WO2004069828A1 - Compose a base de piperidine et ses applications medicinales - Google Patents

Compose a base de piperidine et ses applications medicinales Download PDF

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Publication number
WO2004069828A1
WO2004069828A1 PCT/JP2004/001114 JP2004001114W WO2004069828A1 WO 2004069828 A1 WO2004069828 A1 WO 2004069828A1 JP 2004001114 W JP2004001114 W JP 2004001114W WO 2004069828 A1 WO2004069828 A1 WO 2004069828A1
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title compound
methyl
piperidine
benzo
bipiperidinyl
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PCT/JP2004/001114
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English (en)
Japanese (ja)
Inventor
Shinichiro Ono
Seiji Hamaguchi
Hideki Horiuchi
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Mitsubishi Pharma Corporation
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Priority to JP2005504851A priority Critical patent/JPWO2004069828A1/ja
Publication of WO2004069828A1 publication Critical patent/WO2004069828A1/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
    • C07D401/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel pyridin compound having an action of stimulating muscarinic acetylcholine receptor M4, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • M4 receptor is involved in memory-improving effects (Neuroreport, 1998, 9 (7), 1407-: 11) and is involved in physiological effects such as schizophrenia (Journal of Pharmacology & Experimental Therapeutics, 1997, 283 (2), 750-756 and Life Sciences, 1999, 64 (6-7), 527-534) Therefore, a compound having an action of stimulating the M4 receptor can be used as a therapeutic drug for schizophrenia (schizophrenia) and the like.
  • Compounds having an action of stimulating M4 receptor include 7-oxo-12-azabicyclo [2,2,1] heptane compounds (see International Publication No. 00/75140) , New heterocycline scarygonists (see WO 01/833472), new substituted imidazolidinone derivatives (see WO 01/27104), Indane derivatives (see WO 97/25983) and the like are known. However, these compounds are not always satisfactory in terms of side effects Ming disclosure
  • An object of the present invention is to provide a compound exhibiting the action of stimulating muscle acetylacetylcholine receptor M4, a pharmaceutical composition containing the same, and a therapeutic agent for schizophrenia.
  • the present inventors have conducted various studies in order to solve the above-mentioned problems. As a result, a pyridin compound having a specific structure has been described as a mucin-potential acetylcholine receptor M4. The present inventors have found that they have a stimulating action and that almost no side effects appear when this pyridin compound is administered, and thus the present invention has been completed.
  • the gist of the present invention is as follows.
  • R 1 , R 2 , R 3 and R 4 are the same or different and are hydrogen or halogen, lower alkyl, aranolekyl, lower alkyl, hydroxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy).
  • G indicates carbon or nitrogen.
  • J represents carbon or nitrogen, which is hydrogen or halogen, lower alkyl, halogen-substituted lower alkyl, lower alkenyl, lower acyl, hydroxy, lower alkoxy, lower alkylamino, Di-lower alkylamino, lower alkylthio, lower alkynolesulfur, lower alkylsulfonyl, lower alkoxy It may have a substituent selected from the group consisting of shikanoleponyl, lipamoyl, lower alkyl carbamoyl, di-lower alkyl rubamoyl and cyano.
  • L represents carbon, nitrogen, oxygen or sulfur.
  • L is carbon or nitrogen
  • L is hydrogen or halogen, lower alkyl, lower acyl, lower alkenyl, hydroxy, lower alkoxy, lower alkylamino, di-lower alkylamino
  • Z is hydrogen, lower alkynoles, alkenylsulfonyl, cycloalkenylsulfonyl, heterocyclic sulfonyl, lower acetyl, lower alkanolsulfonyl, low alkenylsulfonyl, zinc
  • a lipstick or a lower lipocanolepamoyl a lipstick, a lipstick or a hetero is indicated on the ring. Do not have a password, mouth, mouth, lower, lower alkoxy or cyano
  • a, b and C each independently represent 0, 1 or 2
  • a bond represented by a dotted line and a solid line indicates a single bond or a double bond.
  • a condensed ring consisting of a ring consisting of G, J and L and a benzene ring is represented by indazole, benzoimidazolone, benzo [b] furan, benzo [b] thiophene, A benzo [d] isoxazole, benzo [d] isothiazole or indole, or a pharmacologically active compound thereof according to the above (1). Acceptable salt.
  • a condensed ring consisting of a ring consisting of G, J and L and a benzene ring is an indazole, benzo [b] furan, benzo [b] thiophene, benzo [d] isoxane
  • a pharmaceutical composition comprising the piperidine compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (7).
  • R 1 , R 2 , R 3 and R 4 may be the same or different and are hydrogen or halogen, lower alkyl, arano quinole, lower anoreqenyl, hydroxy, lower alkoxy, amimino.
  • G represents carbon or nitrogen.
  • J represents carbon or nitrogen, which is hydrogen or halogen lower alkyl, halogen-substituted lower alkyl, lower alkoxy, lower acyl, hydroxy, lower alkoxy, lower alkoxy, lower alkyl, A group consisting of lower alkylamino, lower alkylthio, lower alkylsulfone, lower alkylsnorefonyl, lower alkoxysilica noreponyl, dilupamoyl, lower alkynorepyrpamoyl, di-lower alkyl dilupamoyl and cyano. It may have a substituent selected.
  • L represents carbon, nitrogen, oxygen or sulfur.
  • L is hydrogen or halogen ⁇ lower alkyl, lower acyl, lower alkenyl, hydroxy, lower alkoxy, lower alkylamino, di-lower alkylamino Or a substituent selected from the group consisting of lower alkylthio, lower alkylsulfinyl, lower alkynolesphenol, lower alkoxycarbonyl and cyano, or having these substituents on the ring.
  • a 0, 1 or 2.
  • FIG. 1 is a graph comparing the spasm, tremor and salivation effects of the piperidine compound of the present invention with those of a known piperidine compound.
  • Geneogen means fluorine, chlorine, bromine or iodine.
  • lower alkyl means a straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopyl pill, butyl, isobutynole, sec— Butinole, tert-butyl, pentyl, 1,1-dimethylpropyl and 1,2,2-trimethylpropyl.
  • Alkyl means a group in which the above-mentioned lower alkyl is substituted by an aryl, for example, benzyl, phenylethyl , Fermented mouth, pill, naphthyl methyl, etc.
  • ⁇ Lower alkyl J refers to a linear or branched alcohol having 26 ash, for example, vinyl, 1-open-mouth, 2-open-mouth, Butanol, 1-butenyl, 2-butenyl and 3-butenyl, etc.
  • ⁇ Lower alkyl J means an alkoxy having a lower alkyl, such as ⁇ methoxy, ethoxy, propoxy, isopoxy and butoxy.
  • JLower Jarki is a J, which means that the lower Jarki is a monument that was placed in the lower Jarki, and exemptions include, but are not limited to, Methyla Mino, Echil ⁇ a ⁇ no, Pupira, ⁇ , ⁇ , Suppila And putila, etc.
  • lower-alkyl refers to the amino placed by lower-alkyl, for example, dimethylamino, getylamino, zipiraminino, jisopiraminino, and so on. Etilme chilua, heno, etc.
  • the lower cyclic ring J may have oxygen, sulfur, or nitrogen in the lower ring, and may have lower ring on the ring.
  • a cyclic amine having 2 to 10 carbon atoms examples thereof include pyridine, pyridino, monoreholino, pyrazino, and 4-methylpyrazino.
  • lower alkirchio refers to alkirchio having lower aralkyl and includes, for example, methylthio, ethylthio, pipiruchi and isopirchio.
  • ⁇ Lower alkylsulfinyl J means an alkylsulfinyl having a lower alkynole, such as methylsulfinyl, ethylsulfinyl, pupilsnorefininole, and non-pillusulfinyl.
  • Be ⁇ Lower alkirnosulfonyl J refers to alkylsulfonyl having a lower alkyl, for example, X., methinolesnorehonyl, ethylsulfonyl, propylsulfonyl and isophi.
  • lower alkyl J means a group in which a lower gene is substituted with nitrogen, for example, trifluomethyl methyl, difluomethyl, and 2,22-yfluomethyl. Etc.
  • acyl J means an acyl having lower alkyl, that is, a straight or branched asinole having 27 ash ropes, for example, 'acetinole., Propio; Petitil, isobutyryl, norrelyl and isoparrelyl
  • ⁇ Lower alkoxy resin J refers to an alkoxy resin having the above-mentioned lower alkoxy, and includes, for example, ⁇ mexyloxy resin, Positive power bottles, dispensers, etc.
  • ⁇ Lower level killer power J is a breath of power that has been placed by lower level killer.
  • methyl power lower power peter power lower, power lower power, And lip-powered Nolmoyl and butyl-powered Renomoyl.
  • Lower arkir power Lupamoyl J refers to the lower power arkyl dipyrmoyl, such as dimethyl power Reno S-moles, getyl power norepa-moles, zip-up pill-power pill-powers, jisop. Mouth pill power lupamoir and etilmethyl power renomoir can be fisted
  • the library J is composed of a circle, a lower alkyl, a lower alkyl, a lower alcohol, a lower alkyl, a lower alkyl, a lower alkyl, and a lower alkyl. And phenyl, naphthyl, etc., which have a group selected from the group consisting of phenyl and lower dialkylamino.
  • cycloalkyl refers to cyclic nitrogen, lower alkyl, lower alcohol, lower alkoxy, lower alkylano, and lower alkyl.
  • Hetero ring means an aromatic hetero ring, a saturated hetero ring or
  • Aromatic heteroj means a 5-6 shell or fused aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. And, for example, franc, pi-n-norre, pyrazol-thiophene, thiazole, imidazole,
  • Saturated tetrahydrofuran J refers to a 5-6 shell mono- or condensed saturated heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, for example, Traffic, mouth flank,
  • Unsaturated heterocyclic ring J is a monocyclic ring of 5 to 6 shells containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, or a fused unsaturated heterocyclic ring.
  • Means for example, Jihide, Franc,
  • the condensed ring consisting of a ring consisting of G, J and L and a benzene ring includes, but is not limited to, benzobenzene, benzo [b] furan and benzo [b] thiophen. , Benzo [d] isoxazole, benzo [d] thiazole or indole, and then, benzo [b] franc, benzo [b] ] Thiophene, benzo [d] isoxazole or indole, especially indole, benzo or benzothiophene
  • the substituents that may be present in J are lower-alkyl radicals, lower-alkenyl-substituted lower alkyls, lower acyls, lower phenols, lower phenols, lower phenols, lower phenols, and lower phenols. Preference is preferred.
  • the substituents may be lower alkyl, lower acyl, lower alkoxy, lower alcohol, or lower hydroxyl.
  • ⁇ Is preferably lower anolesquinolesulfonyl, or may have a substituent, preferably arylsulfonyl, heterocyclic sulfonyl or arylsulfonyl.
  • Z is preferably lower alkoxy, lower alkyl, sulfonyl, arylsulfonyl, or heterocyclic ring snorrefonyl.
  • 1 is preferable for a, 0 is preferable for b, and 1 is preferable for c.
  • Examples of pharmacologically acceptable salts of the piperidine compound represented by the general formula (1) include, for example, salts of inorganic acids such as hydrochloric acid and nitric acid; Acid addition salts such as acids; sulfonic acid addition salts such as methansulfonate and tonolenesulfon;
  • the isomers (for example, geometric isomers) can be added to the piperidine compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
  • the piperidine compound represented by the general formula (1) can be produced by various methods including the production methods 1 to 4 described below. Manufacturing method 1
  • the compound in which b is 0 can be produced by the method shown in the following formula.
  • Examples of the compound hydrogen compound include triacetoxy hydrogen sodium boron, cyano borohydride sodium, hydrogen borohydride, and the like. And hydrogenated lithium hydride, lithium hydride aluminum, and the like. Of these, preferred is hydrogenated sodium borohydride.
  • Examples of the catalytic reduction catalyst include palladium monocarbon and Raney nickel catalyst. Depending on the compound of the general formula (2) or the general formula (3) to be used for the reaction, the complex hydrogen compound and the catalytic reduction catalyst may be appropriately used. The type and amount used can be determined.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction.
  • N, N-dimethylformamide (DMF), N, N-dimethylformacetamide (DMA), dimethylsulfoxide N, N-dimethylformamide (DMF), N, N-dimethylformacetamide (DMA), dimethylsulfoxide
  • reaction im and the reaction time may be appropriately determined according to the compound to be subjected to the reaction and the reaction solvent. Usually, about 1 78 to 10
  • the reaction may be performed at 0 ° C for several tens of minutes to 5 days.
  • the compound represented by the general formula (1) can be obtained by performing a usual treatment.
  • the compound having b force s1 or 2 can be produced by the method shown in the following formula.
  • Q is, for example, chlorine, bromine or iodine; meth- ance norehoninore, ethanes norehoninore, or vennce norehoninore, etc.
  • Examples of the base include, for example, ethylamine, disopropylethylamine, pyridine, and organic salts such as 4 —dimethylethyl, nobilizine;
  • Examples of bases include sodium, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, etc., and the base is selected from the compounds represented by the general formulas (2) and (5) used in the reaction. The type and amount may be determined as appropriate. Usually, 1 mol or excess, preferably 1 mol, or 10 mol of a base is used per 1 mol of the compound of the formula (2).
  • the reaction solvent is not limited as long as it does not inhibit the reaction.
  • DMF, DMA, DMS; O pyridine, dioxane,
  • the reaction temperature and reaction time may be appropriately determined depending on the compound to be subjected to the reaction and the reaction solvent. Usually about -78 to 100. In c, let it react for several tens of liters to 24 hours.
  • the compound to be subjected to the reaction may be an amino compound.
  • the reactive functional group When there is a reactive functional group that inhibits a reaction such as hydroxy, the reactive functional group may be protected before the reaction.
  • protecting groups for primary or secondary amino include, for example, benzinole, ⁇ -co-mouth benzyl, m-trif-norreolo-methino-lebenzinole, ⁇ -phenylethyl, benzhydryl and tol.
  • Replacement benzoinole such as lytyl; aliphatic ash such as horminore, acetinole, propionole, butylinole, norrelyl, hexanoyl and piperoyl; Halogen-substituted aliphatic acyls such as mouth acetylenole and trifnorolelo acetylenol; aromatic acylones which may have a substituent such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl; Phenyl acetyl, 3- phenylpropioninole, 3- ( ⁇ -methoxyphenyl) propionyl, 3— ( ⁇ —cloth phenyl) pro
  • aralkyl acyls such as onyl; having substituents such as ceryl acetyl, imidazolyl acetyl, furinole
  • penzinoleoxycanolevonyl methylsolenorhinol such as pentoinoleoxycarbonyl, p_methoxybenzyloxyl-norrebonyl, etinoles / levoninole, propinolesulfonyl, pentylsulfonyl, etc.
  • Examples of the protecting groups for the hydr and hydroxyl groups include, for example, tert-butyldimethyl phenol, tert-butyltin phenyl phenol, methyl sulfide, etc .; Caulking chill, 2-main preparative Kishe preparative Kishime chill like Anoreko Kishime Chi le 5 Bae Njiru, P Ichime preparative shore Njiru, 2 3 - dimethyl carboxymethyl base Njiru, 1 0 -.
  • the piperidine compound represented by the general formula (1) produced by the above-mentioned method can be produced by a conventional production method, for example, concentration, extraction chromatography, reprecipitation, recrystallization, etc. By performing the above-mentioned means, it is possible to purify to an arbitrary purity. In addition, if necessary, conventional salt-forming means may be applied to obtain a pharmacologically acceptable salt.
  • a pharmacologically and pharmaceutically acceptable additive is added to or removed from the piperidine compound or a pharmaceutically acceptable salt thereof according to the present invention, and tablets, capsules, granules, fine granules, Pharmaceutical compositions containing a piperidine compound or a pharmacologically acceptable salt thereof can be produced by preparing a preparation known to those skilled in the art, such as a powder or an injection.
  • compositions include, for example, sucrose,? Excipients such as sucrose, D-mannitol, starch or tl-cellulose;
  • Disintegrants or tobaccos such as T-starch or lipoxime tylsenorate, etc .; auxiliaries; hydr, xypi pinoresenolace, lip mouth pilme cilme tylsenolose, poV vinolepiride, n Or binders such as gelatin; lubricating agents such as magnesium stearate or talc; copper such as porcine K mouth xip mouth pilmethyl cell ⁇ -isocyanate, sucrose, polyethylene glycol or titanium oxide; Coating agent; cellulose, liquid paraffin, polyethylene, gelatin, porin, glycerin, purified water or Base such as hardfax; solubilizer or solubilizer that can prepare aqueous or ready-to-use injections such as distilled water for injection, physiological saline or propylene glycol Sugar, sodium chloride, V-cum, D—A tonicity agent such as mannitol or glycerin? C, P, such as organic acid
  • H regulator dye H regulator dye; diluent; stabilizer; propellant and adhesive. It is desirable to manufacture a pharmaceutical composition such that the piperidine compound represented by the general formula (1) or a pharmacologically acceptable salt thereof is contained in an amount of about 1 to 500 mg. I like it
  • the administration method of the pharmaceutical composition may be oral administration or parenteral administration, and the dose may be determined as appropriate in consideration of the patient's age, weight, and symptoms.
  • parenteral administration usually 0.01 to 100 mg / kg, preferably 0 • 1 to 1 mg / kg, of the pyridine compound or its pharmacologically per day is administered.
  • Also in the case of oral administration, 1 or more, usually 0.5 to 10 mg / kg, preferably 1 to 5 mg / kg of a piperidine compound or its pharmacologically Administer an acceptable salt.
  • the pharmaceutical composition may be administered alone or as a mixture with another doctor.
  • the compound of- was dissolved in 20 mL of chloroform, 10 mL of 4N hydrogen chloride dioxane was added, and the mixture was stirred for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and water was added to make an aqueous solution.
  • the aqueous solution of o was washed with ethyl acetate, then potassium oxalate was added to make it alkaline, and the solution was extracted with a black hole honolem. did.
  • the extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • This compound was dissolved in 20 mL of concentrated hydrochloric acid and 20 mL of acetic acid.
  • the extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • To the residue obtained by concentrating the ethyl acetate solution were added 45 mL of quinoline and 2.5 g of copper powder, and the mixture was stirred at 200 ° C for 1 hour. After the reaction solution was filtered through celite, chloroform was added to form a chloroform solution.
  • the black-mouthed form solution was washed successively with 3N hydrochloric acid, water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by concentrating the form solution is purified by silica gel chromatography (hexane / ethyl acetate) and [4— (5—c ]----------------------------------------------------------------------------------------------------------------------------------------------------------------
  • This compound was dissolved in 25 mL of concentrated hydrochloric acid and 25 mL of acetic acid.
  • This compound was hydrolyzed using concentrated hydrochloric acid and acetic acid in the same manner as in Production Example 3 to obtain 10 g of the title compound.
  • This mesyl form is mixed with 223 mL of xylene, 4.6 mL of methylhydrazine and 8.4 g of ammonium acetate are added, and the mixture is heated at 135 ° C for 2.5 days. Stirred. After cooling, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the ethyl acetate solution is purified by gel chromatography.
  • reaction solution was poured into a saturated aqueous solution of ammonium chloride to form an aqueous solution, and the aqueous solution was extracted with ethyl acetate.
  • the extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by concentrating the ethyl acetate was added with 200 mL of ethanol and 20 mL of water. 0 mL and 5 g of sodium hydroxide were added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and water was added to the obtained residue to form an aqueous solution.
  • the aqueous solution was washed with ethyl acetate, acidified by adding dilute hydrochloric acid, and extracted with black-mouthed form.
  • the extract was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the form solution in the mouth was concentrated to obtain 8.03 g of carboxylic acid.
  • This compound was heated and refluxed in 25 mL of concentrated hydrochloric acid and 25 mL of acetic acid for 18 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, water was added to the obtained residue to make an aqueous solution, and the mixture was extracted with a porcine. The extract was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The form solution was concentrated to give the title compound (1.30 g).
  • Example 15 4 (6 — Fluoro-21-methinolecanolenomoylbenzo [b] thiophene 1 3 -yl) _ [1, 4,] Bipiperidinyl-1, Methinole fumarate
  • Example 6 Fluoro-3 — (piperidine_4-yl) — 1 H-Indazole instead of 4-(6 — Fluoro-2 — methyl power lupamoyl benzo [b] thiophene 1 — 3-yl)
  • the procedure of Example 1 was repeated, except that benzene was used, to obtain a title compound of the title compound. According to the method, this was always converted into a fumarate to give the title compound as a white solid.
  • Example 20 A free form of the title compound was obtained according to Example 20 using propionyl chloride in place of acetyl chloride. This was converted to oxalate by a conventional method to give the title compound as a pale yellow solid.
  • Example 1 was replaced with petitil-mouthed lid instead of acetyl chloride.
  • a free form of the title compound was obtained according to 20. This was converted to an oxalate by a conventional method to give the title compound as a pale yellow solid.
  • the title compound was obtained as a pale-yellow oil according to Example 20 using octaethyl carbonate instead of acetyl chloride.
  • the title compound was obtained as a pale yellow oil according to Example 20 using propyl carbonate in place of acetyl chloride.
  • Example 1 was replaced by chlorophenyl carbonate instead of acetyl chloride.
  • the title compound was obtained as a pale yellow solid according to 20.
  • the title compound was obtained as a white solid in the same manner as in Example 20 except that ethane sulfoyluclide was used instead of acetyl chloride.
  • a free form of the compound was obtained. This can be converted to oxalic acid by a conventional method.
  • the title compound was obtained as a pale yellow solid by converting it into a salt.
  • Example 4 1 4 1- (1-, 4-,)-Bipiperidinyl- 1 'one-methyl rubonate' fumarate 6 — Fluoro_3 — (piperidine 1 4 —Indole) 1 1H—Indonezolone 1-benzene (4-piperidine—4-yl) Indole was used in the same manner as in Example 1 except that indole was used instead of indole. A compound solid was obtained. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • Example 2 The procedure of Example 1 was repeated, except that methyl ethyl carbonate was used instead of methyl methyl carbonate to obtain a complete compound of the title compound. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • a free form of the title compound was obtained in the same manner as in Example 1, except that phenylmethyl carbonate was used in place of methylphenylcarbonate. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • the free form of the title compound was prepared in the same manner as in Example 1 except that benzenesulfoeric chloride was used instead of methyl carbonate. Got. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • ⁇ Silica gel force is applied to silica gel.
  • the title compound was obtained as a white solid according to Example 1 using ethyl ethyl carbonate.
  • the toluene solution was concentrated and concentrated to 41 m (4-diphenylmethylen-a, no-11-methylindole-13-yl) [1,4 '] bipiridinyl-1
  • Ethyl was purified by silica gel gel granule (chloro ⁇ -form / methanol), which was added to ⁇ HF 400 m1 and 6N hydrochloric acid 2 ⁇ 0 ml was added and the mixture was stirred for 1 hour according to the room dish. Next, the reaction solution was poured into water, and a mixture of ethyl acetate and hexane was used.
  • the toluene solution was heated and stirred overnight at 85 ° C. under a nitrogen atmosphere in substantially the same manner as in Example 11 except that morpholine was used instead of benzofuenominin. After cooling, the reaction solution was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. Residue obtained by concentrating the toluene solution is applied to gel gel Purification by chromatography (form-form / methanol) gave the free form of the title compound. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • Example 1 1 7 4 1 [4 1 (1 _ methylindol 3-yl) azepan 1 1 yl] piperidin 1 1-ethyl carboxylate fumarate 6-funoreolol 3-(pipet Resin-14-inole)
  • 1-H-indazole was replaced with 3-azepan-14-ylindole and kuroguchi methyl carbonate was used instead of black methyl carbonate.
  • a free form of the title compound was obtained. This was converted to a fumarate by a conventional method to give the title compound as a white solid.
  • Tables 11 to 14 among the typical examples of the compounds included in the present invention, those in which the condensed compound is an indazole are shown in Tables 11 to 14.
  • Table 2 shows the benzo [1)] furan
  • Table 4 shows the benzo [b] thiophene
  • Table 4 shows the benzo [d] isoxazole.
  • Table 5 shows the benzo
  • Table 6 shows the results obtained by using the method and Tables 7-1 to 7-8 show the results obtained by using the inodes.
  • the compound of No. 24 is not a [1,4 '] bipiperazine compound, but is shown in Table 4 for convenience.
  • Table 5 The compound of No. 24 is not a [1,4 '] bipiperazine compound, but is shown in Table 4 for convenience. Table 5

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Abstract

L'invention concerne un composé à base de pipéridine représenté par la formule générale (1) ou un de ses sels de qualité pharmaceutique ; une composition médicinale contenant ce composé ou ce sel ; et un agent thérapeutique destiné au traitement de la schizophrénie, utilisant ce composé ou ce sel comme un ingrédient actif.
PCT/JP2004/001114 2003-02-04 2004-02-04 Compose a base de piperidine et ses applications medicinales WO2004069828A1 (fr)

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WO2005117883A1 (fr) * 2004-05-28 2005-12-15 Vertex Pharmaceuticals Incorporated Modulateurs de récepteurs muscariniques
WO2007142583A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes des récepteurs muscariniques qui sont efficaces dans le traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
WO2007142585A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes du récepteur muscarinique convenant au traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
JP2008037850A (ja) * 2006-08-10 2008-02-21 Mitsubishi Tanabe Pharma Corp 新規置換ピペリジン誘導体
US7482461B2 (en) 2006-04-05 2009-01-27 Wyeth Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands
US7696229B2 (en) 2006-02-17 2010-04-13 Memory Pharmaceuticals Corporation Compounds having 5-HT6 receptor affinity
US8119661B2 (en) 2007-09-11 2012-02-21 Astrazeneca Ab Piperidine derivatives and their use as muscarinic receptor modulators
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
WO2014038623A1 (fr) * 2012-09-07 2014-03-13 大日本住友製薬株式会社 Dérivé 3-(4-pipéridyl)-indazole
WO2014102594A2 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine de type benzimidazole substitué et leurs utilisations
WO2014122474A1 (fr) * 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Carboxylates de pipéridin-1-yle et d'azépin-1-yle à titre d'agonistes du récepteur muscarinique m4
CN104211635A (zh) * 2013-06-03 2014-12-17 中国科学院上海药物研究所 一类哌啶类化合物及其制备方法、药物组合物和用途
EP3044218A4 (fr) * 2013-09-10 2017-02-22 Board Of Regents Of the University Of Texas System Thérapie ciblant des protéines polypose adénomateuse familiale (apc) tronquées
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US11834407B2 (en) 2016-10-14 2023-12-05 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
US11999745B2 (en) 2020-12-18 2024-06-04 Heptares Therapeutics Limited Pharmaceutical compounds
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists

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US4196209A (en) * 1976-08-26 1980-04-01 Roussel Uclaf Treating psychic disorders with piperidyl-indoles
US4232031A (en) * 1978-12-22 1980-11-04 Roussel Uclaf Process for preparation of piperidyl-indoles
EP0135781A1 (fr) * 1983-08-22 1985-04-03 Hoechst-Roussel Pharmaceuticals Incorporated (Pipéridinyl)-3 et (pyrrolidinyl)-3-1H-indazoles, procédé pour leur préparation et leur application en tant que médicaments
EP0357134A1 (fr) * 1988-09-02 1990-03-07 Janssen Pharmaceutica N.V. Dérivés de 3-pipéridinyl-indazole antihypertensifs
JPH03264583A (ja) * 1990-03-14 1991-11-25 Dai Ichi Seiyaku Co Ltd ピペリジン誘導体及びその製造中間体
JPH05255308A (ja) * 1992-03-11 1993-10-05 Ajinomoto Co Inc ピペリジン誘導体
WO1995011680A1 (fr) * 1993-10-28 1995-05-04 Hoechst-Roussel Pharmaceuticals Inc. Heteroarylpiperidines, pyrrolidines et piperazines et leur utilisation comme antipsychotiques et analgesiques
WO1996013262A1 (fr) * 1994-10-27 1996-05-09 Merck & Co., Inc. Antagonistes de muscarine
EP0722942A1 (fr) * 1995-01-12 1996-07-24 MERCK PATENT GmbH Dérivés d'indole-pipéridines
WO1998038189A1 (fr) * 1997-02-26 1998-09-03 Merck Patent Gmbh Oxazolidinones s'utilisant comme 5-ht2a-antagonistes
WO2000044376A1 (fr) * 1999-01-28 2000-08-03 Bristol-Myers Squibb Company Composes antidepresseurs heterocycliques
WO2000073299A1 (fr) * 1999-06-01 2000-12-07 Smithkline Beecham P.L.C. Composes sulfonamide a activite pharmaceutique
WO2001021590A1 (fr) * 1999-09-22 2001-03-29 Schering Corporation Antagonistes muscariniques
WO2001027104A1 (fr) * 1999-10-13 2001-04-19 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
WO2001083472A1 (fr) * 2000-04-28 2001-11-08 Acadia Pharmaceuticals, Inc. Agonistes muscariniques
WO2002014271A1 (fr) * 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Dérivés de proline et leur utilisation comme médicaments
WO2002062788A1 (fr) * 2001-02-02 2002-08-15 Smithkline Beecham P.L.C. Composes de sulfonamide, preparation et utilisation
WO2002079190A1 (fr) * 2001-03-29 2002-10-10 Smithkline Beecham P.L.C. Indoles substitues en 3eme position servant d'antagonistes de chimiokine

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117883A1 (fr) * 2004-05-28 2005-12-15 Vertex Pharmaceuticals Incorporated Modulateurs de récepteurs muscariniques
US7696229B2 (en) 2006-02-17 2010-04-13 Memory Pharmaceuticals Corporation Compounds having 5-HT6 receptor affinity
US7482461B2 (en) 2006-04-05 2009-01-27 Wyeth Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands
US7956069B2 (en) 2006-06-09 2011-06-07 Astrazeneca Ab Compounds
JP2009539831A (ja) * 2006-06-09 2009-11-19 アストラゼネカ・アクチエボラーグ 疼痛、アルツハイマー病および統合失調症の治療に有効なムスカリン受容体アゴニスト
JP2009539833A (ja) * 2006-06-09 2009-11-19 アストラゼネカ・アクチエボラーグ 疼痛、アルツハイマー病および統合失調症の治療に有効なムスカリン受容体アゴニスト
WO2007142585A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes du récepteur muscarinique convenant au traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
WO2007142583A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes des récepteurs muscariniques qui sont efficaces dans le traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
AU2007256014B2 (en) * 2006-06-09 2011-06-30 Astrazeneca Ab Muscarinic receptor agonists that are effective in the treatment of pain, Alzheimer's disease and schizophrenia
JP2008037850A (ja) * 2006-08-10 2008-02-21 Mitsubishi Tanabe Pharma Corp 新規置換ピペリジン誘導体
US8119661B2 (en) 2007-09-11 2012-02-21 Astrazeneca Ab Piperidine derivatives and their use as muscarinic receptor modulators
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
WO2014038623A1 (fr) * 2012-09-07 2014-03-13 大日本住友製薬株式会社 Dérivé 3-(4-pipéridyl)-indazole
WO2014102594A2 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine de type benzimidazole substitué et leurs utilisations
US9598411B2 (en) 2012-12-27 2017-03-21 Purdue Pharma L.P. Substituted benzimidazole-type piperidine compounds and uses thereof
US9090618B2 (en) 2012-12-27 2015-07-28 Purdue Pharma L.P. Substituted benzimidazole-type piperidine compounds and uses thereof
WO2014122474A1 (fr) * 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Carboxylates de pipéridin-1-yle et d'azépin-1-yle à titre d'agonistes du récepteur muscarinique m4
US9593106B2 (en) 2013-02-07 2017-03-14 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
JP2016507548A (ja) * 2013-02-07 2016-03-10 武田薬品工業株式会社 ムスカリンｍ４受容体アゴニストとしてのピペリジン−１−イル及びアゼピン−１−イルカルボキシレート
US10030012B2 (en) 2013-02-07 2018-07-24 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
CN104211635A (zh) * 2013-06-03 2014-12-17 中国科学院上海药物研究所 一类哌啶类化合物及其制备方法、药物组合物和用途
EP3044218A4 (fr) * 2013-09-10 2017-02-22 Board Of Regents Of the University Of Texas System Thérapie ciblant des protéines polypose adénomateuse familiale (apc) tronquées
US10577344B2 (en) 2013-09-10 2020-03-03 The Board Of Regents Of The University Of Texas System Therapeutics targeting truncated adenomatous polyposis coli (APC) proteins
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists
US11834407B2 (en) 2016-10-14 2023-12-05 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
US11999745B2 (en) 2020-12-18 2024-06-04 Heptares Therapeutics Limited Pharmaceutical compounds

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