WO1997045414A1 - Derives de piperidine a disubstitution en positions 1,4 - Google Patents

Derives de piperidine a disubstitution en positions 1,4 Download PDF

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Publication number
WO1997045414A1
WO1997045414A1 PCT/JP1997/001770 JP9701770W WO9745414A1 WO 1997045414 A1 WO1997045414 A1 WO 1997045414A1 JP 9701770 W JP9701770 W JP 9701770W WO 9745414 A1 WO9745414 A1 WO 9745414A1
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group
methyl
ring
atom
lower alkyl
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PCT/JP1997/001770
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English (en)
Japanese (ja)
Inventor
Yoshimi Tsuchiya
Takashi Nomoto
Hirokazu Ohsawa
Kumiko Kawakami
Kenji Ohwaki
Masaru Nishikibe
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU27931/97A priority Critical patent/AU2793197A/en
Publication of WO1997045414A1 publication Critical patent/WO1997045414A1/fr

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    • 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

Definitions

  • the present invention relates to a novel 1,4-disubstituted piperidine derivative, a method for producing the same, a medicament containing the same, and a use thereof as a medicament, particularly various respiratory diseases, urinary diseases or digestive systems. It relates to the use for the treatment or prevention of diseases. More specifically, the present invention has a selective muscarinic 11! 3 receptor antagonistic action, and is safe and effective with less side effects, and has a respiratory system such as asthma, chronic airway obstruction and pulmonary fibrosis.
  • Diseases Urinary diseases with dysuria such as frequent urination, urgency and urinary incontinence: Provide therapeutic or preventive agents for digestive diseases such as irritable large intestine and gastrointestinal convulsions or hypermotor function. is there.
  • Compounds with muscarinic receptor antagonism are known to cause bronchodilation, suppression of gastrointestinal motility, suppression of acid secretion, depression, mydriasis, suppression of bladder contraction, reduced sweating, tachycardia, etc. [Basicand Clinical Pharmacology 4 th Ed., (AP PL ETON & LANG E) PP 83 -PP 92, () 989); Drug News & Perspective, 5 (6), PP 3 4 5— PP 3 5 2 (1992) etc.].
  • Mus force phosphate receptor present 3 subtypes, M mainly brain receptor, M 2 receptors in the heart or the like, and M 3 receptors exist in smooth muscle and glandular tissue You.
  • M Mus force phosphate receptor present 3 subtypes
  • M 2 receptors in the heart or the like M 3 receptors exist in smooth muscle and glandular tissue You.
  • Many compounds that have an antagonistic effect on muscarinic receptors have been known to date, but existing compounds non-selectively antagonize the three subtypes of muscarinic receptors, and are therefore useful in treating respiratory diseases. If it is to be used as a therapeutic or prophylactic agent, b thirst, nausea, adverse effects of mydriasis or the like, in particular become side effects relating to cardiac Shinki increased such that due to the M 2 receptor is a problem, the improvement is strongly demanded You.
  • the present invention provides a compound represented by the general formula [I]:
  • Ar may be condensed with an aryl group or a benzene ring, and a heteroaryl group having one or two hetero atoms selected from the group consisting of L, a nitrogen atom, an oxygen atom, and a sulfur atom ( However, represents water atom of the lower alkyl group on the ring of Ariru groups and to Teroari Ichiru group, a halogen atom, a lower alkoxy group, a which may be optionally) substituted with an amino group or a hydro Kin methyl, R 1 is ⁇ ⁇ ⁇ represents a cycloalkyl group having 3 to 6 carbon atoms having 2 to 2 hydroxyl groups on the ring, and R 2 is a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, or an aralkyl group.
  • the hydrogen atom on the ring of the alkenyl group and the heteroarylalkyl group may be substituted with a lower alkyl group, a halogen atom, a lower alkoxy group, an amino group or a hydroxymethyl group), and X is 0 or NH
  • the present invention provides a novel 1,4-disubstituted piperidine derivative represented by the formula: and a pharmaceutically acceptable salt thereof.
  • Compound of the formula [I] provided by this invention has an effective selective muscarinic M 3 receptor antagonistic activity, therefore, Ri fewer side effects safety der, asthma, chronic airway obstruction, pulmonary Respiratory diseases such as fibrosis; Urinary diseases accompanied by dysuria such as urinary frequency, urgency and urinary incontinence; Treatment of gastrointestinal diseases such as irritable colon, gastrointestinal convulsions or increased motor function Or it is extremely useful for prevention.
  • the aryl group means a monocyclic or bicyclic aryl group having 6 to 11 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
  • a heteroaryl group having one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which is condensed with a benzene ring is, for example, a 2-pyridyl group, a 3-pyridyl group , 4-pyridyl, 2-thiazolyl, 2-thenyl, 3-thenyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-virazolyl, 5-virazolyl, 2-furyl Group, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-virazinyl, 3-pyridazinyl, 4-pyridazinyl, 2- Examples include a quinolinyl group, a 2-benzothienyl group and a 2-indolyl group.
  • cycloalkyl group having 3 to 6 carbon atoms having 1 to 2 hydroxyl groups on the ring include, for example, 1-hydroxycyclopropyl group, 1-hydroxycyclobutyl group, 1-hydroxycyclopentyl group, and 1-hydroxycyclopentyl group.
  • Hydroxycyclohexyl group 2-hydroxycyclopropyl group, 2-hydroxycyclobutyl group, 2-hydroxycyclopentyl group, 2-hydroxycyclohexyl group, 3-hydroxycyclobutyl group, 3-hydroxy Cyclopentyl group, 3-hydroxycyclohexyl group, 4-hydroxycyclohexyl group, 2,3-dihydroxycyclobutyl group, 1,2 dihydroxycyclopentyl group, 1,3-dihydroxycyclopentyl group, 2 2,3-dihydroxycyclopentyl, 2,4-dihydroxycyclopentyl, 3,4-dihydroxycyclo Examples include a pentyl group, a 2,3-dihydroxycyclohexyl group, and a 3,4-dihydroxycyclohexyl group.
  • a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms is a straight or branched chain having 5 to 15 carbon atoms, for example, an alkyl group, an alkenyl group, an alkynyl group, A cycloalkylalkyl group and a cycloalkylalkenyl group in which any hydrogen atom on the cycloalkyl ring may be substituted with lower alkyl, and a bicyclo in which any hydrogen atom on the bicycloalkyl ring may be substituted with lower alkyl An alkylalkyl group, a bicycloalkylalkenyl group, or any hydrogen atom on a cycloalkenyl ring is substituted by lower alkyl; A cycloalkenylalkyl group, a cycloalkenylalkenyl group, a bicycloalkenyl ring in which any hydrogen atom on the ring is substituted with lower alkyl, and
  • Such an aliphatic hydrocarbon group include: 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, pentyl group, neopentyl group, 1-methylpentyl group, 2-methylpentyl group, and 3-methylpentyl group.
  • Alkenyl group Alkenyl group:
  • the aralkyl group means a monocyclic or bicyclic aralkyl group having 7 to 12 carbon atoms, and examples thereof include a benzyl group, a phenyl group and a naphthylmethyl group.
  • An arylalkenyl group means a monocyclic or bicyclic arylalkenyl group having 8 to 12 carbon atoms, and examples thereof include a styryl group, a phenylpropyl group, and a naphthylethenyl group. it can.
  • a heteroarylalkyl group having one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may be condensed with a benzene ring includes, for example, a 2-pyridylmethyl group, —Pyridylethyl group, 2-pyridylpropyl group, 3—pyridylmethyl group, 4—pyridylmethyl group, 2—thiazolylmethyl group, 2 —thenylmethyl group, 3 —thenylmethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group, 3-imidazolylmethyl group, 4-imidazolylmethyl group, 3-birazolylmethyl group, 5-birazolylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2-pyrrolylmethyl group, 3-pyrrolylmethyl group, 2-pyrimidinylmethyl group , 4-pyrimidinylmethyl, 5-pyrimidinylmethyl, 2-pyrazin
  • halogen includes fluorine, chlorine, bromine and iodine.
  • lower alkyl group refers to a direct or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t Monobutyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.
  • the lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group and an isopropo group. Examples thereof include a xy group, a butoxy group, a sec-butoxy group, a t-butyne group, a pentyloxy group, an isopentyloxy group, a hexyloxy group and an isohexyloxy group.
  • the lower alkoxycarbonyl group refers to a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy. Examples thereof include a carbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a hexyloxycarbonyl group and an isohexylcarbonyl group.
  • aralkyloxycarbonyl group means an aralkyloxycarbonyl group having 7 to 10 carbon atoms, such as a benzyloxycarbonyl group or a phenyloxycarbonyl group.
  • a protected hydroxyl group is defined as a hydroxyl group protected in the form of an acyl group such as an acetyl group, an alkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group, a trityl group, an isopropylidene ketal, an ethylene ketal, or a trimethylene ketal. means.
  • an acyl group such as an acetyl group, an alkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group, a trityl group, an isopropylidene ketal, an ethylene ketal, or a trimethylene ketal.
  • the protected amino group means an amino group protected by a protecting group such as an acetyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a trityl group.
  • deprotection means the removal of protecting groups usually used in the field of organic chemistry, for example, hydrolysis, hydrolysis and the like.
  • deprotection means the removal of protecting groups usually used in the field of organic chemistry, for example, hydrolysis, hydrolysis and the like.
  • Ar is a heteroaryl group having one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may be condensed with an aryl group or a benzene ring (provided that Ar is , A hydrogen atom on the ring of an aryl group or a heteroaryl group represents a lower alkyl group, a halogen atom, a lower alkoxy group, an amino group or a hydroxymethyl group, and a phenyl group is preferable (/ ⁇ 0 (2) R 1 represents a cycloalkyl group having 3 to 6 carbon atoms having 1 to 2 hydroxyl groups on the ring, particularly 1-hydroxycyclopropyl group, 1-hydroxycyclobutyl group, 1-hydroxycyclopentyl Group, 1-hydroxycyclohexyl group, 2-hydroxycyclopropyl group, 2-hydroxycyclobutyl group, 2-hydroxycyclopentyl group, 2-hydroxycyclohexyl group, 3-hydroxycyclo
  • X represents 0 or NH, and NH is particularly preferred.
  • R 2 is a nitrogen or oxygen atom which may be condensed with a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, an aralkyl group, an aryl alkenyl group or a benzene ring.
  • Q represents an alkylene group having 1 to 4 carbon atoms, for example, a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and the like.
  • ⁇ And! ⁇ represents a hydrogen atom, or R a and IT together form a single bond
  • R b , R d, and FT are the same or different and each represents a hydrogen atom, a lower alkyl group
  • R b and R d or R d and R e are taken together to form a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkenyl group, a bincroalkyl group or a bicycloalkenyl group], a benzyl group, Phenethy
  • the compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of substitution, but the compounds of the present invention include all of these stereoisomers and those And mixtures thereof.
  • the compounds of the present invention can also exist in the form of pharmaceutically acceptable salts, such as, for example, hydrochloride, sulfate, nitrate, phosphate, perchlorate and the like.
  • Organic carboxylate such as maleate, fumarate, succinate, tartrate, citrate, ascorbate; methanesulfonate, isethionate, benzenesulfonate And organic sulfonates such as p-toluenesulfonate.
  • the compound of the general formula [I ⁇ ] of the present invention is, for example,
  • R 2 D represents a nitrogen atom, an oxygen atom and a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, which may be condensed with an aralkyl group, an aryl alkenyl group or a benzene ring.
  • R 2 t) is a protected amino group, a protected hydroxymethyl group, a lower alkoxycarbonyl group or an aralkyl group having an aryloxycarbonyl group, an arylalkenyl group or a heteroaryl group.
  • R 2 t is a protected amino group, a protected hydroxymethyl group, a lower alkoxycarbonyl group or an aralkyl group having an aryloxycarbonyl group, an arylalkenyl group or a heteroaryl group.
  • R 21 may be condensed with a saturated or unsaturated aliphatic hydrocarbon group having 4 to 14 carbon atoms, an aryl group, an aralkyl group, an aryl alkenyl group, or a benzene ring.
  • a heteroaryl or heteroarylalkyl group having one or two heteroatoms selected from the group consisting of an atom, an oxygen atom and a sulfur atom (provided that the aryl, aralkyl, arylalkyl or benzene ring Even if condensed, a hydrogen atom on the ring of a heteroaryl group or a heteroarylalkyl group having one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom is lower.
  • the “leaving group” represented by L includes, for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; an alkyl such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group And a sulfonyloxy group or an arylsulfonyloxy group.
  • the “protecting group for imino group” represented by E includes, for example, a benzyl group, a p-methoxybenzyl group, a p-122-benzyl group, Aralkyl groups such as benzhydryl group and trityl group; lower alkenyl groups such as formyl group, acetyl group and propionyl group; aryl alkanol groups such as phenylacetyl group and phenyloxyacetyl group; Lower alkoxycarbonyl groups such as ethoxycarbonyl group, ethoxycarbonyl group and t-butoxycarbonyl group; alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl group; benzyloxycarbonyl group and p-nitrobenzoyloxy group; An aralkyloxycarbonyl group such as a carbonyl group; for example, a trimethylsilyl group,
  • the carboxylic acid of the formula [III] used as a starting material can be produced, for example, by the method described in Reference Examples described later.
  • the condensing agent used in the above reaction includes a carboxyl group and water Usually used in the field of synthetic organic chemistry in the condensation reaction with an acid group or an amino group, for example, N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid And diphenylphosphoryl azide, dipyridyl disulfido triphenyl phosphine and the like, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is particularly preferred.
  • the condensation reaction can be carried out in the presence of a base, if necessary.
  • a base examples include pyridine, 4-dimethylaminopyridin, picoline, lutidine, quinoline, and isoquinoline.
  • 4-dimethylaminopyridine is particularly preferable.
  • the condensation reaction is preferably carried out in an inert solvent.
  • an inert organic solvent include dimethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane, benzene, toluene, and chloroform.
  • the reaction temperature can be generally from -70 ° C to the boiling point of the solvent used in the reaction, preferably from 120 ° C to 100 ° C. Usually, it can be completed in 5 minutes to 7 hours, preferably in 10 minutes to 24 hours.
  • the ratio of the compound of the formula [IV] or a salt thereof to the compound of the formula [III] is not strictly limited, and can be changed according to the kind of the compound, the reaction conditions used, and the like.
  • the compound of the formula [IV] or a salt thereof can be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound of the formula [III].
  • the coupling compound of the formula [X] is a carboxylic acid of the formula [II ⁇ ] Can be obtained by converting into a reactive derivative and then condensing with a compound of the formula [IV] or a salt thereof.
  • Examples of the reactive derivative of the carboxylic acid of the formula [III] include those commonly used in the field of synthetic organic chemistry for the activation of carboxyl groups in esterification or amidation reactions, for example, mixed anhydrides. , Active esters, active amides and the like.
  • the mixed acid anhydride of the carboxylic acid of the formula [III] can be prepared by converting the carboxylic acid of the formula [III] according to a conventional method, for example, an alkyl carbonate such as ethyl ethyl carbonate; an aliphatic carboxylic acid such as acetyl chloride and pivaloyl chloride.
  • the active ester can be obtained by reacting a carboxylic acid of the formula [III] according to a conventional method, for example, with N, N'-dicyclohexylcarposimide, 1-ethyl-3- (3- Dimethylaminopropyl) In the presence of a condensing agent such as carbodiimide, diphenylphosphorylazide, dipyridyldisulfide triflateylphosphine, etc., for example, N-hydroxysuccinimid, N-hydroxyphthalimid, 1 N-hydroxy compounds, such as 4-hydroxybenzotriazole; 41-2 trophenol, 2,4-dinitrophenol, 2,4, It can react with phenolic compounds such as 5-trichlorophenol and pentachlorophenol, and the active amide can be prepared by converting the carboxylic acid of the formula [III] according to a conventional method. For example, it can be obtained by reacting with 1.1′-carbonyldiimidazole, 1,1′-carbony
  • the condensation reaction between the reactive derivative of the carboxylic acid of the formula [III] and the compound of the formula [IV] or a salt thereof is preferably carried out in an inert solvent.
  • an inert organic solvent for example, examples include dimethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trifluoroethylene or a mixture of the above solvents.
  • diethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane and the like are examples of the above solvents.
  • the reaction temperature is usually from -70 ° C to the boiling point of the solvent used in the reaction, preferably It can be in the range of 120 ° C to 100 ° C.
  • the ratio of the compound of the formula [IV] or the salt thereof to the reactive derivative of the carboxylic acid of the formula [III] is not strictly limited, and varies depending on the type of the reactive derivative.
  • the compound of the formula [IV] or a salt thereof can be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the reactive derivative of the carboxylic acid of the formula [III]. it can.
  • a cycloalkyl having 3 to 6 carbon atoms having 1 to 2 protected hydroxyl groups or an unprotected or protected oxo group on the ring When it is an alkyl group, the protecting group is removed and / or reduced, and R 2 D has a protected amino group, a protected hydroxymethyl group, a lower alkoxy group, a luponyl group or an aryloxycarbonyl group.
  • an aralkyl group an arylalkenyl group or a heteroarylalkyl group, if necessary, deprotection or reduction of a lower alkoxycarbonyl group or an aralkyloxycarbonyl group to a hydroxymethyl group or a conversion reaction to an amino group.
  • deprotection or reduction of a lower alkoxycarbonyl group or an aralkyloxycarbonyl group to a hydroxymethyl group or a conversion reaction to an amino group can be performed by ordinary methods well known in the field of organic chemistry.
  • the removal of the protecting group from the hydroxyl group and the oxo group protected in the form of a ketal in the compound of the formula [IX] can be usually carried out using an inorganic acid, an organic acid, a weak acid salt or the like in a water-containing solvent.
  • the inorganic acid include hydrochloric acid and sulfuric acid
  • examples of the organic acid include paratoluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, and acetic acid. Examples thereof include ammonium chloride, pyridinium paratoluenesulfonate and the like.
  • hydrated solvent hydrated methanol, hydrated ethanol, hydrated tetrahydrofuran, hydrated dioxane and the like are preferable.
  • the reaction is usually carried out at a temperature of 0 ° C to 100 ° C, preferably room temperature to 80 ° C, using a catalytic amount to 5 equivalents, preferably a catalytic amount to 1 equivalent of the acid or salt. it can.
  • the oxo group obtained by the deprotection can be reduced using, for example, a metal hydride complex such as sodium borohydride or lithium aluminum hydride.
  • the condensation reaction between the carboxylic acid of the formula [III] or a reactive derivative thereof and the piperidine derivative of the formula [V] in the first step is carried out as follows: It can be carried out in the same manner as in the condensation reaction between the carboxylic acid of the formula [III] or a reactive derivative thereof and the compound of the formula [IV] in the production step (a). In the compound of the formula [VI] obtained by this condensation reaction, the protecting group for the imino group is then removed.
  • the removal of the imino protecting group from the compound of formula [VI] can be carried out in a manner known per se, for example, Protective Groups in Organic Synthesis, TW Greene.
  • solvolysis using an acid or a base for example, solvolysis using an acid or a base, chemical reduction using a metal hydride complex, etc., according to the method described in John Wiley & Sons, Inc. (1981) or a method analogous thereto, It can be carried out by catalytic reduction using a palladium-carbon catalyst, a Raney-nickel catalyst or the like.
  • the solvolysis with an acid is usually carried out in an inert solvent such as methylene chloride, anisol, tetrahydrofuran, dioxane, methanol, ethanol or a mixed solvent thereof and water, or in the absence of a solvent.
  • the treatment can be carried out using an acid such as formic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid, preferably at a temperature in the range of about 0 ° C to about 100 ° C for 10 minutes to 24 hours.
  • the solvolysis with a base is usually carried out in an inert solvent that does not adversely affect the reaction of, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, or the like, or a mixed solvent thereof with water, for example, lithium hydroxide, hydroxyl Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate, etc., preferably at a temperature in the range of about 20 ° C to about 80 ° C. It is performed by acting for 10 minutes to 24 hours.
  • an inert solvent that does not adversely affect the reaction of, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, or the like, or a mixed solvent thereof with water, for example, lithium hydroxide, hydroxyl Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbon
  • Catalytic reduction is usually carried out in an inert solvent such as methanol, ethanol, water or acetic acid or a mixed solvent thereof using a catalyst such as a palladium-carbon catalyst, palladium hydroxide, Raney nickel or a platinum oxide catalyst. It is preferably carried out by catalytic reduction under a hydrogen pressure of about 1 to about 20 kgZcm 2 , preferably at a temperature in the range of about 0 ° C to about 40 ° C for 10 minutes to 24 hours.
  • a hydrogen pressure of about 1 to about 20 kgZcm 2 , preferably at a temperature in the range of about 0 ° C to about 40 ° C for 10 minutes to 24 hours.
  • reaction of the compound of the formula [X] with the compound of the formula [VII] is usually carried out in a suitable solvent in an approximately equimolar amount or in a slight excess of either (eg per mole of the compound of the formula [X]
  • the reaction can be carried out using a large excess of one of them, if necessary. If necessary, the reaction can be carried out using an appropriate base or a reaction aid.
  • the solvent examples include ethers such as getyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, cyclobenzene, and xylene; dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile. And non-protonic polar solvents such as hexamethylphosphoric triamide, or a mixed solvent thereof.
  • ethers such as getyl ether, tetrahydrofuran, and dioxane
  • aromatic hydrocarbons such as benzene, toluene, cyclobenzene, and xylene
  • dimethyl sulfoxide N, N-dimethylformamide, and acetonitrile.
  • non-protonic polar solvents such as hexamethylphosphoric triamide, or a mixed solvent thereof.
  • Examples of the base that can be used include alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carbonates such as sodium carbonate and lithium carbonate; and trimethylamine and triethylamine , N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] Tertiary aliphatic amines such as diene (DBU), 1,5-diazabicyclo [4.3.0] nonane 5-ene (DBN); for example, pyridine, 4-dimethylaminopyridine, picoline, lutidine, Aromatic amines such as quinoline and isoquinoline are exemplified, and N, N-diisopropylethylamine and triethylamine are particularly preferred.
  • alkali metal bicarbonates such as sodium bicarbonate and potassium bi
  • reaction aid examples include, for example, alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide. Potassium iodide is preferred.
  • the reaction temperature is between about 0 temperature up to the boiling point of the e Celsius to solvents is used, also the force can be the reaction time is 1 0 minute to 48 hours, no more or less than this condition as required It can also be used.
  • the reductive alkylation reaction of the compound of the formula [X] with the aldehyde of the formula [VIII] according to the production step (c) is usually carried out in an inert solvent which does not adversely influence the reaction.
  • the active solvent include alcohols such as methanol and ethanol; ethers such as getyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof.
  • methanol, ethanol, tetrahydrofuran, toluene and the like are preferable.
  • the reaction temperature can be generally about 130 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 10 minutes. 77 days, preferably from 10 minutes to 24 hours.
  • the above-mentioned reductive alkylation reaction is preferably carried out under a weak acidic condition in which a Schiff base is easily generated, and examples of the acid that can be used for pH adjustment include, for example, P-toluenesulfonic acid, hydrochloric acid, acetic acid, and trifluoroacetic acid. And the like.
  • the reductive alkylation is carried out by using a metal hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, or the like.
  • the reduction can be carried out by catalytic reduction using a radium-carbon catalyst, a Raney nickel catalyst or the like.
  • a hydride complex such as sodium borohydride or sodium cyanoborohydride.
  • sodium cyanoborohydride which is relatively stable under an acidic condition.
  • the amount of the reducing agent used is usually expressed by the formula
  • the amount can be from 1 mol to an excess mol, preferably from 1 to 10 mol, per 1 mol of the compound of [XI]. If necessary, the conversion reaction of R 1Q and R 21 described in the production step (a) is performed.
  • This reaction is usually carried out in an inert solvent such as getyl ether or tetrahydrofuran at a temperature in the range of -80 ° C to room temperature.
  • inert solvent such as getyl ether or tetrahydrofuran
  • examples of usable bases include n-butyllithium and lithium diisopropylamide.
  • the production process (a), (b), (c) described above and the compound of the formula [I] obtained by the above-mentioned alternative method can be carried out by a method known per se, for example, column chromatography using silica gel, an adsorption resin, etc. Purification and isolation can be performed using ordinary ffl separation means such as liquid chromatography, thin-layer chromatography, solvent extraction or recrystallization / reprecipitation.
  • the compounds and intermediates of the present invention exist as stereoisomers such as optical isomers, diastereoisomers, and geometric isomers. Also includes mixtures.
  • Optical resolution in the case where the compound of the present invention and the intermediate are racemates can be achieved by ordinary means such as high performance liquid chromatography using a chiral carrier or fractional crystallization of diastereomeric salts.
  • the compound of the general formula [I] obtained by the above method can be converted into a pharmaceutically acceptable salt by a conventional method, and conversely, the conversion of the salt to a free amine can be performed according to a conventional method. it can.
  • the compound of the formula [I] of the present invention exhibits a potent and selective muscarinic receptor binding inhibitory action and a muscarinic receptor antagonistic action in vitro and in vivo.
  • the effects of the compounds of the present invention are as follows: Demonstrated by a receptor binding inhibition test and a musculin phosphorous receptor antagonism test. In these tests, the inhibitory and antagonistic effects were determined by the concentration of the test compound that inhibited the binding of [ 3 H] —N-methylscopolamine by 50% as a labeled ligand.
  • This test method was performed according to a conventional method. Male Japanese White Heron (about 3 kg) was bled to death from the femoral artery under pentobarbital anesthesia, and the vas deferens were removed. A vas deferens specimen was used in a portion (1 cm long) close to the prostate. Specimens 20 m l click Repusu -. Henzerai DOO nutrient solution [95% 0 2 5% C0 2 ventilation, 3 2. was suspended longitudinally in initial tension 1. 0 g in Magnus tube filled with C 1 / M yohi mb containing ine (alpha 2 antagonist). Specimen tension was recorded isometrically.
  • This test method was performed according to a conventional method.
  • An SD male rat 300-500 g was bled to death and the trachea was removed. After making the trachea a 2 mm wide ring, the ventral cartilage was cut open to prepare a transverse specimen.
  • the cells were contracted twice with 1% of carbachol, and the second contraction of carbachol was used as the reference contraction.
  • administering a test compound (or no treatment) were administered carbachol (10 8 to 1 0 3 M) after the 10 minutes cumulatively three times doses, dose A response curve was obtained.
  • the dose-response curves were expressed with the reference shrinkage in each sample as 100%.
  • the antagonistic potency ( ⁇ ,, value) of the compound of the present invention was determined from the degree of shift of the dose-response curve due to the test compound treatment.
  • the - (1 0 8 ⁇ 1 0 3 M) was administered cumulatively at three times the dose from a low concentration to obtain a dose response curve.
  • Dose-response curves were expressed as 100% of the contraction of the reference in each sample.
  • the antagonistic potency ( Ku value) of the test compound was determined from the degree of shift of the dose-response curve due to the test compound treatment.
  • This test method was performed according to a conventional method.
  • An SD male rat (200-400 g) was bled to death and the bladder was removed.
  • the bladder was cut into eight pieces along the normal axis, and specimens were prepared.
  • the specimens 5 m 1 Krebs - Henzerai Bok nutrient solution (9 5% 0 2, 5 % C 0 2 ventilation, 3 2 C) 'in Magnus tube filled with, and vertical suspension at an initial tension 0. 5 g. Specimen tension was recorded isometrically. After 1 hour equilibration, 1 0 4 M carbachol by deflating twice, the second carbachol contraction was contraction of Reference. After washing with the neoplasm and returning to the baseline, the test compound was administered.
  • the compounds of the invention antagonize each to the vas deferens Micromax ,, atrial Micromax 2, trachea Micromax 3, ileum Micromax 3 and the muscarinic receptors of the bladder Micromax 3, the The effect is greater on ⁇ 3 receptors in the trachea, ileum and bladder It is selective, particularly antagonistic strongly to the trachea M 3 receptor. That is, the present onset Ming compounds trachea M 3 receptor, which is more selective compounds.
  • the compound of the present invention showed a strong bronchodilator effect when administered orally.
  • the compounds of the formula [I] of the present invention has a potent and selective muscarinic M 3 receptor antagonistic action, and showed a strong bronchodilatory effect in oral administration. Therefore, it is a safe medicine with few side effects, especially respiratory diseases such as asthma, chronic airway obstruction and pulmonary fibrosis: urinary diseases accompanied by dysuria such as urinary frequency, urgency and urinary incontinence; It can be administered orally or parenterally to patients for the treatment or prevention of gastrointestinal diseases such as irritable large intestine, gastrointestinal convulsions or hypermotor function.
  • the compound of the present invention When the compound of the present invention is actually used for treatment or prevention of the above-mentioned diseases, it may be formulated into a dosage form suitable for administration together with pharmaceutically acceptable additives according to a conventional method. it can.
  • pharmaceutically acceptable additives various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and the like.
  • Corn starch microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, calcium anhydrous calcium, citrate, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxy Ethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light gay anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol , Polyalkylene glycol, cyclodextrin or hydroxypropyl Cyclo Dextrin and the like.
  • Dosage forms formulated using these additives include solid preparations such as tablets, capsules, granules, powders and suppositories: liquid preparations such as syrups, elixirs, injections, etc. These can be prepared according to a usual method in the pharmaceutical field.
  • the liquid preparation may be in the form of being dissolved or suspended in water or another appropriate medium before use.
  • the injection may be in the form of being dissolved or suspended in a physiological saline or glucose solution in advance, or in the form of a powder to be dissolved or suspended in a physiological saline or glucose solution before use.
  • a buffer or a preservative may be contained.
  • These preparations may contain the compounds of the present invention in a proportion of from 0.1 to 100% by weight, preferably from 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
  • the platform on which the compound of the present invention is used as a bronchodilator the dosage and the number of administrations vary depending on the sex, age, weight, degree of symptoms and the kind and range of the intended therapeutic effect of the patient, but generally, For oral administration, 0.1 to 10 O mg / kg per adult per day in 1 to several divided doses, and for parenteral administration, for 0.001 to IO mgZ kg 1 to 1 It is preferable to administer in several divided doses.
  • EXAMPLES The present invention will be described specifically with reference to examples, but the present invention is not limited thereto.
  • This was dissolved in 16 ml of methanol, 4 ml of 4 N hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 1.5 hours.
  • the solvent was distilled off under reduced pressure, and the resulting residue was solidified with methanolic luethyl ether to give 1.46 g of the title compound as a white solid.
  • the title compound was produced in the same manner as in Step 1 of Example 1 using cycloheptylmethyl p-toluenesulfonate.
  • Example 1 Step 1 using 2-hydroquinine 2-[(1S) -3-oxocyclopentyl] -2-phenylacetic acid and 4-amino-1- (1-cycloheptylmethyl) piberidine dihydrochloride The title compound was produced in the same manner as in 2, 4.
  • Step 1 Synthesis of 5- (1,4-dioxaspiro "4.51 deca 7-en-8-yl") 1,2,2-dimethyl-15-phenyl-1,3-dioxolan-14
  • the organic layer was washed with saturated saline, and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 483 mg of a yellow oily substance. This was dissolved in 4 ml of pyridine, 1 ml of thionyl chloride was added under ice cooling, and the mixture was stirred for 1.5 hours.
  • the reaction solution was diluted with ethyl acetate, water was added, and the organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel gel chromatography (developing solvent: hexane / ethyl acetate 2.5-1) to obtain 339 mg of the title compound as an oil.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the residue obtained by distilling off the solvent under reduced pressure was dissolved in 120 ml of methanol, 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution, methanol was distilled off under reduced pressure, and the residue was extracted with chloroform.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound.
  • Step 2 5- (2-cyclopentene-1-yl) -1,2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one and 5- (3-cyclopentene-1-yl) -1,2 1,2-Dimethyl-5-phenyl-1,3-dioxolan-1-ion
  • 5- (3-Hydroxycyclopentyl) 1,2,2-dimethyl-5-phenyl 1,3-dioxolane-41-one 3.7 g of ethyl acetate 15 Om 1 solution in ice-cooled triethylamine 5 ml 1 Then, 2 ml of methanesulfonic acid chloride was sequentially added, and the mixture was stirred at the same temperature for 30 minutes.
  • the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the residue obtained by distilling off the solvent under reduced pressure is dissolved in toluene 10 Om 1, and 1,8-diazabicyclo [5.4.0] pendecar 7-ene 1 Om 1 is added, and the mixture is added to 100 ° C. And stirred for 20 hours.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (developing solvent: hexane ethyl acetate 50-1) to give 477 mg of a mixture of the title compounds as an oil.
  • the three-dimensional object was decided by NOE.
  • Step 1 (2 R, 5R) — 2— (t-butyl) 1 5— [(1 R) 13-oxocyclopentyl] 1—5-phenyiru 1,3-dioxolan 1-4ion and (2 R, 5R) -2- (t-butyl) -1-5-((1S) -13-oxocyclopentyl) -1-5-phenyl-1,3-dioxolan-1-4-one

Abstract

L'invention concerne des dérivés de pipéridine à disubstitution en positions 1,4 représentés par la formule générale (I) ainsi que leurs sels pharmaceutiquement acceptables, formule dans laquelle Ar représente hétéroaryle présentant un ou deux hétéro-atomes choisis dnas le groupe constitué par l'azote, l'oxygène et le soufre et facultativement fusionnés à aryle ou benzène (où chaque hydrogène sur les cycles aryle et hétéroaryle peut être substitué par alkyle, halogéno inférieur, alcoxy, amino ou hydroxyméthyle inférieur); R1 représente cycloalkyle C¿3-6? présentant un ou deux groupes hydroxyle sur le cycle; R?2¿ représente hétéroarylalkyle présentant un ou deux hétéro-atomes choisis dans le groupe constitué d'hydrogène, d'oxygène et de soufre et facultativement fusionnés à un hydrocarbure C¿5-15? aliphatique saturé ou insaturé, aralkyle, arylalcényle ou benzène (où chaque hydrogène se trouvant sur les cycles aralkyle, arylalcényle et hétéroarylalkyle peut être substitué par alkyle, halogéno inférieur, alcoxy, amino ou hydroxyméthyle inférieur); et X représente O ou NH. Du fait de leur antagonisme vis-à-vis du récepteur muscarinique M3, ces composés sont utiles en tant que remèdes sans danger ou agents préventifs présentant peu d'effets secondaires contre des maladies respiratoires telles que l'asthme, l'obstruction respiratoire chronique et la fibrose pulmonaire; contre des maladies urologiques en association avec des troubles de la miction fréquente, la miction urgente et l'incontinence urinaire; et contre des maladies de l'appareil digestif telles que le colon irritable et l'hyperénergie convulsive ou motrice des voies digestives.
PCT/JP1997/001770 1996-05-31 1997-05-27 Derives de piperidine a disubstitution en positions 1,4 WO1997045414A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2816940A1 (fr) * 2000-11-23 2002-05-24 Lipha Derives de 4-(biphenylcarbonylamino)-piperidine, compositions les contenant et leur utilisation
WO2004052857A1 (fr) * 2002-12-10 2004-06-24 Ranbaxy Laboratories Limited Derives d'azabicyclo [3.1.0] hexane 3,6-disubstitues utilises comme antagonistes du recepteur muscarinique
WO2004067510A1 (fr) * 2003-01-28 2004-08-12 Ranbaxy Laboratories Limited Derives de 3,6-disubstitues azabicyclo hexane utilises en tant qu'antagonistes du recepteur de muscarinique
WO2007045979A1 (fr) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'antagonistes du recepteur muscarinique
US7265147B2 (en) 2002-07-31 2007-09-04 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonists
US7288562B2 (en) 2002-08-23 2007-10-30 Ranbaxy Laboratories Limited Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists
US7399779B2 (en) 2002-07-08 2008-07-15 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists
US7410993B2 (en) 2002-08-09 2008-08-12 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0] hexane deriviatives useful as muscarinic receptor antagonists
US7446123B2 (en) 2003-04-11 2008-11-04 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
US7465751B2 (en) 2002-12-23 2008-12-16 Ranbaxy Laboratories Limited 1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists
US7501443B2 (en) 2002-12-23 2009-03-10 Ranbaxy Laboratories Limited Flavaxate derivatives as muscarinic receptor antagonists
US7517905B2 (en) 2003-04-09 2009-04-14 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US7560479B2 (en) 2003-04-10 2009-07-14 Ranbaxy Laboratories Limited 3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US7592359B2 (en) 2003-04-10 2009-09-22 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042291A1 (fr) * 2000-11-23 2002-05-30 Merck Patent Gmbh Derives de 4-(biphenylcarbonylamino)piperidine utilises comme inhibiteurs de l'mtp
FR2816940A1 (fr) * 2000-11-23 2002-05-24 Lipha Derives de 4-(biphenylcarbonylamino)-piperidine, compositions les contenant et leur utilisation
US7544708B2 (en) 2002-07-08 2009-06-09 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
US7399779B2 (en) 2002-07-08 2008-07-15 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists
US7265147B2 (en) 2002-07-31 2007-09-04 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonists
US7410993B2 (en) 2002-08-09 2008-08-12 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0] hexane deriviatives useful as muscarinic receptor antagonists
US7288562B2 (en) 2002-08-23 2007-10-30 Ranbaxy Laboratories Limited Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists
WO2004052857A1 (fr) * 2002-12-10 2004-06-24 Ranbaxy Laboratories Limited Derives d'azabicyclo [3.1.0] hexane 3,6-disubstitues utilises comme antagonistes du recepteur muscarinique
US7232835B2 (en) 2002-12-10 2007-06-19 Ranbaxy Laboratories Limited 3,6-Disubstituted azabicyclo derivatives as muscarinic receptor antagonists
US7465751B2 (en) 2002-12-23 2008-12-16 Ranbaxy Laboratories Limited 1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists
US7501443B2 (en) 2002-12-23 2009-03-10 Ranbaxy Laboratories Limited Flavaxate derivatives as muscarinic receptor antagonists
US7488748B2 (en) 2003-01-28 2009-02-10 Ranbaxy Laboratories Limited 3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonists
WO2004067510A1 (fr) * 2003-01-28 2004-08-12 Ranbaxy Laboratories Limited Derives de 3,6-disubstitues azabicyclo hexane utilises en tant qu'antagonistes du recepteur de muscarinique
US7517905B2 (en) 2003-04-09 2009-04-14 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US7560479B2 (en) 2003-04-10 2009-07-14 Ranbaxy Laboratories Limited 3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US7592359B2 (en) 2003-04-10 2009-09-22 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US7446123B2 (en) 2003-04-11 2008-11-04 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
WO2007045979A1 (fr) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'antagonistes du recepteur muscarinique

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