EP0863881A1 - Benzimidazolderivate und ihre verwendung in der verhütung und/oder der behandlung von knochenkrankheiten - Google Patents

Benzimidazolderivate und ihre verwendung in der verhütung und/oder der behandlung von knochenkrankheiten

Info

Publication number
EP0863881A1
EP0863881A1 EP96929540A EP96929540A EP0863881A1 EP 0863881 A1 EP0863881 A1 EP 0863881A1 EP 96929540 A EP96929540 A EP 96929540A EP 96929540 A EP96929540 A EP 96929540A EP 0863881 A1 EP0863881 A1 EP 0863881A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
benzimidazole
alkylcarbamoyl
trifluoromethyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP96929540A
Other languages
English (en)
French (fr)
Inventor
Teruo Oku
Yoshio Kawai
Takumi Yatabe
Shigeki Sato
Hitoshi Yamazaki
Natsuko Kayakiri
Kousei Yoshihara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
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
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0863881A1 publication Critical patent/EP0863881A1/de
Withdrawn legal-status Critical Current

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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof- More particularly, it relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which are the inhibitors of V-type H + -ATPase, especially osteoclast H + -ATPase, the inhibitors of bone resorption, the inhibitors of bone metastasis and useful for the prevention and/or the treatment of bone diseases caused by abnormal bone metabolism in human being or animals.
  • the present invention relates to processes for the preparation of said compounds, to a pharmaceutical composition comprising the same and to a method for the prevention and/or the treatment of above-mentioned diseases in human being or animals, and to a use of said compounds and pharmaceutically acceptable salts thereof for the prevention and/or the treatment of above-mentioned diseases in human being or animals.
  • R 1 is acyl, lower alkenyl or lower alkyl optionally substituted with substituent (s) selected from the group consisting of aryl, substituted aryl, a heterocyclic group, a substituted heterocyclic group, hydroxy, substituted hydroxy, cyano, halogen, ammo, substituted ammo, acyl, mercapto, substituted mercapto, hydroxya idmo, substituted hydroxyamidmo and substituted hydrazono, and
  • R ⁇ is hydrogen, lower alkyl, hydroxy(lower) alkyl, halo (lower)alkyl, lower alkoxy, lower alkylthio, acyl or cyano, or
  • R 1 and R 2 are taken together to form lower alkylene or lower alkenylene, each of which may include 0, S or N-R 5 the chain, in which R ⁇ is hydrogen or lower alkyl, R J is hydrogen or halogen, R 4 is a heterocyclic group or aryl, each of which may be e substituent (s] and
  • R 9 is hydrogen, lower alkyl or substituted lower alkyl
  • R-*- 0 is hydrogen, lower alkyl or substituted lower alkyl
  • R 6 is hydrogen or lower alkyl optionally substituted with a substituent selected from the group consisting of hydroxy and lower alkoxy
  • R 7 is hydrogen; acyl; lower alkoxy; amino; acylamino; aryl optionally substituted with a substituent selected from the group consisting of lower alkoxy, halo(lower)alkyl and lower alkylamino; a heterocyclic group optionally substituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo(lower)alkyl and acyl; or lower alkyl optionally substituted with substituent (s) selected from the group consisting of hydroxy, lower alkoxy, halogen, cyano, acyloxy, acyl, aryl optionally having halo (lower) alkyl and a heterocyclic group optionally having lower alkyl; or R 6 and R are taken together with the attached nitrogen atom to form a heterocyclic group optionally
  • lower alkenyl moiety in the various definitions is intended to mean a group having 2 to 6 carbon atoms.
  • lower in cyclo(lower) alkyl moiety in the various definitions is intended to mean a group having 3 to 6 carbon atoms.
  • acyl and all acyl moieties in the various definitions mentioned in this specification and claims such as in the term “acylamino”, “acyloxy”, etc. may be substituted or unsubstituted lower alkanoyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, 3,3-dimethylbutyryl, etc.], halo(lower)alkanoyl [e.g.
  • carboxy(lower) alkanoyl e.g. oxalo, carboxyacetyl, 3-carboxypropionyl, 3-carboxybutyryl, 4-carboxybutyryl, 4-carboxyvaleryl, etc.
  • esterified carboxy(lower)alkanoyl for example, lower alkoxycarbonyl (lower) alkanoyl [e.g.
  • succinimidooxycarbonyl (lower)alkanoyl e.g. succinimidooxycarbonylbutyryl, etc.
  • carbamoyl (lower) alkanoyl e.g. carbamoylacetyl, carbamoylpropionyl, etc.
  • lower alkylcarbamoyl (lower) alkanoyl e.g.
  • cyclopropylcarbamoyl cyclobutylcarbamoyl , cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.]
  • halo (lower) alkylcarbamoyl e.g. chloromethylcarbamoyl, trif luoromethylcarbamoyl, trifluoroethylcarba oyl, etc.
  • cyano (lower) alkylcarbamoyl e.g. cyanome thyl carbamoyl, etc.] hydroxy (lower) alkylcarbamoyl [e.g.
  • lower alkoxy (lower) alkylcarbamoyl e.g. methoxyethylcarbamoyl, methoxypropylcaramoyl, di (methoxyethyl) carbamoyl, etc.
  • lower alkanoyloxy (lower) alkylcarbamoyl e.g.
  • acetoxyethylcarbamoyl acetoxypropylcarbamoyl, diacetoxypropylcarbamoyl, etc.
  • lower alkoxycarbamoyl e.g. methoxycarbamoyl, ethoxycarbamoyl, etc.
  • protected or unprotected aminocarbamoyl e.g. aminocarbamoyl, tert- butoxycarbonylaminocarbamoyl, etc.
  • carbamoyl (lower) alkylcarbamoyl e.g.
  • hydroxy (lower) alkylcarbamoyl (lower) alkylcarbamoyl e.g. hydroxyethyl carbamoylmethylcarbamoyl, hydroxyethylcarbamoylethylcarbamoyl, etc.
  • arylsulfonylcarbamoyl e.g.
  • arylcarbamoyl e.g. phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, naphthylcarbamoyl, ethylphenylcarbamoyl, etc.
  • arylcarbamoyl e.g. phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, naphthylcarbamoyl, ethylphenylcarbamoyl, etc.
  • lower alkoxy- arylcarbamoyl e.g. methoxyphenylcarba oyl, etc.
  • halo-arylcarbamoyl e.g.
  • ar(lower) alkylcarbamoyl for example, ar(lower) alkylcarbamoyl [e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.], halo (lower)alkyl- ar (lower)alkylcarbamoyl [e.g.
  • heterocyclic(lower)alkylcarbamoyl substituted or unsubstituted heterocyclic(lower)alkylcarbamoyl, for example, heterocyclic(lower) alkylcarbamoyl [e.g.
  • heterocycliccarbamoyl substituted or unsubstituted heterocycliccarbamoyl, for example, heterocycliccarbamoyl [e.g.
  • furylcarbamoyl thienylcarbamoyl, pyridylcarbamoyl, quinolylcarbamoyl, isoquinolylcarbamoyl, pyrimidinylcarbamoyl, pyrazolylcarbamoyl, morpholinocarbamoyl, thiazolylcarbamoyl, oxazolylcarbamoyl, isoxazolylcarbamoyl, thiadiazolylcarbamoyl, etc.], lower alkyl- heterocycliccarbamoyl [e.g.
  • Suitable "lower alkenyl” may be vinyl, allyl, methylpropenyl, butenyl, pentenyl or the like.
  • Suitable “lower alkyl” and lower alkyl moiety in the terms “heterocyclic(lower)alkyl”, “hydroxy(lower)alkyl”, “lower alkylthio” and “lower alkylamino” may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C ⁇ _-C 4 alkyl such as methyl, ethyl, propyl, isobutyl or tert-butyl.
  • Suitable "aryl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl, naphthyl and tolyl.
  • lower alkyl e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl)phenyl, etc.
  • heterocyclic group and all heterocyclic moieties in the various definitions mentioned in this specification and claims such as in the term “heterocyclic (lower) alkyl", “heterocycliccarbonyl”, etc., may include saturated or unsaturated, monocyclic or polycyclic one containing at least one hetero atom such as nitrogen atom, oxygen atom or sulfur atom, preferably N, 0 and/or S containing heterocyclic group, in which preferable ones may be morpholinyl, piperazinyl, pyridyl, tetrahydropyridyl, pyrimidinyl, piperidyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxadiazolyl, dihydrooxadiazolyl, thiadiazolyl, tetrazolyl, imidazolyl, imidazolidinyl, pyrrolidin
  • Suitable “halogen” may be fluorine, chlorine, bromine and iodine.
  • Suitable “halo(lower)alkyl” may be chloromethyl, bromoethyl, dichloromethyl, difluoromethyl, trifluoromethyl, or the like.
  • Suitable "lower alkoxy” may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is C ⁇ _-C_ j alkoxy such as methoxy, ethoxy or isopropoxy.
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, methylmethylene, tetramethylene, ethylethylene, propylene, pentamethylene, hexamethylene or the like, in which the most preferable one is methylene.
  • Suitable "lower alkenylene” may be a straight or branched 2 ⁇ Cg alkenylene such as vinylene, ethylvinylene, propenylene, 1, 3-butadienylene or the like, in which the most preferable one is vinylene.
  • Preferable lower alkylene or lower alkenylene each of which includes 0, S or N-R 5 in the chain formed by R 1 and R 2 may be a group of the formula : — CH —CHo — CHo ⁇ S — ,
  • R 8 -C CH-S-
  • R-* is as defined above, or the like.
  • Suitable substituents of aryl in the term "substituted aryl" may be nitro, cyano, the above-mentioned lower alkoxy or the above-mentioned halo(lower) alkyl, or the like.
  • Suitable substituents of a heterocyclic group in the term "a substituted heterocyclic group" may be oxo, the above-mentioned lower alkyl, the above-mentioned halogen, the above-mentioned heterocyclic group, or the like.
  • Suitable substituents of hydroxy in the term "substituted hydroxy" may be the above-mentioned lower alkyl, the above-mentioned acyl, the above-mentioned aryl, the above-mentioned a heterocyclic group, ar(lower)alkyl such as phenyl (lower) alkyl [e.g. benzyl, phenethyl, phenylpropyl, etc. ] or the like.
  • Suitable substituents of amino in the term "substituted amino" may be the above-mentioned acyl, or the like.
  • Suitable substituents of mercapto in the term “substituted mercapto” may be the above-mentioned a heterocyclic group which may be substituted by the above- mentioned lower alkyl; the above-mentioned aryl; or the like.
  • Suitable substituents of hydroxya idino in the term “substituted hydroxyamidino” may be the above-mentioned acyl.
  • Suitable substituents of hydrazono in the term “substituted hydrazono” may be the above-mentioned lower alkyl, the above-mentioned a heterocyclic group, or the like.
  • Suitable substituents in the term "a heterocyclic group or aryl, each of which may be substituted with suitable substituent (s) " for R 4 may be the above-mentioned halogen; the above-mentioned lower alkyl; hydroxy(lower) alkyl; the above-mentioned lower alkoxy; lower alkoxy(lower)alkoxy; the above-mentioned halo (lower) alkyl; halo (lower) alkoxy; nitro; amino optionally substituted with lower alkyl or acyl; the above-mentioned aryl; the above-mentioned acyl; lower alkoxycarbonyl (lower) alkenyl; hydroxy(lower) alkyl optionally substituted with lower alkyldiarylsilyl; or the like, in which preferable ones are halogen, lower alkyl or lower alkoxy.
  • Suitable "heterocyclic group" formed by R , R 7 and the attached nitrogen atom may be morpholino, thiomorpholino, pyrrolidin-1-yl, piperidino, 1,2, 3, 6-tetrahydropyridin-l-yl, piperazin-1-yl, or the like.
  • substituted lower alkyl for R 9 and R 1 may be the above- mentioned acyl.
  • Suitable “a leaving group” may be a conventional acid residue such as halogen [e.g. fluoro, chloro, bromo and iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy [e.g. mesyloxy, ethanesulfonyloxy, etc.], and the like.
  • halogen e.g. fluoro, chloro, bromo and iodo
  • arenesulfonyloxy e.g. benzenesulfonyloxy, tosyloxy, etc.
  • alkanesulfonyloxy e.g. mesyloxy, ethanesulfonyloxy, etc.
  • Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g.
  • a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenz
  • Preferred embodiments of the object compound [I] are as follows :
  • R 1 is lower alkanoyl; haloaroyl; lower alkenyl; lower alkyl; or lower alkyl substituted with substituent(s) selected from the group consisting of aryl, aryl substituted with nitro, aryl substituted with cyano, aryl substituted with lower alkoxy, a heterocyclic group, a heterocyclic group substituted with a heterocyclic group, a heterocyclic group substituted with lower alkyl, a heterocyclic group substituted with halogen, a heterocyclic group substituted with one or two oxo(s), hydroxy, hydroxy substituted with lower alkyl, hydroxy substituted with acyl [more preferably hydroxy substituted with lower alkanoyl, hydroxy substituted with carboxy(lower)alkanoyl, hydroxy substituted with succinimidooxycarbonyl (lower)alkanoyl, hydroxy substituted with diphosphono (lower)alkylcarbamoyl- (lower
  • R 2 is hydrogen, lower alkyl, hydroxy(lower)alkyl, halo(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, carbamoyl or cyano, in which more preferable ones are lower alkyl, halo(lower)alkyl or cyano, or
  • R 1 and R 2 are taken together to form a group of the formula :
  • R 5 and R 8 are each hydrogen or lower alkyl
  • R 3 is hydrogen or halogen
  • R 4 is aryl substituted with substituen (s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkoxy(lower)alkoxy, halo(lower) alkoxy, lower alkanoyl, lower alkoxycarbonyl (lower)alkenyl, hydroxy(lower)alkyl and lower alkyldiarylsilyloxy-
  • R 9 is hydrogen, lower alkyl or lower alkoxycarbonyl (lower)alkyl
  • R 10 is hydrogen, lower alkyl or lower alkoxycarbonyl(lower)alkyl
  • the object compound [I] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.
  • Suitable salts of the compounds [II] and [III] may be the same as those exemplified for the compound [I] .
  • the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkali metal alkoxide [e.g. sodium ethoxide, sodium ethoxide, potassium tert-butoxide, etc.], triethylamine, or the like.
  • a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkali metal alkoxide [e.g. sodium ethoxide, sodium ethoxide, potassium tert-butoxide, etc.], trie
  • This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, dichloromethane, ethylene chloride, N,N-dimethylformamide, acetone, or the like.
  • a conventional solvent such as tetrahydrofuran, dioxane, dichloromethane, ethylene chloride, N,N-dimethylformamide, acetone, or the like.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the object compound [la] or its salt can be prepared by reacting a compound [IV] or its reactive derivative at the amino group or a salt thereof with a compound [V] or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound [IV] may be a silyl derivative formed by the reaction of the compound [IV] with a silyl compound such as bis (trimethylsilyl) acetamide or mono (trimethylsilyl)acetamide, or the like.
  • Suitable salts of the compound [IV] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .
  • Suitable reactive derivative at the carboxy group of the compound [V] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as dialkylphosphoric acid, sulfuric acid, aliphatic carboxylic acid or aromatic carboxylic acid; a symmetrical acid anhydride; an activated amide with imidazole; or an activated ester [e.g. p-nitrophenyl ester, etc.].
  • These reactive derivatives can optionally be selected from them according to the kind of the compound [V] to be used.
  • Suitable salts of the compound [V] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .
  • the reaction is usually carried out in a conventional solvent, such as methylene chloride, chloroform, pyridine, dioxane, tetrahydrofuran, N,N-dimethylformamide, or the like.
  • a conventional solvent such as methylene chloride, chloroform, pyridine, dioxane, tetrahydrofuran, N,N-dimethylformamide, or the like.
  • a conventional condensing agent such as
  • the reaction temperature is not critical and the reaction can be carried out under cooling, at ambient temperature, or under heating.
  • This reaction is preferably carried out in the presence of a conventional inorganic base or in the presence of a conventional organic base.
  • the object compound [lb] or its salt can be prepared by reacting a compound [VI] or its reactive derivative at the carboxy group or a salt thereof with a compound [VII] or its reactive derivative at the amino group or a salt thereof.
  • Suitable salts of the compounds [VI] and [VII] and their reactive derivatives can be referred to the ones as exemplified for the compound [I] .
  • This reaction can be carried out in substantially the same manner as Process 2. and therefore the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 2.
  • the object compound [Id] or its salt can be prepared by reacting a compound [Ic] or its reactive derivative at the carboxy group or a salt thereof with a compound [VIII] or its reactive derivative at the amino group or a salt thereof.
  • Suitable salts of the compound [VIII] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .
  • This reaction can be carried out in substantially the same manner as Process 2. and therefore the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 2.
  • R , R 3 and R 4 are each as defined above.
  • the compound [Ila] or its salt can be prepared by reacting a compound [IX] or its reactive derivative at the amino group or a salt thereof with a compound [V] or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable salts of the compound [IX] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .
  • This reaction can be carried out in substantially the same manner as Process 2. and therefore the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 2.
  • the compound [lib] or its salt can be prepared by reacting a compound [X] or its reactive derivative at the carboxy group or a salt thereof with a compound [VII] or its reactive derivative at the amino group or a salt thereof.
  • Suitable salts of the compound [X] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .
  • This reaction can be carried out in substantially the same manner as Process 2. and therefore the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 2.
  • the object compound [I] and the starting compounds can also be prepared by the methods of Examples mentioned below or similar manners thereto or conventional manners.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, chromatography, reprecipitation or the like.
  • the compound [I] and the other compounds may include one or more stereoisomers and geometrical isomers due to asymmetric carbon atoms and double bonds, and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compound [I] and pharmaceutically acceptable salts thereof are the inhibitors of vacuolar-type (V-type) H + -adenosine triphosphatase (ATPase) , especially osteoclast H + -ATPase, the inhibitors of bone resorption, the inhibitors of bone metastasis and useful for the prevention and/or the treatment of bone disease caused 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 metastasis; rheumatoid arthritis; periodontitis; osteoarthritis; ostealgia; osteopenia; cancer cachexia; malignant tumor; or the like in human being or animals.
  • V-type vacuolar-type H + -adenosine triphosphatase
  • osteoclast H + -ATPase adenosine triphosphata
  • the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for the prevention and/or the treatment of tumors, especially those related to renal cancer, melanoma, colon cancer, lung cancer and leukemia; viral conditions (e.g. those involving Semliki Forest, Vesicular Stoma ti tis, Newcastl e Di sease, Infl uenza A and B, HIV viruses); ulcers (e.g.
  • Calvariae from Wistar rats were excised and cultured in wells of 12-well culture plates containing 2 ml of Dulbecco's modified minimum essential medium supplemented with 10% fetal bovine serum and 10 _8 M human parathyroid hormone fragment (1- 34) [PTH] in the presence of the test compound (dose : 1 X 10 _5 M) . In control dishes, PTH was not added. Control and PTH control were exposed to an equivalent concentration of the vehicle. Six days later, the concentration of calcium ([Ca]) in the medium was measured by methylxylenol blue method and the percentage of inhibition of PTH-induced bone resorption was calculated according to following formula : c p -c D
  • the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral such as intravenous, intramuscular, subcutaneous or intraarticular, external such as topical, enteral, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like.
  • auxiliary substances for preventing and/or treating the above-mentioned diseases.
  • amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • Example 1 The following Examples are given for the purpose of illustrating this invention.
  • Example 1 The following Examples are given for the purpose of illustrating this invention.
  • Example 3 A solution of 3-nitro-l,2-phenylenediamine (1.0 g) in trifluoroacetic acid (10 ml) was refluxed overnight. The reaction mixture was cooled and evaporated in vacuo. The residue was diluted with water and the solution was adjusted to pH 4 with aqueous IN sodium hydroxide. Then, the mixture was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n- hexane to give 4-nitro-2-trifluoromethyl-lH-benzimidazole (1.26 g) . mp : 145-146 ⁇ C
  • Example 5 A mixture of 4- (2, 6-dichlorobenzoylamino) -2- trifluoromethyl-lH-benzimidazole (993 mg) , tert-butyl bromoacetate (621 mg) and potassium carbonate (477 mg) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into 0.8% hydrochloric acid and the separated oil was extracted with ethyl acetate. The extract was washed with water, aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo.
  • the obtained oil was dissolved in N,N-dimethylformamide (2 ml) and to the solution was added 1-methylpiperazine (100 mg) .
  • the solution was stirred at 50°C overnight and poured into water.
  • the mixture was extracted with ethyl acetate.
  • the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo.
  • the residue was purified by column chromatography on silica gel and the obtained oil containing 4- (2, 6-dichlorobenzoylamino) -1-[3-(4-methylpiperazin-l- yl)propyl]-2-trifluoromethyl-lH-benzimidazole was dissolved in 10% methanolic hydrogen chloride.
  • Example 10 The following compounds were obtained according to a similar manner to that of Example 9.
  • Oxalyl chloride (48 ⁇ l) was added to a suspension of 1- carboxymethyl-4- (2, 6-dichlorobenzoylamino) -2-trifluoromethyl- lH-benzimidazol.e (135 mg) in dichloromethane. Then, to a mixture was added N,N-dimethylformamide (1 drop) . The mixture was stirred at ambient temperature for 2 hours and evaporated in vacuo. The residue was dissolved in dioxane (1 ml) and to the solution was added 28% aqueous ammonia (5 ml) in one portion with well stirring.
  • Oxalyl chloride (40 ⁇ l) was added to a suspension of 1- carboxymethyl-4- (2, 6-dichlorobenzoylamino) -2-trifluoromethyl- lH-benzimidazole (150 mg) in dichloromethane. Then, to a mixture was added N,N-dimethylformamide (1 drop) . The mixture was stirred at ambient temperature for 1 hour and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and 1-methylpipera ⁇ ine (61 mg) was added to the solution. The solution was stirred for 30 minutes at ambient temperature, washed with water and brine, dried over sodium sulfate and evaporated in vacuo.
  • (32) 4- (2, 6-Dichlorobenzoylamino) -1-[N-(1, l-dimethyl-2- hydroxyethyl) carbamoylmethyl]-2-trifluoromethyl-lH- benzimidazole (from l-carboxymethyl-4- (2, 6-dichlorobenzoylamino) -2- trifluoromethyl-lH-benzi idazole and 2-amino-l-hydroxy- 2-methylpropane) p : 242-244°C
  • Example 18 To IM solution of methylmagnesium bromide in tetrahydrofuran (3 ml) was dropwise added a solution of 4- (2, 6-dichlorobenzoylamino) -2-methyl-l- (2-oxopropyl) -IH- benzimidazole (188 mg) in tetrahydrofuran (1 ml), and the mixture was stirred for 3 hours at ambient temperature. The mixture was cooled to 4°C, and saturated ammonium chloride solution was dropwise added thereto. The mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated in vacuo.
  • Example 21 4- (2, 6-Dichlorobenzoylamino) -1- (2-hydroxyethyl) -2- trifluoromethyl-lH-benzimidazole was obtained according to a similar manner to that of Example 17. mp : 183-185°C
  • Example 22 To a suspension of 4- (2, 6-dichlorobenzoylamino) -2- methyl-1- (2-oxopropyl) -lH-benzimidazole (188 mg) in methanol (5 ml) was added sodium borohydride (38 mg) , and the mixture was stirred for 2 hours at ambient temperature. Water was added thereto, and the precipitate was collected by filtration, washed with water and dried to give 4- (2, 6- dichlorobenzoylamino)-1- (2-hydroxypropyl)-2-methyl-lH- benzimidazole (155 mg) . mp : >250°C
  • Example 24 A mixture of 4- (2, 6-dichlorobenzoylamino) -1- (2- hydroxyethyl) -2-methyl-lH-benzimidazole (95 mg) , carbon tetrabromide (100 mg) and triphenyl phosphine (99 mg) in dichloromethane was stirred at ambient temperature for 1 day. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from diisopropyl ether to give 1- (2-bromoethyl) -4-(2,6-dichlorobenzoylamino) -2-methyl-lH- benzimidazole (42 mg) .
  • Example 31 To a solution of 1- (2-aminoethyl)-4- (2, 6- dichlorobenzoylamino)-2-trifluoromethyl-lH-benzimidazole (105 mg) in pyridine was added acetic anhydride (77.1 mg) and the mixture was stirred for 1 hour at ambient temperature. The mixture was poured into water and extracted with ethyl acetate.
  • Example 3 A mixture of 4- (2, 6-dichlorobenzoylamino)-2-methyl-l- (2- oxopropyl)-IH-benzimidazole (100 mg) and 2-hydrazinopyridine (29 mg) in ethanol (2 ml) was stirred at 50°C for 1 hour. The mixture was cooled and the resulting solid was collected. The obtained solid was dissolved in methanolic hydrogen chloride and the solution was evaporated in vacuo.
  • Example 35 To a mixture of hydroxylamine hydrochloride (42 mg) and sodium carbonate (64 mg) in water (0.4 ml) and ethanol (7.4 ml) was added l-cyanomethyl-4- (2, 6-dichlorobenzoylamino)-2- trifluoromethyl-lH-benzimidazole (200 mg) , and the mixture was refluxed for 1 hour. After cooling, water was added thereto, and the resulting precipitate was collected by filtration. The residue was purified by column chromatography to give 4- (2, 6-dichlorobenzoylamino)-1- (N- hydroxyamidino)methyl-2-trifiuoromethyl-lH-benzimidazole (150 g) .
  • Example 37 4- (2, 6-Dichlorobenzoylamino)-1-[N-[N- (2- hydroxyethyl)carbamoylmethyl]carbamoylmethyl]-2- trifluoromethyl-lH-benzimidazole was obtained from 1-[N- (carboxymethyl) carbamoylmethyl]-4- (2, 6-dichlorobenzoylamino) - 2-trifiuoromethyl-lH-benzimidazole and (2-hydroxyethyl)amine according to a similar manner to that of Example 13. mp : >250°C
  • the mixture was stirred at ambient temperature for 2 hours, washed with IN-hydrochloric acid, aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo.
  • the residue was crystallized from a mixture of 2- ⁇ ropanol and diisopropyl ether. The obtained crystal was added to phosphorus oxychloride (1.5 ml) and the mixture was refluxed for 2 hours.
  • the reaction mixture was evaporated in vacuo, diluted with cold water, neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated m vacuc.
  • Example. 39 4- (2, 6-Dichlorobenzoylamino)-1-[N- (5-methyl-l, 3, 4- oxadiazol-2-ylmethyl)carbamoylmethyl]-2-trifluromethyl-lH- benzi idazole was obtained from 1-[N-(carboxymethyl) - carbamoylmethyl]-4- (2, 6-dichlorobenzoylamino)-2- trifluoro ethyl-lH-benzimidazole according to a similar manner to that of Example 38. mp : 156-158°C
  • Example 41 1-[N- (1, 3-Diacetoxy-2-propyl)carbamoylmethyl]-4- (2, 6- dichlorobenzoylamino)-2-trifluromethyl-lH-benzimidazole was obtained by reacting 4- (2, 6-dichlorobenzoylamino) -1- [N- (1, 3- dihydroxy-2-propyl)carbamoylmethyl]-2-trifluoromethyl-lH- benzimidazole with acetic anhydride according to a similar manner to that of Example 40. mp : 162-164°C
  • Example 44 A mixture of 4- (2, 6-dichlorobenzoylamino) -1- (2- hydroxyethyl) -2-trifluoromethyl-lH-benzimidazole (418 mg) , glutaric anhydride (137 mg) , pyridine (103 mg) , catalytic amount of N, -dimethylaminopyridine in dichloromethane (10 ml) was stirred overnight at ambient temperature. The mixture was washed with IN hydrochloric acid and brine, dried and concentrated in vacuo.
  • Example 47 2-Hydroxymethyl-4-nitro-lH-benzimidazole was obtained by reacting 3-nitro-l, 2-phenylenediamine with glycolic acid according to a similar manner to that of Example 3-(l) . mp : 206-207°C
  • Example 49 (1) 4- (2, 6-Dimethoxybenzoylamino) -2-trifluoromethyl-lH- benzimidazole was obtained by reacting 4-amino-2- trifluoromethyl-lH-benzimidazole with 2,6- dimethoxybenzoyl chloride according to a similar manner to that of Example l-(2). mp : 214-215°C
  • Example 50 A suspension of 2-hydroxymethyl-4-nitro-lH-benzimidazole (300 mg) in aqueous 0.5N sodium hydroxide (3.2 ml) was stirred at 110°C and to the suspension was added dropwise a solution of potassium permanganate (368 mg) in hot water (10 ml) . The mixture was stirred at HO'C for 20 minutes and the insoluble solid was filtered and washed with hot water and a small amount of hot aqueous IN sodium hydroxide. The filtrate was acidified (pH 3) and cooled in an ice bath. The separated solid was collected to give 2-carboxy-4-nitro-lH- benzimidazcle (290 mg) . mp : 246-248°C (dec.)
  • Example 52 (1) l-tert-Butoxycarbonylmethyl-4-ethoxycarbonyl-2- trifiuoromethyl-lH-benzimidazole was obtained by reacting 4-ethoxycarbonyl-2-trifluoromethyl-lH- benzimidazole with tert-butyl bromcacetate according to a similar manner to that of Example 5. mp : 122-124°C
  • Example 54 A mixture of 3-nitro-l, 2-phenylenediamine (0.5 g) and difluoroacetic acid (314 mg) in 4N hydrochloric acid (9 ml) was heated at 100°C for 42 hours. After cooling, ethyl acetate was added thereto, and insoluble material was filtered off. The separated organic layer was washed with water, dried and concentrated in vacuo to give 2- difluoromethyl-4-nitro-lH-benzimidazole (265 mg) . mp : 136-137 ⁇ C
  • Example 58 To a solution of 4- (2, 6-dichlorobenzoylamino) -2- methylthio-lH-benzimidazole (100 mg) in dichloromethane (2 ml) was added a solution of hydrogen peroxide in trifluoroacetic acid (IM solution, 0.56 ml) at 4°C. The mixture was stirred at 4°C for 30 minutes, neutralized with aqueous saturated sodium bicarbonate and extracted with a mixture of dichloromethane and ethanol (8:2, V/V). The extract was dried over sodium sulfate and evaporated in vacuc.
  • IM solution trifluoroacetic acid
  • Example 59 A mixture of 2-mercapto-4-nitro-lK-benzimidazole (400 mg) and 2-cxo ⁇ ropyl chloride (248 mg) in ethanol (6 ml) was refluxed for 18 hours. After cooling, the mixture was adjusted pK 8 with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuc. The residue was purified by column chromatography on silica gel to give 4- nitro-2- (2-oxopropylthio) -IH-benzimidazole (388 mg) . mp : 228-231°C (dec.)
  • Example 61 A mixture of 4-aminc-lH-benzimidazoie (260 mg) , 2,6- dichlorobenzoyl chloride (436 mg) and triethylamine (300 mg) in dichloromethane (5 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel to give 4-amino-l- (2, 6-dichlorobenzoyl)-1H- benzimidazole (251 mg) . p : l.l-l.S'C NMR (CDC1 3 , ⁇ ) : 4.38-4.48 (2H, m) , 6.73 (IK, d,
  • Example 62 (1) 1- (tert-Butoxycarbonyl)methyl-2-tert-butoxycarbonyl- methoxycarbonyl-4-nitro-lK-benzimidazole was obtained by reacting 2-carboxy-4-nitro-lH-benzimidazole with tert- butyl bromoacetate according to a similar manner to that of Example 5. mp : 149-151°C
  • Example 64 The following compounds were obtained according to a similar manner to that of Example 5.
  • Example 65 (1) l-tert-3utoxycarbonylmethyl-4-nitro-2-trifluoromethyl- IK-benzimidazole was obtained by reacting 4-nitro-2- trifluoromethyl-lH-benzimidazole with tert-butyl bromoacetate according to a similar manner to that of Example 5.
  • Example 66 A mixture of 4-ethoxycarbonyl-2-trifluoromethyl-lH- benzimidazole (258 mg) , 2-benzyloxyethyl bromide (301 mg) , potassium iodide (33 mg) and potassium carbonate (345 mg) in N, -dimethylformamide (2 ml) was stirred for 14 hours at 70°C. The mixture was partitioned between ethyl acetate and 3% aqueous sodium bicarbonate. The separated organic phase was concentrated.
  • Example 67 (1) To a solution of 4- (2, 6-dichlorobenzoylamino) -1- (2- hydroxyethyl) -2-trifluoromethyl-lH-benzimidazole (126 g) in dichloromethane was added triphenylphosphine (119 mg) and carbon tetrabromide (150 mg) , and the mixture was stirred at ambient temperature overnight. The resulting mixture was purified by column chromatography on silica gel and the obtained oil was crystallized from hexane to give l-(2- bromoethyl)-4- (2, 6-dichlorobenzoylamino) -2-trifluoromethyl- IH-benzimidazole (99 mg) . mp : 175-176°C
  • Example 72 Methyl 2-chloro-6- (2-methoxyethoxy)benzoate was obtained from methyl 2-chloro-6-hydroxybenzoate and 2-chloroethyl methyl ether according to a similar manner to that of Example 70- (3) .
  • Example 73 The following compounds were obtained according to a similar manner to that of Example 66- (3).

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EP96929540A 1995-09-11 1996-09-05 Benzimidazolderivate und ihre verwendung in der verhütung und/oder der behandlung von knochenkrankheiten Withdrawn EP0863881A1 (de)

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GBGB9518552.6A GB9518552D0 (en) 1995-09-11 1995-09-11 New heterocyclic compounds
PCT/JP1996/002530 WO1997010219A1 (en) 1995-09-11 1996-09-05 Benzimidazole derivatives and their use in the prevention and/or the treatment of bone diseases

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