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WO1992003427A1 - Compose de cetone et remede pour l'osteoporose - Google Patents

Compose de cetone et remede pour l'osteoporose Download PDF

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Publication number
WO1992003427A1
WO1992003427A1 PCT/JP1991/001079 JP9101079W WO9203427A1 WO 1992003427 A1 WO1992003427 A1 WO 1992003427A1 JP 9101079 W JP9101079 W JP 9101079W WO 9203427 A1 WO9203427 A1 WO 9203427A1
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WIPO (PCT)
Prior art keywords
alkyl
pyridine
optionally substituted
substituted
hydroxy
Prior art date
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PCT/JP1991/001079
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English (en)
Japanese (ja)
Inventor
Takanori Ohe
Takeshi Akagi
Kenji Chiba
Yusaku Amano
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Japan Tobacco Inc.
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Application filed by Yoshitomi Pharmaceutical Industries, Ltd., Japan Tobacco Inc. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to JP6900992A priority Critical patent/JPH0586064A/ja
Publication of WO1992003427A1 publication Critical patent/WO1992003427A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Ketone compounds and therapeutic agents for osteoporosis are Ketone compounds and therapeutic agents for osteoporosis
  • the present invention has an excellent bone resorption inhibiting action, and is useful as a therapeutic agent for osteoporosis, a novel ketone compound and a pharmaceutically acceptable salt thereof, and a ketone compound including the novel compound and a pharmaceutically acceptable salt thereof. Related to the use of salt.
  • Osteoporosis is a syndrome that refers to a condition in which the amount of bone per unit volume is abnormally reduced without changing the chemical composition of the bone itself (the ratio between organic and inorganic substances). Calcium and phosphorus reduction are its physiological characteristics.
  • bone loss as a pathological condition is accompanied by a decrease in bone mass due to physiological aging, the definition of bone loss is more pronounced than that due to physiological aging. It can be said that the patient had clinical symptoms such as a mechanical fracture and vertebral deformity.
  • Osteoporosis increases with age and usually affects the spinal cord, causing lower back and back pain and shorter height. Especially in advanced cases, the long bones are also affected, and sometimes fractures may occur. It is said that most of the causes of femoral fractures in the elderly are due to senile osteoporosis.
  • osteoporosis The causes of osteoporosis are diverse, including endocrine abnormalities, including menopause, and nutritional disorders.However, vitamin D, calcium, calcitonin, and bisphosphonate, which have been used as treatments for osteoporosis, are targeted Or its effect But it is not certain. Although female hormone preparations can be expected to be effective, serious side effects (eg, genitals caused by long-term use) are problematic.
  • a (cycloalkylamino) methylenebis (phosphonic acid) derivative (US Pat. No. 4,970,335), a heterocyclic bisphosphonic acid derivative (US Pat. No. 0503) and benzofuroquinoline derivatives (Japanese Patent Publication No. 3571172).
  • thieno or furopyridine compounds include 3-hydroxyl xyph [2,3-b] pyridin-l-2-ethyl ethyl ribonate and 3-hydroxythieno [2,3-b] pyridine-12-cal J. Heterocyclic Chem. 23, 1465-1469, 1986 Year, Vol. 24, pp. 85-89, reported in 1987. However, these are all synthesized for the purpose of confirming their interest in synthesis or chemical reactivity, and do not describe any pharmacological activity. Further, Canadian Published Patent Application No. 2009-171 discloses a 3-hydroxybenzthiophene or chenoviridine compound for controlling in vivo parasites. In addition, British Patent No. 1119496 discloses a benzothiophene compound having an analgesic and anti-inflammatory effect and the like.
  • the present inventors have synthesized various ketone compounds for the purpose of developing a better therapeutic agent for osteoporosis, and have conducted intensive studies on their pharmacological actions.
  • the inventors have found ketone compounds and have completed the present invention.
  • the present invention is as follows.
  • the ketone compound (I) represented by or a pharmaceutically acceptable ili 0 Ring X represents a pyridine ring.
  • Y represents an oxygen atom or a sulfur atom.
  • Z represents a single bond, alkylene, alkenylene, or alkynylene.
  • R 1 and R 2 may be the same or different, and may be hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, rubamoyl optionally substituted with alkyl, alkoxycarbonyl, Optionally substituted phenyl, nitro, acetyl, sulfamoyl optionally substituted with alkyl, alkylthio, aryloxy, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy Represents hydroxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl which may be substituted with alkyl, aminoalkyl which may be substituted with alkyl, or acylaminoalkyl.
  • R 1 and R 2 alkylene which may have a bond to
  • R 3 represents a hydroxyl group, an acyloxy, an alkody, an aminoalkoxy optionally substituted with an alkyl, an alkylsulfonylamino, an aminoaminosulfonylamino optionally substituted with an alkyl, or an arylsulfonylamino.
  • R is alkyl, aralkyl which may have a substituent, aromatic ring which may have a substituent or heteroaromatic group which may have a substituent (the substituent is halogen, Alkyl, Arco W
  • Xy hydroxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino, alkamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoyl Alkenyl, haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and 1-3 amino substituents).
  • Cyclic X ′ represents a benzene ring or a pyridine ring.
  • R 3A represents a hydroxyl group or acyloxy.
  • R 4A represents aminoalkyl optionally substituted with alkyl or acylaminoalkyl optionally substituted with alkyl.
  • a therapeutic agent for osteoporosis comprising, as an active ingredient, a ketone compound (1 ') represented by the formula: or a pharmaceutically acceptable salt thereof.
  • Z ′ represents a single bond, alkylene, alkenylene, alkynylene or 1 NR 5 —.
  • R 5 represents hydrogen, alkyl, acyl, aralkyl which may have a substituent, or a group which forms a nitrogen-containing heterocycle by bonding with R * ′.
  • R 4 ′ is hydrogen, alkyl, an optionally substituted arylalkyl, an optionally substituted aromatic ring group or an optionally substituted heteroaromatic ring group (substituent and Are halogen, alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acsyl. Alkoxycarbonyl, carboxyl, carboxyl, amino, alkylamino.
  • Rings X ′, Y, R 1 , R 2 , and R 3 have the same meaning as defined above. 4.
  • the alkylene may be linear or branched, and usually has 1 to 4 carbon atoms, and specific examples include methylene, ethylene, trimethylene, propylene, and tetramethylene.
  • Alkenylene may be linear or branched, and usually has 1 to 4 carbon atoms, and specific examples thereof include vinylene, bronylene, butenylene and the like.
  • Alkynylene may be linear or branched, and usually has 1 to 4 carbon atoms. Specific examples thereof include ethynylene, brovinylene, and petinylene.
  • examples of the alkyl include those similar to the alkyl for R 1 and R 2 described below.
  • examples of the acyl include the same as those described below for R 1 and R 2 .
  • Examples of the aralkyl which may have a substituent with respect to R 6 of ⁇ ′ include the same as the aralkyl which may have a substituent with respect to R 4 and below.
  • Examples of the nitrogen-containing heterocyclic ring formed by bonding Z ′ to R 4 ′ include oxygen, sulfur, or a nitrogen atom which may be substituted as a hetero atom (substituents such as alkyl, phenylalkyl, and a And a 5- to 7-membered ring which may have pyrrolidine, piperidine, morpholine, virazine, 4-methylbiperazine and the like.
  • C D-gen means fluorine, chlorine, bromine, and iodine.
  • Alkyl may be either straight or branched, and usually has 1 to 10, preferably 1 to 8, and more preferably 1 to 6, carbon atoms. Specifically, methyl, ethyl, propyl, isopropyl Butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, octyl and the like.
  • Alkoxy may be linear or branched, and usually has 1 to 10, preferably 1 to 8, and more preferably 1 to 6, carbon atoms. Specifically, methoxy, ethoxy , Propoxy, isopropoxy, butoxy, isobutoxy, second-butoxy, third-butoxy, pentyloxy, hexyloxy, octyloxy and the like.
  • the alkyl moiety in the haloalkyl may be either linear or branched, and usually has 1 to 4, preferably 1 to 3 carbon atoms.
  • Specific examples of haloalkyl include fluoromethyl, difluoromethyl, Bromomethyl, chloromethyl, trifluoromethyl, trifluorethyl, and pentafluorov mouth building are exemplified.
  • Amino in amino which may be substituted with alkyl may be mono- or di-substituted with alkyl having 1 to 4 carbon atoms, preferably in a linear or branched form, In addition, No. may be annular. Specific examples of such amino include amino, methylamino, dimethylamino, ethylamino, ethylamino, pyrrolidino, biperidino, morpholino, and the like.
  • Alkyl as a substituent in the sorbamoyl which may be substituted with alkyl has usually 1 to 5, preferably 1 to 3 carbon atoms.
  • the amino may be cyclic.
  • Specific examples of such rubamoyl include rubamoyl, methylcarbamoyl, dimethylcarbamoyl, and morpholino rubamoyl.
  • the alkoxy moiety in the alkoxycarbonyl may be linear or branched, and has 1 to 4 carbon atoms.
  • Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. , Isopropoxycarbonyl, butoxycarbonyl, isobutoxydicarbonyl, third-butoxycarbonyl and the like.
  • the substituent in the phenyl which may have a substituent is the same as the substituent in the aromatic ring which may have a substituent or the heteroaromatic ring which may have an S group described below for R 4.
  • Examples are preferably alkyl, halogen, alkoxide, hydroxyl group, aminoalkoxy optionally substituted with nitroalkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl.
  • phenyl examples include chlorophenyl, methylphenyl, methoxyphenyl, nitrophenyl, dimethylaminoethylphenyl, dimethylaminobromoboxyl Phenyl, hydroxyphenyl, acetylaminoethylphenyl and the like.
  • the acyl may be any of an aliphatic acyl, an aromatic acyl, and a heterocyclic acyl.
  • the aliphatic acyl is preferably an Al-oil, and particularly preferably an Al-oil having 2 to 5 carbon atoms.
  • Specific examples of acetyl include acetyl, bropionyl, butyryl, bivaloyl, benzoyl, floyl, tenyl, nicotinyl, and isonicotinyl.
  • the alkyl as a substituent in the sulfamoyl optionally substituted with argyl may be either linear or branched, and may be mono-substituted or di-substituted.
  • the alkyl has usually 1 to 4, preferably 1 to 2, carbon atoms.
  • Examples of such sulfamoyl include sulfamoyl, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, and getylsulfamoyl.
  • Alkyl in alkylthio may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.As alkylthio, methylthio, ethylthio, propylthio, isobrovirthio, Butylthio and the like.
  • arylthio examples include phenylthio, tolylthio, and chlorofluorothio.
  • Alkyl in alkylsulfinyl may be linear or branched, and usually has 1 to 4, preferably 1 to 2, carbon atoms.
  • alkylsulfinyl include methylsulfinyl, ethylsulfiel, butylsulfinyl and the like. Is exemplified You.
  • arylsulfinyl examples include phenylsulfinyl, tolylsulfenyl, and chlorophenylsulfinyl.
  • Alkyl in alkylsulfonyl may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.
  • alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and butylsulfoyl. Is exemplified.
  • arylsulfonyl examples include phenylsulfonyl, trisulfonyl, and chlorophenylsulfonyl.
  • aryloxy examples include phenyloxy, trioxy, chlorooxy, nitrooxy, and the like.
  • aralkyloxy include benzyloxy, phenylethoxy, and fuyunylbutoxy.
  • the alkyl moiety in the hydroxyalkyl may be linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, and includes hydroxymethyl, hydroxyxetyl and the like.
  • acyl moiety in the acyloxyalkyl examples include the acyl as described above, and the alkyl moiety may be either linear or technical, and usually has 1 to 4, preferably 1 to 2 carbon atoms.
  • examples of the acyloxyalkyl include acetoxmethyl, acetoxityl, acetooxybutyl, bropionoxyloxymethyl, and bivaloyloxymethyl.
  • the alkoxy moiety in the alkoxyalkyl may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. The carbon number is usually 1 to 4, preferably 1 to 2, and the alkoxyalkyl is exemplified by methoxymethyl, methoxyl, ethoxyl, methoxybutyl and the like.
  • Alkyl as a substituent in the aminoalkoxy which may be substituted with alkyl may be either mono-substituted or di-substituted, and the alkyl may be any of straight-chain or branched-chain, and its carbon number is Usually, it is 1-4, preferably 1-2, and the alkoxy moiety may be either linear or branched, and its carbon number is usually 1-4, preferably 1-2.
  • the amino alkoxy may be a cyclic amino alkoxy. Examples of the aminoalkoxy include aminoethoxy, methylaminomethoxy, dimethylaminoethoxy, 1-pyrrolidinylmethoxy, biperidinomethoxy, morpholinomethoxy and the like.
  • Alkyl as a substituent in aminoamino which may be substituted with alkyl may be either mono-substituted or di-substituted, and the alkyl may be either linear or branched, and the number of carbon atoms is usually
  • the alkyl moiety may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.
  • the aminoalkyl may be a cyclic aminoalkyl. Examples of the aminoalkyl include aminomethyl, methylaminomethyl, and dimethylaminomethyl. Examples thereof include methyl, ethylaminomethyl, dimethylaminobutyrol, 1-pyrrolidinylmethyl, piberidinomethyl, and morpholinoethyl.
  • the acyl moiety as a substituent in the acylaminoalkyl may be linear or branched, and usually has 2 to 4 carbon atoms.
  • the alkanoyl or cyclic substituent halogen, alkyl (1 to 4 carbon atoms) may be used.
  • the alkyl moiety may be either linear or branched, and usually has 1-4 carbon atoms, preferably 1-2 carbon atoms.
  • acetylaminoalkyl examples include acetylaminomethyl, acetylaminoethyl, brovonylaminomethyl, propionylaminoethyl, benzoylaminoethyl and the like.
  • Examples of the substituent in the alkylene, alkylenedioxy and benzene ring which may be substituted, which are formed by bonding R 1 and R 2 to each other, include R ′ and R 2 .
  • R ′ and R 2 are included, and preferably, for example, the following are exemplified as preferred.
  • Alkyl (It may be straight-chain or divided, and its carbon number is usually 1 to 4, preferably 1 to 2.)
  • Alkoxy (It may be either straight-chain or branched, and its carbon number is usually 1-4, preferably 1-2.)
  • Haloalkyl (The alkyl moiety may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.)
  • ⁇ Amino may be substituted by alkyl (the alkyl moiety may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms.)
  • the alkylene which may have a substituent preferably has 1 to 4 carbon atoms, and examples thereof include methyltrimethylene, dimethyltrimethylene, methyltetramethylene, dimethyltetramethylene, and dimethylpentamethylene.
  • Alkylene in alkylenedioxy which may have a substituent has 1 to 4 carbon atoms, and alkylenedioxy includes methylenedioxy, ethylenedioxy, isopropylidenedioxy and the like.
  • Examples of the group which forms a benzene ring which may have a substituent include benzene, methylbenzene, hydroxybenzene, methoxybenzene, trifluoromethylbenzene, cyanobenzene, nitrobenzene, dimethylaminobenzene and the like. Is exemplified.
  • acyl in the acyloxy examples include those described for R 1 and R 2.
  • examples include cetoxy, bropionyloxy, benzoyloxy and the like.
  • alkoxy examples include those as described for R 1 and R 2 .
  • aminoalkoxy which may be substituted with alkyl include those described for R 1 and R 2 .
  • the alkyl moiety in the alkylsulfonylamino may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. Sulfonylamino, ethylsulfonylamino, butylsulfonylamino and the like can be mentioned.
  • alkyl and the alkyl moiety as the substituents in the aminoalkylsulfonylamino which may be substituted with alkyl may be either straight-chain or branched, respectively, and usually have 1 to 4 carbon atoms. Preferably, it is 1-2, and the alkyl substitution may be either mono or di substitution.
  • aminoalkylsulfonylamino examples include aminomethylsulfonylamino, aminoethylsulfonylamino, aminobutylsulfonylamino, methylaminoethylsulfonylamino, dimethylaminoethylsulfonylamino, dimethyl Pyrsulfonylamino amino and the like.
  • the aminoalkylsulfonylamino may be a cyclic aminoalkylsulfonylamino, such as pyrrolidinomethylsulfonylamino, piperidinomethylsulfonylamino, and the like.
  • Phenylsulfonylamino as phenylsulfonylamino Mino, tolylsulfonylamino, black phenylsulfonylamino, and the like.
  • alkyl examples include those described with respect to R 1 and R 2 .
  • the substituent in the aralkyl which may have a substituent is the same as the substituent in the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent for R 4 described below. And preferably include halogen, alkyl, alkoxy, aminoalkoxy optionally substituted with alkyl, aminoamino optionally substituted with alkyl, acylaminoalkyl, and the like.
  • aralkyl examples include benzyl, phenylethyl, phenylpropyl, phenylbutyl, chlorobenzyl, methylbenzyl, methoxyphenylethyl, dimethylaminobromoboxylbenzyl, dimethylaminoethylbenzyl, acetylaminomethylmethylbenzyl and the like. Is done.
  • the substituent on the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent is as follows.
  • 1Halogen such as fluorine, chlorine and bromine
  • C 1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc .
  • Alkoxy with 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy;
  • Alkylthio having usually 1 to 4 carbon atoms in the alkyl moiety, such as methylthio, ethylthio, brovirthio, isopropylthio, butylthio, isobutylthio, and tert-butylthio;
  • Alkyl sulfiel whose alkyl group moiety such as methylsulfiel, ethylsulfinyl and propylsulfinyl usually has 1 to 4 carbon atoms;
  • alkylsulfonyl wherein the alkyl moiety such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like is usually 1 to 4;
  • Haloalkyl in which the alkyl portion of the alkyl moiety such as trifluoromethyl, trifluorethyl and the like usually has 1 to 4 carbon atoms;
  • acyl as described above, including diacetyl, propionyl, butyryl, benzoyl and the like;
  • alkoxycarbonyl having 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl; 13carboxyl;
  • Amino which may be mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as diamino, methylamino, ethylamino, pyrrolidino, pyridino, morpholino;
  • ⁇ Capacyl which may be mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as carbamoyl, methylcarbamoyl and ethylcarbamoyl; ⁇ ⁇ ⁇ ⁇ ⁇ alkylene dioxy having alkylene having 1 to 4 carbon atoms, such as methylene dioxy and ethylene dioxy;
  • alkyl moiety such as cyanomethyl, cyanoethyl, cyanobutyl pill, cyanobutyl, etc., which may be straight or branched, and whose carbon number is usually 1 to 4;
  • Alkyl and alkoxy moieties such as methoxycarbonylethyl and ethoxycarbonylethyl may be either linear or branched, each having 1 to 4 carbon atoms, alkoxycarbonylalkyl;
  • the alkyl group portion such as carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and the like may be linear or branched, and a carboxylalkyl having an alkyl group usually having 1 to 4 carbon atoms;
  • alkoxy moiety such as chloroethoxy, trifluoromethoxy, trifluorethoxy, etc. may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms;
  • @Amino alcohol optionally substituted with alkyl such as dimethylamino methoxy, getyl amino methoxy, dibutyl amino methoxy, dimethyl amino ethoxy, dimethyl amino bromoboxy;
  • ®Aminomethyl, methylaminomethyl, dimethylaminomethyl Alkyl, dimethylaminoethyl, ethylaminomethyl, dimethylaminophenol and the like as the alkyl moiety and the substituent may be either straight-chain or branched, and usually have 1 to 4 carbon atoms.
  • the alkyl as a substituent may be either mono- or di-substituted, aminoalkyl optionally substituted with alkyl;
  • the alkyl moiety of the alkyl moiety such as @acetylaminomethyl, acetylaminoethyl, propionylaminomethyl, brovonylaminoethyl, benzoylaminoethyl, etc., may be either straight-chain or branched, and usually has 1-4 carbon atoms, preferably 1-4 carbon atoms. 2, wherein the acyl moiety is the same as the above-mentioned acyl group, acylamino alkyl.
  • aromatic ring and the heteroaromatic ring which may have a substituent include benzyl, phenylethyl, phenylpropyl, phenyl, naphthyl, indenyl, chenyl, frill, phenyl, imidazolyl, virazolyl, and thiazolyl.
  • aromatic ring and the heteroaromatic ring which may have a substituent include benzyl, phenylethyl, phenylpropyl, phenyl, naphthyl, indenyl, chenyl, frill, phenyl, imidazolyl, virazolyl, and thiazolyl.
  • examples thereof include oxazolyl, indolyl, pyridyl, virazyl, pyrimidinyl, quinolyl, isoquinolyl, and thionaphthene 1-2 or 3-yl.
  • the compound of the present invention is converted into a pharmaceutically acceptable salt if necessary.
  • the salts include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and addition with organic acids such as maleic acid, fumaric acid, cunic acid, succinic acid, tartaric acid, and methanesulfonic acid. Salt or sodium, calcium, calcium, magnesium, ammonium And other salts. Hydrates (1/2 dihydrate, monohydrate, dihydrate, 3Z dihydrate, etc.) are also included in the present invention. When the compound of the present invention has an asymmetric carbon, optically active substances and mixtures thereof are also included in the scope of the present invention.
  • the production methods of the compounds (I) and (1 ′) are as follows.
  • the compound (1 ′) is used as a concept including the compound (I ′′).
  • a dehydrating agent such as polyborinic acid or phosphorus pentoxide.
  • a solvent such as benzene, toluene, or xylene.
  • R ′ represents a lower alkyl group such as methyl and ethyl, and other symbols are as defined above.
  • the compound ( ⁇ ') is represented by the following formula: In an alcohol solvent such as methanol, ethanol, bromonol, isobromo alcohol, or butanol, a base (sodium methoxide, potassium tertiary butoxy-'node, sodium hydride) , Triethylamine, etc.) at 0 to 100 for 5 minutes to 5 hours.
  • an alcohol solvent such as methanol, ethanol, bromonol, isobromo alcohol, or butanol
  • a base sodium methoxide, potassium tertiary butoxy-'node, sodium hydride
  • Triethylamine Triethylamine, etc.
  • R 4 or R ⁇ ′ is an aromatic or heteroaromatic ring group substituted by an optionally substituted aminoalkoxy
  • R ⁇ or R 4 'Is produced by subjecting a compound in which' is an aromatic or heteroaromatic group substituted by haloalkoxy such as cycloalkoxy to an amination reaction known per se.
  • R 4 or R * ′ is an aromatic or heteroaromatic group substituted by carboxyl or carboxyalkyl
  • R * or R ⁇ ′ is cyano Alkoxycarbonyl, alkoxycarbonyl, cyanoalkyl, alkenylcarbonyl or alkenylcarbonyl, etc. It is produced by subjecting a compound which is an aromatic ring group or a heteroaromatic ring group substituted by a susceptible group to a hydrolysis reaction known per se.
  • the method 2 Z is NR 5 compounds of (I ') produced
  • R 7 represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and other symbols are as defined above.
  • R 7 is a lower alkyl group
  • the reaction is carried out in a suitable solvent (any solvent may be used as long as it does not interfere with the reaction; for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, dichloroethane, and chloroform).
  • aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, dichloroethane, and chloroform
  • Halogenated hydrocarbons such as methanol, ethanol, propanol, alcohols such as isobromovir alcohol, ethylene glycol and diethylene glycol, and any mixed solvents thereof
  • Triethylamine, sodium hydride, sodium methoxide, potassium butoxide, potassium carbonate In the presence or absence.
  • the reaction temperature is not particularly limited, and the reaction usually proceeds from room temperature to 200 for 5 minutes to 10 hours.
  • R 7 is a hydrogen atom
  • the reaction is carried out in the presence of a dehydrating agent such as dicyclohexyl carpamide, or thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, chlorocarbonate, etc. Is performed after the active ester is once formed.
  • a dehydrating agent such as dicyclohexyl carpamide, or thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, chlorocarbonate, etc.
  • Method 4 Production of compounds (I) and (I ') in which R 3 is alkoxydi or an aminoalkoxy optionally substituted with alkyl.
  • Compound (1Y) or ( ⁇ ) and alkyl halide, aminoalkyl halide, alkylamino Alkyl halide, dialkylaminoalkyl halide or cyclic aminoalkyl halide is used as a deoxidizing agent (potassium carbonate, sodium hydroxide, calcium hydroxide, sodium methoxide, triethylamine, pyridine, etc.) It is produced by reacting in a solvent inert to the reaction (toluene, methanol, ethanol, dimethylformamide, acetone, dioxane, etc.) at a temperature between room temperature and 150 ° C.
  • R 3 is substituted with alkylsulfonylamino or alkyl
  • compounds (I) and ( If ) which are aminoalkylsulfonylamino or arylsulfonylamino which may be
  • R 8 - S 0 2 - H a £ ( ⁇ ) wherein, R 8 is alkyl, alkyl optionally substituted ⁇ Mi Noarukiru (i.e., amino Noarukiru, alkylamino Noah alkyl, Jiarukiruami Noarukiru, cyclic ⁇ Mi Noarukiru ), Aryl or haloalkyl, and H a represents halogen.
  • Mi Noarukiru i.e., amino Noarukiru, alkylamino Noah alkyl, Jiarukiruami Noarukiru, cyclic ⁇ Mi Noarukiru
  • H a represents halogen.
  • a deoxidizing agent such as potassium carbonate, sodium carbonate, sodium bicarbonate, dimethylamine, triethylamine, pyridine, quinoline, etc.
  • an inert solvent toluene, methylene chloride, chloroform, dichloroethane, pyridine, dimethylformamide, etc.
  • the amount of c- sulfonyl halide produced by reacting at a temperature of 100 ° C. from 100 ° C. and the reaction conditions are appropriately selected. By this, either the mono-substituted product or the bis-substituted product can be predominantly synthesized.
  • the compounds (I) and (I) of the present invention can be produced by a known method or a method known per se.
  • the ketone compound according to the present invention obtained in this manner can be purified individually by a common method such as a recrystallization method, a chromatographic method, and distillation alone or in combination.
  • the racemic compound can be split into optically active substances by the action of, for example, an optically active acid (tartaric acid, diacetyltartaric acid, tartronic acid, dibenzoyltartaric acid, mandelic acid, etc.).
  • an optically active acid tartaric acid, diacetyltartaric acid, tartronic acid, dibenzoyltartaric acid, mandelic acid, etc.
  • it can be separated into optically active substances by using an optically active chromatographic method.
  • a compound having a desired configuration can be stereoselectively obtained by using an optically active raw material compound.
  • the ketone compound according to the present invention may be an addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or an organic salt such as maleic acid, fumaric acid, cunic acid, succinic acid, tartaric acid, methanesulfonic acid or the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid
  • organic salt such as maleic acid, fumaric acid, cunic acid, succinic acid, tartaric acid, methanesulfonic acid or the like.
  • Addition salts with acids and sodium, potassium, calcium, Pharmaceutically acceptable salts such as magnesium salts, ammonium salts and the like can be used.
  • the compound (I) used as a raw material in the present invention has the general formula
  • Ra represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and other symbols are as defined above.
  • ⁇ ⁇ ⁇ ⁇ represents a halogen atom (as defined above) or a sulfonic acid residue such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluorosulfone methanesulfonyloxy group, and the other symbols are as above. Is synonymous with.
  • compound (X) or (X ′) represented by the following formula By reacting the compound (X) or (X ′) represented by the following formula with 0 to 100 for 5 minutes to 20 hours.
  • compound (H) which is a raw material compound, passes through compound (I). It can be produced by esterification using a conventional method. Further, other starting compounds can be synthesized by a method known per se.
  • the compounds (I) and (I ') of the present invention show a strong inhibitory action on bone resorption in an in vitro bone resorption measuring system using femurs or parietal bones of mice or rats, and have low cytotoxicity. In addition, it has the effect of suppressing hypercalcemia (increased serum calcium concentration) induced by tumor-bearing mice or tumor-bearing rats, and is useful as a highly safe therapeutic agent for osteoporosis.
  • the in vitro bone resorption inhibitory action using mouse femurs was measured according to the following method.
  • test compound was once dissolved in dimethyl sulfoxide to prepare a solution of 100 ingZml, which was diluted 100-fold with a culture solution to obtain a solution of 10 gZml.
  • ICR mouse femurs were placed in a 24-hole plate for 6 days with 5% carbon dioxide and 95% air. Culture was performed under the following conditions. After completion of the culture, the culture supernatant was collected, and the amount of calcium released in the culture supernatant was quantified by a chelate method using orthocresol phthalein.
  • the bone resorption inhibiting effect of the test compound was determined by the following formula using the femoral culture in the absence of the test compound as a control.
  • Compound 103.2.3 Compounds (I) and ( If ) and pharmaceutically acceptable salts thereof according to the present invention can be used as they are or as pharmaceutically acceptable carriers, excipients, and disintegrants. Tablets, by mixing with binders, lubricants, bulking agents, diluents, solubilizing agents, etc., and dispensing according to the usual methods. Preparations, powders, granules, pills, capsules, syrups, injections, ointments, suppositories and the like can be administered to patients.
  • the dosage varies depending on the subject of administration, administration route, symptoms, etc., but is usually 1 to 100 mg / day for oral administration and 0.1 to 100 mg / day for nasal, intravenous and rectal administration per adult. It is appropriate and can be administered in one or several doses.
  • a tablet containing 5 ng of the compound of the present invention can be prepared according to the following formulation.
  • 2- (4-1- (3-hydroxy) was used in the same manner as in Example 1 except that 2- (4- (1-ylrubamoylethyl) phenacylthio) nicotinic acid was used.
  • Cithieno (2,3-b] pyridin-1-2-carbonyl) phenyl) propionic acid was obtained, mp 164-16.5.
  • Sodium methoxide was prepared with methanol 30 rol and sodium gold sodium 0.7 g, and 5.0 g of methyl thiosalicylate was added under ice cooling. Then, 9.2 g of ⁇ -bromo-41- (3-chlorobromobox) acetophenone was gradually added, and the mixture was reacted at 0 for 1 hour and further at 20 at 1 hour. The precipitated crystals were collected, washed with water and purified from methanol to obtain methyl 2- [4- (3-chlorobromobox) phenacylthio] benzoate. With a melting point of 103.
  • Example 2 was repeated in the same manner as in Example 14 except that 3,5-di-tert-butyl-4-hydroxyhydroxypromide bromide was used instead of N-acetyl-4-chloroacetylphenethylamine. — (3, 5-di-tert-butyl-4-hydroxybenzoyl) 1-3-hydroxybenzothiophene was obtained. Melting point 13 8-13 9 'Co Example 18
  • Example 2 1 3-Amino 2-benzoyl 6-Isobrovirfur [2,3-b] Pyrididine 1.4 g, chloroform 10 ml, triethylamine 0.6 g, and methane under ice-cooling 0.68 g of sulfoyurc-mouth ride was added dropwise over 40 minutes, and the mixture was reacted at 10 for 2 hours and at 30 for 1 hour, and then water was added for liquid separation. After separation, the chloroform was distilled off, and the residue was extracted with toluene.
  • N- (2,4) was prepared in the same manner as in Example 7 except that methyl 2- (2,4-difluorophenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate.
  • —Difluorophenyl) -13-hydroxythieno [2,3-b] pyridine-12-carboxamide was obtained. With a melting point of 25 1 to 25 4.
  • Example 7 In the same manner as in Example 7 except that methyl 6-methyl-2-phenylphosphonicotinate instead of using methyl 2- (2,4-difluorophenylcarbamoylmethylthio) -1-6-methylnicotinate was used. (2,4-Difluorophenyl) -13-hydroxy-6-methylthieno [2,3-b] pyridine-12-carboxamide was obtained. Mp 274-278.
  • Example 7 Same as Example 7 except that methyl 2- (2,6-dimethylphenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate Thus, N- (2,6-dimethylphenyl) -13-hydroxythieno [2,3-b] pyridin-12-carboxamide was obtained. With a melting point of 210-212.
  • N— (3-—) was prepared in the same manner as in Example 7 except that methyl 2- (3-trifluoromethylphenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate.
  • Trifluoromethylphenyl) -3-Hydroxyxythieno (2,3-b) pyridine-12-caproloxamide was obtained with a melting point of 223-224 (decomposition).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

On décrit l'utilisation d'un composé répondant à la formule générale (I') ou d'un sel de celui-ci pour le traitement de l'ostéoporose, ainsi qu'un nouveau composé compris dans ledit composé. Dans ladite formule, l'anneau X' représente benzène ou pyridine; Y représente oxygène ou soufre; Z' représente une liaison simple, alkylène, alcénylène, alcynylène ou NR?5, où R5¿ représente hydrogène, alkyle, acyle, aralkyle éventuellement substitué ou un groupe formant conjointement avec R4' un anneau hétérocyclique azoté; R1 et R2 représentent chacun hydrogène, halogène, alkyle, alcoxy, hydroxy, cyano, haloalkyle, carboxyle, amino éventuellement substitué par alkyle, carbamoyle éventuellement substitué par alkyle, sulfamoyle éventuellement substituté par alkyle, alkythio, arylthio, alkylsulfinyle, arylsulfinyle alkylsulfonyle, arylsulfonyle, aryloxy, aralkyloxy, hydroxyalkyle, acyloxyalkyle, alcoxyalkyle, aminoalkyle éventuellement substitué par alkyle, ou acylaminoalkyle; sinon R1 et R2 peuvent s'associer l'un à l'autre pour représenter alkylène éventuellement subsitué, alkylènedioxy ou un cycle benzénique; R3 représente hydroxy, acyloxy, alcoxy, aminoalcoxy éventuellement substitué par alkyle, alkylsulfonylamino, aminoalkylsulfonylamino éventuellement substitué par alkyle, ou arylsulfonylamino; et R4' représente hydrogène, alkyle, aralkyle éventuellement substitué, un groupe aromatique éventuellement substitué ou un groupe hétéroaromatique éventuellement substitué.
PCT/JP1991/001079 1990-08-17 1991-08-14 Compose de cetone et remede pour l'osteoporose WO1992003427A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
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US5350748A (en) * 1993-08-18 1994-09-27 Warner-Lambert Company 3-thio or amino substituted-benzo[b]thiophene-2-carboxamides and 3-oxygen, thio, or amino substituted-benzofuran-2-carboxamides as inhibitors of cell adhesion
US5656638A (en) * 1995-04-18 1997-08-12 Geron Corporation Telomerase inhibitors
US5925636A (en) * 1996-05-20 1999-07-20 Darwin Discovery Limited Benzofuran carboxamides and their therapeutic use
US6239142B1 (en) 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US6620810B2 (en) 2001-08-30 2003-09-16 Pharmacia & Upjohn Company 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
WO2003103661A1 (fr) * 2002-06-06 2003-12-18 Boehringer Ingelheim Pharmaceuticals, Inc. COMPOSES AMIDE D'ACIDE 3-AMINO-THIENO[2,3-b]PYRIDINE-2-CARBOXYLIQUE SUBSTITUES ET PROCESSUS DE PREPARATION ET D'UTILISATION DE CES COMPOSES
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
US6974870B2 (en) 2002-06-06 2005-12-13 Boehringer Ingelheim Phamaceuticals, Inc. Substituted 3-amino-thieno [2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
WO2006068618A1 (fr) * 2004-12-23 2006-06-29 Astrazeneca Ab Nouveaux composés
US7091216B2 (en) 2002-08-02 2006-08-15 Merck & Co., Inc. Substituted furo[2,3-b]pyridine derivatives
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7592353B2 (en) 2006-06-06 2009-09-22 Boehringer Ingelheim International Gmbh Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
US7674822B2 (en) 2004-11-24 2010-03-09 Wyeth PTP1b inhibitors
WO2014207213A1 (fr) 2013-06-28 2014-12-31 Medizinische Universität Innsbruck Nouveaux inhibiteurs de la signalisation de la protéine kinase c epsilon
CN115805103A (zh) * 2021-09-14 2023-03-17 万华化学集团股份有限公司 一种失活钛硅分子筛的再生方法

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JPS60226875A (ja) * 1984-04-02 1985-11-12 メルク　エンド　カムパニー　インコーポレーテツド シクロオキシゲナーゼおよびリポキシゲナーゼに対する二重酵素阻害剤としてのＮ‐アルケニル‐３‐ヒドロキシベンゾ〔ｂ〕チオフエン‐２‐カルボキサミド誘導体
JPS61171479A (ja) * 1984-12-10 1986-08-02 ワ−ナ−−ランバ−ト・コンパニ− 新規なベンゾチオフェン

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350748A (en) * 1993-08-18 1994-09-27 Warner-Lambert Company 3-thio or amino substituted-benzo[b]thiophene-2-carboxamides and 3-oxygen, thio, or amino substituted-benzofuran-2-carboxamides as inhibitors of cell adhesion
US5656638A (en) * 1995-04-18 1997-08-12 Geron Corporation Telomerase inhibitors
US5925636A (en) * 1996-05-20 1999-07-20 Darwin Discovery Limited Benzofuran carboxamides and their therapeutic use
US5972936A (en) * 1996-05-20 1999-10-26 Darwin Discover Limited Benzofuran carboxamides and their therapeutic use
US6239142B1 (en) 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US6495683B2 (en) 1999-03-09 2002-12-17 Pharmacia And Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
US6620810B2 (en) 2001-08-30 2003-09-16 Pharmacia & Upjohn Company 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides as antiviral agents
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
US6964956B2 (en) 2002-06-06 2005-11-15 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted 3-amino-thieno [2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
EP2008654A1 (fr) * 2002-06-06 2008-12-31 Boehringer Ingelheim Pharmaceuticals, Inc. 3-amino-thieno[2,3-b]pyridine-2-amides
US6974870B2 (en) 2002-06-06 2005-12-13 Boehringer Ingelheim Phamaceuticals, Inc. Substituted 3-amino-thieno [2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
JP2009102447A (ja) * 2002-06-06 2009-05-14 Boehringer Ingelheim Pharmaceuticals Inc 置換３−アミノ−チエノ［２，３−ｂ］ピリジン−２−カルボン酸アミド化合物、その製造方法及び使用
EA008706B1 (ru) * 2002-06-06 2007-06-29 Бёрингер Ингельхайм Фармасьютиклз, Инк. АМИДЫ ЗАМЕЩЕННЫХ 3-АМИНОТИЕНО[2,3-b]ПИРИДИН-2-КАРБОНОВЫХ КИСЛОТ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
US7405225B2 (en) 2002-06-06 2008-07-29 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
WO2003103661A1 (fr) * 2002-06-06 2003-12-18 Boehringer Ingelheim Pharmaceuticals, Inc. COMPOSES AMIDE D'ACIDE 3-AMINO-THIENO[2,3-b]PYRIDINE-2-CARBOXYLIQUE SUBSTITUES ET PROCESSUS DE PREPARATION ET D'UTILISATION DE CES COMPOSES
US7091216B2 (en) 2002-08-02 2006-08-15 Merck & Co., Inc. Substituted furo[2,3-b]pyridine derivatives
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7674822B2 (en) 2004-11-24 2010-03-09 Wyeth PTP1b inhibitors
WO2006068618A1 (fr) * 2004-12-23 2006-06-29 Astrazeneca Ab Nouveaux composés
US7592353B2 (en) 2006-06-06 2009-09-22 Boehringer Ingelheim International Gmbh Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
WO2014207213A1 (fr) 2013-06-28 2014-12-31 Medizinische Universität Innsbruck Nouveaux inhibiteurs de la signalisation de la protéine kinase c epsilon
CN115805103A (zh) * 2021-09-14 2023-03-17 万华化学集团股份有限公司 一种失活钛硅分子筛的再生方法
CN115805103B (zh) * 2021-09-14 2024-04-09 万华化学集团股份有限公司 一种失活钛硅分子筛的再生方法

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