WO1994025427A1 - Derives d'ethanolamine utilises pour le traitement de troubles gastro-intestinaux - Google Patents

Derives d'ethanolamine utilises pour le traitement de troubles gastro-intestinaux Download PDF

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Publication number
WO1994025427A1
WO1994025427A1 PCT/JP1994/000671 JP9400671W WO9425427A1 WO 1994025427 A1 WO1994025427 A1 WO 1994025427A1 JP 9400671 W JP9400671 W JP 9400671W WO 9425427 A1 WO9425427 A1 WO 9425427A1
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Prior art keywords
compound
salt
formula
bis
substituted
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PCT/JP1994/000671
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English (en)
Inventor
Youichi Shiokawa
Kiyoshi Taniguchi
Masanobu Nagano
Kazuhiko Take
Takeshi Kato
Kazunori Tsubaki
Seiichiro Tabuchi
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from GB939308618A external-priority patent/GB9308618D0/en
Priority claimed from GB939322238A external-priority patent/GB9322238D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP6524095A priority Critical patent/JPH08509491A/ja
Priority to AU65812/94A priority patent/AU6581294A/en
Publication of WO1994025427A1 publication Critical patent/WO1994025427A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • Some ethanolamine derivatives having spasmolytic activity and relaxing activity on smooth muscle contraction have been known as described, for example, in European Patent Application Publication Nos. 0 211 721, 0 255 415 and 0 383 686, and International Publication Nos. WO 92/18461 and WO 93/15041.
  • This invention relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said ethanolamine derivatives and pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said ethanolamine derivatives and pharmaceutically acceptable salts thereof.
  • R is aryl, ar ⁇ loxy(lower)alkyl or a heterocyclic group, each of which may be substituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo(lower)alkoxy, nitro, cyano, amino and acylamino,
  • R is hydrogen or an N-protective group
  • R " is lower alkoxy substituted with acyl
  • R is lower alkoxy substituted with acyl
  • A is lower alkylene
  • the object compound [I] or its salt can be prepared by the following processes.
  • R 2 i.s an N-protective group
  • R a 3 is lower alkoxy substituted with esterified carboxy
  • Ra is lloowweerr aallJkoxy substituted with esterified carboxy
  • R is lower alkoxy substituted with carboxy
  • R 5 is lower alkyl substituted with acyl
  • x is acid residue.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • halo(lower)alkoxy may be fluorine, chlorine, bromine, and iodine, in which preferable one is chlorine or bromine.
  • Suitable "lower alkyl” and lower alkyl moiety in the term “aryloxy(lower)alkyl” may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or the like.
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylethylene, ethylethylene, dimethylethylene or the like, in which preferable one is .,-C 4 ones and more preferably ethylene, methylethylene, ethylethylene or dimethylethylene.
  • Suitable "lower alkoxy” and lower alkoxy moiety in the term “halo(lower)alkoxy” may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy or the like, in which preferable one is C.-C.
  • Protected hydroxy may be commonly protected hydroxy such as substituted lower alkoxy such as lower alkoxy(lower)alkoxy [e.g. methoxy ethoxy, etc.], lower alkoxy(lower)alkoxy(lower)alkoxy [e.g. methoxyethoxymethoxy, etc.], substituted or unsubstituted ar(lower)alkoxy [e.g. benzyloxy, nitrobenzyloxy, etc.], etc., acyloxy such as lower alkanoyloxy [e.g. acetoxy, propionyloxy, pivaloyloxy, etc.], aroyloxy [e.g.
  • lower alkoxycarbonyloxy e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc.
  • substituted or unsubstituted ar(lower)alkoxycarbonyloxy e.g. benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy, etc.] etc., tri(lower)alkylsilyloxy [e.g. tri ethylsilyloxy, etc.] or the like.
  • Suitable "aryl” and aryl moiety in the terms “aryloxy” and “aryloxy(lower)alkyl” may be uncondensed or condensed aromatic hydrocarbon group such as phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.], indenyl, indanyl or the like, in which preferable one is phenyl or naphthyl.
  • Suitable “aryloxy(lower)alkyl” may be phenoxy(lower)- alkyl such as phenoxymethyl, phenoxyethyl, etc.
  • heterocyclic group may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered hetero onocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, guinolyl, isoguinolyl,
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms for example, thienyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc. ] , etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. orpholinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.]
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g.
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzothiadiazolyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms e.g. benzofuranyl, benzodioxolyl, etc.] and the like, in which preferable one is pyridyl.
  • acyl and acyl moiety in the term “acylamino” may be carboxy; esterified carboxy; carbamoyl optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, arylsulfonyl, lower alkylsulfonyl or a heterocyclic group; lower alkanoyl; aroyl; a heterocycliccarbonyl and the like.
  • the esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl,
  • 2,2,2-trichloroethoxycarbonyl, etc. substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl.
  • aryloxycarbonyl e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbony
  • the carbamoyl substituted with lower alkyl may be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like.
  • the carbamoyl substituted with lower alkoxy(lower)alkyl may be methoxymethylcarbamoyl, methoxyethylcarba oyl, ethoxymethylcarbamoyl, ethoxyethylcarbamoyl and the like.
  • the carbamoyl substituted with arylsulfonyl may be phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.
  • the carbamoyl substituted with lower alkylsulfonyl may be methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.
  • the carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above.
  • the lower alkanoyl may be substituted or unsubstitued one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is acetyl, propionyl, butyryl or pivaloyl.
  • the aroyl may be benzoyl, naphthoyl, toluoyl, di(tert-butyl)benzoyl and the like.
  • heterocyclic moiety in the term "a heterocyclic- carbonyl” may be one mentioned above as a heterocyclic group.
  • “N-Protective gro ⁇ p” may be common N-protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g.
  • benzyloxycarbonyl, p-nitrobenzylox ⁇ carbonyl, etc. ] substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phenyl(lower)alkyl such as benzyl.
  • Suitable "aryloxy(lower)alkyl which is substituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo( lower)alkoxy, nitro, cyano and acyla ino" may be lower alkyl which is substituted with aryloxy substituted with substituent(s) selected from the group mentioned above.
  • Suitable “acid residue” may be halogen [e.g. fluoro, chloro, bro o, iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy
  • Preferable compound [I] is one which has phenyl optionally substituted with halogen, naphthyl, phenoxymethyl, or pyridyl for R 1, hydrogen for R2, lower alkoxy substituted with esterified carboxy or carboxy for
  • More preferable compound [I] is one which has phenyl substituted with halogen for R 1, hydrogen for R2, lower alkoxy substituted with lower alkoxycarbonyl or carboxy
  • Most preferable compound [I] is one which has phenyl substituted with halogen for R 1, hydrogen for R2, methoxy
  • Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluen
  • the object compound [I] or its salt can be prepared by reacting a compound [II] with a compound [III] or its salt.
  • Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkyla ine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
  • a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkyla ine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
  • a conventional solvent such as an alcohol [e.
  • reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the object compound [lb] or its salt can be prepared by subjecting a compound [Ia] or its salt to elimination reaction of the N-protective group.
  • Suitable salts of the compounds [Ia] and [lb] may be the same as those exemplified for the compound [I].
  • This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like .
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]- non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • the hydroxide or carbonate or bicarbonate thereof hydrazine
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] and an acid addition salt compound [e.g. pyridine hydrochloride, etc. ] .
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.
  • an acid addition salt compound e.g. pyridine hydrochloride, etc.
  • trihaloacetic acid e.g. trichloroacetic acid, trifluoroacetic acid, etc.
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nikel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ull an copper, etc.] and the like.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g.
  • the reduction is preferably carried out in the presence of a combination of palladium catalysts [e.g. palladium black, palladium on carbon, etc. ] and formic acid or its salt ' [e.g. ammonium formate, etc.].
  • palladium catalysts e.g. palladium black, palladium on carbon, etc.
  • formic acid or its salt ' e.g. ammonium formate, etc.
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], chlorobenzene, N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
  • the reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • the object compound [Id] or its salt can be prepared by subjecting a compound [Ic] or its salt to deesterification reaction.
  • Suitable salt of the compound [Ic] may be an inorganic or organic acid addition salt as exemplified for the compound [I] .
  • Suitable salt of the compound [Id] may be the same as those exemplified for the compound [I].
  • the reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • the hydrolysis is_ preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. lithium, sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.] and Lewis acid [e.g. boron tribromide, etc. ] .
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.
  • Lewis acid e.g. boron tribromide, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, ⁇ 2-iodoethyl, 2,2,2-trichloroethyl, or the like.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • Suitable reduction agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc. ] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid., etc.].
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid., etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalyst [e.g. reduced nickel nickel oxide, Raney nickel,i etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.
  • platinum catalyst e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalyst e.g. spongy palladium, palladium black
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. , or a mixture thereof.
  • the reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound [Id] having hydrogen for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.
  • the object compound [Ic] or its salt can be prepared by reacting a compound [Id] or its reactive derivative at the carboxy group or a salt thereof with a hydroxy compound.
  • Suitable salts of the compounds [Ic] and [Id] and its reactive derivative at the carboxy group may be the same as those exemplified for the compound [I].
  • Suitable reactive derivative at the carboxy group of the compound [Id] may be acid halide [e.g. acid chloride, acid bromide, etc. ] and the like.
  • Suitable hydroxy compound may be an alcohol [e.g. methanol, ethanol, propanol, benzyl alcohol,
  • the reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride or any other organic solvent which does not adversely influence the reaction.
  • the above-mentioned hydroxy compound is in liquid, it can also be used as a solvent.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • reaction is preferably carried out in the presence of an acid or a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • N,N' -carbonylbis-(2-methylimidazole) pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene;
  • 1-alkoxy-l-chloroethylene trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; diphenyl chlorophosphate; diphenylphosphinic chloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
  • phosphorus oxychloride phosphoryl chloride
  • phosphorus trichloride diphenyl phosphorylazide
  • diphenyl chlorophosphate diphenylphosphinic chloride
  • thionyl chloride thionyl chloride
  • Suitable acid may be an organic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, etc.], an inorganic acid [e.g. hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.].
  • organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, etc.
  • an inorganic acid e.g. hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound [Ie] or its salt can be prepared by reacting a compound [IV] or its salt with a compound [V].
  • Suitable salts of the compounds [Ie] and [IV] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g.
  • a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc
  • alkaline earth metal alkoxide e.g. magnesium methoxide, magnesium ethoxide, etc.
  • alkali metal iodide e.g. sodium iodide, potassium iodide, etc.
  • reaction is also preferably carried out in the presence of phase transfer catalyst [e.g. tetra-n-butylammonium bromide, etc.].
  • phase transfer catalyst e.g. tetra-n-butylammonium bromide, etc.
  • This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dime hylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction.
  • a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dime hylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction.
  • a solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dime hylformamide, di
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the starting compounds [Ilia], [Illb], [IIIc], [IV] and [IVb] or a salt thereof can be prepared by the following processes.
  • R 2, R3, R4 R5, A and X are each as defined above,
  • R a 6 is lower alkyl
  • R is lower alkyl
  • the compound [VII] or its salt can be prepared by subjecting a compound [VI] or its salt to dealkylation reaction.
  • Suitable salt of the compound [VI] may be an inorganic or organic acid addition salt as exemplified for the compound [I] .
  • Suitable salt of the compound [VII] may be the same as those exemplified for the compound [I].
  • the reaction is carried out in the presence of an acid including Lewis acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.], boron tribromide-methyl sulfide complex, or tri(lower alkyl)silyliodide [e.g. trimethylsilyliodide, etc.].
  • Lewis acid e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.
  • boron tribromide-methyl sulfide complex e.g. trimethylsilyliodide, etc.
  • tri(lower alkyl)silyliodide e.g. trimethylsilyliodide, etc.
  • the reaction is usually carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound [Vllb] or its salt can be prepared by subjecting a compound [Vila] or its salt to elimination reaction of the N-protective group.
  • Suitable salts of the compounds [Vila] and [Vllb] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in substantially the same manner as Process 2 , and therefore the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.
  • the reaction mode and the reaction condition e.g. solvent, reaction temperature, etc.
  • the compound [Vila] or its salt can be prepared by subjecting a compound [Vllb] or its salt to introduction reaction of the N-protective group.
  • Suitable salts of the compounds [Vila] and [Vllb] may be the same as those exemplified for the compound [I].
  • Suitable introducing agent of the N-protective group used in this reaction may be a halogen compound of the N-protective group afore-mentioned such as acetyl chloride, tert-butoxycarbonyl chloride, benzyl chloride,., benzyl bromide or the like, di-tert-butyl dicarbonate, a combination of benzaldehyde and a reducing agent [e.g. sodium cyanoborohydride, etc.], and the like.
  • a halogen compound of the N-protective group afore-mentioned such as acetyl chloride, tert-butoxycarbonyl chloride, benzyl chloride,., benzyl bromide or the like, di-tert-butyl dicarbonate, a combination of benzaldehyde and a reducing agent [e.g. sodium cyanoborohydride, etc.], and the like.
  • the reaction is preferably carried out in the presence of a base as explained in Process 1.
  • the reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane, pyridine,
  • a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane, pyridine,
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the compound [Ilia] or its salt can be prepared by reacting a compound [VII] or its salt with a compound [V] .
  • Suitable salts of the compounds [Ilia] and [VII] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc. ] , the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g.
  • a base such as alkali metal [e.g. lithium, sodium, potassium, etc. ]
  • the hydroxide or carbonate or bicarbonate thereof e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.
  • alkaline earth metal e.g. calcium, magnesium, etc.
  • alkali metal hydride e.g. sodium hydride, etc.
  • alkaline earth metal hydride e
  • reaction is also preferably carried out in the presence of phase transfer catalyst [e.g. tetra-n-butylammonium bromide, etc.].
  • phase transfer catalyst e.g. tetra-n-butylammonium bromide, etc.
  • This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dimethylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction.
  • a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dimethylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction.
  • a solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dimethylformamide, dimethyl sulfoxide, ace
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound [IIIc] or its salt can be prepared by subjecting a compound [Illb] or its salt to elimination reaction of the N-protective group.
  • Suitable salts of the compounds [Illb] and [IIIc] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.
  • reaction mode and reaction condition e.g. solvent, reaction temperature, etc.
  • the compound [Illb] or its salt can be prepared by subjecting a compound [IIIc] or its salt to introduction reaction of the N-protective group.
  • Suitable salts of the compounds [Illb] and [IIIc] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in substantially the same manner as Process C, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process C.
  • reaction mode and reaction condition e.g. solvent, reaction temperature, etc.
  • the compound [IV] or its salt can be prepared by reacting a compound [II] with a compound [VII] or its salt. Suitable salts of the compounds [IV] and [VII] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 1.
  • reaction mode and reaction condition e.g. solvent, reaction temperature, etc.
  • the compound [IVb] or its salt can be prepared by subjecting a compound [IVa] or its salt to elimination reaction of the N-protective group.
  • Suitable salts of the compounds [IVa] and [IVb] may be the same as those exemplified for the compound [I].
  • This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.
  • reaction mode and reaction condition e.g. solvent, reaction temperature, etc.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
  • the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compound [I] and pharmaceutically acceptable salts thereof possess gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, doudenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, doudenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or
  • Test Method Male SD rats (180-230 g) were used. Animals were fasted for 24 hours prior to experiment. Distal colon was removed immediately after sacrifice and placed in an organ bath containing 25 ml Tyrode solution aerating with 95% 0 2 , 5% CO- at 37°C. The strip was mounted under 0.5 g tension and spontaneous contractions were recorded isometrically. After the mobility was of a uniform size, test compound was added to an organ bath and the contractions were observed over a 30 minutes period. Effect of test compound was calculated by comparing contractions before and after test compound.
  • the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solutions, lotion, inhalant, ophthalmic preparations, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 g, 10 g, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases. in general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • the following Preparations and Examples are given for the purpose of illustrating this invention.
  • reaction mixture was partitioned between ethyl acetate and IN hydrochloric acid.
  • the organic layer was washed with IN sodium hydroxide solution and brine, dried over magnesium sulfate, and evaporated in vacuo.
  • Preparation 28 The following compound was obtained by reacting a compound, which was prepared according to a similar manner to that of Preparation 12, with hydrogen chloride.
  • AD-mix- ⁇ purchased from Aldrich Chemical Company, Inc..
  • tert-butanol 10 ml
  • water 12.5 ml
  • 3-chlorostyrene 346.5 mg
  • tert-butanol 2.5 ml
  • solid sodium sulfite 3.75 g
  • Trimethylsilyl chloride (0.35 ml) was added to a solution of (R)-l-(3-chlorophenyl)-1,2-ethanediol (0.4 g) and trimethyl orthoacetate (0.35 ml) in dichloromethane (6.8 ml) at 0°C. The solution was stirred for 2.5 hours, and then evaporated to obtain crude (2S)-2-chloro-2-(3- chlorophenylethyl)acetate. The crude product was dissolved in dry methanol (4.5 ml) and potassium carbonate (770 mg) was added. The suspension was stirred vigorously for 3 hours and then filtered, and the residue was washed with dichloromethane.
  • IR (film) 3450, 1730, 1600, 830, 790, 740,
  • IR (CHC1 3 ) 3250, 2700, 2560, 2470, 2330, 1750,
  • Example 11 The following compound was obtained according to similar manners to those of Examples 1 and 3, except that the obtained compound was converted to the oxalate instead of the hydrochloride.
  • Ethyl bromoacetate (133 mg) was added to the reaction mixture under ice-cooling and the resulting mixture was stirred at ambient temperature for 3 days. The reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was wa ⁇ hed with water (twice) and brine, dried over ⁇ odium sulfate, and evaporated in vacuo.

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Abstract

L'invention concerne des nouveaux dérivés d'éthanolamine présentant des activités sympathomimétiques sélectives de l'intestin, antiulcéreuses, antipancréatitiques, lipolytiques et antipollakiurie, représentés par la formule générale (I) dans laquelle R1 représente aryle, aryloxyalkyle (inférieur) ou un groupe hétérocyclique, chacun pouvant être substitué par des substituant(s) choisis dans le groupe comprenant halogène, hydroxy, hydroxy protégé, aryloxy, alcoxy inférieur, haloalcoxy (inférieur), nitro, cyano, amino et acylamino, R2 représente hydrogène ou un groupe protecteur N, R3 est un alcoxy inférieur à substitution acyle, R4 représente un alcoxy inférieur à substitution acyle, et A est un alkylène inférieur. L'invention porte également sur des sels pharmaceutiquement acceptables desdits composés, des procédés de préparation de ces derniers et une composition pharmaceutique les contenant.
PCT/JP1994/000671 1993-04-26 1994-04-22 Derives d'ethanolamine utilises pour le traitement de troubles gastro-intestinaux WO1994025427A1 (fr)

Priority Applications (2)

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JP6524095A JPH08509491A (ja) 1993-04-26 1994-04-22 胃腸疾患の治療に有用なエタノールアミン誘導体
AU65812/94A AU6581294A (en) 1993-04-26 1994-04-22 Ethanolamine derivatives useful for the treatment of gastrointestinal disorders

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GB939308618A GB9308618D0 (en) 1993-04-26 1993-04-26 Ethanolamine derivatives
GB9308618.9 1993-04-26
GB939322238A GB9322238D0 (en) 1993-10-28 1993-10-28 Enthanolamine derivatives
GB9322238.8 1993-10-28

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US5977124A (en) * 1995-05-10 1999-11-02 Pfizer Inc. β-adrenergic agonists
WO2001036375A1 (fr) * 1999-11-16 2001-05-25 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'amino alcools utiles pour le traitement de troubles gastro-intestinaux
JP2004509161A (ja) * 2000-09-18 2004-03-25 グラクソ　グループ　リミテッド Ｌｘｒのアゴニストとして有用な置換アミノプロポキシアリール誘導体
USRE44872E1 (en) 2002-11-07 2014-04-29 Astellas Pharma Inc. Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient
WO2018009618A1 (fr) * 2016-07-07 2018-01-11 Dow Agrosciences Llc Procédés de préparation de 4-alcoxy-3-(acyl ou alkyl)oxypicolinamides

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AU2004287849A1 (en) * 2003-10-30 2005-05-19 Merck Sharp & Dohme Corp. Aralkyl amines as cannabinoid receptor modulators

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EP0023385A1 (fr) * 1979-06-16 1981-02-04 Beecham Group Plc Dérivés d'éthanamines, leur préparation et leur utilisation dans des compositions pharmaceutiques
EP0099707A1 (fr) * 1982-07-16 1984-02-01 Beecham Group Plc Dérivés d'éther 2-aminoéthyles, leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0164700A2 (fr) * 1984-06-15 1985-12-18 Beecham Group Plc Bis-(bêta-hydroxyphényléthyl)amines
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977124A (en) * 1995-05-10 1999-11-02 Pfizer Inc. β-adrenergic agonists
WO2001036375A1 (fr) * 1999-11-16 2001-05-25 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'amino alcools utiles pour le traitement de troubles gastro-intestinaux
JP2004509161A (ja) * 2000-09-18 2004-03-25 グラクソ　グループ　リミテッド Ｌｘｒのアゴニストとして有用な置換アミノプロポキシアリール誘導体
USRE44872E1 (en) 2002-11-07 2014-04-29 Astellas Pharma Inc. Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient
US8835474B2 (en) 2002-11-07 2014-09-16 Astellas Pharma Inc. Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient
WO2018009618A1 (fr) * 2016-07-07 2018-01-11 Dow Agrosciences Llc Procédés de préparation de 4-alcoxy-3-(acyl ou alkyl)oxypicolinamides
KR20190025990A (ko) * 2016-07-07 2019-03-12 다우 아그로사이언시즈 엘엘씨 4-알콕시-3-(아실 또는 알킬)옥시피콜린아미드의 제조 방법
CN109640657A (zh) * 2016-07-07 2019-04-16 美国陶氏益农公司 制备4-烷氧基-3-(酰基或脂族饱和烃基)氧基吡啶甲酰胺的方法
CN109640658A (zh) * 2016-07-07 2019-04-16 美国陶氏益农公司 制备4-烷氧基-3-(酰基或脂族饱和烃基)氧基吡啶甲酰胺的方法
CN109640657B (zh) * 2016-07-07 2020-10-30 美国陶氏益农公司 制备4-烷氧基-3-(酰基或脂族饱和烃基)氧基吡啶甲酰胺的方法
CN109640658B (zh) * 2016-07-07 2021-07-27 美国陶氏益农公司 制备4-烷氧基-3-(酰基或脂族饱和烃基)氧基吡啶甲酰胺的方法
TWI737763B (zh) * 2016-07-07 2021-09-01 美商陶氏農業科學公司 製備4-烷氧基-3-(醯基或烷基)氧基吡啶醯胺之方法
KR102384529B1 (ko) 2016-07-07 2022-04-08 코르테바 애그리사이언스 엘엘씨 4-알콕시-3-(아실 또는 알킬)옥시피콜린아미드의 제조 방법

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