WO2001085732A1 - Derives de pyridobenzodiazine et procedes de preparation de ces derives - Google Patents

Derives de pyridobenzodiazine et procedes de preparation de ces derives Download PDF

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Publication number
WO2001085732A1
WO2001085732A1 PCT/JP2001/003779 JP0103779W WO0185732A1 WO 2001085732 A1 WO2001085732 A1 WO 2001085732A1 JP 0103779 W JP0103779 W JP 0103779W WO 0185732 A1 WO0185732 A1 WO 0185732A1
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group
ring
optionally substituted
substituents
substituted
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PCT/JP2001/003779
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English (en)
Japanese (ja)
Inventor
Shigeki Seto
Yasumichi Fukuda
Sigeru Izawa
Makoto Ikeda
Asao Tanioka
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Kyorin Pharmaceutical Co., Ltd.
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Priority to AU2001252671A priority Critical patent/AU2001252671A1/en
Publication of WO2001085732A1 publication Critical patent/WO2001085732A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • 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
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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

Definitions

  • the present invention relates to a novel pyridobenzodiazine derivative or a pharmacologically acceptable salt thereof having an inhibitory action on evening kininin receptor, a method for producing the same, and a pharmaceutical composition containing the pyridobenzodiazine derivative.
  • Tachykinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors in the body (neurokinin 1 (NK1), neurokinin 2 (NK2), neurokinin 3 (NK 3)) is known to express various physiological activities.
  • substance P acts as a transmitter of central and peripheral primary sensory neurons, as well as physiology such as hyperdiuresis, neuronal excitability, vascular hyperpermeability, vasodilation, smooth muscle contraction, and immunity.
  • NK1 neurokinin 1
  • NK2 neurokinin 2
  • NK 3 neurokinin 3
  • X represents a hydrogen atom or an oxygen atom
  • Y represents a nitrogen atom or an oxygen atom which may be alkylated or acylated
  • R 1 represents a hydrogen atom, a lower alkyl group, a lower alkanol group, or a nitrogen atom.
  • R 2 a hydrogen atom, lower alkyl group, and hydroxyl group.
  • a lower alkyl group, a lower alkanoyl group, a lower alkoxy group, and a ring A and a ring B each represent a benzene ring which may have a substituent.
  • a ring, or same or different hydrogen atom or M ring Ring A and ring B are each an optionally substituted homo- or heterocyclic ring, at least one of which is an optionally substituted heterocyclic ring;
  • ring C is substituted A homo- or heterocyclic ring which may have a group; a ring Z which may be substituted; and n represents an integer of 1 to 6.
  • An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism against kinkinin receptor, especially a NK1 receptor antagonism, which has a different chemical structure from known compounds including the above compounds, and a tachykinin receptor antagonist.
  • Another object of the present invention is to provide an agent for preventing or treating dysuria, an agent for preventing or treating gastrointestinal disorders, and an agent for preventing or treating vomiting.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkyl group of C i to C 6
  • R 3 is a hydrogen atom, or an optionally substituted C i to C 6
  • ring A may have 1 to 3 independently selected substituents (two adjacent substituents may be bonded to each other to form a ring) A good homo or heterocyclic ring, wherein ring B is a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) The ring C has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form ⁇ ) The benzene ring which may be possessed is shown.
  • the present invention provides a pyridobenzodiazine derivative represented by the formula or a salt, hydrate and solvate thereof.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or C i Ce alkyl
  • R 3 is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C ⁇ C 6 optionally substituted, substituted alkylsulfonyl group of C 1 ⁇ C 6 which may have an alkyl group ⁇ C 6 which may be substituted A substituted or unsubstituted arylmethyl group or an alkoxycarbonyl group;
  • Ring A is a halogen atom, an optionally substituted C i -C 6 alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C i C alkoxy group, C 3 ⁇ C 1.
  • Ring B is a halogen atom, an optionally substituted C i -C 6 alkyl group -C 3 -C ⁇ .
  • Sik port alkyl group it may also be substituted I ⁇ Li Ichiru group.
  • C ring is a halogen atom, an optionally substituted alkyl group of C i to C 6 also inhibit de port hexyl group, an optionally substituted C i to C 6 alkoxy group, optionally substituted c 1 Arca noisy Ruo alkoxy group to c 6, optionally substituted ⁇ Li Roiruokishi group, it may also be substituted i Ariru Mechiruokishi group, cycloalkoxy group of C 3 ⁇ C i 0, cycloalkyl of c 3 to c 10 Alkanoyloxy group, amino group, mono- or di-substituted
  • the present invention provides a pyridobenzodiazine derivative represented by the formula: or a salt, hydrate and solvate thereof.
  • R 4 is a hydrogen atom, an amino group, a mono- or di-substituted Ci-C 6 alkylamino group, a 4- to 9-membered group which may be substituted and may contain 1 to 3 hetero atoms.
  • R 5 is a hydrogen atom, an amino group, an alkylamino group of mono- or di-substituted C ⁇ Ce, a 4- to 9-membered cyclic group which may be substituted and may contain 1 to 3 hetero atoms.
  • the pyridobenzodiazine derivative according to claim 2, which is represented by an integer of 1 to 6, or a salt, hydrate or solvate thereof is provided.
  • R 6 is an optionally substituted C ⁇ to C 6 alkyl S or an optionally substituted aryl group.
  • the present invention provides the pyridobenzodiazine derivative or the salt, hydrate and solvate thereof according to claim 2, wherein R 3 in the general formula (1) is represented by a C ⁇ to C 6 alkyl group.
  • R 3 is 7
  • R 7 is C port Gen atom, human de port hexyl group, an optionally substituted alkoxy group C ⁇ C 6 also, ⁇ S 0 2 R 12 (R 1 2 is halogen-substituted There may be oc ⁇ alkyl group ⁇ c 6, which may be substituted Ariru group), i is an integer of 1-6.
  • R 8 is a nitrogen atom, a hydroxyl group, an optionally substituted C ⁇ to C 6 alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.
  • R 3 in the general formula (1) is a hydrogen atom, an optionally substituted arylmethyl group or an alkoxycarbonyl group, or a salt or hydrate thereof. And a solvate.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a C i Ce alkyl group, and ring B has 1 to 3 substituents (when two adjacent substituents are bonded to each other, R 3 represents a hydrogen atom, an optionally substituted C 6 -C 6 alkylcarbonyl group, an optionally substituted C i ⁇ C 6 al X represents a alkyl group of C i Ce, a substituted or unsubstituted C i C e alkyl group, a substituted or unsubstituted arylmethyl group or an alkoxycarbonyl group; ⁇ 2 R 13 (R 13 represents a C i -C 6 alkyl group which may be substituted with nitrogen, an aryl group which may be substituted), and the C ring has 1 to 3 It represents a benzene ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring). And a salt
  • Y is a halogen atom, ⁇ S 0 2 R 14 (R 14 is a halogen-substituted C i -C 6 alkyl group, an optionally substituted aryl group))
  • B (R 15 ) 2 R 15 may be a hydroxyl group, a C ⁇ Cs alkyl group or a C i Ce alkoxy group, or R 15 may be bonded to each other to form a ring.
  • Li, MgBr or ZnCl wherein the ring A is independently selected from one to three substituents (two adjacent substituents are bonded to each other to form a ring 2.
  • the present inventors have the following general formula (4)
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a C 6 -C 6 alkyl group, and the ring A is independently selected from one to three substituents (adjacent 2 Substituents may be bonded to each other to form a ring), and may represent a homo- or heterocyclic ring, and the ring B has 1 to 3 substituents (two adjacent substituents).
  • a benzene ring which may have a benzene ring which may be bonded to each other to form a ring, and the C ring has 1 to 3 substituents (two adjacent substituents are bonded to each other)
  • R 3 represents a benzene ring which may have a ring
  • R 7 is a halogen atom, human de port hexyl group, an optionally substituted C ⁇ -C 6 alkoxy group, OS 0 2 R 12 (R 1 2 is an optionally halogen-substituted C i ⁇ C 6 An alkyl group, a substituted or unsubstituted aryl group), and i represents an integer of 1 to 6.) or
  • R 8 is a halogen atom, a hydroxyl group, a substituted or unsubstituted C ⁇ to c 6 alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.
  • R 9 is an amino group, a mono- or di-substituted C i -C 6 alkylamino group, a 4- to 9-membered group which may be substituted and may contain 1 to 3 hetero atoms. 5.
  • the present invention provides a method for producing a gin derivative or a salt, hydrate and solvate thereof, wherein the following general formula (6)
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a C i C s alkyl group, and ring A is independently selected from one to three substituents (adjacent two A substituent may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have 1 or 3 ring (s), and 1 to 3 substituents (when two adjacent substituents A benzene ring, which may have a ring, which may combine with each other to form a ring), and ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring).
  • Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C i Ce
  • R 7 is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C-C 6 alkoxy group, OS 0 2 R 1 2 ( R 1 2 is an alkyl group which may be substituted Ariru group optionally C i to C 6 be halogenated), i is an integer from 1 to 6 )
  • R 1 2 is an alkyl group which may be substituted Ariru group optionally C i to C 6 be halogenated
  • i is an integer from 1 to 6
  • V is a halogen atom, an optionally substituted C i Ce alkoxy group or ⁇ S 0 2 R 16
  • R 16 is an optionally halogenated C i Cs alkyl group
  • R 8 is a hydroxyl group, an optionally substituted C 6 -C 6 alkoxy group, an arylmethyloxy group or a reactive residue
  • j is an integer of 1-6.
  • W is a halogen atom, human de port hexyl group, an alkoxy group of C i C s, OS_ ⁇ 2: 1 7 (R 1 7 is an alkyl group optionally C i to C 6 be halogen-substituted , An aryl group which may be substituted) or a reactive residue, and R 6 is a compound represented by a hydrogen atom or a C i -C 6 alkyl group). Or a process for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to item 8.
  • R 3 is a hydrogen atom, an optionally substituted alkyl carbonyl group of C i Cs, and an optionally substituted C i -C 6 alkyl sulfo group.
  • Group, optionally substituted C. 1 to alkyl groups of C 6, optionally substituted also shows a good Arirumechiru group and alkoxycarbonyl two Le group
  • R 1 0 is a halogen atom, arsenic Dorokishiru group
  • C 1 ⁇ C 6 represents an alkoxy group, arylmethyloxy group or a reactive residue
  • ring A represents one to three independently selected substituents (two adjacent substituents are bonded to each other Represents a homo or complex ring which may have a ring, and the ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other Which may form a ring).
  • a salt, hydrate and solvate thereof represented by the following general formula (11):
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or a C i C s alkyl group, and ring B has 1 to 3 substituents.
  • Benzene ring which may have a compound represented by the formula: wherein the compound is a compound represented by the formula (I), wherein the pyridobenzodiazine derivative or a salt, hydrate or solvate thereof is used. A manufacturing method is provided.
  • the present inventors provide a tachykinin receptor antagonist comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. '
  • the present inventors provide a ⁇ 1 receptor antagonist comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • the present inventors need to include a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. It is intended to provide a preventive or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence characterized by the following.
  • the present inventors have proposed a gastrointestinal tract comprising ulcerative colitis and Crohn's disease, which comprises a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • a gastrointestinal tract comprising ulcerative colitis and Crohn's disease, which comprises a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • the present inventors have proposed a X-ray irradiation, a chemotherapeutic agent, a pregnancy, a prescription, comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • a prophylactic or therapeutic agent for vomiting induced by headache, postoperative disease, gastrointestinal hypomotility or side effects of drug administration.
  • the present inventors have asthma, cough, pain, migraine, migraine, toothache, comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • R 11 is a halogen atom, a hydroxyl group, a C ⁇ Ce alkoxy group, an arylmethyloxy group or a reactive residue and
  • R 1 and R 2 are the same or different and are each a hydrogen atom or an alkyl of C i to C 6
  • the ring B and the ring B represent a benzene ring which may have 1 to 3 substituents (adjacent two substituents may combine with each other to form a ring).
  • R 3 is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C ⁇ C 6 optionally substituted, an alkylsulfonyl group optionally C. 1 to C 6 optionally substituted, an optionally substituted in C. 1 to C 6 also An alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group,
  • X is a halogen atom, a hydroxyl-containing xyl group or ⁇ S ⁇ 2 R 13 (R 13 is a C i -C 6 alkyl group which may be substituted with a nitrogen atom, optionally substituted Group)
  • C ring is a halogen atom, a substituted optionally alkyl group which may C i to C 6, human de port hexyl group, an optionally substituted C. 1 to C 6 alkoxy group, optionally substituted C i C 6 to C 6 alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C 3 to C 10 cycloalkoxy group, C 3 to C 10 Cycloalkanoyloxy, amino, mono- or di-substituted
  • Alkylamino of C 6 amino group from 1 to 3 heteroatom to comprise also have good 4-9 membered cyclic ⁇ Mi amino group, an alkylcarbonyl ⁇ Mi amino group of C ⁇ C 6, C i to C 6 Independently selected from the group consisting of an alkoxycarbonylamino group of the formula: It represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring).
  • the present invention provides a pyridobenzodiazine derivative represented by the formula: or a production intermediate in the form of a salt, hydrate or solvate thereof.
  • R 3 is a hydrogen atom, an optionally substituted C-C 6 alkylcarbonyl group, an optionally substituted C-C 6 alkylsulfonyl group, an optionally substituted C i alkyl group -C 6, indicates an optionally substituted Arirumechiru group and alkoxycarbonyl two Le group
  • R 1 0 is a halogen atom, arsenic Dorokishiru group, an alkoxy group of C 1 -C 6, ⁇ reel methyl O alkoxy group Or represents a reactive residue
  • Ring A is a halogen atom, an optionally substituted C 1 -C 6 alkyl group-an optionally substituted aryl group, a hydroxyl group, an optionally substituted C i Ce alkoxy group, a C 3- C 1 0 cycloalkoxy group, alkanoyloxy noisy Ruo alkoxy group optionally C ⁇ substituted ⁇ C 6, optionally substituted Ariroiruokishi group, an optionally substituted Ari Rumechiruokishi group, C 3 ⁇ C i .
  • Cycloalkadienyl noisy Ruo alkoxy group substitution is optionally C 1 -C 6 alkylthio group, alkylsulfinyl group optionally substituted C ⁇ C 6, optionally substituted C i to C 6 an alkylsulfonyl group, an amino group, mono- or di-substituted alkyl amino group -C 6,. 1 to 3 or may contain heteroatoms of 4-9 membered cyclic amino groups, the C.
  • 1 to C 6 alkylcarbonyl amino group an alkoxycarbonyl ⁇ Mi amino group of C i C s, C i ⁇ ⁇ Le kills sulfonyl ⁇ amino group of C 6, optionally substituted Arirusuruho Niruamino group, an alkylcarbonyl group of C i C 6, formyl, force Rupokishiru group, an alkoxycarbonyl group having C 1 -C 6, mono- or di location
  • the ring C is a halogen atom, an optionally substituted C i -C 6 alkyl group-hydroxyl group, an optionally substituted C i Cs alkoxy group, an optionally substituted C -C 6 An alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C 3 -C ⁇ .
  • R 1 represents a halogen atom, a hydroxyl group, a C 1 -C 6 alkoxy group, an arylmethyloxy group or a reactive residue
  • R 3 is a hydrogen atom, which may be substituted.
  • X represents a halogen atom, a hydroxyl group or ⁇ S 02 R 13 (R 13 is a C ⁇ -C 6 alkyl group which may be halogen-substituted, And the ring C represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring).
  • Y is a halogen atom, 0 S 0 2 R 14 (R 14 is the same as described above), B (R 15 ) 2 (R 15 is a hydroxyl group, an alkyl group of C i to C 6 or C The alkoxy groups j to C 6 or R 15 may be bonded to each other to form a ring.), L i, MgBr or ZnC 1, wherein the ring A is independently 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring).
  • R 11 is a halogen atom, a hydroxyl group, a C i Ce alkoxy group, an arylmethyloxy group or a reactive residue;
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or a C i -C 6 alkyl group; ring B has 1 to 3 substituents (adjacent 2 substituents are bonded to each other to form a ring formed shows a benzene ring which may have a well may) have.) indicates, X is a halogen atom, human Dorokishiru group or 0 S ⁇ 2 R 1 3 (R 1 3 is being Nono androgenic substituted A C i -C 6 alkyl group or an optionally substituted aryl group), and the C ring has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) R 3 represents a benzene ring which may have
  • R 7 is a halogen atom, a hydroxyl group, an optionally substituted C ⁇ -C 6 alkoxy group, ⁇ S 0 2 R 12 (R 12 is an optionally substituted C i- An alkyl group of C 6 , an aryl group which may be substituted), and i represents an integer of 1 to 6.) or
  • R 8 is a halogen atom, a hydroxy group, an optionally substituted C 6 alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.
  • R 9 is an amino group, a mono- or di-substituted Ci-C 6 alkylamino group, and may be substituted and may have 1-3 hetero atoms. 21.
  • R 11 is a halogen atom, a hydroxyl group, an alkoxy group of CiCs, an arylmethyloxy group or a reactive residue.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or a C i Cs alkyl group; ring B has 1 to 3 substituents (adjacent two substituents are bonded to each other to form A benzene ring which may have Show.
  • X is a halogen atom, human de port hexyl group, 0 S 0 2 R 1 3 (R 1 3 is halogen optionally substituted C ⁇ -alkyl C 6, optionally substituted Ariru And the ring C represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) And a salt, hydrate and solvate thereof represented by the following general formula (7):
  • Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of ( ⁇ to ⁇ );
  • R 7 is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C ⁇ ⁇ ⁇ ⁇ ⁇ to C 6 alkoxy group or 0 S 0 2
  • R 12 R 12 is a substituted or unsubstituted C i -C 6 alkyl group or an optionally substituted aryl group ), I represents an integer of 1 to 6.
  • V is a halogen atom, an optionally substituted C i to C 6 of the alkoxy group, OS 0 2 R 1 6 ( R 1 6 is an alkyl group having optionally C i C s be halogen-substituted An optionally substituted aryl group), R 8 is a hydroxy group, an optionally substituted C i Cs alkoxy group, an arylmethyloxy group or a reactive residue, and j is 1 to Or an integer of 6) or the following general formula (9)
  • R 6 is pyrido benzo O Kisa derivative of claim 2 0, wherein the reacting a compound represented by the alkyl group) hydrogen atom or a C i C s or Provided are methods for producing salts, hydrates and solvates.
  • R 1 represents a hydroxyl group, a C 6 -C 6 alkoxy group, an arylmethyloxy group or a reactive residue
  • each ring A is independently selected from 1 to 3
  • Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C i to C 6
  • R 7 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C 1 ⁇ alkoxy or 0 S_ ⁇ 2 1 2 C 6 (R 1 2 is an alkyl group of Nono androgenic optionally substituted C i C e, which may be substituted Ariru group), i is the 1-6 Represents an integer.
  • R 1 2 is an alkyl group of Nono androgenic optionally substituted C i C e, which may be substituted Ariru group
  • i is the 1-6 Represents an integer.
  • V is a halogen atom, an optionally substituted C i -C 6 alkoxy group, ⁇ S ⁇ 2 R 16 (R 16 is an optionally substituted C 1 -C 6 An alkyl group, an optionally substituted aryl group), R 8 is a hydroxyl group, an optionally substituted C i -C 6 alkoxy group, an arylmethyloxy group or a reactive residue, and j is 1 Or an integer of 6 to 6) or the following general formula (9)
  • W is a halogen atom, a hydroxyl group, a C 1 -C 6 alkoxy group or a reactive residue, and R 6 is a hydrogen atom or a C i -C 6 alkyl group
  • W is a halogen atom, a hydroxyl group, a C 1 -C 6 alkoxy group or a reactive residue
  • R 6 is a hydrogen atom or a C i -C 6 alkyl group
  • R 3 is a hydrogen atom, an optionally substituted alkyl carbonyl group of C i Ce, an optionally substituted C i -C 6 alkylsulfonyl group, an optionally substituted C i represents an alkyl group of Ce, an arylmethyl group which may be substituted, and an alkoxycarbonyl group; Rio represents a halogen atom, a hydroxyl group, an alkoxy group of CiC, an arylmethyloxy group or a reactive residue; X represents a halogen atom, A hydroxyl group or 0 S 0 2 R 13 (R 13 is a C ⁇ -C 6 alkyl group which may be substituted by halogen, an aryl group which may be substituted); A benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring); And a salt, hydrate and solvate thereof represented by the following general formula (11):
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group of Ci'Cs; ring B has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring; 20.
  • R 3 is a hydrogen atom, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted C i Cs alkylsulfonyl group, an optionally substituted C Represents a C 6 alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group, wherein the ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have a benzodiazine derivative represented by the following general formula (20): HC (COR 10 ) 3 (20)
  • R 1 is the same or different and is a halogen atom, a hydroxyxyl group-
  • the alkylcarbonyl group optionally c 1 to c 6 be substituted, a halogen atom, arsenic Dorokishiru group, an alkoxy group of C i to C 6, an alkylthio group having C i ⁇ C 6, amino group, mono Or a di-substituted CiCe alkylamino group, a 4- to 9-membered linear amino group which may be substituted and which may contain 1 to 3 hetero atoms, a formylamino group,
  • An alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a phenylmethoxycarbonyl group, etc.), Sulfonyl group (methylsulfonyl group, trifluoromethylsulfonyl group, 4-methylphenylsulfonyl group, etc.), mono- or di-substituted C 1 -C 6 alkylcarno ' Moyl group, which may contain 1 to 3 hetero atoms, may be substituted, may
  • C 1 -C 6 alkylcarbonyl group It means a good C 1 -C 6 alkylcarbonyl group.
  • the alkyl group may be substituted C ⁇ C 6, C androgenic atom, arsenic Dorokishiru group, C ⁇ alkoxy group ⁇ C 6, C i alkylthio group C 6, amino, mono- or di-substituted C Al Kiruami amino group of i-C 6, substituted 4 may Idei contain heteroatoms is good 1-3 of the optionally to 9-membered cyclic amino group, Horumiruami amino group, (alkyl ⁇ C 6 Carbonylamino group, C i -C 6 alkylsulfonylamino group, optionally substituted arylsulfonylamino group, carbonyl group (formyl group, acetyl group, propionyl group, benzoyl group, etc.
  • Alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, 2,2,2-trichloromouth ethoxycarbonyl group, Rume butoxycarbonyl group), a sulfonyl group (a methylsulfonyl group, Application Benefits Full O b methylsulfonyl group, 4-methyl-phenylalanine sulfonyl group, etc.), alkyl force Rubamoiru group C i ⁇ C 6 mono or di-substituted - It may contain 1-3 heteroatoms and may be substituted 4 A C 1 to C 6 alkyl group which may have 1 to 5 substituents selected from a 9-membered cyclic rubamoyl group and the like.
  • An optionally substituted arylmethyl group includes a halogen atom, a CiCe alkyl group, a hydroxy group, a CiCe alkoxy group, a CiCe alkylthio group, an amino group and a mono group.
  • Arirumechiru group phenylmethyl Group, naphthylmethyl group, pyridylmethyl group, quinolylmethyl group, indolylmethyl group, etc.
  • the alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, a 2,2,2-trichloromouth ethoxycarbonyl group, a phenylmethoxycarbonyl group, or the like.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the aryl group which may be substituted includes a halogen atom, a C i -C 6 alkyl group, a hydroxy group, a C -C 6 alkoxy group, a C i Cs alkylthio group, an amino group, a mono- or di-substitution A C i -C 6 alkylamino group, a 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 heteroatoms, a formylamino group, a C C to C 6 alkylcarbonyl amino group, C ⁇ Arukirusu Ruhoniruami amino group of C 6, substituted 1 also selected from good ⁇ reel sulfonyl amino group or the like have to 5 substituents which may have a Ariru group ( Phenyl, naphthyl, etc.).
  • the optionally substituted C 1 -C 6 alkoxy group includes a nodogen atom, a hydroxyl group, a C i -C 6 alkoxy group, a C i -C 6 alkylthio group, an amino group, Mono- or di-substituted alkylamino group having C ⁇ C 6, substituted 4 may contain a hetero atom may 1-3 pieces of the optionally 9 membered ⁇ Mi amino group, formylamino group, alkylcarbonyl ⁇ amino group C i C e alkylsulfonyl ⁇ amino group of the C. 1 to C 6, have chosen 1-5 substituents from optionally substituted ⁇ reel sulfonylamino group optionally etc.
  • the cycloalkoxy group means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, or the like.
  • the optionally substituted C 1 -C 6 alkanoyloxy group is a nodogen atom, a hydroxy group, a C ⁇ -C 6 alkoxy group, a C 1 -C 6 alkylthio group, an amino group.
  • substituted 4 may contain a hetero atom may 1-3 pieces of the optionally 9-membered cyclic amino group, formylamino group, It has 1 to 5 substituents selected from C i Ce alkylcarbonylamino group, C i Cs alkylsulfonylamino group, and optionally substituted arylsulfonylamino group. And a C i Cs alkanoyloxy group (such as an acetyloxy group, a propionyloxy group, an isopropionyloxy group, and a hexanoyloxy group).
  • the substituted optionally may be Ariroiruokishi group, a halogen atom, an alkyl group of C i ⁇ C 6, human Dorokishiru group, C i C s alkoxy group, an alkylthio group of C i to C 6, amino group, mono Or a disubstituted C ⁇ Ce alkylamino group, a 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 hetero atoms, a formylamino group, C ⁇ to C 6 alkylcarbonyl ⁇ Mi amino group of, C i to ⁇ Le kills sulfonyl ⁇ amino group of C 6, which may have a substituted 1 selected from which may Arirusuruho Niruamino group have 5 substituents Aryloxy group (benzoyloxy group, naphthyloxy group, Lyloxy group, pyrimidyloxy group, quinolyloxy group, indyloxy group, etc.
  • Oxy group (phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, quinolylmethyloxy group, indolylmethyloxy group, etc.).
  • Cg C i.
  • the cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclobutanoinoleoxy group, a cyclopentanoinoleoxy group, a cyclohexanoyloxy group or the like.
  • the optionally substituted C i -C 6 alkylthio group means a halogen atom, a hydroxyl group, a C -C 6 alkoxy group, a C i -C 6 alkylthio group, an amino group, a mono- or di-substituted C 1 -C 6 alkylthio group.
  • Cs alkylamino group from 1 to 3 of the hetero atom may be free Ndei 4-9 membered cyclic amino group, formylamino group, an alkylcarbonyl ⁇ amino group -C 6, alkyl sulfo C i Ce It means an alkylthio group optionally having 1 to 5 substituents selected from a nilamino group, an optionally substituted arylsulfonylamino group and the like.
  • the alkyl sulfide alkylsulfonyl group optionally C i Ce substituted, a halogen atom, human de port hexyl group, an alkoxy group of C i ⁇ C 6, an alkylthio group of C i to C 6, amino group, mono or alkylamino group C i Cs disubstituted from 1 to 3 of the cyclic amino group may 4-9 membered also contain heteroatoms, formylamino group, al of C i ⁇ C 6 Kill carbonyl ⁇ amino group, C i to alkylsulfonyl ⁇ amino group of C 6, which may have a substituted 1 selected from which may ⁇ Li one Le sulfonylamino group optionally 5 substituents It means an alkylsulfinyl group (methylsulfenyl group, ethylsulfinyl group, propylsulfinyl group, etc.).
  • the mono- or di-substituted C ⁇ Ce alkylamino group includes a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a t-butylamino group, a hexylamino group, a dimethylamino group, a acetylamino group, and a dipropylamino group.
  • a 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group and 4-dimethylamino Piperidino, 4-pyrrolidinylbiperidino, 4-piperidinylpiperidino, 4-hydroxypiperidino, morpholino, thiomorpholino, piperazino, 4-methylbiperazino, homopi ⁇ means radino group, 4-methylhomopiperazino group and the like.
  • the alkylcarbonylamino group of C ⁇ Ce means an acetylamino group, a propionylamino group, a butyrylamino group, or the like.
  • Alkoxy force of C i C s A ruponylamino group means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexoxycarbonylamino group or the like.
  • the alkylsulfonyl Niruamino group C i to C 6, means methylsulfonyl ⁇ amino group, a Echirusuruhoniru Amino group.
  • the optionally substituted ⁇ Li one also be Rusuruhoniru Amino group, a halogen atom, an alkyl group of 6, human Dorokishi group, an alkoxy group of C ⁇ C 6, an alkylthio group having C i to C 6, ⁇ Mi Bruno Group, mono- or di-substituted CiCs alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, holmi Ruami Roh groups, C ⁇ alkylcarbonyl ⁇ Mi amino group of ⁇ C 6, C 1 alkylsulfonyl ⁇ Mi amino group of ⁇ C 6, 1 ⁇ 5 selected from such optionally substituted ⁇ Li one also be Luz Ruhoniruamino group Means an arylsulfonylamino group which may have one or more substituents. A ring in which two adjacent substituents may be bonded to each other to form And so on.
  • a 4- to 9-membered cyclic carbamoyl group which may contain 1 to 3 hetero atoms includes azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group and 4-methylbiphenyl. It means a peridinylcarbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, a 4-methylbiperazinylcarbonyl group and the like.
  • the homocyclic ring of the ring A means a benzene ring, a naphthalene ring or the like.
  • the heterocyclic ring of the ring A is a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, or 9 members or i. Means a membered aromatic fused heterocycle.
  • Halogen optionally substituted € ⁇ 0 6 alkyl group, 1 Means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group, etc. which may be substituted with up to 13 fluorine atoms or chlorine atoms.
  • the ring which may be formed by bonding to each other of R 15 is as follows: 10 (CH 2 ) 2 , 1 CH (M e) CH (M e) 0—,-0 C (Me) 2 C (Me) 2 0 or - 0 (CH 2) means 3 0- like.
  • the reactive residue means a 1-imidazolyl group, 412 trophenoxy group, imidoyloxy succinate group or the like.
  • Preferred compounds of the present invention include N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-11, N-dimethyl-7- (3-fluorophenyl) -15-oxo-1-5 H-pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide, ⁇ — [3,5-bis (trifluoromethyl) benzyl] 17- (3-chlorophenyl) 1,2,3-Dihydro 1, 1-dimethyl-5-oxo-5-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide, ⁇ — [3,5 —Bis (trifluoromethyl) benzyl] — 2,3-Dihydro 1, ⁇ -dimethyl 7- (3 12 trophenyl) 1 5-oxo-1 5 ⁇ -pyrido [1,2,3-d ⁇ ] 1 1,4-benzodiazine-1 6-carboxamide, 7-
  • N-methyl-5-oxo-1 1 (1—piperidinyl aceti — 5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine-1 6—carboxamide, N— [3,5 —Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) —N-methyl-5-oxo-1 — [(4- (1—piperidinyl) piperidinyl) acetyl ] 1-5H-pyrido [1,2,3—de] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1 1 1 [(4-Hydroxypiperidinyl) acetyl] 100 — (3-Methoxyphenyl) 1 N-Methyl-1 5-oxo-1 5H-Pyrido [1,2,3-de]
  • 1,4-I-benzodiazine-6-carboxamide N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro N-methyl-7- (2-methylphenyl) 1-1— (4-1) Morpholinylacetyl) 1-5-oxo-5H-pyrido [1,2,3-de] -1, 4—benzodiazine_6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1 2, 3—Jihidoro 1—
  • N-methyl-5-oxo1-1-1 [(4- (1,1,1-dioxo) Sothiomorpholinyl)) acetyl] 1-5H-pyrido [1,2,3-d d] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] — 2,3-Dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-1 1- (1—piperazylacetyl) 1-5 H-pyrido [1,2,3 -de]-1,4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -1-1-1 (1-homopiperazinylacetyl) 1-2,3-dihydro-1 7— (3-Methoxyphenyl) 1 N—methyl mono 5—oxo mono 5 H—pyrido [1,2,3-de] -1,4—benz
  • 6-carboxamide 1-benzyl-l- [3,5-bis (trifluoromethyl) benzyl] -l, 3-dihydro 7- (3-fluorophenyl) l-methyl-5-oxo-5 ⁇ —pyrido [1,2,3-d ⁇ ] — 1,4-benzodiazine-16-carboxamide, 1-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihi Draw 7— (2-Fluorophenyl) -N-methyl—5-Oxo-5H-pyrido [1,2,3-de] —1,4-Benzodiazine-1 6-Carboxamide, 1-Benzyl N — [3, 5— Bis (trifluoromethyl) benzyl] — 7 _ (3,4-difluoromethyl) -1,2,3-dihydro-1-N-methyl-5-oxo-5H—pyrid [1,2,3-d ⁇ ] 1,4-benzodia
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, lingoic acid, tartaric acid, citrate
  • organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.
  • the compound of the present invention or a salt thereof includes optically active isomers, stereoisomers, and rotamers in addition to the racemate.
  • the compound of the present invention can be produced by various synthetic methods. Next, typical production steps of the compound of the present invention and a salt thereof will be described.
  • compound (I) (where R 3 and C ring are the same as above) and compound (II) (where R 1 is the same as above) are reacted to obtain compound (III) (where R 3 , R 10 and Ring C is the same as described above).
  • the compound (II) is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, and preferably 100 to 300 ° C, preferably 150 to 25 ° C, based on the compound (I). Performed at 0 ° C.
  • an inert solvent which does not participate in the reaction for example, xylene, mesitylene, nitrobenzene, diphenyl ether, dautherm (a mixture of diphenyl ether and biphenyl) and the like are used.
  • the condensing agent used is dicyclohexyl carboximide (DCC;), 3-ethyl-1- (3-dimethylaminopropyl)
  • DCC dicyclohexyl carboximide
  • EDCI carbodimid hydrochloride
  • DMC dimethylimidazolidinyl chloride
  • an alkali carbonate such as sodium bicarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5] .
  • —7-Pendecene pyridine, 4-dimethylaminopyridine or tertiary amines such as 1,8-bis (dimethylamino) naphthylene.
  • an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran , Dioxane, ethyl ether, dimethoxetane, ethyl acetate, and dichloromethane.
  • This condensation reaction proceeds smoothly from-20 ° C to 80 ° C.
  • R 1 Q is a carboxylic acid halide represented by a reactive residue (for example, a halogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc.)
  • a reactive residue for example, a halogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc.
  • imidazolides of carboxylic acids active esters of carboxylic acids, mixed anhydrides of carboxylic acids (for example, anhydrides with ethyl carbonic acid, anhydrides with isobutyl carbonic acid, etc.) or triethylamine in the case of symmetrical acid anhydrides N, in the presence or absence of an inorganic base such as sodium bicarbonate or potassium carbonate, or an organic base such as diisopropylethylamine, pyridine, or 4-dimethylaminopyridine.
  • an inorganic base such as sodium bicarbonate or potassium carbon
  • R 1 ° is an ester residue such as an alkoxy group or a benzyloxy group of C to C 6 , in the presence or absence of trimethyl alcohol or tetraisopropoxythiamine, or p — N, N-dimethyl in the presence or absence of an acid or base catalyst such as toluenesulfonic acid, or sodium methoxide, or potassium—t-butoxide, sodium hydride, etc.
  • the chlorinating agent may be phosphines such as triphenylphosphine, tributylphosphine or triphenoxyphosphine and carbon tetrachloride, N-chlorosuccinimide or chlorine, thionyl chloride.
  • the reaction is carried out using phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride.
  • an inert solvent which does not participate in the reaction for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine, etc. Used.
  • the reaction is carried out from room temperature to the boiling point of the chlorinating agent or the solvent if a solvent is used. Proceed smoothly up to the boiling point of
  • X is a bromine atom, the reaction can be carried out in the same manner as in chlorination using a corresponding brominating agent.
  • the sulfonating reagent used in this reaction is methanesulfonyl chloride, p-toluenesulfonyl chloride, Methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonyl imide, etc.
  • reaction is carried out in a solvent in the form of triethylamine, triethylamine
  • a solvent in the form of triethylamine, triethylamine
  • a base such as butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamide.
  • a base such as butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamide.
  • an inert solvent which does not participate in the reaction, preferably, dichloromethane, tetrahydrofuran or the like is used.
  • the reaction is carried out at a temperature of 170 ° C. to 100 ° C., preferably at a temperature of 130 ° C. to 80 ° C. o
  • the compound (VI) (X, RR 2 , R 3 , the rings B and C are the same as described above) and the compound (VI I) (the rings Y and A are the same as described above) are mixed with a palladium or nickel complex.
  • the Kurosukatsupuri ring reaction under transition metal catalyst etc., the compound (VI II) (RR 2, 3, a ring, the B ring ⁇ beauty ring C as defined above) is a step for preparing a. This reaction is preferably performed using an inert solvent that does not participate in the reaction.
  • N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, Trahydrofuran, dioxane, dichloromethane, toluene, ethanol or water can be exemplified. These solvents are used alone or in a mixture at an arbitrary ratio.
  • the palladium complex used in this reaction include palladium chloride, palladium acetate, acetyl acetonato palladium, and tetrax Phenylphosphine) palladium and the like.
  • nickel complex used in this reaction examples include bis (acetylacetonato) nickel, bis (1,5-cyclooxengen) nickel, and tetrakis (triphenylphosphine) nickel. These palladium or nickel complexes are used in the range of 0.001 to 1 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (VI).
  • triphenylphosphine When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri0-tolylphosphine, tri1-2-furylphosphine, 1,2-bis (diphenyl) Examples thereof include phosphino) ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) -11,1, -binaphthyl. These ligands are used in the range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex.
  • X of the compound (VI) is 0 S 0 2 R 1 3, with a palladium or nickel complex, it can be used copper iodide or lithium chlorambucil I de like if necessary.
  • This reaction is preferably carried out in the presence of a suitable base.
  • a suitable base such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, etc .;
  • inorganic bases such as sodium, sodium carbonate, calcium carbonate, calcium carbonate, cesium carbonate, and tricalcium phosphate. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (VI).
  • the cross-force pulling reaction in this step can be carried out at room temperature to 150 ° C, preferably at 50 to 120 ° C.
  • a Y is B (R 1 5) is not a 2 compound of the cross power Uz pre ring compounds in the reaction of this step (VII) as a starting material
  • the compound (VI) or the compound (VII) (wherein Y is B (Not R1 5 ) 2 ) and HB (R 1 5 ) 2 Or (B (R 1 5) 2) 2 is reacted with a compound obtained (VI) (X is B (R 1 5) 2) or the compound (VII) ( ⁇ 8 (1 5) 2) of engagement things (VII) (wherein Y is not a B (R 1 5) 2) or the compound
  • Compound (VIII) can also be produced by reacting (VI).
  • the protecting group of the amino group of the compound (VIII) (R ⁇ R 2 , R 3 , A ring, B ring and C ring are the same as described above) is converted into a hydrogen atom, and the compound (IX) ( R ⁇ RA ring, B ring and C ring are the same as described above).
  • This step is carried out, for example, by hydrogenating reductively when R 3 is a phenylmethyl group.
  • R 3 is a phenylmethyl group.
  • the hydrogen donor is hydrogen gas, ammonium formate, hydrazine or the like.
  • a polar solvent such as ethanol or methanol is used.
  • compound (IX) (RR 2 , ring A, ring B and ring C are the same as described above) is acylated to produce compound (XI).
  • This step is for example R 7 is a bromine atom, when n is 1, blanking opening Moasechiruburo mi de a promo acetylating agent, Ru performed using promo acetylchloride Li de like. This reaction is preferably carried out in the presence of a suitable base.
  • organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, etc.
  • carbonic acid Sodium hydrogen, sodium carbonate, carbon dioxide realm, carbon dioxide
  • inorganic bases such as lime, cesium carbonate and triphosphate lysate.
  • This reaction is preferably performed using an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, Examples thereof include tetrahydrofuran, dioxane, dichloromethane, and toluene. These solvents may be used alone or as a mixture in any ratio.
  • the compound (XI) with R 7 R 9 in the (R ⁇ R 2, R 7 , A ring, B ring and C ring are the same) (R 9 is as defined above) is converted into, the compounds ( ⁇ ) (R ⁇ R 2 , R 9 , ring A, ring B and ring C are the same as described above).
  • This reaction can be carried out in the presence or absence of salt groups using HR 9 1 to 2 0 equivalents.
  • suitable bases include, for example, organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, sodium hydrogen carbonate, and sodium carbonate.
  • inorganic bases such as tritium, potassium carbonate, calcium carbonate, cesium carbonate, and tricalcium phosphate.
  • an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol or water, etc. Is used.
  • compound (XVI) can also be produced from compound (XIV) and compound (XV).
  • the compound (XV) is used in an amount of 1 to 10 equivalents of the compound (XV), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium butoxide, hydrogenation is used.
  • an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium butoxide, hydrogenation is used.
  • Compound (XIII) can be produced from compound (XVI) obtained according to the method described above.
  • compound (XVIII) can also be produced from compound (XVII) and compound (XV).
  • the compound (XV) is used in an amount of 1 to 10 equivalents of the compound (XVII), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium tert-butoxide, hydrogen hydride is used.
  • N, N-dimethylforma in the presence of a base such as a stream 30 minutes to 48 hours at 50 to 10 ° C in solvents such as mid, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, and xylene It can be implemented by processing.
  • Compound (XIII) can be produced from the obtained compound (xyni) according to the method described above.
  • the compound (1) of the present invention can be isolated and purified by usual separation means (eg, extraction, recrystallization, distillation, chromatography, etc.).
  • usual separation means eg, extraction, recrystallization, distillation, chromatography, etc.
  • various salts can be produced by a usual method or a method analogous thereto (eg, neutralization).
  • the compound (1) or a salt thereof of the present invention can be used alone or together with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition, and a pharmacologically acceptable carrier, excipient (for example, starch, lactose, calcium phosphate, calcium carbonate, etc., lubricants (eg, magnesium stearate, calcium talc, stearic acid, etc.), binders (eg, starch, crystalline cellulose, carboxymethyl cellulose, Gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose, calcium, etc.), diluents (eg, aqueous solutions of saline, glucose, mannitol, lactose, etc.) ), Tablets, capsules, granules, powders It can be administered orally or parenterally in the form of preparations, fine granules, ampules or injections.
  • the dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, symptoms, etc. 0.001 to 300 mg / kg / day.
  • the administration is performed, for example, once or several times a day.
  • N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-11, N-dimethyl-5-oxo-5H-pyridide was prepared in the same manner as in Example 1.
  • N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-1, N-dimethyl-15-oxo-5H-pyri [1, 2,3 -de] 1,1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 4-fluorophenylboronic acid (42.Omg ⁇ 0.30) mm o 1)
  • N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-11, N—dimethyl-17- (4-fluorophenyl) -15-oxo-5H —Pyrido [1,2,3-de] -11,4-benzodiazine-16-carboxamide (32.8 mg, 57%) was obtained.
  • N— [3,5_bis (trifluoromethyl) benzyl] -17— (4—chlorophenyl) 1-2,3—dihydro1-1, N—dimethyl 1-5-oxo-5H-pyrido [1,2,3-de] 1,4_benzodiazine-16-carboxamide (39.8 mg, 67%) was obtained.
  • N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1,1, N-dimethyl-5-oxo-5H-pyri [1, 2, 3-d ⁇ ] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.10 mm 01) and 3-chloro-1-fluorophenylboronic acid (52.3 mg, 0.30 mm 01) from N— [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-1-4-fluorophenyl) 1-2 , 3-Dihydro 1, N-dimethyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide (61.0 mg, 100 %).
  • One 5-perido [1,2,3-de] -1,4-benzodiazine-16-carboxamide (40.5 mg, 69%) was obtained.
  • N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-1,1-N-dimethyl-15-oxo-5H-pyrido [1,2,3-d ⁇ ]-1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 2,4-dichlorophenylborate (57.3 mg, 0 30 mm o 1) from N- [3,5-bis (trifluoromethyl) benzyl] -17- (2,4-dichlorophenyl) 1-2,3-dihydro ,,-dimethyl-5- Oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (40.8 mg, 65%) was obtained.
  • 6-Carboxamide (3.0 g, 5.1 mmol) and 3-methoxyphenylboronic acid (1.54 g, 10 mmol) were added to toluene (100 ml), 1,4-dioxane. (40 ml) and 2 mol / l sodium carbonate aqueous solution (30.5 ml), and dissolved in the mixture. Tetrax (triphenylphosphine) palladium (584 mg, 0.1%) was added. Then, the mixture was heated and refluxed at 100 ° C. for 3 hours.
  • 2,3 -de]-1,4-I-benzodiazine-16-carboxamide (40.0 mg, 61 / mol) was dissolved in ethanol (0.5 ml), and 1 mo1 / 1 Aqueous aqueous solution (0.1 ml) was added, and the mixture was stirred at room temperature for 3 hours. 1 molZ 1 hydrochloric acid (0.1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography.
  • reaction solution was diluted with methylene chloride, washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid and a saturated saline solution, and then dried over anhydrous sodium sulfate.
  • the solvent is distilled off to give a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 1- (methanesulfonyl) -17- (3-methoxyphenyl)
  • N-methyl-15-oxo-5H-pyrido [1,2,3-de] -11,41-benzodiazine-6-carboxamide 27 mg, 96%).
  • N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro-1-N-methyl-15-oxo17 —Feniru 5 H—Pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide (30.0 mg, 45 mol) and ammonia (6.2 mg, 9 1 mol, 25% aqueous solution) from 1- (aminoacetyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1-N-methyl-5-oxo-1 7- Feuniru 5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (24.1 mg, 89%) was obtained.
  • morpholine (9.1 mg, 0.1 l Ommol) from N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,4-difluorophenyl) 1-2,3- Dihydro-1-N-methyl-1- (4-morpholinyl-2-acetyl) 1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide (54. 0 m ;, 89%).
  • N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methylol 1_ (4-morpholinylacetyl) was prepared in the same manner as in Example 1.
  • 4-Methylphenyl) 1-11 (4-morpholinyl acetyl) — 5-oxo-1 5H-pyrido [1,2,3-de] —1,4-benzodiazine-1 6-carboxamide (45. 8 mg, 70%).
  • N- [3,5-bis (trifluoromethyl) benzyl] 17-chloro-2,3-dihydro-N-methyl-1- (4-morpholinylacetyl) ) 15-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0 mg, 95 zmol) and 2-methylphenyl From the acid (27.5 mg, 0.20 mmol), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N—methyl—7— (2— Methylphenyl) 1- (4-morpholinylacetyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4—benzodiazine-16-carboxamide (55.5 mg, 85) %).
  • One 6-carboxamide (57.1 mg, 83%) was obtained.
  • N- [3,5-bis (trifluoromethyl) benzyl] 17-chloro-2,3-dihydro-N-methyl-1- (4-morpholinylacetyl) was prepared in the same manner as in Example 1.
  • 1-5-oxo-5H-pyrido [1,2,3-de] 1,4-benzodiazine-16-carboxamide (60.0 mg, 95 zmol) and 3,5-difluorophene N- [3,5-bis (trifluoromethyl) benzyl] -17— (30.3 mg, 0.19 mmol, 50% tetrahydrofuran monofuran aqueous solution) , 5-Difluorophenyl) — 2,3-Dihydro N-methyl-1- (4-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1 , 4-Benzodiazine-1-carboxamide (63.6 mg, 94%) was obtained.
  • N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (3-methoxyphenyl) -1-N-methyl-1 1 L (41- (methylamino) piridinyl) acetyl] — 5-oxo-5 H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (84.7 mg, 0.12 mm 01) and acetic anhydride (14.2 mg, 0.14 mmo 1) from 1-[(4- (N-acetyl-N-methylamino) piperidinyl) acetyl] 1 N— [3,5-bis (trifluoromethyl) pentyl] —2,3-dihydro-1 7— (3-methoxyphenyl) 1 N—methyl-15-oxo-5H—pyrido [1 [2,3-d ⁇ ] —1,4,1-benzodiazine-16-carboxamide 84.7 mg, 0.12 mm 01)
  • the solvent is distilled off to give a colorless amorphous ⁇ N— [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo 1- (1-biperazyl acetyl) 1-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (66.2 mg, 80%) Obtained.
  • Example 1 11—N- [3,5-bis (trifluoromethyl) benzyl] —1— [4- (N— (t-butoxycarbonyl) -1-N-methylamino) piperidinylacetyl ] — 2,3-Dihydro 7- (3-Methoxyphenyl) 1 N-methyl _ 5 -oxo 1 5 H-pyrido [1,2,3-d ⁇ ] — 1,4 benzodiazine — From 6-carboxamide (290 mg, 0.35 mmol), N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-7- (3-methoxyphene) Nyl) 1 N-Methyl-1 1- [4- (Methylamino) piperidinylacetyl] — 5-oxo-5 H-Pyrido [1,2,3-de] —1,4-Benzoazine-6 —Carboxamide (255 mg, 100%) was obtained.
  • Example 1 1 6> 55.35%, H 4.60%, N 7.05%
  • N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (3-fluorophenyl) -1-N-methyl-5-oxo by a method similar to that of Example 12 25
  • One 5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (2.0 g, 3.6 mmol) gives N— [3,5-bis ( Trifluoromethyl) benzyl] 1 1- (bromoacetyl) 1,2,3-dialdehyde 1 7- (3-fluorophenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3 — De] — 1,4-benzodiazine-1 6-carboxamide (2.13 g, 87%) was obtained.
  • N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (2-fluorophenyl) -1-N-methyl-15-oxo by a method similar to that of Example 125.
  • N- [3,5-bis ( Trifluoromethyl) pendyl] ⁇ 1- (bromoacetyl) 1-2,3-dihydro 7- (2-fluorophenyl) 1-N-methyl-15-oxo-5H-pyrido [1,2,3-de ] — 1,4-benzodiazine-1 6-carboxamide (303 mg, 31%) was obtained.
  • Example 1 3 1> According to a method similar to that of Example 1 25, N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-difluorophenyl) —2,3-dihydro N-methyl From 5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (200g, 3,4mmol), N— [3,5— Bis (trifluoromethyl) benzyl] 1-1- (bromoacetyl) -17- (2,4-difluorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1, [2,3-de] —1,4-benzodiazine-6-carboxamide (2.05 g, 85) was obtained.
  • Example 13 By the same method as in 32, 1 1-benzyl-1,2,3,4-tetrahydrodraw 1,4-benzodiazine (7.00 g, 31 mmol) and methane tricarboxylate were prepared. From Lietyl (14.5 g, 62 mm 0 1), 1-benzyl-1,2,3-dihydro-7-hydroxy-1-5-oxo-5H-pyrid [1,2,3-d ⁇ ] -11,4-benzodiazine-16-carboxylic acid ethyl ester (10.1 g, 88) was obtained.
  • Example 1 3 5> 1-Benzyl-1,2,3-dihydroxy 7-hydroxy-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzodiazine From 6-potassium ethyl ribonate (34.3 g, 94 mmol) and 3,5-bis (trifluoromethyl) -N-methylbenzylamine (29.2 g, 0.1 llmol) , 1—Benzyl mono N— [3,5—Bis (trifluoromethyl) benzyl] , 3-de] — 1, 4-benzodiazine — 6 — carboxamide (54.2 g, 100%).
  • reaction solution was concentrated under reduced pressure, water and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to 10, then extracted with ethyl acetate, and dried over anhydrous sodium sulfate.
  • residue obtained by distilling off the solvent was washed with diisopropyl ether, and pale yellow crystals of N- [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-diethyl 1,4-N-dimethyl-5-oxo-5H-pyrido [1,2,3-d ⁇ ] -11,41-benzodiazine-6-carboxamide (2.31 g, 73%) Obtained.
  • the reaction solution was diluted with methylene chloride, washed with water, and dried over anhydrous sodium sulfate.
  • the experiment started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration-response curve of the substance P in the absence of the test compound was used as a control.
  • the NK1 receptor antagonism of the test compound was determined from a concentration-response curve of substance P, which was pretreated with at least three concentrations of the test compound for 10 minutes and then cumulatively applied.
  • the K b value is obtained by the method of Schi 1 d (“British Journal of Pharmaceutical Science” (Brit. J. Pharmacol)), Vol. 14, p. 48 (1959). The results are shown in Table 1.
  • the composition of the Tyrode solution was as follows. Na C l; 1 3 6. 9 ⁇ KC 1; 2. 7, C a C l 2 '2 H 2 0; 2. 5, M g C 1 2 ⁇

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Abstract

L'invention concerne des dérivés de pyridobenzodiazine présentant un antagonisme du récepteur de la tachykinie, plus particulièrement, un antagonisme du récepteur de la NK1, et des procédés permettant de préparer ces dérivés. L'invention concerne également des dérivés de pyridobenzodiazine représentés par la formule générale (1) et des sels de ceux-ci, des procédés de préparation associés, et des compositions pharmaceutiques contenant ces dérivés ou des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne, en outre, des dérivés de pyridobenzodiazine représentés par la formule générale (1) ou des sels de ceux-ci, ainsi que des hydrates et des solvates de ceux-ci.
PCT/JP2001/003779 2000-05-12 2001-05-02 Derives de pyridobenzodiazine et procedes de preparation de ces derives WO2001085732A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8048894B2 (en) 2007-04-18 2011-11-01 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
US8097620B2 (en) 2007-05-04 2012-01-17 Amgen Inc. Diazaquinolones that inhibit prolyl hydroxylase activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015083A1 (fr) * 1992-01-27 1993-08-05 Fujisawa Pharmaceutical Co., Ltd. Derives heterotricycliques, leur procede de preparation, et compositions pharmaceutiques les contenant
WO2000006578A1 (fr) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Derives de pyridobenzoxazine et leur procede de production
WO2000006572A1 (fr) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Derives de benzoquinolizine et procede de production

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015083A1 (fr) * 1992-01-27 1993-08-05 Fujisawa Pharmaceutical Co., Ltd. Derives heterotricycliques, leur procede de preparation, et compositions pharmaceutiques les contenant
WO2000006578A1 (fr) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Derives de pyridobenzoxazine et leur procede de production
WO2000006572A1 (fr) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Derives de benzoquinolizine et procede de production

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US7928139B2 (en) 2006-12-18 2011-04-19 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
US8048894B2 (en) 2007-04-18 2011-11-01 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
US8349868B2 (en) 2007-04-18 2013-01-08 Amgen Inc. Azaquinolones that inhibit prolyl hydroxylase
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
US8097620B2 (en) 2007-05-04 2012-01-17 Amgen Inc. Diazaquinolones that inhibit prolyl hydroxylase activity

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