WO2000006580A1 - Derives de pyridobenzothiazine et leur procede de production - Google Patents

Derives de pyridobenzothiazine et leur procede de production Download PDF

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Publication number
WO2000006580A1
WO2000006580A1 PCT/JP1999/004108 JP9904108W WO0006580A1 WO 2000006580 A1 WO2000006580 A1 WO 2000006580A1 JP 9904108 W JP9904108 W JP 9904108W WO 0006580 A1 WO0006580 A1 WO 0006580A1
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group
ring
substituents
optionally substituted
bonded
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PCT/JP1999/004108
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English (en)
Japanese (ja)
Inventor
Yasumichi Fukuda
Shigeki Seto
Asao Tanioka
Makoto Ikeda
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Kyorin Pharmaceutical Co., Ltd.
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Priority to AU49311/99A priority Critical patent/AU4931199A/en
Publication of WO2000006580A1 publication Critical patent/WO2000006580A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 pyridobenzothiazine derivative or a pharmacologically acceptable salt thereof having an inhibitory activity on evening kinkinin receptor, a method for producing the same, and a pharmaceutical composition containing the pyridobenzothiazine derivative.
  • Yukinkinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their receptors in the body (neurokinin 1, neurokinin 2 ( ⁇ ⁇ 2 ) 'neurokinin). 3 ( ⁇ ⁇ 3)) is known to express various physiological activities. Among them, substance ⁇ acts as a transmitter of central and peripheral primary sensory neurons, as well as enhancing diuresis, stimulating nerve cells, enhancing vascular permeability, vasodilating, smooth muscle contracting, and immunizing. It is considered to be deeply involved in various disease states (frequent urination, urinary incontinence, vomiting, inflammation, allergy, airway disease, pain, central nervous system disease, etc.).
  • kinkinin receptor antagonism especially substrate ⁇ receptor antagonism, as a preventive and therapeutic agent for the above-mentioned various disease states, and has excellent safety and long-lasting properties. It is desired to develop a compound having such a compound.
  • R 1 is hydrogen or an amino protecting group
  • R 2 is hydrogen, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group, or a protected carboxy (lower) alkyl group
  • R 3 is an alk (lower) alkyl group, —N (R 4 ) (R 5 ) group (wherein R 4 and R 5 are each a hydrogen-aryl group or a lower alkyl which may have a suitable substituent)
  • R 4 and R 5 are bonded to each other to form a benzene-condensed lower alkylene group, or —OR 6 group, wherein R 6 is hydrogen, aryl group or a suitable substituent.
  • A represents a single bond or one or two amino acid residues
  • A is: D—amino acid of Trp When one residue is meant, R 4 is not hydrogen.
  • the compound represented by) and a salt thereof are disclosed. Have been
  • 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 represents a hydrogen atom, a lower alkyl group, a hydroxyl group And a lower alkenyl group, a lower alkanol group and a lower alkoxy group, and the ring A and the ring B each represent a benzene ring which may have a substituent.
  • An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism to tachykinin receptor, particularly a substance P receptor antagonism, which has a different chemical structure from known compounds including the above-mentioned compounds, and a quinkinin receptor antagonist
  • Another object of the present invention is to provide a prophylactic or therapeutic agent for dysuria, a prophylactic or therapeutic agent for gastrointestinal disorders and a prophylactic or therapeutic agent for vomiting. Disclosure of the invention
  • R 1 R 2 and R 3 are the same or different and are a hydrogen atom or a C 6 -C 6 alkyl group, and A ring is each independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring) may have a homo- or heterocyclic ring, and the ring B has 1 to 5 substituents (two adjacent substituents are May combine to form a ring).
  • the benzene ring and the C ring may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) Shows a good benzene ring.
  • the present invention provides a pyridobenzothiazine derivative represented by the formula or a salt, hydrate and solvate thereof.
  • ring A is a halogen atom, an optionally substituted to C 6 alkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i to C 6 an alkoxy group, a cycloalkoxy group of C 3 ⁇ C i 0, the optionally substituted C i to Al Kanoiruokishi group C 6, optionally substituted ⁇ Li Roiruokishi group, which may be substitution ⁇ Reel methyloxy group, Cs C!.
  • Cycloalkadienyl noisy Ruo alkoxy group a substituted alkyl optionally C ⁇ C 6 even if Chiomoto, alkylsulfinyl group ⁇ C 6 optionally C 1 substituted - the optionally substituted C i C s Alkylsulfonyl group, amino group, mono- or di-substituted CiCe alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, CiC e, an alkylcarbonylamino group, CiCe, an alkoxycarbonylamino group, C!
  • a homo- or heterocyclic ring optionally having 1 to 3 substituents (each of which may be bonded to two adjacent substituents to form a ring) Indicates that
  • B ring is a halogen atom, a substituted optionally alkyl group which may C ⁇ C 6, C 3 ⁇ C t.
  • Alkylthio groups C 6, alkyl sulfinyl group which may be substituted, an alkylsulfonyl group optionally C i to C 6 which may be substituted, an amino group, mono- or di-substituted C, in ⁇ C 6 alkylamino Group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms.
  • C ring is a halogen atom, an optionally substituted alkyl group of C ⁇ C 6 also, human Dorokishiru group, an optionally substituted C i C e alkoxy group, optionally substituted C, of ⁇ C 6 Arca noisy Ruo carboxy group, it may also be substituted I ⁇ Li Roiruokishi group, it may also be substituted I ⁇ Li - Rumechiruokishi group, C 3 ⁇ C! . Cycloalkoxy group, cycloalkadienyl noisy Ruo alkoxy group of C 3 ⁇ C 1 0, amino group, mono- or di-substituted C!
  • Alkylamino amino group of ⁇ C 6, 1 ⁇ 3 or may also be 4-9 membered contain heteroatoms of the cyclic ⁇ Mi amino group, an alkylcarbonyl amino group of C! C e, alkoxy of C i C e Carbonylamino group, C i Ce alkylsulfonylamino group, optionally substituted arylsulfo 1 to 3 substituents independently selected from a nilamino group, a cyano group, or a nitro group (two adjacent substituents may be bonded to each other to form a ring) 3.
  • R 3 is a hydrogen atom or a C i C alkyl group
  • R 4 is a hydroxyl group, a C i C alkoxy group, a benzyloxy group or a reactive residue, even if the A ring is a halogen atom or is substituted.
  • cycloalkanoyloxy group optionally substituted ( ⁇ - ( ⁇ ( ⁇ alkylthio group, a substituted alkyl sulfide alkylsulfonyl group may optionally have good C i C e, alkylsulfonyl group - C 6 which may be substituted, amino amino group, Al of ⁇ C 6 mono or di-substituted Ruami amino group, one to three of the may contain heteroatoms 4-9 membered cyclic Amino group, an alkylcarbonyl amino group of C ⁇ C 6, C i C e alkoxycarbonyl ⁇ Mi amino group, Alkylsulfonylamino group of C i Ce, arylsulfo which may be substituted Nilamino group, C i -C 6 alkylcarbonyl group, formyl group, carbonyl group, C i -C 6 -alkoxycarbonyl group, mono- or di-substituted C i
  • R 3 is a hydrogen atom or a C i Ce alkyl group
  • R 5 is
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 0 S 0 2 R 6 (where R 6 is optionally substituted C) i-C 6 alkyl group, aryl group which may be substituted), C ring is a halogen atom, and optionally substituted C!
  • Cycloalkadienyl noisy Ruo alkoxy group amino group, mono- or di-substituted alkylamino amino group of C i ⁇ C 6, 1 ⁇ 3 amino 4 may contain a hetero atom 9-membered cyclic ⁇ Mi amino group
  • the present invention provides a pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.
  • the present inventors have the following general formula (4)
  • R 3 is a hydrogen atom or a C i Ce alkyl group
  • R 5 is
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, and the ring C is a halogen atom, an optionally substituted C 6 -C 6 alkyl group, a hydroxyl group, or a substituted benzene ring.
  • the alkoxy group of the mouth C 3 -C i.
  • a benzene ring which may have The present invention provides a pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.
  • R 3 is a hydrogen atom or a C i Ce alkyl group
  • R 4 is a hydroxyl group, a C alkoxy group, a benzyloxy group or a reactive residue
  • each of the A rings is independently selected from 1 to 3
  • two adjacent substituents may be bonded to each other to form a ring
  • the C-ring may have 1 to 3 substituents.
  • the two adjacent substituents may be bonded to each other to form a ring).
  • the present invention provides a method for producing a compound or a salt thereof, a hydrate and a solvate according to claim 1 by reacting the compound represented by the formula or a salt, hydrate and solvate thereof.
  • R 3 is a hydrogen atom or an alkyl group of CiCe
  • R 7 is a hydroxyl group, an alkoxy group of C to C 6 , a benzyloxy group
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or ⁇ S 0 2 R 6 (R 6 is a halogen-substituted C i- C 6 alkyl group, aryl group which may be substituted), and ring C has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring).
  • ⁇ is a halogen atom
  • OS ⁇ 2 R 6 (R 6 is the same as described above)
  • B (R 8 ) 2 (R 8 is a hydroxyl group, a C i -C 6 alkyl group or a C i -C 6 Or an alkoxy group, or R 8 may be bonded to each other to form a ring.)
  • MgBr or ZnCl, and the A ring are each independently selected from 1 to 3 substituents (The two or more adjacent substituents may be bonded to each other to form a ring.)
  • a homo- or heterocyclic ring which may have a compound represented by the following formula: 3.
  • the present inventors have the following general formula (8)
  • R 3 is the same or different and is a hydrogen atom or a C 6 -C 6 alkyl group
  • R 7 is a hydroxyl group, a C! -C 6 alkoxy group, a benzyloxy group
  • R 1 and R 2 are the same or different and are each a hydrogen atom or an alkyl of C i Ce And the ring B and the ring B represent a benzene ring which may have 1 to 5 substituents (two adjacent substituents may combine with each other to form a ring).
  • Z is hydroxyl
  • X is a halogen atom or an OS 0 2 R 6 (R 6 is Kill group optionally C i C e be halogen-substituted, optionally substituted Ariru Group)
  • a ring where A ring is independently selected from 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) An aryl or heterocyclic ring which may be present), and P represents 0 or 1.
  • a salt, hydrate or solvate thereof represented by the following general formula (9)
  • the present inventors provide a tachykinin receptor antagonist characterized by comprising a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • the present inventors have developed a substance P receptor antagonist comprising the pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. provide.
  • the present inventors require that the pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof be contained 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 provided a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition, which is characterized by ulcerative colitis and Crohn's disease. And a prophylactic or therapeutic agent for gastrointestinal diseases comprising:
  • the inventors of the present invention provide a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition, which is characterized by X-ray irradiation, chemotherapeutic agent,
  • the present invention provides a preventive or therapeutic agent for vomiting induced by migraine, postoperative illness, gastrointestinal motility depression, side effects of drug administration, and the like.
  • the present inventors have ascertained tachykinin-related asthma, cough, and the like, comprising a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the C i -C 6 alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group and the like.
  • the alkoxy group of c 1 to c 6 means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexoxy group, or the like.
  • the cycloalkoxy group of C 3 ⁇ C i 0, cyclo propyl O alkoxy group, cyclobutyl O alkoxy group, means a Shikuropenchiruo alkoxy group, Kishiruokishi group cyclohexylene.
  • the cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclopentanoyloxy group, a cyclopentanoyloxy group, a cyclohexanoyloxy group and the like.
  • the C i -C 6 alkylcarbonyl group means an acetyl group, a propionyl group, a butyryl group or the like.
  • alkoxycarbonyl group of i to C 6, main butoxycarbonyl group refers to E-butoxycarbonyl group, a propoxycarbonyl group, it isopropoxy force Lupo sulfonyl group, t one-butoxycarbonyl group, a hexyl O propoxycarbonyl two Le group I do.
  • a 4- to 9-membered cyclic rubamoyl group which may contain 1 to 3 heteroatoms is defined as azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, 4-methylbiperidyl group
  • ACiCe alkylthio group means a carbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, a 4-methylpiperazinylcarbonyl group, etc. , Ethylthio, propylthio, isopropylthio, t-butylthio, hexylthio and the like.
  • the alkylamino group of CiCe 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.
  • the 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group, morpholino group and thiomorpholino. Group, piperazino group, 4-methylbiperazino group and the like.
  • the CiCe alkylcarbonylamino group means an acetylamino group, a propionylamino group, a petyrylamino group and the like.
  • the alkoxycarbonylamino group of the above means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group and the like.
  • the alkylsulfonylamino group of C e means a methylsulfonylamino group, an ethylsulfonylamino group, and the like.
  • the arylsulfonylamino group means a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, a naphthylsulfonylamino group, or the like.
  • the homocyclic ring of the ring A means a benzene ring, a naphthylene ring or the like.
  • 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 It means a 9- or 10-membered fused aromatic heterocycle.
  • an alkyl group which may 6, halogen atom, human Doroki sill group, an alkoxy group of C i C e, alkylthio group CC e, amino group, alkylamino of C ⁇ C 6 mono or di-substituted amino group from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic amino groups, Hol Miruami amino group, an alkylcarbonyl ⁇ Mi amino group of C i to C 6, of C 1 ⁇ C 6 alkylsulfonyl amino group, means an alkyl group optionally C 1 ⁇ C 6 optionally having 1 to 5 substituents selected from such optionally substituted Ariru Suruhoniruami cyano group.
  • the optionally substituted C i C alkoxy group means a halogen atom, a hydroxyl group, a d-C 6 alkoxy group, a C-C 6 alkylthio group, an amino group, a mono- or di-substituted C i C s of alkylamino amino group from 1 to 3 of the TeroHara child to contain an be 4-9 membered cyclic amino groups, Horumiruami amino group, an alkylcarbonyl amino group of C 1 ⁇ C 6, C i A C t C 6 alkoxy group which may have 1 to 5 substituents selected from an alkylsulfonylamino group of Ce and an optionally substituted arylsulfonylamino group, etc.
  • the optionally substituted aryloxy group includes a halogen atom, a C i C alkyl group, a hydroxy group, a C i C alkoxy group, a C to C 6 alkylthio group, an amino group, a mono or mono group.
  • CiC alkyl amino group Di-substituted CiC alkyl amino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, formyl amino group, CiC alkylcarbonyl amino group
  • Aryloxy which may have 1 to 5 substituent (s) selected from a group, a C to C 6 alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc.
  • Substituted and which may ⁇ reel methyl O alkoxy group, c androgenic atom, an alkyl group of C i C e, human Dorokishiru group, an alkoxy group of C ⁇ C s, alkylthio group of C i to C 6, amino group, mono- or alkylamino amino group of C i C s disubstituted from 1 to 3 hetero atoms may be free Ndei to the 4-9 membered cyclic amino group, formylamino group, a C i ⁇ C 6 alkylcarbonyl ⁇ Mi amino group, C t ⁇ alkylsulfonyl Niruami amino group of C 6, may have a selected 1-5 substituents from such optionally substituted ⁇ Li one also be Rusuruhoniruami amino group Ariel Mech Roxy group (phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, -quinolylmethyloxy group, in
  • the substituents on these ⁇ Li one Rusuru Honiruami amino group also, Bruno, mouth Gen atom, an alkyl group of ci ⁇ c 6, human de port hexyl group, C! C e alkoxy group, an alkylthio group, an amino group, alkylamino amino group of C i to C 6 mono- or di-substituted, 1-3 may contain a hetero atom of 4-9 membered cyclic ⁇ Mi amino group, Horumiruami amino group, C i to C 6 alkylcarbonyl ⁇ Mi amino group of, have a C i alkylsulfonyl amino group-C 6, substituted 1 also selected from good ⁇ Li one Rusuruhoniruami amino group or the like have to 5 substituents Means an arylsulfonylamino group.
  • the aryl group which may be substituted includes a halogen atom, an ⁇ -( ⁇ ( ⁇ alkyl group, a hydroxyl group, a C i -C 6 alkoxy group, a C i -C 6 alkylthio group, an amino group, ⁇ Rukiruami amino group of C ⁇ C 6 mono or di-substituted, 1-3 may contain a hetero atom of 4-9 membered cyclic amino group, formylamino group, alkyl C i to C 6 Aryl which may have 1 to 5 substituents selected from a carbonylamino group, an alkylsulfonylamino group of CiCe, an optionally substituted arylsulfonylamino group, etc.
  • the optionally substituted alkylthio group includes a halogen atom, a hydroxyl group, a C alkoxy group, and ( ⁇ ⁇ .
  • Alkylthio group, amino group, mono- or alkyl Ruami amino group of C i to C 6 disubstituted from 1 to 3 may contain heteroatoms of 4-9 membered cyclic amino group, Horumiruami Bruno group, C. 1 to alkylcarbonylamino group C 6, C i C e alkylsulfonyl ⁇ Mi amino group, an optionally substituted good i ⁇ reel sulfonyl ⁇ amino group 1-5 amino substitution selected from etc.
  • alkylthio group which may have a group.
  • 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic ⁇ Mi amino group, formyl Ruami amino group, an alkylcarbonyl ⁇ Mi amino group of C i to C 6,
  • An alkylsulfenyl group which may have 1 to 5 substituents selected from a C i C fi alkylsulfonylamino group, a substituted or unsubstituted arylsulfonylamino group (a methylsulfinyl group, Ethylsulfinyl group, propylsulfinyl group, etc.).
  • the optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxy group, a C to C 6 alkoxy group, a C i to C 6 alkylthio group, an amino group, a mono- or di-substituted C t to alkylamino amino group of C 6,.
  • 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic ⁇ Mi 'amino group, formyl Ruami amino group, an alkylcarbonyl ⁇ Mi amino group of C i to C 6 , ( ⁇ To ( ⁇ ( ⁇ ) alkylsulfonylamino group optionally having 1 to 5 substituents selected from an optionally substituted arylsulfonylamino group, etc. (Methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, etc.)
  • the reactive residue is a halogen atom, 111-imidazolyl group, 412-trophenoxy group, imidoylsuccinate group, etc.
  • the emissions may be substituted C ⁇ 0 6 alkyl group, 1 to 3 full Tsu atom or chlorine It 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 by an atom.
  • the ring which may be formed by bonding R 8 to each other is 10 (CH 2 ) 20 —, 10 CH (Me) CH (Me) 0 —, — OC (Me) 2 C (M e) 2 0— or _ 0 (CH 2 ) 3 means one or more.
  • Preferred compounds of the present invention include N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-1-N-methyl-15-oxo-17-phenyl-1-H-pyri.
  • 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, Methanesulfonic acid, p-toluenes
  • organic acids such as sulfonic 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 as well as racemic isomers.
  • 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.
  • the compound (I) (R 3 and the ring C are the same as described above) and the compound (II) (R 9 is the same or different and a C i -C 6 alkyl group or a benzyl group) are reacted to obtain a compound (III) (R 3 , R 9 and the C ring are the same as described above).
  • the compound (II) is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, to 100 to 300 ° (preferably 150 to 250 °) relative to the compound (I).
  • the hydroxyl group of compound (III) R 3 , R 9 and the C ring are the same as described above) is converted into X (X is the same as above) to obtain compound (IV) (X, R 3 , R The 9 and C rings are the same as described above).
  • the chlorinating agent is a phosphine such as triphenylphosphine, tributylphosphine or triphenyloxyphosphine, and carbon tetrachloride, N-chlorosuccinimide.
  • the reaction is carried out using chlorine, thionyl chloride, oxychloride, pentachloride or oxalyl chloride.
  • a solvent an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used.
  • This reaction proceeds smoothly at a temperature from room temperature to the boiling point of the chlorinating agent or, if a solvent is used, the boiling point of the solvent.
  • 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 triethylamine, tributylamine, diethylamine, etc.
  • the reaction is performed in the presence of a base such as isopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamine.
  • a base such as isopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamine.
  • solvent an inert solvent which does not participate in the reaction, preferably dichloromethane, methane, tetrahydrofuran or the like is used.
  • the reaction is carried out at a temperature of -80 ° C to 100 ° C, preferably -30 ° C;
  • N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, Trahydrofuran, dioxane, dichloromethane, toluene, ethanol, water and the like can be exemplified. These solvents are used alone or in a mixture at any ratio.
  • the palladium complex used in this reaction include palladium chloride, palladium acetate, acetylacetonato palladium, and tetrax (triphenylphosphine) palladium.
  • the nickel complex used in this reaction is bis
  • Examples thereof include 2-bis (diphenylphosphino) ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) -11,1, -binaphthyl. These ligands are used in a range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex.
  • X of compound (IV) is 0
  • S_ ⁇ 2 R 6 together with the palladium or nickel complex, it can be used copper iodide or lithium chloride Lai de like if necessary.
  • This reaction is preferably performed in the presence of a suitable base, for example, organic compounds such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine.
  • a suitable base for example, organic compounds such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine.
  • Inorganic bases such as a base, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate or triphosphate lithium can be exemplified. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (IV).
  • the cross-coupling reaction in this step can be carried out at room temperature to 150 ° C., preferably at 50 to 120 ° C.
  • compound (IV) or compound (V) (where Y is B and (R 8) not 2), HB (R 8) 2 or (B (R 8) 2) 2 was reacted to give et compound (IV) (X is B (R 8) 2) or Compound (VI) is produced by reacting compound (V) (Y is B (R 8 ) 2 ) with compound (V) (but Y is not B (R 8 ) 2 ) or compound (IV) You can do it.
  • This time is a production intermediate obtained compound (IV) (in 8 (13 ⁇ 4 8) 2) or the compound (V) (Y is B (R 8) 2), A ring same above) is a single It can be subjected to the next step after isolation and purification, or can be continuously applied to the next step without isolation and purification.
  • DCC dicyclohexyl carpoimide
  • EDCI 3-ethyl-1- (3-dimethylaminopropyl) carposimid hydrochloride
  • DMC Dimethylimidazonium Chloride
  • alkali carbonates such as sodium hydrogencarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5 .
  • an inert solvent which does not participate in the reaction for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran , Dioxan, ethyl ether, dimethoxetane, ethyl acetate, dichloromethane and the like are used.
  • This condensation reaction proceeds smoothly from-20 ° C to 80 ° C.
  • R 4 is a carboxylic acid represented by a reactive residue (eg, a halogen atom, 1-imidazolyl group, 412 trophenoxy group, imidyloxy succinate group, etc.)
  • a reactive residue eg, a halogen atom, 1-imidazolyl group, 412 trophenoxy group, imidyloxy succinate group, etc.
  • organic bases such as triethylamine, diisoprovirethylamine, pyridine and 4-dimethylaminopyridine, in the presence of inorganic bases such as sodium bicarbonate and carbon dioxide, or In the presence of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran, dioxane, etilue It can be carried
  • R 4 is an ester residue such as an alkoxy group of benzyl, a benzyloxy group, etc.
  • R 4 is an ester residue such as an alkoxy group of benzyl, a benzyloxy group, etc.
  • tetraisopropoxytitanium or an acid catalyst such as p-toluenesulfonic acid, or sodium methoxide or potassium
  • the treatment can be carried out by treating in a solvent such as toluene, xylene, or dichloromethane at room temperature to 150 ° C. for 30 minutes to 48 hours.
  • a solvent such as toluene, xylene, or dichloromethane
  • compound (X) (R 3 , R 3 , Z and m is converted to the compound (IX) (R 3 , R 3 , Z and p are the same as described above) by oxidation.
  • This oxidation reaction can be performed according to a known method (for example, “Experimental Chemistry Lecture, 4th edition, VI, pp. 350-372, (1991), Maruzen”).
  • compound (XIII) can also be produced from compound (XI) and compound (XII).
  • the compound (XII) is used in an amount of 1 to 10 equivalents with respect to the compound (XI), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium butoxide, hydrogen N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene in the presence of a base such as sodium fluoride It can be carried out by treating in a solvent such as these at 50 to 150 ° C for 30 minutes to 48 hours.
  • Compound (VIII) can be produced from the obtained compound (XIII) according to the method described above.
  • compound (XV) can also be produced from compound (XIV) and compound (XII).
  • p-toluenesulfonic acid is used by using 1 to 10 equivalents of the compound (XII) with respect to the compound (XIV).
  • Acid catalysts such as sodium or bases such as sodium methoxide, potassium-t-butoxide, sodium hydride, etc. in the presence of N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, etc. by treating at 50 to 150 ° C for 30 minutes to 48 hours. be able to.
  • Compound (VIII) can be produced from the obtained compound (XV) 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 in combination with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition.
  • Excipients eg, starch, lactose, calcium phosphate, calcium carbonate, etc.
  • lubricants eg, magnesium stearate, calcium stearate, talc, stearate, etc.
  • binders eg, starch, lactose, Crystalline cellulose, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose calcium, etc.), diluents (eg, physiological saline, glucose, mannitol, lactose) Solution, etc.) and tablets, capsules, granules, It can be administered orally or parenterally in the form of powders, 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, and the like.
  • the compound of the present invention (1) or a salt thereof may be administered to mammals including humans. 0.0 0.001 to 300 mg / kg / day It is. For example, administration is performed once or several times a day.
  • 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 applied cumulatively.
  • p A 2 value is S chi 1 d of the method ( "Breakfast literals I Tsu Xu journal 'O Breakfast' off Amako Russia Gee (Brit. J. Pharmaco" 1 4 Certificates, 4 page 8 (1 9 5 9 years) ), And the results are shown in Table 1.
  • the composition of the Tyrode solution was as follows. N a C l; 1 3 6.
  • N Metal-1,3,5-bis (trifluoromethyl) benzylamine from 0.22 ml of colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-dichlorophenyl) one 2,3-Dihydro-1-N-methyl-1-oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-1-6-ruboxamide (477. Omg, 88%) Obtained.
  • N— [3,5-Bis (trifluoromethyl) benzyl] —2,3 dihydro-17- (3-methoxyphen-2-N-methyl-1-oxo) was prepared in the same manner as in Example 11.
  • One 5H—Pirido [1,2,3 -de]-1, 4_Benzothiazine _ 6 Carboxamide (116.5 mg, 0.2 mmo to colorless amorphous N— [3,5 _Bis (trifluoromethyl) benzyl)] — 2,3 —Dihydro-7 — (3—Methoxyphenyl) — N-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-6-carboxamide-1-1-oxide ( 118.4 mg, 99%).
  • the reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1), and the colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] —7— (2 , 4-Dichlorophenyl) —2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4 —benzothiazine-16-carboxamido 1,1 —dioxy (70.5 mg, 100%).
  • Triphenylphosphine (93.4 mg, 0.356 mmol) and carbon tetrachloride (0.11 ml, 110 mmol) were added, and the mixture was refluxed for 2 hours.
  • the residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained crystals were recrystallized from hexane-ether to give colorless crystals of 7-chloro-1,2-dihydro-1.
  • 5-oxo-5H-pyrido [1,2,3-de] -1,4, -benzothiazine-16-carboxylic acid ethyl ester 1,1,1-dioxide (489.5 mg, 80%) was obtained.
  • N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-15—oxo-5 From H-pyrido [1,2,3-de] -1, 4-benzothiazine-16-carboxamide (200mg, 0.38mmol) and 3,5-dichlorophenylboric acid (220mg, 1.2mmol), the colorless amorphous N — [3,5—Bis (trifluoromethyl) benzyl] — 7— (3,5—Dichlorophenyl) -1,2,3—dihidro N—Methyl-5—Oxo-1 5H—Pyrido [1,2 , 3-de] — 1,4-benzothiazine-16-carboxamide (162 mg, 675 were obtained.
  • Example 2 9 According to a method similar to that in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro N-methyl-15-oxo-5H— From the pyrido [1,2,3-de] —1,4-benzothiazine-6-carboxamide (200mg, 0.38mmol) and 4-formylphenylboronic acid (172mg, 1.2mmol), N- [3,5 —Bis (trifluoromethyl) benzyl] — 2,3 —Dihydro 7 — (4-Formylphenyl) 1 N—methyl-1 5 —oxo 1 5 H—pyrido [1,2,3, -de] —1, 4 Benzothiazine-16-carboxamide (218 mg, 96%) was obtained.
  • N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,5-dichlorophenyl) -1,2,3-dihydro-1-N-methyl-5- Oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-16-carboxamide (50.Omg, 79 / mol) was converted to colorless amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 7 — (3,5-dichlorophenyl) 1, 2,3-dihydro N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1 , 4-Benzothiazine-1 6-carboxamide 1-oxide (44. Omg, 86) was obtained.
  • Example 3 9 According to a method similar to that of Example 32, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-7— (4—methoxyphenyl) one 5 —oxo-5H-pyrido [1,2,3—de] —1,4—benzothiazine-16 —carboxamide (60.
  • Example 4 1 According to a method similar to that of Example 32, ⁇ — [3,5-bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) _2,3-dihydro-1-methyl-methyl 5 —oxo-5-pyrido [1,2,3-de] — 1,4 —benzothiazine _ 6 —carboxamide (60.
  • One 5H-pyrido [1,2,3-de]-1,4—benzothiazine-16-carboxamide (60.0mg, 98zmol) was converted to a colorless amorphous N— [3,5—bis (trifluorome Benzyl] —2,3-dihydro-1-N-methyl-1- (1-naphthyl) -1-5-oxo-5H-pyrido [1,2,3—de] —1,4-benzothiazine 6—Carboxamido 1-oxide (40.3 mg, 65%) was obtained.
  • Example 4 6 According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (4-formylphenyl) -N-methyl-5-oxo One 5H-pyrido [1,2,3-de] — 1,4,1-benzothiazine-16-carboxamide (60.
  • Oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-16-carboxamide (50.0 mg, 79 mol) was converted to colorless amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 7 — (3,5-dichlorophenyl) 1, 2,3-dihydro-1N-methyl-1 5 —oxo-5H-pyrido [1,2,3—de] —1,4— Benzothiazine-1-6-carboxamide-1,1-dioxide (42.1 mg, 80%) was obtained.
  • Example 5 5 According to a method similar to that in Example 49, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-methoxyphenyl) -1-N—methyl-1 5— Oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxamide (60.
  • N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-fluorophenyl) -1-N—methyl—5 _Oxo-1 5H-pyrido [1,2,3-de] 11,4,1-benzothiazine-16-carboxamide (60.0mg, O.lOmmol) from the colorless amorphous N- [3,5-bis (Trifluoromethyl) benzyl] — 2,3-dihydro-7- (4-fluorophenyl) -1-N-methyl-5-oxo-5H-pyrido [1,23-de] —1,4 —Benzothiazine-1 6 —carboxamide 11-1 —dioxide (50.0 mg, 795 was obtained.
  • N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (2-methoxyphenyl) -N-methyl-5-oxo From 1H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16-carboxamide (60.Omg, O.lOmmol), N- [3,5-bis of colorless amorphous (Trifluoromethyl) benzyl] — 2,3-Dihydro 7- (2-Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4 1-benzothiazine-16-carboxamide-11-dioxide (37.1 mg, 595 was obtained.
  • Example 6 1 According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (4-formylphenyl) -1-N-methyl-15— Oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxamide (60.
  • the compounds of the present invention and salts thereof have excellent tachykinin receptor antagonistic activity, have low toxicity, and are safe as pharmaceuticals. Therefore, the compounds of the present invention and salts thereof are useful as pharmaceutical compositions, tachykinin receptor antagonists, therapeutic agents for dysuria, and the like.

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Abstract

L'invention concerne des dérivés de pyridobenzothiazine présentant un antagonisme pour la tachykinine, en particulier, un antagonisme pour le récepteur de la substance P, à savoir, des dérivés de pyridobenzothiazine représentés par la formule générale (1), des sels de ceux-ci, et des compositions médicinales contenant ces composés ou leurs sels pharmaceutiquement utiles. Dans cette formule, R?1, R2 et R3¿ sont identiques ou différents et chacun représente hydrogène ou alkyle C¿1?-C6; le composé cyclique A est un homocycle ou un hétérocycle possédant éventuellement 1 à 3 substituants choisis indépendamment (où 2 substituants adjacents l'un à l'autre peuvent être liés pour former un composé cyclique); le composé cyclique B est un composé cyclique de benzène possédant éventuellement 1 à 5 substituants (où 2 substituants adjacents l'un à l'autre peuvent être liés pour former un composé cyclique); et le composé cyclique C est un composé cyclique de benzène possédant éventuellement 1 à 3 substituants (où 2 substituants adjacents l'un à l'autre peuvent être liés pour former un composé cyclique).
PCT/JP1999/004108 1998-07-31 1999-07-30 Derives de pyridobenzothiazine et leur procede de production WO2000006580A1 (fr)

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Cited By (1)

* 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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07503248A (ja) * 1992-01-27 1995-04-06 藤沢薬品工業株式会社 複素三環式誘導体、それらの製造法およびそれらを含有する医薬組成物
JPH10324631A (ja) * 1997-05-22 1998-12-08 Fujisawa Pharmaceut Co Ltd ＩｇＥ抗体産生抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07503248A (ja) * 1992-01-27 1995-04-06 藤沢薬品工業株式会社 複素三環式誘導体、それらの製造法およびそれらを含有する医薬組成物
JPH10324631A (ja) * 1997-05-22 1998-12-08 Fujisawa Pharmaceut Co Ltd ＩｇＥ抗体産生抑制剤

Cited By (1)

* 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

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