bromine, iodine, etc.
  • C, . _ 6 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
  • acylamino group include, for example, -NHCOOR 3 , -NHCONHR 3 , -NHCOR 3 or -NHS0 2 R 3 (R 3 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, preferably optionally substituted hydrocarbon group) .
  • the substituent that may be present on the "optionally substituted aromatic ring in any position" for Ar , Ar and Ar includes, for preferred example, a halogen atom, an optionally halogenated C - 6 alkyl group, optionally halogenated C x . 6 alkoxy group, a Cj_ 3 alkylenedioxy group (particularly methylenedioxy) , a cyano group, a hydroxyl group, etc.
  • a halogen atom, an optionally halogenated C ⁇ g alkyl group and an optionally halogenated Ct_ 6 alkoxy group are particularly preferred, and an halogen atom is commonly used.
  • the preferred one for Ar and Ar include independently, for example, optionally halogenated phenyl (e.g. phenyl, 4-chlorophenyl, 4-fluorophenyl, etc.) 2-pyridyl, 3-pyridyl and 4-pyridyl. Among them, phenyl and 2-pyridyl are more preferred. As Ar and Ar , phenyl is commonly used independently.
  • a C ! _ 3 alkyl group optionally substituted with 1 to 3 halogen atoms
  • a C ⁇ _ 3 alkoxy group optionally substituted with 1 to 3 halogen atoms
  • a phenyl group optionally substituted with halogen (preferably, chlorine, fluorine, etc.) (e.g.
  • 4-pydridyl are preferred. Among them, optionally halogenated phenyl is preferred and 4-chlorophenyl is particularly preferred.
  • the "optionally substituted hydrocarbon group" for R and R represents a group obtained by eliminating one hydrogen from a hydrocarbon compound and examples thereof include acyclic or cyclic hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, aryl, aralkyl, etc. Preferred are acyclic or cyclic hydrocarbon groups having 1 to 16 carbon atoms as described below.
  • a lower alkyl group e.g. C ⁇ _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • a lower alkenyl group (C 2 _ 6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.)
  • a lower alkynyl group (C 2 _ 6 alkynyl such as propargyl, ethynyl, butynyl, 1-hexynyl, etc.)
  • a lower cycloalkyl group e.g. C 3 _ 6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally fused with a benzene ring optionally having 1 to 3 lower alkoxy groups (e.g. C,_ ⁇ alkoxy such as methoxy, etc.)
  • a lower cycloalkyl group e.g. C 3 _ 6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally fused with a benzene ring optionally having 1 to 3 lower alkoxy groups (e.g. C,_ ⁇ alkoxy such as methoxy, etc.)
  • an aryl group e.g. C 6 . 17 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl, etc., preferably phenyl
  • an aralkyl group e.g. C 7 _ 16 aralkyl group such as benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., preferably benzyl).
  • a lower alkyl group, an aryl group and an aralkyl group are preferred.
  • substituents which may be present on the "optionally substituted hydrocarbon group" for R and R may have 1 to 5, preferably 1 to 3 substituents in substitutable positions, and where the number of substituents is 2 or more, the substituent groups may be the same or different.
  • the substituent that may be present on the "optionally substituted hydrocarbon group” includes, for example, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (e.g. Ci. 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), a nitro group, a cyano group, an optionally halogenated lower alkyl group, a lower cycloalkyl group (e.g. C 3 .
  • a halogen atom e.g. fluorine, chlorine, bromine, iodine, etc.
  • a lower alkylenedioxy group e.g. Ci. 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a cyano group e.g. C 3 .
  • cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as methylamino, ethylamino, etc.
  • a di-lower alkylamino group e.g. di-C__ 6 alkylamino such as dimethylamino, diethylamino, etc.
  • a lower alkyl-carbonyl group e.g.
  • C ⁇ alkyl-carbonyl such as acetyl, ethylcarbonyl, etc.
  • a carboxyl group such as acetyl, ethylcarbonyl, etc.
  • a carboxyl group such as acetyl, ethylcarbonyl, etc.
  • a lower alkoxy-carbonyl group e.g. C)_ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group a mono-lower alkyl-carbamoyl group (e.g. mono-C__ 6 alkyl-carbamoyl such as methylcarbamoyl , ethylcarbamoyl, etc.), a di-lower alkyl-carbamoyl group (e.g.
  • di-C__ 6 alkyl-carbamoyl such as dimethylcarba oyl , diethylcarbamoyl, etc.
  • a sulfo group such as dimethylcarba oyl , diethylcarbamoyl, etc.
  • a sulfo group such as dimethylcarba oyl , diethylcarbamoyl, etc.
  • a sulfo group e.g. C ⁇ alkylsulfonyl such as ethylsulfonyl, ethylsulfonyl, etc.
  • an aryl group e.g. C 6 _ 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 .
  • aryloxy such as phenyloxy, naphthyloxy, etc.
  • a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a group fused with a benzene ring.
  • aryl group preferably phenyl
  • aryloxy group preferably phenyloxy
  • the "5- to 7-membered heterocyclic group or a group fused with a benzene ring” include, for example, 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group having 1 to 3, preferably 1 or 2 hetero atoms of 1 or 2 kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • Specific examples thereof include 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, orpholino, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl , 3-isothiazolyl, 3-isoxazolyl, etc.
  • These groups may be fused with a benzene ring in any position.
  • the "5- to 7-membered heterocyclic group or a group fused with a benzene ring” may have 1 to 3 substituents in substitutable positions.
  • the substituent include substituents that may be present on the "optionally substituted hydrocarbon group" for Ar 1 , Ar 2 and Ar 3 .
  • the preferred one include, for example, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (e.g. C j _ 3 alkylenedioxy such as ethylenedioxy, ethylenedioxy, etc.), a nitro group, a cyano group, an optionally halogenated lower alkyl group, a lower cycloalkyl group (e.g. C 3 .
  • a halogen atom e.g. fluorine, chlorine, bromine, iodine, etc.
  • a lower alkylenedioxy group e.g. C j _ 3 alkylenedioxy such as ethylenedioxy, ethylenedioxy, etc.
  • a cyano group e.g. C 3
  • cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • an optionally halogenated lower alkoxy group such as cyclopropyl, cyclobut
  • di-C ⁇ alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- to 7-membered cyclic amino group e.g. morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.
  • a lower alkyl- carbonyl group e.g. C ⁇ alkyl-carbonyl such as acetyl, propionyl, etc.
  • carboxyl group e.g.
  • C ⁇ _ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • di-C__ 6 alkyl- carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.
  • an aryl-carbamoyl group e.g. C 6 . 10 aryl- carbamoyl such as phenylcarbamoyl, naphthylcarba oyl, etc.
  • a sulfo group e.g. Ci.g alkylsulfonyl such as ethylsulfonyl, ethylsulfonyl, etc.
  • an aryl group e.g.
  • C 6 _ 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 _ 10 aryloxy such as phenyloxy, naphthyloxy, etc .
  • the "optionally halogenated lower alkyl group, " “optionally halogenated lower alkoxy group” and “optionally halogenated lower alkylthio group” include the same substituents mentioned for the "optionally
  • the preferred "optionally substituted hydrocarbon” 2 for R is a C 1-6 alkyl group which may be substituted with a Cj_ 6 alkoxy-carbonyl group, a carboxyl group, a Ci.g alkyl-carbonyl group, or a for yl group.
  • C j _ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , butoxycarbonyl, etc.
  • an optionally substituted mono-lower alkylaminocarbonyl group e.g. C__ 6 alkyl- carbamoyl such as ethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, etc.
  • an optionally substituted di-lower alkylaminocarbonyl group e.g. C ⁇ .
  • 6 alkyl- carbamoyl such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, etc.
  • an optionally substituted 5- or 7-membered cyclic amino group e.g. 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl, etc.
  • aryloxy group e.g. C 6 _ 10 aryloxy group such as phenyloxy etc.
  • R is a hydrogen atom or a lower alkyl group (e.g. C x .
  • alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., where C ⁇ _ 3 alkyl such as methyl, ethyl, propyl, isopropyl, etc. are particularly preferred) ) .
  • R 2 is (1) a C ⁇ .
  • hydrocarbon group of the "optionally substituted hydrocarbon group” for R represents a group obtained by eliminating one hydrogen from a hydrocarbon compound, and examples thereof include acyclic or cyclic hydrocarbon groups such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc.
  • acyclic or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferred, particularly lower (Cj.e) alkyl group, lower (C 2 _ 6 ) alkenyl group or lower (C 6 _ 10 ) aryl group is preffered.
  • a lower (C[_ 6 ) alkyl group is commonly used.
  • the preferred substituent which may be present on the "hydrocarbon group”, “heterocyclic group”, “lower alkyl-carbonyl group”, “a carboxyl group”, “lower alkoxy-carbonyl group”, “mono-lower alkylaminocarbonyl group”, “di-lower alkylaminocarbonyl group”, “5- or 7-membered cyclic amino group” and “aryloxy group” for R* includes, for example, (i) a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (e.g.
  • C ⁇ alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a nitro group such as methylenedioxy, ethylenedioxy, etc.
  • a cyano group such as a C ⁇ _ 6 alkyl group optionally substituted with (1) a halogen atom, (2) a Ci. 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • alkyl-carbamoyl group (17) a di-C__ 6 alkyl-carbamoyl group, (18) a C 6 . 10 aryl- carbamoyl group, (19) a sulfo group, (20) a C j _ 6 alkylsulfonyl group, (21) a C 6 _ ]0 aryl group, (22) a C 6 _ ⁇ n aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (vi) a C 3 _ 6 cycloalkyl group, (vii) an optionally halogenated lower alkoxy group, (viii) an optionally halogenated lower alkylthio group, (ix) a C 7 _, 6 aralkyl group, (x) a
  • alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • a di-lower alkylamino group e.g. di-lower alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- or 7-membered cyclic amino group optionally having hydroxy or oxo (e.g.
  • _ 6 alkylamino group (12) a Cy.r, alkyl-carbonyl group, (13) a carboxyl group, (14) a 6 alkoxy-carbonyl group, (15) a carbamoyl group, (16) a mono-C ⁇ alkyl-carbamoyl group, (17) a di-C ⁇ _ 6 alkyl-carbamoyl group, (18) a C 6 _, n aryl-carbamoyl group, (19) a sulfo group, (20) a C j _ 6 alkylsulfonyl group, (21) a C 6 _ 10 aryl group, (22) a C 6 _, 0 aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xvi) a carboxy
  • C 1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a formyl group which may be substituted with a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring
  • a carbamoyl group e.g.
  • mono-C__ 6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.
  • alkyl portion may be substituted with (1) a halogen atom, (2) a Cj_ alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 _ 6 cycloalkyl group, (6) a C,_ 6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C,_ ⁇ alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a mono- Cj.g alkylamino group, (11) a di-C__ 6 alkylamino group, (12) a C__ 6 alkyl-carbonyl group, (13) a carboxyl group, (14) a Cj_ 6 alkoxy-carbonyl group, (15
  • aryl- carbamoyl group (19) a sulfo group, (20) a C__ 6 alkylsulfonyl group, (21) a C 6 . 10 aryl group, (22) a C 6 . ⁇ n aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxi) a di-lower alkyl-carbamoyl group (e.g.
  • di-Cj_ 6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.
  • alkyl portion may be substituted with (1) a halogen atom, (2) a C,_ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxii) an optionally halogenated aryl-carbamoyl group (e.g. C 6 _ 10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiii) an optionally halogenated aryl-carbonyl group (e.g. C 6 .
  • aryl-carbamoyl group e.g. C 6 _ 10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • aryl-carbonyl group e.g. C 6 .
  • aryl-carbonyl such as phenylcarbonyl, haphthylcarbonyl , etc.
  • a sulfo group optionally substituted with amino group e.g. Ci. 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.
  • a lower alkylsulfonyl group e.g. Ci. 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.
  • an aryl group e.g. C 6 _ 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 .
  • aryloxy such as phenyloxy, naphthyloxy, etc.
  • a C 2 _ 6 alkenylamino
  • a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring
  • a sulfamoyl group
  • a mono-lower alkyl-sulfamoyl group e.g.
  • mono-C___ 6 alkyl-sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, etc.
  • a di-lower alkyl-sulfamoyl group e.g. di-C__ 6 alkyl- sulfamoyl such as dimethylsulfamoyl, diethylsulfamoyl , etc.
  • xxxiii) a lower alkoxy-carbamoyl group e.g. C,_ 6 alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • xxxiv) a carbamoyloxy group e.g. C,_ 6 alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • the preferred one includes, for example, a lower alkylenedioxy group (e.g. C ⁇ alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.); a nitro group; a cyano group; a C l , 6 alkyl group optionally substituted with (1) a halogen atom, (2) a C 1 _ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 _ 6 cycloalkyl group, (6) a C 6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C__ 6 alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a mono-Cj.g alkylamino group, (11) a di-C..
  • a lower alkylenedioxy group e.g. C ⁇ alkylenedioxy such as
  • aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring; a C 3 . 6 cycloalkyl group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkylthio group; a hydroxyl group; a C 7 _ 16 aralkyl group; an amino group optionally substituted with a Cj.g alkyl-carbonyl group; a mono-lower alkylamino group (e.g.
  • mono-C__ 6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • a di-lower alkylamino group e.g. di-C,_ 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- or 7-membered cyclic amino group optionally having hydroxy or oxo e.g.
  • morpholino piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidon-l-yl, 2-pyridon-l-ly, etc.
  • a lower alkyl-carbonyl group e.g. C__ 6 alkyl- carbonyl such as acetyl, propionyl, etc.
  • alkyl portion may be substituted with (1) a halogen atom, (2) a C !
  • _ 3 alkylenedioxy group (3) a nitro group, (4) a cyano group, (5) a C 3 _ 6 cycloalkyl group, (6) a Cj_ 6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C 1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a alkylamino group, (11) a di-C,_ ⁇ alkylamino group, (12) a C ⁇ _ 6 alkyl-carbonyl group, (13) a carboxyl group, (14) a Ci .
  • e alkoxy-carbonyl group (15) a carbamoyl group, (16) a ono-C ⁇ alkyl-carbamoyl group, (17) a di-C ⁇ g alkyl-carbamoyl group, (18) a C 6 _
  • C__ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc,); a formyl group which may be substituted with a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring; a mono-Cj.g alkyl-carbamoyl group whose alkyl portion may be substituted with (1) a halogen atom, (2) a C__ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • aryl group (22) a C 6 _, n aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring; an optionally halogenated C 6 _ ⁇ 0 aryl-carbamoyl group; an optionally halogenated C fl _ 10 aryl-carbonyl group; a sulfo group which may substituted with amino group; an aryl group (e.g.
  • C 6 _ ⁇ n aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 _ 10 aryloxy such as phenyloxy, naphthyloxy, etc.
  • a C 2 _ 6 alkenyla ino a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring; a sulfamoyl group; a mono-lower alkyl-sulfamoyl group (e.g.
  • C ⁇ _ 6 alkyl-sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, etc.
  • a di-lower alkyl-sulfamoyl group e.g. di-C__ 6 alkyl-sulfamoyl such as dimethylsulfamoyl, diethylsulfamoyl, etc.
  • a lower alkoxy-carbamoyl group e.g. C]_ 6 alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • a carbamoyloxy group e.g. C]_ 6 alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • the more preferred one includes, for example, (i) a Cj. 6 alkyl group optionally substituted with (1) a halogen atom, (2) a C ⁇ alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 . 6 cycloalkyl group, (6) a C__ 6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a Cj.g alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a mono-C j .
  • aryl-carbamoyl group (19) a sulfo group, (20) a C x _ 6 alkylsulfonyl group, (21) a C 6 _, rule aryl group, (22) a C 6 _ 10 aryloxy group or (23) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (ii) a C 3 _ 6 cycloalkyl group, (iii) an C 7 _ I6 aralkyl group, (iv) a hydroxyl group, (v) an amino group optionally having a C,_ 6 alkoxy, (vi) a mono-lower alkylamino group (e.g.
  • alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc
  • a di-lower alkylamino group e.g. di-Cj.g alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- or 7-membered cyclic amino group optionally having hydroxyl or oxo e.g.
  • morpholino piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidon-l-yl, 2-pyridon-l-yl, etc.), (ix) a lower alkyl-carbonyl group (e.g. C 6 alkyl-carbonyl such as acetyl, propionyl, etc.) whose alkyl portion may be substituted with (1) a halogen atom, (2) a C ⁇ _ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • a lower alkyl-carbonyl group e.g. C 6 alkyl-carbonyl such as acetyl, propionyl, etc.
  • C j .g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • formyl group which may be substituted with a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring
  • alkyl-carbonyl group (13) a carboxyl group, (14) a C 6 alkoxy- carbonyl group, (15) a carbamoyl group, (16) a mono-C,., alkyl-carbamoyl group, (17) a di-Cj.g alkyl-carbamoyl group, (18) a C 6 _ 10 aryl-carbamoyl group, (19) a sulfo group, (20) a C ⁇ g alkylsulfonyl group, (21) a C 6 _ 10 aryl group, (22) a C 6 .
  • C 6 _ 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 . ]0 aryloxy such as phenyloxy, naphthyloxy, etc.
  • a C 2 . 6 alkenylamino (xx) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring;
  • a lower alkoxy-carbamoyl group e.g. C ⁇ g alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • a carbamoyloxy group e.g. C ⁇ g alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • heterocyclic group of the “optionally substituted heterocyclic group” for R and R include, for example, a 5- to 11-membered (cyclic or bicyclic) heterocyclic group having at least one (e.g. 1 to 4, preferably 1 to 3, more preferably 1 or 2) hetero atoms of 1 or 2 kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • Examples thereof include 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, non-aromatic heterocyclic group such as 3- or 4-azepinyl (preferably 5- to 7-membered saturated cyclic amino group such as 1- or 2-piperazinyl) and heteroaromatic groups (e.g.
  • a heteroaromatic group or a 5- to 7-membered saturated cyclic amino group is preferred.
  • the more preferred one includes, for example, a 5- or 7-membered heteroaromatic group having 1 to 3 hetero atoms of 1 or 2 kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (e.g.
  • R* is (i) a hydrogen atom, (ii) a C__ 6 alkyl group which may have 1 to 5 substituents selected from (a) a hydroxyl group, (b) an amino group which may be substituted with a Cj_ 6 alkyl- carbonyl group, (c) a mono-C ⁇ _ 6 alkylamino group, (d) a di-Cj.
  • alkylamino group (e) a carboxyl group, (f) a C,_ 6 alkoxy-carbonyl group, (g) a mono-C_. 6 alkyl-carbamoyl group, (h) a sulfo group which may be substituted with amino group (i) a 5- to 7-membered cyclic amino group which may have an oxo group or which may be substituted with a hydroxyl group, (j) a C 1 . 6 alkoxy-carbamoyl group, and (k) a carbamoyloxy group, (iii) a C 2 _ 6 alkenyl group, (iv) a C 6 _ 10 aryl group,
  • R is a group represented by the formula:
  • R and R independently represent (a) a hydrogen atom, (b) a C__ 6 alkyl group optionally substituted with (b-1) a halogen atom, (b-2) a C ⁇ alkylenedioxy group, (b-3) a nitro group, (b-4) a cyano group, (b-5) a C 3 _ 6 cycloalkyl group, (b-6) a C ⁇ _ 6 alkoxy group optionally having 1 to 3 halogen atoms, (b-7) a Cj.g alkylthio group optionally having 1 to 3 halogen atoms, (b-8) a hydroxyl group, (b-9) an amino group, (b-10) a mono-C
  • alkylamino group (b-11) a di-C,_ 6 alkylamino group, (b- 12) a Cj.g alkyl-carbonyl group, (b-13) a carboxyl group, (b-14) a C_. 6 alkoxy-carbonyl group, (b-15) a carbamoyl group, (b-16) a mono-Ci.g alkyl-carbamoyl group, (b-17) a di-Ci.
  • alkyl-carbamoyl group (b-18) a C 6 _ 10 aryl-carbamoyl group, (b-19) a sulfo group, (b-20) a Cj.g alkylsulfonyl group, (b-21) a C 6 . 10 aryl group, (b-22) a Cg_ 10 aryloxy group or (b-23) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (c) a C 3 .
  • alkoxy group optionally having 1 to 3 halogen atoms
  • (k-7) a Cj.g alkylthio group optionally having 1 to 3 halogen atoms, (k-8) a hydroxyl group, (k-9) an amino group, (k-10) a mono-Cj.g alkylamino group, (k-11) a di-C__ 6 alkylamino group, (k-12) a C__ 6 alkyl-carbonyl group, (k-13) a carboxyl group, (k-14) a C 1-6 alkoxy-carbonyl group, (k-15) a carbamoyl group, (k-16) a mono-C,.
  • alkylamino group (p-11) a alkylamino group, (p-12) a C__ alkyl-carbonyl group, (p-13) a carboxyl group, (p-14) a C ⁇ _ 6 alkoxy-carbonyl group, (p-15) a carbamoyl group, (p-16) a mono-C,_ 6 alkyl-carbamoyl group, (p-17) a di-Cj_ 6 alkyl-carbamoyl group, (p-18) a C 6 _ 10 aryl-carbamoyl group, (p-19) a sulfo group, (p-20) a C__ 6 alkylsulfonyl group, (p-21) a C 6 - ⁇ o aryl group, (p-22) a C 6 .
  • aryloxy group or (p-23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (q) a di- Cj_ 6 alkyl-carbamoyl group whose alkyl portion may be substituted with (q-1) a halogen atom, (q-2) a C ⁇ alkylenedioxy group, (q-3) a nitro group, (q-4) a cyano group, (q-5) a C 3 . 6 cycloalkyl group, (q-6) a Cj.
  • alkyl-carbamoyl group (q-18) a C 6 _ 10 aryl-carbamoyl group, (q-19) a sulfo group, (q-20) a C j _ 6 alkylsulfonyl group, (q-21) a C 6 . 10 aryl group, (q-22) a C 6 .
  • aryl group (w) a C 6 _ 10 aryloxy group, (x) a C 2 _ 6 alkenylamino group or (y) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring.
  • R and R is, independently, (a) a hydrogen atom, (b) a Cj.g alkyl group optionally substituted with (b-1) a hydroxyl group, (b-2) a di-C . _ 6 alkylamino group, (b-3) a C b alkoxy-carbonyl group, or (b-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (c) a C 7 ., 6 aralkyl group, (d) a C j .g alkyl-carbonyl group whose alkyl portion may be substituted with (d-1) a halogen atom, (d-2) a alkylamino group, (d-3) a C]_ 6 alkoxy-carbonyl group, or (d-4) a 5- to 7-membered
  • the "lower alkyl group" of the "optionally substituted lower alkyl group” for R is, for example, a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • lower alkyl-carbonyl group of the "optionally substituted lower alkyl-carbonyl group” for R is, for example, an C ⁇ _ 6 alkyl-carbonyl group such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.
  • the substituent which may be present on the "lower alkyl group” and “lower alkyl-carbonyl group” includes, for example, the same substituents as mentioned for the "optionally substituted hydrocarbon group" for R .
  • R examples include a hydrogen atom or a lower alkyl group (e.g. C,_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.).
  • a hydrogen atom and methyl are particularly preferred.
  • R is a hydrogen atom.
  • the "nitrogen-containing heterocyclic group formed by bonding R 1 and R2 together with adjacent nitrogen” is, for example, a 4- to 8-membered ring optionally having at least one nitrogen atom and 1 to 3 (preferably 1 to 2 ) ring-constituting atoms such as an oxygen atom, a sulfur atom, etc. in addition to a carbon atom, or the 4- to 8-membered ring fused with a benzene ring.
  • Examples thereof include an aromatic heterocyclic group (e.g. 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 1-pyrazolyl, 2-isoindolyl, 1-indazolyl, etc. ), a cyclic amino group (e.g. morpholino, piperidino, 1-piperazinyl, 1-pyrrolidinyl, 1-pirazolidinyl ,
  • aromatic heterocyclic group e.g. 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 1-pyrazolyl, 2-isoindolyl, 1-indazolyl, etc.
  • a cyclic amino group e.g. morpholino, piperidino, 1-piperazinyl, 1-pyrrolidinyl, 1-pirazolidinyl ,
  • 1-azepinyl, etc. or the cyclic amino group fused with a benzene ring (e.g. 1-indolinyl, 2-isoindolinyl , 1,2,3, 4-tetrahydroquinolin-l-yl, 1,2,3, 4-tetrahydro- isoquinolin-2-yl, 3-benzazepin-3-yl , etc.) or a lactam or an imide group (e.g. phthalimide, succinimide,
  • the "nitrogen-containing heterocyclic group formed by bonding R and R together with adjacent nitrogen” may have the same substituent as that may be present on the "optionally substituted hydrocarbon group" for R .
  • the group fused with a benzene ring may have one or plurality (preferably 1 to 5, more preferably 1 to 3, further more preferably 1 or 2 ) of substituents selected from a halogen group (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (e.g. C__ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a halogen group e.g. fluorine, chlorine, bromine, iodine, etc.
  • a lower alkylenedioxy group e.g. C__ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • di-Cj.g alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a carboxyl group e.g. Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a lower alkocycarbonyl group e.g. Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group in any position on the benzene ring e.g. Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • the preferred substituent on the nitrogen atom at the 4-position of the "1-piperazinyl” includes, for example, a lower alkyl group (e.g. Cj_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), aryl (e.g.
  • a lower alkyl group e.g. Cj_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • aryl e.g.
  • C 6 _ ⁇ _ aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl, etc., preferably phenyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, an aralkyl group (e.g.
  • C 7 _ 16 aralkyl such as benzyl, phenethyl , diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., preferably benzyl), a phenacyl group or a nicotinoyl group.
  • an aryl group, an aralkyl group, a phenacyl group and a nicotinoyl group may have one or plurality (preferably 1 to 5, more preferably 1 to 3, further more preferably 1 or 2) of substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (e.g.
  • C x _ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a nitro group such as methylenedioxy, ethylenedioxy, etc.
  • a cyano group optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, an optionally halogenated lower alkylthio group, a hydroxyl group, an amino group, a mono-lower alkylamino group (e.g. mono-C_. 6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), a di-lower alkylamino group (e.g.
  • di-C__ 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a carboxyl group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a lower alkoxy- carbonyl group e.g. C ⁇ alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • carbamoyl group in any position on the benzene ring.
  • divalent aliphatic hydrocarbon group of the "optionally substituted divalent aliphatic hydrocarbon group optionally having oxygen or sulfur in the carbon chain" for Q 1 and Q 2 means a group obtained by eliminating each one hydrogen (two hydrogens in total) bound to the same or different carbon atoms from the saturated or unsaturated aliphatic hydrocarbon and preferably have not more than 6 carbon atoms. Specific examples thereof include the following:
  • a C,_ 6 alkylene group e.g. -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, etc.
  • a C 2 _ 6 alkynylene group e.g.
  • Preferred one is a C ⁇ alkylene group and particularly preferred one is a C__ 3 alkylene group.
  • These groups may have an oxygen atom or an optionally oxidized sulfur atom in the carbon atom, or any carbon atom may be substituted with an oxo group or a thioxo group in the carbon chain.
  • Q 1 and Q2 is a Ci. alkylene group optionally having an oxo group, for example, -CH 2 -, -(CH-)--, -(CH 2 ) 3 -, -(CH 2 )_,-, -(CH 2 ) 2 CO-, -CH ? CO-, -CO-, etc.
  • Q is a Cj. 4 alkylene group optionally having an oxo group, for example, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 )_,-, -(CH 2 ) 2 CO- and-CH 2 CO- .
  • Particularly preferred are -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 CO- and -CH 2 CO- .
  • -(CH 2 ) 3 - is commonly used.
  • Q are -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) «-, -(CH 2 ) 2 CO-, -CH 2 CO- and -CO-.
  • Particularly preferred are -CH 2 -, -(CH 2 ) 2 - and -(CH 2 ) 3 -.
  • -CH 2 - is commonly used.
  • the divalent aliphatic hydrocarbon group may have ether oxygen or sulfur in the carbon chain, and examples thereof include -CH 2 -0-CH 2 -, -CH 2 -0-CH 2 -CH 2 -, -CH 2 -CH 2 -0-CH 2 -CH 2 -, -(CH 2 ) 2 -CH 2 -0-CH 2 -CH 2 -, (CH 2 ) 7 -CH 2 -0-CH 2 -(CH 2 ) 2 -, (CH 2 ) 3 -CH 2 -0-CH 2 -CH 2 -, -CH 2 -S-CH 2 -, -CH 2 -S-CH 2 -CH 2 -, -CH 2 -CH 2 -S-CH 2 -CH 2 -, -(CH 2 ) 2 -CH 2 -S-CH 2 -CH 2 -, (CH 2 ) 2 -CH 2 -S-CH 2 -CH 2 -, (CH 2 ) 2 -CH
  • the preferred "monocyclic nitrogen-containing heterocyclic ring" of the "optionally substituted monocyclic nitrogen-containing heterocyclic ring” includes, for example, the following:
  • —N Z— is preferred.
  • These monocyclic nitrogen-containing heterocyclic ring may be fused with a 3- to 10-membered cyclic hydrocarbon group, for example, a lower cycloalkane group (e.g. C 3 _ 8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.), a lower cycloalkene group (e.g. C 3 . 6 cycloalkene such as cyclopropene, cyclopentene, cyclohexene, etc.) or an aryl group (e.g. C 6 .
  • a lower cycloalkane group e.g. C 3 _ 8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.
  • a lower cycloalkene group e.g. C 3 . 6 cycloalkene such as
  • aryl such as benzene, etc.
  • pyrrolidine, piperidine, azepine or one of these three groups fused with a benzine ring are preferred.
  • Particularly preferred is piperidine.
  • substituents which may present on the monocyclic or fused nitrogen-containing heterocyclic ring include an optionally substituted lower alkyl group (e.g. Cj_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), an optionally substituted lower alkoxy group (e.g. C_. 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), an optionally substituted lower alkylthio group (e.g.
  • Cj_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc
  • alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.
  • a hydroxyl group an amino group, a mono-lower alkylamino group (e.g. mono-C ⁇ _ 6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), a di-lower alkylamino group (e.g. di-Cj.
  • alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a lower alkyl-carbonyl group e.g. Cj_ 6 alkyl-carbonyl such as acetyl, propionyl, etc.
  • a carboxyl group e.g. C . .,, alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group a mono-lower alkyl-carbamoyl group (e.g.
  • mono-C ⁇ _ 6 alkyl-carbamoyl such as methylcarbamoyl , ethylcarbamoyl, etc.
  • a di-lower alkyl-carbamoyl group e.g. di-Cj.g alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.
  • an aryl-carbamoyl group e.g. C 6 .
  • aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • a sulfo group such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • a sulfo group e.g. Cj.g alkylsulfonyl such as ethylsulfonyl, ethylsulfonyl, etc.
  • an aryl group C 6 _ 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 . 10 aryloxy such as phenyloxy, naphthyloxy, etc .
  • substituents which may present on the "optionally substituted lower alkyl group, " “optionally substituted lower alkoxy group” and “optionally substituted lower alkylthio group” include, for examples, a lower alkoxy group (e.g. C l . 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), a lower alkylthio group (e.g.
  • alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.
  • a hydroxyl group an amino group, a mono-lower alkylamino group (e.g. mono-C j .g alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), a di-lower alkylamino group (e.g. di-C,.
  • 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a lower alkyl- carbonyl group e.g. C t . 6 alkyl-carbonyl such as acetyl, propionyl, etc.
  • a carboxyl group e.g. C t . 6 alkyl-carbonyl such as acetyl, propionyl, etc.
  • a carboxyl group e.g. C ⁇ g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group a mono-lower alkyl-carbamoyl group (e.g.
  • alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.
  • a di-lower alkyl-carbamoyl group e.g. di-Ci. alkyl- carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.
  • an aryl-carbamoyl group e.g. C 6 _ 10 aryl- carbamoyl such as phenylcarbam ⁇ yl, naphthylcarbamoyl, etc.
  • a sulfo group an alkylsulfonyl group(e.g.
  • C,_ ⁇ alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.
  • an aryl group(C 6 . 10 aryl such as phenyl, naphthyl, etc.) or an aryloxy group (e.g. C 6 _ 10 aryloxy such as phenyloxy, naphthyloxy, etc.).
  • Z is, for example, the following:
  • Ar and n have the same meanings as defined above; and Y is an hydrogen atom, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, an optionally halogenated lower alkylthio group, a hydroxyl group, a cyano group, an alkyl-carbonyl group (e.g. C j _ 6 alkyl- carbonyl such as acetyl, propionyl, etc.), a lower alkyl-carbonyloxy group (e.g. Cj.
  • alkyl-carbonyloxy such as acetyloxy, propionyloxy, etc.
  • a formylamino group an amino group
  • a mono-lower alklylamino group e.g. mono-C__g alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • a di-lower alkylamino group e.g. di-Cj.g alkylamino such as dimethylamino, diethylamino. dipropylamino, dibutylamino, etc.
  • carboxyl group e.g.
  • Cj. alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a lower alkyl-carbonylamino group e.g. C,_g alkyl-carbonylamino such as acetylamino, propionylamino, etc.
  • Y include hydrogen atom, a hydroxyl group, a cyano group, a Cj.g alkoxy group, an amino group and a mono-Ci.g alkylamino group and, among them, a hydrogen group, a hydroxyl group, an amino group and a mono-C___ 6 alkylamino group are preferred.
  • Particularly preferred alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • Y include hydrogen atom, a hydroxyl group, a cyano group, a Cj
  • n is an integer of 0 to 2. More preferred is 0 or 1. Among them, 0 is particularly preferred.
  • Z include a group of the formula:
  • Ar and n have the same meanings as defined above; and Y is a hydrogen atom or a hydroxyl group, preferably a hydroxyl group] .
  • the substituent which may be present on the "1,2-phenylene” includes, for example, the same substituents as mentioned for the substituents of the "optionally substituted aromatic group".
  • Preferred examples thereof include a halogen atom (particularly preferably fluorine, chlorine), a lower alkylendioxy group (e.g. C j _ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), a nitro group, a cyano group, an optionally halogenated lower alkyl group or an optionally halogenated lower alkoxy group.
  • the "optionally halogenated lower alkyl group” and “optionally halogenated lower alkoxy group” include the same groups as mentioned for the substituents of the "optionally substituted aromatic group” for Ar , Ar and Ar .
  • Preferred compound (I) or a salt thereof is one wherein Q 1 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 )_,- or -(CH 2 ) 2 CO-;
  • Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) A , -CO-,
  • Ar 3 is a C ⁇ alkyl group optionally substituted with 1 to 3 halogen atoms, a C,_ 3 alkoxy group substituted with 1 to 3 halogen atoms or a phenyl group optionally substituted with a halogen atom (preferably chlorine, fluorine) (e.g. phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, ,5-dichlorophenyl, 3,5-difluorophenyl,
  • a halogen atom preferably chlorine, fluorine
  • Ar and n have the same meanings as defined above; and Y is a hydrogen atom, a hydroxyl group, an amino group or a mono-C,_ 6 alkylamino group (particularly a hydrogen atom and a hydroxyl group are preferred) ] or
  • R is a hydrogen atom or methyl
  • R is a hydrogen atom or a C ⁇ alkyl group such as methyl, ethyl, propyl, isopropyl, etc.
  • R is a hydrogen atom, a lower alkyl group (e.g. C__ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a lower alkenyl group (e.g. C 2 _ 6 alkenyl such as vinyl, allyl, isopropenyl, etc.), a lower alkyl- carbonyl group (e.g. C 1 .
  • C__ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • a lower alkenyl group e.g. C 2 _ 6 alkenyl such as vinyl, allyl, isopropenyl, etc.
  • alkyl-carbonyl such as acetyl, propionyl, butyryl, etc.
  • carboxyl group such as acetyl, propionyl, butyryl, etc.
  • a lower alkoxy-carbonyl group e.g. Cj.g alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a mono-lower alkylaminocarbonyl group e.g.
  • alkylaminocarbonyl such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, etc.
  • a di-lower alkylaminocarbonyl group e.g. di-Cj.g alkylaminocarbonyl such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, etc.
  • C 5 . 10 aryl group such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, etc.
  • lower alkyl group preferably phenyl or a 5- to 7-membered cyclic amino group (preferably 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazinyl, etc.) .
  • lower alkyl group preferably 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazinyl, etc.
  • _, 7-membered cyclic amino group" for R may have 1 to 3 substituents on any carbon atom.
  • the substituent include, for example, (i) a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (e.g. C,_ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (iii) a nitro group, (iv) a cyano group, (v) a C__ 6 alkyl group optionally substituted with (1) a halogen atom, (2) a Ci.
  • a halogen atom e.g. fluorine, chlorine, bromine, iodine, etc.
  • a lower alkylenedioxy group e.g. C,_ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a nitro group
  • alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a mono- Cj_ 6 alkylamino group, (11) a di-Cj.g alkylamino group, (12) a C j .g alkyl-carbonyl group, (13) a carboxyl group, (14) a Cj.g alkoxy-carbonyl group, (15) a carbamoyl group, (16) a mono-Ci.g alkyl-carbamoyl group, (17) a di-Cj.g alkyl-carbamoyl group, (18) a C 6 _ 10 aryl- carbamoyl group, (19) a sulfo group, (20) a Cj_ 6 alkylsulfonyl group, (21) a C 6 .
  • 6 alkoxy such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoromethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
  • an optionally halogenated lower alkylthio group e.g.
  • Cj.g alkylthio such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.
  • a C 7 . 16 aralkyl group (x) a hydroxyl group, (xi) an amino group, (xii) a mono-lower alkylamino group (e.g. _i.ono-C .
  • alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • a di-lower alkylamino group e.g. di-C j . f , alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (e.g.
  • a lower alkyl-carbonyl group (C ⁇ alkyl-carbonyl such as acetyl, propionyl, etc.), whose alkyl portion may be substituted with (1) a halogen atom, (2) a Cj_ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 _ 6 cycloalkyl group, (6) a C__ 6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C,_ ⁇ alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) an amino group, (10) a mono- C ⁇ g alkylamino group, (11) a di-C_.
  • aryl group (2) a C 6 _, n aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xvi) a carboxyl group, (xvii) a lower alkoxy-carbonyl group (e.g. Cj.
  • mono-C__ 6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.
  • alkyl portion may be substituted with (1) a halogen atom, (2) a C__ 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • aryl- carbamoyl group (19) a sulfo group, (20) a Cj. alkylsulfonyl group, (21) a C 6 . 10 aryl group, (22) a C 6 _, n aryloxy group or (23) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxi) a di-lower alkyl-carbamoyl group (e.g. di-Cj.
  • alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc., whose alkyl portion may be substituted with (1) a halogen atom, (2) a Cj. 3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C 3 .
  • aryl group e.g. C 6 . 10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • aryl-carbamoyl group e.g. C 6 . 10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • a sulfo group e.g.
  • C,_ 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.
  • an aryl group C 6 . 10 aryl such as phenyl, naphthyl, etc.
  • an aryloxy group e.g. C 6 . 10 aryloxy such as phenyloxy, naphthyloxy, etc.
  • a sulfamoyl group e.g.
  • C 6 alkyl-sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, etc.
  • a di-lower alkyl- sulfamoyl group e.g. di-C__ 6 alkyl-sulfamoyl such as dimethylsulfamoyl, diethylsulfamoyl, etc.
  • a lower alkoxy-carbamoyl group e.g. C]_ 6 alkoxy-carbamoyl such as methoxycarbamoyl, ethoxycarbamoyl, etc.
  • xxxi) a carbamoyloxy group More preferred is a compound wherein Q is -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 -;
  • Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH-) 3 -, -CH 2 C0- or -(CH 2 ) 2 CO-;
  • Ar 1 and Ar 2 independently represent phenyl or 2-pyridyl; a group of the formula: _ ⁇
  • Ar 3 is a phenyl group optionally substituted with 1 to 3 (preferably 1 or 2) halogen atoms (preferably chlorine, fluorine) (e.g. phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl , 3,5-difluorophenyl, etc.) or 2-pyridyl; and n represents 0];
  • R is a hydrogen atom or methyl;
  • R is a hydrogen atom; and R is a hydrogen atom, an optionally substituted lower alkyl group (e.g. C j _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a carboxyl group, a lower alkoxy-carbonyl group (e.g. C,_ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), a phenyl group or 1-piperazinyl.
  • C j _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • the "lower alkyl group" for R may have 1 substituent on any carbon atom.
  • the substituent include, for example, a hydroxyl group, an amino group, a di-lower alkylamino group (e.g. di-C,_ 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (e.g.
  • morpholino piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidon-l-yl, 2-pyridone-l-yl, etc.), a lower alkyl-carbonyl group (Cj.g alkyl-carbonyl such as acetyl, propionyl, etc.), a carboxyl group, a lower alkoxy-carbonyl group (e.g.
  • C ⁇ t alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • Q 2 is -CH 2 - or -(CH 2 ) 2 -;
  • Ar is a phenyl group or 2-pyridyl;
  • Ar is a phenyl group; a group of the formula:
  • Ar 3 is 4-chlorophenyl; n is 0; and Y is hydrogen atom or a hydroxyl group] ; R is a hydrogen atom;
  • R is a hydrogen atom;
  • R is a (1) hydrogen atom or (2) a lower alkyl group (Ci.g alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having one substituent selected from (a) a hydroxyl group, (b) a 5- to
  • 7-membered cyclic amino group optionally having (b-1) a hydroxyl group or (b-2) an oxo group (e.g. morpholino, piperzin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidon-l-yl, 2-pyridon-l-yl, etc.) or (c) a sulfamoyl group.
  • a hydroxyl group optionally having (b-1) a hydroxyl group or (b-2) an oxo group (e.g. morpholino, piperzin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidon-l-yl, 2-pyridon-l-yl, etc.) or (c) a sulfamoyl group.
  • oxo group e.g. morpholino, piperzin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyr
  • preferred compound (I) is one wherein Ar and Ar independently represent, phenyl, 4- chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl, or
  • QQ i iss aa CCjj._._, alkylene group
  • Q z is a methylene group
  • Ar is a phenyl group optionally substituted with a halogen atom, n is an integer of 0 to 3, and Y is a hydrogen atom or a hydroxyl group]; R is a hydrogen atom or methyl;
  • R 2 is (1) an alkyl group which may be substituted with a C__ 6 alkoxy-carbonyl group, a carboxyl group, a C ⁇ _ 6 alkyl-carbonyl group, a formyl group or (2) an acyl group represented by the formula: [wherein R is (i) a hydrogen atom, (ii) a C 6 alkyl group which may have 1 to 5 substituents selected from (a) a hydroxyl group, (b) an amino group which may be substituted with a C,_ 6 alkyl- carbonyl group, (c) a ono-Ci.g alkylamino group, (d) a di-C,_ 6 alkylamino group, (e) a carboxyl group, (f) a C,_ 6 alkoxy-carbonyl group, (g) a ⁇ ono-C 1-6 alkyl-carbamoyl group, (h) a sulfo group which may be substituted with amino group (
  • a 5- to 11-membered heterocyclic group having at least one hetero atoms of 1 or 2 kinds selected from nitrogen, oxygen and sulfur in addition to a carbon atom, said heterocyclic group being optionally fused with a benzene ring,
  • a Ci.g alkoxy-carbonyl group or (a-4) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring,
  • alkyl-carbamoyl group whose alkyl portion may be substituted with a halogen atom or a C,. fl alkyl-carbonyl group, (g) an optionally halogenated C r ,_ 10 aryl-carbamoyl group, (h) an optionally halogenated C 6 _ 10 aryl-carbonyl group or (i) a C,_ 6 alkoxy-carbamoyl group, or
  • R 5 is a hydrogen atom or a C ⁇ _ 6 alkyl group] .
  • More preferred compound (I) is one wherein Ar and Ar independently represent, phenyl, 4-chlorophenyl, 4- fluorophenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
  • Q1 is a Ci... alkylene group;
  • Q 2 is a methylene group; a group of the formula:
  • Ar is a phenyl group optionally substituted with a halogen atom, n is an integer of 0 to 3, and Y is a hydrogen atom or a hydroxyl group]; R is a hydrogen atom or methyl; R is an acyl group represented by the formula: [wherein R is represented by the formula: (1)
  • R 6 and R independently represent (a) a hydrogen atom, (b) a C j _ 6 alkyl group optionally substituted with
  • (b-1) a hydroxyl group, (b-2) a di-C ⁇ _ 6 alkylamino group, (b-3) a Cj_g alkoxy-carbonyl group, or (b-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (c) a C 7 _ ⁇ 6 aralkyl group, (d) a C ⁇ _ 6 alkyl-carbonyl group whose alkyl portion may be substituted with (d-1) a halogen atom, (d-2) a mono-C ⁇ _ 6 alkylamino group, (d-3) a Cj.g alkoxy-carbonyl group, or (d-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optional
  • Preferred compound (II) is one wherein Q is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) ⁇ - or -(CH 2 ) 2 CO-; Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -CO-,
  • Ar and Ar independently represent phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; Ar is (1) a phenyl optionally substituted with
  • a C j _ 3 alkyl group optionally substituted with 1 to 3 halogen atoms
  • a C ⁇ _ 3 alkoxy group optionally substituted with 1 to 3 halogen atoms
  • a halogen atom preferably chlorine, fluorine
  • R is a hydrogen atom or a C ⁇ _ 3 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.;
  • R is (1) a hydrogen atom, (2) an optionally substituted lower alkyl group (e.g. C,_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (3) an optionally substituted lower alkyl-carbonyl group (e.g. Cj.g alkyl-carbonyl such as acetyl, propionyl, butyryl, etc.), (4) a carboxyl group, (5) an optionally substituted lower alkoxy-carbonyl group (e.g.
  • alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • an optionally substituted mono-lower alkylaminocarbonyl group e.g. mono-Ci.g alkylaminocarbonyl such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, etc.
  • an optionally substituted a di-lower alkylaminocarbonyl group e.g.
  • di-C ⁇ _ 6 alkylaminocarbonyl such as dimethylarainocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, etc.
  • a Cg_ ⁇ o aryl group preferably phenyl
  • an optionally substituted 5- to 7-membered cyclic amino group preferably 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazinyl, etc.
  • the "lower alkyl group,” “lower alkyl-carbonyl group, “lower alkoxy-carbonyl group, “ “mono-lower alkylaminocarbonyl group, “ “di-lower alkylaminocarbonyl” and “5- to 7-membered cyclic amino group” for R* may have 1 to 3 substituents on any carbon atom.
  • the substituent include, for example, a (1) halogen group (e.g. fluorine, chlorine, bromine, iodine, etc.), (2) a lower alkylenedioxy group (e.g.
  • C ⁇ _ 3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.
  • a nitro group such as methylenedioxy, ethylenedioxy, etc.
  • a cyano group such as a halogenated lower alkoxy group (e.g. optionally halogenated Ci_ 5 alkoxy such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 ,2,2-trifluoromethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), (6) an optionally halogenated lower alkylthio group (e.g.
  • Ci_ 5 alkoxy such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 ,2,2-trifluoromethoxy, propoxy, isopropoxy, butoxy, 4,4,4-tri
  • alkylthio such as methylthio, difluoromethylthio, trifluoromethylthion, ethylthio, propylthio, isopropylthio, butylthio,
  • di-C ⁇ _ 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (e.g.
  • acylamino group include, for example, the same groups as mentioned for the substituents of the "optionally substituted aromatic group” for Ar 1 , Ar 2 and Ar and preferred examples thereof include -NHC00R 3 , -NHCONHR 3 and -NHCOR 1 (R is a lower alkyl group (e.g.
  • C ⁇ _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • a lower alkoxy group e.g. C ⁇ _ 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • a lower alkyl-carbonyl group e.g.
  • Ci.g alkyl-carbonyl such as acetyl, propionyl, etc.
  • a carboxyl group such as acetyl, propionyl, etc.
  • a lower alkoxy- carbonyl group e.g. C ⁇ _ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a carbamoyl group e.g.
  • mono-C ⁇ _ 6 alkyl- carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.
  • a di-lower alkyl-carbamoyl group e.g. di-C ⁇ _ 6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.
  • an aryl-carbamoyl group e.g.
  • Cg.io aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • a sulfo group (21) a lower alkylsulfonyl group (e.g. C ⁇ _ 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), (22) an aryl group (C .io aryl such as phenyl, naphthyl, etc.), (23) an aryloxy group (e.g. C 6 .
  • aryloxy such as phenyloxy, naphthyloxy, etc.
  • a sulfamoyl group (24) a sulfamoyl group, (25) a mono-lower alkyl-sulfamoyl group (e.g. mono-C ⁇ _ 6 alkyl- sulfamoyl such as methylsulfamoyl, ethylsulfamoyl , etc.) or (26) a di-lower alkyl-sulfamoyl group (e.g. di-Ci.g alkyl-sulfamoyl such as dimethylsulfamoyl, diethylsulfamoyl, etc.).
  • a mono-lower alkyl-sulfamoyl group e.g. mono-C ⁇ _ 6 alkyl- sulfamoyl such as methylsulfamoyl, ethylsulfam
  • Q is -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 -;
  • Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 CO- or -(CH 2 ) 2 CO-;
  • Ar 1 and Ar 2 independently represent phenyl or 2-pyridyl;
  • Ar 3 is a phenyl group optionally substituted with 1 to 3 halogen atoms (preferably chlorine, fluorine) (e.g. phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, etc.) or 2 -pyridyl ;
  • halogen atoms preferably chlorine, fluorine
  • R is an hydrogen atom
  • R is a hydrogen atom, an optionally substituted lower alkyl group (e.g. C ⁇ _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a carboxyl group, a lower alkenyl group (e.g. C 2 _ 6 alkenyl such as vinyl, allyl, isopropenyl, etc.), a lower alkoxy-carbonyl group (e.g. C ⁇ _ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), a phenyl group or 1-piperazinyl.
  • C ⁇ _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-buty
  • the "lower alkyl group" for R may have 1 to 3 substituents on any carbon atom.
  • the substituent include, for example, a hydroxyl group, an amino group, a di-lower alkylamino group (e.g. di-C ⁇ _ 6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (e.g.
  • acylamino group include -NHCOOR 3 , -NHCONHR 3 and -NHCOR 3 (R 3 is a lower alkyl group (e.g. C ⁇ _ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) or a lower alkoxy group (e.g.
  • C ⁇ _ 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
  • a lower alkyl-carbonyl group C ⁇ g alkyl-carbonyl such as acetyl, propionyl, etc.
  • a carboxyl group e.g. Ci_ 6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
  • a sulfamoyl group a mono-lower alkyl-sulfamoyl group (e.g.
  • mono-C ⁇ _ 6 alkyl-sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, etc.
  • a di-lower alkyl-sulfamoyl group e.g. di-C ⁇ _ 6 alkyl- sulfamoyl such as dimethylsulfamoyl, diethylsulfamoyl , etc .
  • Q is -(CH 2 ) 3 -;
  • Q 2 is -CH 2 - or -(CH 2 ) 2 -;
  • Ar is phenyl or 2-pyridyl
  • Ar is phenyl
  • R is a hydrogen atom
  • R is (1) a hydrogen atom or (2) a lower alkyl group (C j .g alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) an optionally having one substituent selected from a (a) hydroxyl group, (b) a
  • 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (e.g. morpholino, piperzin-1-yl, piperidino, pyrrolidin-1-yl,
  • preferred Compound (II) is one wherein Ar and Ar independently represent, phenyl, 4- chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl, or
  • Q 1 is a C j . . . alkylene group
  • Q 2 is a methylene group
  • R 2 is (1) an alkyl group which may be substituted with a C j .g alkoxy-carbonyl group, a carboxyl group, a C ⁇ _ 6 alkyl-carbonyl group, a formyl group or (2) an acyl group represented by the formula: [wherein R is (i) a hydrogen atom, (ii) a C j .g alkyl group which may have 1 to 5 substituents selected from (a) a hydroxyl group, (b) an amino group which may be substituted with a C ⁇ _ 6 alkyl- carbonyl group, (c) a mono-Ci.g alkylamino group, (d) a di-C__ 6 alkylamino group, (e) a carboxyl group, (f) a C,_ 6 alkoxy-carbonyl group, (g) a mono-Ci.g alkyl-carbamoyl group, (h) a sulfo group which may be substituted with
  • a 5- to 7-membered cyclic amino group which may be substituted with (a) a Cj.g alkyl group optionally substituted with (a-l) a hydroxyl group, (a-2) a di-Ci_ 6 alkylamino group, (a- 3) a Ci_ 6 alkoxy-carbonyl group or (a-4) a 5- to 7- membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (b) a C 7 _i 6 aralkyl group, (c) a C ⁇ _ 6 alkyl-carbonyl group whose alkyl portion may be substituted with (c-1) a halogen atom, (c-2) a mono-C ⁇ _ 6 alkylamino group, (c- 3) a Ci_ 6 alkoxy-carbonyl group or (c-4) a 5- to 7-
  • alkoxy-carbonyl group (e) a formyl group which may be substituted with a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (f) a mono-Ci.g alkyl-carbamoyl group whose alkyl portion may be substituted with a halogen atom or a C,_ f , alkyl-carbonyl group, (g) an optionally halogenated C 6 _ ⁇ o aryl-carbamoyl group, (h) an optionally halogenated c 6 - ⁇ o aryl-carbonyl group or (i) a C ⁇ _ 6 alkoxy-carbamoyl group, or
  • R 5 is a hydrogen atom or a C ⁇ _ 6 alkyl group]; and Ar is a phenyl group optionally substituted with a halogen atom.
  • preferred Compound (II) is one wherein Ar and Ar independently represent, phenyl, 4- chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; Q 1 is a C ⁇ __, alkylene group; Q 2 is a methylene group; R 2 is (1) an alkyl group which may be substituted with a Ci.g alkoxy-carbonyl group, a carboxyl group, a Cj.g alkyl-carbonyl group, a formyl group or (2) an acyl group represented by the formula: [wherein R is a group represented by the formula: ( 1 )
  • R and R independently represent (a) a hydrogen atom, (b) a C g alkyl group optionally substituted with
  • (b-1) a hydroxyl group, (b-2) a di-C ⁇ _ 6 alkylamino group, (b-3) a C ⁇ _ 6 alkoxy-carbonyl group, or (b-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (c) a C 7 _ ⁇ 6 aralkyl group, (d) a C j .g alkyl-carbonyl group whose alkyl portion may be substituted with (d-1) a halogen atom, (d-2) a mono-C 1-6 alkylamino group, (d-3) a C ⁇ -6 alkoxy-carbonyl group, or (d-4) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being
  • R is a hydrogen atom or a Cj_ 6 alkyl group]; and Ar is a phenyl group optionally substituted with a halogen atom.
  • Examples of the preferred compound include the following.
  • L is a leaving group and the other symbols have the same meanings as defined above.
  • the reaction is carried out applying a usual alkylation of an amino group [e.g. procedure described in Organic Functional Group Preparations, Vol. 2, Academic Press Inc.].
  • the leaving group include a halogen atom (preferably chloro, bro o, iodo, etc.), a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, etc.
  • the reaction is carried out by stirring in an inert solvent within the range from room temperature to 100°C (preferably room temperature to 50°C) for 0.5 to 1 day. Usually, 1 to 3 equivalents of a base is added to the reaction system but is not essential.
  • an inert solvent alcoholic solvent, etheral solvent, halogenated solvent, aromatic solvent, acetonitrile, N,N-dimethylformylamido (DMF), acetone, methyl ethyl ketone and dimethyl sulfoxide can be used alone or in combination thereof. Among them, acetonitrile, DMF, acetone and ethanol are preferred.
  • the base include strong bases (1) such as hydrides of alkaline or alkaline earth metals (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkaline or alkaline earth metals (e.g. lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.) and lower (C ⁇ ,,) alkoxides of alkaline or alkaline earth metals (e.g.
  • strong bases (1) such as hydrides of alkaline or alkaline earth metals (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkaline or alkaline earth metals (e.g. lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohe
  • inorganic salts (2) such as hydroxides of alkaline or alkaline earth metals (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), carbonates of alkaline or alkaline earth metals (e.g. sodium carbonate, potassium carbonate, cesium carbonate, etc.) and hydrogencarbonates of alkaline or alkaline earth metals (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, etc.); and organic bases (3) such as amines (e.g. triethylamine, diisopropylethylamine,
  • the compound (I) or (II) obtained by the above process can be further converted to the objective product of this invention by a usual organic synthesis reaction such as hydrolysis, halogenation, oxidation, reduction, alkylation, acylation, ring formation etc.
  • reaction examples include the following process.
  • the compound When the compound has carbonyl in the molecule, it can be converted to the following compound having a hydroxyl group by the Grignard reaction.
  • M is a metal (e.g. lithium, sodium, bromomagnesium, etc.) used for so-called Grignard reaction; and the other symbols have the same meanings as defined above) .
  • M is a metal (e.g. lithium, sodium, bromomagnesium, etc.) used for so-called Grignard reaction; and the other symbols have the same meanings as defined above) .
  • the Grignard reaction is conducted by reacting 1 to 10 equivalents of a so-called Grignard reagent prepared separately or alkyl lithium or alkyl sodium with the compound (VII) or (VII') in an etheral solvent at room temperature to 80°C (preferably 30 to 60°C) for 1 to 24 hours.
  • the reaction is preferably conducted under the condition of deoxidation in the absence of water. It is preferred to conduct the reaction in the presence of anhydrous cerium chloride (catalytic amount to 2 equivalent, preferably 1 equivalent) .
  • R and R independently represent an acyl group or an alkyl-carbonyl group, the group can be converted into an alkyl group by the reduction.
  • the reduction can be conducted by the procedure using metal hydrides or catalytic reduction process.
  • the catalytic reduction process can be conducted by reacting with a catalytic amount of a metal catalyst such as Raney-nickel, platinum oxide, palladium metal, palladium-on-carbon, etc. in an inert solvent (e.g. alcoholic solvent) at room temperature to 100°C under a hydrogen pressure of 1 to 100 atm for 1 to 48 hours.
  • a metal catalyst such as Raney-nickel, platinum oxide, palladium metal, palladium-on-carbon, etc.
  • an inert solvent e.g. alcoholic solvent
  • the reduction using the metal hydride can be easily conducted in an inert solvent using a metal hydride (e.g.
  • the inert solvent include etheral solvents (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.), alcoholic solvents (e.g. methanol, ethanol, tert-butanol, etc.), toluene and hexane.
  • the preferred metal hydride include lithium aluminum hydride.
  • the amount of the metal hydride to be used is from 4 to 20 equivalents, more preferably from 6 to 12 equivalents.
  • the reaction is conducted at the reaction temperature of -70 to 100°C for 30 minutes to 18 hours.
  • the preferred reaction temperature varies depending on the kind of a reducing agent to be used, but is usually from 30 to 70°C. It is also possible to selectively reduce only a cyano or ester group.
  • the conversion from a ketone represented by the compound (VII) or (VII') to an alcohol of -CH(OH) can be easily accomplished by reacting with the metal hydride (e.g. lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) in an inert solvent.
  • the inert solvent include etheral solvents (e.g. ethyl ether, tetrahydrofura, dioxane, etc.) and alcoholic solvents (e.g. methanol, ethanol, tert-butanol, etc), toluene and hexane.
  • the amount of the metal hydride to be used is from 1 to 20 equivalents, more preferably from 3 to 12 equivalents.
  • the reaction temperature is from -70 to 100°C.
  • the preferred reaction temperature and reaction time vary depending on the kind of a reducing agent to be used. In case of the metal hydride, the reduction is preferably conducted at 0 to 30°C for 30 minutes to 18 hours .
  • R or R independently represents an acyl group
  • the group can also be converted into another acyl group, directly or through hydrolysis.
  • the hydrolysis includes an alkali hydrolysis and an acid hydrolysis.
  • an alkali hydrolysis a compound is reacted with an alkali (e.g. inorganic hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc.) in a solvent (e.g. water, alcohols, ethers alone or a mixed solvent using two or more kinds of them) .
  • a solvent e.g. water, alcohols, ethers alone or a mixed solvent using two or more kinds of them
  • the solvent a mixed solvent of water and methanol is preferred.
  • sodium hydroxide is preferred.
  • the usage amount of the alkali is about 2 to 100 equivalents, preferably about 5 to 100 equivalents, relative to the compound.
  • the reaction temperature is from about 10 to 120°C, preferably from about 50 to 120°C.
  • the reaction time is from about 5 minutes to 100 hours, preferably from about 10 to 50 hours.
  • the solvent is a mixed solvent of water and methanol and the reaction temperature is from about 50 to 120°C and, the reaction time is from about 10 to 50 hours.
  • a compound may be heated with stirring in water, acetic acid or an alcoholic solvent in the presence of an excess amount of mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.) at room temperature to 120°C for 0.5 to 18 hours.
  • mineral acid e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the heating is conducted in the presence of dilute hydrochloric acid alone or in combination with acetic acid at room temperature to 60°C.
  • R and R 2 independently represent a "protective group of an amino group
  • Typical examples of the "reduction process” include a catalytic reduction process.
  • starting materials are stirred in an inert solvent (e.g. water, alcoholic solvent, ethyl acetate, etheral solvent, etc.) in the presence of metal catalysts (catalytic amount to one equivalent) such as palladium catalyst (e.g. palladium acetate, palladium-carbon, palladium black, palladium-barium carbonate, etc.), platinum oxide and Ranney-nickel, etc.
  • an inert solvent e.g. water, alcoholic solvent, ethyl acetate, etheral solvent, etc.
  • metal catalysts catalytic amount to one equivalent
  • palladium catalyst e.g. palladium acetate, palladium-carbon, palladium black
  • R is an acyl group; and the other symbols have the same meanings as defined above].
  • the acylation can be conducted according to the per se known procedure described in Organic Functional Group Preparations, Vol. 2, Academic Press Inc.
  • the acylation reaction is conducted by reacting 1 to 5 equivalents, preferably 1 to 3 equivalents, of a reactive derivative of the corresponding organic acid with the compound (IX) or (IX') in an inert solvent at the reaction temperature of -20 to 50°C (preferably 0°C to room temperature) for 5 minutes to 100 hours.
  • the inert solvent there can be used etheral solvent, halogenated solvent, aromatic solvent, acetonitrile, N,N-dimethylformulamido (DMF), acetone, methyl ethyl ketone, dimethylsulfoxide (DMSO), water, etc. alone or in combination thereof. Among them, acetonitrile, dichloromethane and chloroform are preferred.
  • the reaction sometimes proceed more smoothly in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base.
  • the base both inorganic and organic bases are effective.
  • the inorganic base includes hydroxides, hydrides, carbonates, hydrogencarbonates, organic acid salts of alkaline or alkaline earth metals.
  • the reactive derivative includes acid anhydride, acid halide (e.g. acid chloride, acid bromide, etc.) and active ester. Among them, acid halide is preferred.
  • Acylation using carboxylic acid can be used a procedure of reacting 1 to 1.5 equivalents of carboxylic acid in an inert solvent (e.g. halogenated solvent, acetonitrile, etc.) with a dehydration condensing agent such as dicyclohexylcarbodiimide (DCC) (1 to 1.5 equivalents) at room temperature for 0.5 to 24 hours.
  • an inert solvent e.g. halogenated solvent, acetonitrile, etc.
  • DCC dicyclohexylcarbodiimide
  • an acyl group represented by R is has the same meanings as defined above
  • the acylation is conducted in an inert solvent (e.g. halogenated solvent, acetonitrile, etc.) at the reaction temperature of -20 to 50°C (preferably 0°C to room temperature) for 5 minutes to 100 hours, using one equivalent or excess amount of the corresponding isocyanate (OCN-R'' (R 4 has the same meanings as defined above) and isothiocyanate (SCN-R (R has the same meanings as defined above) .
  • the reaction is sometimes conducted in the presence of 1 to 10 equivalents of an organic base such as triethylamine.
  • the acyl group represented by R 2 is -C0NR 5 -R 4 (R and R 5 have the same meanings as defined above) (hydrogen is preferred as R )
  • reaction proceeds by reacting one equivalent to excess amount of amine (HN-R -R (R and R have the same meanings as defined above)) with the compound (X) or (X') in an inert solvent such as acetonitrile, DMF, water, etc. in the presence of 1 to 10 equivalents of an inorganic base (e.g. potassium carbonate, sodium carbonate, etc.) at room temperature to 50°C for 1 to 24 hours.
  • an inorganic base e.g. potassium carbonate, sodium carbonate, etc.
  • the objective product can be obtained by reacting 1 equivalent to excess amount of:
  • the reaction conditions are the same as those of the alkylation reaction of the amino group in the "process 1.”
  • the base the above strong base, inorganic base or organic base is used.
  • the leaving group L' used in the "process 5" includes the same one for L. Among them, bro o and iodo are preferred.
  • the objective product can be synthesized by introducing the corresponding nitrogen-containing heterocycle according to the "process 5.”
  • morpholino, piperazino, 1-piperazinyl, 1-imidazolyl, phthalimide, etc. can be easily introduced.
  • the compound used as the starting material in the above “process 1” and “process 2” can be synthesized by using the synthesis procedures which are known in references in combination. For example, the following compound used in the above "process 1" is easily available or synthesized.
  • the compound wherein Z is -C(0H)-(CH 2 )n-Ar can be produced from the corresponding ketone according to the same manner as that described in “process 2. "
  • the compound (III) or (III') as the starting material can be synthesized by the per se known procedure, and examples thereof include the following schema 1.
  • J is a cyano group, a carboxyl group, a lower (C ⁇ _ 3 ) alkoxy-carbonyl group or a formyl group; j' is a group capable of converting into a leaving group (e.g. cyano, carboxyl, lower (C ⁇ _ 3 ) alkoxy-carbonyl, protected hydroxyl group, etc.); L" is the same meanings as defined in L; and the other symbols have the same meanings as defined above.]
  • the compound (XVII) It is possible to convert to the compound (XVII) by reacting the compound (XV) with one equivalent to excess amount of the compound (XVI) in any inert solvent (e.g. etheral solvent, DMF, DMSO, alcoholic solvent, acetonitrile, acetone, etc.) or mixed solvent thereof in the presence of a base (usually 1 to 3 equivalents) at -20 to 120°C for 5 minutes to 24 hours.
  • a base usually 1 to 3 equivalents
  • the compound (XVII) can also be obtained by heating the compound (XV) and excess acrylonitrile or lower alkyl acrylate (2 to 10 equivalents) in the presence of a base catalyst.
  • the base include strong bases (1) such as hydrides of alkaline or alkaline earth metals (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkaline or alkaline earth metals (e.g. lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.) and lower (C ⁇ __,) alkoxides of alkaline or alkaline earth metals (e.g.
  • strong bases (1) such as hydrides of alkaline or alkaline earth metals (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkaline or alkaline earth metals (e.g. lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclo
  • inorganic salts (2) such as hydroxides of alkaline or alkaline earth metals (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), carbonates of alkaline or alkaline earth metals (e.g. sodium carbonate, potassium carbonate, cesium carbonate, etc.) and hydrogencarbonates of alkaline or alkaline earth metals (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, etc.); and organic bases (3) such as amines (e.g.
  • the compound (XVII) can be converted to the compound (III) or (III') by appropriately combining per se known processes, for example, general organic synthesis reactions such as hydrolysis, halogenation. oxidation, reduction , alkylation , acylation, ring formation etc .
  • the reaction example include the following process .
  • T is a bond, an oxygen atom or an optionally oxidized sulfur atom;
  • L and L" independently represent a leaving group;
  • a and m independently represent an integer of 0 to 5 and the total of them is 1 to 6;
  • h is an integer of 0 to 2; and
  • Q' is a group obtained by removing one methylene group from Q .
  • the reduction reaction of the compound (XX) and the compound (XXIV) can be conducted by the process using metal hydrides or catalytic reduction process.
  • the catalytic reduction process can be conducted by reacting with a catalytic amount of a metal catalyst such as Ranney-nickel, platinum oxide, metallic palladium, palladium-carbon, etc. in an inert solvent (e.g. alcoholic solvent) at room temperature to 100°C under a hydrogen pressure of 1 to 100 atm for 1 to 48 hours.
  • a metal catalyst such as Ranney-nickel, platinum oxide, metallic palladium, palladium-carbon, etc.
  • an inert solvent e.g. alcoholic solvent
  • the reduction reaction using the metal hydride can be easily conducted by reacting in an inert solvent using a metal hydride (e.g. lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) or a metal (e.g. zinc, iron, sodium, potassium, etc.).
  • the inert solvent include etheral solvents (e.g. dyiethyl ether, tetrahydrofuran, dioxane, etc.), alcoholic solvents (e.g. methanol, ethanol, tert-butanol, etc.), toluene and hexane.
  • the preferred metal hydride include lithium aluminum hydride.
  • the amount of the metal hydride to be used is from 4 to 20 equivalents, more preferably from 6 to 12 equivalents.
  • the reaction temperature is from -70 to 100°C.
  • the preferred reaction temperature varies depending on the kind of a reducing agent to be used, but is normally from 30 to 70°C.
  • the reaction time is from 30 minutes to 18 hours. It is also possible to selectively reduce only a cyano or ester group.
  • the conversion from a hydroxyl group to a leaving group or introduction of a protective group of an amino group can be conducted according to the procedure described in Comprehensive Organic Transformations, VCH Publishers Inc.
  • the compound (XXII) can be converted to the compound (XXIII) by the Wittig reaction.
  • the reaction can be conducted in an inert solvent (e.g. alcoholic solvent, etheral solvent, etc.), if necessary, in the presence of a base at 20 to 60°C for 5 minutes to 18 hours, using 1 equivalent to excess amount of a Witting reagent (e.g. ethyl triphenylphosphoranilidene-acetate, ethyl diethylphosphonoacetate, etc.).
  • the base include strong bases (1) such as sodium hydride, t-butoxy potassium, etc.); inorganic bases (2) such as hydroxides of alkaline or alkaline earth metals (e.g.
  • sodium hydride, potassium hydroxide, lithium hydroxide, barium hydroxide, etc. carbonates of alkaline or alkaline earth metals (e.g. sodium carbonate, potassium carbonate, cesium carbonate, etc.) and hydrogencarbonates of alkaline or alkaline earth metals (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate, etc.); and organic bases (3) amines (e.g. triethylamine, DBU, etc.).
  • any of the aforementioned reactions and any of the reactions for synthesizing the starting compounds when the raw materials have amino, carboxyl or hydroxyl group as a substituent, these functional groups may be protected with protective groups which are commonly used in peptide chemistry or related art.
  • the desired compounds can be then be obtained by eliminating such protective groups when needed.
  • the amino-protective group that can be used includes, for example, Ci.g alkyl-carbonyl (e.g. formyl, acetyl, ethylcarbonyl, etc.), C ⁇ _ 6 alkyloxycarbonyl (e.g.
  • N,N-dimethylaminomethylene may respectively have 1 to 3 substituents, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc . ) and nitro.
  • the carboxyl-protective group which can be used includes, for example, C ⁇ _ 6 alkyl (e.g. methyl, ethyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl and silyl.
  • These groups may respectively have 1 to 3 substitutes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), Ci.g alkyl-carbonyl (e.g. formyl, acetyl, propionyl, butylcarbonyl, etc.) and nitro.
  • the hydroxyl-protective group which can be used includes, for example, Ci_ 6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7 _ ⁇ o aralkyl group (e.g. benzyl, etc.), formyl, C ⁇ _ 6 alkyl-carbonyl group (e.g. acetyl, propionyl, etc.), benzoyl, C 7 _ 10 aralkyl-carbonyl (e.g. benzylcarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, and silyl.
  • Ci_ 6 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.
  • C 7 _ ⁇ o aralkyl group
  • These groups may respectively have 1 to 3 substituents, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C j .g alkyl (methyl, ethyl, n-propyl, etc.), phenyl, C 7 _ ⁇ 0 aralkyl (e.g. benzyl, etc.) and nitro.
  • halogen e.g. fluorine, chlorine, bromine, iodine, etc.
  • C j alkyl (methyl, ethyl, n-propyl, etc.)
  • phenyl C 7 _ ⁇ 0 aralkyl (e.g. benzyl, etc.) and nitro.
  • These protective groups can be removed by the per se known procedures or any procedures analogous thereto.
  • a process using an acid, a base, a reducing agent, an ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate, tetrabutylammonium fluoride or palladium acetate can be utilized.
  • the salt of the compound (I) or (II) include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids and salts with basic or acidic amino acids.
  • the preferred salts with inorganic bases include, for example, alkaline metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.) and aluminum salt and ammonium salt.
  • the preferred salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.
  • the preferred salts with inorganioc acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • the preferred salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • the preferred salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc.
  • the preferred salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc.
  • the pharmaceutically acceptable salts include, for example, inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide, etc., or organic salt such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate, tartrate, etc.
  • inorganic salt such as alkaline metal salt (e.g. sodium salt, potassium salt, etc.) or alkaline metal salt (e.g. calcium salt, magnesium salt, etc.) and ammonium salt.
  • the compounds (I) and (II) of this invention and their salts can be separated and purified by known procedures such as solvent extraction, pH change, redistribution, crystallization, recrystallization, chromatography, etc.
  • the starting compounds of the compounds (I) and (II) of this invention and their salts can be separated and purified by the same known procedures as those described above, but the reaction mixture containing them may be respectively be submitted to the next reaction steps.
  • optical isomers When the compounds (I) and (II) of this invention and their salts include optical isomers, stereoisomers, position isomers or rotational isomers, these are also included as the compounds of this invention and can be obtained by the per se known synthesis and isolation procedures.
  • optical isomers resolved from the compounds can also be included in this invention.
  • the optical isomers can be produced by the per se known method. Specifically, a desired optically active isomer can be obtained by using an optically active intermediate, or by optically resolving a mixture of racemic modifications as a final product according to a usual procedure.
  • optical resolution procedure for example, there can be used the following fractional recrystallization process, chiral column process, diastereomer process, etc,.
  • Fractional recrystallization process A process comprising reacting a racemic modification with an optically active compound to form a salt and separating the salt according to a fractional recrystallization method and optionally producing a free optical isomer through a neutralizing step.
  • a process of separating a racemic modification or a salt thereof using a column for separating an optical isomer chiral column
  • the optical isomer is separated by adding a mixture of optical isomers to a chiral column such as ENANTIO-OVM (manufactured by Toso Co.) and developing with water, various buffers (e.g. phosphate buffer, etc.) and an organic solvent (e.g. ethanol, methanol, acetonitrile, etc.) alone or in combination thereof.
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by G Science Co. ).
  • Diastereomer process A process comprising reacting a mixture of racemic modifications with an optically active reagent to form a mixture of diasteromers, separating the mixture into a single substance through normal means (e.g. fractional recrystallization, chromatography, etc.) and cleaving the optically active reagent site due to a chemical treatment such as hydrolysis reaction.
  • a diastereomer as an ester or amide can be obtained by subjecting the compound and an optically active organic acid (e.g.
  • the diastereomer as the ester or amide can be obtained by subjecting the compound and an optically active amine or an alcohol reagent to a condensation reaction.
  • the separated diastereomer is converted into an optical isomer of the original compound by subjecting to an acid hydrolysis or basic hydrolysis reaction.
  • the compounds (I) and (II) of this invention and their salts can be safely administered as they are or as a pharmaceutical composition containing a medicinally acceptable carrier in various dosage forms such as tablest (inclusive of dragees and film-coated tablets), powders, granules, capsules (inclusive of soft capsules), solutions, injections, suppositories, controlled-release preparations, etc. by the oral route or parenteral route (e.g. local, rectal or intravenous administration) according to the per se known method.
  • An amount of the compound (I) or a salt thereof contained in the preparation of this invention is from 0.1 to 100% by weight based on the total weight.
  • the dosage is dependent on the subject, route of administration, administration route, diseases, etc., but for the treatment of viral encephalitis, etc., for instance, the recommend oral regimen for an adult patient (b.wt. 60 kg) is about 0.1 to 500 mg/day, preferably about 1 to 100 mg/day, more preferably about 5 to 100 mg/day, to be administered once a day or in a few divided doses daily.
  • the pharmaceutically acceptable carrier includes a variety of organic and inorganic carriers or vehicles which are commonly used in the pharmaceutical field.
  • excipients, lubricants, binders, disintegrators, etc. are all subsumed in the concept of carrier for solid preparations, while solvents, solubilizers, suspending agents, isotonizing agents, buffers, anallgesics, etc. can be used in the formulation of liquid preparations.
  • various additives such as preservatives, antioxidants, coloring agents, sweeteners, absorbents, moistening agents, etc. can also be added.
  • the preferred excipient includes lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light silicic anhydride.
  • the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • the binder includes crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and carboxymethylcellulose.
  • the disintegrator includes starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.
  • the solvent include water for injection, alcohol, propylene glycol, macrogols, sesame oil, and corn oil.
  • the solubilizer includes polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, choresterol, triethanolamine, sodium carbonate, and sodium citrate.
  • the suspending agent includes surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate, etc. and hydrophilic macromolecular substances such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • the isotonizing agent includes glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.
  • the buffer includes various buffer solutions such as phosphate, acetate, carbonate, and citrate.
  • the anallgesic includes benzyl alcohol.
  • the preservative includes paraoxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic
  • the antioxidant includes sulfite, and ascorbic acid.
  • the drug comprising the diphenylmethane derivative of this invention and it's medicinally acceptable salt have an excellent MIP-let/RANTES receptor antagonism and, therefore, they are useful as an medicament for mammals (e.g. humans, dogs, cats, rats, mice, bovines, etc.) for preventing or treating viral diseases or infectionary diseases (e.g.
  • tumors e.g. bladder cancer, mammary cancer, cervical carcinoma, chronic lymphatic leukemia, chronic myelocytic leukemia, colon cancer, multiple myeloma, malignant myeloma, prostatic cancer, lung cancer, stomach cancer, Hodgkin's disease, etc.
  • allergic diseases e.g.
  • bronchial asthma atopic dermatitis, allergic rhinitis, etc.
  • inflammatory disease e.g. arteriosclerosis, arterial sclerosis broken out after heart transplantation, (chronic) rheumatism, etc.
  • diabetic diseases e.g. diabetes, diabetic nephropathy, diabetic complication, diabetic retinopathy, diabetic microangiopathy, etc.
  • central diseases e.g.
  • the compound used for MIP-l ⁇ ,/RANTES receptor antagonism of this vomon is low toxic and has a low risk of side effect.
  • the oral acute toxicity (LD 5n ) of the compound of this invention in rats is not less than 100 mg/kg.
  • room temperature means any temperature within the range of 0 to 30°C.
  • the organic solvents were dried over anhydrous magnesium sulfate or anhydrous sodium sulfate.
  • % means percent by weight otherwise specified. The other symbols have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad
  • ⁇ -NMR proton nuclear magnetic resonance (The sample was measured in a free form and when a conformational isomer existed, the only main peak was read.)
  • DMEM Dulbecco's modified Eagle's medium
  • PBS phosphate buffered saline
  • Reference Example 2-2 The compound of Reference Example 2-2 was synthesized in the same manner as Reference Example 2- 1.
  • Reference Examples 3-2 and 3-3 were synthesized in the same manner as Reference Example 3-1.
  • Reference Example 3-2 (4-Methoxyphenyl)phenylacetonitrile
  • Reference Example 3-3 (4-Methoxyphenyl)phenylacetonitrile
  • Reference Example 4-7 The compound of Reference Example 4-7 was synthesized in same manner as Reference Example 4-6.
  • Reference Example 5-2 The compounds of Reference Examples 5-2 - 7 were synthesized in the same manner as Reference Example 5- 1.
  • Reference Example 6-2 The compounds of Reference Example 6-2 - 7 were synthesized in the same manner as Reference Example 6- 1.
  • 5-Formylamino-l-iodo-4,4-diphenylpentane To a solution of 5-formylamino-4,4- diphenylpentanol (38.3 g) in methylene chloride (600 ml) were added p-toluenesulfonyl chloride (29.2 g), triethylamine (15 g) , and 4-(dimethylamino)pyridine (catalytic amount). The mixture was stirred at room temperature for 4 hours and concentrated to dryness. The residue was stirred with Sodium Iodide (46.6 g) in acetone (600 ml) for 2 hours at 50°C.
  • the reaction mixture was concentrated to dryness and the residue was diluted with ethyl acetate and water.
  • the organic layer was taken, washed with an aqueous solution of sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • the residue was purified by silica gel column chromatography to provide the titled compound (46.5 g) as yellow syrup.
  • Reference Example 7-3 - 7 and 7-9 were respectively synthesized in the same manner as Reference Example 7-1.
  • Reference Example 7-2 l-Iodo-4,4-diphenyl-5-(tosylamino)pentane
  • the obtained oily substance was dissolved in dichloromethane (20 ml). To the solution were added a mixture of triethylamine (1 ml), 4- dimethyla inopyridine (catalytic amount), and p- toluenesulfonylchloride (687 ml) and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in ethyl acetate-lN hydrochloric acid. The organic layer was separated, washed serially with water and saturated aqueous sodium chloride, and dried. The solvent was distilled off under reduced pressure to give 7-formylamino-4,4-diphenylheptyl 7-p- toluenesulfonate (1.3 g) as an oil.
  • Reference Examples 11-2 and 11-3 were synthesized in a manner similar to that described above.
  • Reference Example 11-2 l-Benzyl-4-(4-trifluoromethylphenyl)-4- hydroxypiperidine r H-NMR (CDC1 3 ) ⁇ : 1.64-1.85(3H,m) , 2.16(2H,dt), 2.46(2H,dt), 2.71(2H,d), 3.59(2H,s), 7.20-7.39( 5H,m) , 7.62(4H,ABq)
  • Reference Example 11-3 l-Benzyl-4-(3,5-dichlorophenyl)-4- hydroxypiperidine Melting point: 75°C - 77°C
  • Reference Example 12-1 4-[3,5-Bis(trifluoromethyl)phenyl]-4- hydroxypiperidine
  • the reaction mixture was concentrated under reduced pressure and neutralized with lN-hydrochloric acid.
  • the aqueous layer was extracted with ethyl acetate.
  • the organic extract was washed serially with water and a saturated aqueous sodium chloride solution and dried.
  • the solvent was distilled off under reduced pressure to give the titled compound (2.7 g) .
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the organic extract was washed serially with water and a saturated aqueous sodium chloride solution, and dried.
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography eluting with ethyl acetate- hexane (1:1) to give the titled compound (1.5 g) as a noncrystalline powder.
  • 2-Benzoylthiophenecyanohydrin A mixture of 2-benzoylthiophene (10 g) , trimethylcyanide (6 g) , and zinc iodide (0.15 g) acetonitrile (50 ml) was stirred at 50°C for 16 hours. The solvent was distilled off under reduced pressure. lN-Hydrochloric acid (60 ml) and ethanol (30 ml) were added to the residue and the mixture was stirred at
  • Example 1-2 5-[4-(4-Fluorophenyl)piperadin-l-yl]-1- formylamino-2,2-diphenylpentane dihydrochloride
  • the obtained residue was purified by silica gel column chromatography eluting with ethyl acetate- methanol (9:1). The solvent was distilled off and the obtained residue was treated with 4N-hydrochloric acid/ethyl acetate to give the titled compound (85 mg) as noncrystalline powder.
  • Example 2-2 l-Formylamino-5-[4-hydroxy-4-(4-methoxyphenyl ) piperidino]-2,2-diphenylpentane hydrochloride
  • Example 3-2 l-Acetoacetylamino-5-[4-(4-chlorophenyl)-4- hydroxypiperidino]-2,2-diphenylpentane hydrochloride
  • the obtained residue was purified by silica gel column chromatography eluting with ethyl acetate- methanol (9:1). The solvent was distilled off and the residue was treated with 4N-hydrochloric acid/ethyl acetate to give the titled compound (205 mg) as a noncrystalline powder.
  • Recrystallization solvent methanol/isopropyl ether
  • Example 5-2 The compounds of Examples 5-2 to 5-5 were synthesized in the same manner as Example 5-1.
  • Example 5-2
  • Example 6-2 The compound of Example 6-2 was synthesized in the manner similar to Example 6-1.
  • Example 6-2 The compound of Example 6-2 was synthesized in the manner similar to Example 6-1.

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Abstract

Un antagoniste du récepteur MIP-1α/RANTES comprend un composé de formule (I), dans laquelle: Ar?1 et Ar2¿ représentent indépendamment un groupe aromatique éventuellement substitué; Q1 et Q2 représentent indépendamment un groupe hydrocarbure C¿1-6? aliphatique divalent éventuellement substitué pouvant contenir de l'oxygène ou du soufre dans la chaîne carbonée; R?1¿ représente un atome d'hydrogène, un groupe alkyle inférieur éventuellement substitué ou un groupe alkyle inférieur-carbonyle éventuellement substitué; R2 représente un groupe hydrocarbure éventuellement substitué ou un groupe acyle éventuellement substitué, ou bien R1 et R2 forment ensemble, avec l'atome d'azote adjacent, un groupe hétérocyclique contenant de l'azote, éventuellement substitué; et le groupe de la formule (a) représente un groupe hétérocyclique mono ou fusionné contenant de l'azote, éventuellement substitué, ou un de ses sels.
PCT/JP1996/003820 1995-12-28 1996-12-26 DERIVES DE DIPHENYLMETHANE UTILISES COMME ANTAGONISTES DU RECEPTEUR MIP-1α/RANTES WO1997024325A1 (fr)

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AU12083/97A AU1208397A (en) 1995-12-28 1996-12-26 Diphenylmethane derivatives as mip-1alpha/rantes receptor antagonists

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JP7/343905 1995-12-28
JP34390595 1995-12-28
JP8/187375 1996-07-17
JP18737596 1996-07-17

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EP1013276A1 (fr) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
WO2000037455A1 (fr) * 1998-12-21 2000-06-29 Takeda Chemical Industries, Ltd. Derives de benzothiepin-anilide, production et utilisation comme antagoniste de ccr-5
WO2000039125A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Piperidines utilises comme modulateurs de ccr5
WO2000038680A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Azabicycloalcanes modulateurs de ccr5
WO2000068203A1 (fr) * 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Composes cycliques et leurs utilisations
WO2000044408A3 (fr) * 1999-01-29 2000-12-14 Leukosite Inc Methode de traitement des troubles inflammatoires demyelinisants utilisant des agonistes de la fonction ccr1
WO2001021169A1 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone de concentration de la melanine
EP1091741A1 (fr) * 1998-06-30 2001-04-18 Eli Lilly And Company Derives d'azepine jouant un role dans des systemes associes a la serotonine
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US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
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WO2002051414A1 (fr) * 2000-12-22 2002-07-04 Takeda Chemical Industries, Ltd. Compositions médicinales s'administrant par voie orale
WO2001098268A3 (fr) * 2000-06-21 2002-08-08 Bristol Myers Squibb Pharma Co Amides de piperidine utilises comme modulateurs de l'activite des recepteurs des chimiokines
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US6667314B2 (en) 2000-05-26 2003-12-23 Pfizer, Inc. Tropane derivatives useful in therapy
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WO2004009550A1 (fr) * 2002-07-18 2004-01-29 Pfizer Products Inc. Derives de piperidine et leur utilisation comme inhibiteurs selectifs de la liaison mip-1alpha a son recepteur ccr1
EP1393728A1 (fr) * 2002-08-30 2004-03-03 Vrije Universiteit Agonistes inverses agissant sur les recepteurs couplés à une protéine G codées par un virus
US6809113B2 (en) 2001-03-01 2004-10-26 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6962926B2 (en) 2001-01-31 2005-11-08 Telik, Inc. Antagonist of MCP-1 function, and compositions and methods of use thereof
WO2006024160A1 (fr) * 2004-08-30 2006-03-09 Neuromed Pharmaceuticals Ltd. Dérivés de l'urée agissant comme agents bloquant un canal de calcium
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US7067117B1 (en) 1997-09-11 2006-06-27 Cambridge University Technical Services, Ltd. Compounds and methods to inhibit or augment an inflammatory response
WO1999012968A3 (fr) * 1997-09-11 1999-07-29 Neorx Corp Peptides de chemokines, variants, derives et analogues. leur utilisation dans des procedes pour inhiber ou renforcer une reaction inflammatoire
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US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
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US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
EP1091741A4 (fr) * 1998-06-30 2002-12-18 Lilly Co Eli Derives d'azepine jouant un role dans des systemes associes a la serotonine
EP1091741A1 (fr) * 1998-06-30 2001-04-18 Eli Lilly And Company Derives d'azepine jouant un role dans des systemes associes a la serotonine
US6503926B2 (en) 1998-09-04 2003-01-07 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
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EP1013276A1 (fr) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
WO2000044408A3 (fr) * 1999-01-29 2000-12-14 Leukosite Inc Methode de traitement des troubles inflammatoires demyelinisants utilisant des agonistes de la fonction ccr1
US7238711B1 (en) 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US6627651B1 (en) 1999-05-07 2003-09-30 Takeda Chemical Industries, Ltd. Cyclic compounds and uses thereof
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US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
WO2001021169A1 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone de concentration de la melanine
US6410566B1 (en) 2000-05-16 2002-06-25 Teijin Limited Cyclic amine derivatives and their use as drugs
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