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WO2005092882A1 - Derives de 4-amino-5-halogeno-benzamide utiles comme agonistes du recepteur 5-ht4 dans le traitement des troubles gastro-intestinaux, du systeme nerveux central, neurologiques et cardio-vasculaires - Google Patents

Derives de 4-amino-5-halogeno-benzamide utiles comme agonistes du recepteur 5-ht4 dans le traitement des troubles gastro-intestinaux, du systeme nerveux central, neurologiques et cardio-vasculaires Download PDF

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WO2005092882A1
WO2005092882A1 PCT/IB2005/000389 IB2005000389W WO2005092882A1 WO 2005092882 A1 WO2005092882 A1 WO 2005092882A1 IB 2005000389 W IB2005000389 W IB 2005000389W WO 2005092882 A1 WO2005092882 A1 WO 2005092882A1
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group
formula
methyl
reaction
compound
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Chikara Uchida
Kiyoshi Kawamura
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Pfizer Corp Belgium
Pfizer Japan Inc
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Japan Inc
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel 4-amino-5-halogeno-be ⁇ zamide derivatives. 5 These compounds have selective 5 ⁇ HT receptor agonistic activity.
  • the present invention also relates to a pharmaceutical composition, a method of treatment and a use, comprising the above derivatives for the treatment of disease conditions mediated by 5 ⁇ T 4 receptor agonistic activity.
  • 5 ⁇ T 4 receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral 15 disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, and apnea syndrome (See ⁇ Ps, 1992, 13, 141; Ford A. P. D. W. et al., Med. Res.
  • diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesoph
  • Compound A WO 9902156 discloses 4-aminomethyl piperidine derivatives as gastrointestinal motility stimulators. Especially, the compound represented by the following formula is disclosed as compound No. 25:
  • Compound B JP 11001472 discloses 4-amino-5-halo _ 2-alkoxy-N(4-piperidinylalkyl or
  • compounds of this invention have stronger selective 5 ⁇ T 4 agonistic activity with improved caco2 permeability, compared with the prior art, and thus are useful for the treatment of disease conditions mediated by 5 _ HT 4 activity such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome (especially caused by an opioid administration).
  • the compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, less protein binding affinity, less drug-drug interaction, and good metabolic stability.
  • the present invention provides compounds of the following formula (I) or pharmaceutically acceptable salts thereof.
  • R 1 represents a halogen atom
  • R 2 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R 3 represents an alkyl group having from 1 to 4 carbon atoms; or R 2 and R 3 may form an alkylene bridge having from 2 to 3 carbon atoms to yield a 5 or 6 membered ring;
  • R 4 represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH 2 )n"R 5 (in which n represents integer 1 to 4 and R 5 represents a hydroxy group, a carboxy group or a group of formula -COOR 6 (in which R 6 represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group ⁇ )),' A represents an oxygen atom or a group of the formula -C(R 7 )(R 8 )- (in which R 7 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R 8 represents
  • R 10 represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group )); said group ⁇ is consisting of a cycloalkyl, alkylated-cycloalkyl, lieterocyclyl, alkylated-heterocyclyl, aryl and alkylated-aryl.
  • the present invention provides the use of a compound of formula (I) or its pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of a condition mediated by 5 ⁇ T 4 receptor activity.
  • the present invention also provides the use of a compound of formula (I) or its pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier for said compound.
  • the present invention provides a method for the treatment of a condition mediated by 5"HT 4 receptor activity, in a mammalian subject, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.
  • the present invention provides a method for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.
  • diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart
  • R 2 represents an alkyl group having from 1 to 4 carbon atoms
  • R 3 represents an alkyl group having from 1 to 4 carbon atoms
  • R 6 represents an alkyl group having from 1 to 4 carbon atoms
  • R 7 represents an alkyl group having fr-om 1 to 4 carbon atoms
  • R 10 represents an alkyl group having from 1 to 4 carbon, atoms.
  • R 2 represents an alkyl group having from 1 to 4 carbon atoms
  • R 3 represents an alkyl group having from 1 to 4 carbon atoms
  • R 6 represents an alkyl group having from 1 to 4 carbon atoms
  • R 7 represents an alkyl group having fr-om 1 to 4 carbon atoms
  • R 10 represents an alkyl group having from 1 to 4 carbon, atoms.
  • These may be a straight or branched chain group, and examples include a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
  • alkyl groups having from 1 to 3 carbon atoms, preferably a methyl, ethyl, propyl and isopropyl, and most preferably a methyl and ethyl.
  • R 1 represents a halogen atom, this may be a fluorine, clilorine, bromine or iodine atom. Of these, we prefer a fluorine and chlorine atom.
  • R 2 and R 3 represent an alkylene bridge, this may be an ethylene or trimethylene. Of these, we prefer an ethylene.
  • the group ⁇ represents a cycloalkyl, this preferably has from. 3 to 8 carbon atoms in a single carbocyclic ring.
  • examples include a cyclopropyl, cyclopentyl or cyclohexyl. Of these, we prefer a cyclopropyl and cyclohexyl.
  • group ⁇ represents an alkylated-cycloalkyl, this represents the cycloalkyl group which is substituted by an alkyl group having lto 4 carbon atoms defined above.
  • examples include a 2-methylcyclopropyl, 2-ethylcyclopropyl, 2-propylcylopropyl, 2-butylcyclopropyl, 2-methylcyclopentyl, 2-ethylcyclopentyl, 2-metylcyclohexyl, 3-metylcyclohexyl and 2-ethylcyclohexyl.
  • 2-methylcyclopropyl and 3-methylcyclohexyl we prefer 2-methylcyclopropyl and 3-methylcyclohexyl.
  • group ⁇ represents a heterocyclyl, this preferably has 5 or 6 ring atoms, of which one is a nitrogen atom, 0 or 1 is an additional hetero-ato selected from the group consisting of a nitrogen, oxygen and sulfur atoms, and the remaining atoms are carbon atoms.
  • Examples include 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-pyperidyl, 2-pyperidyl, 3-pyperidyl, 4-pyperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperadinyl, 2-morpholinyl, 3-morpholinyl, 2-thiomorphonyl and 3-thiomorphonyl. Of these, we prefer 2-pyrrolidinyl and 3-pyrrolidinyl.
  • group ⁇ represents an alkylated-heterocyclyl
  • this represents the heterocycle group which is substituted by an alkyl group having lto 4 carbon atoms defined above.
  • examples include l-methyl-pyrrolidin-2-yl, l-methyl-pyrrolidin-3-yl, 2-methyl-pyrrolidin-3-yl, l-ethyl-pyrrolidin-3-yl, l-propyl-pyrrohdin-3-yl, l-butyl-pyrrolidin-3-yl, l-methyl-pyrazolidin-2-yl, l-methyl-piperidin-2-yl and l-methyl-piperidin-3-yl.
  • group ⁇ represents an aryl, this preferably has 6 to 10 carbon atoms. And examples include a phenyl, ⁇ -naphthyl and ⁇ -naphthyl. Of these, we prefer a phenyl.
  • group ⁇ represents an alkylated-aryl, this represents the aryl group which is substituted by an alkyl group having lto 4 carbon atoms defined above.
  • examples include 2-metylphenyl, 3-metylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-metylphenyl and l-metyl-napht-2-yl. Of these, we prefer 3-methylphenyl.
  • R 8 represents an alkoxy group having from 1 to 4 carbon atoms, this represents the oxy group which is substituted by an alkyl group having from 1 to 4 carbon atoms defined above and may be a straight or branched chain group.
  • examples include a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy.
  • alkoxy groups having from 1 to 3 carbon atoms preferably a methoxy, ethoxy, propoxy and isopropoxy, and most preferably a methoxy and ethoxy groups.
  • R 4 represents a group of formula -(CH2)n"R 5
  • preferred substituent includes a group of formula -(CH2)n-COOR 6 such as a group of formula -(CH 2 )2-COOCH 3 , -(CH 2 )2-COOCH 2 CH3, -(CH 2 )3-COOCH 3 , -(CHsD ⁇ -COOCEfeCH ⁇ ,
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • Preferred classes of compounds of tlie present invention are those compounds of formula (I) and salts thereof in which:
  • R 1 represents a chlorine atom or a fluorine atom
  • R 2 represents a hydrogen atom
  • R 3 represents an alkyl group having from 1 to 2 carbon atoms, " (D) R 2 and R 3 form a group of formula -(CTb to yield 5 membered ring, "
  • R 4 represents a hydroxy group or a- carboxy group
  • (F) A represents an oxygen atom or a group of formula -CH(OH)-.
  • Particularly preferred compounds of the present invention are those compounds of formula (I) and salts thereof in whicli
  • R 1 represents a chlorine atom or a fluorine atom
  • R 2 represents a hydrogen atom
  • R 3 represents an alkyl group having from 1 to 4 carbon atoms
  • R 4 represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH2)n-R 5 (in which n represents integer 1 to 4 and R 5 represents a hydroxy group, a carboxy group or a group of formula -COOR 6
  • Gn which R 6 represents an alkyl group having from 1 to 4 carbon atoms which is unsubstituted or is substituted one substituent selected from group ⁇ )
  • A represents an oxygen atom or a group of formula -CH(OH)-
  • R 1 represents a halogen atom
  • R 2 and R 3 form a group of formula -(CH2)2- to yield 5 membered ring
  • R 4 represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH2)
  • R 1 represents a chlorine atom or a fluorine atom
  • R 2 and R 3 form a group of formula -(CH2)2- to yield 5 membered ring
  • R 4 represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH 2 )n-R 5 (in which n represents integer 1 to 4 and R 5 represents a hydroxy group, a carboxy group or a group of formula -COOR 6 (in which R 6 represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group ⁇ )); and A represents an oxygen atom or a group of formula -CH(OH).
  • the more preferred classes of compounds of the present invention are those in which : (K) R 1 represents a chlorine atom or a fluorine atom, R 2 represents a hydrogen atom,
  • R 3 represents an alkyl group having from 1 to 4 carbon atoms
  • R 4 represents a hydrogen atom, a hydroxy group or a carboxy group
  • A represents an oxygen atom or a group of formula -CH(OH)-
  • R 1 represents a halogen atom
  • R 2 represents a hydrogen atom
  • R 3 represents an alkyl group having from 1 to 2 carbon atoms
  • R 4 represents a hydrogen atom, a hydroxy group or a carboxy group
  • A represents an oxygen atom or a group of formula -CH(OH)S
  • R 1 represents a halogen atom
  • R 2 and R 3 form a group of formula -(CH2)2- to yield 5 membered ring
  • R 4 represents a hydrogen atom', a hydroxy group or a carboxy group
  • A represents an oxygen atom or a group of formula -CH(OH)-,'
  • R 1 represents a chlorine atom or a fluorine atom
  • R 2 represents a hydrogen atom
  • R 3 represents an alkyl group having from 1 to 2 carbon atoms
  • R 4 represents a hydrogen atom, a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)-
  • (O) R 1 represents a chlorine atom or a fluorine atom
  • R 2 and R 3 form a group of formula -(CH 2 )2- to yield 5 membered ring
  • R 4 represents a hydrogen atom, a hydroxy group or a carboxy group
  • A represents an oxygen atom or a group of formula -CH(OH)-.
  • the compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following Methods A to G.
  • the following Methods A and B illustrate the preparation of compounds of formula (I).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and A in the following Methods are defined as above.
  • the term "protecting group”, as used hereinafter, means a hydroxy, carboxy or amino-protecting group which is selected from typical hydroxy, carboxy or amino-protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art.
  • TThhiiss iilllluusi trates the preparation of compounds of formula (I).
  • R 4a represents R 4 defined as above, a group of formula -(CH2)kCOOR n , wherein k represents integer 0 to 4 and R 11 represents R 6 defined as above or a carboxy-protecting group, or a group of formula -(CH2) ⁇ OR 12 , wherein 1 represents integer 0 to 4 and R 12 represents a hydroxy-protecting group;
  • a a represents A defined as above or a group of formula -CH((CH2)qCOOR 13 )-, wherein q represents integer 1 to 4 and R 13 represents R 10 defined as above or a carboxy-protecting group or a group of formula -CH((CH2)rOR 14 )-, wherein r represents integer 0 to 4 and R 14 represents a hydroxy-protecting group.
  • carboxy-protecting group signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such carboxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).
  • Typical carboxy-protecting groups include methyl, ethyl, t-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, t-butyldimethylsilyl and allyl. Of these groups, we prefer t-butyl or ethyl.
  • hydroxy-protecting group signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such hydroxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).
  • the desired compound of formula (I) of the present invention is prepared by amide coupling (Al-a) with the compound of formula (III) or forming amide(Al-b) via acyl halide.
  • Al-a) Amide coupling In this reaction, carboxyl group of the compound of formula (II) is coupled with the compound of formula (III) under the presence of the condensing agent and base.
  • the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, ' and amides, such as A N-dimethylformamide and iV-N-dimethylacetamide. Of these solvents, we prefer - ⁇ Ndimethylformamide. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • bases examples include: amines, such as triethylamine, A N-diisopropylethylamine, tributylamine, pyridine, picoline and 4-( ⁇ N-dimethylamino)pyridine. Of these, we prefer iV . N-diisopropylethylamine.
  • amines such as triethylamine, A N-diisopropylethylamine, tributylamine, pyridine, picoline and 4-( ⁇ N-dimethylamino)pyridine.
  • iV N-diisopropylethylamine.
  • condensing agents there is likewise no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type may equally be used here.
  • Examples of such condensing agents include: an azodiearboxylic acid di-lower alkyl ester- triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine," an A ⁇ N ⁇ dicycloalkylcarbodiimide such as N,N ieyclohexylcarbodiimide (DCC), ' a 2-halo-l-lower alkyl pyridinium halide such as 2-chloro-l-methy pyridinium iodide, " a diarylphosphorylazide such as diphenylphosphorylazide (DPPA); a chloroformate such as ethyl chloroformate and isobutyl chloroformate," a phosphoryl chloride such as diethyl phosphorryl chloride,” a phosphorocyanidate such as diethyl phosphorocyanidate (DEPC);.
  • an imidazole derivative such as N,N L carbodiimidazole (CDI); a carbodiimide derivative such as l-ethyl-3-(3" diethylaminopropyl)carbodiimide hydrochloride (EDAJPC); and a sulfonyl chloride derivative such as 2,4,6-triisopropylbenzenesulfonyl chloride.
  • CDI N,N L carbodiimidazole
  • EDAJPC l-ethyl-3-(3" diethylaminopropyl)carbodiimide hydrochloride
  • a sulfonyl chloride derivative such as 2,4,6-triisopropylbenzenesulfonyl chloride.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 80°C, more preferably from 10°C to 40°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under "the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • Suitable reagents include: chlorinating agents, su-ch as oxyalyl chloride or thionyl chloride, " and brominating agents, such as thionyl. ⁇ bromide.
  • the quantity of the reagent required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the reagent as chemical equivalent to the starting material from 2 to 5, will usually suffice.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 40°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 10 hours, more preferably from 60 minutes to 5 hours, will usually suffice. (Coupling with the compound (III))
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Of these solvents, we prefer dichloromethane or 1,2-dichloroethane.
  • the reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • bases examples include: amines, such as triethylamine, diisopropylethylamine, tributylamine, pyridine, picoline and 4-(A N-dimethylamino)pyridine. Of these, we prefer triethylamine, diisopropylethylamine or pyridine.
  • the quantity of the base required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the base as chemical equivalent to the starting material from 1 to 4, more preferably from 1 to 1.4, will usually suffice. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 18 hours, will usually suffice.
  • R 4a represents a group of formula -(CH2)kCOOR 11 and/or A a represents -CH((CH2)qCOOR 13 )
  • the deprotection reaction will follow to yield a carboxy group.
  • This reaction is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 369-453, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-butyl.
  • the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," and aromatic hydrocarbons, such as benzene, toluene and nitrobenzene. Of these solvents, we prefer halogenated hydrocarbons.
  • the reaction is carried out in the presence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here. Examples of such acids include: acids, such as hydrochloric acid, acetic acid p-toluenesulfonic acid or trifluoroacetic acid. Of these, we prefer trifluoroacetic acid.
  • the reaction may be carried out in the presence of a radical scavenger.
  • a radical scavenger there is likewise no particular restriction on the nature of the radical scavenger used, and any radical scavenger commonly used in reactions of this type may equally be used here.
  • examples of such radical scavengers include ⁇ Br, dimethylsulfoxide or (CH 3 CH2) 3 SiH. Of these, we prefer (CH 3 CH2) 3 SiH.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 1 hours to 24 hours, will usually suffice.
  • R 4a represents a group of formula -(CH 2 ) ⁇ CH(OR 12 ) and/or A a represents a group of formula -CH((CH2)rCH(OR 14 )
  • the deprotection reaction will follow to yield a hydroxy group.
  • This reaction is described in detail by T. W Greene et al. [Protective Groups in Organic Synthesis, 17-245, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-butyldiphenylsilyl.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvents there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Of these, we prefer ethers.
  • the reaction is carried out in the presence of a catalyst. There is likewise no particular restriction on the nature of the catalyst used, and any catalyst commonly used in reactions of this type may equally be used here.
  • catalysts examples include-" acids, such as HCL' bases such as sodium hydroxide or potassium hydroxide," fluorine reagents such as HF, HF -pyridine or tetrabuthylammonium fluoride (TBAF). Of these, we prefer TBAF.
  • HCL' bases such as sodium hydroxide or potassium hydroxide
  • fluorine reagents such as HF, HF -pyridine or tetrabuthylammonium fluoride (TBAF).
  • TBAF tetrabuthylammonium fluoride
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 1 hours to 24 hours, will usually suffice.
  • R 15 represents an amino-protecting group.
  • amino-protecting group signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such amino-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).
  • Step Bl the piperidine compound (V) is prepared by the deprotection of the compound of fomula (IV) which may have been prepared, for example, as the same method as described in Method A.
  • This method is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1999)], the disclosures of which are incorporated herein by reference.
  • the following is a typical method, provided the protecting group is t-buthoxycarbonyl.
  • the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols.
  • the reaction is carried out in the presence of excess amount of an acid. There is likewise no particular restriction on the nature of the acids used, and any base commonly used in reactions of this type may equally be used here. Examples of such acids include: acids, such as hydrochloric acid, or trifluoroacetic acid. Of these, we prefer hydrochloric acid.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 24 hours, will usually suffice.
  • the desired compound of formula (la) is prepared by the epoxy-opening substitution of the compound of formula (V) prepared as described in
  • Step Bl The reaction is normally and preferably effected in the presence of solvent.
  • solvents include: ethers, such as diethyl ether, dhsopropyl ether, tetrahydrofuran and dioxane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols.
  • ethers such as diethyl ether, dhsopropyl ether, tetrahydrofuran and dioxane
  • alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 24 hours, will usually suffice.
  • a a represents a group of formula -CH((CH2)qCOOR 13 ) and/or a group of formula -CH((CH2)rCH(OR 14 )
  • the deprotection reaction will follow to yield a carboxy group and/or a hydroxy group.
  • the reaction may be carried out under the same conditions as described in Step Al of Method A.
  • the desired compound of formula (lb) is prepared by the reductive amination of the compound of formula (V) prepared as described in Step Bl.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; acetic acid; and water. Of these solvents, we prefer halogenated hydrocarbons.
  • the reaction is carried out in the presence of a reducing reagent.
  • any reducing reagent commonly used in reactions of this type may equally be used here.
  • examples of such reducing reagent include: sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Of these, we prefer sodium triacetoxyborohydride.
  • the quantity of the reducing reagent required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the reducing reagent as chemical equivalent to the starting material from 1 to 3, will usually suffice. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from -20°C to 60°C, more preferably from 0°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 1 hour to 12 hours, will usually suffice.
  • a a represents a group of formula -CH((CH2)qCOOR 13 ) and/or a group of formula -CH((CH2)rCH(OR 14 ))
  • the deprotection reaction will follow to yield a carboxy group and/or a hydroxy group.
  • the reaction may be carried out under the same conditions as described in Step Al of Method A.
  • Method C This illustrates the preparation of the compound of formula (III) wherein R 4 is a hydroxy group or a hydrogen atom.
  • a a is defined as above," R 4b represents a hydroxy group or a hydrogen atom, " and R 16 represents an amino-protecting group.
  • the compound of formula (IX) is prepared by the epoxy-opening substitution of the compound of formula (VIII).
  • the reaction may be carried out under the same conditions as described in Step B2 of Method B, provided the deporotection process is unnecessary.
  • the compound of formula (X) is prepared by the reductive amination of the compound of formula (VIII).
  • the reaction may be carried out under the same conditions as described in Step B3 of Method B, provided the deporotection process is unnecessary.
  • the compound of formula (Ilia) is prepared by the deprotection of the compound of formula (IX) or (X) prepared as described in Step Bl or B2.
  • the reaction may be carried out under the same conditions as described in Step Bl of Method B.
  • Method D This illustrates the preparation of the compound of formula (III) wherein R 4a is a group of formula -COOR 11 .
  • each of R and R' represents an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, or an aralkyl group such as a benzyl or phenethyl group preferably a benzyl group; and X represents a halogen atom such as a iodine atom, a chlorine atom or a bromine atom.
  • the compound of formula (XIII) is prepared by annulation with the compound of formula (XII). The reaction is normally and preferably effected in the presence of solvent.
  • solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane; and amides, such as A Ndimethylformamide and A N-dimethylacetamide. Of these, we prefer N . N-dimethylformamide.
  • the reaction is carried out in the presence of a base.
  • any base commonly used in reactions of this type may equally be used here.
  • examples of such bases include: alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; and alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Of these, we prefer sodium hydride.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 48 hours, more preferably from 60 minutes to 24 hours, will usually suffice.
  • the compound of formula (XIV) is prepared by reduction of the cyano group of the compound of formula (XIII).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane," aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer methanol.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane
  • aromatic hydrocarbons such as benzene, toluene and nitrobenzene
  • alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer methanol.
  • the reaction is carried out in the presence of a reducing agent.
  • any reducing agent commonly used in reactions of this type may equally be used here.
  • reducing agents include: metal borohydrides such as sodium borohydride and sodium cyanoborohydride; combinations of hydrogen gas and a catalyst such as palladium-carbon, platinum and Raney nickel," and hydride compounds such as lithium aluminum hydride, sodium borohydride and diisobutyl aluminum hydride. Of these, we prefer Raney nickel.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 10°C to 40°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • the compound of formula (XVI) is prepared by forming piperidinone ring from the compound of formula (XIV).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: water, " and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer the mixture of water and methanol.
  • the reaction is carried out in the presence of a base.
  • any base commonly used in reactions of this type may equally be used here.
  • examples of such bases include: alkali metal hydroxides, alkah metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide! and alkah metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, we prefer potassium carbonate.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 50°C to 100°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • the compound of formula (XVII) is prepared by converting the carbonyl group of the compound of formula (XVI) to a cyano group under the presence of jrtoluenesulfonylmethyl isocyanide.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofiiran and dioxane," and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer the mixture of ethylene glycol dimethyl ether and ethanol.
  • ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofiiran and dioxane
  • alcohols such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer the mixture of ethylene glycol dimethyl ether and ethanol.
  • the reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal
  • reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • the compound of formula (Illb) is prepared by reduction of the cyano group of the compound of formula (XVII).
  • the reaction may be carried out under the same conditions as described in Step D2 of Method D.
  • Step El the compound of formula (IV) is prepared by conveting the carbonyl group of the compound of formula (XVIII) into the epoxide group.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: amides, such as formamide, ⁇ Ndimethylformamide, A iV-dimethylacetamide and hexamethylphosphoric triamide," sulfoxide such as • dimethyl sulfoxide or sulfolane. Of these solvents, we prefer dimethyl sulfoxide.
  • the reaction is carried out in the presence of a base.
  • bases include-" alkah metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium t-butoxide; and alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate.
  • reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 10°C to 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice. In the case the resulting compound of formula (IV) has the diastereomer, such diastereomer may be separated by chromatographic separation.
  • Method F This illustrates the preparation of compounds of formula (III) wherein R 4a is neither a hydroxy group nor a group of formula —COOR 11 .
  • R 11 is defined as above or R 17 represents an amino-protecting group.
  • the compound of formula (XIX) is prepared by reducing the ester group and the cyano group of the compound of formula (XIII).
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane," and amides, such as formamide, iV-N-dimethylformamide, A Ndimethylacetamide and hexamethylphosphoric triamide.
  • tetrahydrofiiran we prefer tetrahydrofiiran.
  • the reaction is carried out in the presence of a reducing agent.
  • a reducing agent there is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here.
  • reducing agents include: hydride compounds such as lithium aluminum hydride, sodium borohydride and diisobutyl aluminum hydride. Of these, we prefer lithium aluminium hydride.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials.
  • reaction in general, we find it convenient to carry out the reaction at a temperature of from -78°C to 25°C, more preferably from -78°C to 0°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • the compound of formula (IIIc) is prepared by forming the piperidine methyl amino group from the compound of formula (XIX).
  • the reaction may be carried out under the same conditions as described in Steps D3 to D5 of
  • Step F3 the compound of formula (XX) is prepared by oxidizing the hydroxy group of the compound of formula (XIX).
  • an introduction of the amino-protecting group (F3-a) is carried out before the oxidization (F3-b) (F3-a) Introduction of the amino-protecting group.
  • reaction is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-buthoxycarbonyl.
  • the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: water; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane; and sulfoxide such as dimethyl sulfoxide and sulfolane. Of these solvents, we prefer tetrahydrofiiran.
  • the reaction is carried out in the presence of reagent. There is likewise no particular restriction on the nature of the reagents used, and any reagent commonly used in reactions of this type may equally be used here. Examples of such reagents include: di- tert-butyl carbonate and l-(tert-butoxycarbonyl)benztriazole. Of these, we prefer di- tert-butyl carbonate.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • the reaction is normally and preferably effected in the presence of solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane. Of these solvents, we prefer tetrahydorfuran.
  • the reaction is carried out in the presence of an oxidizing agent.
  • oxidizing agents used, and any oxidizing agent commonly used in reactions of this type may equally be used here.
  • condensing agents include: a manganese oxide such as manganese dioxide; a chromic acid compound such as chromic anhydride -pyridine complex," a reagent used for Swern oxidation (a combination of dimethyl sulfoxide and an activating agent (dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and pyridine-trifluoroacetic acid, oxalyl chloride, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric anhydride, sulfur trioxide- pyridine, mercury acetate, chlorine or N-chlorosuccinimide)); a transition metal oxidizing agent such as tetrapropylammonium perruthenate; or a high valence iodine oxidizing agent such
  • reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from O°C to 120°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.
  • Step F4 the compound of formula (XXI) is prepared by converting the carbonyl group of the compound of formula (XX) to a cyano group under the presence of /rtoluenesulfonylmethyl isocyanide.
  • the reaction may be carried out under the same conditions as described in Step D4 of Method D.
  • Step F5 the compound of formula (XXII) is prepared by converting the cyano group of the compound of formula (XXI) to a ester group.
  • This reaction is accomphshed (F5-a) hydrolyzing the cyano group of the compound of formula (XXI) to result a carboxy group and (F5-b) condensing the carboxy group and the compound of formula R"-OH. (F5-a) Hydrolyzing the cyano group
  • the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include: water, " amides, such as formamide, A ⁇ Ndimethylformamide, ⁇ iV-dimethylacetamide and hexamethylphosphoric triamide; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer the mixture of water and methanol.
  • the reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • alkah metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide.
  • sodium hydroxide we prefer sodium hydroxide.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice. (F5"b) Condensing the carboxy group The reaction may be carried out under the same conditions as described in
  • Step F6 the compound of formula (XXIII) is prepared by reducing the ester group of the compound of formula (XXII).
  • the reaction may be carried out under the same conditions as described in Step FI of Method F.
  • the compound of formula (XX) is prepared by oxidizing the hydroxy group of the compound of formula (XXIII). The reaction may be carried out under the same conditions as described in (F3"b) of Step FI of Method F.
  • Step F8 In this step, the compound of formula (Hie) is prepared by forming the piperidine methyl amino group from the compound of formula (XXIII). The reaction may be carried out under the same conditions as described in Step F2 of Method F.
  • the compound of formula (IIIc) is prepared by forming the piperidine methyl amino group from the compound of formula (XXII).
  • the reaction may be carried out under the same conditions as described in Step F2 of Method F.
  • Step Gl the compound of formula (XXV) is prepared by converting the carbonyl group of the compound of formula (XXTV) to a cyano group under the presence of jrtoluenesulfonylmethyl isocyanide. The reaction may be carried out under the same conditions as described in Step D4 of Method D.
  • Step G2 the compound of formula (XXVI) is prepared by converting the cyano group of the compound of formula (XXV) to a ester group.
  • the reaction may be carried out under the same conditions as described in Step F5 of Method F.
  • the compound of formula (XXVII) is prepared by reducing the ester group the compound of formula (XXVI).
  • the reaction may be carried out under the same conditions as described in Step FI of Method F.
  • Step G4 the compound of formula (XXVIII) is prepared by oxidizing the hydroxy group the compound of formula (XXVII).
  • the reaction may be carried out under the same conditions as described in Step F7 of Method F.
  • the compound of formula (XXIX) is prepared by converting the carbonyl group of the compound of formula (XXVIII) to a cyano group under the presence of -toluenesulfonylmethyl isocyanide.
  • the reaction may be carried out under the same conditions as described in Step D4 of Method D.
  • the compound of formula (XXVI) is prepared by converting the cyano group of the compound of formula (XXIX) to a ester group.
  • the reaction may be carried out under the same conditions as described in Step F5 of Method F.
  • the compound of formula (Hid) is prepared by forming the piperidine methyl amino group from the compound of formula (XXVT). The reaction may be carried out under the same conditions as described in Step F2 of Method F.
  • Step G8 In this step, the compound of formula (Hid) is prepared by forming the piperidine methyl amino group from the compound of formula (XXVII). The reaction may be carried out under the same conditions as described in Step F2 of Method F.
  • the compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as distillation, recrystalhzation or chromatographic purification.
  • the optically active compounds of this invention can be prepared by several methods.
  • the optically active compounds of this invention may be obtained by chromatographic separation, enzymatic resolution or fractional crystallization from the final compounds.
  • Several compounds of this invention possess an asymmetric center.
  • the compounds can exist in separated (+)- and (-)-optically active forms, as well as in racemic one thereof.
  • the present invention includes all such forms within its scope.
  • Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • compositions of the present invention prodrugs thereof, pharmaceutically acceptable esters of said compounds and pharmaceutically acceptable salts of said compounds, of said esters or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as ⁇ H and l ⁇ C are incorporated, are useful in drug and/or substrate tissue distribution assay. Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of presentation and detectability.
  • Isotopically labeled compounds of formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedure disclosed in above-disclosed Schemes and/or Examples and Preparations below, by submitting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the invention may take up water upon exposure to the atmosphere to absorb water or to produce a hydrate.
  • the present invention covers such hydrates.
  • compositions of the present invention may be taken up by the compounds of the present invention to produce solvates, which also form pa t of the present invention.
  • the present invention includes salt forms of the compounds (I) as obtained.
  • Certain compounds of the present invention may be capable of forming pharmaceutically acceptable non-toxic cations.
  • Pharmaceutically acceptable non-toxic cations of compounds of formula (I) may be prepared by conventional techniques by, for example, contacting said compound with a stoichiometric amount of an appropriate alkah or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropanol, mixtures thereof, or the like.
  • the bases which are used to prepare the pharmaceuticaUy acceptable base addition salts of the acidic compounds of this invention of formula (I) are those which form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benethamine (i.e., Nbenzyl-2-phenyletylamine), benzathine (i.e., A ⁇ N-dibenzylethylenediamine), choline, diolamine (i.e., diet anolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumineG.e., N-methylglucamine), nicotinamide, olamineG.e., ethanolamine), ornithine, procaine, prohne, pyridoxine, serine, tyrosine, valine and tromethamineG.e.
  • the base addition salts can be prepared by conventional procedures.
  • the certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceuticaUy acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi _ tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, adipate, aspartate camsylate, e
  • bioprecursors also called pro-drugs
  • a bioprecursor of a compound of the formula (I) is a chemical derivative thereof which is readily converted back into the parent compound of the formula (I) in biological systems.
  • a bioprecursor of a compound of the formula (I) is converted back to the parent compound of the formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, e.g., a human subject.
  • a bioprecursor of the compounds of formula G) in which one or both of R 4 and A include hydroxy groups by making an ester of the hydroxy group.
  • R 4 and A include hydroxy groups
  • mono-ester is possible.
  • mono- and di-esters which can be the same or different
  • Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc.
  • bioprecursors can be made by converting the hydroxy group to an acyloxymethyl derivative (e.g., a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e.g., pivaloyloxymethyl chloride).
  • an acyloxymethyl halide e.g., pivaloyloxymethyl chloride.
  • the 5-HT4 receptor binding affinities of the compounds of this invention are determined by the following procedures.
  • Human 5-HT4 binding Human 5"HT 4 (d) transfected HEK293 cells were prepared and grown in-house. The collected cells were suspended in 50 mM HEPES (pH 7.4 at 4°C) supplemented with protease inhibitor cocktail (Boehringer, 1:1000 dilution) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 30 sec on ice. The homogenates were centrifuged at 40,000 x g at 4 °C for 30 min. The pellets were then resuspended in 50 mM HEPES (pH 7.4 at 4 °C) and centrifuged once more in the same manner.
  • protease inhibitor cocktail Boehringer, 1:1000 dilution
  • Nonspecific binding was determined by 1 ⁇ M GR113808 (Tocris) at the final concentration. Incubation was terminated by centrifugation at 1000 rpm. Receptor-bound radioactivity was quantified by counting with MicroBeta plate counter (Wallac).
  • Agonist-induced cAMP elevation in human 5-HT 4 (d) transfected HEK293 cells Human 5"HT (d) transfected HEK293 cells were established in-house. The cells were grown at 37°C and 5% C0 2 in DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4), 200 ⁇ g/ml hygromycin B (Gibco), 100 units/ml penicillin and 100 ⁇ g/ml streptomycin.
  • the cells were grown to 60-80% confluence. On the previous day before treatment with compounds dialyzed FCS (Gibco) was substituted for normal and the cells were incubated overnight.
  • Triton X-100 was added to stop the reaction (25 ⁇ l/well) and the plates were left for 30 minutes at room temperature.
  • Homogenous time-resolved fluorescence-based cAMP (Schering) detection was made according to the manufacturer's instruction.
  • ARVOsx multilabel counter (Wallac) was used to measure HTRF (excitation 320 nm, emission 665 nm/620 nm, delay time 50 ⁇ s, window time 400 ⁇ s).
  • Human dofetilide binding Human HERG transfected HEK293S cells were prepared and grown in-house. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4°C) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates were centrifuged at 48,000 x g at 4 °C for 20 min. The pellets were then resuspended, homogenized, and centrifuged once more in the same manner.
  • the final peUets were resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl 2 (pH 7.4 at 4°C), homogenized, aliquoted and stored at -80°C until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays were conducted in a total volume of 200 ⁇ l in 96-well plates.
  • test compounds Twenty ⁇ l of test compounds were incubated with 20 ⁇ l of [ 3 H]- dofetilide (Amersham, final 5 nM) and 160 ⁇ l of membrane homogenate (25 ⁇ g protein) for 60 minutes at room temperature. Nonspecific binding was determined by 10 ⁇ M dofetilide at the final concentration. Incubation was terminated by rapid vacuum filtration over 0.5% presoaked GF/B Betaplate filter using Skatron cell harvester with 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCb, pH 7.4 at 4°C. The filters were dried, put into sample bags and filled with Betaplate Scint. Radioactivity bound to filter was counted with Wallac Betaplate counter.
  • Caco-2 permeability Caco-2 permeability was measured according to the method described in
  • Caco-2 cells were grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium was removed from both the apical and basolateral compartments and the monolayers were preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.5 hour at 37°C in a shaker water bath at 50 cycles/min.
  • the apical buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 M MES Biological Buffer, 1.25 mM CaCb and 0.5 mM MgC (pH 6.5).
  • the basolateral buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCb and 0.5 mM MgCl 2 (pH 7.4).
  • test compound solution lO ⁇ M
  • the inserts were moved to wells containing fresh basolateral buffer at 1 hr.
  • Drug concentration in the buffer was measured by LC MS analysis.
  • Flux rate (F, mass/time) was calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (Papp) was calculated from the following equation.
  • Papp (cm/sec) (F * ND) / (SA * MD) where SA is surface area for transport (0.3 cm 2 ), VD is the donor volume (0.3ml),
  • the compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals.
  • these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 0.3 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
  • a dosage level that is in the range of from 0.004 mg to 7 mg per kg of body weight per day is most desirably employed for treatment of gastroesophageal reflux disease.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the hke.
  • various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions,
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oralpharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weigiit, preferably 10% to 50% by weight.
  • tablets containing various excipients such as microcrystalhne cellulose, sodium citrate, calcium carbonate, dijpotassium phosphate and glycine may be employed along with various disintegr antes such as starch and preferably corn, potato or tapioca starch, alginic acid and certa_in complex silicates, together with granulation binders like polyvinylpyrrohdone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules ⁇ preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various hke combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the hquid diluent first rendered isotonic.
  • These a_queous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection* purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of tlie present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
  • Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex® DU3050 (Amino Type, 30-50 ⁇ m).
  • Low-resolution mass spectral data (El) were obtained on a Integrity (Waters) mass spectrometer or a Automass 120 (JEOL) mass spectrometer.
  • Low-resolution mass spectral data (ESI) were obtained on a ZMD2 (Waters) mass spectrometer or a Quattro II (Micromass) mass spectrometer.
  • IR spectra were measured by a Shimazu infrared spectrometer GR'47 ⁇ ).

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Abstract

Cette invention porte sur un composé de formula (I): dans laquelle Rl représente un atome d'halogène; R2 représente un atome d'hydrogène etc.; R3 représente un groupe alkyle possédant de 1 à 4 atomes de carbone, etc.;R4 représente un atome d'hydrogène, un groupe hydroxy, un groupe carboxy, etc.; A représente un atome d'oxygène, etc. L'invention porte également sur des sels acceptables d'un point de vue pharmaceutique de ces composés. Ces composés ont une activité agonistique du récepteur 5-HT4 et sont donc utiles dans le traitement du reflux gastro-oesophagien, de la dyspepsie non ulcéreuse, de la dyspepsie fonctionnelle, du syndrome du côlon irritable ou autre chez un mammifère tel qu'un être humain.
PCT/IB2005/000389 2004-03-01 2005-02-16 Derives de 4-amino-5-halogeno-benzamide utiles comme agonistes du recepteur 5-ht4 dans le traitement des troubles gastro-intestinaux, du systeme nerveux central, neurologiques et cardio-vasculaires Ceased WO2005092882A1 (fr)

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WO2007068739A1 (fr) * 2005-12-16 2007-06-21 Glaxo Group Limited Nouveaux composes
WO2007096352A1 (fr) * 2006-02-22 2007-08-30 Glaxo Group Limited 5-amino-6-bromo-n-{[1-(tétrahydro-2h-pyrann-4-ylméthyl)-4-pipéridinyl] méthyl}-3,4 -dihydro-2h-chromène-8-carboxamide en tant qu'agoniste du récepteur 5-ht4
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EP2305652A2 (fr) 2005-12-08 2011-04-06 Novartis AG Dérivés de quinazolinone trisubstituée en tant qu'agonistes de vanilloïde
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
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US7875629B2 (en) 2005-03-02 2011-01-25 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
WO2007048643A1 (fr) * 2005-10-28 2007-05-03 Glaxo Group Limited Nouveau composé
EP2305652A2 (fr) 2005-12-08 2011-04-06 Novartis AG Dérivés de quinazolinone trisubstituée en tant qu'agonistes de vanilloïde
WO2007068739A1 (fr) * 2005-12-16 2007-06-21 Glaxo Group Limited Nouveaux composes
WO2007096352A1 (fr) * 2006-02-22 2007-08-30 Glaxo Group Limited 5-amino-6-bromo-n-{[1-(tétrahydro-2h-pyrann-4-ylméthyl)-4-pipéridinyl] méthyl}-3,4 -dihydro-2h-chromène-8-carboxamide en tant qu'agoniste du récepteur 5-ht4
US8569344B2 (en) 2008-06-02 2013-10-29 Zalicus Pharmaceuticals Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US8377968B2 (en) 2008-06-02 2013-02-19 Zalicus Pharmaceuticals, Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US9096522B2 (en) 2008-06-02 2015-08-04 Zalicus Pharmaceuticals, Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US9593102B2 (en) 2008-10-14 2017-03-14 Sk Biopharmaceuticals Co., Ltd. Piperidine compounds, pharmaceutical composition comprising the same and its use
US9676718B2 (en) 2008-10-14 2017-06-13 Sk Biopharmaceuticals Co., Ltd. Piperidine compounds, pharmaceutical composition comprising the same and its use
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US8642772B2 (en) 2008-10-14 2014-02-04 Sk Biopharmaceuticals Co., Ltd. Piperidine compounds, pharmaceutical composition comprising the same and its use
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
US8232315B2 (en) 2009-06-26 2012-07-31 Sk Biopharmaceuticals Co., Ltd. Methods for treating drug addiction and improving addiction-related behavior
US9688620B2 (en) 2009-11-06 2017-06-27 Sk Biopharmaceuticals Co., Ltd. Methods for treating fibromyalgia syndrome
US9663455B2 (en) 2009-11-06 2017-05-30 Sk Biopharmaceuticals Co., Ltd. Methods for treating attention-deficit/hyperactivity disorder
US10202335B2 (en) 2009-11-06 2019-02-12 Sk Biopharmaceuticals Co., Ltd. Methods for treating attention-deficit/hyperactivity disorder
US8895609B2 (en) 2009-11-06 2014-11-25 Sk Biopharmaceuticals Co., Ltd. Methods for treating attention-deficit/hyperactivity disorder
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WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
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