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WO1996034866A1 - Derives de l'imidazo 1,2-a pyridine et de l'imidazo 1,2-a pyridezine et leur utilisation en tant qu'inhibiteurs de la resorption osseuse - Google Patents

Derives de l'imidazo 1,2-a pyridine et de l'imidazo 1,2-a pyridezine et leur utilisation en tant qu'inhibiteurs de la resorption osseuse Download PDF

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Publication number
WO1996034866A1
WO1996034866A1 PCT/JP1996/001103 JP9601103W WO9634866A1 WO 1996034866 A1 WO1996034866 A1 WO 1996034866A1 JP 9601103 W JP9601103 W JP 9601103W WO 9634866 A1 WO9634866 A1 WO 9634866A1
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WIPO (PCT)
Prior art keywords
alkyl
pyridine
nmr
suitable substituent
compound
Prior art date
Application number
PCT/JP1996/001103
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English (en)
Inventor
Yoshio Kawai
Shigeki Satoh
Hitoshi Yamazaki
Natsuko Kayakiri
Kousei Yoshihara
Teruo Oku
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9508826.6A external-priority patent/GB9508826D0/en
Priority claimed from GBGB9512972.2A external-priority patent/GB9512972D0/en
Priority claimed from GBGB9516647.6A external-priority patent/GB9516647D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU53483/96A priority Critical patent/AU5348396A/en
Priority to JP8533169A priority patent/JPH11505524A/ja
Publication of WO1996034866A1 publication Critical patent/WO1996034866A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel imidazopyridine or imidazopyrazine (hereinafter referred to as
  • imidazopyridine compound and a pharmaceutically acceptable salt thereof which are useful as a medicament.
  • the present invention relates to a novel imidazopyridine compound and a pharmaceutically acceptable salt thereof which are the inhibitors of bone resorption, the inhibitors of bone metastases and useful for the prophylactic and/or therapeutic treatment of bone disease characterized by abnormal bone metabolism such as osteoporosis (especially, postmenopausal osteoporosis); hyper-calcemia; hyperparathyroidism; Paget's bone diseases; osteolysis; hypercalcemia of malignancy with or without bone metastases; rheumatoid arthritis;
  • osteoporosis especially, postmenopausal osteoporosis
  • hyper-calcemia hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis a periodontitis; osteoarthritis; ostealgia; osteopenia; cancer cachexia; calculosis; lithiasis (especially, urolithiasis); or the like in a human being or an animal.
  • the present invention relates to processes for the preparation of the imidazopyridine derivatives, to a pharmaceutical composition comprising the same and to a method for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal, and to a use of the imidazopyridine compound and pharmaceutically acceptable salts thereof for the prophylactic and/or
  • the imidazopyridine compounds of this invention are new and can be represented by the following general formula (Ii :
  • R 1 is hydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogen or hydroxy (lower) alkyl which may have one or more suitable substituent (s),
  • R 2 is hydrogen, lower alkyl, an acyl group, lower alkoxy,
  • R 3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkyl (lower) alkyl, halogen, an acyl group, acyl (lower) alkyl, acylamino,
  • acylamino (lower) alkyl acyl (lower) alkenyl
  • acyloxy (lower) alkyl acyl (lower) alkylthio (lower) alkyl, amino (lower) alkyl, mono- (or di-) lower alkylamino, lower alkylthio (lower) alkyl, hydrcxyimino (lower) alkyl which may have one or more suitable substituent (s),
  • hydroxy (lower) alkyl which may have one or more suitable substituent (s), hydroxy (lower) alkylthio (lower) alkyl, cyano (lower) alkyl, mono- (or di-) lower alkoxy (lower) alkyl which may have one or more suitable substituent (s), lower alkyl substituted with aryl which may have one or more suitable substituent (s), mono- (or di-) lower alkylamino (lower) alkyl, tri (lower) alkylammonio (lower) - alkyl, lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), hydrazino (lower) alkyl which may have one or more suitable substituent (s), mono- or di- (lower) alkoxy (lower) alkylamino (lower) alkyl,
  • heterocyclicthio heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s),
  • heterocyclicoxy heterocyclicoxy (lower) alkyl
  • heterocyclicaminoimino (lower) alkyl aryl which may have one or more suitable substituent (s), amino, nitro, halo (lower) alkyl, hydroxy (lower) alkylimino (lower) alkyl, hydroxy (lower) alkylamino (lower) alkyl, bis- [hydroxy (lower) alkyl] amino (lower) alkyl,
  • a 1 and A 2 are each lower alkylene which may have one or more suitable substituent (s) or lower alkenylene which may have one or more suitable substituent (s),
  • W is -S-, - (wherein R 4 is hydrogen
  • n are each an integer of 0 or 1]
  • X is vinylene, or a group of the formula : -NHCO-, -NHSO 2 -, -OCO-, -OCH 2 -, -NHCOCO-,
  • -NHCOCH CH-, -NHCOCH 2 -, -NHCONH- or
  • Y is heterocyclic group which may have one or more suitable substituent (s), or aryl which may have one or more suitable substituent (s),
  • Q is CH or N
  • l is an integer of 0 or 1
  • the object compound (I) or a salt thereof can be
  • R 1 , R 2 R 3 X, Y, Q and l are each as defined above,
  • heterocyclicthio (lower) alkyl lower
  • alkylamino (lower) alkyl which may have one or more suitable substituent (s),
  • E is lower alkylene, lower alkenylene or a group of the formula :
  • V is heterocyclic group which may have one or more suitable substituent (s), heterocyclicthio, or lower alkylamino which may have one or more suitable substituent (s), hydroxy (lower) alkylamino, bis-hydroxy (lower) alkylamino, amidinothio or tri-lower alkylphosphite,
  • a 5 is lower alkylene
  • R' is hydrogen or lower alkyl
  • R" is leaving group
  • R"' is lower alkyl, cyclo (lower) alkyl, lower alkyl
  • heterocyclic group which may have one or more suitable substituent (s), lower alkoxy (lower) alkyl, hydroxy (lower) alkyl, amino, heterocyclic group, carboxy (lower) alkyl, protected carboxy (lower) alkyl, lower alkyl substituted with aryl which may have one or more suitable substituent (s) or arylsulfonyl or cyano (lower) alkyl,
  • G 1 is -COOH or -SO 3 H
  • G 2 is -CO- or -SO 2 -
  • X' is halogen
  • a is an integer of 0 to 6
  • b, r, q and u are each an integer of 0 or 1.
  • R 1 , R 2 , R 3 and Q are each as defined above, and X"' is halogen.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.);
  • a salt with an inorganic base for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate,
  • toluenesulfonate etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid, etc.
  • lower is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable example of .”one or more may be the number of 1 to 6, in which the preferred one may be the number of 1 to 4.
  • Suitable “lower alkyl” and “lower alkyl moiety” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like, preferably one having 1 to 5 carbon atom(s).
  • Suitable “lower alkane” may include straight or branched one having 1 to 6 carbon atom(s), such as methane, ethane, propane, isopropane, butane, iscbutane, sec-butane, tert- butane, pentane, 3-pentane, isopentane, tert-pentane,
  • neopentane hexane, isohexane, and the like, i nwhich the more preferred one may be (C 1 -C 4 ) alkane, and the most
  • preferred one may be methane.
  • Suitable “lower alkenyl” and “lower alkenyl moiety” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1- (or 2- or 3 ⁇ or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)- hexenyi, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1- (or 2-)propenyl, 1-(or 2- or 3-) ethyl-1- (or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example nay be (C 6 -C 4 ) alkenyl, and the most preferred one may be methylvinyl.
  • Suitable "lower alkynyl” may include ethynyl,
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • Suitable "aryl” and “aryl moiety” may include phenyl, naphthyl, anthryl and the like.
  • Suitable “leaving group” may include acid residue,
  • tri (lower) alkylammonio as defined below and the like, and suitable examples of “acid residue” may be halogen (e.g., fluorine, chlorine, bromine, iodine.), acyloxy [e.g.,
  • sulfonyioxy e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.
  • lower alkanoyloxy e.g., acetyloxy, propionyloxy, etc.
  • lower alkyl e.g., methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.
  • aryl e.g., phenyl, naphthyl, anthryl, etc.
  • ar (lower) alkyl such as phenyl (lower) alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.),
  • di (lower) alkylamino e.g., dimethylaminc, diethylamino, aiiscprcpylamino, ethylmethylaminc, iscpropyimethylaminc, ethylmethylamino, ethylpropyiamino, etc.
  • alkyl (lower) alkoxyamino e.g., methylmethoxyamino
  • tri (lower) alkylammonio may be trimethylammonio, triethylammonio, tripropylammonio, tributylammonio, tripentylammonio, trihexylammonio, or the like, in which the preferred one may be tri(C 1 -C 4 )- aikylammonio, and the most preferred one may be
  • Suitable “acid residue” may include halogen (e.g., fluorine chlorine, bromine, iodine, etc.), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyioxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
  • halogen e.g., fluorine chlorine, bromine, iodine, etc.
  • acyloxy e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyioxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • Suitable "lower alkenylene” may include straight or branched one having 2 to 6 carbon atom(s) such as vinyiene, propenylene, 1-(or 2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-) hexenylene, methylvinylene, ethylvinyiene, 1-(or 2- or 3-)methyIpropenylene, 1-(or 2- or 3-)- ethylprcpenylene, 1-(or 2- or 3- or 4-)methyl-1-(or 2-)- butenylene, and the like.
  • Suitable "cyclo (lower) alkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which the preferred one may be cyclo (C 4 -C 6 ) alkyl.
  • Suitable "halogen” and “halo” moiety may include
  • Suitable "an acyl group” and “acyl” moiety may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • Suitable example of said acyl may be illustrated as follows :
  • aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyi, nonanoyl, decanoyl, undecancyl, dodecanoyl,
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyi, nonanoyl, decanoyl, undecancyl, dodecanoyl,
  • cyclo (lower) alkylcarbonyl e.g., cyclopropylcarbonyl
  • cyclobutylcarbonyl cyclopentylcarbonyi, cyclohexylcarbonyl, etc.
  • protected carboxy such as commonly protected carboxy [e.g., esterified carboxy such as lower or higher
  • alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, iso-propyloxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.]; lower or higher alkylsulfonyl (e.g.,
  • alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • di (lower) alkoxyphosphoryl e.g., dimethoxyphosphoryl
  • diethcxyphosphoryl dipropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.
  • a 3 and A 4 are lower alkylene, amino (lower) alkylene or aminophenylene,
  • R 11 is lower alkyl or hydrogen
  • S and t are each integer of 1 to 6, or the like); aromatic acyl such as
  • aroyl e.g., benzoyl, toluoyl, naphthoyl, etc.
  • ar (lower) alkanoyl e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
  • phenylisobutanoyl phenylpentanoyl, phenyIhexanoyl, etc.
  • naphthyl (lower) alkanoyl e.g., naphthylacetyl
  • ar (lower) aikenoyl e.g., phenyl (lower) alkenoyl (e.g., phenylprcpenoyl, phenylbutenoyl, phenylmethaoryloyl, phenylpentenoyi, phenyihexenoyi, etc.),
  • naphthyl (lower) alkenoyl e.g., naphthylpropenoyl
  • ar (lower) alkoxycarbonyl e.g., phenyl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
  • aryloxycarbonyl e.g., phenoxycarbonyl
  • aryloxy (lower) alkanoyl e.g., phenoxyacetyl
  • arylcarbamoyl e.g., phenylcarbamoyl, etc.
  • arylthiocarbamoyl e.g., phenylthiocarbamoyl, etc.
  • arylglyoxyloyl e.g., phenylgiyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.
  • heterocyclic acyl such as
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyciicpropanoyl, heterocyclicbutanoyl,
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropencyl, heterocyclicbutenoyl, heterocyclicpentenoyi,
  • heterocyclichexenoyl etc.
  • heterocyclicglyoxyloyl
  • heterocyclicsulfinyl may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group such as
  • heterocyclic group and “heterocyclic moiety” as stated above may have one or more suitable substituent (s) such as exo; halogen (e.g., fluorine, chlorine, bromine, iodine, etc.); hydroxy; aforementioned "heterocyclic group”; tri- halo (lower) alkyl (e.g., trichloromethyl, trifluoromethyl, trichloroethyl, trifiuoroethyl, etc.); lower alkanoyl (e.g., formyl, acetyl, prcpancyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.); aryl (e.g., phenyl, naphthyl, anthryl, etc.); lower alkyl (e.g., methyl, ethyl, propyl
  • acyl moiety as stated above may have one to ten, same or different, suitable substituent (s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.);
  • lower alkoxy e.g., methoxy.. ethoxy, propoxy, etc.
  • lower alkylthio e.g., methylthio, ethylthio, etc.
  • mono- (or di-) lower alkylamino which may have one or more suitable substituent (s) (e.g., methylamino, ethylamino, oropylamino, dimethylamino, diethylamino, dipropylamino, N- methoxy-N-methylamino, N-ethoxy-N-ethylamino, N- methoxymethyl-N-methylamino, N-methoxyethyl-N-methylamino, etc.); lower alkanoylamino (e.g., acetylamino,
  • prcpionylamino butyrylamino, pentanoylamino, hexanoylamino, etc.
  • cyclo (lower) alkylamino e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminc, etc.
  • mono-(or di-) lower alkoxy (lower) alkylamino e.g.,
  • lower alkanoyloxy e.g., acetyloxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, etc.
  • heterocyclic group in which "heterocyclic group" is
  • di-lower alkoxy (lower) alkyl e.g., dimethoxymethyl
  • cyano (lower) alkylamino e.g., cyanomethylamino
  • arylsulfonylamino e.g., phenylsulfonyiamino
  • cyclo (lower) alkyl e.g., cyciopentyl, cyclohexyl, etc.
  • cyclo (lower) alkenyl e.g., cyclohexenyl, cyclohexadienyl, etc.
  • halogen e.g., fluorine, chlorine, bromine, iodine, etc.
  • amino commonly protected amino as mentioned above; hydroxy; commonly protected hydroxy as mentioned below; cyano; nitro; carboxy; carboxy (lower) alkyl;
  • sulfamoyl sulfamoyl; imino; oxo; hydrazino; amino (lower) alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoylcxy; hydroxy (lower) alkyl (e.g., hydroxymethyl, 1-(or 2-)- hydrcxyethyl, 1-(or 2- or 3-) hydroxypropyi, etc.), or the like.
  • amino (lower) alkyl e.g., aminomethyl, aminoethyl, etc.
  • carbamoylcxy hydroxy (lower) alkyl (e.g., hydroxymethyl, 1-(or 2-)- hydrcxyethyl, 1-(or 2- or 3-) hydroxypropyi, etc.), or the like.
  • Suitable "hydroxy protective group” in the term commonly “protected hydroxy” may include acyl as mentioned above, phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyI, trityl, etc.), trisubstituted silyl [e.g., tn (lower) alkylsiiyl (e.g., trimethylsilyl, t-butyldimethylsilyi, etc.), etc.],
  • suitable substituent e.g., benzyl, 4-methoxybenzyI, trityl, etc.
  • trisubstituted silyl e.g., tn (lower) alkylsiiyl (e.g., trimethylsilyl, t-butyldimethylsilyi, etc.
  • Suitable commonly "protected carboxy” may include esterified carboxy and the like.
  • suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.);
  • lower alkenyl ester e.g., vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g., ethynyl ester, propynyl ester, etc.
  • lower alkoxy (lower) alkyl ester e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxy ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.
  • lower alkylthio (lower) alkyl ester e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester,
  • lower alkanoyloxy (lower) alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
  • lower alkoxycarbonyloxy (lower) alkyl ester e.g.,
  • lower alkanesulfonyl (lower) alkyl ester e.g., mesylmethyl ester, 2-mesyethyl ester, etc.
  • lower alkoxycarbonyloxy (lower) alkyl ester e.g.,
  • ar (lower) alkyl ester for example, phenyl (lower) alkyl ester which may have one or more suitable substituent (s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester,
  • suitable substituent e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester
  • aryl ester which may have one or more suitable substituent (s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyi ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,
  • lower alkyl silyl ester e.g., methylthioester, ethylthioester, etc.
  • lower alkylthioester e.g., methylthioester, ethylthioester, etc.
  • an acyl group may be carboxy protected carboxy, carbamoyl, lower alkanoyl, lower alkylsulfonyl, aroyl, heterocyclic carbonyl which may have one or more suitable substituent (s), in which the more preferred one may be carboxy, (C 1 -C 4 ) alkoxy carbonyl, carbamoyl, (C 1 -C 4 ) alkanoyl, (C 1 -C 4 ) alkylsulfonyl, benzoyl, carbonyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoyl substituted with saturated 3 to 8-membered
  • acyl moiety in the term of "acylamino” can be referred to aforementioned “acyl” moiety.
  • acylamino may be ureido, lower alkanoylamino, lower alkoxycarbonylamino, heterocyclic carbonylamino, lower alkanoylamino (lower) alkanoylamino (e.g. acetylaminoacetylamino, acetylaminopropionylamino,
  • propionylaminoacetylamino, propionylaminopropionylamino, etc. mono-(or di-) lower alkylamino (lower) alkanoylamino (e.g., methylaminoacetylamino, dimethylaminoacetylamino, ethylaminoacetylamino, diethylaminoacetylaminc, etc.), lower alkanoyloxy (lower) alkanoylamino [e.g., acetyloxyacetylamino, acetyloxypropionylamino, propionyloxyacetylamino,
  • heterocyclic (lower) alkanoylamino e.g., heterocyclic- carbonylamino, heterocyclic-acetylamino, heterocyclic- propionylamino, etc .
  • lower alkoxy (lower) alkanoylamino e.g., lower alkoxy (lower) alkanoylamino
  • hydroxy (lower) alkanoylamino e.g., hydroxyacetylamino, hydroxypropionylamino, etc.
  • lower alkylsulfonylamino e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, etc.
  • mono-(or di-) lower alkoxy (lower) alkylamino (lower)- alkanoylamino e.g., methoxymethylaminoacetylamino,
  • Suitable "hydroxy (lower) alkyl" moiety in the term of "hydroxy (lower) alkyl which may have one or more suitable substituent (s)" may be hydroxymethyl, 1-(or 2-)hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxypropyl, 1-hydroxy-1- ethylethyl, 1-hydroxy-1-ethylpropyl, 1-hydroxybutyl, 1- (or 2- or 3-)hydroxy-1-(or 2- or 3-)methylpropyl, 1-(or 2- or 3- or 4-)hydroxy-1-(or 2- or 3- or 4-)methylbutyl, 1-(or 2- or 3- or 4- or 5-) hydroxy-1-(or 2- or 3- or 4- or 5-)methylpentyl, 1- (or 2- or 3- or 4- or 5- or 6-) hydroxy-1-(or 2- or 3- or 4- or 5- or 6-)methylhexyl, or the like.
  • hydroxy (lower) alkyl may be hydroxy (C 1 -C 4 )alkyl, and the most preferred one may be hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydrcxy-1-ethylpropyl, 1-hydrcxybuty ⁇ , 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 1-hydroxybutyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl.
  • suitable substituent (s) in the term of "hydroxy (lower) aikyl which may have one or more suitable substituent (s)” may be mono- (or di- or tri-)- haio (lower) alkyl, protected carboxy, hydroxy, aryl,
  • acyl moiety in the term of "acyl (lower) alkyl” can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkyl may be carboxy (lower) alkyl, protected carboy (lower) alkyl,
  • heterocyclic group which may have one or more suitable substituent (s), sulfinyl (lower) alkyl substituted with
  • heterocyclic group which may have one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s),
  • a 3 is lower alkylene, amino lower alkylene or
  • R 11 is lower alkyl or hydrogen
  • s and t are each integer of 1 to 6
  • methylaminocarbonylmethyl dimethylaminocarbonylmethyl, methylaminocarbonylethyl, 2-dimethylaminocarbonylethyl,
  • lower alkoxy (lower) alkyiaminocarbonyl (lower) alkyl e.g., methoxymethylaminocarbonylmethyl
  • di- (lower) alkoxyphosphoryl (lower) alkyl e.g., di- (lower) alkoxyphosphoryl (lower) alkyl
  • aminocarbonyl (lower) alkyl substituted with heterocyclic group which may have one or more suitable substituent (s) (e.g.
  • thiazolylaminocarbonylmethyl piperidinoaminocarbonylmethyl, morpholinoaminomethyl, methyloxadiazolylaminocarbonylmethyl, trifluoromethylthiadiazolylaminocarbonylmethyl, pyridylaminocarbonylmethyl, aminopyridylaminocarbonylmethyl, etc.), heterocyclic (lower) alkyiaminocarbonyl (lower) alkyl
  • hydrazinocarbonyl (lower) aikyl e.g., hydrazinocarbonylmethyl, hydrazinocarbonylethyl, hydrazinocarbonyipropyl, etc.
  • aminocarbonyl (lower) alkyl substituted with aryl which may have one or more suitable substituent (s) e.g.,
  • arylsulfonylaminocarbonyl (lower) alkyl e.g.,
  • a 3 is (C 1 -C 6 )alkylene, amino (C 1 -C 6 ) alkylene or
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen
  • s and t are each integer of 1 to 6), carbonyl (C 1 -C 4 )alkyl substituted with heterocyclic group which may have 1 to 3 suitable substituent (s),
  • hydrazinocarbonyl (C 1 -C 4 )alkyl aminocarbonyl (C 1 -C 4 ) alkyl substituted with phenyl which may have 1 to 3 suitable substituent (s), cyano (C 1 -C 4 )alkyiaminocarbonyl (C 1 -C 4 )alkyl, phenyisulfonylaminocarbonyl (C 1 -C 4 )alkyl,
  • (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkyiaminocarbonyl (C 1 -C 4 )alkyl and the most preferred one may be carboxymethyl
  • lower alkylthio may be methyl.thio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, or the iike, in which the preferred one nay be (C 1 -C 4 ) alkylthio, and the most preferred one may be
  • cyclo (lower) aikyl (lower) alkyl may be cyclopropylmethyl, cyciobutylmethyl, cyclopentylmethyl, cyciohexylmethyl. cyciopropylethyl, cyclobutylethyl, cyciopentylethyl,
  • cyclohexylethyl or the like, in which the preferred one may be cyclo (C 3 -C 6 ) alkyl (C 1 -C 4 ) alkyl, and the most preferred one may be cyciohexylmethyl.
  • acylamino moiety in the term cf "acyiamino- (lower) alkyl" can be referred to aforementioned “acylamino”.
  • acylamino (lower) alkyl may be lower alkoxycarbonylamino (lower) alkyl, lower
  • alkanoylamino (lower) aikyl alkanoylamino (lower) aikyl, heterocyciic-carbonylamino- (lower) alkyl,
  • the preferred one may be (C 1 -C 4 ) aikoxycarbonylamino- (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkanoylamino (C 1 -C 4 ) alkyl,
  • a 3 and A 4 are each (C 1 -C 6 ) alkylene, amino (C 1 -C 6 )
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen), and the most preferred one may be t-butoxycarbonyl
  • acyl moiety in the terms of "acyl (lower) - alkenyl” can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkenyl can be referred to aforementioned “lower alkenyl”.
  • acyl (lower) alkenyl may be protected carboxy (lower) aikenyl, in which the preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkenyl, and the most preferred one may be ethoxycarbonyivinyl.
  • acyloxy (lower) alkyl can be referred to aforementioned
  • acyloxy (lower) alkyl may be lower alkanoyloxy (lower) alkyl
  • alkylaminocarbonyloxy (lower) alkyl aroyloxy (lower) alkyl, or lower aikyl substituted with
  • a 3 is lower alkyiene, amino (lower) alkylene or
  • R 11 is lower alkyl or hydrogen
  • Ln which the preferred one may be (C 1 -C 4 ) alkanoyloxy- (C 1 -C 4 ) aikyl, cycle (C 3 -C 6 ) alkylcarbamoyloxy- (C 1 -C 4 ) alkyl, carboxy (C 2 -C 4 ) alkanoyloxy- (C 1 -C 4 ) alkyl, succinimidoxycarbonyl- (C 2 -C 4 ) alkanoyloxy (C 1 -C 4 ) alkyl, (C 1 -C 4 )- alkyiaminocarbcnyioxy (C 1 -C 4 ) alkyl,
  • a 3 is (C 1 -C 6 ) alkylene, amino ( C 1 -C 6 ) aikylene or
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen) ,
  • acyl (lower) alkylthio (lower) aikyl can be referred to aforementioned "acyl" moiety.
  • carboxy (lower) alkylthio (lower) aikyl in which the preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be
  • amino (lower) alkyl may be amino (C 1 -C 4 ) alkyl, in which the most preferred one may be aminomethyl.
  • alkylamino may be methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropyiamino, butylamino,
  • dihexyiamino or the like, in which the preferred one may be mono-(or di-) (C 1 -C 4 ) alkylamino, and the most preferred one may be methylamino, dimethylamino or diethylamino.
  • the preferred examples of "lower alkylthio (lower) alkyl” may be methylthiomethyl, methylthioethyl, methylthiopropyi, methylthiobutyl, ethylthiomethyl, ethylthioethyl,
  • propylthiopropyl or the like, in which the preferred one may be (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be methylthiomethyl.
  • hydroxyimino (lower) alkyl which may have one or more suitable substituent (s)
  • (2-hydrcxyethyl) thiomethyl 2-(1-hydrcxyethyl) thioethyl, (1- or 2-hydroxyethyl) thiopropyl, (1- or 2-hydroxyethyl)- thiobutyl, (1- or 2-hydroxyethyl) thiopentyl, (1- or 2- hydroxyethyl) thiohexyl, or the like, in which the preferred one may be hydroxy (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be (2-hydrcxyethyl) thiomethyl.
  • cyano (lower) alkyl may be cyanomethyl, 1- (or 2-) cyanoethyl, 1-(or 2- or 3-) cyanopropyl, 1-(or 2- or 3- or 4-) cyanobutyl, 1- (or 2- or 3- or 4- or 5-)- yanopentyl, 1- (or 2- or 3- or 4- or 5- or 6-) cyanohexyl, or the like, in which the preferred one may be cyano (C 1 -C 4 ) - aikyl, and the most preferred one may be cyanomethyl or 2- cyanoethyl.
  • Suitable "mono- (or di-) lower alkoxy (lower) alkyl” may be methoxymethyl, methoxyethyl, dimethoxymethyl, dimethoxyethyl, ethoxymethyl, ethoxyethyl, diethoxymethyl, diethoxyethyl, propoxymethyl, propoxyethyl, propoxypropyl, dipropoxymethyl, dipropoxyethyl, dipropoxypropyl, or the like, in which the preferred one may be mono-(or di-) (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, and the most preferred one may be methoxymethyl,
  • alkoxy (lower) alkyl which may have one or more suitable substituent (s)" may be (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl or
  • the most preferred one may be methoxymethyl, 2-methoxyethyl, 3-diethoxypropyl or trifluoromethylmethoxymethyl .
  • Suitable "lower alkyl substituted with aryl" nay be benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl,
  • naphthylethyl anthryimethyl, 1-anthryiethyl, or the like, in which the more preferred one may be phenyl (C 1 -C 4 ) alkyl, naphthyl (C 1 -C 4 ) alkyl or anthryl (C 1 -C 4 ) alkyl, and the most preferred one may be benzyi.
  • lower alkyl substituted with aryl which may have one or more suitable substituent (s) may be the one which may have 1 to 3 nitro or cyano, such as phenyl (C 1 -C 4 ) aikyl, nitrophenyi (C 1 -C 4 ) alkyl or
  • cyanophenyi (C 1 -C 4 ) aikyl, in which the most preferred one may be benzyl, 4-nitrobenzyl or 3-cyanobenzyl.
  • alkylamino (lower) alkyl may be mono-(or di-) (C 1 -C 4 )- ikylamino (C 1 -C 4 ) alkyl, in which the more preferred one may be dimethvlaminomethyl.
  • tri (lower) alkylammonio (lower)- alkyl may be trimethylammoniomethyl, triethylammonioethyl, tripropylammoniopropyl, tributylammoniobutyl,
  • tripentylammoniopentyl trihexylammoniohexyl, or the like, in which the preferred one may be tri (C 1 -C 4 ) alkylammonio (C 1 -C 4 )- alkyl, and the most preferred one may be
  • heterocyclic group moiety in the term of "lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned “heterocyclic group”.
  • substituent (s) may be imidazoiyi (lower) alkyl, pyridyl (lower) alkyl, morpholino (lower) alkyl,
  • oxiranyl (C 1 -C 4 ) alkyl
  • piperidino (C 1 -C 4 ) aikyl
  • 2-methylimidazolylmethyl 4-ethoxycarbonylpiperidinomethyl, pyrrolidinylmethyl, piperidinomethyl, benzimidazolylmethyl, triazolylmethyl, 3-methyl-5-hydroxypyrazolylmethyl,
  • hydrazino (lower) alkyl having lower alkoxycarbonyl in which the more preferred one may be hydrazino (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkoxycarbonyl, and the most preferred one may be tert-butoxycarbonylhydrazinomethyl.
  • [mono or di (lower) alkoxy- (lower) alkyl] amino (lower) alkyl may be [mono or di(C 1 -C 4 )- alkoxy(C 1 -C 4 ) alkyl] amino (C 1 -C 4 ) alkyl, in which the more preferred one may be [di (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl] amino- (C 1 -C 4 ) alkyl, and the most preferred one may be
  • (lower) alkylamino (lower) alkyl which may have one or more suitable substituent (s)
  • heterocyclic (lower) alkyl (lower) alkylamino (lower) alkyl having lower alkoxycarbonyl (lower) alkyl,
  • (lower) alkylamino] (lower) alkyl in which the more preferred one may be (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having pyridyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having cyclo (C 3 -C 6 ) alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkoxy (C 1 -C 4 )- alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having pyridyl (C 1 -C 4 )- alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having (C 1 -C 4 )- alkoxycarbonyl (C 1 -C 4 )
  • preferred one may be N-methyl-N-pyridylaminomethyl, N-methyl- N-cyclohexylaminomethyl, N-methyl-N-methoxyethylaminomethyl, N-methyl-N-pyridylmethylaminomethyl,
  • heterocyclic group moiety in the term of "heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned “heterocyclic group”.
  • heterocyclic group which may have one or more suitable substituent (s) may be furyl, pyridyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen, lower alkoxycarbonyl, and lower alkyl, thiazolyl which may have 1 to 3 lower
  • alkanoylamino benzothienyl which may have 1 to 3 halogen, indolyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen and lower alkyl, oxazolyl which may have 1 to 3 lower alkyl, pyranyl which may have 1 to 3 substituent (s) selected from the group consisting of lower alkyl and oxo, pyrrolyl which may have 1 to 3 lower alkyl, phthalimido which may have nitro, phthalimidine which may have nitro, piperidyl which may have 1 to 3 lower alkyl, dihydropyridyl which may have lower alkoxycarbonyl.
  • heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)
  • heterocyclic group can be referred to aforementioned to “heterocyclic group”.
  • heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)
  • imidazopyridylthio (lower) alkyl in which the preferred one may be imidazolylthio (C 1 -C 4 ) alkyl, imidazolylthio (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkyl, benzimidazolyl (C 1 -C 4 ) alkyl,
  • pyridylthio (C 1 -C 4 ) alkyl or imidazopyridylthio (C 1 -C 4 ) alkyl, and the most preferred one may be imidazolylthiomethyl,
  • heterocyclic moiety in the term of “heterocyclicthio” can be referred tc aforementioned
  • heterocyclicthio may be pyridylthio or imidazolylthio.
  • heterocyclic oxy can be referred to aforementioned
  • heterocyclic oxy may be pyridyloxy.
  • heterocyclic oxy (lower) aikyl can be referred to
  • heterocyclic oxy (lower) alkyl may be pyridyloxy (lower) aikyl, in which the more preferred one may be pyridyloxy (C 1 -C 4 ) alkyl, and the most preferred one may be pyridyloxynethyl.
  • aryl which may have one or more suitable eubstituents may be phenyl, naphthyl, anthryl, phenyl having amino, phenyl having di (lower; alkylamino, phenyl having heterocyclic (lower) alkylamino, phenyl having di (lower) alkylamino (lower) alkanoylamino, phenyl having lower aikylsulfcnyiaminc, phenyl having higher alkanoylamino, in which the most preferred one may be phenyl, aminophenyl, dimethylaminophenyl, furyimethylaminophenyl,
  • heterocyclic amincimino (lower) alkyl can be referred to aforementioned “heterocyclic group”.
  • aminoiminc (lower) alkyl may be amincimino (lower) alkyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 ro 4 nitrogen atom(s), in which the more preferred one may be pyridylaminoimino (C 1 -C 4 ) alkyl, and the most preferred one may be 2-pyridylaminoiminopropyl.
  • suitable substituent (s) in the terms cf "lower alkylene which may have one or more suitable substituent (s)” and “lower aikenylene which may have one or more suitable substituent (s)” may be lower alkyl, hydroxy, oxo, or the like, in which the preferred one may be (C 1 -C 4 ) alkyl, hydroxy or oxo, and the most preferred one may be methyl, hydroxy or oxo.
  • suitable substituent (s) in the terms of "aryl which may have one or more suitable substituent (s)” may be halogen, lower alkyl, nitre, lower alkoxy, an acyl group, cyclo (lower) alkyl, mono- (or di- or tri-) halo (lower) alkyl, acylamino, aryl, amino, mono- (or di-)- lower alkylamino, aryloxy, acyl (lower) alkyl, hydroxy,
  • hydroxy (lower) alkyl which may have one or more suitable substituent (s), heterocyclic group which may have one or more suitable substituent (s), mono-(or di-) lower
  • alkylamino (lower) alkyl or acyl (lower) alkyl are preferred examples of "mono-(or di-) lower
  • alkylamino (lower) alkyl may be mono-(or di-) (C 1 -C 4 )- alkylamino (C 1 -C 4 ) alkyl, in which the preferred one nay be di (C 1 -C 4 ) alkylamino (C 1 -C 4 ) aikyl, and the most preferred one may be dimethylaminomethyl.
  • acyl (lower) alkoxy can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkoxy may be protected carboxy (lower) alkoxy, m which the more preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkoxy, and the most preferred one may be ethoxycarbonyimethoxy.
  • suitable substituent (s) in the term cf "naphthyl which may have one or mere suitable substituent (s) " may be lower alkoxy, in which the more preferred one may be (C 1 -C 4 ) alkoxy, and the most preferred one may be methoxy.
  • acyl (lower) alkenyl can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkenyl can be referred to aforementioned “lower alkenyl”.
  • acyl (lower) alkenyl may be protected carboxy (C 2 -C 6 ) alkenyi, in which the more preferred one may be lower alkoxycarbonyl (C 2 -C 4 ) alkenyl, and the most preferred one may be ethoxycarbonylvinyl.
  • aryloxy may be phenoxy, naphthyloxy, anthryloxy, or the like, in which the most preferred one may be phenoxy.
  • aryl (lower) alkoxy may be phenyl (C 1 -C 6 ) alkoxy, naphthyl (C 1 -C 6 ) alkoxy, anthryl (C 1 -C 6 ) - alkoxy, or the like, in which the preferred one may be phenyl (C 1 -C 4 ) alkoxy, and the most preferred one may be phenylmethoxy.
  • halo (lower) alkyl may be chloromethyl, chloroethyl, bromomethyl, bromoethyl,
  • hydroxy (lower) aikylimino- (lower) alkyl may be hydroxy (C 1 -C 4 ) alkylimino (C 1 -C 4 ) alkyl, in which the more preferred one may be hydroxyethyliminomethyl.
  • ;lower) aikyl may be hydroxy (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl, in which the more preferred one may be hydroxyethylaminomethyl.
  • bis-[hydroxy (lower) alkyl]- amino (lower) alkyl may be bis- [hydroxy (C 1 -C 4 ) alkyl]amino- (C 1 -C 4 ) alkyl, in which the more preferred one may be
  • mercapto (lower) alkyl may be mercapto (C 1 -C 4 ) alkyl, in which the more preferred one may be mercaptomethyl.
  • amidinothio (lower) alkyl may be amidinothio (C 1 -C 4 ) alkyl, in which the more preferred one may be amidinothiomethyl.
  • the compound (la) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or sulfo group or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as
  • Suitabie reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g., methanesulfonic acid,
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorus acid e.g., sulfurous acid, thiosulfuric acid, alkanesulfuric acid (
  • ethanesulfonic acid etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid
  • pentanoic acid isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g., benzoic acid, etc.
  • a symmetrical acid anhydride
  • an activated amide with imidazoie, 4-substituted imidazoie, dimethylpyrazole, triazole or tetrazole an activated ester (e.g. cyanomethyl ester, methoxymethyl ester,
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
  • an alkali metal e.g., sodium, potassium, etc.
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) aikylamine e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphoiine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike.
  • the compound (lb) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the carboxy group or a salt thereof with the compound (V) or its reactive derivative at the amme group or a salt thereof.
  • the compound (Ic) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (VII) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike.
  • the base, the acid and/or the starting compound are liquid, they can be used also as a solvent.
  • the compound (Id) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof to Wittig Reaction.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the
  • reaction is usually carried out under cooling to heating.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine,
  • N,N-di (lower) alkylbenzylamine N,N-di (lower) alkylaniline, methyllitium, n-butyllitium, phenyliitium,
  • the compound (le) or a salt thereof can be prepared by reacting the compound (X) or its reactive derivative at the amino group or a salt thereof with the compound (XI) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metai hydrogencarbonate e.g., sodium
  • alkali metal carbcnate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkyiamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) aikyianiline or the like.
  • the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (If) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (XII) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the hydroxy group of the compound (VI) may include halide, sulfonate, sulfate, diazo compound, and the like.
  • Suitable reactive derivative at the carboxy group of the compound (XII) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.,
  • diphenylphosphoric acid diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorus acid sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g.,
  • methanesuifonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid, pentanoic acid, isopentanoic acid
  • 2-ethylbutyric acid, trichloroacetic acid, etc. aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole,
  • an ester with a N-hydroxy compound e.g.,
  • This reaction is usually carried out in the presence of a base.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaiine earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonate
  • alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkaiine earth metal hydroxide e.g., magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkali metai bicarbonate e.g., sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metai acetate e.g., sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g., magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine (e.g., trimethylamine, triethylamine, etc.), pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine,
  • This reaction is usually carried out in a sumble such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a slute such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the
  • the object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or its reactive
  • Suitable reactive derivative at the carboxy group of the compound (Ig) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples cf the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkyiphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.], diaikyiphosphorous acid, suifurous acid, thiosulfuric acid, sulfuric acid, sulfcnic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g., acetic acid,
  • N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.] N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivativee can optionally be selected from them according to the kind of the compound (Ig) tc be used.
  • Suitable salts of the compound (Ig) and its reactive derivative can be referred tc the ones as exemplified for the compound (I).
  • Suitable reactive derivative at the amine group of the compound (XIII) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XIII) with a carbonyl compound such as aidehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (XIII) with a silyl compound such as
  • Suitable salts of the compound (XIII) and its reactive derivative can be referred to the ones as exempiified for the compound (I).
  • the reaction is usually carried cut in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, aceton
  • reaction when the compound (Ig) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide
  • ethyl polyphosphate ethyl polyphosphate
  • isopropyl polyphosphate phosphorous oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal
  • N,N-di (lower) alkylbenzylamine or the like.
  • the reaction temperature is not oritical, and the reaction is usually carried out under cooling to warming.
  • the compound (Ij) or a salt thereof can be prepared by reacting the compound (Ii) or a salt thereof with Grignard Reagent .
  • Suitable Grignard reagent to be used in the present reaction nay include the compound of the formula : R 12 - MgX" (XIV) (wherein R 12 is lower alkyl, and
  • X is halogen.
  • This reaction is usually carried out in a solvent such as tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction ie usually carried out under cooling to heating.
  • the object compound (Il) or a salt thereof can be prepared by subjecting a compound (Ik) or a salt thereof to de-acylation reaction of acylamino group.
  • This reaction is carried out in accordance with a conventional method réelle ae hydrolysis, reduction or the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonte thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline,
  • alkali metal e.g., sodium, potassium, etc.
  • an alkaline earth metal e.g., magnesium, calcium, etc.
  • trialkylamine e.g., trimethylamine, triethylamine, etc.
  • picoline e.g., trimethylamine, triethylamine, etc.
  • Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g., an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • trihaloacetic acid e.g. trichloroacetic acid
  • trifluoroacetic acid, etc. or the iike is preferably carried out in the presence of cation trapping agents [e.g. anisoie, phenol, etc.].
  • cation trapping agents e.g. anisoie, phenol, etc.
  • the reaction is usually carried cut in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adverseiy influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling tc warming.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • metal e.g., tin, zing, iron, etc.
  • metallic compound e.g., chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-tolueneeulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts tc be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum cxide, platinum wire, etc.], palladium catalysts
  • nickel catalysts e.g., reduced nickel, nickel oxide, Raney nickei, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Uliman copper, etc.
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not oritical and the reaction is usually carried out under cooling tc warming.
  • the compound (Ik) or a salt thereof can be prepared by subjecting the compound ( Ii) or its reactive derivative at the amino group, or a salt thereof to acylation reaction.
  • Suitable acylating agent to be used in the present acylation reaction may include the comoound of the formula :
  • Suitable reactive derivative at the amino group of the compound ( Ii) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound ( Ii) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (IC) with a silyl compound such as
  • Suitable reactive derivative of the compound (XV) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable exampie may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, suifurous acid, thiosulfuric acid, alkaneeulfcnic acid (e.g., methanesulfonic acid,
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid suifurous acid, thiosulfuric acid, alkaneeulfcnic acid (
  • ethanesulfonic acid etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid
  • pentanoic acid isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g., benzoic acid, etc.
  • a eymmetrical acid anhydride
  • an activated amide with imidazoie, 4-eubstituted imidazoie, dimethylpyrazole, triazole or tetrazole an activated ester (e.g., cyanomethyl, ester methoxymethyl ester,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiinu.de;
  • 1-aikoxy-1-chloroethylene triaikyl phcephite; isopropyl poiyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;
  • the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal
  • N-(lower) alkylmorphorine N,N-di (lower) alkylbenzyiamine, or the iike.
  • the reaction temperature is not oritical, and the reaction is usually carried out under cooling to heating.
  • the compound (Im) or a salt thereof can be prepared by subjecting the compound (Ij) or a salt thereof to acylation reaction. This reaction can be carried out in a similar manner to that of the afore-mentioned Process 10.
  • the reagents to be used and the reaction conditions e.g., solvent, reaction temperature, etc.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (lo) or a salt thereof can be prepared by reacting the compound (In) or a salt thereof with lower alkane eubetituted with oxo (XIV) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformanu.de, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformanu.de, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • reaction ie usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the acid and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (Iq) or a salt thereof can be prepared by reacting the compound (Ip) or a salt thereof with the
  • This reaction can be carried out in a similar manner to that of the afore-mentioned Process 3. and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 3.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Ila) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or a salt thereof.
  • This reaction is usually carried out in a sumble such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, 1,2- dimethoxyethane, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • alcohol e.g., methanol, ethanol, etc.
  • benzene N,N-dimethylformamide
  • tetrahydrofuran toluene
  • methylene chloride ethylene dichloride
  • chloroform 1,2- dimethoxyethane
  • dioxane dioxane
  • diethyl ether diethyl ether
  • the reaction temperature is not oritical and the
  • reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. eodium methoxide, eodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphcline, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniiine or the like.
  • the base and/or the etarting compound are in liquid, they can be used also as a solvent.
  • the object compound (I) can be prepared by any process known in this field of the art except the above Processes 1 to 13 and Process A.
  • each of the object compound (I) may include one or more stereoieomer euch ae optical
  • iecmer(s) and geometrical isomer (s) due to asymmetric carbon atom(s) and double bond(s) and all eternal ieomers and mixture thereof are included within the scope of this invention.
  • the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular;
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable
  • carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsulee, or euppositories; oreame;
  • the object compound (I) or a pharmaceutically acceptable salt thereof include solvated compound [e.-g., encloeure compound (e.g., hydrate, etc.)].
  • the object compound (I) or a pharmaceutically acceptable salt thereof include both its orystal form and non-orystal form.
  • the object compound (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceuticai
  • composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavaiiability of a drug can be .applied to the pharmaceutical composition of the present invention.
  • the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being or an animal, in the case of intramuecular adminietration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being of an animal, in case of oral administration, a daily dose of 0.001-200 mg of the object compound (I) per kg weight of a human being or an animal ie generally given for the prevention and/or the treatment of aforeeaid dieeases 1 to 4 times a day in a human oemg or an animal .
  • the pharmacological test data of the object compound (I) In order to illuetrate the usefuinees of the object compound (I), the pharmacological test data of the object compound (I).
  • N-Bromosuccinimide (3.74 g) was added to a solution of 8-ethoxycarbonyl-2-methylimidazo [1,2-a]pyridine (4.243 g) in ethanol (40 ml). After stirring at ambient temperature for 30 minutes, the mixture was evaporated in vacuo and the residue was dieeolvea in dichloromethane. The solution was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The orystalline residue was reorystallized from diisopropyl ether to give 3-bromo-8-ethoxycarbonyl-2-methylimidazo [1,2-a]- pyridine (5.1 g).
  • 2,6-Dichlorobenzoyl chloride (2.51 g) wae added to a eolution of 8-amino-2-trifluoromethyIimidazo [1,2-a]pyridine (2.01 g) and triethylamine (1.31 g) in dichloromethane (30 ml). The mixture- wae etirred at ambient temperature for 1 hour ana refluxed overnight. The mixture was diluted with dichloromethane, washed with aqueous saturated eodium bicarbonate and water, dried over sodium sulfate, and evaporated in vacuo.
  • Methyl iodide (354 mg) was added to a solution of 8- (2,6-dichlorobenzoylamino)-3-dimethylaminomethyl-2- methylimidazo [1,2-a] pyridine (940 mg) in a mixture of acetone (30 ml) and tetrahyarofuran (10 ml) at 4°C. The solution was stirred at ambient temperature for 6 hours and evaporated in vacuo.

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Abstract

L'invention porte sur un nouveau composé d'imidazopyridine de la formule (I), dans laquelle X représente vinylène, ou un groupe de la formule (a), Y un groupe hétérocyclique à un ou plusieurs substituants adéquats ou aryle à un ou plusieurs substituants, Q représente CH ou N et 1 vaut 0 ou 1. Ces éléments agissent en tant qu'inhibiteurs de la résoprtion et du métabolisme osseux. L'invention se rapporte également à des procédés permettant de les préparer et à une composition pharmaceutique à base de ce composé. Elle décrit également une méthode de traitement des maladies provoquées par une anomalie du métabolisme osseux chez l'homme ou chez l'animal.
PCT/JP1996/001103 1995-05-01 1996-04-23 Derives de l'imidazo 1,2-a pyridine et de l'imidazo 1,2-a pyridezine et leur utilisation en tant qu'inhibiteurs de la resorption osseuse WO1996034866A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU53483/96A AU5348396A (en) 1995-05-01 1996-04-23 Imidazo 1,2-a pyridine and imidazo 1,2-a pyridezine derivati ves and their use as bone resorption inhibitors
JP8533169A JPH11505524A (ja) 1995-05-01 1996-04-23 イミダゾ１，２−ａピリジンおよびイミダゾ１，２−ａピリデジン誘導体、および骨吸収阻害剤としてのその用途

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBGB9508826.6A GB9508826D0 (en) 1995-05-01 1995-05-01 New Compound
GBGB9512972.2A GB9512972D0 (en) 1995-06-26 1995-06-26 New compound
GBGB9516647.6A GB9516647D0 (en) 1995-08-14 1995-08-14 New compound
GB9508826.6 1995-08-14
GB9516647.6 1995-08-14
GB9512972.2 1995-08-14

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WO1996034866A1 true WO1996034866A1 (fr) 1996-11-07

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