WO1995006635A1 - Derive de carbamate et medicament le contenant - Google Patents

Derive de carbamate et medicament le contenant Download PDF

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Publication number
WO1995006635A1
WO1995006635A1 PCT/JP1994/001436 JP9401436W WO9506635A1 WO 1995006635 A1 WO1995006635 A1 WO 1995006635A1 JP 9401436 W JP9401436 W JP 9401436W WO 9506635 A1 WO9506635 A1 WO 9506635A1
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Prior art keywords
group
compound
piperidyl
benzhydryl
formula
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PCT/JP1994/001436
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English (en)
Japanese (ja)
Inventor
Makoto Takeuchi
Ryo Naito
Koichiro Morihira
Masahiko Hayakawa
Ken Ikeda
Yasuo Isomura
Kenichi Tomioka
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU75458/94A priority Critical patent/AU7545894A/en
Publication of WO1995006635A1 publication Critical patent/WO1995006635A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to a medicament, in particular, a levbamate derivative having a muscarinic receptor antagonistic action, a salt thereof, a hydrate thereof or a solvate thereof, and a pharmaceutical composition containing the compound.
  • a medicament in particular, a levbamate derivative having a muscarinic receptor antagonistic action, a salt thereof, a hydrate thereof or a solvate thereof, and a pharmaceutical composition containing the compound.
  • muscarinic receptors Conventionally, studies have been conducted on muscarinic receptors, and compounds having muscarinic receptor antagonistic activity include bronchodilation, suppression of gastrointestinal motility, suppression of acid secretion, blood loss, mydriasis, suppression of bladder contraction, reduction of sweating and tachycardia. It is known to cause. It is known that at least three subtypes exist in this muscarinic receptor. Mainly M, the receptors brain etc., M 2 receptors in the heart or the like, and M 3 receptors are present in smooth muscle and glandular tissue.
  • Atotopin Merck index, 11th edition, p. 138
  • M is a subtype of muscarinic receptors, M 2
  • M 3 lengthening has substantially the same affinity to Te base, non-selectively so antagonize the (biological chemistry, 4 2 (5), 38 1 (1991))), which may cause adverse effects such as palpitations, oral stomach, nausea, and mydriasis, which are thought to be caused by muscarinic receptor antagonism other than the intended effect.
  • selectivity for muscarinic M 3 receptors of the compounds can not be said to be sufficient yet, also as a structural Toku ⁇ , in that it has an ester bond in the basic skeleton, the compound of the present invention, clearly It is different.
  • the present invention compounds, as compared with those of substituted acetic acid ami de compound, below street, a compound having an excellent affinity for muscarinic M 3 receptors. Disclosure of the invention
  • the present inventors have intensively studied the results for compounds with selective antagonistic action on muscarinic M 3 receptors, and create a new force Rubameto derivatives chromatic following general formula (I), the present invention has been completed .
  • the force Rubameto derivative having the following formula (I), a salt thereof, a hydrate thereof, relates arm Sukarin M 3 receptor antagonist as an active ingredient solvates and said compound.
  • R optionally substituted aryl group (the substituent is 1 to 5 substituents selected from the following group D.)
  • R 1 cycloalkyl group or optionally substituted aryl group
  • the substituent may be 1 to 5 substituents selected from Group D below. It is a substitution group.
  • R 2 hydrogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, cycloalkyl group or aryl group
  • R 3 hydrogen atom or lower alkyl group
  • a ring a group represented by the following general formula (la), (lb) or (He),
  • Y an oxygen atom, a sulfur atom, a group represented by the formula NR 8 —, a methylene group, or a group represented by the formula —0—CH 2 —
  • Z ' group represented by the formula ⁇ : N ( ⁇ ) q or the formula ⁇ N ⁇ R 6
  • R 4 a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a group represented by the formula B-R 7
  • R 5 lower alkyl group, lower alkenyl group, lower alkynyl group, Or a group of the formula one B- R 7
  • R 6 lower alkyl group, lower alkenyl group or lower alkynyl group
  • R 7 cycloalkyl group, lower alkoxy group optionally substituted by hydroxyl group, benzhydryl group, optionally substituted aryl group, or benzene
  • a heterocyclic group containing 1 or 2 heteroatoms which may be condensed with 3 ⁇ 4 or may be substituted
  • R 8 a hydrogen atom, a lower alkyl group or an alkylene group having 2 to 4 carbon atoms integrated with R 3
  • n the same or different and an integer of 1 to 4 (however, m + n means an integer of 3 to 5)
  • r, s, t the same or different and an integer of 0 to 3 (however, r + s + t means 2 or 3)
  • Group D a halogen atom, a lower alkyl group or a lower alkoxy group (the same applies hereinafter), and preferred compounds in the present compound include carbamate derivatives wherein Y is an oxygen atom in the above general formula (I) or a salt thereof;
  • R is a phenyl group
  • R ′ is a cycloalkyl group or a phenyl group which may be substituted
  • R 2 is a hydrogen atom, a lower alkyl group or a phenyl group
  • p is 0, or a carbamate derivative or a carbamate derivative thereof.
  • a carbamate derivative or a salt thereof in which the ring is a group represented by the general formula (ITb) or (Ec);
  • ring A is a group represented by the general formula (la), or a salt thereof;
  • irritable bowel syndrome muscarinic M 3 receptor is involved, spasticity colitis, and gastrointestinal disorders such as diverticulitis, chronic obstructive pulmonary disease, chronic bronchitis, asthma and respiratory diseases such as rhinitis, and neurogenic urinary frequency, neurogenic bladder, enuresis disease, unstable bladder, bladder spasm, muscarinic M 3 receptor antagonist is a prophylactic or therapeutic agent for urinary diseases such as urinary incontinence and urinary frequency in diseases such as chronic cystitis Provided.
  • Preferred pharmaceutical compositions in this pharmaceutical composition include:
  • a ring general formula is a group represented by (Ha) Mus force phosphoric M 3 receptors Antagonists;
  • a ring is a group represented by the general formula (la), R 4 or R 5 is a group represented by the formula BR 7 , and R 7 is condensed with an optionally substituted aryl group or a benzene ring
  • a musculin receptor antagonist which is a heterocyclic group containing 1 or 2 heteroatoms which may or may not be substituted;
  • a ring is a group represented by the general formula (Hb) or (Hc)! ) Mus force Li emissions M 3 receptor antagonists;
  • Y is a group represented by the formula: 10—, —S—, —NR 8 —, one CH 2 —, one OCH 2 —.
  • Y is a group shown above, the compound of the present invention is as follows:
  • R 8e represents an alkylene group having 2 to 4 carbon atoms integrated with R 3 in R 8.
  • p is 0 or 1
  • the ring A is saturated as shown by the general formula (Ha), (lb) or (Ic), and contains a nitrogen atom in the ring skeleton.
  • the ring A of the general formula (Ha) or (lb) is a 5- to 7-membered ring since m + n or m + 1 is an integer of 3 to 5. (0) q ,
  • Z ′ is a group represented by ⁇ N (0) q or —R 6 ⁇ Q-
  • Z is represented by a compound (IVa) represented by> N—R 4 and ⁇ N + (R s ) R 6 -Q- Compound (Wb).
  • the ring A represented by the general formula (la) includes a 5- to 7-membered ring, and specifically includes a pyrrolidine ring, a piperidine ring, and a hexahydroazepine ring.
  • the ring A When the ring A is represented by the general formula (Hb) or (Ic), a bridge exists in the ring A. In general formula (Hb), one nitrogen atom and one carbon atom are bridgeheads, but in general formula (Ic), two carbon atoms are bridgeheads.
  • the carbon atom bonded to Y may be any carbon atom on the ring, that is, a quaternary carbon atom serving as a bridgehead. In this case, a carbon atom represented by CH 2 in the general formula (lb) or (Ic) may be converted to a methine carbon by its bond.
  • the ring A represented by the general formula (Hb) includes a 5- to 7-membered ring. Specific examples of these groups include a quinuclidinyl group, a 1-azabicyclo [2.2.1] heptyl group, -Azabicyclo [3.2.1] octyl group and the like.
  • examples of the anion of the quaternary ammonium salt represented by QJ include a halogen atom ion, triflate, tosylate, and mesylate.
  • a halogen atom ion that is, a halide ion (
  • chloride ion, bromide ion, iodide ion, and triiodide ion are preferable), but not limited thereto.
  • Oxer anions such as nitrate ion, sulfate ion, phosphate ion
  • Further examples include inorganic anions such as carbonate ion, carboxylate such as formate (HC ⁇ ), acetate (CH 3 COO “), propionate, oxalate and malonate, and anion of amino acid such as glutamic acid.
  • bromide ions or iodide ions are preferred.
  • the anion can be appropriately converted to a prefer
  • lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
  • an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group is preferable, a methyl group and an ethyl group are more preferable, and a methyl group is further preferable.
  • the “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyloxy and the like.
  • a lower alkoxy group having an alkyl group having 1 to 4 'carbon atoms such as a methoxy group, an ethoxyquin group, a propoxy group and a butoxy group is preferable, and a methoxy group and an ethoxyquin group are more preferable.
  • Examples of the “cycloalkyl group” include those having 3 to 8 carbon atoms. Specifically, a cyclopropyl group, a cyclobutyl group, a cyclopen Examples include a tyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Of these, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are preferred, and a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are more preferred.
  • aryl group is preferably an aryl group having 6 to 14 carbon atoms, for example, phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl Or a phenanthryl group, more preferably a phenyl group or a naphthyl group.
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a propenyl group, a butenyl group, a methylpropyl group, a methylpropyl group. Dimethylvinyl group, pentenyl group, methylbutenyl group, dimethylpropenyl group, ethylpropyl group, hexenyl group, dimethylbutenyl group, methylpentenyl group and the like. Propenyl and butenyl are preferred, and propyl is more preferred.
  • the “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, specifically, ethynyl, propynyl, butynyl, methylpropynyl, pentynyl, methylbutynyl. And a hexynyl group.
  • An ethynyl group and a propynyl group are preferred, and an ethynyl group is more preferred.
  • R 4 and R 5 may be groups represented by Formula B-R 7 .
  • Examples of the “lower alkylene group” that can be B include an alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, a dimethylmethylene group, and a tetramethylene group.
  • methylene, ethylene, methylmethylene, trimethylene, and dimethylmethylene are preferably alkylene groups having 1 to 3 carbon atoms, more preferably methylene and ethylene, and methylene is preferred. Groups are more preferred.
  • the “lower alkynylene group” is a linear or branched alkynylene group having 2 to 6 carbon atoms, specifically, an ethynylene group (1 c ⁇ C-1) propynylene group (—CH 2 C ⁇ C—) Pentynylene group, methylpropynylene group, pentynylene group, methylbutynylene group, hexynylene group and the like.
  • an alkynylene group having 2 to 3 carbon atoms such as an ethynylene group (1-C ⁇ C-1) propynylene group, is preferred.
  • R 7 may be condensed with a cycloalkyl group, a lower alkoxy group optionally substituted with a hydroxyl group, a benzhydrido group, or a benzene ring, and a hetero atom containing 1 or 2 hetero atoms which may be substituted. It is a ring group or an aryl group which may be substituted. Number of substituents on heterocyclic and aryl groups Is not particularly limited, but is preferably 3 or less.
  • the “lower alkoxy group optionally substituted with a hydroxyl group” means, in addition to the above lower alkoxy group, a lower alkoxy group substituted at any position with a hydroxyl group, such as a hydroxymethoxy group or a hydroxyethoxy group.
  • a hydroxyl group such as a hydroxymethoxy group or a hydroxyethoxy group.
  • heterocyclic group containing one or two heteroatoms means an unsaturated or saturated monocyclic or fused heterocyclic group. Preferred is a monocyclic or bicyclic unsaturated heterocyclic group containing one or two oxygen atoms, sulfur atoms or nitrogen atoms.
  • preferred groups are a furyl group, a cyenyl group, a pyrrolyl group, an imidabryl group, a pyridyl group, a pyrazinyl group, a benzimidazolyl group, a quinolyl group, and a dihydrobenzofuranyl group.
  • heterocyclic group and aryl group represented by R 7 may be substituted with one or more substituents.
  • substituents Specifically, halogen atom, carboxyl group, nitro group, cyano group, hydroxyl group, trihalogenome , Lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower acryl, mercapto, lower alkylthio, sulfonyl, lower alkylsulfonyl, sulfinyl, lower alkylsulfinyl, sulfonamide, Lower alkane sulfonamide group, carbamoyl group, thiocarbamoyl group, mono- or di-lower alkyl group rubamoyl group, amino group, mono- or di-lower alkylamino group, lower acetylamino group, methylenedioxy group, ethylenedioxy group, pyrrolidinyl Group, an amidino group, a formyl group,
  • Halogen atom refers to a fluorine, chlorine, bromine, or iodine atom. When two or more halogen atoms substitute, any combination of these atoms may be used. When the substituent is a halogen atom, the number of substituents is not particularly limited.
  • trihalogenomethyl group examples include a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, a triodomethyl group, a dichlorobromomethyl group and the like. Of these, a trifluoromethyl group is preferred.
  • the “lower alkoxycarbonyl group” includes a methoxycarbonyl group, an ethoxyquincarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbon group.
  • Nyl group pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxyquincarbonyl group, 2-methylbutoxycarbonyl Group, 1, 2-dimethyl-propoxycarbonyl group, 1 one Echirupurobo alkoxycarbonyl group, such as cyclohexyl O alkoxycarbonyl group to c
  • lower acetyl group examples include a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, a bivaloyl group and the like, and preferred are a formyl group, an acetyl group and a propionyl group.
  • lower alkylthio group means a group in which a hydrogen atom in a mercapto group is substituted with the above lower alkyl group, and includes methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, and the like.
  • lower alkylsulfonyl group examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group and the like.
  • lower alkylsulfinyl group examples include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group and a hexylsulfinyl group.
  • the “lower alkane sulfonamide group” includes methane sulfonamide group, ethane sulfonamide group, propane sulfonamide group, isopropane sulfonamide group, butane sulfonamide group, pentane sulfonamide group, Xansulfonamide groups and the like.
  • “Mono- or di-lower alkyl group” refers to a group in which one or two hydrogen atoms in the group are replaced with the above lower alkyl group, methylcarbamoyl group, ethyl ethyl group. Groups, propyl-carbamoyl group, dimethylcarbamoyl group and the like.
  • the “mono- or di-lower alkylamino group” means an amino group in which one or two hydrogen atoms in an amino group are substituted with the above-mentioned lower alkyl group, such as a methylamino group, an ethylamino group, a propylamino group, A dimethylamino group, a getylamino group, a dipropylamino group and the like.
  • lower acylamino group means an amide group in which one or two hydrogen atoms in the amide group have been substituted with the above-mentioned lower acyl group, and is an acetamido group, a propionamide group, a butyrylamide group, or an isobutyrylamide group. And a valeryl amide group and a hexane amide group.
  • the compound (I) of the present invention optionally has one or more asymmetric carbon atoms, optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers and the like based on the compounds are present. Exists. Further, depending on the type of the substituent, it has a double bond, and therefore, there are geometric isomers such as (Z) -form and (E) -form.
  • the present invention includes all separated or mixtures of these isomers.
  • Some of the compounds (I) of the present invention can form salts with acids.
  • Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
  • acid addition salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid.
  • the compound (I) of the present invention is isolated as a hydrate, a solvate such as ethanol, or a polymorphic substance.
  • the compound (I) of the present invention can be produced by applying various production methods. Hereinafter, a typical production method will be described. First manufacturing method
  • R, R ′, R 2 , p, X, and ring A are as described above.
  • Y 1 represents a group other than methylene in Y.
  • the compound (la) of the present invention can be obtained by reacting a compound represented by the general formula (I) with a compound represented by the general formula (K).
  • This reaction is carried out by stirring the compound (Cor) and a corresponding amount of the compound (K) in an inert solvent at room temperature or under reflux with heating.
  • the inert solvent include dimethylformamide (DMF) dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethoxymethane, and dimethoxetane , Ethyl acetate, benzene, toluene, acetonitril, dimethyl sulfoxide and the like, and a mixed solvent thereof, which are appropriately selected according to various reaction conditions.
  • T 1 represents a leaving group, halogen atom, lower alkoxy group, phenoxy group Group, imidazolyl group, etc.).
  • a method the present compound (I b) of the general formula (X) c
  • This reaction obtained by reacting a compound represented by the compound of the general formula (K) represented by the compound (X) and its Stir the reaction corresponding amount of compound (K) in the above-mentioned inert solvent under ice-cooling to room temperature and, optionally, heating. It is performed by
  • a Lewis acid eg, aluminum trisopropoxide, etc.
  • a base eg, sodium, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, etc.
  • Method B The compound (lb) of the present invention can be obtained by reacting the compound represented by the general formula (XI) with the compound represented by the general formula (XH).
  • the compound (Ic) of the present invention can be produced by reacting a compound represented by the general formula (XI) with a (thio) carboxylic acid represented by the general formula (XIII) or a reactive derivative thereof. . That is, as a method for synthesizing the compound of the present invention, a coupling method in which a free acid or an N-hydroxylamine-based active ester is used as the compound (XDI) and the reaction is carried out in the presence of a condensing agent can be applied.
  • Examples of the condensing agent for the coupling method include N, N'-dicyclohexyl carbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) and digetyl phosphoryl cyanide. It is suitable.
  • active esters, monoalkyl carbonates, and the like obtained by reacting with phenolic compounds such as 412 trophenol, N-hydroxysuccinimide, and N-hydroxylamine compounds such as 1-hydroxybenzotriazole.
  • phenolic compounds such as 412 trophenol, N-hydroxysuccinimide, and N-hydroxylamine compounds such as 1-hydroxybenzotriazole.
  • a mixed acid anhydride obtained by reacting with an organic acid a mixed acid anhydride obtained by reacting with diphenylphosphoryl chloride or N-methylmorpholine
  • a mixed acid anhydride obtained by reacting with acid hydrazide and nitrous acid (acid and nitrous acid)
  • the reaction can also be carried out by applying an acid azide obtained by reacting with an alkyl), an acid halide such as an acid chloride or an acid bromide, or a symmetrical acid anhydride.
  • a base such as N-methylmorpholine, triethylamine, trimethylamine, pyridine or the like in order to make the reaction proceed smoothly.
  • the compound (f) of the present invention can be obtained by reacting a compound represented by the general formula (Id) with a compound represented by the general formula (XIV).
  • a compound represented by the general formula (XIV) e.g, sodium hydride, lithium diisopropylamide, etc.
  • a base e.g, sodium hydride, lithium diisopropylamide, etc.
  • the compound (Hf) of the present invention is obtained by reacting a compound represented by the general formula (XV) with a phosgene (or tiophosgene) represented by the general formula (XVI), carbodildimidazole (CDI), or thiocarbodilidimidazole. can get.
  • This reaction is carried out while stirring the compound (XV) and a corresponding amount of the compound (XVI) in the inert solvent at room temperature or under heating.
  • a base for example, an inorganic base such as sodium carbonate or carbonated lime, or an organic base such as triethylamine. 6th manufacturing method
  • R, R 1 , R 2 , R 3 , R 5 , p, X, Y, and the ring A are as described above.
  • R 3 and R 3 are lower or lower alkyl groups.
  • a ′ The ring means a ring in which Z in the ring A is NH, and T 2 means the above-mentioned leaving group or formyl group.
  • Production Process 6 is A lower alkyl group as a substituent R 4 rings, a lower alkenyl group or a compound having a lower alkynyl group or in the production of the compound having a lower alkyl group as a substituent R 3 N - alkylation reaction (Hereinafter, this reaction is referred to as N-alkylation reaction).
  • This reaction may follow a conventional N-alkylation reaction method.
  • reducing agent for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like are used. This reaction is carried out in an alcohol or the above-mentioned inert solvent with stirring under cooling to heating (under reflux). Further, catalytic hydrogenation may be performed under normal pressure or under pressure in the presence of a catalyst such as palladium carbon or platinum oxide.
  • Method B When the compound (XH) is an alkyl halide or an alkyl sulfonate (where X is an oxygen atom): The reaction amount of the compound (If) is cooled in the inert solvent. The heating is performed while stirring. In order to promote this reaction, it is preferable to add a base such as sodium hydride. When ⁇ in the compound (I ⁇ ) is an oxygen atom or a sulfur atom, it is preferable to add a strong base such as tert-butyllithium or silver oxide instead of the above base.
  • Ar means the above aryl group.
  • This production method comprises reacting a compound (Ie) in which the amine of the A ring in the compound (I) of the present invention is secondary with an N-aryl compound to form a compound (Ii) which is an aryl substituted tertiary amine. ).
  • the compound of the present invention in which R 4 of ring A is a hydrogen atom is produced from the compound of the present invention in which R 4 is a group represented by the formula B-R 7 .
  • the compound of the present invention in which R 4 is a group represented by the formula —B—R 7 and a corresponding amount of a chloroformate are reacted with an inert solvent. It is manufactured by stirring at room temperature to room temperature or under heating, followed by a conventional solvolysis reaction.
  • the compound of the present invention in which R 4 is a group represented by the formula B-R 7 is hydrogenated by a conventional method in the presence of a catalyst (for example, palladium carbon, palladium, platinum oxide or palladium hydroxide).
  • a catalyst for example, palladium carbon, palladium, platinum oxide or palladium hydroxide.
  • This production method comprises the step of subjecting a compound (Ii) in which the amine of the A ring in the compound of the present invention is a secondary or tertiary amine to a quaternary ammonium compound (Ij) by an N-alkylation reaction.
  • a compound (Ii) in which the amine of the A ring in the compound of the present invention is a secondary or tertiary amine to a quaternary ammonium compound (Ij) by an N-alkylation reaction.
  • the compound (I j) is a secondary amine
  • a quaternary ammonium compound (I k) is obtained by reacting at least 2 mol of the alkylating agent (XX) with respect to 1 mol of the compound (I j). Get.
  • the compound (Ij) and the corresponding amount of the alkylating agent (XX) are reacted with an inert solvent such as dimethylformamide, chloroform, benzene, 2-butanone, acetone or tetrahydrofuran.
  • an inert solvent such as dimethylformamide, chloroform, benzene, 2-butanone, acetone or tetrahydrofuran.
  • the alkylating agent performed by stirring under ice-cooling to room temperature, or in some cases under heating, include lower alkyl halides, lower alkyl triflates, lower alkyl tosylates, lower alkyl mesylate, and the like.
  • This production method is a method for producing a compound having an amidinophenyl group as a substituent on the A ring. That is, a.
  • Compound (I) having a midino group can be synthesized by the following methods (i), (ii) and (iii).
  • Nitriles I for methylamine, triethylamine, pyridi Hydrogen sulfide in the presence of an organic base such as thione and picoline to obtain a thioamide.
  • This thioamide form can be obtained by reacting nitrile form (I £) with ⁇ , 0-diethyl dithiophosphate in the presence of hydrogen chloride.
  • a lower alkyl halide such as methyl iodide or thiolated iodide is reacted with the thioamide to form a thioimidate, which is then reacted with an amine or an amine salt such as ammonium, ammonium carbonate, ammonium chloride, or ammonium acetate.
  • an amine or an amine salt such as ammonium, ammonium carbonate, ammonium chloride, or ammonium acetate.
  • the solvent methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate and the like are used.
  • Nitrile form (Ammonia, ammonium chloride and ammonia, ammonium thiocyanate, alkyl ammonium thiocyanate, Me A 1 (CI) NH 2 , NaN H 2 , 3 ) 2 It can be synthesized by adding a reagent such as NMgBr, etc.
  • the solvent include chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide, etc.
  • Hydrogen is used as a catalyst.
  • a base such as sodium chloride or an acid such as aluminum chloride or p-toluenesulfonic acid may significantly accelerate the reaction The reaction can be carried out from cooling to room temperature to heating. No. 1 manufacturing method
  • N-oxide (In) is obtained by oxidizing the compound (Ij) in which the amine of the A ring is a tertiary amine in the compound of the present invention.
  • the compound (I j) and a corresponding amount or an excess amount of the oxidizing agent are added under cooling in an inert solvent such as chloroform and dichloromethane, an alcohol such as methanol and ethanol, water, or a mixed solvent thereof.
  • an inert solvent such as chloroform and dichloromethane, an alcohol such as methanol and ethanol, water, or a mixed solvent thereof.
  • the reaction is carried out by stirring at room temperature or, optionally, while heating.
  • oxidizing agent examples include organic peracids such as m-chloroperbenzoic acid, sodium periodate, hydrogen peroxide and the like.
  • the compounds of the present invention compounds having a lower alkyl group substituted with an amino group or a mono-lower alkylamino group among heterocyclic groups and aryl groups in which R 7 may be substituted with a substituent,
  • the method of manufacturing the compound of the present invention in which R 7 is a heterocyclic group substituted with a lower acryl group or an aryl group is reacted with a corresponding amine under the same conditions as in the above-mentioned sixth method. It is manufactured by
  • R 7 is Aminofuweniru group
  • R 7 is prepared from a compound of the invention which is Nitorofuyuniru group.
  • a compound of the present invention in which R 7 is a nitrophenyl group is subjected to a hydrogenation reaction in the presence of a catalyst (for example, Raney nickel, palladium carbon, palladium, platinum oxide or palladium hydroxide) at room temperature or under heating. It is obtained.
  • a catalyst for example, Raney nickel, palladium carbon, palladium, platinum oxide or palladium hydroxide
  • the compound of the present invention in which R 7 is a nitrophenyl group is prepared by reacting the compound of the present invention in the presence of a reaction-corresponding amount of a metal such as iron powder, tin or zinc, in an active solvent, under ice-cooling to room temperature, and optionally under heating. It is obtained by a reduction reaction.
  • a metal such as iron powder, tin or zinc
  • the production of the compound of the present invention requires protection of a functional group. In that case, it can be produced by a conventional method by adding an appropriate deprotection operation.
  • the compound of the present invention thus produced is subjected to salt formation treatment by a conventional method as it is, or isolated and purified as a salt thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the present invention compounds have affinity and selectivity for muscarinic M 3 receptors, as M 3 receptor antagonists, various diseases M 3 receptor is involved, especially Gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, and diverticulitis, chronic obstructive pulmonary disease, respiratory diseases such as chronic bronchitis, asthma and rhinitis, and frequent urinary frequency, neurogenic bladder, Enuresis, unstable bladder, bladder spasm It is useful as a prophylactic or therapeutic agent for urinary diseases such as urinary incontinence and pollakiuria in diseases such as atrophy and chronic cystitis.
  • urinary diseases such as urinary incontinence and pollakiuria in diseases such as atrophy and chronic cystitis.
  • the compounds of the present invention high selectivity for M 3 receptor existing in the smooth muscle or gland tissues and the like as compared with the M 2 receptor existing in the heart or the like, few side effects M 3 receptor to mind ⁇ As a body antagonist, it is particularly useful as a preventive or therapeutic agent for irritable bowel syndrome, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, and urinary incontinence and pollakiuria.
  • the affinity and antagonism of the compound of the present invention for the musculin phosphorous receptor were confirmed by the following tests.
  • HEPES buffer pH 7.5, hereinafter abbreviated as HEPES buffer
  • Subcutaneous submandibular gland specimen was used as the membrane specimen, and [ 3 H] -N-methylscopolamine was used as the labeling ligand, except that the same method as in b) Musculin phosphorus! went.
  • Table 1 shows the test results of representative compounds among the compounds of the present invention.
  • the present invention compound (I) has a K i value of 1 0_ 8 to 1 0- '° M relative to M 3 receptors, as compared with the M 2, ten It had several times to several tens times higher binding.
  • Compound A Compound (I) described in GB.
  • Compound D Compound of Example 1 described in JP-A-2-76851 Atropine: Merck Index (11th edition, page 138)
  • Table 2 shows the values of representative compounds.
  • the compound (I) of the present invention showed an ID50 value on the order of several g / kg to several hundred g / kg.
  • the injection was performed at a rate of 400 ⁇ 1 min ⁇ 1, and the intravesical pressure at the time of injection was recorded with a pressure transducer.
  • the test compound was cumulatively administered from a catheter placed in the external jugular vein, and the increase in intravesical pressure during the micturition reflex was measured. Calculated percent inhibition for intravesical pressure rise during micturition reflex prior to administration test compound, the dosage of 50% inhibition of the test compound intravesical pressure increase before administration was ED 50 value.
  • Table 2 shows the values of representative compounds.
  • the compound of the present invention has almost the same effect as or more than Oxybutynin (Oxybutynin), a non-selective anticholinergic agent used for the treatment of urological diseases (Merck Index 11th edition, p. 110).
  • Oxybutynin Oxybutynin
  • Wistar male rats (6 weeks old) were anesthetized with urethane (0.8 g / kg ip).
  • the test compound (solvent in the control group) was administered, and 15 minutes later, 0.8 amol / kg of oxotremorine was administered. All drugs were administered through the femoral vein. Saliva secreted 5 minutes after the administration of oxotremorine was collected and its weight was measured. The inhibitory rate of the control group against the amount of secreted saliva was determined, and the dose of the test compound that inhibited the amount of secreted saliva by 50% in the control group was defined as the ID 50 value.
  • test compound (2 ml / kg) was subcutaneously administered to male Wistar rats (6 to 7 weeks old), and the pupil diameter 20 minutes later was scored (0 to 6 points) in 0.5 mm increments.
  • Wistar male rats (12-16 weeks old) were anesthetized with sodium pentobarbital (50 mg / kg ip), and the vagus nerve was cut off after cervical incision. After inserting a forcenula into the trachea to secure the airway, a stainless steel rod was inserted through the orbit to destroy the spinal cord. Under artificial respiration (10 cc / kg, 50 times per minute), the rectal temperature was kept at 37.5, and the heart rate was monitored from the common carotid artery. An indwelling needle was fixed to the femoral vein, and the drug was administered from this.
  • Example 1 the compounds of Example 1, Examples 73 and 84, etc., did not show any effect on bradycardia even when administered at 4.0 to 4.9 mg / kg.
  • the reference compound, atropine had a DRI of 0.032 mg / kg, and oxyptinin had a Dri of 1.9 mg / kg. The value was shown.
  • the Mus force phosphoric M 3 antagonism test (in vivo) results, the present invention of compound (I) for the micturition pressure and airway constriction showed good muscarinic M 3 antagonistic activity. Further, the action against the bradycardia involved in muscarinic M 2 receptor is low, act hundred times or more as compared to Atoropin is was weak. Accordingly, the present invention compound (I) was shown to be one that antagonizes selection ⁇ to Mus force phosphoric M s receptor. Furthermore, the side effects of the conventional anticholinergic agents, such as locus and mydriasis, were also low.
  • One or more of the compounds of the present invention or salts thereof are contained as active ingredients.
  • the pharmaceutical preparations are prepared using carriers, excipients, and other additives that are used in general formulation.
  • carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceutical substances.
  • examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones.
  • Administration is by oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous injections and intramuscular injections, suppositories, dermal preparations, inhalants or intravesical injections, etc.
  • Parenteral administration may be in any form.
  • the dosage is determined as appropriate according to the individual case, taking into account symptoms, age of the subject, gender, etc.
  • the dose is about 0.05 to 10 Omg, which is administered once or in 2 to 4 divided doses. When given intravenously due to symptoms, it is usually administered in the range of 0.001 mg to 1 Omg once a day or more than once per adult.
  • the one or more active substances include at least one inert diluent, such as lactose, mantonyl, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrroli. Don, meta-mate mixed with magnesium aluminate.
  • the composition may be formulated in a conventional manner with additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium fiber glycolate, and stabilizing agents such as lactose. Agents, solubilizing agents such as glutamic acid or aspartic acid. Tablets or pills If necessary, the film may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
  • Such compositions may further comprise adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, perspartic acid). .
  • the compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the above general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, a geometry thereof and an optical structure thereof. Includes all isomers and polymorphs It is.
  • Example 54 The following corresponding starting compounds were used in place of 2-furaldehyde in the same manner as in Example 53 to obtain the compounds of Examples 54 to 61.
  • Example 54
  • Example 5 1- (4-ethoxybenzyl) 1-4-piperidyl N-benzhydryl power rubamate fumarate
  • Elemental folding value (as C 28 H 3 .N 2 0 6 S ⁇ 0. 2 5 H 2 0)
  • the reaction solution was poured into ice water and extracted with a mixture of ethyl acetate-toluene (1: 1).
  • the organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • 50 Omg was recrystallized from ethyl acetate-hexane to give 25 Omg of N-benzhydryl-12- (1-benzylidyl-piperidyl) acetamide as colorless needles.
  • 1- (3-Nitrobenzyl) 1-4-piperidyl N-benzhydryl carbamate 2.50 g was dissolved in a mixed solvent of ethanol 100 ml and methanol 100 ml, and hydrogen was added in the presence of Raney nickel. Catalytic reduction was performed in an atmosphere. After removing the Raney nickel by filtration, the solvent was distilled off under reduced pressure to obtain 2.60 g of 1- (3-aminobenzyl) -14-piperidyl N-benzhydryl dilubamate as a crude product.
  • Example 69 the compound of Example 69 was obtained in the same manner as in Example 68.
  • N-Venzhydryl-N-methylamine 2.60 g, Triethylamine 1.47 g in dichloromethane solution 50 ml in ice-cooled solution Ethyl lologate (1.50 g) was added dropwise, and the mixture was stirred at room temperature for 4 days.
  • the reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the resulting aqueous layer was adjusted to pH 9 with sodium bicarbonate, and then extracted with chloroform.
  • the organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (form: black form) to give 2.77 g of S- (1-benzyl-4-piperidyl) thioacetate as a pale yellow solid.
  • N—benzhydryl 1—3 — [(1 benzylyl 4-piperidyl) amino] 0.85 g of propionamide is dissolved in 5 ml of ethanol and treated with 2 ml of 4N hydrogen chloride / ethyl acetate solution Then, the obtained colorless solid was recrystallized from ethanol to give 0.65 g of N-benzhydryl-3-[(1-benzylidyl-piperidyl) amino] propionamide dihydrochloride. Obtained as colorless needles.
  • Example 75 The following compound of Example 75 was obtained in the same manner as in Example 74.
  • Example 8 9 1-[(1-Methyl-1H-pyrrol-1--2-yl) methyl] 1-4piperidyl N-benzhydrylcarbamate oxalate Starting compound: 1-methyl-1H-pyro 1-ru 2-carbaldehyde Melting point 15 5—15 7 ° C (decomposition) (Me OH—CH 3 CN—E t 20 )
  • Example 9 1 The following compound of Example 91 was obtained in the same manner as in Example 90.
  • Example 9 1 The following compound of Example 91 was obtained in the same manner as in Example 90.
  • Example 9 1 The following compound of Example 91 was obtained in the same manner as in Example 90.
  • N, N'-Di (4-chlorobenzene hydryl) urea 6.94 g, 1 benzene di-41-piperidinol 7.52 g toluene suspension 16 Om 1 in sodium hydride (600.
  • the reaction solution was cooled to room temperature, water and ethyl acetate were added, insolubles were removed by filtration, and the obtained organic layer was dried over anhydrous sodium sulfate.
  • Example 101 In the same manner as in Example 101, the following compounds of Examples 102 to 105 were obtained.
  • Example 14 In the same manner as in Example 14, the following compounds of Examples 106 to 108 were obtained.

Abstract

On décrit un dérivé de carbamate et un de ses sels, hydrates ou solvates. Ce dérivé est représenté par la formule génerale (I). Il présente un antagonisme au récepteur de muscarine M3 et permet de prévenir ou traiter des maladies digestives, respiratoires ou urologiques.
PCT/JP1994/001436 1993-09-02 1994-08-31 Derive de carbamate et medicament le contenant WO1995006635A1 (fr)

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AU75458/94A AU7545894A (en) 1993-09-02 1994-08-31 Carbamate derivative and medicine containing the same

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP21862093 1993-09-02
JP5/218620 1993-09-02
JP7757594 1994-04-15
JP6/77575 1994-04-15

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