WO2002057255A1 - Derives du pyrrole substitues en 4 ou 5 - Google Patents

Derives du pyrrole substitues en 4 ou 5 Download PDF

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Publication number
WO2002057255A1
WO2002057255A1 PCT/JP2002/000401 JP0200401W WO02057255A1 WO 2002057255 A1 WO2002057255 A1 WO 2002057255A1 JP 0200401 W JP0200401 W JP 0200401W WO 02057255 A1 WO02057255 A1 WO 02057255A1
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group
substituent
substituent group
fluorophenyl
methyl
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PCT/JP2002/000401
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English (en)
Japanese (ja)
Inventor
Tomio Kimura
Nobuyuki Ohkawa
Kazumasa Aoki
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Sankyo Company, Limited
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Publication of WO2002057255A1 publication Critical patent/WO2002057255A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to heteroaryl-substituted pyrrolyl derivatives useful as pharmaceuticals. More specifically, antipyretic * analgesic * anti-inflammatory drugs, which have an inhibitory effect on the production of inflammatory site power-ins such as interleukin (IL) -1, IL-6, IL-8, and tumor necrosis factor (TNF)
  • IL interleukin
  • IL-6 interleukin-6
  • IL-8 tumor necrosis factor
  • TNF tumor necrosis factor
  • the present invention also relates to a heteroaryl-substituted pyranyl derivative useful as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis, bone diseases such as osteoporosis, and other diseases involving the above-mentioned cytokines.
  • NSA IDs non-steroidal anti-inflammatory drugs
  • PG prostaglandin
  • DMARD immunomodulator
  • cytodynamics produced by immunocompetent cells have been found.
  • IL interleukin
  • IL-6 IL-6
  • IL-8 tumor necrosis factor
  • TNF tumor necrosis factor
  • a variety of functions as inflammatory mediators have been elucidated, such as migration of inflammatory cytokines, induction of acute phase proteins, and activation of osteoclasts.
  • a new generation of antipyretics, analgesics, anti-inflammatory drugs, autoimmune diseases such as rheumatoid arthritis, bone diseases such as osteoporosis, and other therapeutic agents involving the aforementioned cytokines Is expected.
  • the following compounds are specifically disclosed as heteroaryl compounds having an action of suppressing the production of inflammatory cytokines.
  • it is hoped that compounds having better drug efficacy, pharmacokinetics and safety will be developed. It is rare.
  • the present inventors have conducted intensive studies over many years on the synthesis of the compound capable of suppressing the production of the above-mentioned inflammatory cytokine and its pharmacological action, and as a result, it has a 1 H-pyrrolyl ring, The present inventors have found that a compound in which 4 or 5 atoms on the pyrrole ring are substituted has an excellent inhibitory action on inflammatory cytokine production, and completed the present invention.
  • the present invention is a.
  • A represents a pyrrolyl ring
  • R 1 is an aryl group; an aryl group substituted with a group selected from the substituent group ⁇ and the substituent group) 3); a heteroaryl group; or a group selected from the substituent group a and the substituent group 3) Indicates a heteroaryl group,
  • R 2 represents a heteroaryl group having at least one nitrogen atom; or a heteroaryl group having at least one nitrogen atom, substituted with a group selected from substituent group ⁇ and substituent group / 3. ,
  • R 3 is a group having the following general formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):
  • a bond containing a dotted line represents a single bond or a double bond, -m represents 1 or 2, R 6 represents 1 to 3 groups arbitrarily selected from a hydrogen atom, a substituent group ⁇ , a substituent group 3 and a substituent group a,
  • One of D and ⁇ represents a nitrogen atom, and the other represents> C (R 7 ) 1 (where R 7 is a hydrogen atom, a group selected from substituent group a and a substituent group i3 Is shown.)
  • B is a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom, wherein the ring is saturated or unsaturated; an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group; May be condensed.
  • One of Y and Z represents> NR 8 (R 8 represents one group selected from a hydrogen atom and a substituent group / 3), and the other represents> CR 9 R 1 Q (R 9 And R 1 Q represent one group selected from a hydrogen atom, a substituent group ⁇ and a substituent group / 3.)
  • R 4 and R 5 are the same or different and each is a hydrogen atom; one group selected from substituent group 3); substituted with a group selected from substituent group ⁇ , substituent group 3) and substituent group a Cycloalkyl group; aryl group; aryl group substituted with a group selected from substituent group ⁇ , substituent group and substituent group r; heteroaryl group; substituent group ⁇ , substituent group “3/3” and A heterocyclyl group substituted with a group selected from substituent group a; a heterocyclyl group; or a heterocyclyl group substituted with a group selected from substituent group a, substituent group ⁇ and substituent group III.
  • the atoms on the pyrrole ring to which R 1 and R 3 are attached are each adjacent to the atom on the pyrrole ring to which R 2 is attached,
  • At least one of R 4 and R 5 is a group selected from substituent group / 3; a substituent group 0; a substituent group) a cycloalkyl substituted with a group selected from 3 and a substituent group a Group; aryl group; substituent group ⁇ , substituent group; aryl group substituted with a group selected from 8 and substituent group a; heteroaryl group; substituent group; A heterocyclyl group substituted by a group selected from substituent group a; a heterocyclyl group; or a heterocyclyl group substituted by a group selected from substituent group ⁇ , substituent group ⁇ , and substituent group a.
  • ⁇ [Substituent group ⁇ ]
  • preferred compounds include
  • R 1 is an aryl group; or an aryl group substituted with a group selected from the group of substituents ⁇ ; and the group of substituents;
  • R 1 is phenyl or naphthyl substituted with phenyl, naphthyl, or a group selected from substituent group and substituent group / 3;
  • R 1 is phenyl, or compounds that are Fuweniru substituted with a group selected from Substituent group alpha 1 and substituent group 1,
  • R 1 is phenyl or phenyl substituted with a group selected from the following substituent group; (Substituent groups: halogen atom, halogeno lower alkyl group, halogeno lower alkoxy group)
  • R 1 is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4 A compound which is fluorophenyl, 3-difluoromethoxyphenyl or 3-trifluoromethylphenyl,
  • R 2 is a 5- or 6-membered heteroaryl group containing one or two nitrogen atoms; or a substituent group ⁇ and a substituent group).
  • R 2 is pyridyl, pyrimidinyl, or pyridyl or pyrimidinyl substituted with a group selected from the substituent group j and the substituent group j3;
  • R 2 is 4-pyridyl, 4-pyrimidinyl, or 4-pyridyl or 4-pyrimidinyl substituted with a group selected from substituent group ⁇ and substituent group 3.
  • R 2 is 4-pyridyl, 4-pyrimidinyl, or 4-pyridyl or 4-pyrimidinyl substituted at the 2-position with one group selected from the following substituent group,
  • R 3 is a group having the general formula (IIa) or (IIb),
  • B is, contains one nitrogen atom, contain further nitrogen atom, an oxygen atom, a sulfur atom, group> S_ ⁇ beauty group> one atom or group selected from the group consisting of S_ ⁇ 2
  • a 5- or 6-membered heterocycle ring (the ring is saturated or unsaturated; and may be condensed with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group).
  • R 3 is a group having the general formula (I la) or (I lb), B is D; E; and a 5- or 6-membered heterocycle ring consisting of 3 or 4 carbon atoms (the ring is saturated or unsaturated; an aryl group, a heteroaryl group, a cycloalkyl group or Which may be condensed with a terocyclyl group.)
  • R 3 is a group having the general formula (IIa) or (IIb),
  • R 6 is one or two groups arbitrarily selected from a hydrogen atom, a substituent group ⁇ , a substituent group 3 and a substituent group r 1 ;
  • R 6 is a hydrogen atom, a hydroxyl group, an halogen atom, a lower alkoxy group, a lower alkylthio group, an octogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, an oxo group, an aryl group, a substituent group Compounds that are one or two groups selected from an aryl group, a lower alkylene group, a lower alkylenedioxy group, or a lower alkylsulfonyl group substituted with ⁇ and a group selected from substituent group / 3 ,
  • R 6 is selected from hydrogen atom, hydroxyl group, fluorine atom, chlorine atom, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, phenyl, or a group of substituents and a group of substituents) 3
  • R 3 is a group having the general formula (IIa) or (IIb),
  • D is> C (R 5 ) — (wherein, R 5 represents one group selected from a hydrogen atom, a substituent group ⁇ and a substituent group i3), and E is a nitrogen atom Compound, (24)
  • R 4 and R 5 are the same or different and are each a hydrogen atom; a halogen atom; a lower alkyl group; a lower alkyl group substituted with a group selected from substituent group ⁇ ; An aryl group substituted with a group selected from the group ⁇ and the substituent group; a heterocyclyl group; or a heterocyclyl group substituted with a group selected from the group ⁇ , the group j8 and the group r.
  • R 4 and R 5 are the same or different and are each a hydrogen atom; a halogen atom; a lower alkyl group; a halogeno lower alkyl group; or a substituent group or a substituent group) 8 or A compound which is a phenyl group substituted with a selected group,
  • R 4 and R 5 are the same or different and are each a hydrogen atom, a halogen atom or a lower alkyl group,
  • a compound comprising the compound according to any one of the above (1) to (26), a pharmacologically acceptable salt or derivative thereof as an active ingredient, and
  • Administering to the mammal preferably a human
  • a method for inhibiting the production of inflammatory site force-in particularly preferably, a method for treating or removing pain and Z or inflammation; a method for preventing or treating rheumatoid arthritis; or a method for preventing osteoarthritis). Or treatment method)
  • Aryl group in the definition of R 1 , R 4 , R 5 and [substituent group a]; selected from “substituent group ⁇ and substituent group 3 in the definition of R 1 and [substituent group a] of Ariru group "which is substituted with a group” Ariru group ";and” substituent group in the definition of R 4 and R 5 alpha, substituted with a group selected from substituent group] 3 and substituent group ⁇ Ariru
  • the “aryl group” of the group is, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl, naphthyl, phenanthryl and anthracenyl, and is preferably phenyl or naphthyl. Is phenyl.
  • the “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include 5-indanyl.
  • the “aryl group substituted with a group selected from the group consisting of the substituent group ⁇ and the group of the substituent groups / 3” in the definition of R 1 and the group of the “substituent group a” is preferably a group consisting of the substituent group ⁇ and the group j8 Represents an aryl group substituted with 1 to 4 groups selected from, more preferably, an aryl group substituted with 1 to 3 groups selected from a substituent group ⁇ and a substituent group 3) Group.
  • Preferred examples include 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,4,5-trifluorophenyl, Examples of such groups include 3-fluorophenyl, 4-fluorophenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl, and 3-trifluoromethylphenyl.
  • aryl group substituted with a group selected from substituent group, substituent group / 3 and substituent group r is preferably a substituent group
  • a substituent group i3 represents an aryl group substituted with 1 to 4 groups selected from substituent group a, more preferably 1 to 4 groups selected from substituent group ⁇ , substituent group 3 and substituent group r
  • Is an aryl group substituted with one group selected from is 4-methylthiophenyl, 4-ethylthiophenyl, 4-propylthiophenyl, 4-methylsulfinylphenyl, 4-ethylsulfinylphenyl, 4-propylsulfinylphenyl, 4-methylsulfonylphenyl And groups such as 4-ethylsulfonylphenyl and 4-propylsulfoerphenyl.
  • Heteroaryl group in the definition of R 1 , R 4 and R 5 ; “heteroaryl group” in the “heteroaryl group substituted with a group selected from the group consisting of the substituent group ⁇ and the substituent group 3) in the definition of R 1
  • heteroaryl group may be condensed with another cyclic group (for example, an aryl group or a cyclic group such as a cycloalkyl group having 3 to 10 carbon atoms).
  • cyclic group for example, an aryl group or a cyclic group such as a cycloalkyl group having 3 to 10 carbon atoms.
  • examples of the group include indolyl, benzofuranyl, benzochenyl, quinolyl, isoquinolyl, quinazolinyl, tetrahydroquinolyl, and tetrahydroisoquinolyl.
  • heteroaryl group substituted by a group selected from the substituent group ⁇ and the substituent group ⁇ ” in the definition of R 1 is preferably a substituent group ⁇ and a substituent group selected from 3)
  • Preferred examples are 5-fluoro-2-furyl, 4-chloro-2-phenyl, 5-chloro-2-phenyl.
  • Groups such as difluoromethoxy-3-furyl, 5-trifluoromethyl-3-phenyl, and 5-fluoro-2-oxazolyl can be mentioned.
  • heteroaryl group substituted with a group selected from substituent group i, substituent group i3 and substituent group a is preferably a substituent group ⁇ , a substituent group ) Represents a heteroaryl group substituted with 1 to 3 groups selected from 3 and substituent group a, and more preferably selected from substituent group ⁇ , substituent group and substituent group a It is a heteroaryl group substituted with one or two groups.
  • Preferred examples include 2-methylthio-5-pyridyl, 3-methylthio-16-pyridazinyl, 2-methylthio-15-pyrimidinyl, 2-methylsulfinyl 5-pyridyl, 3-methylsulfinyl 6-pyridazinyl, 2-methylpyridinyl
  • Examples of such groups include methylsulfinyl-5-pyrimidinyl, 2-methylsulfonyl 5-pyridyl, 3-methylsulfonyl-6-pyridazinyl, and 2-methylsulfonyl-5-pyrimidinyl.
  • heteroaryl group having at least one nitrogen atom of the "heteroaryl group having” includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrimidinyl.
  • it contains one nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and further contains one sulfur atom, oxygen atom or nitrogen atom.
  • a 5- or 6-membered heteroaryl group which may contain one or more nitrogen atoms, such as imidazolyl, pyridyl, pyridazinyl, pyrimidinyl or birazinyl. Yes, particularly preferably pyridyl or pyrimidinyl, most preferably 4-pyridyl or 4-pyrimidinyl.
  • the “heteroaryl group having at least one nitrogen atom substituted with a group selected from the substituent group ⁇ and the substituent group i3” in the definition of R 2 is preferably a substituent group ⁇ and a substituent group represents a group substituted with 1 to 3 groups selected from ⁇ , more preferably, a group substituted with 1 to 2 groups selected from Substituent Group ⁇ and Substituent Group 3) And more preferably a group substituted with one group selected from the group of substituents and the group of substituents j8, particularly preferably selected from the group of substituents ⁇ and the group of substituents 4-pyridyl or 4-pyrimidinyl substituted at the 2-position with one group.
  • a group having one NR a R b wherein R a and R b are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, or A lower alkylsulfonyl group, or a heterocyclyl group together with the nitrogen atom to which R a and R b are bonded, and a group having —NR a R b ; , R a and R b have the same meaning as defined above.
  • Is 4-pyridyl or 4-pyrimidinyl substituted at the 2-position with one group selected from a lower alkyl group substituted with Preferred examples include 2-amino-4-pyridyl, 2-amino-4-pyrimidinyl, 2-methylamino-4-pyridyl, 2-methylamino-4-pyrimidinyl, 2-methoxy-14-pyridyl, 2-meth
  • cyclic group ⁇ “4- to 7-membered heterocycle ring containing at least one nitrogen atom” is: D; ⁇ ; and a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a group > S Omicron and group> S 0 means hetero cycle ring from 2 to 5 atoms or groups selected from the group consisting of 2 to 4 to 7 membered becomes, 4 to 7 containing at least one nitrogen atom A member's heterocycle ring (ie, a saturated or unsaturated heterocycle ring).
  • containing one nitrogen atom, further nitrogen atom, an oxygen atom, a sulfur atom, also one atom selected from the group consisting of radicals> SO and groups> SO 2 contain group Exhibit a 5- or 6-membered heterocycle ring, more preferably Oral lysine, pyrroline, imidazolidin, imidazoline, virazolidine, pyrazoline, oxazolidin, thiazolidine, piperidine, tetrahydropyridine, dihydropyridine, piperazine, morpholine, thiomorpholine, and particularly preferably pyrrolidine, pyrroline, imidazoline And most preferably, pyrrolidine and pyrroline.
  • the above “heterocycle ring” is the above “aryl group”, the above “heteroaryl group”,
  • cycloalkyl group or a "heterocyclyl group”.
  • examples of such a ring include tetrahydroquinoline, octahydroquinoline, decahydr quinoline, tetrahydroisoquinoline, octahydroisoquinoline, and decahydroisoquinoline.
  • Cycloalkyl group refers to a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and preferably 3 to 6 carbon atoms. Is a cycloalkyl group.
  • Heterocyclyl group refers to a 4- to 7-membered heterocyclyl group having 1 to 3 sulfur atoms, oxygen atoms and nitrogen or nitrogen atoms, preferably 1 or 2 sulfur atoms, oxygen atoms And a 4- to 7-membered heterocyclyl group containing Z or a nitrogen atom. More preferably, it represents a 5- or 6-membered heterocyclyl group which contains one nitrogen atom and may further contain one oxygen atom, sulfur atom or nitrogen atom.
  • Examples of such a group include, for example, Azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, vilazolidinyl, pyrazolinyl, oxazolidinyl, thiazolidinyl, piperidyl, tetrahydropyridyl, dihydropyridyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl ]
  • Cycloalkyl group in the definition of [Substituent group j8], and “cycloalkyl substituted with a group selected from the substituent group, the substituent group / 3 and the substituent group a in the definition of R 4 and R 5.
  • the “cycloalkyl group” of the “alkyl group” refers to a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl.
  • a cycloalkyl group preferably a cycloalkyl group having 3 to 6 carbon atoms, more preferably cyclopentyl or cyclohexyl.
  • ⁇ heterocyclyl group '' and ⁇ heterocyclyl group '' of ⁇ heterocyclyl group substituted with a group selected from substituent group i, substituent group i8 and substituent group a '' Represents a 4- to 7-membered heterocyclyl group having 1 to 3 sulfur atoms, oxygen atoms, and / or nitrogen atoms, and preferably 4 to 7 containing 1 or 2 sulfur atoms, oxygen atoms, and / or nitrogen atoms. Shows a cyclyl group to 7 members.
  • it represents a 5- or 6-membered heterocyclyl group which contains one nitrogen atom and may further contain one oxygen atom, sulfur atom or nitrogen atom. Dinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, birazolinyl, oxazolidinyl, thiazolidinyl, piperidyl, tetrahydropyridyl, dihydropyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidyl.
  • the "lower alkyl group” in the above means methyl, ethyl, propyl, isopropyl, n-butyl, isoptyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n- Xyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,1-dimethylbutyl Show
  • the lower alkenyl group of the "group” includes pinyl, 2-probenyl, 1-methyl-2-propyl, 2-methyl-2-propyl, 2-ethyl-2-propyl, 2-butyl Thenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-ethyl-3-butenyl, 1-ethyl-3-butenyl
  • the lower alkynyl group of the "lower alkynyl group” is ethynyl, 2-propynyl, 1-methyl-2-propyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl- 3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2--2-pentynyl, 3-pentyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4 —C 2-6 straight chain such as pentyny
  • the “aralkyl group” in the definitions of R a , R b and [Substituent group 3] refers to a group in which the above “aryl group” is bonded to the above “lower alkyl group”. , For example, benzyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, diphenylmethyl, triphenylmethyl, 0!
  • aryl moiety of the “aralkyl group” may be substituted with one to three groups selected from the above “substituent groups” and “substituent groups”, and such substituted Examples of the aralkyl group include 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, and 4-bromobenzyl.
  • Bromobenzyl 3,5-difluorobenzyl, 2,5-difluorophenethyl, 2,6-difluoroopentyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5- Dibromophenethyl, 2,6-dichloromouth benzyl, 2,4-dichlorophenethyl, 2, 3,6-Trifluorobenzyl, 2,3,4-Trifluorophenethyl, 3,4,5-Trifluorobenzyl, 2,5,6-Trifluorophenethyl, 2,4,6-Trifluorobenzyl Robenzyl, 2,3,6-tripromophenethyl, 2,3,4-tribromobenzyl, 3,4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,4, 6-trichlorophenethyl, 1-fluoro-2-naphthylmethyl, 2-flu
  • Aralkyl groups substituted with halogen atoms such as 6-dichlorophenylphenylmethyl, bis (2,4-dichlorophenyl) methyl, bis (2,3,6-trifluorophenyl) methyl; 2-trifluoromethyl Benzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl, 2-tribromo Methylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5-bistrifluoromethylbenzyl, 2,6-pistrifluoro Methylphenethyl, 2,4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl, 2,5-bisdibutymomethylpentyl
  • it is an unsubstituted aralkyl group or an aralkyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group. More preferably, it is an unsubstituted aralkyl group or an octane atom atom or a lower alkyl group. And most preferably an unsubstituted aralkyl group.
  • the “lower alkylsulfonyl group” in the definition of R a , R b and [substituent group] refers to a group in which sulfonyl (1-S ⁇ 2 —) is bonded to the above “lower alkyl”. It is preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, more preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and butylsulfonyl, and particularly preferably. Is methylsulfonyl, ethylsulfonyl, propylsulfonyl.
  • R a and R b the Teroshi acrylic group to which they are connexion formed such together with the nitrogen atom to which they are bonded, a nitrogen atom containing one further contain one oxygen atom, a sulfur atom or a nitrogen atom
  • these groups may be condensed with an aryl group or a heteroaryl group, and such groups include, for example, tetrahydroquinoline_1-yl and tetrahydroisoquinoline-2-yl Groups.
  • octogen atom in the definition of [Substituent group ⁇ ], a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned, and a fluorine atom and a chlorine atom are preferred.
  • lower alkoxy group in the definition of the “substituent group” refers to a group in which an oxygen atom is bonded to the above “lower alkyl group”. It is preferably a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, and particularly preferably methoxy, ethoxy, propoxy. It is. '
  • the “octogeno lower alkoxy group” in the definition of [Substituent group ⁇ ] refers to a group in which one or more hydrogen atoms of the above “lower alkoxy group” have been substituted with the above “halogen atom”. It is preferably a halogeno lower alkoxy group having 1 to 4 carbon atoms, more preferably difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and particularly preferably difluoro. Methoxy.
  • lower alkylthio group in the definition of the “substituent group” refers to a group in which a sulfur atom is bonded to the above “lower alkyl group”.
  • it is a linear or branched alkylthio group having 1 to 4 carbon atoms, more preferably, methylthio, ethylthio, propylthio, isopropylthio, butylthio, particularly preferably methylthio, These are ethylthio and propylthio.
  • halogeno lower alkylthio group in the definition of [Substituent group ⁇ ] refers to a group in which one or more hydrogen atoms of the above “lower alkylthio group” have been substituted with the above “octogen atoms”. .
  • it is a halogeno lower alkylthio group having 1 to 4 carbon atoms, more preferably difluoromethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio.
  • the “lower alkoxyimino group” in the definition of [Substituent group a] is a group in which a hydrogen atom of a hydroxyimino group is replaced by the above “lower alkyl group”.
  • it is an alkoxyimino group having 1 to 4 carbon atoms, and more preferably, methoxyimino, ethoxyimino or propoxyimino.
  • the “lower alkylene group” in the definition of [Substituent group a] includes ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, It represents a linear or branched alkylene group having 2 to 6 carbon atoms, such as 1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene, and hexamethylene. Preferably, it is a linear or branched alkylene group having 2 to 4 carbon atoms, and more preferably, ethylene, trimethylene, propylene, or tetramethylene. In addition, these may form a spiro ring by substituting on the cyclic group.
  • lower alkylenedioxy group in the definition of [Substituent group a] means that the alkylene moiety is methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1 -Dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene, hexamethylene, etc.
  • a group which is a branched alkylene is shown. Preferably, it is a straight-chain or branched-chain alkylenedioxy group having 1 to 4 carbon atoms, and more preferably, methylenedioxy or ethylene. Ndoxy, trimethylenedioxy, propylenedioxy and tetramethylenedioxy. In addition, these may form a spiro ring by substituting on the cyclic group B.
  • the “lower alkylsulfinyl group” in the definition of [Substituent group a] indicates a group in which sulfinyl (—SO—) is bonded to the above “lower alkyl”.
  • it is a linear or branched alkylsulfenyl group having 1 to 4 carbon atoms, more preferably, methylsulfiel, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfiel,
  • they are methylsulfinyl, ethylsulfinyl, and propylsulfinyl.
  • the aryloxy group of “aryloxy group” and “aryloxy group substituted with a group selected from the substituent group and the substituent group / 3” is the above-mentioned aryl group "Represents a group having an oxygen atom bonded thereto.
  • aryl group represents a group having an oxygen atom bonded thereto.
  • it is phenoxy, naphthyloxy, phenanthryloxy or anthracenyloxy, more preferably phenoxy or naphthyloxy, most preferably phenoxy.
  • lower alkylidenyl group in the definition of [Substituent group r] refers to a straight-chain or branched-chain alkylidenyl group having 1 to 6 carbon atoms, preferably methylidenyl, ethylidenyl, propylidenyl, 1-methyl It is a linear or branched alkylidenyl group having 1 to 4 carbon atoms such as ethylidenyl, butylidenyl and 1-methylpropylidenyl, and more preferably methylidenyl, ethylidenyl or propylidenyl.
  • the “aralkylidenyl group” in the definition of [substituent group a] refers to a group in which one to three hydrogen atoms of the above “lower alkylidenyl group” have been replaced by the above “aryl group”.
  • a set of suitable groups are 1 J shed "substituent group, this is a halogen atom, a lower alkoxy group, a halogeno-lower alkoxy Moto ⁇ beauty one NR a A group having Rb (wherein one of Ra and Rb represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group).
  • Substituent group 1 is a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, a nitro group. It comprises a lower alkyl group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di (lower alkyl) amino lower alkyl group, and an aralkylamino lower alkyl group.
  • octogeno lower alkyl group in the definition of “substituent group” 3 ⁇ means a group in which one or more hydrogen atoms of the above “lower alkyl group” have been substituted with the above “halogen atom”.
  • It is preferably a halogenoalkyl group having 1 to 4 carbon atoms, and more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2 , 2, 2, 2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, and even more preferably, trifluoromethyl, trichloromethyl, difluoromethyl, and fluoromethyl. Most preferably, it is trifluoromethyl.
  • Hydro lower alkyl group in the definition of “substituent group” 3 ⁇ refers to a group in which one or more hydrogen atoms of the above “lower alkyl group” have been substituted with the above “hydroxyl group”.
  • it is a hydroxyalkyl group having 1 to 4 carbon atoms, and more preferably, hydroxymethyl, 2-hydroxyethyl, or 3-hydroxypropyl.
  • nitro lower alkyl group in the definition of the “substituent group” refers to a group in which one or two or more hydrogen atoms of the above “lower alkyl group” are substituted with a nitro group. It is preferably a nitroalkyl group having 1 to 4 carbon atoms, and more preferably nitromethyl, 2-nitroethyl or 3-nitropropyl.
  • amino lower alkyl group “lower alkylamino lower alkyl group”, “di (lower alkyl) amino lower alkyl group” and “aralkylamino lower alkyl group” refer to the aforementioned “ A group in which one or more hydrogen atoms of the “lower alkyl group” have one NR a R b in the definition of the “substituent group 1 ” (where one of Ra and R b is a hydrogen atom or a lower alkyl The other is a hydrogen atom, a lower alkyl group or an aralkyl group).
  • the alkyl moiety is a group having 1 to 4 carbon atoms, and more preferably, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, 3- (methylamino) propyl, ethylaminomethyl, 2- (ethylamino) ethyl, 3- (ethylamino) propyl, dimethylaminomethyl, 21- (dimethylamino) ethyl, 3- (dimethylamino) propyl, getylaminomethyl , 2- (Jethylamino) ethyl, 3- (Jethylamino) propyl, benzylaminomethyl, 21- (benzylamino) ethyl and 3- (benzylamino) propyl.
  • Substituent group ⁇ Of the groups defined as “Substituent group ⁇ ", the set of suitable groups are "Substituent group ⁇ 1," which, Okiso group, hydroxy I amino group, a lower Arukokishiimino group, lower alkylene group A lower alkylenedioxy group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aryl group, an aryl group substituted with a group selected from the substituent group ⁇ and the substituent group i8.
  • Substituent group ⁇ 1 which, Okiso group, hydroxy I amino group, a lower Arukokishiimino group, lower alkylene group A lower alkylenedioxy group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aryl group, an aryl group substituted with a group selected from the substituent group ⁇ and the substituent group
  • the “ester or other derivative” is obtained by modifying a functional group (eg, a hydroxyl group, an amino group, an imino group, a sulfonamide group, etc.) of a compound of the present invention with a protecting group or the like according to a conventional method.
  • a functional group eg, a hydroxyl group, an amino group, an imino group, a sulfonamide group, etc.
  • the compound of the present invention when the compound of the present invention has a hydroxyl group, the hydroxyl group is protected with a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”. As a result, such an “ester or other derivative” is obtained.
  • the “general protecting group” refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is preferably formyl, acetyl, or pionyl.
  • Lower aliphatic acryl group arylcarbonyl groups such as benzoyl, ⁇ -naphthoyl and J3-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trifluorobenzoyl Halogenated aryl Lower alkylated arylcarbonyl group such as ponyl group, 2,4,6-trimethylbenzoyl, 4-toluoyl, lower alkoxylated arylcarbonyl group such as 4-anisole, 412trobenzoyl N-arylated arylcarbonyl, such as 2-nitrobenzoyl; lower alkoxylated arylaryl, such as 2- (methoxycarbonyl) benzoyl; arylated arylcarbonyl, such as 4-phenylbenzoyl
  • An “aromatic acyl group” such as a group; a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxy
  • Protective group that can be cleaved in vivo by a biological method such as hydrolysis '' means a protective compound that is cleaved in a human body by a biological method such as hydrolysis and is the original compound or its pharmacologically acceptable.
  • Such “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” is preferably formyloxymethyl, acetooxymethyl, propionyloxymethyl, ptyryloxymethyl, Piperyloxymethyl, Valeryloxymethyl, Isopareryloxymethyl, Hexanoyloxymethyl, 1-Formyloxetil, 1-Acetoxetil, 1-Propionyloxetil, 1 —Ptyryloxyethyl, 1—Bivaloyloxicetyl, 1-Valeryloxicetyl, 1—Isovaleliloxicetyl, 1—Hexanoyloxyxetil, 1—Formyloxypropyl, 1—Acetoxypropyl, 1-propionyloxypropyl, 1-ptyriloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl , 1-Sovaleryloxypropyl, 1-hexanoyloxy
  • the compound (I) of the present invention has an amino group, an imino group and / or a sulfonamide group, it can be converted into a “derivative” by modifying the functional group.
  • a derivative for example, the aforementioned “aliphatic acyl group” or the aforementioned “aromatic acyl group” is bonded to the nitrogen atom of the amino group, imino group and / or sulfonamide group of compound (I). Amide derivatives.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) of the present invention or a pharmaceutically acceptable ester or other derivative thereof has an acid when it has a basic group such as an amino group. By reacting, it also has an acidic group such as a sulfonamide group In some cases, a salt can be formed by reacting with a base.
  • the salt based on a basic group preferably, hydrochloride, hydrobromide, hydrooctiodide such as hydroiodide, nitrate, perchlorate, sulfate, phosphate Inorganic salts such as methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonates such as ethanesulfonate, arylsulfonates such as benzenesulfonate and P-toluenesulfonate; Organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine, lysine, arginine, and ol Amino acid salts such as ditin salts, glutamates and aspartates can be mentioned.
  • an alkali metal salt such as a sodium salt, a potassium salt and a lithium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, an aluminum salt, and an iron Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts N, N'-dibenzylethylenediamine, N-N-dibenzylethylenediamine, N-N-benzylphenethylamine, N-benzylphenethylamine, N-benzylphenethylamine Salt, tetramethylammonium salt, tris (hydroxymethyl)
  • the compound of the present invention having the general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof absorbs moisture when left in the air or recrystallized, There is a case where water is adsorbed or a hydrate is formed, and such a hydrate is also included in the present invention.
  • the compound having the general formula (I) of the present invention includes a geometric isomer (cis, trans or Z-, E-isomer) and an optical isomer based on an asymmetric center in the molecule, etc. There is.
  • these isomers and mixtures of these isomers All compounds are represented by a single formula, ie, general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in any ratio.
  • Specific examples of the compound having the general formula (I) of the present invention include, for example, the following Table 1. And the compounds described in Table 4 can be given.
  • R 6 represents a substituent on the tetrahydropyridinyl group, for example, “1 Me” is tetrahydropyridinyl Indicates a methyl group bonded to the 1-position of a pyridinyl group.
  • R 6 is a hydrogen atom
  • R 6 is to show the substituent on hexa hydro indolizidine group, what is displayed only "one" in the column of R 6 means that R 6 is a hydrogen atom.
  • “Allyl” represents aryl
  • “Bn” represents benzyl
  • “Bu” represents butyl
  • “Et” represents ethyl
  • “Me” represents methyl
  • “Ph” represents phenyl. Show,
  • “Phet” indicates phenethyl
  • “Pip” indicates piperidinyl
  • “: Pr” indicates propyl
  • “Pym” indicates pyrimidinyl
  • “Pyr” indicates pyridyl
  • “> CH 2 ” indicates methylidenyl.
  • CHMeJ represents ethylidenyl
  • CHEtJ represents propylidenyl
  • C (Me) 2 represents isopropylidenyl
  • > CHPr represents butylidenyl
  • > CHPh represents benzylidenyl. Is shown.
  • position 1 to “position 25” represent the following groups, respectively.
  • suitable compounds include the exemplified compound numbers 1-1 to —20, 1-27 to 1-38, 1-45 to 1-64, and 1-171 to 1-82, -89. 1 to 108, 1 to 115 to 1 to 126, 1 to 133 to 1 to 152, 1 to 159 to 1 to 170, 1 to 177 to 1 to 328, 1 to 335 to 1 to 34 6, 1-353 to 1-372, 1-379 to 1-390, 1-397 to 1-416, 1-423 to 1-434, 1-441 to 1-460, 1-467-
  • Examples include compound numbers 1-1 to 1-4, 118 to 1 to 12, 1 to 14 to 1-18, 1 to 20, 1 to 45 to 1 to 48, 1 to 52 to 1 to 56 , 1-58 to 1-62, 1-64, 1-177 to 1-180, 1-184 to 1-188, 1-190 to 11-194, 1-196, 1-21-2 to 1-2 24, 1—228 to 1—232, 1 234 to 1 238, 1—240, 1—265 to 1—268, 1—272 to 1—276, 1—278 to 1—282,
  • Particularly preferred compounds include the following compounds: • 2- (4-fluorophenyl) -1-methyl-4-1 (1-phenethyl-1,2,3,6-tetrahydropyridine-4-1 1) 3_ (pyridine 4-41) 1H 1-pyrrol • 2— (4-Monofluorophenyl) —4— (1,2,3,5,8,8a—Hexahydrid Indolizine-1-7-yl) -1-5-Methyl-3- (pyridine-14-yl) ) 1 H—pyrrole
  • Compound (I) of the present invention can be produced according to the following method. Ku A-1 method>
  • Method A-1> is a method for producing a compound having the general formula (1-1) among the compounds having the general formula (I).
  • R 1 R 2 , R 3 , R 4 and R 5 are as defined above.
  • Step 1a is a step of reacting the aminonitrile compound (1a) ′ with a,] 3-unsaturated ketone compound (2a) to produce a pyrrolidine compound (3a).
  • Step 2a is a method for producing a pyrrolidine derivative (1-1) of the present invention by subjecting the pyrrolidine compound (3a) to a hydrogen cyanide reaction and a dehydration reaction,
  • ⁇ A_2 method>, ⁇ A-3 method>, ⁇ A-4 method> and ⁇ A-5 method> are the general formulas
  • Step 1b, Step 1c, Step 1d, and Step 1 Step e is performed in the same manner as step 1a, and steps 2b, 2c, 2d, and 2e are performed in the same manner as step 2a.
  • Method B-1 is a method for producing a compound having the general formula (1-1) among the compounds having the general formula (I), and is another method of the method A-1.
  • the step 3a is a step of reacting the 1,4-diketone compound (4a) with the amine compound (5a) to produce the compound (I-11) of the present invention, and comprises a known method (for example, L. Knorr, Chem. Ber., 18, 299 (1885)).
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • ⁇ B-2 method>, ⁇ B-3 method>, ⁇ B-4 method>, and ⁇ B-5 method> are the general formulas
  • a method for producing a compound having (I-I), (I-I), (I-4) and (I-I), comprising steps 3b, 3c, 3d and 3d Step e is performed in the same manner as step 3a.
  • Compound (1-1) of the present invention can also be produced by the following Method C. C method>'''
  • R 11 represents a hydrogen atom or the aforementioned “silyl group” (particularly preferably, t-butyldimethylsilyl);
  • R 12 represents a protecting group for a lipoxyl group
  • the cyclic group Hy is a group in which the bond containing a dotted line in the general formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) is a single bond. Show,
  • the cyclic group Hy ′ is a group in which the bond containing a dotted line in the general formula (IIa), (lib), (IIc), (IId), (IIe) or (IIf) is a double bond. Is shown.
  • protecting group for carboxyl group indicates a protecting group for a carbonyl group commonly used in the field of organic synthesis, and examples of such protecting groups include the aforementioned “lower alkyl group”, Examples of the above-mentioned “lower alkenyl group”, the above-mentioned “aralkyl group” and the like are preferable, and the above-mentioned “lower alkyl group” or the above-mentioned “aralkyl group” is preferable. ]
  • the fourth step is a step of reacting the ketoether compound (6) with the ketoester derivative (7) and the ammonium acetate salt (8) to produce a pyrocarboxylic acid ester derivative (9).
  • EP 103 1572 Is carried out according to the method described in (1).
  • the fifth step is a step of producing a substituted pyrrole compound (10) by removing the protecting group (R 12 ) of the pyrocarboxylic acid ester derivative (9) and performing a decarboxylation reaction.
  • EP 103 1572 Is carried out according to the method described in (1).
  • the sixth step is a step of producing a bromopyrrolyl compound (11) by brominating the substituted pyrrole compound (10) with a brominating agent (for example, N-bromosuccinimide).
  • Step 7 is a step of producing the compound (I-la) of the present invention by reacting the bromopyrrole compound (11) with a heterocyclyl ketone (12) after lithiation. Steps 6 and 7 can be performed according to the method described in detail in Brian L. Bray et al., J. Org. Chem., II., 6317-6318 (1990).
  • the eighth step is a step of subjecting the compound (I-1a) of the present invention to a dehydration reaction to produce the compound '(I-1b) of the present invention.
  • This dehydration reaction is usually performed in the presence of an acid catalyst such as sulfuric acid, a solid catalyst such as alumina, or a halogenating agent such as thionyl chloride.
  • an acid catalyst such as sulfuric acid
  • a solid catalyst such as alumina
  • a halogenating agent such as thionyl chloride.
  • the dehydration reaction in this step is a reaction using trialkylsilane such as triethylsilane, tripropylsilane, triptylsilane, and trifluoroacetic acid [for example, Francis A. Carey & Henry S. Tremper, J. Am. Chem. .Soc, 91, 2967-2972 (1969)].
  • trialkylsilane such as triethylsilane, tripropylsilane, triptylsilane, and trifluoroacetic acid
  • the ninth step is a step of reducing the double bond of the compound (I-lb) of the present invention to produce the compound (I-1c) of the present invention.
  • SMKerwin et al. J. Org. Chem., 52, 1686 (1987), T. Hudlicky et al "J. Org. Chem., 52, 4641 (1987), and the like.
  • Step 10 is a step of producing a substituted pyrrole compound (10) by reacting a 1,4-diketone compound (13) with an amine compound (5a), and is carried out in the same manner as in step 3a. Is done.
  • the first and twelfth steps comprise reacting an aminonitrile compound (la) with an ⁇ , 3-unsaturated ketone compound (14) to produce a pyrrolidine compound (15) (step 11),
  • This is a step of producing a substituted pyrrole compound (10) by performing a hydrogen cyanide reaction and a dehydration reaction (Step 12), and is carried out in the same manner as Steps 1a and 2a, respectively.
  • Method C> describes the production of compound (1-1), but the starting material is appropriately selected, and the reaction is carried out in accordance with each step of Method C to obtain the compound (I) of the present invention. 1-2), (1-4) and (1-5) can also be manufactured.
  • the general formula (I one la), in (I one lb) and (I- 1 c), compounds wherein R 5 is hydrogen atom can also be prepared by the following rather Method D>.
  • R 1 , R 2 , R 4 , R 5 , Hy and Hy ′ are as defined above, and R 13 is a protecting group for an amino group.
  • Protecting group Amino group in the definition of R 13 represents a protecting group of Amino groups typically need for in the field of organic synthesis, as such protecting groups, for example, the “fat-aliphatic Ashiru group”
  • the 13th step is a step of protecting the nitrogen atom on the pyrrole ring of the compound (16).
  • Examples are TWGreene et al "Protective Groups m Organic Synthesis, dohn vVilley & Sons, Inc., Brian L.
  • the reaction is carried out according to the reaction described in Bray et al "J. Org. Chem., 55, 6317-6318 (1990).
  • the 14th, 15th, 16th and 17th steps are performed in the same manner as the 6th, 7th, 8th and 9th steps, respectively.
  • the protecting group (R 13 ) is removed to remove the compound of the present invention [that is, the compound (I-11a ′), (I-11b) ') And (I-c')], for example, according to the reaction described in TWGreene et al., Protective Groups in Organic Synthesis, John Willey & Sons, Inc.
  • the compound in which the nitrogen atom on the pyrrole ring is substituted is prepared by first preparing a compound in which the nitrogen atom on the pyrrole ring is not substituted. The compound can be produced by substituting an atom.
  • a compound in which a nitrogen atom on a pyrrole ring in the general formula (I-11) is substituted can be produced according to the following Method E.
  • R 5a represents a group other than a hydrogen atom defined as R 5 ,
  • X ′ represents a hydrogen atom, a propyloxyl group, a protected propyloxyl group, a bromine atom or R 3 , L represents a leaving group.
  • Protected lipoxyl group in the definition of X, indicates a lipoxyl group protected by “protecting group of propyloxyl group” in the definition of R 12 . .
  • leaving group in the definition of L usually indicates a group which leaves as a nucleophilic residue, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; a trihalogenomethyl such as trichloromethoxy.
  • a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; a halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy;
  • Examples include arylsulfonyloxy groups such as benzenesulfonyloxy, monotoluenesulfonyloxy, and p-nitrobenzenesulfonyloxy. It is preferably a halogen atom, and particularly preferably a bromine atom.
  • the second step is a step of reacting the N-unsubstituted pyrrole compound (22) with the compound (23) to produce an N-substituted pyrrole compound (24).
  • the reaction is carried out in a solvent, in the presence or absence of a base.
  • Solvents used include, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; dimethylformamide, dimethyla Aprotic polar solvents such as cetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; pentane And aliphatic hydrocarbons such as hexane and heptane; or a mixed solvent thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane
  • ethers such as getyl ether, diisopropyl ether, t
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • sodium hydroxide alkali metal hydroxides
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • the reaction temperature is usually from 120 ° C. to 150 ° C., preferably from 0 ° C. to 1 O Ot.
  • the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
  • the compound (Ia) wherein R 2 is a heteroaryl group having at least one nitrogen atom substituted with NR a R b can be obtained by the following method F ⁇ .
  • the group —R 2 ′ —L ′ is a “heteroaryl group having at least one nitrogen atom” having a leaving group (group L ′) (for example, 2-methanesulfonylpyrimidine-4-yl, 2 — Methanesulfonylpyridine-14-yl) and the “heteroaryl group having at least one nitrogen atom” is the same group as the “heteroaryl group having at least one nitrogen atom” in the definition of R 2 .
  • group L ′ for example, 2-methanesulfonylpyrimidine-4-yl, 2 — Methanesulfonylpyridine-14-yl
  • the leaving group in the definition of L ′ is the same group as the leaving group in the definition of L; lower alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl, propanesulfonyl and butanesulfonyl; or benzenesulfonyl, p-toluene Represents an arylsulfonyl group such as sulfonyl and p- 12-nitrobenzenesulfonyl, preferably a lower alkylsulfonyl group, and more preferably methanesulfonyl.
  • the 22nd step is a step of producing the compound (Ia) of the present invention by reacting the compound (25) with the amine compound (26) to convert the leaving group into NR a R b. You. This reaction is usually performed in a solvent in the presence or absence of a base.
  • solvents examples include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; dimethylformamide, dimethylacetamide Aprotic polar solvents such as dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; pentane and hexane And aliphatic hydrocarbons such as heptane.
  • alcohols such as methanol, ethanol, propanol and isopropanol
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • dimethylformamide dimethylacetamide
  • Aprotic polar solvents such as dimethyl s
  • Examples of the base used include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; sodium hydroxide; Alkali metal hydroxides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylamine, triptylamine, pyridine, picolin, 1,8-diazabicyclo [5.4.0] _7- Amins such as dendecene may be mentioned.
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • sodium hydroxide Alkali metal hydroxides
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • the reaction temperature is usually from ⁇ 20 ° C. to 150 ° C., but is preferably from 0 ° C. to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • the compound (I) of the present invention is produced by introducing an R 3 group into a pyrrole compound having R 1 , R 2 , R 4 and R 5 groups.
  • a compound having the general formula (1-1) can be produced according to the following Method G.
  • a bromopyrrole compound (27) is prepared in the same manner as in the 7th step.
  • the compound having the above general formula (12) can also be produced by the following Method H to Method L>.
  • R 14 and R 15 are the same or different and represent the “lower alkyl group” or the “aralkyl group”.
  • the 24th step is a step for producing a cyclic amine ester compound (31) by adding the cyclic amino acid ester compound (29) and the carboxylic acid ester compound (30) having a leaving group (L). .
  • This reaction is usually performed in a solvent in the presence or absence of a base.
  • Solvents that can be used include, for example, alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; dimethylformamide, dimethylacetamide, and dimethyl Aprotic polar solvents such as sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; pentane, hexane, heptane And aliphatic hydrocarbons such as
  • Examples of the base used include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; sodium hydroxide; Alkali metal hydroxides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylamine, triptylamine, pyridine, picolin, 1,8-diazabicyclo [5.4.0] Examples include amines such as dendecene.
  • the reaction temperature is usually from ⁇ 20 ° C. to 150 ° C., preferably from 0 ° C. to 100 ° C.
  • the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
  • the cyclic amine diester compound (31) was subjected to a Dieckmann reaction (step 25) to obtain a ketoester compound [compound (32) and compound (33)], and for each compound, Hydrolysis and decarboxylation are performed to produce the desired cyclic aminoketone compound [Compound (34) and Compound (35)]. Step 26 and Step 27).
  • the reaction employed in the above-mentioned 25th to 27th steps is carried out according to the method described in R. Harrison et al., J. Chem. Soc, Perkin Trans. 1, 1999, 3623-3631.
  • the 20th step and the 21st step can be performed, for example, as follows.
  • the reaction of the 26th step and the 27th step is usually carried out in the presence or absence of a solvent, or in the presence or absence of an acid or a base.
  • the solvent examples include water, or water and an organic solvent (for example, aliphatic hydrocarbons such as pentane, hexane, and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; methanol, ethanol, propanol, isopropanol, butanol, s-butanol, and isobutanol Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; nitriles such as acetonitrile; acetic acid Esters, such as methyl and ethyl acetate) If solvent can be mentioned.
  • the acid to be used is not particularly limited as long as it is used as an acid in a usual hydrolysis reaction, and examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, and trifluoroacetic acid. Carboxylic acids such as methanesulfonic acid and ethanesulfonic acid. The progress of this reaction is accelerated by adding an acid.
  • the base to be used is not particularly limited as long as it is used as a base in a usual hydrolysis reaction.
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • sodium hydroxide, potassium hydroxide Alkali metal hydroxides such as sodium carbonate and potassium carbonate
  • Such amines can be mentioned.
  • the reaction temperature is usually from 120 ° C. to 150 ° C., preferably from 0 ° C. to 1 ° C. 00 ° C.
  • the reaction time is generally 0 minute to 48 hours, preferably 30 minutes to 12 hours.
  • R 16 and R 17 are the same or different and represent the “lower alkyl group” or the “aralkyl group”;
  • R 18 and R 19 are the same or different and represent the aforementioned “lower alkyl group”, or R 18 and R 19 together represent the “lower alkylene group”;
  • W may be interrupted by one or two atoms or groups selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, a group> SO and a group> SO 2 , and 1 to 3 R 6 Represents a lower alkylene group substituted with
  • the cyclic group containing W is a group corresponding to the cyclic group B (the B is unsubstituted or has 1 to 3 R 6 ). Show. ]
  • Steps 28 and 29 are described in O. Pollet et al "Heterocycles, 43, 1391 (1996) or Anet et al" Austral. J. scient. Ees., ⁇ A> 3, 635-640 (1950).
  • the reaction can be carried out according to the reaction described in detail. ⁇ J method>
  • R 20 represents a protecting group for an amino group
  • Ha 1 represents a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom), and Y represents a halogenocarbonyl group (for example, —CO—Cl, —CO—Br or —CO— 1)
  • a N-lower alkoxy-N-lower alkyl group rubamoyl group eg, N-methoxy N-methylcarbamoyl, N-ethoxy N-methylcarbamoyl, ethyl N-methoxycarbamoyl, etc.
  • a cyano group eg, N-methoxy N-methylcarbamoyl, N-ethoxy N-methylcarbamoyl, ethyl N-methoxycarbamoyl, etc.
  • protecting group for an amino group in the definition of R 2 Q means a protecting group for an amino group commonly used in organic synthesis, and examples of such groups include the above “aliphatic acyl group” and the above “ Examples include the “aromatic acyl group”, the “silyl group”, the “aralkyl group”, the “alkoxycarbonyl group”, the “alkenyloxycarbonyl” group, and the “aralkyloxycarbonyl group”. ]
  • Step 30 consists of the cyclic amino acid derivative (41) and olefin Grignard reagent (4 2) to produce an a, i3-unsaturated ketone (43).
  • a reaction well known as a reaction for synthesizing a ketone from a carboxylic acid derivative and a Grignard reagent can be employed.
  • Step 31 the protecting group (R 2 Q ) of the nitrogen atom of the ⁇ , —unsaturated ketone compound (43) is removed to give a free compound (44) (Step 31), and the obtained compound is closed ( Step 32) By doing so, the desired cyclic aminoketone compound (45) can be produced.
  • a deprotection reaction generally used in organic synthesis for example, a reaction described in TWGreene et al "Protective Groups in Organic Synthesis, John Willey & Sons, Inc." can be employed.
  • the deprotection reaction under neutral or acidic conditions is employed.After this deprotection reaction, the resulting compound (44) is immediately closed to form the desired aminoketone compound (45) In the case where deprotection is performed under acidic conditions in the third step, the aminoketone compound (45) is immediately produced by neutralizing the reaction solution.
  • L is a leaving group in the definition of L, the above-mentioned" lower alkylsulfonyl group ", the above-mentioned” arylsulfonyl group ", or octogeno lower alkylsulfonyl group (for example, trifluoromethanesulfonyl, pentafluoroethanesulfonyl and the like) ).
  • octogeno lower alkylsulfonyl group for example, trifluoromethanesulfonyl, pentafluoroethanesulfonyl and the like
  • the protecting group ( 2. ) of the ketone compound (46) having a leaving group is removed to obtain a free form (47).
  • the compound (46) as a starting material in this method is known or can be obtained from a known compound by a known method (for example, see SWGoldstein et al "J. Org. Chem” 57, 1179-1190 (1992), B Achille et al "J. Comb. Chem., 2, 337-340 (2000), etc.).
  • R 6 , R 2 Q and B are as defined above,
  • R 21 represents a hydrogen atom or a protecting group for a propyloxyl group
  • R 22 and R 23 are the same or different and each represent a hydrogen atom, the above “lower alkyl group” or the above “aralkyl group”, or R 22 and R 23 are bonded to each other Together with the nitrogen atom, it contains one nitrogen atom, such as piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, and may also contain one oxygen, sulfur or nitrogen atom. Forming an aromatic heterocyclic group;
  • the “protecting group for a carbonyl group” in the definition of R 21 represents the same group as the “protecting group for a carboxyl group” in the definition of R 12 . ]
  • the thirty-fifth and thirty-sixth steps are as follows: First, an ⁇ -keto acid compound having a leaving group (49) The protecting group (R 2 D ) is removed to obtain a free form (50), and then the free form is closed to produce a ketolactam compound (51). Step 31 And the same method as the method described as the 32nd step.
  • the 37th step is a step for producing a cyclic enaminolactam compound (53) by reacting the ketolactam compound (51) with the secondary amine compound (52).
  • an enamine synthesis method widely used in the field of organic synthesis reaction can be employed. For example, G. Stork et al., J. Am. Chem. Soc, 85, 207 (1963) It is carried out according to the method described, for example, as follows.
  • the reaction is usually carried out in a solvent, in the presence or absence of an acid.
  • solvent used examples include aliphatic hydrocarbons such as pendant, hexane, and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, carbonaceous form, carbon tetrachloride, and dichloroethane.
  • Halogenated hydrocarbons such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol, and t-butanol Alcohols; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate And the like.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane
  • aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide
  • nitriles such as aceton
  • the acids used include inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; and acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid.
  • inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid
  • acetic acid formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoroacetic acid
  • Organic acids such as methanesulfonic acid can be mentioned, and preferably, sulfuric acid, hydrogen chloride or p-toluenesulfonic acid is used.
  • the reaction is efficiently carried out by adding a molecular sieve or removing water using a water separator (eg, Dean Staak Water Separator: manufactured by Aldrich).
  • a water separator eg, Dean Staak Water Separator: manufactured by Aldrich.
  • the reaction temperature is usually from 120 to 150 ° C, but is preferably from 0 to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • the 38th step is a step of producing a cyclic enamine compound (54) by reducing the cyclic enaminolactam compound (53).
  • a reduction reaction for producing an amine from an amide commonly used in the field of organic synthesis can be employed, and S. Cortes et al., J. Org. Chem., 48, 2246 (1983); .Tsuda et al "Synthesis, 652 (1977); HCBrown et al., J. Am. Chem. Soc., 86, 3566 (1964) and RJ Sundberg et al" J. Org. Chem., 46, 3730 (1981).
  • the method is performed according to the method described in, for example, as follows.
  • This reaction is usually performed in a solvent in the presence of a reducing agent.
  • reducing agent to be used for example, sodium borohydride, aluminum hydride metal such as lithium borohydride, aluminum aluminum hydride, aluminum hydride compound such as lithium hydride triethoxide aluminum
  • a hydride reagent such as aluminum chloride, tin tetrachloride, and titanium tetrachloride in combination with the above-mentioned "hydride reagent"; and a boron compound such as dipolane.
  • a non-polar solvent can be used, and preferred are aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as mouth form, carbon tetrachloride and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane are used.
  • aliphatic hydrocarbons such as pentane, hexane and heptane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • Halogenated hydrocarbons such as mouth form, carbon tetrachloride and dichloroethane
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane are used.
  • the reaction temperature is usually from ⁇ 20 to 150 ° C., preferably from 0 to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • the 39th step is a step of producing a cyclic aminoketone compound (55) by hydrolyzing the cyclic enamine compound (54).
  • the cyclic enamine compound (54) is produced by the hydrolysis of the cyclic enamine compound (54) in the presence or absence of a solvent.
  • the reaction is carried out by contacting with water in the presence or absence of an acid or a base.
  • solvent water, or water and an organic solvent
  • an organic solvent for example, aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene
  • Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane
  • Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide
  • alcohols such as butyl alcohol, S-butanol, isobutanol, and t-butanol
  • Mixed solvents such as nitriles such as acetonitrile; esters such as methyl
  • the acid to be used is not particularly limited as long as it is used as an acid in a usual hydrolysis reaction, and examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, and trifluoroacetic acid. Carboxylic acids such as methanesulfonic acid and ethanesulfonic acid. The progress of this reaction is accelerated by adding an acid.
  • the base to be used is not particularly limited as long as it is used as a base in a usual hydrolysis reaction.
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • sodium hydroxide, potassium hydroxide Alkali metal hydroxides such as sodium carbonate and potassium carbonate
  • the reaction temperature is usually from 120 ° to 150 ° C., preferably from 0 ° C. to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • 'Compound (53) which is an intermediate in the production of cyclic aminoketone compound (55), can also be produced by the following ⁇ Method M>. M method>
  • R 6 , R 14 , R 15 , R 22 and R 23 have the same meanings as above,
  • R 24 represents a hydrogen atom or a protective group for a propyloxyl group.
  • the term "protecting group for a carbonyl group” in the definition of R 24 means a protecting group for a carbonyl group commonly used in organic synthesis, and such a group is preferably a "lower alkyl group” described above. And the aforementioned “aralkyl group”.
  • the fortieth step is a step of producing an amino diester compound (58) by reacting the cyclic amino acid ester compound (56) with a malonic acid derivative (57) or a reactive derivative thereof. In this step, an amidation reaction commonly used in the field of organic synthesis can be employed, and is carried out, for example, as described in (a), (b) and (c) below.
  • R 24 is a hydrogen atom
  • the reaction is carried out in a solvent, in the presence of a condensing agent, in the presence or absence of a base.
  • solvent used examples include aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, Halogenated hydrocarbons such as carbon form, carbon tetrachloride and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; methanol, ethanol, propanol, isopropanol, butanol, s-butanol, iso Alcohols such as butanol and t-butanol; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile; methyl acetate And esters such as ethyl acetate; water; or a mixed solvent thereof.
  • condensing agent examples include dicyclohexylcarposimide, 1-ethyl-3- (3-dimethylaminopropyl) carposimide, and N, N'-carbonyldi'midazole.
  • Examples of the base used include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium-t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; sodium hydroxide; Alkali metal hydroxides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylamine, triptylamine, pyridine, picolin, 1,8-diazabicyclo [5.4.0] Examples include amines such as dendecene.
  • the reaction temperature is usually from 120 ° C to 150 ° C, but is preferably from 0 ° C to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • R 24 is a hydrogen atom
  • the compound (57) can be converted into a reactive derivative, and then the reaction can be carried out according to the method described in (c).
  • R 2 4 is carboxyl protecting group (preferably, the "lower alkyl group” or pre-Symbol “Ararukiru group”), then the reaction is be heated presence or absence of a solvent Rukoto Is achieved by
  • reaction temperature is between 30 and 100 ° C., preferably in the range of ⁇ 5 ° C. of the boiling point of the solvent used.
  • the reaction is carried out by heating the reaction under reflux.
  • the reaction can be carried out by mixing the compound (56) and the compound (57) and heating the mixture.
  • the reaction temperature is from 30 ° C. to 150, preferably from 50 ° C. to 120.
  • the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
  • reactive derivative refers to acid octaprogenated compound, mixed acid anhydride, active ester, active amide, and the like. It is carried out in the presence of an agent, in the presence or absence of a base.
  • “Acid octalogenide” can be obtained by reacting compound (57) wherein R 24 is hydrogen with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.); "Can be obtained by reacting a compound (57) wherein R 24 is hydrogen with an acid octalogenide (eg, methyl methyl carbonate, ethyl ethyl carbonate, etc.); Reacting the compound (57) wherein R 24 is hydrogen with a hydroxy compound (eg, N-hydroxysuccinimide, N-hydroxyphthalimide) in the presence of the “condensing agent” described in (a) You can get one good especially; "active amide” (for example, Weinreb amide) are compounds R 24 is hydrogen (57) and N- lower alkoxy -N- lower alkyl hydroxy ⁇ Min (eg if Can be obtained by reacting in the presence of said N- methoxy one N- methyl hydroxy ⁇ Min, etc
  • the solvent As the solvent, the condensing agent and the base, the solvent, the condensing agent and the base described in (a) can be used.
  • the reaction temperature is usually from ⁇ 20 ° C. to 150 ° C., preferably from 0 to 100 ° C.
  • the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 12 hours.
  • the amide diester compound (58) is subjected to a Dieccman reaction to produce a ketolactam ester compound (59), which is then hydrolyzed and decarboxylated to carry out the ketolactam compound (60). ), And is carried out in the same manner as in the 25th and 26th steps.
  • the forty-third step is a step for producing a cyclic enaminolactam compound (53) by reacting the ketolactam compound (60) with the secondary amine compound (52), and is carried out in the same manner as in the thirty-seventh step.
  • compound (59) which is an intermediate in the above-mentioned Method M, can also be produced by the following Method N>.
  • the forty-fourth step is a step of producing an amide monoester compound (62) by reacting the cyclic amino acid (61) with the malonic acid derivative (57) or a reactive derivative thereof. ) And (c).
  • the forty-fifth step is a step of producing a ketolactam ester compound (59) by condensing the carbonyl group of the amide monoester compound (62) and the active methylene group in the molecule to close the ring.
  • compound (62) is used as it is, or compound (62) is converted into a reactive derivative and used.
  • solvent used examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; methanol, ethanol, propanol, Alcohols such as isopropanol, butanol, s-butanol, iso-butanol, t-butanol; non-protons such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide A polar solvent; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; water; or a mixed solvent thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane
  • ethers such as get
  • condensing agent examples include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and N, N'-monolupoerdiimidazole.
  • Examples of the base used include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium-t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; sodium hydroxide; Alkali metal hydroxides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylamine, triptylamine, pyridine, picolin, 1,8-diazapiciclo [5.4.0] Examples include amines such as dendecene.
  • the reaction temperature is usually from 120 ° C. to 150 ° C., preferably from 0 ° C. to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • the compound (62) is used as a reactive derivative, and when it is used, examples of the reactive derivative include acid halides, mixed acid anhydrides, active esters, and active amides.
  • the acid halide can be obtained by reacting the compound (62) with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.); the mixed acid anhydride can be obtained by reacting the compound (62) with the compound (62).
  • Acid halides eg, methyl methyl carbonate, black carbon
  • the active ester can be obtained by reacting the compound (62) with a hydroxy compound (for example, N-hydroxysuccinimide, N-hydroxyphthalimide).
  • the ring closure reaction of the reactive derivative is usually performed in a solvent, in the presence or absence of a base.
  • the solvent As the solvent, the condensing agent and the base, the solvent, the condensing agent and the base described in (a) can be used.
  • the reaction temperature is usually from 120 to 150 ° C, preferably from 0 to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
  • R 3 which is a partial structure of the compound of the general formula (I) may have various substituents (R 6 ). This R 6 can be converted to another substituent in each of the above steps, and can be converted as follows, for example, according to a conventional method.
  • R 25 represents the ⁇ lower alkyl group '', the ⁇ octogeno lower alkyl group '', the ⁇ aryl group '' or the ⁇ aryl group substituted with a group selected from the substituent group and the substituent group J3 '',
  • R 26 is the same or different and represents the “lower alkyl group” or the “halogeno lower alkyl group”, or two R 26s together represent a lower alkylene group;
  • R 27 represents the above “lower alkyl group”.
  • R 28 represents a hydrogen atom or the above “lower alkyl group”.
  • R 29 is selected from “lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “aralkyl group”, “cycloalkyl group” and “substituent group ⁇ ” in the definition of substituent group 3 ′.
  • a lower alkyl group substituted with a selected group a lower alkenyl group substituted with a group selected from a substituent group ⁇ , or an alkynyl substituted with a group selected from a substituent group ⁇ .
  • aryl group or “aryl group substituted with a group selected from substituent group III and substituent group / 3” in the definition of substituent group a.
  • R 6 is a halogen atom, a hydroxyl group, a cyano group, or a lower alkylsulfonyl group
  • a double bond is formed as described below, and then a reduction reaction is carried out according to a conventional method.
  • the substituent may be replaced by a hydrogen atom.
  • R 6 represents the same meanings as defined above, R 6 a represents a halogen atom, a hydroxyl group, a Shiano group or a lower alkyl sulfonyl Le group.
  • R 6 is a lower alkylidenyl group or an aralkylidenyl group
  • R 6 is a lower alkylidenyl group or an aralkylidenyl group
  • the corresponding lower aralkyl-substituted compounds or aralkyl-substituted compounds can be produced.
  • 13 () and 13 1 are the same or different and each represent a hydrogen atom, the “lower alkyl group”, the “aryl group” or the “aralkyl group”).
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating the organic layer containing, drying with anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or A method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, magnesium-silicon gel-based florisil; Sephadex LH-20 (Pharmacia) Synthetic adsorbents such as partition column chromatography using carriers such as Amberlite XAD-11 (Rohm and Space) and Diaion HP-20 (Mitsubishi Chemical).
  • the method used the method using ion exchange chromatography, or the appropriate combination of normal phase and reversed phase column chromatography with silica gel or alkylated silica gel (preferably high performance liquid chromatography), and appropriate elution Separation and purification can be achieved by eluting with an agent. Since the compound of the present invention exhibits an excellent inhibitory action on inflammatory site force-in production, it is effective as a medicine (in particular, a preventive or therapeutic agent for diseases mediated by inflammatory site force-in).
  • Such medicaments include, for example, analgesic * anti-inflammatory agents, antiviral agents, and rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis, autoimmune diseases (eg, Prophylactic or therapeutic agents for systemic erythematosus, ulcerative colitis, Crohn's disease, etc., diabetes mellitus, nephritis, hepatitis, tumors, ischemic heart disease, Alzheimer's disease, arteriosclerosis,
  • analgesic anti-inflammatory agents, and preventive or therapeutic agents for rheumatoid arthritis, osteoarthritis, allergic diseases, sepsis, psoriasis, osteoporosis, ulcerative colitis, diabetes, hepatitis, arteriosclerosis be able to.
  • the compound of the present invention having the general formula (I), or a pharmacologically acceptable salt or derivative thereof may be administered in the form of, for example, tablets, capsules, granules, powders or syrups, orally, or injections. Alternatively, parenteral administration with a suppository or the like can be mentioned. These preparations are manufactured by a known method using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • excipient examples include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch; and crystalline cellulose.
  • Organic excipients such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose monocalcium, internally crosslinked cellulose derivatives such as sodium carboxymethylcellulose; Arabic gum; dextran; pullulan; And silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; inorganic phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; System excipients.
  • Lubricants include, for example, stearic acid metal salts such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay; boric acid: adipic acid; sulfuric acid such as sodium sulfate Salts: daricol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; Derivatives and the like can be given.
  • stearic acid metal salts such as stearic acid, calcium stearate and magnesium stearate
  • talc colloidal silica
  • waxes such as veegum and gay
  • boric acid adipic acid
  • sulfuric acid such as sodium sulfate Salts: daricol
  • binder examples include polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients.
  • disintegrant examples include the same compounds as the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • the stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid And sorbic acid.
  • paraoxybenzoic acid esters such as methylparaben and propylparaben
  • alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol
  • benzalkonium chloride examples include phenols such as phenol and cresol; thimerosal; dehydroacetic acid And sorbic acid.
  • the flavoring agent examples include commonly used sweeteners, acidulants, flavors and the like.
  • the dosage varies depending on symptoms, age, administration method, etc.
  • the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 2000 mg (preferably) per adult per day. It is advisable to administer 500 mg) once or in several divided doses according to the symptoms.
  • the lower limit is 0.0 lmg (preferably 0.05 mg) and the upper limit is 200 mg (preferably 50 mg) once or several times a day. It is desirable to administer according to the symptoms.
  • reaction solution was added to a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in 4 Om 1 of dichloroethane, and 1.95 ml (25.3 mmo 1) of trifluoroacetic acid was added. The mixture was heated under reflux for 1 hour, and the reaction solution was concentrated under reduced pressure.
  • reaction solution was poured into 500 ml of concentrated aqueous ammonia, and the precipitated crystals were taken out and washed with water and hexane to obtain 20.64 g of the title compound as a slightly brown powder (yield; quantitative). Target).
  • the preparation of the present invention containing the compound having the general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient can be produced, for example, by the following method.
  • Peripheral blood was collected from healthy volunteers in the presence of heparin.
  • Whole blood 10001 is added to an eppendorf tube to which a test compound dimethyl sulfoxide solution 21 has been added in advance, and lipopolysaccharide (LPS) (derived from E. coli ⁇ 26: B6, D ⁇ fco Co.) (final concentration 1 0 beta g / 1) 1 0 1 well mixed after the addition, at 37, was subjected to 6-hour culture under the condition of 5% C_ ⁇ 2. After completion of the culture, the reaction was stopped by cooling at 4 and immediately centrifuged at 14,000 rpm for 5 minutes, and the plasma of the supernatant was separated and collected. IL-11i3 and TNF ⁇ produced and released in plasma were measured with an enzyme immunoassay ( ⁇ LISA) kit (Cayman and Genzyme). The inhibition rate was determined from the amount of cytokine production in the presence and absence of the test compound.
  • LPS lipopolysaccharide
  • the compound of the present invention showed an excellent inhibitory action on cytoforce in production.
  • TNF ⁇ was measured using an enzyme immunoassay (ELISA) kit (mouse TNF ELISAKIT, Genzyme).
  • ELISA enzyme immunoassay
  • test compound was suspended in 0.5% tragacanth solution and orally administered at a ratio of 10 ml / body weight 1 kg 30 minutes before the injection of LPS.
  • a minimum of 3 doses per test compound were administered to 5 mice each. For each dose, the average inhibition rate for the control group was calculated.
  • washing solution from the intraperitoneal cavity was immediately transferred to a 1.5 ml eppendorf tube, and centrifuged at 4 ° C and 7,500 rpm to separate the supernatant. This supernatant was stored at 120 ° C until the measurement of IL-1; 8.
  • the amount of IL-1; 3 was measured using an enzyme immunoassay (ELISA) kit (mousse ELISAKIT, Genzyme).
  • test compound was suspended in 0.5% tragacanth solution and orally administered at a ratio of 10 kg / Z body weight 1 kg 30 minutes before the injection of LPS.
  • a minimum of 3 doses per test compound were administered to 5 mice each. For each dose, the average inhibition rate for the control group was calculated.
  • the method was performed according to the method of Winder et al. (Arthritis Rheum., 12, 472-482, 1969).
  • Heat-killed mycelium of Mycobacterium butyricum (Difco Laboratories, lot 679123) is refined in an agate mortar, and then dried and heat-sterilized in liquid paraffin (Wako Pure Chemical Industries, Ltd., first grade) to 2 mgZm 1.
  • An adjuvant was prepared by suspending and sonicating. This adjuvant (100 g / 0.05 ml / paw as heat-killed cells) was injected into the right hind paw of a Lewis female rat (9 weeks old, weighing about 190 g, Charles-Lipper Co., Ltd. Japan). Caused arthritis.
  • test compound is suspended in a 0.5% aqueous solution of sodium carboxymethylcellulose, and once a day from the day of adjuvant injection (Day 0: DavO) to Day 20, 5m1Z Oral administration was performed at a rate of kg.
  • the volume of right foot (foot injected with adjuvant) and left foot (foot not injected) was measured and swelling was observed.
  • the volume (the volume of the hind paw of the adjuvant-injected animal minus the volume of the hind paw of the healthy group) was calculated.
  • the paw volume was measured using a rat paw volume measuring device (Plesthymometer, Ugo Basile), with the hairline of the hind limb and the foot apex placed in the tank of the measuring device.

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Abstract

L'invention concerne des composés permettant d'inhiber la production de cytokines inflammatoires. L'invention concerne des composés de formule (I) ou des sels acceptables sur le plan pharmaceutique, des esters ou autres dérivés desdits composés, où A désigne pyrrole; R1 représente un aryle éventuellement substitué ou un hétéroaryle éventuellement substitué; R2 représente un hétéroaryle éventuellement substitué; R3 représente un acide aminé bicyclique; et R4 et R5 sont chacun H, cycloalkyle substitué, aryle éventuellement substitué, hétéroaryle éventuellement substitué, ou un groupe hétérocyclique éventuellement substitué, à la condition que les atomes constituant l'anneau auquel R1 et R2 sont liés soient chacun adjacents à l'atome, constituant de l'anneau, auquel R2 est relié.
PCT/JP2002/000401 2001-01-22 2002-01-22 Derives du pyrrole substitues en 4 ou 5 WO2002057255A1 (fr)

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JP2001013591 2001-01-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015781A1 (fr) * 2001-08-15 2003-02-27 Sankyo Company, Limited Nouvelles compositions pharmaceutiques antidiabetiques
WO2003022832A1 (fr) * 2001-09-05 2003-03-20 Smithkline Beecham P.L.C. Pyridylfurans et pyrroles inhibiteurs de la kinase raf
WO2004009592A1 (fr) * 2002-07-19 2004-01-29 Sankyo Company, Limited Compose amine tertiaire bicyclique insature

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005877A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2, compositions contenant de tels composes et leurs modes d'utilisation
WO1997005878A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation
WO1997016442A1 (fr) * 1995-10-31 1997-05-09 Merck & Co., Inc. Pyrroles de pyridyle substitues, compositions contenant de tels composes et mode d'utilisation
WO2000001688A1 (fr) * 1998-07-02 2000-01-13 Sankyo Company, Limited Composes heteroaryle a cinq elements
WO2000066124A1 (fr) * 1999-04-28 2000-11-09 Sankyo Company, Limited Agents preventifs ou inhibiteurs destines a une hepatopathie
EP1070711A2 (fr) * 1999-07-21 2001-01-24 Sankyo Company Limited Dérivés de pyrrole hétéroaryl substitués, leur préparation et leur utilisation thérapeutique
JP2001181187A (ja) * 1999-12-27 2001-07-03 Sankyo Co Ltd ５員ヘテロアリール化合物を含有する組成物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005877A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2, compositions contenant de tels composes et leurs modes d'utilisation
WO1997005878A1 (fr) * 1995-08-10 1997-02-20 Merck & Co., Inc. Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation
WO1997016442A1 (fr) * 1995-10-31 1997-05-09 Merck & Co., Inc. Pyrroles de pyridyle substitues, compositions contenant de tels composes et mode d'utilisation
WO2000001688A1 (fr) * 1998-07-02 2000-01-13 Sankyo Company, Limited Composes heteroaryle a cinq elements
WO2000066124A1 (fr) * 1999-04-28 2000-11-09 Sankyo Company, Limited Agents preventifs ou inhibiteurs destines a une hepatopathie
EP1070711A2 (fr) * 1999-07-21 2001-01-24 Sankyo Company Limited Dérivés de pyrrole hétéroaryl substitués, leur préparation et leur utilisation thérapeutique
JP2001181187A (ja) * 1999-12-27 2001-07-03 Sankyo Co Ltd ５員ヘテロアリール化合物を含有する組成物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015781A1 (fr) * 2001-08-15 2003-02-27 Sankyo Company, Limited Nouvelles compositions pharmaceutiques antidiabetiques
WO2003022832A1 (fr) * 2001-09-05 2003-03-20 Smithkline Beecham P.L.C. Pyridylfurans et pyrroles inhibiteurs de la kinase raf
US7446106B2 (en) 2001-09-05 2008-11-04 Smithkline Beecham Plc Pyridylfurans and pyrroles as Raf kinase inhibitors
WO2004009592A1 (fr) * 2002-07-19 2004-01-29 Sankyo Company, Limited Compose amine tertiaire bicyclique insature

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