Classifications

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  • 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
  • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • 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
  • A61P3/04—Anorexiants; Antiobesity 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
  • C07C311/51—Y being a hydrogen or a carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
• • 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 aminoalcohol derivatives and salts thereof which are beta-3 ( ⁇ 3 ) adrenergic receptor agonists and useful as a medicament.
• This invention relates to new aminoalcohol derivatives which are ⁇ 3 adrenergic receptor agonists and salts thereof.
• new aminoalcohol derivatives and salts thereof which are useful for the treatment and/or prevention of gastro-intestinal disorders, ulcer, overactive bladder, micturition disorders, pancreatitis, obesity, diabetes, etc., 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 the aforesaid disorders in a human being or an animal.
• One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which are useful for the treatment and/or prevention of the aforesaid disorders.
• Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof.
• a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoalcohol derivatives and salts thereof.
• Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of the aforesaid diseases in a human being or an animal, using said aminoalcohol derivatives and salts thereof.
• R 4 , R 5 and R 6 are each independently hydrogen, lower alkyl or hydroxy(lower)alkyl, or
• n 0, 1 or 2
• R 1 is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, aryloxy, nitro, amino, (mono or di) (lower)- alkylamino or arylamino,
• R 2 is hydrogen, lower alkyl or hydroxy(lower)alkyl
• R ⁇ is hydrogen or an amino protective group
• R 7 is hydrogen, lower alkyl, cyclo(lower)alkyl, lower
• alkenyl, -Z-R 9 or -N ⁇ in which -Z- is -O-, -S-,
• each R 9 is independently hydrogen, lower alkyl, cyclo(lower)alkyl, lower alkenyl, carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, aryl or a heterocyclic group
• R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-,
• E is bond or lower alkylene
• R 10 is halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, a heterocyclic group
• each R 11 is independently hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or aryl(lower)alkyl, or a prodrug thereof or a salt thereof.
• the object compounds can be prepared by processes which are illustrated in the following schemes.
• R ⁇ is an amino protective group
• R ⁇ is lower alkyl
• Y ⁇ is a leaving group
• lower is intended to mean a group having 1 to 8, preferably 1 to 7, more preferably 1 to 6, most preferably 1 to 4, carbon atom(s), unless otherwise indicated.
• Suitable "lower alkyl” and “lower alkyl” moiety in the terms of "hydroxy(lower)alkyl", “(mono or di) (lower) - alkylamino” , “lower alkylcarbamoyl) " , “lower alkylsulfonyl” and “aryl(lower)alkyl” may include straight or branched one having 1 to 8, preferably 1 to 7, more preferably 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, and the like, in which preferable one may be methyl, ethyl, propyl, isopropyl or isobutyl
• Suitable "lower alkoxy” and “lower alkoxy” moiety in the term of “lower alkoxycarbonyl” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert- butoxy, pentyloxy, tert-pentyloxy, hexyloxy, and the like, in which preferable one may be methoxy or tert-butoxy.
• Suitable “lower alkanoyl” may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, and the like, in which preferable one may be acetyl.
• Suitable "cyclo(lower)alkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, in which preferable one may be cyclo(C3-C- 7 )alkyl, and more preferable one may be cyclopentyl, cyclohexyl or cycloheptyl.
• Suitable "lower alkenyl” may include vinyl, l-(or 2-)propenyl, l-(or 2- or 3-)butenyl, l-(or 2- or 3- or 4-)pentenyl, l-(or 2- or 3- or 4- or 5-)hexenyl, l-(or 2- )methylvinyl, ethylvinyl, l-(or 2- or 3- )methyl-l-(or 2-)propenyl, l-(or 2- or 3-)ethyl-l-(or 2-)propenyl, l-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which preferable one may be C 2 -C 4 alkenyl.
• Suitable "lower alkylene” may include straight or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2,2-dimethyltri- methylene, 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene and propylene, in which preferable one may be straight alkylene having 1 to 4 carbon atoms.
• Suitable "halogen” may be fluoro, chloro, bromo and iodo, in which preferable one may be fluoro or chloro.
• Suitable "aryl” and “aryl” moiety in the terms of “aryloxy”, “arylamino” and “aryl(lower)alkyl” may include phenyl, naphthyl, indenyl, anthryl, and the like, in which preferable one may be phenyl.
• Suitable “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 heteromonocy ⁇ lic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl., pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.
• indolizinyl benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[l, 5-b]pyridaz,inyl, etc.], quioxalinyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.
• saturated 3 to 6-membered heteromonocyclic group containing an oxygen atom for example, IH- tetrahydropyranyl, tetrahydrofuranyl, etc.
• 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.
• oxazolinyl e.g. 2-oxazolinyl, etc.]
• thiazolidinyl etc.
• unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g. benzothiazoly ⁇ , benzothiadiazolyl, etc.
• unsaturated condensed heterocyclic group containing 1 -to 2 oxygen atoms e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.
• Suitable “leaving group” may include hydroxy, reactive group derived from hydroxy, and the like.
• Suitable "reactive group derived from hydroxy” may- include acid residue and the like.
• Suitable “acid residue” may include halogen [e.g. fluoro, chloro, bromo, iodo] , acyloxy [e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.], and the like.
• halogen e.g. fluoro, chloro, bromo, iodo
• acyloxy e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.
• amino protective group may be common amino protective group such as 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-nitro- benzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g.
• benzenesulfonyl, tosyl, etc.] nitrophenylsulfenyl, aryl(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert- butoxycarbonyl.
• Suitable salts of the object aminoalcohol derivative [I] are pharmaceutically acceptable salts and include 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, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.], and the like, in which preferable one is hydrochloride.
• 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
• the object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
• 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)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, and 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)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, and the like.
• the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethariol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
• a conventional solvent such as an alcohol [e.g. methanol, ethariol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
• the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
• the object compound [Ib] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the amino protective group.
• Suitable salts of the compounds [Ia] and [Ib] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner to that of Example 3 mentioned below.
• the object compound [Ic] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof.
• Suitable salts of the compounds [Ic], [IV] and [V] may be the same as those exemplified for the compound [I].
• the object compound [Ic] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [VI] or a salt thereof.
• Suitable salts of the compounds [Ic], [IV] and [VI] may be the same as those exemplified for the compound [I].
• the object compound [If] or a salt thereof can be prepared by subjecting a compound [Id] or a salt thereof to deesterification reaction followed by reacting the resulting compound [Ie] or a salt thereof with a compound [VII] or a salt thereof.
• Suitable salts of the compounds [If], [Id], [Ie] and [VII] may be the same as those exemplified for the compound
• the object compound [Ig] or a slat thereof can be prepared by reacting a compound [VIII] or a salt thereof with a compound [IX] or a salt thereof.
• Suitable salt of the compounds [Ig], [VIII] and [IX] may be the same as those exemplified for the compound [I].
• the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, and 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.
• isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or rearrangement if also included within the scope of the present invention.
• the object compound [I] or a salt thereof are useful for the treatment and/or prevention of gastro-intestinal disorders in human beings or animals, and more particularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus, and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, and the like; for the treatment and/or prevention of overactive bladder such as nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy, and the like; for the, treatment and/or prevention of micturition disorders such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence, and the like; for the treatment and/or prevention of
• ⁇ 3 adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and to raise high density lipoprotein levels in mammals (US
• the object compound [I] is useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions.
• the object compound [I] is useful for inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea.
• object compound [I] may be expected, when used together with an anticholinergic agent for overactive bladder such as propiverine hydrochloride, oxybutinin hydrochloride, flavoxate hydrochloride. tolterodine tartrate, and the like, to exert an enhanced anti-overactive-bladder effect.
• an anticholinergic agent for overactive bladder such as propiverine hydrochloride, oxybutinin hydrochloride, flavoxate hydrochloride. tolterodine tartrate, and the like, to exert an enhanced anti-overactive-bladder effect.
• 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 or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transpcular administration.
• a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transpcular administration.
• the pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, and the like.
• 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 a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg,
• 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating diseases such as ulcer, overactive bladder, micturition disorders, and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
• Preferred embodiments of the object compound [I] are as follows:
• R ⁇ , R ⁇ and R ⁇ are each independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl) or hydroxy(lower)alkyl (more preferably hydroxy(C 1 -C 4 )alkyl).
• R-I- is hydrogen, halogen (more preferably fluoro or chloro), nitro or amino
• R 2 is hydrogen or lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl)
• R ⁇ is hydrogen
• R 7 is hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably isopropyl or isobutyl)
• cyclo(lower)alkyl more preferably cyclo(C3-Cg)alkyl, most preferably cyclopentyl
• each R 9 is independently hydrogen, lower alkyl
• R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, E is bond or lower alkylene (more preferably
• C 1 -C 4 alkylene most preferably methylene, ethylene, trimethylene, 3,3-dimethyl- trimethylene or tetramethylene
• R 10 is halogen, cyano, carboxy, lower alkoxycarbonyl (more preferably C 1 -C 4 alkoxycarbonyl, most preferably methoxycarbonyl) , carbamoyl, pyridyl.
• each R 11 is independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl or ethyl) , lower alkanoyl (more preferably C 1 -C 4 alkanoyl, most preferably acetyl) or lower alkoxycarbonyl (more preferably C 1 -C 4 alkoxycarbonyl, most preferably tert-butoxycarbonyl) .
• -X- is , in which -Y- is bond, -0-, -NH- or -CH 2 -, and
• R ⁇ , R ⁇ and R° are each hydrogen
• R ⁇ is lower alkyl (more preferably C 1 -C 4 alkyl, most preferably isopropyl or isobutyl), cyclo(lower)alkyl (more preferably cyclo(C 3 -C 6 )alkyl, most preferably cyclopentyl) , -Z-R 9 or
• each R 9 is independently lower alkyl or cyclo(lower)alkyl (more preferably C 1 -C 4 alkyl, most preferably propyl, isopropyl or isobutyl) or cyclo(lower)alkyl (more preferably cyclo(C 3 -C 6 )alkyl, most . preferably cyclopentyl, cy ⁇ lohexyl or cycloheptyl) , and.
• R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, E is bond or lower alkylene (more preferably, C 1 ⁇ C 4 alkylene, most preferably methylene, ethylene, trimethylene, 3,3-dimethyl- trimethylene or tetramethylene) , and R 10 is cyano, carboxy, carbamoyl, pyridyl,
• R i i independently hydrogen lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl or ethyl) .
• Methyl 3-thiocyanatopropanate (2.00 g) was dissolved in water (20 ml) and cooled at 0 0 C. Chlorine gas was bubbled into the solution for 1 hour at the same temperature. The reaction mixture was poured into the mixture of cold water and diethyl ether and the aqueous layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent afforded methyl 3-(chlorosulfonyl)propanoate (2.3I g-).
• Example 3 To a solution of tert-butyl [(2R) -2-(3-chlorophenyl) - 2-hydroxyethyl][2-[4'-[[[(3-hydroxypropyl)sulfonyl]amino] - carbonyl]-3' -isopropoxy-4-biphenyIyI]ethyl]carbamate (231 mg) in 1,4-dioxane (2.3 ml) was added 4N hydrogen chloride in 1,4-dioxane (2.3 ml) and the mixture was stirred at room temperature for 5 hours.
• Example 10 A mixture of tert-butyl [2- [4' - [ [ [ [ [2-(benzyloxy) - ethyl]sulfonyl]amino]carbonyl] -3' - (cyclohexyloxy) -4- biphenylyl]ethyl] [ (2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] - carbamate (215 mg) , 10% palladium on activated carbon (50% wet, 645 mg) , ammonium formate (845 mg) , methanol (6.45 ml) and water (0.65 ml) was refluxed for 20 minutes.
• Example 12 The following compound was obtained according to a similar manner to that of Example 7.
• Example 16 The following compounds were obtained according to a similar manner to that of Example 11.
• Example 23 To a solution of 4' - [2-[ (tert-butoxycarbonyl) [ (2R)-2- (3-chlorophenyl) -2-hydroxyethyl]amino]ethyl]-3- (isopropylthio) ⁇ 4-biphenylcarboxylic acid (150 mg) in tetrahydrofuran (1.5 ml) was added N,N'- carbonyldiimidazole (64 mg) and stirred at room temperature for 30 minutes.
• Example 27 The following compounds were obtained according to a similar manner to that of Example 26.
• methylmagnesium chloride (3.0 M in tetrahydrofuran, 118 ⁇ l) was added to a solution of methyl 3- [ [ [ [4 '- [2- [ (tert-butoxycarbonyl) [ (2R)-2- hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy) -4- biphenylyl]carbonyl]amino]sulfonyl]propanoate (50.0 mg) in tetrahydrofuran (1.0 ml) at -78°C, and the mixture was stirred at 0 0 C for 10 minutes. The mixture was poured into sat. ammonium chloride aq.
• Example 37 The following compounds from Example 37 to Example 39 were obtained according to a similar manner to that of
• reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate.
• the solvent was concentrated under reduced pressure.
• To a solution of the resulting residue in 1,4-dioxane (0.340 ml) was added 4N hydrogen chloride in 1,4-dioxane (0.340 ml) and the mixture was stirred at room temperature overnight.
• the solvent was concentrated under reduced pressure and to the residue was added ethyl acetate.
• Example 44 The following compound was obtained according to a similar manner to that of Preparation 64.
• Example 46 The following compounds from Example 46 to Example 49 were obtained according to a similar manner to that of
• Example 45 3-(Cyclohexyloxy) -N- [ (3-hydroxy-3-methylbutyl)- sulfonyl]-4'-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]- amino]ethyl]-4-biphenylcarboxamide dihydrochloride
• Example 50 To a mixture of 4' -[2-[ (tert-butoxydarbonyl) [ (2R) -2- (6-chloro-3-pyridyl) -2-(tetrahydro-2H-pyran-2-yloxy) - ethyl]amino]ethyl] -3- (cyclohexyloxy)-4-biphenylcarboxylic acid (180 mg) in N,N-dimethylformamide (2 ml) was added 1,1' -carbonyldiimidazole (51.6 mg) at room temperature and. the mixture was stirred at the same temperature for 1 hour.
• N-Ethylsulfamide (46.1 mg) and 1,8-diazabicyclo[5.4.0] - 7-undecene (0.056 ml) were added to the mixture at room temperature.
• the mixture was stirred at room temperature for 0.5 hour and at 120 0 C for 16 hours.
• the mixture was diluted with ethyl acetate, and washed with water, 0.5N hydrochloric acid and brine, and dried over sodium sulfate and evaporated under reduced pressure to give residue (220 mg) .
• the mixture was diluted with ethyl acetate,. and washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give the residue.
• Example 51 The following compound was obtained according to a similar manner to that of Example 41.

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