WO1998054167A1 - Composes d'indole - Google Patents

Composes d'indole Download PDF

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Publication number
WO1998054167A1
WO1998054167A1 PCT/JP1998/002291 JP9802291W WO9854167A1 WO 1998054167 A1 WO1998054167 A1 WO 1998054167A1 JP 9802291 W JP9802291 W JP 9802291W WO 9854167 A1 WO9854167 A1 WO 9854167A1
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WIPO (PCT)
Prior art keywords
group
ethyl
substituent
phenyl
pyrrolidine
Prior art date
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PCT/JP1998/002291
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English (en)
Japanese (ja)
Inventor
Norio Ohno
Jun-Ichi Endoh
Masataka Miura
Hideyuki Aizawa
Sumiko Nagaki
Athushi Fukuzaki
Original Assignee
Mitsubishi-Tokyo Pharmaceuticals, Inc.
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Application filed by Mitsubishi-Tokyo Pharmaceuticals, Inc. filed Critical Mitsubishi-Tokyo Pharmaceuticals, Inc.
Priority to AU74508/98A priority Critical patent/AU7450898A/en
Publication of WO1998054167A1 publication Critical patent/WO1998054167A1/fr

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—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 three or more hetero rings

Definitions

  • the present invention relates to indole compounds, detail Indoru compounds exhibit selective muscarinic M 3 receptor antagonism and pharmaceutical group Narubutsu that it as an active ingredient.
  • Mus force phosphate receptor least three subtypes is Ari, M, receptors in the brain, M 2 receptors in the heart, child present in M 3 receptors smooth muscle and glandular tissue TogaTomo Have been.
  • muscarinic receptor antagonistic action show antispasmodic action, analgesic action and antisecretory action, and are therefore used as therapeutic drugs for dysfunctions such as intestines or bladder.
  • Atto port pins as a pharmaceutical having a muscarinic receptor antagonist activity, score Poramin, Ho Okishipuchinin, propantheline bromide, force is Ibra preparative port Piumu etc.
  • M , M and M 3 receptors of muscarinic receptors It is known that they have almost the same affinity and antagonize acetylcholine non-selectively in these, so that side effects cannot be avoided. Therefore, there has been a demand for a drug having a highly selective muscular phosphorus receptor antagonism, particularly a drug which does not show any side effects on the heart associated with the M receptor.
  • 3-substituted pyrrolidine derivatives as compounds that selectively antagonize the muscarinic M receptor (Japanese Patent Application Laid-Open Nos. Heisei 2-28230, Tokuhyo Hei 4-5509927, Tokaihei 7-14) 9640 publication), 3-substituted piperidine derivatives (Japanese Patent Application Laid-Open No. Hei 4-501502), carbamate derivatives (W ⁇ 95 ⁇ 0.6635), An imidazole derivative (Japanese Patent Application Laid-Open No. 7-215943) and a diphenylacetic acid derivative (Japanese Patent Application Laid-Open No. 8-291141) are known, all of which are muscarinic 1 ⁇ selectivity for the 1 3 receptor is not sufficient.
  • Japanese Patent Publication No. 59-41049 discloses an oxyindole derivative having a gastric acid secretion inhibitory action and an antihypertensive action
  • Japanese Patent Publication No. 8-507092 discloses a vasopressin.
  • 1,3-dihydroindo-1-ru-2-one derivatives which are agonists and Z or antagonists of Z or chytoxin are described. Not listed.
  • muscarinic M i selectivity for receptors, especially high selectivity to Mus force phosphoric M 3 receptor over Mus force phosphoric M receptors, and novel compounds having a potent antagonism and it It is to provide a pharmaceutical composition as an active ingredient. Disclosure of the invention
  • the present inventors have made intensive studies on compounds having a muscular phosphorus M : i receptor antagonistic action, and as a result, the compound represented by the general formula (I)
  • Ar represents a phenyl group, a pyridyl group or a benzyl S which may have a substituent on the ring
  • R represents one A—W—B group
  • A is a lower group which may be branched.
  • W represents absent or represents an oxygen atom or a carbonyl group
  • B represents a phenyl group, a pyridyl group or a furyl group which may have a substituent on the ring.
  • branched 5 to 10 carbon atoms Represents p, 1, 2 or 3, q represents 1 or 2, and r represents ⁇ or 1.
  • Indole compound or a pharmacologically acceptable salt thereof represented by the high selectivity to the muscarinic M 3 receptor, and found Rukoto that have a strong antagonistic action, thereby completing the present invention Was.
  • the “substituent on the ring that Ar may have” refers to a halogen atom, an amino group, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a lower acyloxy group, a lower Examples thereof include a monovalent substituent such as an acylamino group and a cyano group, and a divalent group such as a methylenedioxy group, a trimethylene group, a tetramethylene group, and an ethyleneoxy group, and a halogen atom is preferable.
  • the “lower alkyl group” is an alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group and tributyl group. And a pentyl group, an isopentyl group, a neopentyl group, a topopentyl group, and a hexyl group.
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, and a butyl group are preferable.
  • the “lower alkoxy group” is an alkoxy group having 1 to (; specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy S, s-butoxy group.
  • Butoxy, isobutoxy, s butoxy and t-butoxy groups are preferred.
  • “Mono- or di-lower alkylamino 3 ⁇ 4” is mono- or dialkylamino S substituted with an alkyl group having 1 to 6 carbon atoms, specifically, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group.
  • lower acyloxy group refers to an alkoxy group having 1 to 6 carbon atoms. Specifically, it is a formyloxy group, an acetoxy group, a propionyloxy group, a petyloyloxy group, an isoptiloyloxy group, a pennoyloxy group, or the like. Examples thereof include a xanyloxy group and the like, and an acetoxy group, a propionyloxy group, a petyloyloxy group, and an isoptiloyloxy group are preferable.
  • the “lower acylamino group” is an acylamino group having 1 to 6 carbon atoms, specifically, a formylamino group, an acetoamide group, a propionylamino group, a petyloylamino group, an isoptyloylamino group, and a pentanoylamino group. And hexanoylamino groups, among which an acetate amide group, a propionylamino group, and a ptyroylamino group are preferred.
  • the “optionally branched lower alkylene group” is an alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, a trimethylene group, a tetramethylene, a pentamethylene group, and a hexamethylene group. And methylene group, ethylethylene group, propylene S, dimethylethylene group, dimethylpropylene S, etc., and methylene group, ethylene group, trimethylene group and tetramethylene S are preferable.
  • “Substitution ⁇ ⁇ on the ring which ⁇ ⁇ may have” means a monovalent (replacement S or divalent Groups.
  • the monovalent substituent includes a halogen atom, an amino group, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a lower acryloxy group, a lower acrylamino group, a cyano group, a nitro group, a hydroxyl group, and the like.
  • a halogen atom, an amino group, a methyl group, a t-butyl group, a methoxy group, a dimethylamino group, a nitro group and a hydroxyl group are preferred.
  • the divalent group includes a methylenedioxy group, a trimethylene group, a tetramethylene group, an ethyleneoxy group and the like, and preferably an ethyleneoxy group constituting a dihydroxybenzofuran ring.
  • Alkenyl group which may be branched includes 4-methylpentenyl-3-enyl group, 3-methylbut-3-enyl group, 3-methylbut-2-enyl group, 4-methylpentene-4-enyl group, 8-Methylnone 7-nyl group, 8-methylynone 18-dilyl group, 5-methylhexyl 4-122 group, 5-methylhexyl 5-nyl group, 6-methylheptenyl 5-nyl Group, 6-methylheptene 612 group, 7-methyloct-1-yl group, 7-methyloctene 7-yl group, 3-cyclohexylidenepyl pill group, 2-cyclohexylideneethyl group, A 4-methylpent-3-enyl group is preferred.
  • “Pharmacologically acceptable salts” include inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid.
  • Organic acid salts such as acetic acid, citric acid, fumaric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • Sulfonates and amino acid salts such as alanine, leucine, glumic acid, and glumin.
  • the compound (I) of the present invention contains one or more carbon atoms in the molecule, and thus has an optically active substance. All of these optically active substances and mixtures thereof are included in the present invention.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be isolated as a hydrate, a solvate, or a polymorphic substance. Included.
  • the present invention compound (I) or a pharmaceutically acceptable salt because it has a selective and.
  • Powerful muscarinic M 3 receptor antagonism diseases involving muscarinic receptor, in particular, irritable bowel Gastrointestinal disorders such as syndrome, functional disposia, spastic colitis and diverticulitis; Central illnesses such as nausea, vomiting, sickness and Meniere's disease caused by drug administration; Urinary disorders such as urinary incontinence and pollakiuria It can be used as a prophylactic or therapeutic agent for respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, pulmonary fibrosis and rhinitis.
  • T Compound (I) of the present invention which can be produced by the following method
  • Compound (IV) can be obtained by adding (III) and reacting with stirring at a temperature of from 120 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • X may be a group that functions as a leaving group in a normal chemical reaction, and is a sulfonyloxy group such as a P-toluenesulfonyloxy group, a benzenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • halogen atoms such as chlorine, bromine and iodine are preferred.
  • Z may be a group that functions as a protecting group for the amino group of the secondary amine in a normal chemical reaction, and is a sulfonyl group such as p-toluenesulfonyl (hereinafter referred to as “tosyl group”) or a benzenesulfonyl group. Is preferred.
  • the compound (III) in which r is 0 is produced according to the method described in Japanese Patent Application Laid-Open (JP-A) No. 2-282630, Japanese Patent Application Laid-Open (kokai) No. 4-500521, etc. be able to.
  • Compound ( ⁇ ) in which r is 1 is produced by protecting the amino group of compound (VII) with Z, reducing the ester group to a hydroxymethyl group, and substituting this hydroxyl group with X. can do.
  • Compound (IV) can be treated with hydrobromic acid or hydrobromic acid monoacetic acid in the presence of phenol or anisol to obtain compound (V).
  • compound (V) is condensed with compound ( ⁇ ) to obtain compound (I).
  • ⁇ may be any group that functions as a leaving group in a normal chemical reaction, such as a sulfonyloxy group, a benzenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a salt.
  • Halogen atoms such as nitrogen, bromine and iodine.
  • Compound (V) is dissolved in an organic solvent such as acetonitrile, methanol, ethanol, isopropyl alcohol, or acetone, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or hydrogencarbonate, or an organic base such as triethylamine or pyridine.
  • an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or hydrogencarbonate, or an organic base such as triethylamine or pyridine.
  • Compound (I) can be obtained by reacting with compound (VI) by adding an inorganic catalyst such as sodium iodide or potassium iodide, if necessary, in the presence of a base.
  • Compound (I) can be prepared by reacting compound (V) with a benzaldehyde derivative in an organic solvent such as tetrahydrofuran, chloroform, 1,2-dichlorobenzene or the like in the presence of acetic acid in the presence of acetic acid. It can also be obtained by elementary amination using a homogenous boron stream or the like.
  • Compound (VIU) can be produced by appropriately combining the production methods described in the first to third steps.
  • the pharmacologically acceptable salts of the compound (I) of the present invention include compounds (I) such as inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid; organic acid salts such as acetic acid, citric acid, fumaric acid, and tartaric acid; It can be produced by allowing a sulfonate such as an acid or tosylic acid or an amino acid such as alanine, leucine, glutamic acid or glutamine to act in a conventional manner.
  • compounds (I) such as inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid
  • organic acid salts such as acetic acid, citric acid, fumaric acid, and tartaric acid
  • a sulfonate such as an acid or tosylic acid or an amino acid such as alanine, leucine, glutamic acid or glutamine
  • the optically active form of the compound (I) of the present invention can be made into a crystalline diastereomer salt by reacting the compound (I) with an acidic optical resolving agent, which can be optically resolved by a recrystallization method or the like.
  • the compound (I) or a modified compound thereof can also be optically resolved by using an enantiomer separation technique applied to high performance liquid chromatography using a chiral stationary phase.
  • optically active compound (I) can also be obtained by using an optically active production intermediate in the above production method.
  • Examples of the dosage form of the compound of the present invention include oral administration with tablets, capsules, granules, powders, inhalants or syrups, and parenteral administration with injections or suppositories.
  • reaction solution was poured into iced water, extracted with 50 ml of form (50 ml, 20 ml), washed with water, and dried over anhydrous potassium carbonate.
  • the residue obtained by evaporating the chloroform at reduced pressure is subjected to silica gel column chromatography (eluent: chloropho Then, the title compound was obtained as white crystalline powder (0.14 g, yield 43%).
  • Example 5 (1) 1 3-Feuniru 3-[(S) 1 -pyrrolidine-1-3-yl]-1, 3-dihydroindole 2-one (0.28 g: 1 0.1 mmo 1) and betabromophenetol (0.21 g: 1.00 mmo 1) were reacted to give 0.24 g (yield 6%) of the title compound as white crystalline powder. 0%).
  • Example 7 (—) 1-3-phenyl-3 — “(S) —1— (4-phenylbutyl) -pyrrolidine-1-_3-yl —1,1,3—dihydroindole 2-year-old According to Example 4, (1) 1-3-phenyl-2-[(S) -pyrrolidine-3-yl] —1,3-dihydroindole-1-2-one (0.28 g: 1 0.1 mmo 1) and 4-phenylphenyl tosylate (0.31 g: 1.00 mo 1) to give 0.31 g (yield) of the title compound as a white amorphous substance. Rate 74%).
  • Example 4 3-phenyl-3 — [(S) -pyrrolidine—3-yl] 1-1,3-dihydroindole—2-one (0.28 g: 1 0.1 mm o 1) and 3— (2,3-dihydrobenzofuran-5-yl) propyltosylate (0.37 g: 1.0 mm o 1) 0.37 g (yield 67%) of the title compound was obtained.
  • the obtained syrup-like compound was dissolved in ethyl acetate, and a 4N hydrogen chloride-ethyl acetate solution was added.
  • the reaction solution was concentrated, ether was added, and the precipitated crystalline compound was collected by filtration. The crystals were washed with ether and dried to obtain 0.32 g of the title compound as a white powder.
  • Example 4 (1-) 1-3-phenyl-3 — [(S) 1-pyrrolidine—3-yl] —1,3-dihydroindole-1—2-one (0.17 g: 0 6 1 mm o 1) and 4-methyl-3-pentene-1-yl yl retosylate (0.16 g: 0.60 mmo 1) to give 0.05 g of the title compound as a white crystalline powder ( Yield 25%).
  • Example 1 (Example 1 1) (I) — 3 — [(S) -1-1 [2- (4-chlorophenyl) ethyl] pyrrolidine-3-yl] -13-phenyl-1- 1,3-dihydrindole One two—on According to Example 4, (1) 13-phenyl-2-[(S) 1-pyrrolidine-13-yl] —1,3-dihydroindole-12-one (0.26 g: 0.26 g) 9 4mm o 1) 2 — (4-monoethyl phenyl) ethyl tosylate (0.29 g: 0.93 mmol) 0.19 g (yield 50%) of the title compound as crystalline powder Obtained.
  • Example 4 (1-)-3- (4-chlorophenyl) -3-[((S) -pyrrolidine-1--3-yl]-1,3-dihydroindole-2-one (0. From 3 2 g: 1.0 mm 0 1), 2— (2,3—dihydrobenzofuran-1-yl) ethyl citrate (0.35 g: 1.10 mm o 1) ⁇ ⁇ The compound was obtained as white crystalline powder (0.25 g, yield 53%).
  • Example 17 (—) 1—3 — “(S) —1—“ 2— (4-dimethylaminophenyl) ethyl 1 pyrrolidine-13-yl 13-phenyl-2-1.3-dihydro Indore One 2—On (1-)-1-[(S) -111- [2- (4-aminophenyl) ethyl] pyrrolidine-13-yl] -13-phenyl-1,3-di obtained in Example 16 Hydroindole-1-one (0.22 g: 0.56 mmo1), formalin ( ⁇ .3 m1), 10% palladium activated carbon (0.05 g), 1N hydrochloric acid (1 1 ml) in a solvent (10 ml) solvent under a hydrogen stream at room temperature for 1 hour.
  • Example 4 (-)-1-3-phenyl-3-[(S) -pyrrolidine-3-yl] -1, 3-dihydroindole-2-one (0.28 g: 1. 0 1 mm 0]), 3— (4-methoxyphenyl) propyl tosylate (0 From 32 g: 1.000 mmo 1), 0.41 g (97% yield) of the title compound was obtained as an oil.
  • Example 4 (1-)-1- (2-pyridyl) —3 -— [(S) -pi-lysine-1-3-yl] —1,3-dihydroindole-1-one (0. 15 g: 0.54 mm o 1), 2— (2,3-dihydrobenzofuran-5-yl) ethyl sylate (0.17 g: 0.54 mm o 1) 0.11 g (yield 47%) was obtained as an amorphous substance.
  • Example 5 (1-)-3-phenyl-1-3-[(S) -pyrrolidine-13-yl] —1,3-dihydroindole-2-one (0.28 g: 1.
  • the title compound was obtained as an oily substance from oil (O l mmo l) and base cloche propionofenone (0.20 g: 1.2 mm o 1) (0.03 g, yield 7%).
  • Example 4 3-Feline 3 — [(S) 1-pyrrolidine — 3 — yl] — 1, 3 — Jihidroindo 1-ru 2-one (0.28 g: 1 0.1 mmo 1) and 2- (4-methoxyphenoxy) ethyl tosylate (0.333 g: 1.0 mmol) yielded 0.26 g (yield 60%) of the title compound as a white crystalline substance. %) Obtained.
  • Example 4 (1-)-3-phenyl-3-[(S) -pyrrolidine-3-yl] 1-1,3-dihydroindole-2-one (0.28 g: 1. 0 1 mm o 1), 0.2-g (yield 54%) of the title compound as a white crystalline substance from 2- (4-methylphenoxy) ethylsilicate (0.31 g: 1.0 mmol) ) Obtained.
  • the compound was obtained as crystalline powder in an amount of 0.05 g (yield: 60%). Melting point: 18.7-2-18.9 ° C
  • Example 24 (1) 1-3-benziru 3 — [(S) 1-pyrrolidin-3-yl] 1-1,3-dihydro 1-ru 2—on (0.05 g: 0 1 8 mm o 1), 2-(2,3-Dihydrobenzofuran 1 -yl) ethyl sylate (0.06 g: 0.19 mm o 1) shows the title compound as pale purple crystalline 0.03 g (yield 45%) was obtained as a powder.
  • Example 4 (1) 1-3-phenyl-2-[(S) -pyrrolidine--3-yl] 1-1,3-dihydroindole-2-one (0.10 g: 0 3 6 mm o 1) and 2- (6-methyl-2-pyridyl) ethyl tosylate (0.11 g: 0.37 mmo l) gave 0.12 g (yield Rate 79%).
  • Example 4 3-Feline 3 — [(S) 1-pyrrolidine 13-yl] 1 1, 3-dihydroindole 1-one (0.07 g: 0.
  • Example 4 (1-)-1-phenyl-3--3-[(S) -pyrrolidine-13-yl] 1-1,3-dihydroindole-12-one (0.13 g: 0. 4 7 mm o 1), 2 — (5-Methylfuran-1-yl) (0.13 g: 0.47 mmol) of the title compound as an oily substance (099 g, 51% yield).
  • Example 4 3-phenyl 3 — [(S) 1-pyrrolidine — 3-yl] — 1, 3-dihydroindole-1-2-one ( ⁇ .14 g: 0 .
  • Example 4 (1) 1-3-Feuniru 3 — [(S) 1-pyrrolidine 13-yl] 1-1,3-dihydroindole-2-one (0.28 g: 1 0 1 mm o 1) 2 — (3 — ditrophenyl) ethyl tosylate (0.32 g: 1.0 mm o 1), 0.32 g (yield) of the title compound as a syrup
  • Example 34 (-)-3-([S) i]. — “2- (3-Aminophenyl) ethyl] pyrrolidine-l- 3-yl] 13-phenyl-2-1.3-dihydroindole One two—on According to Example 16 (1) 13-C (S) 1-111 [2- (3-nitrophenyl) ethyl] pyrrolidine-13-yl] — 3-phenyl-1, 3-di From the hydroindole 2-one (0.08 g: 0.19 mmo 1), 0.05 g (68% yield) of the title compound was obtained as an amorphous substance.
  • Example 34 (1) —3 — [(S) 1-1——2- (3-Aminophenyl) ethyl] pyrrolidine-1-3-yl] -13-phenyl-1,3-dihydrindole-1—
  • a mixture of on (0.05 g: 0.11 mm 01), 30% formalin (0.03 g), 10% palladium on carbon (O.Olg) and methanol (10 ml) The mixture was stirred at room temperature for 1 hour under a hydrogen stream. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, a diluted sodium hydroxide aqueous solution was added to the residue, and the mixture was extracted with chloroform. After drying over potassium carbonate, the mixture was concentrated under reduced pressure to obtain 0.05 g (quantitative yield) of the title compound as an oil.
  • Example 4 (1-) 1-3-phenyl-2-[(S) -pyrrolidine-3-yl]-1,3-dihydroindole-1-ru (0.09 g: 0 3 2 mm o 1), 2- (3,4-dimethylphenyl) ethyl tosylate
  • Example 4 (1-)-3-phenyl-3-([(S) -pyrrolidine-3-yl) -11,3-dihydroindole-2-one (0.09 g: 0. 3 2 mm o 1), 2 - (3- methylphenyl) Echirutoshire Bok (0. 1 0 g: 0. 3 2 mm 0 1) than, 0. 1 1 g of the title compound as an amorphous substance (76% yield).
  • Example 4 13-phenyl-3-([(S) -pyrrolidine-13-yl] -11,3-dihydroindole-2-one (0.08 g: 0.08 g)
  • the title compound was obtained as an amorphous substance from 0.19 g (yield: 29 mm 0 1) and 3- (3-methylphenyl) propyl tosylate (0.09 g: 0.29 mmol). 89%).
  • the reaction solution was poured into ice water, made basic with an aqueous solution of sodium hydroxide, extracted with a pore-form, washed with water and dried over anhydrous sodium sulfate.
  • Ethyl acetate was added to the residue obtained by evaporating the filtrate under reduced pressure, and the precipitated white crystalline substance was collected by filtration, washed with ethyl acetate, and dried to obtain 0.31 g of the title compound.
  • Ethyl acetate (32 ml) was added to the obtained crystalline substance (0.29 g: 0.7 Ommo 1), and the mixture was recrystallized.
  • the precipitated white flocculent crystalline substance was collected by filtration, and then added with ethyl acetate. After washing and drying, 0.16 g (yield 55%) of the title compound was obtained.
  • Example 40 (—) — 3 — [(S) —11- (2-picolyl) pyrrolidine—3-yl] —3-phenyl-1-1,3-dihydroindole-2-one
  • Example 3 According to 9 (1) 1-3-Feluru 3-[(S)-Pyrrolidine-3-yl] 1-1, 3-Jihidroin-1 ru 2-on (0.1 Og: From 0.36 mmo 1) and pyridine 12-aldehyde (0.04 g: 0.36 mmo 1), 0.09 g (yield 66%) of the title compound was obtained as a crystalline powder.
  • Example 4 1 (-) 1-3-[(S)-1-(3-picolyl) pyrrolidine-1-3-yl]-3-feneru 1, 3-dihydroindole 2-one According to 39, (1) 1-3-Feline 3-[(S) 1 -pyrrolidin-1-3-yl]-1, 3-dihydroindole-1-2-one (0.1 Og: 0 36 mmo 1) and pyridine-13-aldehyde (0.04 g: 0.36 mmo 1) gave 0.08 g (61% yield) of the title compound as crystalline powder. .
  • Example 4 2 (—) 1 3 — [(S) 1 1 1 (4 1 picolyl) pyrrolidine 13-yl] 13-Feuniru 1, 3-Dihydroindole-2-one
  • (1) 1-3-Feline 3-[(S) 1 -pyrrolidin-3-yl]-1, 3-dihydroindole 1-2-one (0.10 g: 0. 36 mmo 1) and pyridine 14-aldehyde (0.04 g: 0.36 mmo 1) gave 0.08 g (yield 58%) of the title compound as a crystalline powder. .
  • Example 39 (1) 1-3-phenyl-2-[(S) -pyrrolidin-1-3-yl] 1-1,3-dihydroindole-1-2-on (0.07 g : 0.25 mm 01) and 6-methyl-2-pyridinecarboxyaldehyde (0.03 g: 0.25 mmol) as a white crystalline powder of 0.04 g ( Yield 36%). Melting point: 1 47.5-14.9.3 ° C
  • Example 39 (1) 13-Fenru 3-([(S) -pyrrolidin-3-yl) -11,3-dihydroindole-12-one (0.10 g: 0.36 mm 01) and m-tolualdehyde (0.04 g: 0.36 mm o 1) gave 0.13 g (yield 94%) of the title compound as an oil. .
  • Example 39 (1) 1-3-Fe-Ni-Lu 3 — C (S) 1-pyrrolidine 3-yl] — 1, 3-Jihjirodoruru 2-on (0.10 g: 0.36 mm o 1) and 3-2 mouth Benzaldehyde (0.05 g: 0 0.16 g (yield 90%) of the title compound as an oily substance was obtained from .36 mm o 1).
  • Example 39 (1) 1-3-Feuniru 3-[(S) -pyrrolidin-1--3-yl] —1,3-dihydroindole-2-one (0.09 g : 0.32 mm o 1) and 412 trobenz aldehyde (0.05 g: 0.36 mm 0 1) gave the title compound as an oil in the form of ⁇ .13 g (yield 94 %) Obtained.
  • Example 39 (-)-3-phenyl-3-([(S) -pyrrolidin-3--3-yl] —1,3—dihydroindole-2-one (0.10 g: 0 From 0.16 g o 1) and 5 -methylfurfural (0.04 g: 0.36 mm o 1), 0.11 g (yield 85%) of the title compound was obtained as an oil.
  • Yield 85% 0.11 g (yield 85%) of the title compound was obtained as an oil.
  • Example 39 (1) 13-Feuniru 3 — [(S) 1-pyrrolidin-1 3-yl] — 1, 3, 3-dihydroindole-1-one (0.10 g : 0.36 mmo 1) and 4-methoxy-3-methylbenzaldehyde (0.05 g: 0.36 mmol) to give 0.1 g (yield) of the title compound as a crystalline powder. Rate 67%).
  • Example 50 (—) — 3 — [(S) —1— (4-aminobenzyl) pyrrolidine-1--3-yl] -1-3-phenyl-1,3-dihydroindole-2-one
  • Example 16 (1)-3-[(S)-1-(4-12-trobenzyl) pyrrolidine-1-3-yl]-3-phenylu-1, 3-dihydroindole
  • the title compound was obtained as an amorphous substance in an amount of 0.01 g (yield 13%) from 2-one (0.08 g: 0.14 mmol).
  • Example 39 (1-)-1-3-phenyl-3-([S) -pyrrolidin-3-yl) -11,3-dihydroindole-2-one (0.08 g: 0 2.9 mmo 1) and m-anisaldehyde (0.04 g: 0.29 mmo 1) gave 0.08 g (yield 67%) of the title compound as crystalline powder. . Melting point: 150.8-152.0 ° C
  • reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.
  • Ethyl acetate was added to the residue obtained by concentration under reduced pressure, and the precipitated powdery substance was collected by filtration, washed with ethyl acetate, dried, and dried to obtain a light brown powder. g (yield 18.3%).
  • the occipital region of the Hartle-type guinea pig was beaten, exsanguinated and sacrificed, and the ileum was immediately removed while the mesentery was removed. After thoroughly washing the contents of the ileum, insert a 5 to 7 mm diameter glass rod into the lumen, cut only the longitudinal muscle along the intestinal membrane attachment with a razor, and swab the longitudinal and circular muscle swabs. The longitudinal muscle was peeled off while taking care not to dry the tissue. The sample was incubated at 3 7 ° C, 9 5% 0 2 - 5% C_ ⁇ 2 1 O m 1 organ bath full plus with Krebs carbonate buffer through was suspended in resting tension 1 g, 6 0 There was a stable period of minutes.
  • the contractile response by carbachol using the cumulative method was measured in isotonic than 1 0- 9 M in Oyakehi 3. Samples were washed immediately after the measurement, and a 45-minute stabilization period was allowed until the next contraction reaction. The time point at which EC 5 n of the contraction reaction by carbachol became stable was used as a control. Moreover, the test compound was applied to 1 5 minutes before the force Luba call application, the affinity of the test compound (p A 2), the sill blade method (Arunlakshana, 0. and Schi ld, H. 0.: Bri t J. Pharmacol., 14, 48-58 (1959)). Table 1 shows the results.
  • the occipital region of male guinea pigs was beaten, exsanguinated and sacrificed, and the trachea was excised while resecting the connective tissues. After that, the esophagus and the remaining connective tissue were cut, and the tracheal cartilage was excised at intervals of two to prepare a specimen.
  • the specimens were incubated at 3 7 ° C and 95% ⁇ 2 - 5% C_ ⁇ 2 Indome evening thin U ⁇ M) through the 5 m 1 Magnus bath filled with including Krebs bicarbonate buffer, resting tension 1 After suspension in g, a stabilization period of 60 minutes was allowed.
  • the contraction response to carbachol was measured isometrically at a common ratio of 3 from 10 to 8 M at intervals of 7 minutes using a cumulative method. Promptly samples were washed and after measurement, can you a stable period of the next contraction reaction to 6 0 minutes, EC 5 of the contractile response by carbachol. The point at which was stabilized was taken as control. The test compound was applied 15 minutes before the application of carbachol. The affinity (p A 2 ) of the test compound was determined in the same manner as in the case of the ileum. Table 1 shows the results.
  • the occipital region of the Hawley guinea pig was beaten, exsanguinated and sacrificed. Immediately after the cardiopulmonary extirpation, the lungs, connective tissue, etc. were resected in the order of the ventricles, cut into the left atrium and the right atrium, and used as a specimen. The specimen was incubated at 32 ° C. and suspended at a static tension of 0.5 g in a 1 Oml organ bath filled with Krebs carbonate buffer through 95% ⁇ —5% C ⁇ . After that, contraction by field electrical stimulation (4 Hz, 2 msec, 1.5 ⁇ threshold voltage) was measured.
  • the compounds of the present invention showed very selective antagonistic activity especially times intestine.
  • Table 1 Muscarinic receptor antagonistic activity (in vitro)
  • Control solvent group 75 Test for rat salivation (intravenous administration)
  • the inhibitory rate against the amount of secreted saliva in the control group was determined, and the dose of the test compound that suppressed the amount of secreted saliva in the control group by 50 % was defined as ID51.
  • Table 3 shows the results. Table 3 Effects on salivary secretion induced by 5-year-old xotremorine (in vivo)
  • the compound of the present invention has a strong stress-induced diarrhea inhibitory action. Furthermore, it was clear that the oral effect was weaker than that of the control compound darifenacin. Accordingly, the present invention compounds are useful as muscarinic M 3 receptor antagonists that are alleviated side effects, a disease Mus force phosphoric ⁇ receptors are involved, in particular, irritable bowel syndrome, functional disk Bae Pushia, spasmodic colitis , Central illness such as nausea and vomiting, sickness, and menule disease caused by drug administration, including gastrointestinal diseases such as diverticulitis; urinary diseases such as urinary incontinence and frequent urination; chronic obstructive pulmonary disease, chronic It is suitable for use as a prophylactic or therapeutic agent for respiratory diseases such as bronchitis, asthma, pulmonary fibrosis and rhinitis.

Abstract

Cette invention concerne des composés d'indole, ou leurs sels acceptables sur le plan pharmaceutique, lesquels correspondent à la formule générale (I) où Ar représente un phényle éventuellement substitué. R représente -A-W-B où A représente un alcylène inférieur éventuellement ramifié, W représente oxygène ou ne représente rien, et B représente un phényle éventuellement substitué. R peut encore représenter un alcényle C5-10 éventuellement ramifié, tandis que p est égal à 1, 2 ou 3, que q est égal à 1 ou 2 et que r est égal à 0 ou 1. Grâce à leur antagonisme hautement sélectif à l'encontre des récepteurs de muscarine M3, ces composés peut être utilisés comme agents de prévention ou comme remèdes lors de maladies où les récepteurs de muscarine M3 jouent un rôle.
PCT/JP1998/002291 1997-05-28 1998-05-26 Composes d'indole WO1998054167A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076981A1 (fr) * 1999-06-15 2000-12-21 Neurogen Corporation Lactames benzofuses a substitution piperidinyle et piperazinyle
WO2000072835A3 (fr) * 1999-05-27 2002-03-21 Khoury George F El Application topique d'agents muscariniques et opioides conçus pour traiter les bourdonnements d'oreilles
US7071224B2 (en) 2004-03-11 2006-07-04 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
WO2006136606A2 (fr) * 2005-06-24 2006-12-28 F. Hoffmann-La Roche Ag Derives d'oxindole
US7183292B2 (en) 2003-06-13 2007-02-27 Theravance, Inc. Substituted pyrrolidine and related compounds
US7250414B2 (en) 2004-03-11 2007-07-31 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
US7317102B2 (en) 2003-04-01 2008-01-08 Theravance, Inc. Diarylmethyl and related compounds
US8088815B2 (en) 2009-12-02 2012-01-03 Hoffman-La Roche Inc. Spiroindolinone pyrrolidines
US8217044B2 (en) 2010-04-28 2012-07-10 Hoffmann-La Roche Inc. Spiroindolinone pyrrolidines
US8288431B2 (en) 2010-02-17 2012-10-16 Hoffmann-La Roche Inc. Substituted spiroindolinones
US10899738B2 (en) 2016-05-02 2021-01-26 The Regents Of The University Of Michigan Piperidines as menin inhibitors
US11045448B2 (en) 2017-03-31 2021-06-29 The Regents Of The University Of Michigan Piperidines as covalent menin inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021820A1 (fr) * 1994-02-10 1995-08-17 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive du carbamate et composition correspondante
JPH07258250A (ja) * 1994-03-25 1995-10-09 Yamanouchi Pharmaceut Co Ltd エステル誘導体
JPH07291936A (ja) * 1994-03-01 1995-11-07 Kyorin Pharmaceut Co Ltd 新規イミダゾール誘導体及びその製造法
JPH0920758A (ja) * 1995-07-06 1997-01-21 Kyorin Pharmaceut Co Ltd 新規環状ジアミン誘導体及びその製造法
JPH0920759A (ja) * 1995-07-06 1997-01-21 Kyorin Pharmaceut Co Ltd 新規環状ジアミン誘導体及びその製造法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021820A1 (fr) * 1994-02-10 1995-08-17 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive du carbamate et composition correspondante
JPH07291936A (ja) * 1994-03-01 1995-11-07 Kyorin Pharmaceut Co Ltd 新規イミダゾール誘導体及びその製造法
JPH07258250A (ja) * 1994-03-25 1995-10-09 Yamanouchi Pharmaceut Co Ltd エステル誘導体
JPH0920758A (ja) * 1995-07-06 1997-01-21 Kyorin Pharmaceut Co Ltd 新規環状ジアミン誘導体及びその製造法
JPH0920759A (ja) * 1995-07-06 1997-01-21 Kyorin Pharmaceut Co Ltd 新規環状ジアミン誘導体及びその製造法

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072835A3 (fr) * 1999-05-27 2002-03-21 Khoury George F El Application topique d'agents muscariniques et opioides conçus pour traiter les bourdonnements d'oreilles
WO2000076981A1 (fr) * 1999-06-15 2000-12-21 Neurogen Corporation Lactames benzofuses a substitution piperidinyle et piperazinyle
US7317102B2 (en) 2003-04-01 2008-01-08 Theravance, Inc. Diarylmethyl and related compounds
US8008278B2 (en) 2003-04-01 2011-08-30 Theravance, Inc. Diarylmethyl and related compounds
US7829728B2 (en) 2003-04-01 2010-11-09 Theravance, Inc. Diarymethyl and related compounds
US7351718B2 (en) 2003-06-13 2008-04-01 Theravance, Inc. Substituted pyrrolidine and related compounds
US7638639B2 (en) 2003-06-13 2009-12-29 Theravance, Inc. Substituted pyrrolidine and related compounds
US7183292B2 (en) 2003-06-13 2007-02-27 Theravance, Inc. Substituted pyrrolidine and related compounds
US7351717B2 (en) 2003-06-13 2008-04-01 Theravance, Inc. Substituted pyrrolidine and related compounds
US7615566B2 (en) 2003-06-13 2009-11-10 Theravance, Inc. Substituted pyrrolidine and related compounds
US7071224B2 (en) 2004-03-11 2006-07-04 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
US7250414B2 (en) 2004-03-11 2007-07-31 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
US7208515B2 (en) 2004-03-11 2007-04-24 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
US7557126B2 (en) 2004-03-11 2009-07-07 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
US7151115B2 (en) 2004-03-11 2006-12-19 Theravance, Inc. Diphenylmethyl compounds useful as muscarinic receptor antagonists
WO2006136606A2 (fr) * 2005-06-24 2006-12-28 F. Hoffmann-La Roche Ag Derives d'oxindole
US7576082B2 (en) 2005-06-24 2009-08-18 Hoffman-La Roche Inc. Oxindole derivatives
WO2006136606A3 (fr) * 2005-06-24 2007-04-26 Hoffmann La Roche Derives d'oxindole
US8088815B2 (en) 2009-12-02 2012-01-03 Hoffman-La Roche Inc. Spiroindolinone pyrrolidines
US8288431B2 (en) 2010-02-17 2012-10-16 Hoffmann-La Roche Inc. Substituted spiroindolinones
US8217044B2 (en) 2010-04-28 2012-07-10 Hoffmann-La Roche Inc. Spiroindolinone pyrrolidines
US10899738B2 (en) 2016-05-02 2021-01-26 The Regents Of The University Of Michigan Piperidines as menin inhibitors
US11045448B2 (en) 2017-03-31 2021-06-29 The Regents Of The University Of Michigan Piperidines as covalent menin inhibitors

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