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WO2009133861A1 - Composé amine cyclique - Google Patents

Composé amine cyclique Download PDF

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Publication number
WO2009133861A1
WO2009133861A1 PCT/JP2009/058297 JP2009058297W WO2009133861A1 WO 2009133861 A1 WO2009133861 A1 WO 2009133861A1 JP 2009058297 W JP2009058297 W JP 2009058297W WO 2009133861 A1 WO2009133861 A1 WO 2009133861A1
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atom
alkyl
ring
hydrogen atom
substituent
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淳 蓮岡
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a cyclic amine compound useful as an androgen receptor modulator.
  • Androgens are synthesized in the testis and adrenal cortex, bind to androgen receptors in target organs, and exhibit various physiological activities. Natural androgens all belong chemically to C19 steroids. Among them, the main androgen is testosterone synthesized mainly in the testis, and has a strong uptake and physiological activity in target cells. In women, the adrenal cortex is a major source of androgens. Androgen develops and maintains the functions of the reproductive organs (prostate, seminal vesicles, accessory testis, vas deferens, etc.), sex differentiation in the embryonic period, spermatogenesis, expression of secondary sexual characteristics (musculoskeletal, voice, fat distribution, etc.
  • reproductive organs prostate, seminal vesicles, accessory testis, vas deferens, etc.
  • spermatogenesis expression of secondary sexual characteristics (musculoskeletal, voice, fat distribution, etc.
  • An object of the present invention is to provide a compound having a more excellent androgen receptor modulating action.
  • R 1 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 2 represents a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 3 is an optionally substituted heterocyclic group
  • R 4 represents a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 5 represents a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 6 represents a hydrogen atom, a
  • R 3 may be optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl , Optionally substituted thiazolyl, optionally substituted pyrrolyl, optionally substituted 1,2,4-oxadiazolyl, or optionally substituted
  • R 1 is (1) a hydrogen atom or (2) C 1-6 alkyl
  • R 2 is (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms
  • R 3 is (1) a halogen atom and 1 to a substituent selected from hydroxy three optionally having C 1-6 alkyl, (2) a halogen atom, (3) C 3-8 cycloalkyl, ( 4) Cyano
  • Ring Ba is an optionally substituted 5-membered aromatic heterocyclic ring
  • R 1a is a hydrogen atom or C 1-6 alkyl
  • R 2a is a hydrogen atom, a halogen atom or a C 1-6 alkyl optionally having 1 to 3 halogen atoms
  • R 7a is C 1-6 alkyl optionally having 1 to 3 halogen atoms
  • R 8a is a hydrogen atom or C 1-6 alkyl
  • R 9a is hydroxy optionally substituted with C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms
  • R 10a and R 11a are the same or different and each represents a hydrogen atom or C 1-6 alkyl, or R 10a and R 11a together with adjacent carbon atoms form a cyclopropane ring
  • R 12a and R 13a each represent a hydrogen atom, or R 12a and R 13a together form an oxo.
  • ring B a is good thiophene ring which may have a substituent and may furan ring which may have a substituent, may pyrazole ring which may have a substituent, substituted An isoxazole ring which may have a substituent, a thiazole ring which may have a substituent, a pyrrole ring which may have a substituent, a 1,2,4-oxadiazole ring which may have a substituent Or a compound according to the above [4], which is an optionally substituted 1,3,4-oxadiazole ring; [6] Ring B a is (1) a thiophene ring optionally having a substituent selected from a halogen atom, cyano, C 1-6 alkyl-carbonyl and C 1-6 alkyl, (2) Furan ring (3) a pyrazole ring optionally having a C 1-6 alkyl group,
  • Ring Bb is a 5-membered aromatic heterocycle; R b is carbamoyl or C 1-6 alkyl; R 1b is a hydrogen atom or C 1-6 alkyl; R 2b is a halogen atom; R 7b is C 1-6 alkyl; R 8b is a hydrogen atom or C 1-6 alkyl; R 12b and R 13b each represent a hydrogen atom, or R 12b and R 13b together form an oxo.
  • the compound of the above-mentioned [1] represented by: [8] Partial structure
  • [1] is (1) an oxadiazole ring substituted with carbamoyl or C 1-6 alkyl, or (2) a thiophene ring substituted with C 1-6 alkyl; [9] 3- ⁇ 2-Fluoro-4-[(2S, 3S) -3-hydroxy-2,3-dimethylpyrrolidin-1-yl] -3-methylphenyl ⁇ -1,2,4-oxadiazole -5-carboxamide or a salt thereof; [10] (2S, 3S) -1- [3-Fluoro-2-methyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -2,3-dimethylpyrrolidine -3-ol or a salt thereof; [11] (2S, 3S) -1- [3-Chloro-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -2,3-dimethylpyrrolidin-3-ol Or
  • halogen atom represented by R 1 , R 2 , R 4 , R 5 , R 6 or R 8 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Examples of the “group via carbon atom” represented by R 1 , R 2 , R 4 , R 5 , R 6 or R 8 include cyano, a hydrocarbon group which may have a substituent, acyl, Carboxyl which may be esterified, imidoyl which may have a substituent, amidino which may have a substituent, carbamoyl which may have a substituent, which may have a substituent Examples thereof include a good thiocarbamoyl and a heterocyclic group via a carbon atom which may have a substituent.
  • hydrocarbon group optionally having substituent (s) alkyl optionally having substituent (s), alkenyl optionally having substituent (s), and optionally having substituent (s) Alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl and the like can be mentioned.
  • alkyl in the above-mentioned “optionally substituted alkyl” includes, for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , Pentyl, hexyl, etc.).
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
  • Pentyl hexyl, etc.
  • substituents examples include, for example: (i) halogen atoms (eg, fluorine, chlorine, bromine and iodine atoms), (ii) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (iii) C 2-6 alkenyl (eg, vinyl, allyl, etc.), (iv) C 2-6 alkynyl (eg, ethynyl, propargyl etc.), (v) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), (vi) amino, (vii) mono C 1-6 alkylamino (eg.
  • alkenyl in the above-mentioned “optionally substituted alkenyl” include C 2-6 alkenyl (eg, vinyl, allyl, etc.) and the like.
  • substituent that the above “optionally substituted alkenyl” may have include (1) the above “optionally substituted alkyl”.
  • C 1-6 alkyl eg, methyl, ethyl
  • C 1-6 alkyl which may have 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms) and hydroxy , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc., and may have 1 to 3 at substitutable positions.
  • alkynyl in the above “optionally substituted alkynyl” include C 2-6 alkynyl (eg, ethynyl, propargyl, etc.) and the like.
  • substituent which the above-mentioned “alkynyl which may have a substituent” may have include, for example, the substituent which the above-mentioned “alkenyl which may have a substituent” may have. Examples thereof include those similar to the group, and may have 1 to 3 groups at substitutable positions.
  • cycloalkyl of the above-mentioned “cycloalkyl which may have a substituent” is, for example, C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.) Etc.
  • substituents that the above-mentioned “cycloalkyl which may have a substituent” may have include the above-mentioned “alkenyl which may have a substituent”. Examples thereof include the same as the substituent, and may have 1 to 3 substituents at substitutable positions.
  • aryl in the above “aryl optionally having substituent (s)” include C 6-14 aryl (eg, phenyl, naphthyl, anthryl, etc.) and the like.
  • substituents that the above “optionally substituted aryl” may have include, for example, the above “optionally substituted alkenyl” that may be substituted. Examples thereof are the same as those described above, and may be 1 to 3 at substitutable positions.
  • the “aralkyl” of the above-mentioned “aralkyl optionally having substituent (s)” includes, for example, C 7-14 aralkyl (eg, benzyl, phenylethyl, naphthylmethyl etc.) and the like.
  • substituents that the above-mentioned “aralkyl which may have a substituent” may have include, for example, the substituent which the above-mentioned “alkenyl which may have a substituent” may have. Examples thereof are the same as those described above, and may be 1 to 3 at substitutable positions.
  • Examples of the “acyl” include a group in which the “hydrocarbon group which may have a substituent” is bonded to carbonyl.
  • Examples of the “optionally esterified carboxyl” include the carboxyl that may be esterified with the above “optionally substituted hydrocarbon group”.
  • Examples of the “imidoyl optionally having substituent (s)” include imidoyl optionally having one or two of the above “hydrocarbon groups optionally having substituent (s)”.
  • Examples of the above-mentioned “amidino optionally having substituent (s)” include amidino optionally having 1 to 3 “hydrocarbon groups optionally having substituent (s)”.
  • optionally substituted carbamoyl examples include carbamoyl optionally having one or two of the above “optionally substituted hydrocarbon groups”.
  • optionally substituted thiocarbamoyl examples include thiocarbamoyl optionally having one or two “optionally substituted hydrocarbon groups”.
  • heterocyclic group via a carbon atom of the above-mentioned “heterocyclic group via a carbon atom which may have a substituent”, for example, as an atom (ring atom) constituting a ring system, an oxygen atom, An aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) hetero atoms selected from sulfur atom, nitrogen atom and the like. Or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and a group bonded via a carbon atom.
  • aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl , Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., 5- to 6-membered monocyclic aromatic heterocyclic groups and, for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoind
  • non-aromatic heterocyclic group examples include 3 to 8 members (preferably 5 to 5) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
  • 1,2,3,4-tetrahydroquinolyl 1,2,3,4 -Non-aromatic heterocyclic groups in which some or all of the double bonds of the above monocyclic aromatic heterocyclic groups or condensed polycyclic aromatic heterocyclic groups are saturated, such as tetrahydroisoquinolyl It is done.
  • Examples of the substituent which the above-mentioned “heterocyclic group via an optionally substituted carbon atom” may have include the above-mentioned “optionally substituted alkenyl”. And the like, and the like, and the like, which may be substituted, may have 1 to 3 substituents at substitutable positions.
  • Examples of the “group through nitrogen atom” represented by R 1 , R 2 , R 4 , R 5 , R 6 or R 8 include (i) amino, and (ii) the above “group through carbon atom”. And (iii) the above “group via carbon atom” and amino disubstituted by C 1-6 alkyl (eg, methyl, ethyl, propyl, etc.), and the like.
  • Examples of the “group via a sulfur atom” represented by R 1 , R 2 , R 4 , R 5 or R 6 include mercapto which may be substituted with the above “group via a carbon atom”. It is done. The mercapto may be oxidized.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R 3 is 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like (preferably Is an aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic ring) Group).
  • aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl , 5- or 6-membered monocyclic aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • non-aromatic heterocyclic group examples include 3 to 8 members (preferably 5 to 5) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Or a 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group).
  • substituents of the “heterocyclic group optionally having substituent (s)” represented by R 3 for example, the above “alkenyl optionally having substituent (s)” may have Examples of such a substituent are the same as those described above, and may have 1 to 3 substituents at substitutable positions.
  • Examples of the “alkyl optionally having substituent (s)” represented by R 7 include the same as the above-mentioned “alkyl optionally having substituent (s)”.
  • Ring A represents a pyrrolidine ring or piperidine ring which may further have a substituent in addition to R 6 to R 9 .
  • the “pyrrolidine ring or piperidine ring” of the “pyrrolidine ring or piperidine ring optionally having a substituent in addition to R 6 to R 9 ” represented by ring A is preferably a pyrrolidine ring.
  • substituents that the ring A may further have include, for example, (1) the same substituents that the above-mentioned “alkenyl optionally having substituents” may have, (2 ) C 1-3 (poly) methylene (eg, methylene, ethylene, trimethylene) (may be bonded to the same carbon atom or bonded to two carbon atoms), (3) oxo, etc. 1 to 3 may be present at substitutable positions.
  • R 1 and R 5 are the same or different and each is preferably (1) a hydrogen atom or (2) an optionally substituted alkyl. Among them, (1) a hydrogen atom or (2) C 1 1- 6 alkyl is preferred. In particular, (1) hydrogen atom or (2) methyl is preferable. R 1 is preferably (1) a hydrogen atom or (2) an optionally substituted alkyl, and (1) a hydrogen atom or (2) C 1-6 alkyl is particularly preferable. In particular, (1) hydrogen atom or (2) methyl is preferable. R 5 is preferably a hydrogen atom.
  • R 2 and R 4 are preferably the same or different and each is (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted alkyl.
  • (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms is preferable.
  • (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, or (4) methyl optionally having 1 to 3 fluorine atoms is preferable.
  • R 2 is preferably (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted alkyl.
  • (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms is preferable.
  • (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, or (4) methyl optionally having 1 to 3 fluorine atoms is preferable.
  • R 4 is preferably a hydrogen atom.
  • R 3 is preferably a 5- or 6-membered aromatic heterocyclic group which may have a substituent. Of these, an optionally substituted 5-membered aromatic heterocyclic group is preferable.
  • thienyl which may have a substituent
  • furyl which may have a substituent
  • pyrazolyl which may have a substituent
  • isoxazolyl which may have a substituent
  • An optionally substituted thiazolyl, an optionally substituted pyrrolyl, an optionally substituted 1,2,4-oxadiazolyl, or an optionally substituted 1,3,4 -Oxadiazolyl is preferred.
  • R 3 (1) C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy, (2) a halogen atom, (3) C 3-8 cyclo Alkyl, (4) cyano, (5) C 1-6 alkyl-carbonyl, (6) C 1-6 alkoxy-carbonyl, (7) carbamoyl, (8) mono C 1-6 alkyl-carbamoyl and (9) mono 5-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from C 3-8 cycloalkyl-carbamoyl (eg, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, thiazolyl, pyrrolyl, imidazolyl) 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, etc., preferably thienyl, furyl, pyrazolyl
  • R 6 is preferably a hydrogen atom.
  • R 7 is preferably C 1-6 alkyl which may have a substituent. Of these, C 1-6 alkyl which may have 1 to 3 halogen atoms is preferable. In particular, (1) methyl or (2) ethyl which may have 1 to 3 fluorine atoms is preferable.
  • R 8 is preferably a hydrogen atom or an optionally substituted alkyl. Of these, a hydrogen atom or C 1-6 alkyl is preferable. In particular, a hydrogen atom or methyl is preferable.
  • R 9 is preferably hydroxy optionally substituted with an optionally substituted C 1-6 alkyl-carbonyl.
  • hydroxy optionally substituted with C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms is preferable.
  • hydroxy or trifluoromethylcarbonyloxy is preferred.
  • Ring A includes 1 to 3 substituents selected from (1) C 1-6 alkyl, (2) C 1-3 (poly) methylene and (3) oxo in addition to R 6 to R 9
  • the pyrrolidine ring which may have is preferable.
  • a pyrrolidine ring which may further have 1 to 3 substituents selected from methyl, ethylene (bonded to the same carbon atom) and oxo is preferable.
  • R 1 is (1) a hydrogen atom or (2) an optionally substituted alkyl
  • R 2 is (1) a hydrogen atom, (2) a halogen atom or (3) an optionally substituted alkyl
  • R 3 is an optionally substituted 5- or 6-membered aromatic heterocyclic group
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R 6 is a hydrogen atom
  • R 7 is optionally substituted C 1-6 alkyl
  • R 8 is a hydrogen atom or an optionally substituted alkyl
  • R 9 is hydroxy optionally substituted with optionally substituted C 1-6 alkyl-carbonyl
  • ring A is in addition to R 6 to R 9 and (1) C 1-6
  • R 1 is (1) a hydrogen atom or (2) C 1-6 alkyl
  • R 2 is (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms
  • R 3 is (1) a halogen atom and 1 to a substituent selected from hydroxy three optionally having C 1-6 alkyl, (2) a halogen atom, (3) C 3-8 cycloalkyl, ( 4) Cyano, (5) C 1-6 alkyl-carbonyl, (6) C 1-6 alkoxy-carbonyl, (7) carbamoyl, (8) mono C 1-6 alkyl-carbamoyl and (9) mono C 3- 5-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from 8 cycloalkyl-carbamoyl (eg, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, thiazolyl, pyrroly
  • R 1 is (1) a hydrogen atom or (2) methyl
  • R 2 is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom or (4) methyl optionally having 1 to 3 fluorine atoms
  • R 3 is (1) methyl, (2) ethyl, (3) trifluoromethyl, (4) bromine atom, (5) 1-hydroxy-1-methylethyl, (6) cyclopropyl, (7) cyano, (8) 5-membered aromatic heterocycle optionally having 1 to 3 substituents selected from acetyl, (9) ethoxycarbonyl, (10) carbamoyl, (11) methylcarbamoyl and (12) cyclopropylcarbamoyl
  • a cyclic group eg, thienyl, furyl, pyrazolyl, isoxazolyl, thiazolyl, pyrrolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-
  • Preferred examples of compound (I) include compounds of formula (Ia)
  • Ring Ba is an optionally substituted 5-membered aromatic heterocyclic ring;
  • R 1a is a hydrogen atom or C 1-6 alkyl;
  • R 2a is a hydrogen atom, a halogen atom or a C 1-6 alkyl optionally having 1 to 3 halogen atoms;
  • R 7a is C 1-6 alkyl optionally having 1 to 3 halogen atoms;
  • R 8a is a hydrogen atom or C 1-6 alkyl;
  • R 9a is hydroxy optionally substituted with C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms;
  • R 10a and R 11a are the same or different and each represents a hydrogen atom or C 1-6 alkyl, Or R 10a and R 11a together with adjacent carbon atoms form a cyclopropane ring;
  • R 12a and R 13a each represent a hydrogen atom, or R 12a and R 13a together form an oxo.
  • Ring B a is good thiophene ring which may have a substituent and may furan ring which may have a substituent, may pyrazole ring which may have a substituent, substituted An isoxazole ring which may have a substituent, a thiazole ring which may have a substituent, a pyrrole ring which may have a substituent, a 1,2,4-oxadiazole ring which may have a substituent Or a 1,3,4-oxadiazole ring which may have a substituent.
  • the ring Ba has (1) C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy, (2) a halogen atom, (3) C 3- 8 cycloalkyl, (4) cyano, (5) C 1-6 alkyl-carbonyl, (6) C 1-6 alkoxy-carbonyl, (7) carbamoyl, (8) mono C 1-6 alkyl-carbamoyl and (9 ) mono C 3-8 cycloalkyl - a substituent selected from the carbamoyl may have 1 to 3 substituents each thiophene ring, a furan ring, a pyrazole ring, an isoxazole ring, a thiazole ring, a pyrrole ring, 1, 2 , 4-oxadiazole ring or 1,3,4-oxadiazole ring.
  • ring Ba is (1) a thiophene ring optionally having a substituent selected from a halogen atom, cyano, C 1-6 alkyl-carbonyl and C 1-6 alkyl, (2) Furan ring (3) a pyrazole ring optionally having a C 1-6 alkyl group, (4) isoxazole ring, (5) a thiazole ring optionally having a C 1-6 alkyl group, (6) pyrrole ring, (7) (a) C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy, (b) C 3-8 cycloalkyl, (c) cyano, (d) Optionally having a substituent selected from C 1-6 alkoxy-carbonyl, (e) carbamoyl, (f) mono C 1-6 alkyl-carbamoyl and (g) mono C 3-8 cycloalkyl-carbamoyl.
  • Ring Bb is a 5-membered aromatic heterocycle; R b is carbamoyl or C 1-6 alkyl; R 1b is a hydrogen atom or C 1-6 alkyl; R 2b is a halogen atom; R 7b is C 1-6 alkyl; R 8b is a hydrogen atom or C 1-6 alkyl; R 12b and R 13b each represent a hydrogen atom, or R 12b and R 13b together form an oxo. ] (Hereinafter sometimes abbreviated as compound (Ib)).
  • partial structure Preferably, partial structure
  • the present invention provides a compound of formula (I ′)
  • R 1 ′ is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 2 ′ is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 3 ′ is an optionally substituted heterocyclic group
  • R 4 ′ is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • R 5 ′ is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom
  • Examples of the “halogen atom” represented by R 1 ′, R 2 ′, R 4 ′, R 5 ′, R 6 ′ or R 8 ′ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the “group via carbon atom” represented by R 1 ′, R 2 ′, R 4 ′, R 5 ′, R 6 ′ or R 8 ′ may have, for example, cyano or a substituent.
  • hydrocarbon group optionally having substituent (s) alkyl optionally having substituent (s), alkenyl optionally having substituent (s), and optionally having substituent (s) Alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl and the like can be mentioned.
  • alkyl in the above-mentioned “optionally substituted alkyl” includes, for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , Pentyl, hexyl, etc.).
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
  • Pentyl hexyl, etc.
  • substituents examples include, for example: (i) halogen atoms (eg, fluorine, chlorine, bromine and iodine atoms), (ii) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (iii) C 2-6 alkenyl (eg, vinyl, allyl, etc.), (iv) C 2-6 alkynyl (eg, ethynyl, propargyl etc.), (v) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), (vi) amino, (vii) mono C 1-6 alkylamino (eg.
  • alkenyl in the above-mentioned “optionally substituted alkenyl” include C 2-6 alkenyl (eg, vinyl, allyl, etc.) and the like.
  • substituent that the above “optionally substituted alkenyl” may have include (1) the above “optionally substituted alkyl”.
  • C 1-6 alkyl eg, methyl, ethyl
  • C 1-6 alkyl which may have 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms) and hydroxy , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc., and may have 1 to 3 at substitutable positions.
  • alkynyl in the above “optionally substituted alkynyl” include C 2-6 alkynyl (eg, ethynyl, propargyl, etc.) and the like.
  • substituent which the above-mentioned “alkynyl which may have a substituent” may have include, for example, the substituent which the above-mentioned “alkenyl which may have a substituent” may have. Examples thereof include those similar to the group, and may have 1 to 3 groups at substitutable positions.
  • cycloalkyl of the above-mentioned “cycloalkyl which may have a substituent” is, for example, C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.) Etc.
  • substituents that the above-mentioned “cycloalkyl which may have a substituent” may have include the above-mentioned “alkenyl which may have a substituent”. Examples thereof include the same as the substituent, and may have 1 to 3 substituents at substitutable positions.
  • aryl in the above “aryl optionally having substituent (s)” include C 6-14 aryl (eg, phenyl, naphthyl, anthryl, etc.) and the like.
  • substituents that the above “optionally substituted aryl” may have include, for example, the above “optionally substituted alkenyl” that may be substituted. Examples thereof are the same as those described above, and may be 1 to 3 at substitutable positions.
  • the “aralkyl” of the above-mentioned “aralkyl optionally having substituent (s)” includes, for example, C 7-14 aralkyl (eg, benzyl, phenylethyl, naphthylmethyl etc.) and the like.
  • substituents that the above-mentioned “aralkyl which may have a substituent” may have include, for example, the substituent which the above-mentioned “alkenyl which may have a substituent” may have. Examples thereof are the same as those described above, and may be 1 to 3 at substitutable positions.
  • Examples of the “acyl” include a group in which the “hydrocarbon group which may have a substituent” is bonded to carbonyl.
  • Examples of the “optionally esterified carboxyl” include the carboxyl that may be esterified with the above “optionally substituted hydrocarbon group”.
  • Examples of the “imidoyl optionally having substituent (s)” include imidoyl optionally having one or two of the above “hydrocarbon groups optionally having substituent (s)”.
  • Examples of the above-mentioned “amidino optionally having substituent (s)” include amidino optionally having 1 to 3 “hydrocarbon groups optionally having substituent (s)”.
  • optionally substituted carbamoyl examples include carbamoyl optionally having one or two of the above “optionally substituted hydrocarbon groups”.
  • optionally substituted thiocarbamoyl examples include thiocarbamoyl optionally having one or two “optionally substituted hydrocarbon groups”.
  • heterocyclic group via a carbon atom of the above-mentioned “heterocyclic group via a carbon atom which may have a substituent”, for example, as an atom (ring atom) constituting a ring system, an oxygen atom, An aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) hetero atoms selected from sulfur atom, nitrogen atom and the like. Or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and a group bonded via a carbon atom.
  • aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl , Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., 5- to 6-membered monocyclic aromatic heterocyclic groups and, for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoind
  • non-aromatic heterocyclic group examples include 3 to 8 members (preferably 5 to 5) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
  • 1,2,3,4-tetrahydroquinolyl 1,2,3,4 -Non-aromatic heterocyclic groups in which some or all of the double bonds of the above monocyclic aromatic heterocyclic groups or condensed polycyclic aromatic heterocyclic groups are saturated, such as tetrahydroisoquinolyl It is done.
  • Examples of the substituent which the above-mentioned “heterocyclic group via an optionally substituted carbon atom” may have include the above-mentioned “optionally substituted alkenyl”. And the like, and the like, and the like, which may be substituted, may have 1 to 3 substituents at substitutable positions.
  • Examples of the “group through nitrogen atom” represented by R 1 ′, R 2 ′, R 4 ′, R 5 ′, R 6 ′ or R 8 ′ include (i) amino, (ii) the above “ Amino group mono-substituted by “group via carbon atom” and (iii) the above “group via carbon atom” and amino di-substituted by C 1-6 alkyl (eg, methyl, ethyl, propyl, etc.) It is done.
  • Examples of the “group through an oxygen atom” represented by R 1 ′, R 2 ′, R 4 ′, R 5 ′, R 6 ′, R 8 ′ or R 9 ′ include the above-mentioned “through a carbon atom”. And a hydroxy group optionally substituted with a “group”.
  • R 1 ′, R 2 ′, R 4 ′, R 5 ′, R 6 ′ or R 8 ′ for example, the above-mentioned “group through a carbon atom” is substituted.
  • mercapto which may be used. The mercapto may be oxidized.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R 3 ′ is 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like ( An aromatic heterocyclic group containing at least one (preferably 1-2), preferably 1 to 4, more preferably 1-2, or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic). Ring group).
  • aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl , 5- or 6-membered monocyclic aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • non-aromatic heterocyclic group examples include 3 to 8 members (preferably 5 to 5) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Or a 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group).
  • substituted of the “heterocyclic group optionally having substituent” represented by R 3 ′ for example, the above-mentioned “alkenyl optionally having substituent” has And the like, and the like may be used, and may have 1 to 3 substituents at substitutable positions.
  • Examples of the “alkyl optionally having substituent (s)” represented by R 7 ′ include those similar to the above-mentioned “alkyl optionally having substituent (s)”.
  • Ring A ′ represents a 5- or 6-membered ring which may further have a substituent in addition to R 6 ′ to R 9 ′.
  • the “5- or 6-membered ring” of “5- or 6-membered ring optionally having a substituent in addition to R 6 ′ to R 9 ′ represented by ring A ′ includes a pyrrolidine ring and piperidine Examples of the ring include a pyrrolidine ring.
  • substituents that the ring A ′ may further have include, for example, (1) the same substituents that the above-mentioned “alkenyl optionally having substituents” may have, 2) C 1-3 (poly) methylene (eg, methylene, ethylene, trimethylene) (may be bonded to the same carbon atom or bonded to two carbon atoms), (3) oxo, etc. 1 to 3 may be present at substitutable positions.
  • alkenyl optionally having substituents may have, 2) C 1-3 (poly) methylene (eg, methylene, ethylene, trimethylene) (may be bonded to the same carbon atom or bonded to two carbon atoms), (3) oxo, etc. 1 to 3 may be present at substitutable positions.
  • R 1 ′ and R 5 ′ are the same or different and each is preferably (1) a hydrogen atom or (2) an optionally substituted alkyl, particularly (1) a hydrogen atom or (2) C 1-6 alkyl is preferred. In particular, (1) hydrogen atom or (2) methyl is preferable.
  • R 1 ′ is preferably (1) a hydrogen atom or (2) an alkyl which may have a substituent, and (1) a hydrogen atom or (2) C 1-6 alkyl is particularly preferable. In particular, (1) hydrogen atom or (2) methyl is preferable.
  • R 5 ′ is preferably a hydrogen atom.
  • R 2 ′ and R 4 ′ are preferably the same or different and each is (1) a hydrogen atom, (2) a halogen atom or (3) an optionally substituted alkyl.
  • (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms is preferable.
  • (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, or (4) methyl optionally having 1 to 3 fluorine atoms is preferable.
  • R 2 is preferably (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted alkyl.
  • a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms is preferable.
  • (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, or (4) methyl optionally having 1 to 3 fluorine atoms is preferable.
  • R 4 ′ is preferably a hydrogen atom.
  • R 3 ′ is preferably a 5- or 6-membered aromatic heterocyclic group which may have a substituent.
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy
  • C 3-8 cycloalkyl (3) cyano
  • (4) May have one substituent selected from C 1-6 alkoxy-carbonyl, (5) carbamoyl, (6) mono-C 1-6 alkyl-carbamoyl and (7) mono-C 3-8 cycloalkyl-carbamoyl
  • Preferred 5-membered aromatic heterocyclic groups eg, oxazolyl, thiazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, etc.
  • oxazolyl, thiazolyl imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, etc.
  • R 6 ′ is preferably a hydrogen atom.
  • R 7 ′ is preferably C 1-6 alkyl. In particular, methyl or ethyl is preferred.
  • R 8 ′ is preferably a hydrogen atom or an optionally substituted alkyl. Of these, a hydrogen atom or C 1-6 alkyl is preferable. In particular, a hydrogen atom or methyl is preferable.
  • R 9 ′ is preferably hydroxy optionally substituted with an optionally substituted C 1-6 alkyl-carbonyl.
  • hydroxy optionally substituted with C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms is preferable.
  • hydroxy or trifluoromethylcarbonyloxy is preferred.
  • R 8 ′ and R 9 ′ together form oxo.
  • Ring A ′ further includes a substituent selected from (1) C 1-6 alkyl, (2) C 1-3 (poly) methylene and (3) oxo, in addition to R 6 ′ to R 9 ′.
  • a 5-membered ring (pyrrolidine ring) which may have 3 or more is preferable. Among them, in addition to R 6 ′ to R 9 ′, a 5-membered ring (pyrrolidine ring) which may further have 1 to 3 substituents selected from methyl, ethylene (bonded to the same carbon atom) and oxo ) Is preferred.
  • R 1 ′ is (1) a hydrogen atom or (2) an optionally substituted alkyl
  • R 2 ′ is (1) a hydrogen atom, (2) a halogen atom or (3) an optionally substituted alkyl
  • R 3 ′ may have a substituent, a 5- or 6-membered aromatic heterocyclic group
  • R 4 ′ is a hydrogen atom
  • R 5 ′ is a hydrogen atom
  • R 6 ′ is a hydrogen atom
  • R 7 ′ is C 1-6 alkyl
  • R 8 ′ is a hydrogen atom or an alkyl which may have a substituent
  • R 9 ′ is hydroxy optionally substituted with optionally substituted C 1-6 alkyl-carbonyl
  • Ring A ′ in which R 8 ′ and R 9 ′ together form oxo is, in addition to R 6 ′ to R 9 ′, (1) C 1-6 alkyl, (2) C 1-3 (poly A compound which is a 5-membered ring (pyrrolidine ring) which may
  • R 1 ′ is (1) a hydrogen atom or (2) C 1-6 alkyl
  • R 2 ′ has (1) a hydrogen atom, (2) a halogen atom or (3) a C 1-6 alkyl optionally having 1 to 3 halogen atoms
  • R 3 ′ may have (1) 1 to 3 substituents selected from a halogen atom and hydroxy, (1) C 1-6 alkyl, (2) C 3-8 cycloalkyl, (3) cyano, ( 4) having one substituent selected from C 1-6 alkoxy-carbonyl, (5) carbamoyl, (6) mono C 1-6 alkyl-carbamoyl and (7) mono C 3-8 cycloalkyl-carbamoyl.
  • An optional 5-membered aromatic heterocyclic group (eg, oxazolyl, thiazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, etc.);
  • R 4 ′ is a hydrogen atom;
  • R 5 ′ is a hydrogen atom;
  • R 6 ′ is a hydrogen atom;
  • R 7 ′ is methyl or ethyl;
  • R 8 ′ is a hydrogen atom or C 1-6 alkyl;
  • R 9 ′ is hydroxy optionally substituted with C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms;
  • a compound in which ring A ′ is a 5-membered ring (pyrrolidine ring) optionally having 1 to 3 substituents selected from methyl, ethylene and oxo in addition to R 6 ′ to R 9 ′ is preferred. .
  • R 1 ′ is (1) a hydrogen atom or (2) methyl
  • R 2 ′ is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom or (4) methyl optionally having 1 to 3 fluorine atoms
  • R 3 ′ is (1) methyl, (2) trifluoromethyl, (3) 1-hydroxy-1-methylethyl, (4) cyclopropyl, (5) cyano, (6) ethoxycarbonyl, (7) carbamoyl , (8) methylcarbamoyl and (9) a 5-membered aromatic heterocyclic group optionally having one substituent selected from cyclopropylcarbamoyl (eg, 1,2,4-oxadiazolyl, 1,2, 4-thiadiazolyl);
  • R 4 ′ is a hydrogen atom;
  • R 5 ′ is a hydrogen atom;
  • R 6 ′ is a hydrogen atom;
  • R 7 ′ is methyl or ethyl;
  • R 8 ′ is
  • Compound (I) is represented by the formula (IV) which can be produced by using a general organic synthesis method or according to a known synthesis method (eg, WO 2004/016576 pamphlet, WO 2007/15567 pamphlet, etc.). Can be produced as shown in the following formula from the compound (hereinafter sometimes abbreviated as compound (IV), and the same applies to compounds represented by other formulas).
  • the compound can be produced by removing the protecting group.
  • Examples of the “leaving group” represented by M include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy and the like.
  • Compound (III) or a salt thereof is usually used in an amount of 1 to 3 mol per 1 mol of compound (II) or a salt thereof.
  • Bases such as pyridine (DMAP), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN)
  • DMAP 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1,5-diazabicyclo [4.3.0] non-5-ene
  • the reaction is carried out using an inert solvent such as alcohols (eg, methanol, ethanol, propanol, isopropanol, n-butanol, etc.), ethers (eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.) ), Nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), esters (eg, ethyl acetate, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), halogenated hydrocarbons (Eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), amides (eg, N, N-dimethylformamide (DMF), etc.), sulfoxides (eg, dimethyl sulfoxide (DMSO), etc.), or the
  • compound (III) or a salt thereof and compound (II) or a salt thereof are combined with a palladium catalyst and an appropriate coordination.
  • Compound (IV) can be produced effectively by reacting in the presence of a child.
  • Compound (III) or a salt thereof is usually used in an amount of 1 to 3 mol per mol of compound (II) or a salt thereof. If necessary, the reaction proceeds smoothly by adding a base such as lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, etc. You can also.
  • the palladium catalyst palladium acetate (II), tris (dibenzylideneacetone) dipalladium (0) or the like can be used, and tris (dibenzylideneacetone) dipalladium (0) is particularly preferable.
  • the ligands used in the reaction include tris (ortho-tolyl) phosphine, BINAP, 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene Among them, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene is preferable.
  • the reaction can be carried out using an inert solvent such as ethers (eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), amide (Eg, N, N-dimethylformamide (DMF) and the like) or a mixed solvent thereof.
  • ethers eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • amide Eg, N, N-dimethylformamide (DMF) and the like
  • the reaction is carried out in the temperature range of about 0 to 180 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours
  • R 20 of compound (IV) is a bromine atom or an iodine atom
  • a known synthesis method such as J. Org. Org. Chem. 51, 142-148, 1986, Tetrahedron 50, 9583-9608, 1994, J. Am. Heterocycl. Chem. , 31, pp. 1377-1380, 1994, by condensing an aromatic heterocycle having boronic acid or boronic acid ester or trialkyltin as a substituent with compound (IV).
  • R 3 is an aromatic heterocyclic group such as furyl, thienyl, pyrazolyl and the like (I).
  • one or more substituents on ring A of compound (I) can be converted to other substituents.
  • each group in the above formula may be protected with a protecting group used in general organic synthesis, and the protecting group can be removed by a known method as desired after the reaction.
  • the compound (I) thus obtained is isolated and purified by a separation means known per se, such as concentration, concentration under reduced pressure, solvent extraction, liquid conversion, salting out, crystallization, recrystallization, phase transfer, chromatography, etc. be able to.
  • a separation means known per se such as concentration, concentration under reduced pressure, solvent extraction, liquid conversion, salting out, crystallization, recrystallization, phase transfer, chromatography, etc. be able to.
  • compound (I ′) The production method of compound (I ′) is described below.
  • Compound (I ′) can be produced by using a general organic synthesis method or according to a known synthesis method (eg, WO 2004/016576 pamphlet, WO 2007/15567 pamphlet, etc.). From the compound represented by the formula (hereinafter sometimes abbreviated as compound (IV ′), and the same applies to the compounds represented by other formulas).
  • the compound can be produced by removing the protecting group.
  • Examples of the “leaving group” represented by M ′ include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy and the like.
  • Compound (III ') or a salt thereof is usually used in an amount of 1 to 3 mol per 1 mol of compound (II') or a salt thereof.
  • Bases such as pyridine (DMAP), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN)
  • DMAP 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1,5-diazabicyclo [4.3.0] non-5-ene
  • the reaction is carried out using an inert solvent such as alcohols (eg, methanol, ethanol, propanol, isopropanol, n-butanol, etc.), ethers (eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.) ), Nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), esters (eg, ethyl acetate, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), halogenated hydrocarbons (Eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), amides (eg, N, N-dimethylformamide (DMF), etc.), sulfoxides (eg, dimethyl sulfoxide (DMSO), etc.), or the
  • compound (III ′) or a salt thereof and compound (II ′) or a salt thereof are combined with a palladium catalyst and Compound (IV ′) can be produced effectively by reacting in the presence of an appropriate ligand.
  • Compound (III ′) or a salt thereof is generally used in an amount of 1 to 3 mol per mol of compound (II ′) or a salt thereof.
  • the reaction proceeds smoothly by adding a base such as lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, etc.
  • a base such as lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, etc.
  • a base such as lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, etc.
  • the palladium catalyst palladium acetate (II), tris (dibenzylideneacetone) dipalladium (0) or the like can be used, and tris (dibenzylideneacetone) dipalladium (0) is particularly preferable
  • the ligands used in the reaction include tris (ortho-tolyl) phosphine, BINAP, 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene Among them, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene is preferable.
  • the reaction can be carried out using an inert solvent such as ethers (eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), amide (Eg, N, N-dimethylformamide (DMF) and the like) or a mixed solvent thereof.
  • ethers eg, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • amide Eg, N, N-dimethylformamide (DMF) and the like
  • the reaction is carried out in the temperature range of about 0 to 180 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours
  • R 20 ′ of compound (IV ′) is a bromine atom or an iodine atom
  • a known synthesis method such as J. Org. Org. Chem. 51, 142-148, 1986, Tetrahedron 50, 9583-9608, 1994, J. Am. Heterocycl. Chem. , 31, pp. 1377-1380, 1994, condensing an aromatic heterocycle having boronic acid or boronic acid ester or trialkyltin as a substituent with compound (IV ′) according to the synthesis method described in 1994
  • R 3 ′ is an aromatic heterocyclic group such as furyl, thienyl, pyrazolyl
  • one or more substituents on ring A ′ of compound (I ′) can be converted to other substituents.
  • each group in the above formula may be protected with a protecting group used in general organic synthesis, and the protecting group can be removed by a known method as desired after the reaction.
  • the compound (I ′) thus obtained is isolated and purified by separation means known per se, for example, concentration, concentration under reduced pressure, solvent extraction, liquid conversion, salting out, crystallization, recrystallization, transfer dissolution, chromatography, etc. can do.
  • Compound (I ′) or Compound (I) [hereinafter sometimes abbreviated as Compound (I). Can be converted to the desired salt by a method known per se or a method analogous thereto. Further, when compound (I) is obtained as a salt, it can be converted into a free form or other desired salt by a method known per se or a method analogous thereto.
  • Compound (I) may be a hydrate or a non-hydrate.
  • the target optically active substance can be separated by an optical resolution means known per se.
  • Compound (I) may be labeled with an isotope (eg, 2 H, 3 H, 14 C, etc.) and the like.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, for example, a compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which amino of compound (I) is acylated, alkylated or phosphorylated eg, amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylated compounds
  • compounds ( I) hydroxy-acylated, alkylated, phosphorylated or borated compounds eg, compound (I) hydroxy-acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or Dimethylaminomethylcarbonylated compounds, etc.
  • carboxylates of compound (I) Compounds in which the ester is
  • prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • Compound (I) [including prodrug] may form a salt.
  • the salt of the compound is not particularly limited as long as it does not inhibit the reaction.
  • a salt with an inorganic base an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with an amino acid Etc.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) or a salt thereof or a prodrug thereof (hereinafter sometimes abbreviated as a compound of the present invention) has an androgen receptor modulating action, particularly an androgen receptor agonistic action, and an androgen receptor agonist in mammals Can be used to prevent or treat diseases.
  • Diseases for which androgen receptor agonist administration is effective include hypogonadism, osteoporosis, hormone-resistant cancer (especially LHRH agonist-resistant cancer), menopause (especially male menopause), weakness, cachexia (Cychxia), anemia, arteriosclerosis, Alzheimer's disease, erectile dysfunction, depression or debilitating disease and hyper-TGemia (hyperlipidemia).
  • the compound of the present invention is particularly used for the prophylaxis or treatment of hypogonadism, male climacteric disorder, physical weakness, cachexia or osteoporosis.
  • the compound of the present invention has an organ-selective androgen receptor modulating action, for example, has an antagonistic action on the prostate and an agonistic action on the muscle.
  • the compound of the present invention has an action of not increasing the weight of the prostate at a dose that increases the weight of muscle (for example, levator ani). More specifically, at a dose that increases the weight of the levator ani muscle by about 20% or more (preferably about 20% to about 50%), the increase in prostate weight is about 10% or less (preferably 0% or less). .
  • the increase in prostate weight is 0% or less means that the increase in prostate weight is 0%, or the increase in prostate weight is less than 0%, and “the increase in prostate weight is less than 0%” It means that the weight is reduced by its absolute value. Therefore, the compound of the present invention can be used as the following medicaments.
  • An inhibitor of a decrease in physical strength (2) Muscle strengthening agent or muscle increasing agent (having effects such as preventing elderly inpatients from going to bed and shortening the rehabilitation period). (3) An inhibitor of cachexia caused by, for example, AIDS or cancer. (4) Weight loss inhibitor.
  • diseases eg, muscular dystrophy, muscular atrophy, X-linked spinal medullary atrophy (SBMA), cachexia, malnutrition, leprosy, diabetes, kidney disease, COPD (chronic obstructive pulmonary disease), cancer, Preventive and therapeutic agent for muscle loss caused by end stage renal failure, sarcopenia (muscle loss due to aging), emphysema, osteomalacia, HIV infection, AIDS, cardiomyopathy, etc.
  • An inhibitor of muscle weakness in postmenopausal women An inhibitor of decreased bone mineral density in postmenopausal women.
  • An inhibitor of hot flashes eg, hot flashes, sweating, etc.
  • LHRH modulators such as LHRH agonists (leuprorelin, goserelin, buserelin, nafarelin, triptorelin, gonadorelin, etc.), LHRH antagonists (ganilerix, cetrorelix, antarelix, abarelix, sfogo-ryx, etc.) Agent.
  • LHRH agonists leuprorelin, goserelin, buserelin, nafarelin, triptorelin, gonadorelin, etc.
  • LHRH antagonists ganilerix, cetrorelix, antarelix, abarelix, sfogo-ryx, etc.
  • Agent An inhibitor of muscular weakness after administration of a drug such as an LHRH modulator.
  • An inhibitor of bone mineral density reduction after administration of a drug such as an LHRH modulator.
  • An inhibitor of hot flashes eg, hot flashes, sweating, etc.
  • the compound of the present invention is effective as an agent for reducing physical strength, a muscle strengthening agent, or a muscle increasing agent while being used as a prophylactic or therapeutic agent for prostatic hypertrophy or a prostate weight lowering agent. It can be expected to shorten the rehabilitation period. Since there is no side effect of increasing prostate weight, it is expected as a therapeutic or prophylactic agent for prostate cancer in patients with a high possibility of prostate cancer. Furthermore, it has no side effects of masculinization and can be applied to women. It is also expected to be an inhibitor of postmenopausal women's muscular strength or bone mineral loss, or a postmenopausal woman's hot flush (hot flashes, sweating, etc.) Is done.
  • LHRH agonists leuprorelin, goserelin, buserelin, nafarelin, triptorelin, gonadorelin, etc.
  • LHRH antagonists ganirelix, cetrorelix, antarelix, abarelix, sfogoricks, etc.
  • hot flash hot flashes, sweating, etc.
  • the compound of the present invention is highly sensitive to androgen, and by giving excessive stimulation to cancers that have acquired resistance to hormonal treatment, leading to growth inhibition and cell death, among other cancers.
  • hormone-resistant cancer include LHRH derivative-resistant cancer, preferably LHRH agonist-resistant cancer.
  • the compounds of the present invention have low toxicity and are used as mammals (eg, humans, horses, cows, dogs, cats, rats, mice, rabbits) as they are as pharmaceuticals or mixed with pharmaceutically acceptable carriers known per se. , Swine, monkeys, etc.).
  • composition other active ingredients together with the compound of the present invention, such as the following hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors) ), An antiemetic, etc. may be included.
  • hormonal therapeutic agents for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors
  • anticancer agents for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors
  • An antiemetic etc.
  • the administration method is usually oral, for example, as a tablet, capsule (including soft capsules, microcapsules), powder, granule, or the like, It can be administered parenterally as suppositories, pellets and the like.
  • Parenterally includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal and intraperitoneal, intratumoral, proximal to the tumor, etc. Includes administration directly to the lesion.
  • the dose of the compound of the present invention varies depending on the administration route, symptoms and the like.
  • body weight preferably 1 to 100 mg / kg body weight per day, more preferably 1 to 50 mg / kg body weight per day. This amount can be administered once daily or divided into 2-3 times.
  • the compound of the present invention is mixed with a pharmaceutically acceptable carrier and administered orally or parenterally as a solid preparation such as a tablet, capsule, granule or powder; or as a liquid preparation such as a syrup or injection. be able to.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials are used as the pharmaceutically acceptable carrier. Excipients, lubricants, binders, disintegrants in solid preparations; solvents, dissolution in liquid preparations It is added as an adjuvant, suspending agent, tonicity agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. are used.
  • isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
  • buffering agent include buffer solutions such as phosphate, acetate, carbonate and citrate.
  • the soothing agent for example, benzyl alcohol or the like is used.
  • Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite and ascorbic acid.
  • the pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but it should be produced according to a conventional method by containing the compound of the present invention usually in an amount of 0.1 to 95% (w / w) based on the total amount of the preparation.
  • Can do. (1) administering an effective amount of the compound of the present invention; (2) (i) administering an effective amount of another anticancer agent; and (ii) administering an effective amount of another hormone therapeutic agent.
  • cancer can be more effectively prevented and treated by combining one to three selected from the group consisting of non-drug therapies.
  • the non-drug therapy include surgery, pressor chemotherapy using angiotensin II, radiation therapy, gene therapy, hyperthermia, cryotherapy, laser ablation, etc., and two or more of these can be combined.
  • the compound of the present invention inhibits the action of other hormone therapeutic agents, other anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents (including vaccines), antibodies, gene therapeutic agents, cell growth factors and receptors thereof. It can be used in combination with drugs, drugs that inhibit angiogenesis), antiemetics and the like (hereinafter abbreviated as concomitant drugs).
  • the compound of the present invention shows an excellent anticancer activity even when used as a single agent, it can be further enhanced by combining with one or several of the above concomitant drugs (multi-drug combination). QOL can be improved.
  • hormone therapeutic agent examples include phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, azoprisnil, allylestrenol.
  • chemotherapeutic agent examples include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and other chemotherapeutic agents.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, carboquone
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritorexime, idoxyuridine, mitoxifridin Amambamustine etc. are used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emiteful, etc.
  • anticancer antibiotics examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like are used.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan and the like are used.
  • Sobuzoxan and the like are used as “other chemotherapeutic agents”.
  • immunotherapeutic agent examples include, for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, corynebacterium parvum , Levamisole, polysaccharide K, procodazole and the like are used.
  • BCG vaccine, PROVENGE, Onyvax-P, PROSTVAC-VF, GVAX, DCVax-Prostate, SAPOIMMUNE, VPM-4-001, etc. are used.
  • an antibody against EpiCAM an antibody against PSCA, and an antibody against PSMA are used.
  • the “cell growth factor” in the “drug that inhibits the action of cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000. In the following peptides, a factor that exerts an action at a low concentration by binding to a receptor is used.
  • EGF epidermal growth factor
  • IGF insulin receptor -1
  • IGF-2 Etc. insulin or a substance having substantially the same activity
  • FGF fibroblast growth factor
  • Other cell growth factors e.g., CSF (colony timulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), and the like.
  • CSF colony timulating factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • NGF nerve growth factor
  • PDGF platelet-derived growth factor
  • TGF ⁇ transforming growth factor ⁇
  • HGF hepatocyte growth factor
  • VEGF vascular endothelial growth factor
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, specifically, an EGF receptor and a receptor belonging to the same family. HER2, HER3 and HER4, insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2.
  • Examples of the “drug that inhibits the action of cell growth factor and its receptor” include trastuzumab (Herceptin (trademark); HER2 antibody), imatinib mesylate, ZD1839, cetuximab, gefitinib, erlotinib and the like.
  • Examples of the “drug that inhibits angiogenesis” include an antibody against VEGF (eg, bevacizumab), an antibody against VEGF receptor, a VEGF receptor kinase inhibitor (eg, SU11248, etc.), a PDGF receptor kinase inhibitor, and Tie2 kinase inhibition. Agents, thalidomide and the like are used.
  • 5-HT 3 antagonists such as palonosetron, domperidone, mosapride
  • LH-RH derivatives examples include hormone-dependent diseases, particularly sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, liver cancer, etc.), prostatic hypertrophy, endometriosis, uterine fibroids, Sex hormone-dependent diseases such as precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multilocular ovary syndrome, and contraception (or infertility when using the rebound effect after withdrawal) LH-RH derivatives or salts thereof that are effective in Further, LH-RH derivatives or salts thereof that are effective for benign or malignant tumors that are independent of sex hormone but are LH-RH sensitive are also used.
  • hormone-dependent diseases particularly sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, liver cancer, etc.), prostatic hypertrophy, endometriosis, uterine fibroids, Sex hormone-dependent
  • LH-RH derivatives or salts thereof include, for example, Treatment with GnRH Analog: Contraversies and Perspectives (Treatment with GnRH analogs: Controversies and perspectives) [Parthenon Publishing ⁇ ⁇ ⁇ ⁇ Group Ltd. 1996), JP-T-3-503165, JP-A-3-101695, JP-A-7-97334, JP-A-8-259460, and the like.
  • LH-RH derivatives include LH-RH agonists or LH-RH antagonists, and examples of LH-RH antagonists include compounds of the formula X-D2Nal-D4ClPhe-D3Pal-Ser-AB-Leu-C-Pro-DAlaNH 2 [Wherein, X is N (4H 2 -furoyl) Gly or NAc, A is a residue selected from NMeTyr, Tyr, Aph (Atz), NMeAph (Atz), B is DLys (Nic), DCit, DLys A residue selected from (AzaglyNic), DLys (AzaglyFur), DhArg (Et 2 ), DAph (Atz) and DhCi, and C represents Lys (Nisp), Arg or hArg (Et 2 ).
  • An active peptide or a salt thereof is used, and particularly preferably abarelix, ganirelix, cetrorelix, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- ( 3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2 , 6-Difluorobenzyl) -6- [4- (3-ethylureido) phenyl] -3-pheny Thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4 -(3-Ethylure
  • LH-RH agonists include those of the formula 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [Wherein Y represents a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal and DHis (ImBzl), and Z represents NH—C 2 H 5 or Gly-NH 2 , respectively]
  • a physiologically active peptide or a salt thereof is used. For example, goserelin acetate and buserelin.
  • a peptide in which Y is DLeu and Z is NH-C 2 H 5 ie, 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 Peptide A represented: leuprorelin) or a salt thereof (eg, acetate) is preferred.
  • an LH-RH agonist eg, goserelin acetate, buserelin, leuprorelin, etc.
  • an LH-RH agonist eg, goserelin acetate, buserelin, leuprorelin, etc.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such dosage forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug.
  • these administration forms are collectively abbreviated as the combination agent of the present invention.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, and a pharmaceutical composition such as a tablet ( Sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous) Administration, etc.).
  • a pharmaceutical composition such as a tablet ( Sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous) Administration, etc.).
  • Injections can be administered intravenously, intramuscularly, subcutaneously, into organs, intranasally, intradermally, instilled, intracerebral, rectal, intravaginally and intraperitoneally, inside a tumor, proximal to a tumor, etc. Can be administered.
  • the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used for the above-described pharmaceutical composition of the present invention can be used.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . Further, when the compound of the present invention and the concomitant drug are formulated separately, the same content may be used.
  • the compound of the present invention or the concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • a dispersant eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • solubilizers eg, glycerin, ethanol, etc.
  • buffers eg, Phosphoric acid and alkali metal salts thereof, citric acid and alkali metal salts thereof, isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide) Etc.), preservatives (eg, ethyl paraoxybenzoate, Benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.), solubilizer (eg, propylene glycol, sucrose, etc.), soothing agent (eg
  • the compound of the present invention or the concomitant drug is treated with, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.) according to a method known per se. , Adding a binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) etc.
  • an excipient eg, lactose, sucrose, starch, etc.
  • a disintegrant eg, starch, calcium carbonate, etc.
  • a binder eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.
  • lubricant eg, talc, magnesium stearate, polyethylene glycol
  • the preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
  • the compound of the present invention or the concomitant drug can be converted into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se.
  • the oily base used in the above composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) are used.
  • the aqueous base include polyethylene glycols and propylene glycol.
  • the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
  • sustained release preparation sustained release microcapsules and the like are used.
  • a method known per se can be adopted.
  • the compound of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
  • the concomitant drug can be in the dosage form described above depending on the type of drug.
  • injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, benzoate and / or salicylate in water.
  • benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol.
  • the concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the concentration of benzoate or / and salicylate is 0.5 to 50 w / v%, preferably 3 to 20 w / v%.
  • additives generally used in injections such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solubilizers (glycerin, ethanol, etc.) Buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (sodium chloride, potassium chloride, etc.), dispersing agents (hydroxypropylmethylcellulose, dextrin), pH regulators (hydrochloric acid) , Sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (dextrose, benzyl alcohol, etc.) ) And the like can be appropriately blended.
  • stabilizers ascorbic acid, sodium pyro
  • these additives are mix
  • the injection may be adjusted to pH 2 to 12, preferably pH 2.5 to 8.0 by adding a pH adjusting agent.
  • An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, benzoate and / or salicylate, and if necessary, the above-mentioned additives in water.
  • These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably warmed, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, etc. in the same manner as normal injections.
  • the aqueous solution for injection is preferably sterilized by high-pressure heat for 5 to 30 minutes, for example, at 100 to 121 ° C. Furthermore, it is good also as a formulation which provided the antibacterial property to the solution so that it can be used as a multi-dose administration formulation.
  • Sustained-release formulation or immediate-release formulation and preparation thereof Sustained-release formulation comprising a core comprising the compound of the present invention or a concomitant drug, optionally coated with a coating agent such as a water-insoluble substance or a swellable polymer Is preferred.
  • a coating agent such as a water-insoluble substance or a swellable polymer
  • a once-daily administration type sustained-release preparation for oral administration is preferred.
  • water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially oi Ruggit RS-100, RL-100, RS-30D, RL-30D,
  • a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable, and there is little swelling in an acidic region such as the stomach, and a neutral region such as the small intestine and large intestine.
  • a polymer having an acidic dissociation group that causes large swelling is preferable.
  • the polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil (carcium), and the like. polycarbophil) (all of which are manufactured by BF Goodrich) and Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.).
  • the film agent used in the sustained release preparation may further contain a hydrophilic substance.
  • the hydrophilic substance include polysaccharides which may have a sulfate group such as pullulan, dextrin and alkali metal alginate, hydroxyalkyl or carboxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
  • Polysaccharides, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used.
  • the content of the water-insoluble substance in the coating agent of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75% ( w / w), the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w).
  • the above% (w / w) represents the weight% with respect to the coating composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance, a swellable polymer or the like is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug coated with a film agent is not particularly limited, but is preferably formed in the form of particles such as granules or fine granules.
  • the core is a granule or a fine granule, the average particle size is preferably about 150 to 2,000 ⁇ m, more preferably about 500 to about 1,400 ⁇ m.
  • the preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, anti-aggregation agents, lubricants, stabilizers, etc.
  • the drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
  • excipients contained in the core include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch, and the like. Among these, crystalline cellulose and corn starch are preferable.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used.
  • disintegrant for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable.
  • talc, magnesium stearate and its inorganic salt are used as a lubricant and an aggregation inhibitor, and polyethylene glycol is used as a lubricant.
  • acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the nucleus may be prepared by spraying a binder dissolved in an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) It can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little.
  • an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.)
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle diameter of about 100 ⁇ m to about 1,500 ⁇ m are preferable.
  • the surface of the nucleus may be coated with a protective agent.
  • a protective agent for example, the above hydrophilic substances, water-insoluble substances and the like are used.
  • the protective agent preferably a polysaccharide having polyethylene glycol, hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose, hydroxypropylcellulose is used.
  • the protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid as a stabilizer and a lubricant such as talc.
  • the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).
  • the protective agent can be coated by a normal coating method. Specifically, the protective agent can be coated by spray coating the core by, for example, a fluidized bed coating method, a pan coating method or the like.
  • Coating of the core with a coating agent The core obtained in I above is coated with a coating agent solution in which the water-insoluble substance or the pH-dependent swellable polymer and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.
  • a spray coating method or the like is used as a method of coating the core with the coating agent solution.
  • the composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the film agent solution is appropriately selected so that the content of each component in the film is the above content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably with respect to the core (excluding the coating amount of the protective agent). About 5 to about 35% (w / w).
  • water or an organic solvent can be used alone or a mixture of the two can be used.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves a water-insoluble substance.
  • lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred.
  • Water and a mixed solution of water and an organic solvent are preferably used as a solvent for the film agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. may be added to the coating agent solution for stabilizing the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by a usual coating method, specifically, by carrying out spray coating of a film agent solution on the core by, for example, fluidized bed coating method, pan coating method, etc. Can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent. After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.
  • the immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particulate, pill, tablet, etc.). Oral administration agents and parenteral administration agents such as injections are used, and oral administration agents are preferred.
  • the immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient. .
  • the formulation excipient used is not particularly limited as long as it is an excipient commonly used as a formulation excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate L-cysteine and the like are used, and preferably corn starch and mannitol are used.
  • lactose starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.)
  • powdered sugar granulated sugar
  • mannitol light anhydrous silicic acid
  • magnesium carbonate calcium carbonate L-cysteine and the like
  • corn starch and mannitol are used.
  • the content of the excipient is, for example, about 4.5 to about 99.4% (w / w), preferably about 20 to about 98.5% (w / w), based on the total amount of the immediate-release preparation, Preferably, it is about 30 to about 97% (w / w).
  • the content of the drug in the immediate-release preparation is appropriately within the range of about 0.5 to about 95% (w / w), preferably about 1 to about 60% (w / w) with respect to the total amount of the immediate-release preparation. You can choose.
  • the immediate-release preparation When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants include carboxymethyl cellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL) , Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Proprotab), partially pregelatinized starch (Asahi Kasei Co., Ltd.) ), PCS), etc.
  • disintegrants are used, for example, those that disintegrate granules by contacting with water to absorb, swell, or create channels between the active ingredient constituting the core and the excipient. Can do.
  • These disintegrants can be used alone or in combination of two or more.
  • the amount of the disintegrant is appropriately selected depending on the type and amount of the drug used, the design of the releasable preparation, and the like. ), Preferably about 0.5 to about 15% (w / w).
  • an additive conventionally used in the solid preparation may be further included, if desired, in addition to the above composition.
  • additives examples include binders (eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, polyethylene glycol, hydroxypropylmethylcellulose, carboxymethylcellulose, polyethyleneglycol, polyvinylpyrrolidone, pullulan, dextrin, etc.) , Lubricants (eg, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene) Fatty acid esters, polyoxyethylene sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (eg tar dyes, Mel, Bengala, Titanium oxide, Riboflavin), and if necessary, flavoring agents (for example, sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents
  • hydroxypropyl cellulose polyethylene glycol, polyvinyl pyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-mentioned components, further kneading, if necessary, and molding based on the usual preparation manufacturing technology.
  • the above mixing is performed by a generally used method, for example, mixing, kneading and the like.
  • a vertical granulator, a universal kneader manufactured by Hata Iron Works
  • fluidized by the same method as the preparation method of the core of the sustained-release preparation.
  • It can be prepared by mixing using a bed granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
  • the immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or together with appropriate preparation excipients, etc., separately according to a conventional method, and simultaneously or in combination with any administration interval Alternatively, both of them may be formulated into one oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or together with appropriate formulation excipients. Both preparations may be made into granules or fine granules and filled in the same capsule or the like for preparation for oral administration.
  • Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof may be a solid preparation such as a tablet, or an oral mucosa patch (film). There may be.
  • a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin derivatives may be contained in order to facilitate absorption and increase the bioavailability.
  • the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • the lubricant magnesium stearate, calcium stearate, talc, colloidal silica and the like are used, and magnesium stearate and colloidal silica are particularly preferable.
  • the isotonic agent sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like are used, and mannitol is particularly preferable.
  • hydrophilic carrier swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate are used, particularly crystalline cellulose (eg, microcrystalline cellulose). Etc.) is preferred.
  • Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin Water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc.
  • gums eg, tragacanth gum, acacia gum, guar gum
  • alginates eg, sodium alginate
  • cellulose derivatives eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose
  • gelatin Water-soluble starch Water-soluble starch
  • polyacrylic acid eg, carbomer
  • polymethacrylic acid
  • hydroxypropyl methylcellulose polyacrylic acid, alginate Gelatin, carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferable.
  • As the stabilizer cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like are used, and citric acid and ascorbic acid are particularly preferable.
  • a sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
  • auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired.
  • a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting.
  • it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
  • glycols such as polyethylene glycol and propylene glycol to give the film proper elasticity, and contains bioadhesive polymers (eg, polycarbophil, carbopol) to enhance adhesion of the film to the oral mucosal lining. Or you may.
  • Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved.
  • the film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
  • Preferred intraoral quick disintegrating agents include solid rapid diffusion administration comprising a network of a compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the compound of the present invention or the concomitant drug.
  • An agent is used.
  • the network is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in an appropriate solvent.
  • the composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.
  • the matrix forming agent examples include gelatins; dextrins; animal proteins or vegetable proteins such as soybean, wheat, psyllium seed protein; gum substances such as gum arabic, gar gum, agar, and xanthan; polysaccharides Alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and materials derived from gelatin-gum arabic complex and the like.
  • saccharides such as mannitol, dextrose, lactose, galactose, trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine.
  • One or more of the matrix forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded.
  • the matrix-forming agent can help maintain the diffusion state of the compound of the invention or the concomitant drug in the solution or suspension.
  • the intraoral quick disintegrating agent contains secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavoring agents, sweeteners, taste masking agents in the composition. You may do it.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis and Everard.
  • Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations thereof.
  • Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials and microencapsulated apomorphine.
  • Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of a compound of the present invention or a concomitant drug, between about 1 minute and about 60 minutes, preferably about 1
  • a preparation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between about 2 minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in the above sublingual tablets) And buccals etc.) and intraoral quick disintegrating agents that disintegrate within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity are preferred.
  • the content of the excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of ⁇ -cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the above preparation may further contain additives such as colorants, sweeteners, preservatives and the like as necessary.
  • the dose of the concomitant drug of the present invention varies depending on the type of the compound of the present invention, the age, weight, symptom, dosage form, administration method, administration period, etc. of the subject of administration. 60 kg) per person, and usually about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg per day as the compound of the present invention and the concomitant drug, respectively.
  • 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / kg, is intravenously administered once to several times a day.
  • the dosage varies depending on various conditions, so an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal, for example, by oral administration. Is usually administered in 1 to 4 divided doses per day.
  • the concomitant drug of the present invention When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, the compound of the present invention may be administered, or the compound of the present invention is administered first. Thereafter, the concomitant drug may be administered.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably A method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is used.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention.
  • a preferred administration method for example, about 0.001 to 200 mg / kg of a concomitant drug formed into an oral administration preparation is orally administered, and about 0.1 compound of the present invention formed into an oral administration preparation after about 15 minutes. 005-100 mg / kg is orally administered as a daily dose.
  • the pharmaceutical composition of the present invention or the concomitant drug of the present invention can be used, for example, by (1) surgery, (2) pressor chemotherapy using angiotensin II, (3) gene therapy, (4) hyperthermia, (5) freezing It can also be combined with non-drug therapies such as therapy, (6) laser ablation, and (7) radiation therapy.
  • non-drug therapies such as therapy, (6) laser ablation, and (7) radiation therapy.
  • prevention of resistance development, disease-free (Disease- Effects such as prolongation of free survival, suppression of cancer metastasis or recurrence, and prolongation of life can be obtained.
  • treatment with the pharmaceutical composition of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics for co-occurrence of various infectious diseases (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin) (Ii) high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea Administration of drugs that improve side effects such as leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, kidney damage, DIC, fever, etc. (v) administration of drugs to suppress multidrug resistance of cancer Etc.] can also be combined.
  • antibiotics for co-occurrence of various infectious diseases for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin
  • Antiemetics specifically include 5-HT 3 antagonists such as ondansetron, tropisetron hydrochloride, azasetron, ramosetron, granisetron, dolasetron mesylate, palonosetron, etc.
  • NK1 receptor antagonists such as sendide, CP-99994, CP-1000026, CP-122721-1, CP-96345, FK224, RPR100893, NKP608, arepitant (EMEND TM); domperidone, mosapride, metoclopramide, etc.
  • 5-HT 4 prokinetic agents such as antagonists, gastrointestinal motility rhythm agents such as trimebutine; prochlorperazine maleate, promethazine, phenothiazines such as thiethylperazine; haloperidol, phenolphthalein Les Phosphate chlorpromazine, diazepam, tranquilizers such as droperidol; steroids dexamethasone, prednisolone, betamethasone, etc. triamcinolone and the like; dimethyl hydrin acid, can be used diphenhydramine, hyoscine, hydrobromic hyoscine, tetrabenazine, and the like.
  • the pharmaceutical composition of the present invention or the combination agent of the present invention is orally administered (including sustained release), intravenously administered (including bolus, infusion, inclusion body), subcutaneous And intramuscular injection (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
  • the timing of administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention before surgery or the like can be administered once, for example, about 30 minutes to 24 hours before surgery or the like.
  • the administration can be divided into 1 to 3 cycles about 3 to 6 months before.
  • cancer tissue can be reduced, so that surgery and the like are facilitated.
  • the pharmaceutical composition of the present invention or the concomitant drug of the present invention is administered after surgery or the like, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after surgery or the like.
  • the effect of surgery or the like can be enhanced by administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention after surgery or the like.
  • NMR spectrum shows proton NMR, using tetramethylsilane as internal standard, VARIAN Gemini-200 (200 MHz type spectrometer), VARIAN Mercury-300 (300 MHz) or JEOL Ltd. JMTCO400 / 54 (400 MHz) type BRUKER AVANCE It was measured at II 300 and the ⁇ value was expressed in ppm.
  • Ionization method Electron impact ionization (detection of ESI positive and negative ion peaks) The purity of the compound was determined by the percentage value of the peak area detected at UV of 220 nm of the corresponding product peak.
  • the mixture is stirred at ⁇ 78 ° C. for 30 minutes, and a solution of benzyl (2S) -2-methyl-3-oxopyrrolidine-1-carboxylate (18 g) in tetrahydrofuran (60 mL) has a solution temperature of ⁇ 70 ° C. The solution was added dropwise while adjusting.
  • Triethylamine (2.4 mL) and 4-bromobenzonitrile (1.0 g) were added to an ethanol solution (100 mL) of hydroxylammonium chloride (14.0 g), and the mixture was stirred at 80 ° C. for 2.5 hours.
  • the reaction mixture was concentrated under reduced pressure, acetic anhydride (5 mL) was added to the residue (230 mg), and the mixture was stirred at 120 ° C. for 12 hr.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • tert-Butyl 1-[(2S) -2- ⁇ [(Benzyloxy) carbonyl] amino ⁇ -1- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ propyl] cyclopropanecarboxylate (694 mg) in methanol (10 mL ) 10% palladium carbon (80 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere, and then the reaction solution was filtered. After the filtrate was concentrated under reduced pressure, the residue was dissolved in methanol (10 mL), sodium methoxide (404 mg) was added, and the mixture was refluxed for 4 hours.
  • reaction solution was partitioned between water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 38 (5- ⁇ 2-Chloro-4-[(2S, 3S) -3-hydroxy-2,3-dimethylpyrrolidin-1-yl] phenyl ⁇ thiophen-2-yl) ethanone trifluoroacetate
  • Test Example 1 AR binding inhibition test (wild type) 3 nM radiolabel mibolerone and 100 nM test compound were added to a solution containing wild-type androgen receptor (AR) and incubated at 4 ° C. for 3 hours, and then B (Bound) / F (Free) separated. The label count of B was measured, and the inhibition rate of the test compound was calculated. The results are shown in Table 1.
  • Cos-7 was seeded in a 150 cm 2 flask at 5,000,000 cells, and the culture solution (10% Dextran Charcoal (DCC) -Fetal Bovine Serum (FBS), 2 mM) After incubation for 24 hours in DMEM medium containing glutamine, vector DNA containing the AR gene and vector DNA in which the luciferase gene is bound downstream of the MMTV (Mouse Mammary Tumor Virus) -derived androgen-responsive promoter are copied by the liposome method. Transfected.
  • DCC Dextran Charcoal
  • FBS Fetal Bovine Serum
  • the cells After culturing for 4 hours, the cells are collected, seeded at 10,000 cells in a 96-well plate, cultured for 3 hours, added with 1 ⁇ M 5 ⁇ -dihydrotestosterone or 100 nM test compound, further cultured for 24 hours, and then measured for luciferase activity did.
  • the induction rate of the test compound was determined with the luciferase activity induced upon addition of 1 ⁇ M 5 ⁇ -dihydrotestosterone as 100. The results are shown in Table 2.
  • Example 1 Compound-containing injection described in Example 1 (1) 5.0 mg of the compound described in Example 1 (2) Salt 20.0mg (3) Distilled water Total volume 2.0mL The compound described in Example 1 (5.0 mg) and sodium chloride (20.0 mg) are dissolved in distilled water, and distilled water is added to make a total volume of 2.0 mL. The solution is filtered and filled into 2 mL ampoules under aseptic conditions. The ampoule is sterilized and then sealed to obtain an injection solution.
  • the compound of the present invention has an excellent action as an androgen receptor modulator (especially an agonist), and is effective in the prevention and treatment of hypogonadism, male climacteric disorder, physical strength decline, cachexia, osteoporosis, etc. for which androgen administration is effective. Useful.

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Abstract

L'invention concerne un composé amine cyclique de formule (I), utile comme modulateur des récepteurs des androgènes. Dans ladite formule (I), R1 représente un atome d'hydrogène, un atome d'halogène ou similaire; R2 représente un atome d'hydrogène, un atome d'halogène ou similaire; R3 représente un groupe hétérocyclique pouvant comporter un substituant; R4 représente un atome d'hydrogène, un atome d'halogène ou similaire; R5 représente un atome d'hydrogène, un atome d'halogène ou similaire; R6 représente un atome d'hydrogène, un atome d'halogène ou similaire; R7 représente un groupe alkyle pouvant comporter un substituant; R8 représente un atome d'hydrogène, un atome d'halogène ou similaire; R9 représente un groupe comportant un atome d'oxygène par l'intermédiaire duquel le groupe peut se lier; et le cycle A représente un cycle pyrrolidine ou un cycle pipéridine auquel sont attachés les groupes R6 à R9 et pouvant en outre comporter un substituant.
PCT/JP2009/058297 2008-04-28 2009-04-27 Composé amine cyclique Ceased WO2009133861A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
JP2013537919A (ja) * 2010-09-28 2013-10-07 ラジウス ヘルス，インコーポレイテッド 選択的アンドロゲン受容体モジュレーター
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
WO2017110862A1 (fr) * 2015-12-25 2017-06-29 住友化学株式会社 Composé d'oxadiazole et son utilisation
WO2017162868A1 (fr) * 2016-03-24 2017-09-28 Syngenta Participations Ag Dérivés d'oxadiazole microbiocides
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US10696674B2 (en) 2016-07-07 2020-06-30 Bristol-Myers Squibb Company Spirolactams as inhibitors of ROCK
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
CN119280232A (zh) * 2024-10-11 2025-01-10 新乡医学院第一附属医院 一种基于3-苯基-1,2,4-噁二唑-5-甲酰胺骨架的化合物在制备治疗肿瘤疾病药物中的应用

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JP2003084386A (ja) * 2001-09-14 2003-03-19 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
WO2006124447A2 (fr) * 2005-05-13 2006-11-23 Eli Lilly And Company N-arylpyrrolidines substituees utilisees comme modulateurs selectifs du recepteur des androgenes
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US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
US8455525B2 (en) 2008-02-22 2013-06-04 Radius Health, Inc. Selective androgen receptor modulators
US8629167B2 (en) 2008-02-22 2014-01-14 Radius Health, Inc. Selective androgen receptor modulators
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
JP2013537919A (ja) * 2010-09-28 2013-10-07 ラジウス ヘルス，インコーポレイテッド 選択的アンドロゲン受容体モジュレーター
US11779552B2 (en) 2014-03-28 2023-10-10 Duke University Method of treating cancer using selective estrogen receptor modulators
US12263142B2 (en) 2014-03-28 2025-04-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11951080B2 (en) 2014-03-28 2024-04-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US12263141B2 (en) 2015-04-29 2025-04-01 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
WO2017110862A1 (fr) * 2015-12-25 2017-06-29 住友化学株式会社 Composé d'oxadiazole et son utilisation
CN109071520A (zh) * 2016-03-24 2018-12-21 先正达参股股份有限公司 杀微生物的噁二唑衍生物
CN109071520B (zh) * 2016-03-24 2022-06-14 先正达参股股份有限公司 杀微生物的噁二唑衍生物
US11083196B2 (en) 2016-03-24 2021-08-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
WO2017162868A1 (fr) * 2016-03-24 2017-09-28 Syngenta Participations Ag Dérivés d'oxadiazole microbiocides
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US12329746B2 (en) 2016-06-22 2025-06-17 Ellipses Pharma Ltd AR+breast cancer treatment methods
US10696674B2 (en) 2016-07-07 2020-06-30 Bristol-Myers Squibb Company Spirolactams as inhibitors of ROCK
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US12398094B2 (en) 2017-01-05 2025-08-26 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
CN119280232A (zh) * 2024-10-11 2025-01-10 新乡医学院第一附属医院 一种基于3-苯基-1,2,4-噁二唑-5-甲酰胺骨架的化合物在制备治疗肿瘤疾病药物中的应用

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