WO1997010219A1 - Benzimidazole derivatives and their use in the prevention and/or the treatment of bone diseases - Google Patents

Benzimidazole derivatives and their use in the prevention and/or the treatment of bone diseases Download PDF

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Publication number
WO1997010219A1
WO1997010219A1 PCT/JP1996/002530 JP9602530W WO9710219A1 WO 1997010219 A1 WO1997010219 A1 WO 1997010219A1 JP 9602530 W JP9602530 W JP 9602530W WO 9710219 A1 WO9710219 A1 WO 9710219A1
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Prior art keywords
substituted
alkyl
benzimidazole
alkylcarbamoyl
trifluoromethyl
Prior art date
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PCT/JP1996/002530
Other languages
French (fr)
Inventor
Teruo Oku
Yoshio Kawai
Takumi Yatabe
Shigeki Sato
Hitoshi Yamazaki
Natsuko Kayakiri
Kousei Yoshihara
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.)
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Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP9511824A priority Critical patent/JPH11513364A/en
Priority to EP96929540A priority patent/EP0863881A1/en
Publication of WO1997010219A1 publication Critical patent/WO1997010219A1/en

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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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    • 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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Definitions

  • This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereofMore 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
  • substituent(s) selected from the group consisting of aryl, substituted aryl, a heterocyclic group, a substituted heterocyclic group, hydroxy, substituted hydroxy, cyano, halogen, amino, substituted amino, acyl, mercapto, substituted mercapto,
  • R 2 is hydrogen, lower alkyl, hydroxy(lower)alkyl
  • R 1 and R 2 are taken together to form lower alkylene or lower alkenylene, each of which may include O, S or N-R 5 in the chain, in which R 5 is hydrogen or lower alkyl, R 3 is hydrogen or halogen,
  • R 4 is a heterocyclic group or aryl, each of which may be
  • A is or , in which R 9 is hydrogen, lower alkyl or substituted
  • R 10 is hydrogen, lower alkyl or substituted
  • the object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes.
  • R 6 is hydrogen or lower alkyl optionally substituted with a substituent selected from the group consisting of hydroxy and lower alkoxy, and
  • 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
  • R 6 and R 7 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with a substituent selected from the group consisting of lower alkyl, halogen, aryl and acyl,
  • X is a leaving group
  • R 1 , R 2 , R 3 , R 4 , R 9 , R 10 and A are each as defined above.
  • suitable examples of the various definitions to be included within the scope of the invention are
  • 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
  • lower alkanoyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl,
  • lower alkylsulfonyloxy(lower)alkanoyl e.g. mesyloxyacetyl, ethylsulfonyloxyacetyl, mesyloxypropionyl, etc.
  • lower alkoxy(lower)alkanoyl e.g. methoxyacetyl, ethoxyacetyl,
  • carboxy(lower)alkanoyl e.g. oxalo, carboxyacetyl, 3-carboxypropionyl, 3-carboxybutyryl,
  • alkoxycarbonyl(lower)alkanoyl e.g. methoxycarbonylacetyl, ethoxycarbonylacetyl, methoxycarbonylpropionyl, etc.
  • succinimidooxycarbonyl(lower)alkanoyl e.g.
  • carbamoyl(lower)alkanoyl e.g. carbamoylacetyl
  • alkylcarbamoyl(lower)alkanoyl e.g. methylcarbamoylacetyl, ethylcarbamoylpropionyl, dimethylcarbamoylpropionyl, etc.
  • diphosphono(lower)alkylcarbamoyl(lower)alkanoyl e.g.
  • ar(lower)alkanoyl e.g. phenylacetyl, tolylacetyl, naphthylacetyl, etc.
  • optionally substituted heterocyclic(lower)alkanoyl e.g.
  • piperazinylpropionyl pyridylacetyl, imidazolidinylpropionyl, piperidinoacetyl, pyrrolidinylacetyl. hexamethyleneiminoacetyl, imidazolylacetyl, furylacetyl, thienylacetyl, methylpiperazinylacetyl,
  • cyclo(lower)alkylcarbonyl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • carboxy esterified carboxy such as lower
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
  • aroyl such as aroyl [e.g. benzoyl, toluoyl, xyloyl,
  • acylaroyl for example, lower alkoxycarbonylaroyl [e.g. methoxycarbonylbenzoyl, etc.], etc., heterocycliccarbonyl which may be substituted with substituent [e.g. furoyl, thenoyl, pyridylcarbonyl,
  • nitrophenyloxycarbonyl, etc. ar (lower) alkoxycarbonyl which may be substituted with nitro [e.g. benzyloxycarbonyl, nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted carbamoyl such as carbamoyl, lower alkylcarbamoyl [e.g.
  • carboxy(lower)alkylcarbamoyl e.g. carboxymethylcarbamoyl, carboxyethylcarbamoyl, etc.] esterified
  • alkoxycarbonyl(lower)alkylcarbamoyl e.g.
  • allylcarbamoyl, etc. cyclo(lower)alkylcarbamoyl [e.g.
  • halo(lower)alkylcarbamoyl e.g. chloromethylcarbamoyl, trifluoromethylcarbamoyl, trifluoroethylcarbamoyl, etc.
  • cyano(lower)alkylcarbamoyl e.g. cyanomethylcarbamoyl, etc.
  • hydroxy(lower)alkylcarbamoyl e.g. hydroxyethylcarbamoyl, hydroxypropylcarbamoyl, di (hydroxyethyl) carbamoyl,
  • alkoxy(lower)alkylcarbamoyl e.g. methoxyethylcarbamoyl, methoxypropylcaramoyl, di(methoxyethyl)carbamoyl, etc.
  • lower alkanoyloxy(lower)alkylcarbamoyl e.g. methoxyethylcarbamoyl, methoxypropylcaramoyl, di(methoxyethyl)carbamoyl, etc.
  • diacetoxypropylcarbamoyl, etc.] lower alkoxycarbamoyl [e.g. methoxycarbamoyl, ethoxycarbamoyl, etc.], protected or unprotected aminocarbamoyl [e.g. aminocarbamoyl, tert-butoxycarbonylaminocarbamoyl, etc.],
  • arylsulfonylcarbamoyl e.g. phenylsulfonylcarbamoyl
  • arylcarbamoyl for example, arylcarbamoyl [e.g., arylcarbamoyl [e.g., arylcarbamoyl [e.g., arylcarbamoyl [e.g., arylcarbamoyl [e.g., arylcarbamoyl [e.g., arylcarbamoyl [e.g.
  • nitro-arylcarbamoyl e.g. nitrophenylcarbamoyl, etc.
  • cyano-arylcarbamoyl e.g. cyanophenylcarbamoyl, etc.
  • hydroxy(lower)alkyl-arylcarbamoyl e.g.
  • ar(lower)alkylcarbamoyl for example, ar(lower)alkylcarbamoyl [e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.], halo(lower)alkylar(lower)alkylcarbamoyl [e.g. trifluoromethylbenzylcarbamoyl, etc.], etc., substituted or unsubstituted
  • heterocyclic(lower)alkylcarbamoyl for example,
  • heterocyclic(lower)alkylcarbamoyl e.g.
  • heterocycliccarbamoyl for example, heterocycliccarbamoyl [e.g. furylcarbamoyl,
  • lower alkyl- heterocycliccarbamoyl e.g. methylpyridylcarbamoyl
  • phenylsulfonyl, etc. ar(lower)alkylsulfonyl [e.g.
  • ar(lower)alkenylsulfonyl e.g. styrylsulfonyl
  • Suitable "lower alkenyl” may be vinyl, allyl,
  • 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 1 -C 4 alkyl such as methyl, ethyl, propyl, isobutyl or tert-butyl.
  • Suitable "aryl” may be phenyl, naphthyl, phenyl
  • lower alkyl e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl) phenyl, etc.
  • preferable one is phenyl, naphthyl and tolyl.
  • heterocyclic group and all heterocyclic moieties in the various definitions mentioned in this
  • heterocyclic(lower)alkyl 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, O 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,
  • 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,
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene,
  • Suitable "lower alkenylene” may be a straight or
  • branched C 2 -C 6 alkenylene such as vinylene, methylvinylene, 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 O, S or N-R 5 in the chain formed by R 1 and R 2 may be a group of the formula : -CH 2 -CH 2 -CH 2 -S-, ,
  • R 8 is hydrogen or lower alkyl
  • R 5 is as defined above
  • 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.
  • 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 abovementioned lower alkyl; the above-mentioned aryl; or the like.
  • Suitable substituents of hydroxyamidino in the term "substituted hydroxyamidino" may be the above-mentioned acyl.
  • 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;
  • 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 6 , R 7 and the attached nitrogen atom may be morpholino, thiomorpholino, pyrrolidin-1-yl, piperidino, 1,2,3,6-tetrahydropyridin-1-yl, piperazin-1-yl, or the like.
  • substituted lower alkyl for R 9 and R 10 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. formate, acetate, trifluoroacetate, maleate, tartrate, oxalate, methanesulfonate,
  • 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, tri
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • an intramolecular salt and the like e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • 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,
  • heterocyclic group substituted with one or two oxo(s), hydroxy, hydroxy substituted with lower alkyl, hydroxy substituted with acyl [more preferably hydroxy
  • heterocycliccarbonyl substituted with lower alkyl heterocycliccarbonyl substituted with lower alkanoyl, heterocycliccarbonyl substituted with halogen
  • heterocycliccarbonyl substituted with aryl carbamoyl, lower alkylcarbamoyl, carboxy(lower)alkylcarbamoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl,
  • R 2 is hydrogen, lower alkyl, hydroxy(lower)alkyl
  • 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 substituent(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,
  • R 9 is hydrogen, lower alkyl or lower
  • R 10 is hydrogen, lower alkyl or lower
  • 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,
  • hydroxide or carbonate or bicarbonate thereof e.g. sodium hydroxide, potassium carbonate,
  • alkali metal alkoxide e.g.
  • 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
  • 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;
  • 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
  • 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 [Ib] 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
  • 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 2 , R 3 and R 4 are each as defined above.
  • the compound [IIa] 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 [IIb] 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,
  • the compound [I] and the other compounds may include one or more stereoisomers and
  • 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 a periodontitis; osteoarthritis; ostealgia; osteopenia; cancer cachexia; malignant tumor; or the like in human being or animals.
  • 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. chronic gastritis and peptic ulcer induced by Helicobacter pyl ori
  • autoimmune diseases e.g.
  • transplantation hypercholesterolemic and atherosclerotic diseases; AIDS; Alzheimer's disease; angiogenic diseases, such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumors; or the like in human being or animals, and useful for regulating male fertility in human being or animals.
  • 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 :
  • 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,
  • 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.
  • compositions may be capsules, tablets,
  • suspension emulsion, ointment, gel, cream, or the like. If desired, there may be included in these preparations,
  • an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for 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.
  • 4-(2,6-Dichlorobenzoylamino)-2-methyl-1H-benzimidazole was obtained by reacting 4-amino-2-methyl-1H-benzimidazole with 2,6-dichlorobenzoyl chloride according to a similar manner to that of Example 1-(2).
  • Example 1-(2) was obtained according to a similar manner to that of Example 1-(2).
  • Oxalyl chloride 48 ⁇ l was added to a suspension of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl- 1H-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. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated in vacuo.
  • Oxalyl chloride (40 ⁇ l) was added to a suspension of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-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
  • tetrahydrofuran (3 ml) was dropwise added a solution of 4- (2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H- 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.
  • 4-(2,6-Dichlorobenzoylamino)-1-(2-hydroxy-2-methylpropyl)-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 4-(2,6-dichlorobenzoylamino)-1-(2-oxopropyl)-2-trifluoromethyl-1H-benzimidazole with methylmagnesium bromide according to a similar manner to that of Example 18.
  • Acetic anhydride (62 mg) was added to a solution of 4- (2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole (128 mg) in acetic acid (1 ml). The solution was stirred at ambient temperature overnight and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1-acetyl-4-(2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole (93 mg).
  • 4-(2,6-Dichlorobenzoylamino)-1-[2- (morpholinocarbonylamino)ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 1-(2-aminoethyl)-4- (2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole with morpholinocarbonyl chloride,
  • dichloromethane (1 ml) was added oxalyl chloride (71 mg), and the mixture was stirred for 10 minutes and then concentrated. To the residue were added 2-chloro-6-methylaniline (44 mg), triethylamine (57 mg) and dichloromethane (2 ml), and the mixture was stirred for 15 minutes. The mixture was washed with 1N sodium hydroxide solution, brine, 1N hydrochloric acid and brine, dried and concentrated to give 4-[N-(2-chloro-6-methylphenyl)carbamoyl]-1-(morpholinocarbonyl)-methyl-2-trifluoromethyl-1H-benzimidazole (98 mg).

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Abstract

The present invention relates to a new heterocyclic compound of formula (I), wherein R1 is acyl, lower alkenyl or lower alkyl optionally substituted with aryl, a heterocyclic group, etc., R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl, halo(lower)alkyl, etc., R3 is hydrogen or halogen, R4 is a heterocyclic group or aryl, each of which may be substituted with suitable substituent(s), and A is (a) or (b), (wherein R?9 and R10¿ are each hydrogen, lower alkyl or substituted lower alkyl), and pharmaceutically acceptable salts thereof which are the inhibitors of bone resorption and bone metabolism, to processes for preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of diseases caused by abnormal bone metabolism in human being or an animal.

Description

D E S C R I P I O N
BENZIMIDAZOLE DERIVATIVES AND THEIR USE IN THE PREVENTION AND/OR THE TREATMENT OF BONE DISEASES TECHNICAL FIELD
This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereofMore 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.
And further, 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.
BACKGROUND ART
Some heterocyclic compounds have been known as
described, for example, in EP-A-574, 174, Chemical Abstracts 100:133915g (1984), Chemical Abstracts 98:175462c (1983) or Chemical Abstracts 97:49315y (1982). However, it is not known that said compounds are useful for the prevention and/or the treatment of above-mentioned diseases.
DISCLOSURE OF INVENTION
The object heterocyclic compounds of this invention are new and can be represented by the following general formula [I] :
Figure imgf000004_0003
wherein
R1 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, amino, substituted amino, acyl, mercapto, substituted mercapto,
hydroxyamidino, substituted hydroxyamidino and
substituted hydrazono, and
R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl,
halo(lower)alkyl, lower alkoxy, lower alkylthio, acyl or cyano, or
R1 and R2 are taken together to form lower alkylene or lower alkenylene, each of which may include O, S or N-R5 in the chain, in which R5 is hydrogen or lower alkyl, R3 is hydrogen or halogen,
R4 is a heterocyclic group or aryl, each of which may be
substituted with suitable substituent(s), and
A is
Figure imgf000004_0001
or
Figure imgf000004_0002
, in which R9 is hydrogen, lower alkyl or substituted
lower alkyl, and
R10 is hydrogen, lower alkyl or substituted
lower alkyl. The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes.
Process 1
Figure imgf000005_0001
Process 2
Figure imgf000005_0002
Process 3
Figure imgf000006_0001
Process 4
Figure imgf000006_0002
wherein
R6 is hydrogen or lower alkyl optionally substituted with a substituent selected from the group consisting of hydroxy and lower alkoxy, and
R7 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
R6 and R7 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with a substituent selected from the group consisting of lower alkyl, halogen, aryl and acyl,
Q is lower alkylene,
X is a leaving group, and
R1, R2, R3, R4, R9, R10 and A are each as defined above. In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are
explained in detail in the following. The term "lower" is intended to mean a group having 1 to
6 carbon atom(s), unless otherwise provided.
In this respect, the term "lower" in lower alkenyl moiety in the various definitions is intended to mean a group having 2 to 6 carbon atoms .
Further, the term "lower" in cyclo(lower)alkyl moiety in the various definitions is intended to mean a group having 3 to 6 carbon atoms.
Suitable "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.
chloroacetyl, trifluoroacetyl, bromoacetyl, bromobutyryl, heptafluorobutyryl, etc.], hydroxy(lower)alkanoyl [e.g.
glycoloyl, lactoyl, 3-hydroxypropionyl, glyceroyl, etc.], lower alkylsulfonyloxy(lower)alkanoyl [e.g. mesyloxyacetyl, ethylsulfonyloxyacetyl, mesyloxypropionyl, etc.], lower alkoxy(lower)alkanoyl [e.g. methoxyacetyl, ethoxyacetyl, methoxypropionyl, ethoxypropionyl, propoxypropionyl,
methoxybutyryl, etc.], 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. methoxycarbonylacetyl, ethoxycarbonylacetyl, methoxycarbonylpropionyl, etc.], succinimidooxycarbonyl(lower)alkanoyl [e.g.
succinimidooxycarbonylbutyryl, etc. ] ,
carbamoyl(lower)alkanoyl [e.g. carbamoylacetyl,
carbamoylpropionyl, etc.], lower
alkylcarbamoyl(lower)alkanoyl [e.g. methylcarbamoylacetyl, ethylcarbamoylpropionyl, dimethylcarbamoylpropionyl, etc.], diphosphono(lower)alkylcarbamoyl(lower)alkanoyl [e.g.
diphosphonomethylcarbamoylbutyryl, etc.], ar(lower)alkanoyl [e.g. phenylacetyl, tolylacetyl, naphthylacetyl, etc.], optionally substituted heterocyclic(lower)alkanoyl [e.g.
morpholinoacetyl, thiomorpholinopropionyl,
piperazinylpropionyl, pyridylacetyl, imidazolidinylpropionyl, piperidinoacetyl, pyrrolidinylacetyl. hexamethyleneiminoacetyl, imidazolylacetyl, furylacetyl, thienylacetyl, methylpiperazinylacetyl,
pyridylpiperazinylacetyl, etc.], etc.,
cyclo(lower)alkylcarbonyl [e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.], carboxy, esterified carboxy such as lower
alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], aryloxycarbonyl [e.g.
phenoxycarbonyl, etc.], etc., substituted or unsubstituted aroyl such as aroyl [e.g. benzoyl, toluoyl, xyloyl,
naphthoyl, etc.], lower alkoxyaroyl [e.g. methoxybenzoyl, etc.], haloaroyl [e.g. chlorobenzoyl, fluorobenzoyl,
dichlorobenzoyl, etc.], acylaroyl, for example, lower alkoxycarbonylaroyl [e.g. methoxycarbonylbenzoyl, etc.], etc., heterocycliccarbonyl which may be substituted with substituent [e.g. furoyl, thenoyl, pyridylcarbonyl,
morpholinocarbonyl, piperidinocarbonyl, 4-methyl-1-piperazinylcarbonyl, 4-ethyl-1-piperazinylcarbonyl,
dimethylaminopiperidinocarbonyl, 4-methylcarbamoyl-1-piperazinylcarbonyl, 4-acetyl-1-piperazinylcarbonyl,
4-phenyl-1-piperazinylcarbonyl, chlorothenoyl,
1,2,3,6-tetrahydropyridylcarbonyl, pyrrolidinylcarbonyl, indolylcarbonyl, etc.], aryloxycarbonyl which may be
substituted with nitro [e.g. phenyloxycarbonyl,
nitrophenyloxycarbonyl, etc.], ar (lower) alkoxycarbonyl which may be substituted with nitro [e.g. benzyloxycarbonyl, nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted carbamoyl such as carbamoyl, lower alkylcarbamoyl [e.g.
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc.],
carboxy(lower)alkylcarbamoyl [e.g. carboxymethylcarbamoyl, carboxyethylcarbamoyl, etc.], esterified
carboxy(lower)alkylcarbamoyl, for example, lower
alkoxycarbonyl(lower)alkylcarbamoyl [e.g.
methoxycarbonylmethylcarbamoyl,
ethoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl, etc.], lower alkenylcarbamoyl [e.g. vinylcarbamoyl,
allylcarbamoyl, etc.], cyclo(lower)alkylcarbamoyl [e.g.
cyclopropylcarbamoyl, cyclobutylcarbamoyl,
cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.],
halo(lower)alkylcarbamoyl [e.g. chloromethylcarbamoyl, trifluoromethylcarbamoyl, trifluoroethylcarbamoyl, etc.], cyano(lower)alkylcarbamoyl [e.g. cyanomethylcarbamoyl, etc.] hydroxy(lower)alkylcarbamoyl [e.g. hydroxyethylcarbamoyl, hydroxypropylcarbamoyl, di (hydroxyethyl) carbamoyl,
dihydroxypropylcarbamoyl, 1,1-dimetyl-2-hydroxyethylcarbamoyl, etc.], 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.
carbamoylmethylcarbamoyl, carbamoylethylcarbamoyl, etc.], hydroxy(lower)alkylcarbamoyl(lower)alkylcarbamoyl [e.g.
hydroxyethylcarbamoylmethylcarbamoyl,
hydroxyethylcarbamoylethylcarbamoyl, etc.],
arylsulfonylcarbamoyl [e.g. phenylsulfonylcarbamoyl,
tosylcarbamoyl, etc.], substituted or unsubstituted
arylcarbamoyl, for example, arylcarbamoyl [e.g.
phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl,
naphthylcarbamoyl, ethylphenylcarbamoyl, etc.], lower alkoxyarylcarbamoyl [e.g. methoxyphenylcarbamoyl, etc.], halo-arylcarbamoyl [e.g. fluorophenylcarbamoyl, chlorophenylcarbamoyl, etc.], halo (lower) alkyl-arylcarbamoyl [e.g. trifluoromethylphenylcarbamoyl, etc.],
nitro-arylcarbamoyl [e.g. nitrophenylcarbamoyl, etc.], cyano-arylcarbamoyl [e.g. cyanophenylcarbamoyl, etc.], hydroxy(lower)alkyl-arylcarbamoyl [e.g.
hydroxymethylphenylcarbamoyl, hydroxyethylphenylcarbamoyl, etc.], amino-arylcarbamoyl [e.g. aminophenylcarbamoyl, etc.], lower alkylamino-arylcarbamoyl [e.g.
methylaminophenylcarbamoyl, ethylaminophenylcarbamoyl, dimethylaminophenylcarbamoyl, etc.], lower alkanoylaminoarylcarbamoyl [e.g. acetylaminophenylcarbamoyl,
propionylaminophenylcarbamoyl, etc.], etc.,
substituted or unsubstituted ar(lower)alkylcarbamoyl, for example, ar(lower)alkylcarbamoyl [e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.], halo(lower)alkylar(lower)alkylcarbamoyl [e.g. trifluoromethylbenzylcarbamoyl, etc.], etc., substituted or unsubstituted
heterocyclic(lower)alkylcarbamoyl, for example,
heterocyclic(lower)alkylcarbamoyl [e.g.
pyridylmethylcarbamoyl, pyridylethylcarbamoyl,
oxadiazolyimethylcarbamoyl, furylmethylcarbamoyl,
thienylmethylcarbamoyl, tetrahydrofurylmethylcarbamoyl, piperonylcarbamoyl, piperonylmethylcarbamoyl,
indolylethylcarbamoyl, imidazolylethylcarbamoyl, etc.], lower alkyl-heterocyclic(lower)alkylcarbamoyl [e.g.
methylpyridylmethylcarbamoyl,
methyloxadiazolylmethylcarbamoyl, etc.], etc.,
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. methylpyridylcarbamoyl,
methyloxazolylcarbamoyl, methylisoxazolylcarbamoyl,
methylthiadiazolylcarbamoyl, etc.], halo(lower)alkylheterocycliccarbamoyl [e.g. trifluoromethylpyridylcarbamoyl, trifluoromethylthiadiazolylcarbamoyl, etc.], lower alkoxyheterocycliccarbamoyl [e.g. methoxypyridylcarbamoyl,
methoxythiadiazolylcarbamoyl, etc.], lower alkylthioheterocycliccarbamoyl [e.g. methylthiopyridyicarbamoyl, ethylthiothiadiazolylcarbamoyl, etc.], sulfamoylheterocycliccarbamoyl [e.g. sulfamoylthiadiazolylcarbamoyl, etc.], etc., N-heterocyclic-N-(lower alkyl)carbamoyl [e.g. N-pyridyl-N-methylcarbamoyl, N-thiazolyl-N-methylcarbamoyl, etc.], etc., lower alkylsulfonyl [e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, etc.], arylsulfonyl [e.g. tosyl,
phenylsulfonyl, etc.], ar(lower)alkylsulfonyl [e.g.
benzylsulfonyl, phenethylsulfonyl, etc.],
ar(lower)alkenylsulfonyl [e.g. styrylsulfonyl,
cinnamylsulfonyl, etc.], phthaloyl, or the like.
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 C1-C4 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.
Suitable "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, O 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,
pyrrolidinyl, pyrrolyl, oxiranyl, tetrahydrofuryl, piperonyl, indolyl, quinolyl, isoquinolyl, imidazopyridyl,
benzodioxolyl, phthalimido, or the like.
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 C1-C4 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 C2-C6 alkenylene such as vinylene, methylvinylene, 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 O, S or N-R5 in the chain formed by R1 and R2 may be a group of the formula : -CH2-CH2-CH2-S-,
Figure imgf000014_0001
,
-CH2-CH2-CH2-O-,
Figure imgf000014_0002
,
in which R8 is hydrogen or lower alkyl and
R5 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 abovementioned lower alkyl; the above-mentioned aryl; or the like.
Suitable substituents of hydroxyamidino 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 R4 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 R6, R7 and the attached nitrogen atom may be morpholino, thiomorpholino, pyrrolidin-1-yl, piperidino, 1,2,3,6-tetrahydropyridin-1-yl, piperazin-1-yl, or the like.
Suitable substituents of lower alkyl in the term
"substituted lower alkyl" for R9 and R10 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.
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. formate, acetate, trifluoroacetate, maleate, tartrate, oxalate, methanesulfonate,
benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], an intramolecular salt and the like.
With respect to the salts of the compounds [la] to [Id] in the Processes 2 to 4, it is to be noted that those compounds are included within the scope of the compound [I], and accordingly the suitable examples of the salts of these compounds are to be referred to those as exemplified for the object compound [I]. Preferred embodiments of the object compound [I] are as follows :
R1 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)alkanoyl, hydroxy substituted with aryl, hydroxy substituted with ar (lower) alkyl, hydroxy substituted with a heterocyclic group, etc.], cyano, halogen, amino, acylamino [more preferably lower alkanoylamino, lower alkylsulfonylamino, heterocycliccarbonylamino, etc.], acyl [more preferably lower alkanoyl, aroyl, carboxy, lower alkoxycarbonyl, heterocycliccarbonyl,
heterocycliccarbonyl substituted with lower alkyl, heterocycliccarbonyl substituted with lower alkanoyl, heterocycliccarbonyl substituted with halogen,
heterocycliccarbonyl substituted with aryl, carbamoyl, lower alkylcarbamoyl, carboxy(lower)alkylcarbamoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl,
cyclo(lower)alkylcarbamoyl, halo(lower)alkylcarbamoyl, cyano(lower)alkylcarbamoyl, hydroxy(lower)- alkylcarbamoyl, lower alkoxy(lower)alkylcarbamoyl, lower alkanoyloxy(lower)alkylcarbamoyl, lower
alkoxycarbamoyl, aminocarbamoyl,
tert-butoxycarbonylaminocarbamoyl,
carbamoyl(lower)alkylcarbamoyl,
hydroxy(lower)alkylcarbamoyl(lower)alkylcarbamoyl, arylsulfonylcarbamoyl, arylcarbamoyl, lower alkoxyarylcarbamoyl, halo(lower)alkyl-arylcarbamoyl, lower alkylamino-arylcarbamoyl, ar(lower)alkylcarbamoyl, halo(lower)alkyl-ar(lower)alkylcarbamoyl, heterocyclic- (lower)alkylcarbamoyl, lower alkyl-heterocyclic(lower)-alkylcarbamoyl, heterocycliccarbamoyl,
lower alkyl-heterocycliccarbamoyl,
halo(lower)alkyl-heterocycliccarbamoyl,
lower alkoxy-heterocycliccarbamoyl,
lower alkylthio-heterocycliccarbamoyl,
sulfamoyl-heterocycliccarbamoyl, N-heterocyclic-N-(lower alkyl)carbamoyl, phthaloyl, etc.], mercapto, mercapto substituted with a heterocyclic group, mercapto
substituted with a heterocyclic group substituted with lower alkyl, hydroxyamidino, hydroxyamidino substituted with acyl [more preferably hydroxyamidino substituted with lower alkoxycarbonyl], and hydrazono substituted with a heterocyclic group; and
R2 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
R1 and R2 are taken together to form a group of the formula :
-CH2-CH2-CH2-S-,
Figure imgf000018_0001
,
Figure imgf000018_0002
,
in which R5 and R8 are each hydrogen or lower alkyl, R3 is hydrogen or halogen,
R4 is aryl substituted with substituent(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- (lower)alkyl, and A is
Figure imgf000018_0004
or
Figure imgf000018_0003
,
in which R9 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl, and
R10 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl. The processes for preparing the object compound [I] are explained in detail in the following.
Process 1
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 methoxide, sodium ethoxide, potassium tert-butoxide, etc.], triethylamine, or the like.
This reaction is usually carried out in 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.
Process 2
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. In case that the compound [V] is used in the free acid form or salt form, it is preferable to carry out the reaction in the presence of a conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide or the like.
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.
Process 3
The object compound [Ib] 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.
Process 4
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.
Some of the starting compounds in the above Processes are new, and they can be prepared by processes as illustrated in the following reaction schemes.
Process A
Figure imgf000021_0001
Process B
Figure imgf000022_0001
wherein R2, R3 and R4 are each as defined above.
Process A
The compound [IIa] 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.
Process B
The compound [IIb] 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.
It is to be noted that 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.
Further, it is expected that 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. chronic gastritis and peptic ulcer induced by Helicobacter pyl ori ); autoimmune diseases;
transplantation; hypercholesterolemic and atherosclerotic diseases; AIDS; Alzheimer's disease; angiogenic diseases, such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumors; or the like in human being or animals, and useful for regulating male fertility in human being or animals.
In order to illustrate the usefulness of the object compound [I], the pharmacological test data of some
representative compounds of the compound [I] are shown in the following.
Test (Bone organ culture)
Test Method
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 10-8M human parathyroid hormone fragment (1-34) [PTH] in the presence of the test compound (dose :
1 X 10-5M). 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 :
Inhibition
Figure imgf000024_0001
CP : [Ca] in PTH control dishes
CD : [Ca] in the test compound dishes
CO : [Ca] in control dishes As a result of this test, the compound [I] showed over 50% inhibition of PTH-induced bone resorption.
For therapeutic purpose, 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. If desired, there may be included in these preparations,
auxiliary substances, stabilizing agents, wetting or
emulsifying agents, buffers and other commonly used
additives.
While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for preventing and/or treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
The following Examples are given for the purpose of illustrating this invention. Example 1
(1) A mixture of 1,2-dimethyl-4-nitro-1H-benzimidazole (330 mg) and 10% palladium on carbon (40 mg) in methanol (10 ml) was stirred for 1 hour at ambient temperature under 4 atmospheric pressure of hydrogen. Insoluble material was filtered off, and the filtrate was concentrated in vacuo to give 4-amino-1,2-dimethyl-1H-benzimidazole (280 mg).
mp : 172-173°C
NMR (CDCl3, δ) : 2.58 (3H, s), 3.66 (3H, s), 4.27 (2H, br s), 6.50 (1H, d, J=7Hz), 6.68 (1H, d, J=7Hz),
7.04 (1H, t, J=7Hz)
(2) A mixture of 4-amino-1,2-dimethyl-1H-benzimidazole (100 mg), 2,6-dichlorobenzoyl chloride (137 mg) and triethylamine (94 mg) in ethylene chloride (5 ml) was refluxed for 8 hours. After cooling, the mixture was diluted with methylene
chloride, washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 4-(2,6-dichlorobenzoylamino)-1,2-dimethyl-1H-benzimidazole (125 mg).
mp : 251-252°C
NMR (CDCl3, δ) : 2.57 (3H, s), 3.72 (3H, s), 7.08
(1H, d, J=7Hz), 7.20-7.40 (4H, m), 8.52 (1H, d, J=7Hz), 8.57 (1H, br s) its hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.82 (3H, s), 3.93 (3H, s), 7.50- 7.64 (4H, m), 7.72 (1H, d, J=8Hz), 8.09 (1H, d, J=8Hz), 11.36 (1H, br s)
Example 2
4-(2,6-Dichlorobenzoylamino)-2-methyl-1H-benzimidazole was obtained by reacting 4-amino-2-methyl-1H-benzimidazole with 2,6-dichlorobenzoyl chloride according to a similar manner to that of Example 1-(2).
mp : 212-213ºC
Example 3
(1) A solution of 3-nitro-1,2-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 1N 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-1H-benzimidazole (1.26 g).
mp : 145-146ºC
NMR (DMSO-d6, δ) : 7.60 (1H, t, J=7.5Hz), 8.29 (1H, d,
J=7.5Hz), 8.34 (1H, d, J=7.5Hz) (2) A mixture of 4-nitro-2-trifluoromethyl-1H-benzimidazole (1.1 g), activated carbon (100 mg) and ferric chloride hexahydrate (24 mg) in methanol (10 ml) was stirred at 60°C. To the mixture was added hydrazine hydrate (1.55 g) dropwise. The mixture was stirred at 60°C for 3 hours and filtered.
The filtrate was evaporated in vacuo. The residue was treated with brine and 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 was
crystallized from a mixture of dichloromethane and n-hexane to give 4-amino-2-trifluoromethyl-1H-benzimidazole (0.86 g). mp : 130-132°C
NMR (DMSO-d6, δ) : 5.53 (2H, s), 6.45 (1H, d, J=7.5Hz), 6.76 (1H, d, J=7.5Hz), 7.06 (1H, t, J=7.5Hz) (3) 4-(2,6-Dichlorobenzoylamino)-2-trifluromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 1-(2).
mp : 181-182ºC
Example 4
(1) 2-Ethyl-4-nitro-1H-benzimidazole was obtained by reacting 3-nitro-1,2-phenylenediamine with propionic acid
according to a similar manner to that of Example 3-(1). NMR (CDCl3, δ) : 1.52 (3H, t, J=8Hz), 3.05 (2H, q,
J=8Hz), 7.34 (1H, t, J=7Hz), 8.04 (1H, d, J=7Hz), 8.12 (1H, d, J=7Hz)
(2) 4-Amino-2-ethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 3-(2).
(3) 4-(2,6-Dichlorobenzoylamino)-2-ethyl-1H-benzimidazole
was obtained according to a similar manner to that of Example 1-(2).
mp : 241-246°C
NMR (DMSO-d6, δ) : 1.42 (3H, t, J=8Hz), 3.15 (2H, q,
J=8Hz), 7.40-7.65 (7H, m), 8.13 (1H, d, J=8Hz)
Example 5
A mixture of 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-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 residue was crystallized from a mixture of ethyl acetate and n-hexane to give 1-tert-butoxycarbonylmethyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (531 mg).
mp : 166-167°C
NMR (CDCl3, δ) : 1.45 (9H, s), 4.93 (2H, s), 7.14 (1H, d, J=7.5Hz), 7.30-7.45 (3H, m), 7.51 (1H, t,
J=7.5Hz), 8.59 (1H, d, J=7.5Hz), 8.61 (1H, br s)
Example 6
Potassium tert-butoxide (193 mg) was added to a mixture of 4-(2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole
(200 mg), 4-chloromethylpyridine hydrochloride (123 mg) and sodium carbonate (79 mg) in N,N-dimethylformamide at 4°C.
The mixture was stirred at 4°C for 30 minutes and at ambient temperature for 1 hour and to the mixture was added 4- chloromethylpyridine hydrochloride (12 mg). After stirring for 1 hour at ambient temperature, the mixture was
partitioned between ethyl acetate and brine. The organic layer was separated, 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 dissolved in methanolic hydrogen chloride. The solution was evaporated in vacuo and the crystalline residue was
triturated with 2-propanol to give 4-(2,6-dichlorobenzoylamino)-2-methyl-1-(pyridin-4-yl)methyl-1H-benzimidazole dihydrochloride (98 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.80 (3H, s), 6.00 (2H, s), 7.44- 7.62 (5H, m), 7.75 (2H, d, J=8Hz), 8.21 (1H, d, J=8Hz), 8.83 (2H, d, J=8Hz), 11.41 (1H, br s)
Example 7
The following compounds were obtained according to a similar manner to that of Example 5 or 6. (1) 1-(2-Acetoxyethyl)-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2-acetoxyethyl bromide)
mp : 177-178°C
NMR (CDCl3, δ) : 2.00 (3H, s), 2.61 (3H, s), 4.38 (4H, s), 7.11 (1H, d, J=7Hz), 7.25-7.40 (4H, m), 8.44 (1H, d, J=7Hz), 8.59 (1H, br s)
(2) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1-(pyridin-3- yl)methyl-1H-benzimidazole dihydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 3-chloromethylpyridine hydrochloride) mp : >250°C
NMR (DMSO-d6, δ) : 2.88 (3H, s), 5.88 (2H, s), 7.45- 7.65 (5H, m), 7.82 (1H, dd, J=5Hz, 7Hz), 8.70-8.80
(2H, m), 8.79 (1H, d, J=5Hz), 8.92 (1H, s)
(3) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)- 1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2-oxopropyl chloride)
mp : 222-224°C
NMR (CDCl3, δ) : 2.23 (3H, s), 2.47 (3H, s), 4.83 (2H, s), 6.92 (1H, d, J=7Hz), 7.25-7.40 (4H, m), 8.44 (1H, d, J=7Hz), 8.55 (1H, br s) its hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.37 (3H, s), 2.70 (3H, s), 5.61 (2H, s), 7.45-7.70 (5H, m), 8.09 (1H, d, J=7Hz)
(4) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-3- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and pyridin-3-ylcarbonylmethyl bromide hydrobromide)
mp : 240-242°C
NMR (DMSO-d6, δ) : 6.37 (2H, s), 7.45-7.58 (4H, m), 7.62 (1H, d, J=7Hz), 7.77 (1H, dd, J=5Hz, 7Hz),
8.25 (1H, d, J=7Hz), 8.56 (1H, d, J=7Hz), 8.98 (1H, d, J=5Hz), 9.40 (1H, s)
(5) 1-tert-Butoxycarbonylmethyl-4-(2,6- dichlorobenzoylamino)-2-methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and tert-butyl bromoacetate)
mp : 194-195°C
NMR (CDCl3, δ) : 1.47 (9H, s), 2.55 (3H, s), 4.72 (2H, s), 7.03 (1H, d, J=7.5Hz), 7.30-7.40 (4H, m), 8.45
(1H, d, J=7.5Hz), 8.60 (1H, br s)
(6) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1-allyl-1H- benzimidazole hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and allyl bromide)
mp : 248-250°C
NMR (CDCl3, δ) : 2.82 (3H, s), 4.89 (2H, d, J=5Hz),
5.08 (1H, d, J=16Hz), 5.40 (1H, d, J=10Hz), 5.95 (1H, m), 7.20 (1H, d, J=8Hz), 7.27-7.42 (3H, m),
7.50 (1H, t, J=8Hz), 8.78 (1H, d, J=8Hz)
(7) 4-(2,6-Dichlorobenzoylamino)-1-(3,3-diethoxypropyl)-2- methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 3,3-diethoxypropyl chloride)
mp : 130-132°C
NMR (CDCl3, δ) : 1.22 (6H, t, J=7Hz), 2.10 (2H, q,
J=7Hz), 2.59 (3H, s), 3.40-3.51 (2H, m), 3.59-3.70 (2H, m), 4.23 (2H, t, J=7Hz), 4.46 (1H, t, J=5Hz), 7.14 (1H, d, J=8Hz), 7.26-7.39 (4H, m), 8.43 (1H, d, J=8Hz), 8.57 (1H, s)
(8) 4-(2,6-Dichlorobenzoylamino)-1-ethyl-2-methyl-1H- benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and ethyl iodide)
mp : 244-246ºC
NMR (CDCl3, δ) : 1.42 (3H, t, J=7Hz), 2.59 (3H, s), 4.17 (2H, q, J=7Hz), 7.11 (1H, d, J=8Hz), 7.27-7.40
(4H, m), 8.43 (1H, d, J=8Hz), 8.57 (1H, s)
(9) 1-(3-Chloropropyl)-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 1-bromo-3-chloropropane)
NMR (CDCl3, δ) : 2.23-2.35 (2H, m), 2.67 (3H, s), 3.55 (2H, t, J=7Hz), 4.32 (2H, t, J=7Hz), 7.15 (1H, d, J=8Hz), 7.27-7.39 (4H, m), 8.44 (1H, d, J=8Hz), 8.60 (1H, s)
(10) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-2-yl)methyl-2- trifluoromethyl-1H-benzimidazole hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-chloromethylpyridine hydrochloride) mp : 222-224°C
NMR (DMSO-d6, δ) : 5.85 (2H, s), 7.30-7.38 (2H, m),
7.40-7.60 (5H, m), 7.86 (1H, dt, J=8Hz, 2Hz), 8.22 (1H, d, J=8Hz), 8.45 (1H, d, J=8Hz)
(11) 4-(2,6-Dichlorobenzoylamino)-1-(1-ethoxycarbonylethyl)- 2-trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and ethyl 2-bromopropionate)
NMR (CDCl3, δ) : 1.18 (3H, t, J=7Hz), 1.37 (3H, d, J=7Hz), 4.23 (2H, q, J=7Hz), 5.36 (1H, q, J=7Hz), 7.16 (1H, d, J=8Hz), 7.31-7.49 (4H, m), 8.57 (1H, d, J=8Hz), 8.62 (1H, s) (12) 4-(2,6-Dichlorobenzoylamino)-2-ethyl-1-(2-oxopropyl)-1H- benzimidazole hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-ethyl-1H- benzimidazole and 2-oxopropyl chloride)
mp : 246-258°C
NMR (DMSO-d6, δ) : 1.34 (3H, t, J=7Hz), 2.37 (3H, s),
3.05 (2H, q, J=7Hz), 5.63 (2H, s), 7.39-7.64 (6H, m), 8.28 (1H, d, J=8Hz)
(13) 4-(2,6-Dichlorobenzoylamino)-2-ethyl-1-methyl-1H- benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-ethyl-1H- benzimidazole and methyl iodide)
mp : 244-247°C
NMR (CDCl3, δ) : 1.38 (3H, t, J=7Hz), 2.90 (2H, q,
J=7Hz), 3.73 (3H, s), 7.10 (1H, d, J=8Hz), 7.27- 7.39 (4H, m), 8.44 (1H, d, J=8Hz), 8.65 (1H, s)
(14) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-4- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole (from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and pyridin-4-ylcarbonylmethyl bromide hydrobromide)
mp : 179-180°C
NMR (DMSO-d6, δ) : 6.32 (2H, s), 7.40-7.70 (5H, m),
8.03 (2H, dd, J=1Hz, 7.5Hz), 8.25 (1H, d, J=7.5Hz),
8.94 (2H, dd, J=1Hz, 7.5Hz), 11.20 (1H, s) its hydrochloride
mp : 235-246°C
NMR (DMSO-d6, δ) : 6.32 (2H, s), 7.40-7.70 (5H, m), 8 . 09 (2H, d, J=7 . 5Hz) , 8 . 24 ( 1H, d, J=7 . 5Hz ) , 8 . 95 (2H, d, J=7 . 5Hz ) , 11 .20 ( 1H, s )
(15) 1-Benzyl-4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and benzyl bromide)
mp : 204-205°C
NMR (DMSO-d6, δ) : 3.32 (3H, s), 5.48 (2H, s), 7.10- 7.20 (3H, m), 7.20-7.40 (4H, m), 7.40-7.60 (3H, m),
8.04 (1H, d, J=7.5Hz), 10.79 (1H, s) its hydrochloride
mp : 242-252°C
NMR (DMSO-d6, δ) : 2.83 (3H, s), 5.70 (2H, s), 7.20- 7.70 (10H, m), 8.10 (1H, d, J=7.5Hz), 11.28 (1H, s)
(16) 1-Benzoylmethyl-4-(2,6-dichlorobenzoylamino)-2-methyl- 1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and benzoylmethyl bromide)
mp : 228-229°C
NMR (DMSO-d6, δ) : 2.43 (3H, s), 6.03 (2H, s), 7.14
(1H, t, J=7.5Hz), 7.26 (1H, d, J=7.5Hz), 7.40-7.60 (3H, m), 7.64 (2H, t, J=7.5Hz), 7.77 (1H, t,
J=7.5Hz), 8.03 (1H, d, J=7.5Hz), 8.15 (2H, d,
J=7.5Hz) its hydrochloride
mp : 289-298°C
NMR (DMSO-d6, δ) : 2.76 (3H, s), 6.33 (2H, s), 7.50
(1H, t, J=7.5Hz), 7.50-7.70 (6H, m), 7.80 (1H, t, J=7.5Hz), 8.04 (1H, d, J=7.5Hz), 8.16 (2H, d,
J=7.5Hz), 11.25 (1H, br s) (17) 4-(2,6-Dichlorobenzoylamino)-1-(2-methoxyethyl)-2- methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2-methoxyethyl bromide)
mp : 155-156°C
NMR (CDCl3, δ) : 2.60 (3H, s), 3.28 (3H, s), 3.69 (2H, t, J=5Hz), 4.28 (2H, t, J=5Hz), 7.10 (1H, d,
J=7.5Hz), 7.25-7.40 (4H, m), 8.43 (1H, d, J=7.5Hz) 8.62 (1H, br s) its hydrochloride
mp : 196-206ºC
NMR (DMSO-d6, δ) : 2.83 (3H, s), 3.22 (3H, s), 3.73
(2H, m), 4.62 (2H, m), 7.40-7.70 (4H, m), 7.71 (1H, d. J=8Hz), 8.03 (1H, d, J=8Hz), 11.23 (1H, s)
(18) 1-(2-Cyanoethyl)-4-(2,6-dichlorobenzoylamino)-2-methyl- 1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2-cyanoethyl bromide)
mp : 221.5-222.5°C
NMR (DMSO-d6, δ) : 2.61 (3H, s), 3.06 (2H, t, J=7Hz),
4.54 (2H, t, J=7Hz), 7.21 (1H, t, J=8Hz), 7.30-7.60 (4H, m), 8.05 (1H, d, J=8Hz), 10.77 (1H, s) its hydrochloride
mp : 220-245°C
NMR (DMSO-d6, δ) : 2.75 (3H, s), 3.11 (2H, t, J=7Hz), 4.67 (2H, t, J=7Hz), 7.40 (1H, br t, J=8Hz), 7.40- 7.60 (3H, m), 7.64 (1H, br d, J=8Hz), 8.03 (1H, d,
J=8Hz), 11.03 (1H, br s)
(19) 4-(2,6-Dichlorobenzoylamino)-1-(2-oxopropyl)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-oxopropyl chloride)
mp : 228-229°C
NMR (CDCl3, δ) : 2.30 (3H, s), 5.09 (2H, s), 7.03 (1H, d, J=8Hz), 7.30-7.45 (3H, m), 7.50 (1H, t, J=8Hz), 8.59 (1H, d, J=8Hz), 8.60 (1H, s)
(20) 4-(2,6-Dichlorobenzoylamino)-1-methyl-2-trifluoromethyl- 1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and methyl iodide)
mp : 215-216°C
NMR (CDCl3, δ) : 3.97 (3H, s), 7.24 (1H, d, J=7.5Hz),
7.30-7.50 (3H, m), 7.51 (1H, t, J=7.5Hz), 8.58 (1H, d, J=7.5Hz), 8.63 (1H, br s)
(21) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-3-yl)methyl-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 3-chloromethylpyridine hydrochloride) mp : 236-237°C
NMR (DMSO-d6, δ) : 5.79 (2H, s), 7.35 (1H, dd, J=2Hz,
8Hz), 7.40-7.60 (6H, m), 8.26 (1H, d, J=8Hz), 8.40- 8.60 (2H, m), 11.21 (1H, s) its hydrochloride
mp : >250ºC
NMR (DMSO-d6, δ) : 5.89 (2H, s), 7.40-7.60 (5H, m),
7.71 (1H, dd, J=6Hz, 8Hz), 7.88 (1H, d, J=8Hz), 8.28 (1H, d, J=8Hz), 8.70-8.80 (2H, m), 11.23 (1H, s)
(22) 4-(2,6-Dichlorobenzoylamino)-1-(2-morpholinoethyl)-2- trifluromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-morpholinoethyl chloride hydrochloride)
mp : 194-195°C
NMR (DMSO-d6, δ) : 2.40-2.50 (4H, m), 2.70 (2H, t,
J=7Hz), 3.50-3.60 (4H, m), 4.51 (2H, t, J=7Hz), 7.40-7.70 (5H, m), 8.22 (1H, d, J=8Hz), 11.12 (1H, s) its hydrochloride
mp : 226-236°C
NMR (DMSO-d6, δ) : 3.10-4.10 (11H, m), 4.8-5.0 (1H, br), 7.40-7.60 (4H, m), 7.78 (1H, br), 8.26 (1H, d,
J=8Hz), 11.19 (1H, s)
(23) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-4-yl)methyl-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 4-chloromethylpyridine hydrochloride) mp : 187-188ºC
NMR (DMSO-d6, δ) : 5.80 (2H, s), 7.07 (2H, d, J=8Hz), 7.40-7.70 (5H, m), 8.28 (1H, m), 8.52 (2H, d,
J=8Hz), 11.24 (1H, s) its hydrochloride
mp : 225-237°C
NMR (DMSO-d6, δ) : 6.01 (2H, s), 7.40-7.70 (7H, m),
8.30 (1H, dd, J=2Hz, 7Hz), 8.74 (2H, d, J=7Hz), 11.27 (1H, s)
(24) 1-(2-Acetoxyethyl)-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-acetoxyethyl bromide)
mp : 161-162°C
NMR (CDCl3, δ) : 4.47 (2H, t, J=6Hz), 4.60 (2H, t,
J=6Hz), 7.20-7.50 (4H, m), 7.51 (1H, t, J=8Hz), 8 . 58 ( 1H, d, J=8Hz ) , 8 . 62 ( 1H, s)
(25) 1-[(5-Chlorothiophen-2-yl)carbonylmethyl]-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and (5-chlorothiophen-2-yl)carbonylmethyl bromide)
mp : 216-217°C
NMR (DMSO-d6, δ) : 6.18 (2H, s), 7.40-7.70 (6H, m), 8.24 (1H, d, J=8Hz), 8.30 (1H, d, J=2Hz), 11.20
(1H, s)
(26) 4-(2,6-Dichlorobenzoylamino)-1-isopropyl-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and isopropyl iodide)
mp : 182-183°C
NMR (CDCl3, δ) : 1.72 (6H, d, J=7Hz), 4.93 (1H, m),
7.30-7.50 (5H, m), 8.55 (1H, d, J=8Hz), 8.67 (1H, s)
(27) 4-(2,6-Dichlorobenzoylamino)-1-[2-chloro-4,5- (methylenedioxy)benzyl]-2-trifluoromethyl-1H- benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-chloro-4,5-(methylenedioxy)benzyl chloride)
mp : 200-201°C
NMR (CDCl3, δ) : 5.53 (2H, s), 5.93 (2H, s), 5.98 (1H, s), 6.92 (1H, s), 7.03 (1H, d, J=8Hz), 7.30-7.50
(4H, m), 8.59 (1H, d, J=8Hz), 8.65 (1H, s)
(28) 4-(2,6-Dichlorobenzoylamino)-1-[2-(pyrrolidin-1- yl)ethyl]-2-trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-(pyrrolidin-1-yl)ethyl chloride hydrochloride)
NMR (DMSO-d6, δ) : 1.60-1.80 (4H, m), 2.40-2.60 (4H, m), 2.84 (2H, m), 4.51 (2H, m), 7.40-7.60 (5H, m), 8.22 (1H, d, J=8Hz), 11.12 (1H, s) its hydrochloride
mp : 238-242°C
NMR (DMSO-d6, δ) : 1.8-2.2 (4H, m), 3.0-3.2 (2H, m), 3.6-3.8 (4H, m), 4.85 (2H, m), 7.4-7.6 (4H, m),
7.78 (1H, d, J=8Hz), 8.27 (1H, d, J=8Hz), 11.19 (1H, s)
(29) 1-Cyanomethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and cyanomethyl bromide)
mp : 211-213°C
NMR (DMSO-d6, δ) : 5.84 (2H, s), 7.40-7.60 (3H, m), 7.63 (1H, d, J=8Hz), 7.74 (1H, d, J=8Hz), 8.29 (1H, d, J=8Hz), 11.25 (1H, s)
(30) 4-(2,6-Dichlorobenzoylamino)-1-(2-phthalimidoethyl)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-phthalimidoethyl bromide)
NMR (CDCl3, δ) : 4.16 (2H, t, J=7Hz), 4.60 (2H, t,
J=7Hz), 7.20-7.40 (5H, m), 7.70-7.90 (4H, m), 8.49 (1H, d, J=8Hz), 8.57 (1H, s)
(31) 4-(2,6-Dichlorobenzoylamino)-1-(pyridin-3- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole (from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and pyridin-3-ylcarbonylmethyl bromide hydrobromide) mp : 199-200°C
NMR (DMSO-d6, δ) : 6.35 (2H, s), 7.40-7.65 (5H, m), 7.69 (1H, dd, J=5Hz, 8Hz), 8.25 (1H, d, J=8Hz), 8.48 (1H, d, J=8Hz), 8.93 (1H, d, J=5Hz), 9.37 (1H, s)
(32) 1-(3-Cyanobenzyl)-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 3-cyanobenzyl bromide)
mp : 225-227ºC
NMR (DMSO-d6, δ) : 5.79 (2H, s), 7.34 (1H, d, J=8Hz), 7.4-7.6 (6H, m), 7.70-7.90 (2H, m), 8.27 (1H, m) (33) 1-Cyanomethyl-4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and cyanomethyl chloride)
mp : 240-242°C
NMR (CDCl3-CD3OD, δ) : 2.63 (3H, s), 5.03 (2H, s),
7.14 (1H, d, J=8Hz), 7.28-7.40 (4H, m), 8.50 (1H, d, J=8Hz)
(34) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1-(pyridin-2- yl)methyl-1H-benzimidazole dihydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2-chloromethylpyridine hydrochloride) mp : >250°C
NMR (DMSO-d6, δ) : 2.88 (3H, s), 5.85 (2H, s), 7.35
(1H, m), 7.45-7.64 (6H, m), 7.88 (1H, t, J=8Hz),
8.08 (1H, d, J=8Hz), 8.46 (1H, m), 11.31 (1H, br s)
(35) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1-(4-nitrobenzyl)- 1H-benzimidazole hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 4-nitrobenzyl bromide)
mp : >250°C
NMR (DMSO-d6, δ) : 2.80 (3H, s), 5.88 (2H, s), 7.42- 7.62 (7H, m), 8.10 (1H, d, J=8Hz), 8.21 (2H, d, J=8Hz), 11.28 (1H, br s)
(36) 4-(2,6-Dichlorobenzoylamino)-1-(2,3-epoxypropyl)-2- methyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole and 2,3-epoxypropyl bromide)
mp : 198-200°C
NMR (CDCl3, δ) : 2.46 (1H, m), 2.60 (3H, s), 2.83 (1H, t, J=5Hz), 3.30 (1H, m), 4.18 (1H, dd, J=6Hz, 15Hz), 4.52 (1H, dd, J=2Hz, 15Hz), 7.13 (1H, d, J=8Hz), 7.24-7.40 (4H, m), 8.44 (1H, d, J=8Hz),
8.54 (1H, br s)
(37) 4-(2,6-Dichlorobenzoylamino)-1-(2-furylmethyl)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 2-furylmethyl chloride)
mp : 119-121°C
NMR (DMSO-d6, δ) : 5.70 (2H, s), 6.44 (1H, s), 6.62
(1H, s), 7.40-7.55 (4H, m), 7.60 (1H, s), 7.68 (1H, d, J=8Hz), 8.22 (1H, d, J=8Hz)
Example 8
A mixture of 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (187 mg), 1-bromo-3-chloropropane (95 mg) and potassium carbonate (104 mg) in N,N-dimethylformamide (3 ml) was stirred at ambient
temperature overnight. The mixture was poured into a mixture of ice and water. The separated oil 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. 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-1-yl)propyl]-2-trifluoromethyl-1H-benzimidazole was dissolved in 10% methanolic hydrogen chloride. The solution was evaporated in vacuo and the residue was crystallized from ethyl acetate to give 4-(2,6-dichlorobenzoylamino)-1-[3-(4-methylpiperazin-1-yl)propyl]-2-trifluoromethyl-1H-benzimidazole dihydrochloride (98 mg) .
mp : >250°C
NMR (DMSO-d6, δ) : 2.25 (2H, m), 2.90 (3H, s), 3.20- 3.70 (10H, m), 4.51 (2H, t, J=7Hz), 7.45-7.55 (4H, m), 7.69 (1H, d, J=7Hz), 8.23 (1H, d, J=7Hz)
Example 9
A solution of 1-tert-butoxycarbonylmethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (715 mg) in trifluoroacetic acid (5 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated in vacuo and the residue was crystallized from diethyl ether to give 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (636 mg).
mp : >250°C
NMR (CDCl3.CD3OD = 20:1, δ) : 5.03 (2H, s), 7.17 (1H, d, J=8Hz), 7.30-7.50 (3H, m), 7.52 (1H, t, J=8Hz), 8.62 (1H, d, J=8Hz)
Example 10
The following compounds were obtained according to a similar manner to that of Example 9.
(1) 1-Carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-methyl- 1H-benzimidazole trifluoroacetate
mp : >250°C
NMR (DMSO-d6, δ) : 2.66 (3H, s), 5.26 (2H, s), 7.37 (1H, t, J=8Hz), 7.40-7.70 (4H, m), 7.94 (1H, d, J=8Hz), 10.95 (1H, s) (2) 1-Carboxymethyl-4-(2,6-dimethylbenzoylamino)-2- trifluoromethyl-1H-benzimidazole
mp : 158-164°C
NMR (DMSO-d6, δ) : 2.33 (6H, s), 5.30 (2H, s), 7.11
(2H, d, J=8Hz), 7.24 (1H, t, J=8Hz), 7.49 (1H, t, J=8Hz), 7.63 (1H, d, J=8Hz), 7.99 (1H, d, J=8Hz)
Example 11
To a solution of 4-(2,6-dichlorobenzoylamino)-1-(1-ethoxycarbonylethyl)-2-trifluoromethyl-1H-benzimidazole (140 mg) in tetrahydrofuran (15 ml) were added 1N sodium hydroxide solution (0.44 ml) and methanol (0.5 ml), and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo and the residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated in vacuo to give 1-(1-carboxyethyl)-4-(2,6-dicholorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (131 mg).
NMR (CDCl3, δ) : 1.87 (3H, d, J=7Hz), 5.38 (1H, q,
J=7Hz), 7.17 (1H, d, J=8Hz), 7.25-7.36 (3H, m), 7.46 (1H, t, J=8Hz), 8.57 (1H, d, J=8Hz), 8.90 (1H, s)
Example 12
Oxalyl chloride (48 μl) was added to a suspension of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl- 1H-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. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (93 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 5.09 (2H, s), 7.40-7.60 (6H, m),
7.81 (1H, br s), 8.22 (1H, dd, J=1Hz, 7.5Hz), 11.14
(1H, s)
Example 13
Oxalyl chloride (40 μl) was added to a suspension of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-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-methylpiperazine (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. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 4-(2,6-dichlorobenzoylamino)-1-(4-methylpiperazin-1-yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole (141 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.23 (3H, s), 2.25-2.35 (2H, m), 2 . 40-2 . 50 (2H, m), 3 . 40-3 . 50 ( 2H, m), 3 . 55-3 . 65 (2H, m), 5. 49 (2H, s), 7 . 40-7 . 70 (5H, m), 8 .24 ( 1H, d, J=8Hz ) , 11 . 14 ( 1H, s) its hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.4-3.9 (11H, m), 5.54 (2H, s),
7.40-7.60 (5H, m), 8.22 (1H, d, J=8Hz), 11.15 (1H, s)
Example 14
To a solution of 1-carboxymethyl-4-(2,6- dichlorobenzoylamino)-2-methyl-1H-benzimidazole
trifluoroacetate (150 mg) and N-methylmorpholine (37 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg) and 1-hydroxybenzotriazole (50 mg), and the mixture was stirred for 1 hour. To the mixture was added 4-aminopyridine (37 mg), and the mixture was stirred for 2 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1% methanol-dichloromethane) to give 4-(2,6-dichlorobenzoylamino)-2-methyl-1-[N-(pyridin-4-yl)carbamoyl]-methyl-1H-benzimidazole ( 60 mg).
mp : 226-228°C
NMR (CDCl3, δ) : 2.57 (3H, s), 4.90 (2H, s), 7.05 (1H, d, J=8Hz), 7.25-7.45 (6H, m), 7.57 (2H, dd, J=2Hz, 8Hz), 8.38-8.45 (3H, m)
Example 15
The following compounds were obtained according to a similar manner to that of Examples 12, 13 or 14. (1) 4-(2,6-Dichlorobenzoylamino)-2-methyl-1- (morpholinocarbamoyl)methyl-1H-benzimidazole
dihydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole trifluoroacetate and 4- aminomorpholine)
mp : >250°C
NMR (CDCl3, δ) : 2.72-3.20 (7H, m), 3.70-4.05 (4H, m), 5.18 (4/3H, s), 5.33 (2/3H, s), 7.22-7.60 (5H, m), 8.05 (2/3H, d, J=7Hz), 8.52 (1/3H, d, J=7Hz)
(2) 4-(2,6-Dichlorobenzoylamino)-1-[N-(2- hydroxyethyl)carbamoyl]methyl-2-methyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole trifluoroacetate and (2- hydroxyethyl)amine)
mp : >250°C
NMR (CDCl3, δ) : 2.56 (3H, s), 3.34-3.40 (3H, m), 3.61 (2H, t, J=5Hz), 4.78 (2H, s), 7.10 (1H, d, J=8Hz), 7.28-7.43 (4H, m), 8.42 (1H, d, J=8Hz)
(3) 1-[N,N-Bis(2-methoxyethyl)carbamoyl]methyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and bis(2- methoxyethyl)amine
mp : 121-129°C
NMR (CDCl3, δ) : 3.33 (3H, s), 3.48 (3H, s), 3.50-3.60 (4H, m), 3.60-3.72 (4H, m), 5.35 (2H, s), 7.11 (1H, d, J=8Hz), 7.29-7.50 (4H, m), 8.55 (1H, d, J=8Hz), 8.67 (1H, s)
(4) 1-(4-Acetylpiperazin-1-yl)carbonylmethyl-4-(2,6- dichlcrobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 1-acetylpiperazine) mp : 160-188°C
NMR (CDCl3, δ) : 2.15 (3H, s), 3.48-3.82 (8H, m), 5.14 (2H, s), 7.06 (1H, d, J=8Hz), 7.30-7.49 (4H, m), 8.57 (1H, d, J=8Hz)
(5) 4-(2,6-Dichlorobenzoylamino)-1-(4-phenylpiperazin-1- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 1-phenylpiperazine) mp : 120-180°C
NMR (DMSO-d6, δ) : 3.15-3.26 (2H, m), 3.30-3.40 (2H, m), 3.61-3.71 (2H, m), 3.80-3.89 (2H, m), 5.57 (2H, s), 6.95 (1H, t, J=8Hz), 7.15 (2H, d, J=8Hz), 7.31 (2H, t, J=8Hz), 7.44-7.60 (6H, m), 8.22 (1H, d,
J=8Hz)
(6) 4-(2,6-Dichlorobenzoylamino)-1-[N-(pyridin-4- yl)carbamoyl]methyl-2-trifluoromethyl-1H-benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluromethyl-1H-benzimidazole and 4-aminopyridine) mp : >250°C
NMR (DMSO-d6, δ) : 5.57 (2H, s), 7.45-7.68 (5H, m),
8.04 (2H, d, J=8Hz), 8.25 (1H, d, J=8Hz), 8.73 (2H, d, J=8Hz)
(7) 4-(2,6-Dichlorobenzoylamino)-1-[N-(pyridin-4- ylmethyl)carbamoyl]methyl-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 4- aminomethylpyridine)
mp : >250°C
NMR (CDCl3, δ) : 4.41 (2H, s), 5.05 (2H, s), 7.16-7.23 (3H, m), 7.34-7.45 (3H, m) , 7.51 (1H, t, J=8Hz), 8.45 (2H, d, J=8Hz), 8.55 (1H, d, J=8Hz) its hydrochloride
mp : 248-257°C
NMR (DMSO-d6, δ) : 4.61 (2H, d, J=6Hz), 5.35 (2H, s), 7.45-7.60 (5H, m), 7.87 (2H, d, J=8Hz), 8.22 (1H, d, J=8Hz), 8.86 (2H, d, J=8Hz), 9.33 (1H, t, J=7Hz) (8) 4-(2,6-Dichlorobenzoylamino)-1-[N-(4- dimethylaminophenyl)carbamoyl]methyl-2-trifluoromethyl- 1H-benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and N,N-dimethyl-1,4- phenylenediamine)
mp : >250°C
NMR (DMSO-d6, δ) : 3.04 (6H, s), 5.40 (2H, s),
7.30-7.75 (9H, m), 8.25 (1H, d, J=8Hz) (9) 4-(2,6-Dichlorobenzoylamino)-1-[N-methyl-N-(pyridin-2- yl)carbamoyl]methyl-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2- methylaminopyridine)
mp : 194-196°C
NMR (CDCl3, δ) : 3.45 (3H, s), 5.30 (2H, s), 7.17 (1H, d, J=8Hz), 7.28-7.42 (5H, m), 7.48 (1H, t, J=8Hz), 7.89 (1H, dt, J=8Hz, 2Hz), 8.53-8.65 (3H, m) (10) 4-(2,6-Dichlorobenzoylamino)-1-[N-(2- methoxyethyl)carbamoyl]methyl-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and (2- methoxyethyl)amine) mp : 217-220°C
NMR (CDCl3, δ) : 3.25 (3H, s), 3.35-3.49 (4H, m), 4.97 (2H, s), 5.87-5.95 (1H, br), 7.19 (1H, d, J=8Hz), 7.31-7.42 (3H, m), 7.53 (1H, t, J=8Hz), 8.61 (1H, d, J=8Hz), 8.66 (1H, s)
(11) 1-[N-(Cyanomethyl)carbamoyl]methyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and (cyanomethyl) amine) mp : 238-243ºC
NMR (CDCl3, δ) : 4.12 (2H, s), 5.00 (2H, s), 7.15 (1H, d, J=8Hz), 7.30-7.45 (3H, m), 7.51 (1H, t, J=8Hz), 8.56 (1H, d, J=8Hz)
(12) 4-(2,6-Dichlorobenzoylamino)-2-trifluoromethyl-1-[N-(3- trifluoromethylphenyl)carbamoyl]methyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3- trifluoromethylaniline)
mp : 120-124ºC
NMR (CDCl3, δ) : 5.10 (2H, s), 7.18 (1H, d, J=8Hz),
7.32-7.47 (5H, m), 7.51 (1H, t, J=8Hz), 7.58-7.63 (1H, m), 7.74 (2H, s), 8.58 (1H, d, J=8Hz), 8.67 (1H, s)
(13) 4-(2,6-Dichlorobenzoylamino)-1-[N-(2,2,2- trifluoroethyl)carbamoyl]methyl-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluromethyl-1H-benzimidazole and (2,2,2- trifluoroethyl)amine)
mp : >250°C
NMR (CDCl3, δ) : 3.89 (2H, q, J=8Hz), 5.02 (2H, s),
7.17 (1H, d, J=8Hz), 7.31-7.46 (3H, m), 7.52 (1H, t, J=8Hz), 8.59 (1H, d, J=8Hz)
(14) 4-(2,6-Dichlorobenzoylamino)-1-[N-(thiazol-2- yl)carbamoyl]methyl-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-aminothiazole) mp : >250°C
NMR (CDCl3, δ) : 5.25 (2H, s), 7.03 (1H, d, J=4Hz),
7.19 (1H, d, J=8Hz), 7.31-7.45 (4H, m), 7.52 (1H, t, J=8Hz), 8.62 (1H, d, J=8Hz)
(15) 4-(2,6-Dichlorobenzoylamino)-1-[1-(morpholinocarbonyl)- ethyl]-2-trifluoromethyl-1H-benzimidazole
(from 1-(1-carboxyethyl)-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and morpholine) mp : >250°C
NMR (CDCl3, δ) : 1.80 (3H, d, J=7Hz), 3.00-3.73 (8H, m), 5.50 (1H, q, J=7Hz), 7.32-7.50 (5H, m), 8.57 (1H, d, J=8Hz), 8.60 (1H, s)
(16) 1-Carbamoylmethyl-4-(2,6-dichlorobenzoylamino)-2-methyl- 1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole trifluoroacetate and 28% aqueous ammonia)
mp : >250°C
NMR (DMSO-d6, δ) : 2.48 (3H, s), 4.84 (2H, s), 7.10- 7.30 (2H, m), 7.37 (1H, br s), 7.40-7.60 (3H, m), 7.75 (1H, br s), 8.04 (1H, d, J=7.5Hz), 10.75 (1H, br s) its hydrochloride
mp : 182-193°C
NMR (DMSO-d6, δ) : 2.75 (3H, s), 5.10 (2H, s), 7.40- 7.70 (6H, m), 7.90-8.10 (2H, m), 11.16 (1H, br s) (17) 4-(2,6-Dichlorobenzoylamino)-1-(N,N- dimethylcarbamoyl)methyl-2-methyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole trifluoroacetate and
dimethylamine)
mp : 218-219ºC
NMR (DMSO-d6, δ) : 2.40 (3H, s), 2.87 (3H, s), 3.15
(3H, s), 5.20 (2H, s), 7.15 (1H, t, J=7.5Hz), 7.24 (1H, d, J=7.5Hz), 7.40-7.60 (3H, m), 8.01 (1H, d, J=7.5Hz), 10.72 (1H, s) its hydrochloride
mp : 275-284°C
NMR (DMSO-d6, δ) : 2.65 (3H, s), 2.90 (3H, s), 3.17 (3H, s ) , 5.45 (2H, s), 7.44 (1H, br t, J=7.5Hz),
7.50-7.70 (4H, m), 8.00 (1H, d, J=7.5Hz), 11.10 (1H, br s)
(18) 4-(2,6-Dichlorobenzoylamino)-1-[N-(pyridin-3- yl)carbamoyl]methyl-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3-aminopyridine) NMR (DMSO-d6, δ) : 5.40 (2H, s), 7.37 (1H, dd, J=6Hz,
8Hz), 7.40-7.50 (5H, m), 8.01 (1H, dt, J=2Hz, 8Hz), 8.24 (1H, d, J=7Hz), 8.31 (1H, d, J=6Hz), 8.72 (1H, d, J=2Hz), 10.79 (1H, s), 11.18 (1H, s) its hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 5.50 (2H, s), 7.40-7.70 (5H, m),
7.75 (1H, dd, J=6Hz, 8Hz), 8.24 (1H, d, J=8Hz), 8.32 (1H, d, J=8Hz), 8.51 (1H, d, J=6Hz), 9.00 (1H, s), 11.19 (1H, s), 11.51 (1H, s) (19) 4-(2,6-Dichlorobenzoylamino)-1-(morpholinocarbonyl)- methyl-2-trifluoromethyl-1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and morpholine) mp : 269-270°C
NMR (DMSO-d6, δ) : 3.40-3.80 (8H, m), 5.50 (2H, s),
7.40-7.60 (5H, m), 8.23 (1H, d, J=8Hz), 11.15 (1H, s)
(20) 4-(2,6-Dichlorobenzoylamino)-1-(pyrrolidin-1- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and pyrrolidine) mp : 148-150°C
NMR (DMSO-d6, δ) : 1.94 (2H, m) , 2.11 (2H, m), 3.50- 3.60 (4H, m), 5.01 (2H, s), 7.12 (1H, d, J=8Hz),
7.30-7.40 (3H, m), 7.48 (1H, t, J=8Hz), 8.57 (1H, d, J=8Hz), 8.64 (1H, s)
(21) 4-(2,6-Dichlorobenzoylamino)-1-[N-(2-hydroxyethyl)- carbamoyl]methyl-2-trifluoromethyl-1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and (2- hydroxyethyl) amine)
mp : >250°C
NMR (CDCl3, δ) : 3.38 (2H, t, J=7Hz), 3.62 (2H, t,
J=7Hz), 4.99 (2H, s), 7.21 (1H, d, J=8Hz), 7.30- 7.45 (3H, m), 7.51 (1H, t , J=8Hz), 8.59 (1H, d, J=8Hz) (22) 1-[N,N-Bis(2-hydroxyethyl)carbamoyl]methyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and bis(2- hydroxyethyl)amine)
mp : >250ºC NMR (CDCl3, δ) : 3.54 (2H, t, J=7Hz), 3.59 (2H, t,
J=7Hz) , 3.77 (2H, t, J=7Hz), 3.87 (2H, t, J=7Hz), 5.39 (2H, s), 7.18 (1H, d, J=8Hz), 7.30-7.50 (4H, m), 8.58 (1H, d, J=8Hz)
(23) 4-(2,6-Dichlorobenzoylamino)-1-[N- (ethoxycarbonylmethyl)carbamoyl]methyl-2- trifluoromethyl-1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and glycine ethyl ester)
mp : 228-230°C
NMR (CDCl3, δ) : 1.26 (3H, t, J=7Hz), 4.02 (2H, d,
J=5Hz), 4.20 (2H, q, J=7Hz), 5.03 (2H, s), 6.02 (1H, m), 7.22 (1H, d, J=8Hz), 7.31-7.43 (3H, m),
7.53 (1H, t, J=8Hz), 8.49-8.53 (2H, m)
(24) 4-(2,6-Dichlorobenzoylamino)-1-[N-(tetrahydrofuran-2- ylmethyl)carbamoyl]methyl-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2- aminomethyltetrahydrofuran)
mp : 206-208°C
NMR (CDCl3, δ) : 1.45 (1H, m), 1.77-1.99 (3H, m) , 3.23
(1H, m), 3.54 (1H, m), 3.65 (2H, t, J=5Hz), 3.89 (1H, m), 4.87 (2H, s), 5.84 (1H, m), 7.20 (1H, d, J=8Hz), 7.31-7.42 (3H, m), 7.52 (1H, t, J=8Hz), 8.58-8.64 (2H, m)
(25) 1-[N-(Phenylsulfonyl)carbamoyl]methyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and benzenesulfonamide) NMR (CDCl3, δ) : 5.01 (2H, s), 6.93 (1H, d, J=8Hz), 7.31-7.45 (4H, m), 7.57 (2H, t, J=8Hz), 7.70 (1H, t, J=8Hz), 8.00 (2H, d, J=8Hz), 8.54 (2H, d,
J=8Hz), 8.60 (1H, s) (26) 4-(2,6-Dichlorobenzoylamino)-1-[N-(1,3-dihydroxy-2- propyl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 1,3-dihydroxy-2- aminopropane)
mp : 245-247°C
NMR (DMSO-d6, δ) : 3.45 (4H, t, J=4Hz), 3.72 (1H, m), 4.72 (2H, t, J=4Hz), 5.14 (2H, s), 7.40-7.60 (5H, m), 815-8.30 (2H, m)
(27) 4-(2,6-Dichlorobenzoylamino)-1-[N-(2-furylmethyl)- carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-aminomethylfuran) mp : 212-214°C
NMR (CDCl3, δ) : 4.45 (2H, d, J=7Hz), 4.99 (2H, s),
5.78 (1H, m), 6.18 (1H, s), 6.30 (1H, s), 7.16 (1H, d, J=8Hz), 7.32 (1H, s), 7.33-7.45 (3H, m), 7.52 (1H, t, J=8Hz), 8.59 (1H, s), 8.61 (1H, d, J=8Hz)
(28) 4-(2,6-Dichlcrobenzoylamino)-1-[N-(1,3,4-thiadiazol-2- yl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-1,3,4- thiadiazole)
mp : >260°C
NMR (DMSO-d6, δ) : 5.57 (2H, s), 7.40-7.65 (5H, m),
8.24 (1H, d, J=8Hz), 9.20 (1H, s) (29) 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-methoxypyridin-2- yl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-methoxy-5- aminopyridine)
mp : 202-210°C
NMR (DMSO-d6, δ) : 3.82 (3H, s), 5.38 (2H, s), 6.83 (1H, d, J=9Hz), 7.40-7.65 (5H, m), 7.89 (1H, dd, J=4Hz, 9Hz), 8.23 (1H, d, J=8Hz), 8.35 (1H, d, J=4Hz)
(30) 4-(2,6-Dichlorobenzoylamino)-2-trifluoromethyl-1-[N-(5- trifluoromethyl-1,3,4-thiadiazol-2-yl)carbamoylmethyl]- 1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-5- trifluoromethyl-1,3,4-thiadiazole)
mp : >250ºC
NMR (DMSO-d6, δ) : 5.62 (2H, s), 7.40-7.60 (5H, m), 8.25 (1H, d, J=8Hz), 11.20 (1H, s)
(31) 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-methylisoxazol-3- yl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3-amino-5- methylisoxazole
mp : 245-247°C
NMR (CDCl3, δ) : 2.42 (3H, s), 5.21 (2H, s), 6.70 (1H, s), 7.18 (1H, d, J=8Hz), 7.3-7.5 (3H, m), 7.53 (1H, t, J=8Hz), 8.62 (1H, d, J=8Hz), 8.65 (1H, s)
(32) 4-(2,6-Dichlorobenzoylamino)-1-[N-(1,1-dimethyl-2- hydroxyethyl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-1-hydroxy- 2-methylpropane)
mp : 242-244°C
NMR (DMSO-d6, δ) : 1.19 (6H, s), 3.38 (2H, d, J=5Hz), 4.80 (1H, t, J=5Hz), 5.08 (2H, s), 7.40-7.60 (5H, m), 7.93 (1H, s), 8.22 (1H, m)
(33) 4-(2,6-Dichlorobenzoylamino)-1-[N-(4-methyloxazol-2- yl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-4- methyloxazole)
mp : >250°C
NMR (DMSO-d6, δ) : 2.05 (3H, s), 5.45 (2H, br s),
7.40-7.65 (6H, m), 8.23 (1H, d, J=8Hz), 11.18 (1H, s), 11.79 (1H, br s)
(34) 4-(2,6-Dichlorobenzoylamino)-2-trifluoromethyl-1-[N-(3- trifluoromethylbenzyl)carbamoylmethyl]-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 1-aminomethyl-3- trifluoromethylbenzene)
mp : 207-208°C
NMR (DMSO-d6, δ) : 4.43 (2H, d, J=6Hz), 5.24 (2H, s), 7.40-7.70 (10H, m), 8.23 (1H, d, J=8Hz), 8.97 (1H, t, J=6Hz)
(35) 4-(2,6-Dichlorobenzoylamino)-1-[N-(pyridin-3- ylmethyl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3- aminomethylpyridine)
mp : 228-231°C
NMR (DMSO-d6, δ) : 4.50 (2H, d, J=6Hz), 5.27 (2H, s), 7.40-7.60 (5H, m), 7.89 (1H, dd, J=6Hz, 8Hz), 8.23 (1H, d, J=8Hz), 8.27 (1H, d, J=8Hz), 8.70-8.80 (2H, m), 9.18 (1H, t, J=6Hz) (36) 4-(2,6-Dichlorobenzoylamino)-1-[N-(pyridin-2- ylmethyl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole hydrochloride
( from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2- aminomethylpyridine)
mp : >250°C
NMR (DMSO-d6, δ) : 4.60 (2H, d, J=6Hz), 5.31 (2H, s), 7.40-7.70 (7H, m), 8.20-8.30 (2H, m), 8.71 (1H, d, J=6Hz), 9.23 (1H, t, J=6Hz)
(37) 4-(2,6-Dichlorobenzoylamino)-1-[N-[3,4-(methylenedioxy)- benzyl]carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
( from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3,4(methylenedioxy) benzylamine)
mp : 230-231°C
NMR (DMSO-d6, δ) : 4.24 (2H, d, J=6Hz), 5.20 (2H, s), 6.00 (2H, s), 6.75 (1H, d, J=8Hz), 6.83 (1H, s), 6.88 (1H, d, J=8Kz), 7.40-7.60 (5H, m), 8.23 (1H, d, J=8Hz), 8.82 (1H, t, J=6Hz)
(38) 4-(2,6-Dichlorobenzoylamino)-1-(methoxycarbamoylmethyl)- 2-trifluoromethyl-1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and methoxyamine
hydrochloride)
mp : 235-236°C
NMR (DMSO-d6, δ) : 3.61 and 3.79 (3H, s), 5.06 and
5.43 (2H, s), 7.40-7.60 (5H, m), 8.23 (1H, d, J=8Hz)
(39) 4-(2,6-Dichlorobenzoylamino)-1-[N-[2-(indol-3-yl)ethyl]- carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3-(2- aminoethyl)indole)
NMR (CDCl3, δ) : 2.87 (2H, t, J=7Hz), 3.57 (2H, q,
J=7Hz), 4.88 (2H, s), 5.29 (1H, br), 6.50 (1H, s), 6.99 (1H, d, J=8Hz), 7.07 (1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.30-7.50 (6H, m), 7.98 (1H, br s), 8.50 (1H, d, J=8Hz), 8.58 (1H, s)
(40) 4-(2,6-Dichlorobenzoylamino)-1-[N-[2-(pyridin-2- yl)ethyl]carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-(2- aminoethyl)pyridine)
mp : 174-176°C
NMR (CDCl3, δ) : 2.81 (2H, t, J=6Hz), 3.63 (2H, q,
J=6Hz), 5.98 (2H, s), 6.95-7.03 (2H, m), 7.15 (1H, α, J=8Hz), 7.32-7.53 (5H, m), 7.65 (1H, br), 7.82 (1H, d, J=4Hz), 8.60 (1H, d, J=8Hz), 8.65 (1H, s)
(41) 4-(2,6-Dichlorobenzoylamino)-1-[N-[2-(imidazol-4-yl)- ethyl]carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 4-(2- aminoethyl)imidazole)
NMR (CDCl3, δ) : 2.22 (2H, t, J=7Hz), 3.47 (2H, q,
J=7Hz), 4.95 (2H, s), 6.67 (1H, s), 7.12 (1H, d, J=8Hz), 7.30-7.53 (5H, m), 8.54 (1H, d, J=8Hz) (42) 4-(2,6-Dichlorobenzoylamino)-1-[N-(3-hydroxypropyl)- carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and (3-hydroxypropyl)- amine)
mp : 234-236°C
NMR (DMSO-d6, δ) : 1.18 (2H, quint., J=7Hz), 3.16 (2H, σ, J=7Hz), 3.43 (2H, q, J=7Hz), 4.44 (1H, t,
J=7Hz), 5.10 (2H, s), 7.40-7.60 (5H, m), 8.22 (1H, dd, J=2Hz, 8Hz), 8.34 (1H, t, J=7Hz)
(43) 4-(2,6-Dichlorobenzoylamino)-1-[N-(3-methoxyphenyl)- carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3-methoxyaniline) mp : >250°C
NMR (DMSO-d6, δ) : 3.71 (3H, s), 5.36 (2H, s), 6.68
(1H, d, J=8Hz), 7.08 (1H, d, J=8Hz), 7.20-7.30 (2H, m), 7.40-7.60 (5H, m), 8.24 (1H, d, J=8Hz) (44) 4-(2,6-Dimethylbenzoylamino)-1-(morpholinocarbonyl)- methyl-2-trifluoromethyl-1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dimethylbenzoylamino)-2- trifluoromethyl-1H-benzimidazole and morpholine)
mp : 246-247°C
NMR (DMSO-d6, δ) : 2.35 (6H, s), 3.40-3.80 (8H, m),
5.50 (2H, s), 7.11 (2H, d, J=8Hz), 7.23 (1H, t, J=8Hz), 7.46 (1H, t, J=8Hz), 7.53 (1H, d, J=8Hz), 7.99 (1H, d, J=8Hz) (45) 4-(2,6-Dichlorobenzoylamino)-1-[N-(3- dimethylaminophenyl)carbamoylmethyl]-2-trifluormethyl- 1H-benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and N,N-dimethyl-1,3- phenylenediamine) mp : >250°C
NMR (DMSO-d6, δ) : 2.85 (6H, s), 5.34 (2H, s), 6.56
(1H, d, J=8Hz), 6.84 (1H, d, J=8Hz), 7.01 (1H, s), 7.10 (1H, t, J=8Hz), 7.40-7.60 (5H, m), 8.23 (1H, d, J=8Hz)
(46) 4-(2,6-Dimethylbenzoylamino)-1-[N-(pyridin-3- ylmethyl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole hydrochloride
(from 1-carboxymethyl-4-(2,6-dimethylbenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 3- aminomethylpyridine)
mp : 195-200°C
NMR (DMSO-d6, δ) : 2.33 (6H, s), 4.51 (2H, d, J=6Hz), 5.27 (2H, s), 7.11 (2H, d, J=8Hz), 7.24 (1H, t,
J=8Hz), 7.48 (1H, t, J=8Hz), 7.56 (1H, d, J=8Hz), 7.92 (1H, dd, J=7Hz, 8Hz), 7.99 (1H, d, J=8Hz), 8.30 (1H, d, J=8Hz), 8.77 (1H, d, J=7Hz), 8.78 (1H, s), 9.21 (1H, t, J=6Hz)
(47) 4-(2,6-Dichlorobenzoylamino)-2-trifluoromethyl-1-[N-(4- trifluoromethylphenyl)carbamoylmethyl]-1H-benzimidazole (from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 4- trifluoromethylaniline)
mp : >250°C
NMR (CDCl3-CD3OD, δ) : 5.60 (2H, s), 7.21 (1H, d,
J=8Hz), 7.30-7.60 (6H, m), 7.65-7.75 (2H, m), 8.68 (1H, d, J=8Hz)
(48) 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-sulfamoyl-1,3,4- thiadiazol-2-yl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 5-amino-1,3,4- thiadiazole-2-sulfonamide)
mp : >250°C
NMR (DMSO-d6, δ) : 5.57 (2H, s), 7.45-7.62 (5H, m), 8.24 (1H, d, J=8Hz), 8.32 (2H, s)
(49) 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-ethylthio-1,3,4- thiadiazol-2-yl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-5- ethylthio-1,3,4-thiadiazole)
mp : >250°C
NMR (DMSO-d6, δ) : 1.32 (3H, t, J=7Hz), 3.21 (2H, q,
J=7Hz), 5.55 (2H, s), 7.43-7.63 (5H, m), 8.24 (1H, d, J=8Hz)
(50) 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-methyl-1,3,4- thiadiazol-2-yl)carbamoylmethyl]-2-trifluoromethyl-1H- benzimidazole
(from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole and 2-amino-5-methyl- 1,3,4-thiadiazole)
mp : >250°C
NMR (CDCl3:CD3OD = 20:1, δ) : 2.69 (3H, s), 5.32 (2H, s), 7.21 (1H, d, J=8Hz), 7.30-7.45 (3H, m), 7.52
(1H, t, J=8KH), 8.60 (1H, d, J=8Hz)
Example 16
A solution of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg) and 1-hydroxybenzotriazole (75 mg) in N,N-dimethylformamide (2 ml) were stirred for 2 hours at ambient temperature, and to the mixture was added 2-trifluoromethylaniline (90 mg). After stirring for 2 days at 80°C, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, brine and saturated sodium bicarbonate solution, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl1-[N-(2-trifluoromethylphenyl)carbamoylmethyl]-1H-benzimidazole (100 mg) and 4-(2,6-dichlorobenzoylamino)-1-(N,N- dimethylcarbamoyl)methyl-2-trifluoromethyl-1H-benzimidazole (46 mg) as by-product.
4-(2,6-Dichlorobenzoylamino)-2-trifluoromethyl-1-[N-(2- trifluoromethylphenyl)carbamoylmethyl]-1H-benzimidazole
mp : >250°C
NMR (CDCl3-CD3OD, δ) : 5.20 (2H, s), 7.20-7.45 (5H,
m), 7.50-7 70 (3H, m), 7.85 (1H, d, J=8Hz), 8.63
(1H, d, J=8Hz)
4-(2,6-Dichlorobenzoylamino)-1-(N,N-dimethylcarbamoyl)-methyl-2-trifluoromethyl-1H-benzimidazole
mp : 243-244°C
NMR (CDCl3, δ) : 3.02 (3H, s), 3.18 (3H, s), 5.08 (2H, s), 7.09 (1H, d, J=8Hz), 7.28-7.40 (3H, m), 7.47 (1H, t, J=8Hz), 8.56 (1H, d, J=8Hz), 8.63 (1H, br s)
Example 17
A mixture of 1- (2-acetoxyethyl)-4-(2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole (110 mg), 1N sodium
hydroxide solution (0.5 ml) and methanol (5 ml) was refluxed for 30 minutes, and cold water was added thereto. The mixture was extracted with dichloromethane, and the extract was washed with brine, dried and concentrated in vacuo to give a residue containing 4-(2,6-dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-methyl-1H-benzimidazole. The residue was dissolved in 10% methanolic hydrogen chloride, and the solution was concentrated in vacuo to give 4-(2,6- dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-methyl-1H- benzimidazole hydrochloride (85 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.87 (3H, s), 3.79 (2H, t, J=6Hz),
4.50 (2H, t, J=6Hz), 7.50-7.65 (4H, m), 7.73 (1H, d, J=7Hz), 8.09 (1H, d, J=7Hz)
Example 18
To 1M solution of methylmagnesium bromide in
tetrahydrofuran (3 ml) was dropwise added a solution of 4- (2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H- 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. The residue was purified by column chromatography on silica gel to give 4- (2,6-dichlorobenzoylamino)-1-(2-hydroxy-2-methylpropyl)-2-methyl-1H-benzimidazole. It was dissolved in 10% methanolic hydrogen chloride, and the solution was concentrated in vacuo to give 4-(2,6-dichlorobenzoylamino)-1-(2-hydroxy-2-methylpropyl)-2-methyl-1H-benzimidazole hydrochloride (108 mg). mp : >250°C
NMR (DMSO-d6, δ) : 1.21 (6H, s), 2.37 (3H, s), 4.37
(2H, s), 7.50-7.65 (4H, m), 7.79 (1H, d, J=7Hz), 8.12 (1H, d, J=7Hz)
Example 19
4-(2,6-Dichlorobenzoylamino)-1-(2-hydroxy-2-methylpropyl)-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 4-(2,6-dichlorobenzoylamino)-1-(2-oxopropyl)-2-trifluoromethyl-1H-benzimidazole with methylmagnesium bromide according to a similar manner to that of Example 18.
mp : >250°C
NMR (DMSO-d6, δ) : 1.16 (6H, s), 4.37 (2H, s), 4.85 (1H, s), 7.40-7.60 (4H, m), 7.67 (1H, d, J=8Hz), 8.21 (1H, d, J=8Hz), 11.10 (1H, s)
Example 20
Acetic anhydride (62 mg) was added to a solution of 4- (2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole (128 mg) in acetic acid (1 ml). The solution was stirred at ambient temperature overnight and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1-acetyl-4-(2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole (93 mg).
mp : 143-145°C
NMR (CDCl3, δ) : 2.82 (6H, s), 7.30-7.45 (4H, m), 7.48
(1H, d, J=7Hz), 8.53 (1H, d, J=7Hz), 8.58 (1H, br s)
Example 21
4-(2,6-Dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 17.
mp : 183-185°C
NMR (CDCl3. δ) : 1.94 (1H, t, J=6Hz), 4.04 (2H, q,
J=6Hz), 4.49 (2H, t, J=6Hz), 7.30-7.45 (4H, m),
7.48 (1H, t, J=7.5Hz), 8.56 (1H, d, J=7.5Hz), 8.67 (1H, br s)
Example 22
To a suspension of 4-(2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H-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-1H-benzimidazole (155 mg).
mp : >250°C
NMR (CDCl3-CD3OD, δ) : 1.22 (3H, d, J=6Hz), 2.53 (3H, s), 3.99 (2H, m), 4.10 (1H, m), 7.07 (1H, d,
J=7Hz), 7.20-7.45 (4H, m), 8.33 (1H, d, J=7Hz)
Example 23
The following compounds were obtained according to a similar manner to that of Example 22.
(1) 4-(2,6-Dichlorobenzoylamino)-1-(2-hydroxy-2- phenylethyl)-2-methyl-1H-benzimidazole hydrochloride (from 1-benzoylmethyl-4-(2,6-dichlorobenzoylamino)-2- methyl-1H-benzimidazole)
NMR (DMSO-d6, δ) : 2.80 (3H, s), 4.44-4.69 (2H, m),
5.05 (1H, m), 7.30-7.45 (3H, m), 7.48-7.65 (6H, m), 7.75 (1H, d, J=8Hz), 8.10 (1H, d, J=8Hz) (2) 4-(2,6-Dichlorobenzoylamino)-1-[2-hydroxy-2-(pyridin-4- yl)ethyl]-2-trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-1-(pyridin-4-yl)- carbonylmethyl-2-trifluoromethyl-1H-benzimidazole) mp : 230-232°C
NMR (DMSO-d6, δ) : 4.43 (1H, dd, J=8Hz, 15Hz), 4.62
(1H, dd, J=4Hz, 15Hz), 4.90-5.10 (1H, m) , 6.03 (1H, m), 7.40-7.60 (6H, m), 7.67 (1H, d, J=8Hz), 8.23 (1H, d, J=8Hz), 8.58 (2H, d, J=8Hz), 11.14 (1H, s) its hydrochloride
mp : 225-227°C
NMR (DMSO-d6, δ) : 4.47 (1H, dd, J=8Hz, 15Hz), 4.76
(1H, dd, J=4Hz, 15Hz), 5.26 (1H, dd, J=4Hz, 8Hz), 6.44 (1H, br s), 7.40-7.60 (4H, m), 7.23 (1H, d, J=8Hz), 8.06 (2H, d, J=7Hz), 8.24 (1H, d, J=8Hz), 8.89 (2H, d, J=7Hz), 11.14 (1H, s)
(3) 4-(2,6-Dichlorobenzoylamino)-1-[2-hydroxy-2-(pyridin-3- yl)ethyl]-2-trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-1-(pyridin-3- yl)carbonylmethyl-2-trifluoromethyl-1H-benzimidazole) mp : 205-207°C
NMR (DMSO-d6, δ) : 4.52 (1H, dd, J=8Hz, 15Hz), 4.61
(1H, dd, J=4Hz, 15Hz), 5.00-5.10 (1H, m), 5.98 (1H, s), 7.40-7.60 (5H, m), 7.64 (1H, d, J=8Hz), 7.86
(1H, d, J=8Hz), 8.22 (1H, d, J=8Hz), 8.53 (1H, d, J=6Hz), 8.63 (1H, s), 11.13 (1H, s) its hydrochloride
mp : 217-227°C
NMR (DMSO-d6, δ) : 4.53 (1H, dd, J=8Hz, 15Hz), 4.73
(1H, dd, J=4Hz, 15Hz), 5.22 (1H, dd, J=4Hz, 8Hz), 6.30 (1H, br s), 7.40-7.60 (4H, m), 7.70 (1H, d, J=8Hz), 7.91 (1H, dd, J=7Hz, 8Hz), 8.23 (1H, d, J=8Hz), 8.45 (1H, d, J=8Hz), 8.80 (1H, d, J=7Hz),
8.93 (1H, s), 11.15 (1H, s)
(4 ) 4-(2,6-Dichlorobenzoylamino)-1-(2-hydroxypropyl)-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-1-(2-oxopropyl)-2- trifluoromethyl-1H-benzimidazole)
mp : 234-234.5°C
NMR (CDCl3, δ) : 1.34 (3H, d, J=6Hz), 2.03 (1H, d,
J=6Hz), 4.20-4.40 (3H, m), 7.30-7.45 (4H, m), 7.46 (1H, t, J=7.5Hz), 8.55 (1H, d, J=7.5Hz), 8.74 (1H, br s)
Example 24
(1) A mixture of 4-(2,6-dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-methyl-1H-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-1H- benzimidazole (42 mg).
NMR (CDCl3, δ) : 2.66 (3H, s), 3.70 (2H, t, J=8Hz),
4.55 (2H, t, J=8Hz), 7.12 (1H, d, J=8Hz), 7.24-7.42 (4H, m), 8.49 (1H, d, J=8Hz), 8.59 (1H, s)
(2) To a solution of 1-(2-bromoethyl)-4-(2,6- dichlorobenzoylamino)-2-methyl-1H-benzimidazole (37 mg) in N,N-dimethylformamide (0.5 ml) were added 4-mercaptopyridine (11 mg), potassium carbonate (25 mg) and potassium iodide (28 mg), and the mixture was stirred for 5 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2% methanol-dichloromethane) to give 4-(2,6- dichlorobenzoylamino)-2-methyl-1-[2-(pyridin-4-ylthio)ethyl]- 1H-benzimidazole (38 mg).
mp : 229-231°C
NMR (CDCl3, δ) : 2.55 (3H, s), 3.42 (2H, t, J=7Hz),
4.42 (2H, t, J=7Hz), 7.05-7.10 (3H, m), 7.25-7.40 (4H, m), 8.42 (2H, d, J=5Hz), 8.47 (1H, d, J=8Hz), 8.55 (1H, s) Example 25
4-(2,6-Dichlorobenzoylamino)-2-methyl-1-[3-(pyridin-4-ylthio)propyl]-1H-benzimidazole was obtained by reacting 1- (3-chloropropyl)-4-(2,6-dichlorobenzoylamino)-2-methyl-1H-benzimidazole with 4-mercaptopyridine according to a similar manner to that of Example 24-(2). NMR (CDCl3, δ) : 2.18-2.29 (2H, m), 2.57 (3H, s), 2.99 (2H, t, J=7Hz), 4.30 (2H, t, J=7Hz), 7.05-7.12 (3H, m), 7.25-7.40 (4H, m), 8.38-8.45 (3H, m), 8.57 (1H, s)
Example 26
Bromine (93 mg) was added to a solution of 4-(2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H-benzimidazole (200 mg) in dichloromethane (2 ml). The solution was stirred at ambient temperature for 15 minutes and diluted with dichloromethane. Then, the solution was washed with aqueous sodium thiosulfate and aqueous saturated sodium bicarbonate, 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 diisopropyl ether to give 7-bromo-4-(2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H-benzimidazole (220 mg).
mp : >250°C
NMR (CDCl3, δ) : 2.33 (3H, s ) , 2.45 (3H, s), 5.31 (2H, s), 7.28-7.40 (4H, m), 8.32 (1H, d, J=8Hz), 8.55 (1H, s)
Example 27
(1) 1-(2-tert-Butoxycarbonylhydrazino)carbonylmethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole was obtained from 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole and tert-butoxycarbonylhydrazine according to a similar manner to that of Example 14.
mp : 160-164°C
NMR (CDCl3, δ) : 1.56 and 1.59 (9H, s), 5.05 and 5.17 (2H, s), 6.41 and 6.55 (1H, s), 7.10-7.60 (5H, m), 8.50-8.65 (2H, m) (2) A mixture of 1-(2-tert-butoxycarbonylhydrazino)- carbonylmethyl-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole (244 mg) and 4N solution of hydrogen chloride in ethyl acetate was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was triturated with diethyl ether to give 4- (2,6-dichlorobenzoylamino)-1-hydrazinocarbonylmethyl-2- trifluoromethyl-1H-benzimidazole hydrochloride (186 mg).
mp : >250ºC
NMR (CD3OD, δ) : 5.33 (2H, s), 7.40-7.60 (5H, m),
8.40 (1H, d, J=8Hz)
Example 28
A mixture of 4-(2,6-dichlorobenzoylamino)-1-(2- phthalimidoethyl)-2-trifluoromethyl-1H-benzimidazole (462 mg) and hydrazine monohydrate (63.4 mg) in ethanol was refluxed for 5 hours. The mixture was cooled and insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue was triturated with ethanol to give 1-(2-aminoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl- 1H-benzimidazole (160 mg).
mp : 188-190°C
NMR (DMSO-d6, δ) : 2.93 (2H, t, J=7Hz), 4.35 (2H, t, J=7Hz), 7.40-7.60 (4H, m), 7.64 (1H, d, J=8Hz), 8.21 (1H, d, J=8Hz)
Example 29
4-(2,6-Dichlorobenzoylamino)-1-[2- (morpholinocarbonylamino)ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 1-(2-aminoethyl)-4- (2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole with morpholinocarbonyl chloride,
mp : 222-223°C
NMR (DMSO-d6, δ) : 3.10-3.20 (4H, m), 3.40-3.50 (6H, m), 4.40-4.50 (2H, m), 6.77 (1H, m), 7.40-7.60 (5H, m), 8.23 (1H, m), 11.12 (1H, s)
Example 30
To a solution of 1-(2-aminoethyl)-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (114 mg) in pyridine was added mesyl chloride (37.6 mg) and the mixture was stirred for 1 hour at ambient temperature. Mesyl chloride (37.6 mg) was further added thereto, and the mixture was stirred for 1 hour at the same temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with 3.6% hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was treated with ethanol and filtered. The filtrate was concentrated and the residue was crystallized from
dichloromethane - n-hexane to give 4-(2,6-dichlorobenzoylamino)-1-(2-methylsulfonylaminoethyl)-2-trifluoromethyl-1H-benzimidazole (54.7 mg).
mp : 178-180°C
NMR (DMSO-d6, δ) : 2.87 (3H, s), 3.39 (2H, q, J=7Hz),
4.50 (2H, t, J=7Hz), 7.33 (1H, t, J=7Hz), 7.40-7.60 (5H, m), 8.23 (1H, d, J=8Hz)
Example 31
To a solution of 1-(2-aminoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-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. The extract was washed with 3.6% hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 1-(2-acetylaminoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (72.9 mg).
mp : 222-224°C NMR (DMSO-d6, δ) : 1.69 (3H, s), 3.48 (2H, q, J=7Hz), 4.45 (2H, t, J=7Hz), 7.40-7.60 (5H, m), 8.06 (1H, t, J=7Hz), 8.24 (1H, m) Example 32
A mixture of 4-(2,6-dichlorobenzoylamino)-2-methyl-1H- benzimidazole (200 mg), methyl acrylate (538 mg) and sodium carbonate (132 mg) in N,N-dimethylformamide (4 ml) was stirred at 100°C for 24 hours. The mixture was poured into a mixture of ice and water and 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 amorphous was dissolved in methanolic hydrogen chloride. The solution was evaporated in vacuo and the residue was crystallized from 2-propanol to give 4-(2,6-dichlorobenzoylamino)-1-(2-methoxycarbonylethyl)-2-methyl-1H-benzimidazole hydrochloride (51 mg).
mp : 208-210°C
NMR (CDCl3, δ) : 2.94-3.02 (5H, m), 3.68 (3H, s), 4.58
(2H, t, J=5Hz), 7.20-7.40 (4H, m), 7.54 (1H, t, J=8Hz), 8.81 (1H, d, J=8Hz), 11.30 (1H, m)
Example 33
A mixture of 4-(2,6-dichlorobenzoylamino)-2-methyl-1-(2-oxopropyl)-1H-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. The crystalline residue was triturated with 2-propanol to give 4-(2,6-dichlorobenzoylamino)-2-methyl-1-[2-(pyridin-2-ylhydrazono)propyl]-1H-benzimidazole dihydrochloride (99 mg). mp : 210-213°C
NMR (DMSO-d6, δ) : 2.10 (3H, s), 2.84 (3H, s), 5.35 (2H, s), 7.10 (1H, t, J=8Hz), 7.40 (1H, m), 7.48- 7.62 (4H, m), 7.75 (1H, d, J=8Hz), 8.05 (1H, t, J=8Hz), 8.12-8.20 (2H, m), 11.34 (1H, br s), 11.92 (1H, m)
Example 34
A mixture of 1-cyanomethyl-4-(2,6-dichlorobenzoylamino)- 2-trifluoromethyl-1H-benzimidazole (200 mg) and trimethyltin azide (299 mg) in xylene (4 ml) was stirred at 120°C for 18 hours. To the reaction mixture was added dichloromethane and methanol to give a clear solution. Silica gel (2 g) was added to the solution and the mixture was stirred for 30 minutes and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from a mixture of 2-propanol and water to yield 4-(2,6-dichlorobenzoylamino)-1-(1H-tetrazol-5-yl)methyl-2-trifluoromethyl-1H-benzimidazole (103 mg).
mp : 228-231°C
NMR (DMSO-d6, δ) : 6.03 (2H, s), 7.44-7.58 (5H, m),
8.25 (1H, d, J=8Hz)
Example 35
(1) 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 1-cyanomethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-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-trifluoromethyl-1H-benzimidazole (150 mg).
mp : 235-236ºC
NMR (CDCl3, δ) : 4.48-4.53 (2H, m), 4.46 (2H, s), 6.52 ( 1H, m) , 7 . 31 -7 . 45 ( 4H, m) , 7 . 51 ( 1H, t , J=8Hz ) , 8 . 60 ( 1H, d, J=8Hz ) , 8 . 65 ( 1H, br s )
(2) To a solution of 4-(2,6-dichlorobenzoylamino)-1-(N- hydroxyamidino)methyl-2-trifluoromethyl-1H-benzimidazole (56 mg) in acetic acid (1 ml) was added acetic anhydride (15 mg) at ambient temperature, and the mixture was stirred for 30 minutes at the same temperature, and then for 2 hours at 110°C. After cooling, methanol was added thereto, and the mixture was concentrated in vacuo to give 4-(2,6- dichlorobenzoylamino)-1-(5-methyl-1,2,4-oxadiazol-3- yl)methyl-2-trifluoromethyl-1H-benzimidazole (57 mg).
mp : 148-150ºC
NMR (CDCl3, δ) : 2.57 (3H, s), 5.58 (2H, s), 7.29-7.42 (4H, m), 7.50 (1H, t, J=8Hz), 8.58-8.61 (2H, m)
Example 36
1-[N-(Carboxymethyl)carbamoylmethyl]-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole was obtained from 4-(2,6-dichlorobenzoylamino)-1-[N- (ethoxycarbonylmethyl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of
Example 11.
mp : >250ºC
NMR (DMSO-d6, δ) : 3.83 (2H, d, J=6Hz), 5.19 (2H, s),
7.40-7.60 (5H, m), 8.22 (1H, d, J=8Hz), 8.73 (1H, t, J=6Hz)
Example 37
4-(2,6-Dichlorobenzoylamino)-1-[N-[N-(2-hydroxyethyl)carbamoylmethyl]carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole was obtained from 1-[N-(carboxymethyl)carbamoylmethyl]-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole and (2-hydroxyethyl) amine according to a similar manner to that of Example 13. mp : >250°C
NMR (DMSO-d6, δ) : 3.15 (2H, q, J=7Hz), 3.40 (2H, q, J=7Hz), 3.77 (2H, d, J=7Hz), 4.69 (1H, t, J=7Hz), 5.21 (2H, s), 7.40-7.60 (5H, m), 7.95 (1H, t, J=7Hz), 8.23 (1H, m), 8.63 (1H, t, J=7Hz)
Example 39
A mixture of 1-carboxymethyl-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (200 mg), oxalyl chloride (117 mg) and N,N-dimethylformamide (1 drop) in dichloromethane was stirred at ambient temperature for 1 hour. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (2 ml). This solution was added dropwise to a solution of acetylhydrazine (86 mg) in dichloromethane. The mixture was stirred at ambient temperature for 2 hours, washed with 1N-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-propanol 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 in vacuc. The resiαue was crystallized from a mixture of 2-propanol and water to give 4-(2,6-dichlorobenzoylamino)-1-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)-2-trifluoromethyl-1H-benzimidazole (74 mg).
mp : 200-202°C
NMR (CDCl3, δ) : 2.49 (3H, s), 5.68 (2H, s), 7.30-7.45 (4H, m), 7.53 (1H, t, J=8Hz), 8.57 (1H, br s), 8.60 (1H, d, J=8Hz) Example 39 4-(2,6-Dichlorobenzoylamino)-1-[N-(5-methyl-1,3,4- oxadiazol-2-ylmethyl)carbamoylmethyl]-2-trifluromethyl-1H- benzimidazole was obtained from 1-[N-(carboxymethyl)- carbamoylmethyl]-4-(2,6-dichlorobenzoylamino)-2- trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 38.
mp : 156-158°C
NMR (DMSO-d6, δ) : 2.48 (3H, s), 4.54 (2H, d, J=6Hz), 5.21 (2H, s), 7.35-7.60 (5H, m), 8.23 (1H, d, J=8Hz), 9.13 (1H, t, J=6Hz)
Example 40
To a mixture of 4-(2,6-dichlorobenzoylamino)-1-[N-(2- hydroxyethyl)carbamoyl]methyl-2-trifluoromethyl-1H- benzimidazole (143 mg), acetic anhydride (37 mg) and pyridine (31 mg) in dichloromethane (3 ml) was added N,N-dimethylaminopyridine (3 mg), and the mixture was stirred for 3 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was crystallized from methanol-water to give 1-[N-(2-acetoxyethyl)carbamoylmethyl]-4-(2,6- dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (135 mg).
mp : 214-215°C
NMR (CDCl3-CD3OD, δ) : 1.98 (3H, s), 3.49 (2H, t,
J=6Hz), 4.13 (2H, t, J=6Hz), 4.97 (2H, s), 7.19
(1H, d, J=8Hz), 7.30-7.45 (3H, s), 7.52 (1H, t, J=8Hz), 8.60 (1H, d, J=8Hz)
Example 41
1-[N-(1,3-Diacetoxy-2-propyl)carbamoylmethyl]-4-(2,6-dichlorobenzoylamino)-2-trifluromethyl-1H-benzimidazole was obtained by reacting 4-(2,6-dichlorobenzoylamino)-1-[N-(1,3-dihydroxy-2-propyl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole with acetic anhydride according to a similar manner to that of Example 40. mp : 162-164°C
NMR (DMSO-d6, δ) : 2.02 (6H, s), 4.07 (4H, m), 4.25
(1H, m), 5.16 (2H, s), 7.40-7.60 (5H, m), 8.23 (1H, m), 8.59 (1H, d, J=8Hz)
Example 42
A mixture of 4-(2,6-dichlorobenzoylamino)-1-[N-(2-hydroxyethyl)carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (180 mg) in thionyl chloride was stirred overnight at ambient temperature. After concentration, ice water was added to the residue, and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide, and imidazole (77.4 mg) and potassium iodide (6.29 mg) were added thereto. The mixture was stirred for 1 hour at 120°C, and then ethyl acetate was added
thereto. The mixture was washed with water and brine, dried and concentrated in vacuo to give 4-(2,6-dichlorobenzoyl¬amino)-1-[N-[2-(imidazol-1-yl)ethyl]carbamoylmethyl]-2-trifluoromethyl-1H-benzimidazole (103 mg).
mp : >250°C
NMR (CDCl3, δ) : 3.54 (2H, t, J=7Hz), 4 .06 (2H, t,
J=7Hz), 4.93 (2H, s), 6.83 (1H, s), 6.95 (1H, s), 7.09 (1H, d, J=8Hz), 7.24 (1H, s), 7.30-7.50 (3H, m), 7.51 (1H, t, J=8Hz), 8.58 (1H, d, J=8Hz)
Example 43
4-(2,6-Dichlorobenzoylamino)-1-[2-(imidazol-1-yl)ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained from 4-(2,6-dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole and imidazole according to a similar manner to that of Example 42.
mp : 251-253°C
NMR (DMSO-d6, δ) : 4.47 (2H, t, J=6Hz), 4.74 (2H, t, J=6Hz ) , 6 . 81 ( 1H, s ) , 6 . 99 ( 1H, s ) , 7 . 24 ( 1H, d, J=8Hz ) , 7 . 35-7 . 60 ( 5H, m) , 8 .20 ( 1H, d, J=8Hz )
Example 44
(1) A mixture of 4-(2,6-dichlorobenzoylamino)-1-(2- hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (418 mg), glutaric anhydride (137 mg), pyridine (103 mg), catalytic amount of N,N-dimethylaminopyridine in dichloromethane (10 ml) was stirred overnight at ambient temperature. The mixture was washed with 1N hydrochloric acid and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and crystallized from diisopropyl ether to give 1-[2-(4-carboxybutanoyloxy)ethyl]- 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole (220 mg).
mp : 173-175°C
NMR (CDCl3-CD3OD, δ) : 1.86 (2H, quint., J=7Hz), 2.23- 2.35 (4H, m), 4.49 (2H, t, J=6Hz), 4.62 (2H, t, J=6Hz), 7.27-7.45 (4H, m), 7.53 (1H, t, J=8Hz), 8.58 (1H, d, J=8Hz)
(2) A mixture of 1-[2-(4-carboxybutanoyloxy)ethyl]-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (215 mg), disuccinimidyl carbonate (207 mg) and pyridine (96 mg) in acetonitrile (20 ml) was stirred overnight at ambient temperature. To the mixture was added disuccinimidyl
carbonate (103 mg), and the mixture was stirred for 1 day at the same temperature. The mixture was concentrated, and the insoluble material was filtered off. The filtrate was washed with saturated sodium bicarbonate solution, dried and
concentrated in vacuo to give 4-(2,6-dichlorobenzoylamino)-1-[2-[4-(succinimidooxycarbonyl)butanoyloxy]ethyl]-2-trifluoromethyl-1H-benzimidazole (274 mg).
NMR (CDCl3, δ) : 1.98 (2H, quint., J=7Hz), 2.40 (2H, t, J=7Hz), 2.64 (2H, t, J=7Hz), 2.84 (4H, s), 4.48 ( 2H, t , J=6Hz ) , 4 . 60 (2H, t, J=6Hz), 7 .25-7 . 43 ( 4H, m), 7 . 52 ( 1H, t , J=8Hz ) , 8 . 58 ( 1H, d, J=8Hz ) , 8 . 60 ( 1H, s ) (3) To a mixture of aminomethylenebis (phosphonic acid) (77 mg) and triethylamine (162 mg) in N,N-dimethylformamide (2 ml) and water (0.5 ml) was added a solution of 4-(2,6- dichlorobenzoylamino)-1-[2-[4-(succinimidooxycarbonyl)-butanoyloxy]ethyl]-2-trifluoromethyl-1H-benzimidazole (126 mg) in N,N-dimethylformamide (1 ml), and the mixture was stirred overnight at ambient temperature. To the residue was added 1N hydrochloric acid (1.6 ml), and the mixture was concentrated. The residue was treated according to a usual manner to give [4-[2-[4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazol-1-yl]ethyloxycarbonyl]-butanoylaminomethylene]bis(phosphonic acid) (31 mg).
NMR (DMSO-d6, δ) : 1.61 (2H, quint., J=7Hz), 2.10-2.25 (4H, m), 4.35-4.55 (3H, m), 4.70 (2H, t, J=6Hz), 7.42-7.57 (4H, m), 7.62 (1H, d, J=8Hz), 7.82 (1H, br d, J=8Hz), 8.22 (1H, d, J=8Hz)
Example 45
To a solution of 4-carboxy-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (100 mg) in
dichloromethane (1 ml) was added oxalyl chloride (71 mg), and the mixture was stirred for 10 minutes and then concentrated. To the residue were added 2-chloro-6-methylaniline (44 mg), triethylamine (57 mg) and dichloromethane (2 ml), and the mixture was stirred for 15 minutes. The mixture was washed with 1N sodium hydroxide solution, brine, 1N hydrochloric acid and brine, dried and concentrated to give 4-[N-(2-chloro-6-methylphenyl)carbamoyl]-1-(morpholinocarbonyl)-methyl-2-trifluoromethyl-1H-benzimidazole (98 mg).
mp : >250ºC
NMR (DMSO-d6, δ) : 2.30 (3H, s), 3.40-3.51 (2H, m), 3.55-3.78 (6H, m), 5.65 (2H, s), 7.27-7.38 (2H, m), 7.46 (1H, dd, J=8Hz, 2Hz), 7.69 (1H, t, J=8Hz), 8.09-8.18 (2H, m) Example 46
The following compounds were obtained according to a similar manner to that of Example 45.
(1) 4-[N-(2-Methoxy-6-methylphenyl)carbamoyl]-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole
mp : 240-246°C
NMR (DMSO-d6, δ) : 2.23 (3H, s), 3.42-3.50 (2H, m),
3.56-3.75 (6H, m), 3.78 (3H, s), 5.64 (2H, s), 6.92 (1H, d, J=8Hz), 6.97 (1H, d, J=8Hz), 7.22 (1H, t,
J=8Hz), 7.67 (1H, t, J=8Hz), 8.09 (1H, d, J=8Hz), 8.13 (1H, d, J=8Hz)
(2) 4-[N-(2,6-Dimethylphenyl)carbamoyl]-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole
mp : >250°C
NMR (DMSO-d6, δ) : 2.28 (6H, s), 3.44-3.50 (2H, m),
3.57-3.75 (6H, m), 5.64 (2H, s), 7.18 (3H, s), 7.68 (1H, t, J=8Hz), 8.07-8.13 (2H, m)
Example 47
(1) 2-Hydroxymethyl-4-nitro-1H-benzimidazole was obtained by reacting 3-nitro-1,2-phenylenediamine with glycolic acid according to a similar manner to that of Example 3-(1). mp : 206-207°C
NMR (DMSO-d6, δ) : 4.75 (2H, s), 5.63 (1H, br s), 7.39 (1H, t, J=7.5Hz), 8.05 (1H, d, J=7.5Hz), 8.11 (1H, d, J=7.5Hz) (2) 2-Hydroxymethyl-4-nitro-1-(2-oxopropyl)-1H-benzimidazole was obtained by reacting 2-hydroxymethyl-4-nitro-1H- benzimidazole with 2-oxopropyl chloride according to a similar manner to that of Example 5.
mp : 128-129°C
(3) 4-Amino-2-hydroxymethyl-1-(2-oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of Example 1-(1).
mp : 120-121°C
(4) 4-(2,6-Dichlorobenzoylamino)-2-hydroxymethyl-1-(2- oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of Example 1-(2).
mp : >250°C
NMR (DMSO-d6, δ) : 2.24 (3H, s), 4.63 (2H, d,
J=7.5Hz), 5.32 (2H, s), 5.63 (1H, t, J=7.5Hz), 7.10-7.30 (2H, m), 7.40-7.60 (3H, m), 8.05 (1H, d, J=7.5Hz), 10.83 (1H, s)
Example 48
(1) 4-(2,6-Dimethylbenzoylamino)-2-trifluoromethyl-1H- benzimidazole was obtained by reacting 4-amino-2- trifluoromethyl-1H-benzimidazole with 2,6- dimethylbenzoyl chloride according to a similar manner to that of Example 1-(2).
mp : 234-235°C
(2) 4-(2,6-Dimethylbenzoylamino)-1-(2-oxopropyl)-2- trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 206-207°C
NMR (DMSO-d6, δ) : 2.34 (3H, s), 5.55 (2H, s), 7.00- 7.20 (2H, m), 7.24 (1H, t, J=8Hz), 7.45 (1H, t, J=8Hz), 7.51 (1H, d, J=8Hz), 7.98 (1H, d, J=8Hz), 10 . 45 ( 1H, s )
(3) 1-(tert-Butoxycarbonyl)methyl-4-(2,6- dimethylbenzoylamino)-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 145-146°C
NMR (CDCl3, δ) : 1.44 (9H, s), 2.41 (6H, s), 4.92 (2H, s), 7.00-7.15 (3H, m), 7.23 (1H, d, J=8Hz), 7.50 (14H, t, J=8Hz), 8.54 (1H, s), 8.60 (1H, d, J=8Hz)
Example 49
(1) 4-(2,6-Dimethoxybenzoylamino)-2-trifluoromethyl-1H- benzimidazole was obtained by reacting 4-amino-2- trifluoromethyl-1H-benzimidazole with 2,6- dimethoxybenzoyl chloride according to a similar manner to that of Example 1-(2).
mp : 214-215°C (2) 4-(2,6-Dimethoxybenzoylamino)-1-(2-oxopropyl)-2- trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 226-227°C
NMR (DMSO-d6, δ) : 2.32 (3H, s), 3.76 (6H, s), 5.54
(2H, s), 6.73 (2H, d, J=8Hz), 7.37 (1H, t, J=8Hz),
7.40-7.50 (2H, m), 8.22 (1H, m), 9.95 (1H, s)
Example 50
(1) A suspension of 2-hydroxymethyl-4-nitro-1H-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 110ºC for 20 minutes and the insoluble solid was filtered and washed with hot water and a small amount of hot aqueous 1N 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-1H-benzimidazole (290 mg).
mp : 246-248°C (dec.)
(2) To a mixture of oxalyl chloride (0.063 ml), N,N-dimethylformamide (53 mg) and dichloromethane (3 ml) was added a solution of 2-carboxy-4-nitro-1H-benzimidazole (100 mg) in N,N-dimethylformamide, and the mixture was stirred for 1 hour at ambient temperature. The mixture was dropwise added to 28% aqueous ammonia (5 ml), and the mixture was adjusted pH 3 under ice-cooling. Water was added thereto, the resulting precipitate was collected by filtration to give 2-carbamoyl-4-nitro-1H-benzimidazole (53 mg).
mp : >250°C
(3) A mixture of 2-carbamoyl-4-nitro-1H-benzimidazole (136 mg) and 10% palladium on carbon (15 mg) in methanol (2 ml) was hydrogenated. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in 1,2-dichloroethane and to the solution were added
triethylamine (81 mg) and 2,6-dichlorobenzoyl chloride (166 mg). The solution was refluxed for 5 hours and cooled. The mixture was washed with 3.6% hydrochloric acid, aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was
crystallized from dichloromethane to give 2-carbamoyl-4-(2,6-dichlorobenzoylamino)-1H-benzimidazole (40 mg).
mp : >250°C
(4) 2-Carbamoyl-4-(2,6-cichlorobenzoylamino)-1-(2- oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 175-177°C
NMR (DMSO-d6, δ) : 1.60 (3H, s), 4.33 (1H, d, J=13Hz), 4.53 (1H, d, J=13Hz), 6.35 (1H, m), 7.30-7.80 (5H, m), 8.22 (1H, d, J=8Hz), 9.15 (1H, s), 11.22 (1H, s) Example 51
(1) A mixture of ethyl 2-amino-3-nitrobenzoate (1.09 g), 10% palladium on carbon (150 mg) in methanol was stirred for 5 hours at ambient temperature under hydrogen atmosphere.
Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by column
chromatography on silica gel (ethyl acetate : n-hexane = 1:2, V/V) to give ethyl 2,3-diaminobenzoate (0.87 g).
mp : 56-58°C
NMR (CDCl3, δ) : 1.38 (3H, t, J=7Hz), 4.33 (2H, q,
J=7Hz), 6.60 (1H, t, J=8Hz), 6.85 (1H, d, J=8Hz),
7.49 (1H, d, J=8Hz)
(2) 4-Ethoxycarbonyl-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of
Example 3-(1).
mp : 78-80ºC
NMR (CDCi3, δ) : 1.48 (3H, t, J=7Hz), 4.50 (2H, q,
J=7Hz), 7.45 (1H, t, J=8Hz), 8.08 (1H, d, J=8Hz), 8.11 (1H, d, J=8Hz)
(3) 4-Ethoxycarbonyl-1-(pyridin-4-yl)methyl-2- trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 125-126°C
NMR (CDCl3, δ) : 1.49 (3H, t, J=7Hz), 4.3 (2H, q,
J=7Hz), 5.59 (2H, s), 6.93 (2H, d, J=7Hz), 7.40- 7.50 (2H, m), 8.08 (1H, d, J=7Hz), 8.58 (2H, d, J=7Hz) (4) To a solution of 4-ethoxycarbonyl-1-(pyridin-4- yl)methyl-2-trifluoromethyl-1H-benzimidazole (282 mg) in methanol (2 ml) and tetrahydrofuran (1 ml) was added 1N sodium hydroxide (1 ml), and the mixture was stirred for 4 hours at ambient temperature. The solvent was removed, and the residue was dissolved in isopropyl alcohol (2 ml). Water was added thereto with stirring, and the resulting
precipitate was collected by filtration to give 4-carboxy-1- (pyridin-4-yl)methyl-2-trifluoromethyl-1H-benzimidazole (200 mg).
mp : 178-179°C
NMR (DMSO-d6, δ) : 5.84 (2H, s), 7.03 (2H, d, J=7Hz), 7.56 (1H, t, J=8Hz), 7.90-8.00 (2H, m), 8.52 (2H, d, J=7Hz) (5) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(pyridin-4- yl)methyl-2-trifluoromethyl-1H-benzimidazole was
obtained according to a similar manner to that of
Example 45.
mp : 187-188°C
NMR (CDCl3, δ) : 5.63 (2H, s), 7.02 (2H, d, J=7Hz),
7.22 (1H, d, J=8Hz), 7.40-7.50 (3H, m), 7.58 (1H, t, J=8Hz), 8.42 (1H, d, J=7Hz), 8.63 (2H, d,
J=7Hz), 11.09 (1H, s) its hydrochloride
mp : 163-244ºC
NMR (DMSO-d6, δ) : 6.10 (2H, s), 7.45 (1H, t, J=8Hz), 7.53 (2H, d, J=7Hz), 7.60-7.80 (3H, m), 8.06 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz), 8.73 (2H. d,
J=7Hz), 10.93 (1H, s)
Example 52
(1) 1-tert-Butoxycarbonylmethyl-4-ethoxycarbonyl-2- trifluoromethyl-1H-benzimidazole was obtained by
reacting 4-ethoxycarbonyl-2-trifluoromethyl-1H- benzimidazole with tert-butyl bromoacetate according to a similar manner to that of Example 5.
mp : 122-124°C
NMR (CDCl3, δ) : 1.40 (9H, s), 1.47 (3H, t, J=7Hz), 4.51 (2H, q, J=7Hz), 4.95 (2H, s), 7.51 (1H, t,
J=8Hz), 7.57 (1H, d, J=8Hz), 8.08 (1H, d, J=8Hz)
(2) 1-Carboxymethyl-4-ethoxycarbonyl-2-trifluoromethyl-1H- benzimidazole trifluoroacetate was obtained according to a similar manner to that of Example 9.
mp : 118-120°C
NMR (CDCl-d3, δ) : 1.46 (3H, t, J=7Hz), 4.51 (2H, q, J=7Hz), 5.06 (2H, s), 7.51 (1H, t, J=8Hz), 7.59 (1H, d, J=8Hz), 8.07 (1H, d, J=8Hz)
(3) 4-Ethoxycarbonyl-1-(morpholinocarbonyl)methyl-2- trifluoromethyl-1H-benzimidazole was obtained from 1- carboxymethyl-4-ethoxycarbonyl-2-trifluoromethyl-1H- benzimidazole trifluoroacetate and morpholine according to a similar manner to that of Example 14.
mp : 168-169°C
NMR (CDCl3, δ) : 1.47 (3H, t, J=7Hz), 3.0-3.90 (8H,
m), 4.51 (2H, q, J=7Hz), 5.12 (2H, s), 7.48 (1H, t, J=8Hz), 7.52 (1H, d, J=8Hz), 8.05 (1H, d, J=8Kz)
(4) 4-Carboxy-1-(morpholinocarbonyl)methyl-2- trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 51-(4).
NMR (DMSO-d6, δ) : 3.40-3.80 (8H, m), 5.55 (2H, s),
7.55 (1H, t, J=8Hz), 7.92 (1H, d, J=8Hz), 8.02 (1H, d, J=8Hz)
(5) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 45.
mp : >250°C
NMR (CDCl3, δ) : 3.40-3.80 (8H, m), 5.65 (2H, s), 7.44 (1H, t, J=8Hz), 7.60-7.80 (3H, m), 8.10-8.20 (2H, m), 10.95 (1H, s)
Example 53
(1) 4-Methyl-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 3-methyl-1,2-phenylenediamine with
trifluoroacetic acid according to a similar manner to that of Example 3-(1).
mp : 147-148ºC
(2) A suspension of 4-methyl-2-trifluoromethyl-1H-benzimidazole (200 mg) in a mixture of tert-butanol and water was refluxed. The suspension was added potassium
permanganate (600 mg) portionwise and the mixture was
refluxed for 2 hours. The insoluble solid was filtered off and the filtrate was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The
crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-carboxy-2-trifluoromethyl-1H-benzimidazole (132 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 7.45 (1H, t, J=8Hz),
8.00-8.20 (2H, m) (3) A mixture of 4-carboxy-2-trifluoromethyl-1H-benzimidazole (100 mg), chloroacetone (179 mg) and potassium carbonate (179 mg) in N,N-dimethylformamide was stirred at 60°C for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained solid was triturated with diisopropyl ether to give 1-(2-oxopropyl)-4-(2- oxopropoxycarbonyl)-2-trifluoromethyl-1H-benzimidazole (79 mg).
mp : 160-162°C
NMR (CDCl3, δ) : 2.29 (3H, s), 2.36 (3H, s), 4.98 (2H, s), 5.13 (2H, s), 7.40-7.60 (2H, m), 8.67 (1H, d, J=8Hz)
(4) To a solution of 1-(2-oxopropyl)-4-(2- oxcpropoxycarbonyl)-2-trifluoromethyl-1H-benzimidazole (145 mg) in methanol was added 1N sodium hydroxide solution (1 ml), and the mixture was stirred for 6 hours at ambient temperature. The solvent was removed, and the residue was acidified with hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-carboxy-1-(2-oxopropyl)-2-trifluoromethyl-1H-benzimidazole (31.3 mg).
mp : 170-172°C
NMR (CDCl3-CD3OD, δ) : 2.37 (3H, s), 5.22 (2H, s),
7.54 (1H, t, J=8Hz), 7.61 (1H, d, J=8Hz), 8.23 (1H, d, J=8Hz)
(5) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(2-oxopropyl)-2- trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 45.
mp : 223-225°C
NMR (CDCl3, δ) : 2.35 (3H, s), 5.18 (2H, s), 7.22 (1H, t, J=8Hz), 7.40-7.50 (3H, m), 7.61 (1H, t, J=8Hz), 8.40 (1H, d, J=8Hz), 11.07 (1H, s)
Example 54
(1) A mixture of 3-nitro-1,2-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-1H-benzimidazole (265 mg).
mp : 136-137ºC
NMR (DMSO-d6, δ) : 7.32 (1H, t, J=52Hz), 7.53 (1H, t, J=8Hz), 8.23 (1H, d, J=8Hz), 8.27 (1H, d, J=8Hz)
(2) 4-Amino-2-difluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 3-(2). mp : 120-124°C
NMR (CD3OD, δ) : 6.37 (1H, d, J=8Hz), 6.68 (1H, d, J=3Hz), 6.77 (1H, t, J=52Hz), 6.88 (1H, t, J=8Hz)
(3) 4-(2,6-Dichlorobenzoylamino)-2-difluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 1-(2).
mp : 178-180°C
(4) 1-tert-Butoxycarbonylmethyl-4-(2,6- dichlorobenzoylamino)-2-difluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 196-197°C
.NMR (CDCl3, δ) : 1.45 (9H, s), 4.97 (2H, s), 6.87 (1H, t, J=52Hz), 7.13 (1H, d, J=8Hz), 7.30-7.40 (3H, m), 7.46 (1H, z, J=8Hz), 8.52 (1H, d, J=8Hz), 8.54 (1H, br s)
(5) 1-Carboxymethyl-4-(2,6-dichlorobenzoylamino)-2- difluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 9.
mp : >250°C NMR (CDCl3+CD3OD, δ) : 5.07 (2H, s), 6.88 (1H, t,
J=52Hz), 7.16 (1H, d, J=8Hz), 7.30-7.40 (3H, m), 7.47 (1H, t, J=8Hz), 8.55 (1H, d, J=8Hz) (6) 4-(2,6-Dichlorobenzoylamino)-2-difluoromethyl-1- (morpholinocarbonyl)methyl-1H-benzimidazole was obtained according to a similar manner to that of Example 14. mp : 216-217°C
NMR (DMSO-d6, δ) : 3.40-3.80 (8H, m), 5.44 (2H, s), 7.29 (1H, t, J=53Hz), 7.60-7.30 (5H, m), 8.16 (1H, d, J=8Hz), 11.05 (1H, s)
Example 55
(1) A mixture of 3-nitro-1,2-phenylenediamine (500 mg) and tetramethyl orthocarbonate (533 mg) in acetic acid (5 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated in vacuo and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, 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 diisopropyl ether to give 2-methoxy-4-nitro-1H-benzimidazole (479 mg). mp : 171-172°C
NMR (CDCl3, δ) : 4.24 (3H, s), 7.26 (1H, t, J=8Hz),
7.82 (1H, d, J=8Hz), 8.00 (1H, d, J=8Hz), 9.69 (1H, m)
(2) 2-Methoxy-4-nitro-1-(2-oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of
Example 5.
mp : 184-187°C
NMR (CDCl3, δ) : 2.24 (3H, s), 4.33 (3H, s), 4.79 (2H, s), 7.18-7.28 (2H, m), 8.03 (1H, d, J=8Hz) (3) 4-Amino-2-methoxy-1-(2-oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of
Example 1-(1).
NMR (CDCl3, δ) : 2.11 (3H, s), 3.70 (3H, s), 4.60 (2H, s), 6.43 (1H, d, J=8Hz), 6.51 (1H, d, J=8Hz), 6.95 (1H, t, J=8Hz)
(4) 4-(2,6-Dichlorobenzoylamino)-2-methoxy-1-(2-oxopropyl)- 1H-benzimidazoie was obtained according to a similar manner to that of Example 1-(2).
mp : 175-177°C
NMR (CDCl3, δ) : 2.20 (3H, s), 4.14 (3H, s), 4.68 (2H, s), 6.81 (1H, d, J=8Hz), 7.20 (1H, t, J=8Hz), 7.30- 7.43 (3H, m), 8.35-8.40 (2H, m) Example 56
(1) A mixture of 3-nitro-1,2-phenylenediamine (2.0 g), carbon disulfide (3.99 g) and potassium hydroxide (807 mg) in a mixture of ethanol (17 ml) and water (3 ml) was refluxed for 5 hours. The reaction mixture was diluted with water (20 ml) and the mixture was adjusted to pH 5 with 1N hydrochloric acid. The separated solid was collected and washed with water to give 2-mercapto-4-nitro-1H-benzimidazole (2.442 g). mp : >250°C
NMR (DMSO-d6, δ) : 7.30 (1H, t, J=8Hz), 7.51 (1H, d,
J=8Hz), 7.94 (1H, d, J=8Hz)
(2) A mixture of 2-mercapto-4-nitro-1H-benzimidazole (400 mg) and 1-bromo-3-chloropropane (341 mg) in a mixture of 1N aqueous sodium hydroxide (2.2 ml) and N,N-dimethylformamide (6 ml) was stirred at 70°C for 1 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated, washed witn brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatograpny on silica gel to give 2-(3-chloropropylthio)-4-nitro-1H-benzimidazole (200 mg). NMR (CDCl3, δ) : 2.30-2.40 (2H, m), 3.56 (2H, t,
J=5Hz) , 3.72 (2H, t, J=5Hz), 7.31 (1H, t, J=8Hz), 7.96 (1H, d, J=8Hz), 8.08 (1H, d, J=8Hz), 10.31 (1H, m)
(3) A mixture of 2- (3-chloropropylthio)-4-nitro-1H-benzimidazole (190 mg), potassium carbonate (145 mg) and tetrabutylammonium iodide (10 mg) in N,N-dimethylformamide (3 ml) was stirred at ambient temperature for 3 hours and poured into a mixture of ice and water. The separated solid was collected, dried and purified by column chromatography on silica gel. The obtained oil was crystallized from a mixture of ethanol and water to give 3,4-dihydro-9-nitro-2H-[1,3]thiazino[3,2-a]benzimidazole (110 mg).
mp : 154-155°C
NMR (CDCl3, δ) : 2.49-2.58 (2H, m), 3.27-3.32 (2H, m), 4.27 (2H, t, J=5Hz), 7.24 (1H, t, J=8Hz), 7.50 (1H, d, J=8Hz), 8.08 (1H, d, J=8Hz) (4) 9-Amino-3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole was obtained according to a similar manner to that of
Example 3-(2).
mp : 160-162°C
NMR (CDCl3, δ) : 2.42-2.51 (2H, m), 3.20-3.26 (2H, m), 4.14 (2H, t, J=5Hz), 4.18-4.30 (2H, m), 6.52 (1H, d, J=8Hz), 6.64 (1H, d, J=8Hz), 7.00 (1H, t, J=8Hz)
(5) 9-(2,6-Dichlorobenzoylamino)-3,4-dihydro-2H- [1,3]thiazino[3,2-a]benzimidazole was obtained according to a similar manner to that of Example 1-(2).
mp : >250°C
NMR (DMSO-d6, δ) : 2.35-2.46 (2H, m), 3.39-3.45 (2H, m), 4.29-4.37 (2H, m), 7.38 (1H, t, J=8Hz), 7.44- 7.60 (4H, m), 7.98 (1H, d, J=8Hz), 11.10 (1H, br s) Example 57
(1) 2-Methylthio-4-nitro-1H-benzimidazole was obtained by reacting 2-mercapto-4-nitro-1H-benzimidazole with methyl iodide according to a similar manner to that of Example 56-(2).
mp : 163-166ºC
NMR (CDCl3, δ) : 2.84 (3H, s), 7.30 (1H, t, J=8Hz),
7.97 (1H,d, J=8Hz), 8.08 (1H, d, J=8Hz), 10.29 (1H, m)
(2) 4-Amino-2-methylthio-1H-benzimidazole was obtained
according to a similar manner to that of Example 3-(2). NMR (CDCl3, δ) : 2.63 (3H, s), 4.12-4.42 (2H, m), 6.51
(1H, d, J=8Hz), 6.76 (1H, d, J=8Hz), 7.00 (1H, t, J=8Hz)
(3) 4-(2,6-Dichlorobenzoylamino)-2-methylthio-1H- benzimidazole was obtained according to a similar manne: to that of Example 1-(2).
mp : 238-242°C
NMR (DMSO-d6, δ) : 2.70 (3H, s), 7.12 (1H, t, J=8Hz), 7.22 (1H, m), 7.42-7.60 (3H, m), 7.90 (1H, m), 10.60 (1H, m), 12.60 (1H, m) (4) 4-(2,6-Dichlorobenzoylamino)-2-methylthio-1-(2- oxopropyl)-1H-benzimidazole hydrochloride was obtained according to a similar manner to that of Example 5.
mp : 221.5-223ºC
NMR (DMSO-d6, δ) : 2.30 (3H, s), 2.76 (3H, s), 5.30
(2H, s), 7.20-7.34 (2H, m), 7.44-7.60 (3H, m), 8.08
(1H, d, J=8Hz), 10.83 (1H, br s)
Example 58
(1) To a solution of 4-(2,6-dichlorobenzoylamino)-2-methylthio-1H-benzimidazole (100 mg) in dichloromethane (2 ml) was added a solution of hydrogen peroxide in
trifluoroacetic acid (1M 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. The residue was crystallized from ethyl acetate to give 4-(2,6-dichlorobenzoylamino)-2-methylsulfonyi-1H- benzimidazole (79 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 3.08 (3H, s), 7.34 (1H, t, J=8Hz), 7.40-7.64 (4H, m), 8.20 (1H, d, J=8Hz), 10.84 (1H, m) (2) 4-(2,6-Dichlorobenzoylamino)-2-methylsulfonyl-1-(2- oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 232-233°C
NMR (CDCl3, δ) : 2.35 (3K, s), 3.16 (3H, s), 5.26 (1H, d, J=18Hz), 5.54 (1H, d, J=18Hz), 7.04 (1H, d,
J=8Hz), 7.30-7.46 (4H, m), 8.48-8.54 (2H, m)
Example 59
(1) A mixture of 2-mercapto-4-nitro-1H-benzimidazole (400 mg) and 2-oxopropyl chloride (248 mg) in ethanol (6 ml) was refluxed for 18 hours. After cooling, the mixture was adjusted pH 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)-1H-benzimidazole (388 mg).
mp : 228-231°C (dec.)
NMR (CDCl3, δ) : 2.42 (3H, s), 4.26 (2H, s), 7.31 (1H, t, J=8Hz), 7.92 (1H, d, J=8Hz), 8.07 (1H, d, J=8Hz) (2) A suspension of 4-nitro-2-(2-oxopropylthio)-1H-benzimidazole (200 mg) in 1N hydrochloric acid (15 ml) was refluxed for 18 hours. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate. The separated solid was collected, dried and purified by column
chromatography on silica gel. The obtained oil was
crystallized from diisopropyl ether to give 3-methyl-8-nitrothiazolo[3,2-a]benzimidazoie (86 mg).
mp : 240-242°C
NMR (CDCl6, δ) : 2.80 (2H, s), 6.56 (1H, s), 7.33
(1H, t, J=8Hz), 8.10 (1H, d, J=8Hz), 8.30 (1H, d, J=8Hz)
(3) A mixture of 3-methyl-8-nitrothiazolo[3,2-a]-benzimidazole (80 mg), reduced iron (96 mg) and acetic acid (412 mg) in dioxane (1.6 ml) and ethanol (116 ml) was refluxed for 30 minutes. After cooling, the mixture was diluted with ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated sodium-bicarbonate solution. The organic layer was washed with brine, dried and concentrated in vacuc to give 8-amino-3-methylthiazoio[3,2-a]benzimidazole (58 mg).
mp : 155-157°C
NMR (CDCl3, δ) : 2.70 (3H, s), 4.29-4.42 (2H, m), 6.30
(1H, s), 6.75 (1H, d, J=8Hz), 7.05 (1H, t, J=8Hz), 7.20 (1H, d, J=8Hz)
(4) 8-(2,6-Dichlorobenzoylamino)-3-methylthiazolo[3,2-a]- benzimidazole was obtained according to a similar manner to that of Example 1-(2).
mp : >250ºC
NMR (DMSO-d6, δ) : 2.78 (3H, s), 7.03 (1H, s), 7.36 (1H, t, J=8Hz), 7.48-7.60 (3H, m), 7.86 (1H, d, J=8Hz), 8.09 (1H, d, J=8Hz), 11.10 (1H, br s) Example 60
(1) A mixture of 3-nitro-1,2-phenylenediamine (400 mg) and methyl isothiocyanate (420 mg) in ethanol (4 ml) was stirred at 50°C for 3 hours. To the reaction mixture was added water and the separated solid was collected to give 1-(2-amino-3- nitrophenyl)-3-methylthiourea (441 mg).
mp : >250°C
NMR (CDCl3, δ) : 3.14 (3H, d, J=3Hz), 5.74 (1H, m),
6.32-6.52 (2H, m), 6.76 (1H, t, J=8Hz), 7.26 (1H, m), 7.44 (1H, d, J=8Hz), 8.22 (1H, d, J=8Hz)
(2) A mixture of 1-(2-amino-3-nitrophenyl)-3-methylthiourea (340 mg) and iodomethane (639 mg) in acetonitrile (7 ml) was stirred at 50ºC for 8 hours and refluxed for 18 hours. The reaction mixture was cooled, evaporated in vacuo and diluted with dichloromethane. The solution was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtain oil was crystallized from a mixture of ethyl acetate and hexane (1:4, V/V) to give 2-methylamino-4-nitro- 1H-benzimidazole (103 mg).
mp : 250-252°C
NMR (CDCl3:CD3OD = 20:1, δ) : 3.10 (3H, s), 7.11 (1H, t, J=8Hz), 7.61 (1H, m), 7.80 (1H, d, J=8Hz)
(3) 2-Methylamino-4-nitro-1-(2-oxopropyl)-1H-benzimidazole was obtained according to a similar manner to that of Example 5.
mp : 198-200°C
NMR (DMSO-d6, δ) : 2.22 (3H, s), 2.98 (3H, d, J=5Hz),
5.05 (2H, s), 6.98 (1H, t, J=8Hz), 7.23 (1H, m), 7.43 (1H, d, J=8Hz), 7.75 (1H, d, J=8Hz)
(4) A mixture of 2-methylamino-4-nitro-1-(2-oxopropyl)-1H-benzimidazole (40 mg) and cone, hydrochloric acid (0.13 ml) in ethanol (1 ml) was stirred at 60°C for 1 hour. To the mixture was added iron powder (36 mg) and the mixture was refluxed for 3 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was treated with methanolic hydrogen chloride to give 8-amino- 1,2-dimethyl-1H-imidazo[1,2-a]benzimidazole hydrochloride (38 mg).
NMR (CDCl3-CD3OD, 20:1, δ) : 2.47 (3H, s), 3.91 (3H, s), 7.22 (1H, d, J=8Hz), 7.35 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.54 (1H, s)
(5) 8-(2,6-Dichlorobenzoylamino)-1,2-dimethyl-1H- imidazo[1,2-a]benzimidazole hydrochloride was obtained according to a similar manner to that of Example 1-(2). mp : >250°C
NMR (DMSO-d6, δ) : 2.40 (3H, s), 3.76 (3H, s), 7.42
(1H, t, J=8Hz), 7.52-7.66 (3H, m), 7.82 (1H, d, J=8Hz), 7.94 (1H, s), 8.18 (1H, d, J=8Hz), 11.02
(1H, br s)
Example 61
(1) A mixture of 4-amino-1H-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-1-(2,6-dichlorobenzoyl)-1H-benzimidazole (251 mg).
mp : 141-149ºC
NMR (CDCl3, δ) : 4.38-4.48 (2H, m), 6.73 (1H, d,
J=8Hz), 7.30 (1H, t, J=8Hz), 7.47-7.51 (3H, m), 7.57 (1H, br s), 7.80 (1H, d, J=3Hz) (2) 1-(2,6-Dichlorobenzoyl)-4-(2,6-dichlorobenzoylamino)-1H- benzimidazole was obtained according to a similar manner to that of Example 1-(2).
NMR (CDCl3, δ) : 6.30-7.42 (3H, m), 7.48-7.66 (5H, m), 8.22 (1H, m), 8.56 (1H, m), 8.64 (1H, m)
(3) A mixture of 1-(2,6-dichlorobenzoyl)-4-(2,6- dichlorobenzoylamino)-1H-benzimidazole (380 mg) and 1N aqueous sodium hydroxide solution (1 ml) in ethanol (4 ml) was stirred at ambient temperature for 30 minutes and at 60°C for 1 hour. The mixture was neutralized with 1N hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo to give 4-(2,6-dichlorobenzoylamino)-1H-benzimidazole (111 mg).
mp : >250ºC
NMR (CDCl3-CD3OD, δ) : 7.26-7.44 (5H, n), 7.94 (1H,
m), 8.44 (1H, m)
(4) 4-(2,6-Dichlorobenzoylamino)-1-(2-oxopropyl)-1H- benzimidazole hydrochloride was obtained according to a similar manner to that of Example 5.
mp : 227-229°C
NMR (DMSO-d6, δ) : 2.32 (3K, s), 5.54 (2H, s), 7.46- 7.64 (5K, m), 8.04 (1H, d, J=8Hz), 9.00 (1H, m), 11.28 (1H, br s)
Example 62
(1) 1-(tert-Butoxycarbonyl)methyl-2-tert-butoxycarbonylmethoxycarbonyl-4-nitro-1H-benzimidazole was obtained by reacting 2-carboxy-4-nitro-1H-benzimidazole with tert- butyl bromoacetate according to a similar manner to that of Example 5.
mp : 149-151°C
NMR (CDCl3. δ) : 1.44 (9H, s), 1.49 (9H, s), 4.36 (2H, s), 5.33 (2H, s), 7.57 (1H, t, J=8Hz), 7.72 (1H, d, J=8Hz), 8.25 (1H, d, J=8Hz)
(2) To a mixture of cone, aqueous ammonia (5 ml), N,N- dimethylformamide (15 ml) and tetrahydrofuran (5 ml) was added a solution of 1-(tert-butoxycarbonyl)methyl-2-tert-butoxycarbonylmethoxycarbonyl-4-nitro-1H-benzimidazole (1.4 g) in N,N-dimethylformamide (5 ml) at 0°C, and the mixture was stirred for 30 minutes at the same temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 1-(tert-butoxycarbonyl)methyl-2-carbamoyl-4-nitro-1H-benzimidazole (939 mg).
mp : 201-202ºC
NMR (CDCl3-CD3OD, δ) : 1.47 (9H, s), 5.44 (2H, s),
7.55 (1H, t, J=8Hz), 7.73 (1H, d, J=8Hz), 8.28 (1H, d, J=8Hz)
(3) To a solution of 1-(tert-butoxycarbonyl)methyl-2-carbamoyl-4-nitro-1H-benzimidazole (500 mg) in N,N-dimethylformamide (5 ml) was dropwise added thionyl chloride (223 mg), and the mixture was stirred for 3 hours at ambient temperature. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate : n-hexane = 2:3, V/V) to give 1-(tert-butoxycarbonyl)methyl-2-cyano-4-nitro-1H-benzimidazole (349 mg).
mp : 136-138°C
NMR (CDCl3, δ) : 1.48 (9H, s), 7.65 (1H, t, J=8Hz),
7.72 (1H, d, J=8Hz), 8.32 (1H, d, J=8Hz)
(4) 4-Amino-1-(tert-butoxycarbonyl)methyl-2-cyano-1H- benzimidazole was obtained according to a similar manner to that of Example 1-(1).
mp : 160-162°C
NMR (CDCl3, δ) : 1.47 (9H, s), 4.52 (2H, br s), 4.40
(2H, s), 6.59 (1H, d, J=8Hz), 6.66 (1H, d, J=8Hz), 7.26 (1H, t, J=8Hz)
(5) 1-(tert-Butoxycarbonyl)methyl-2-cyano-4-(2,6- dichlorobenzoylamino)-1H-benzimidazole was obtained according to a similar manner to that of Example 1-(2). mp : 187-189°C
NMR (CDCl3, δ) : 1.49 (9H, s), 4.97 (2H, s), 7.23 (1H, d, J=8Hz), 7.30-7.50 (2H, m), 7.55 (1H, t, J=8Hz), 8.50-8.60 (2H, m) (6) 1-Carboxymethyl-2-cyano-4-(2,6-dichlorobenzoylamino)-1H- benzimidazole was obtained according to a similar manner to that of Example 9.
mp : 218-221°C
NMR (DMSO-d6, δ) : 5.40 (2H, s), 7.40-7.65 (5H, m),
8.77 (1H, d, J=8Hz)
Example 63
The following compounds were obtained according to a similar manner to that of Example 14.
(1) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1- (morpholinocarbonyl)methyl-1H-benzimidazole
(from 1-carboxymethyl-2-cyano-4-(2,6- dichlorobenzoylamino)-1H-benzimiazole and morpholine) mp : >250°C
NMR (DMSO-d6, δ) : 3.49 (2H, m), 3.50-3.70 (4H, m),
3.73 (2H, m) , 5.60 (2H, s), 7.40-7.60 (5H, m), 8.25 (1H, m) (2) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1-[N-(5- trifluoromethyl-1,3,4-thiadiazol-2-yl)carbamoylmethyl]- 1H-benzimidazole
(from 1-carboxymethyl-2-cyano-4-(2,6- dichlorobenzoyiamino)-1H-benzimidazole and 2-amino-5- trifluoromethyl-1,3,4-thiadiazole)
mp : >250°C
NMR (DMSO-d6, δ) : 5.65 (2H, s), 7.40-7.60 (5H, m),
8.27 (1H, m) (3) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1-[N-(2- hydroxyethyl)carbamoylmethyl]-1H-benzimiazole
(from 1-carboxymethyl-2-cyano-4-(2,6- dichlcrobenzoylamino)-1H-benzimidazole and (2- hydroxyethyl)amine)
mp : 222-224°C
NMR (DMSO-d6, δ) : 3.19 (2H, m), 3.45 (2H, m), 4.78 (1H, t, J=6Hz), 5.17 (2H, s), 7.40-7.60 (5H, m), 8.25 (1H, d, J=8Hz), 8.56 (1H, t, J=6Hz) (4) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1-[N-(pyridin-2- ylmethyl)carbamoylmethyl]-1H-benzimidazole hydrochloride (from 1-carboxymethyl-2-cyano-4-(2,6- dichlorobenzoylamino)-1H-benzimidazole and 2- aminomethylpyridine)
mp : 215-237°C (dec.)
NMR (DMSO-d6, δ) : 4.63 (2H, d, J=6Hz), 5.37 (2H, s), 7.40-7.80 (7H, m), 8.15-8.30 (2H, m), 8.72 (1H, d, J=5Hz), 9.38 (1H, t, J=6Hz) (5) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1-[N-(2- methoxyethyl)carbamoylmethyl]-1H-benzimidazole
(from 1-carboxymethyl-2-cyano-4-(2,6- dichlorobenzoylamino)-1H-benzimidazole and (2- methoxyethyl)amine)
mo : 196°C NMR (DMSO-d6, δ) : 3.28 (3H, s), 3.28-3.35 (2H, m),
3.39 (2H, t, J=5Hz), 5.17 (2H, s), 7.40-7.60 (5H, m), 8.26 (1H, d, J=8Hz), 8.65 (1H, t, J=5Hz) (6) 2-Cyano-4-(2,6-dichlorobenzoylamino)-1-(N- cyclopentylcarbamoylmethyl)-1H-benzimidazole
(from 1-carboxymethyl-2-cyano-4-(2,6-dichlorobenzoylamino)-1H-benzimidazole and cyclopentylamine)
mp : 217-219ºC
NMR (DMSO-d6, δ) : 1.30-1.90 (8H, m), 4.03 (1H, m),
5.11 (2H, s), 7.40-7.60 (5H, m), 8.26 (1H, d, J=8Hz), 8.52 (1H, d, J=7Hz)
Example 64
The following compounds were obtained according to a similar manner to that of Example 5.
(1) 4-(2,6-Dichlorobenzoylamino)-1-methoxymethyl-2- trifluoromethyl-1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and chloromethyl methyl ether)
mp : 153-155°C
NMR (CDCl3, δ) : 3.36 (3H, s), 5.65 (2H, s), 7.30-7.43 (4H, m), 7.52 (1H, t, J=8Hz), 8.58 (1H, d, J=8Hz), 8.61 (1H, s)
(2) 4-(2,6-Dichlorobenzoylamino)-1-allyl-2-trifluoromethyl- 1H-benzimidazole
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and allyl bromide)
mp : 120-122°C
NMR (CDCl3, δ) : 4.44 (2H, d, J=5Hz), 5.17 (1H, d,
J=16Hz), 5.31 (1H, d, J=10Hz), 5.98 (1H, m), 7.21 (1H, d, J=8Hz), 7.31-7.43 (3H, m), 7.50 (1H, t, J=8Hz), 8.59 (1H, d, J=8Hz), 8.65 (1H, br s) (3) 4-(2,6-Dichlorobenzoylamino)-1-(3,4- methylenedioxybenzyl)-2-trifluoromethyl-1H-benzimidazole (from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 3,4-(methylenedioxy)benzyl chloride) mp : 97-101°C
NMR (CDCl3, δ) : 5.42 (2H, s), 5.94 (2H, s), 6.58 (1H, s), 6.64 (1H, d, J=8Kz), 6.76 (1H, d, J=8Hz), 7.09 (1H, d, J=8Hz), 7.30-7.45 (4K, m), 8.55 (1H, d, J=8Hz), 8.63 (1H, br s)
(4) 4-(2,6-Dichlorobenzoylamino)-1-(5-methylimidazol-4- yl)methyl-2-trifluoromethyl-1H-benzimidazole
hydrochloride
(from 4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H- benzimidazole and 1-(p-toluenesulfonyl)-4-chloromethyl- 5-methylimidazole)
mp : 212-216°C
NMR (DMSO-d6, δ) : 2.26 (3H, s), 5.80 (2H, s), 7.38
(1H, d, J=8Hz), 7.47 (1H, d, J=8Hz), 7.50-7.57 (3H, m), 8.26 (1H, d, J=8Hz), 9.02 (1H, s)
(5) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(2-methylimidazoI- 3-yl)methyl-2-trifluoromethyl-1H-benzimidazole
(from 4-[N-(2,6-dichlorophenyl)carbamoyl]-2- trifluoromethyl-1H-benzimidazole and 1-(p- toluenesulfonyl)-4-chloromethyl-5-methylimidazole) mp : 203-204°C
NMR (DMSO-d6, δ) : 2.30 (3H, s), 5.58 (2H, s), 7.51
(1H, s), 7.53 (1H, t, J=8Hz), 7.63 (2H, d, J=8Hz), 7.66 (1H, t, J=8Hz), 8.11 (1H, d, J=8Hz), 8.15 (1H, d, J=8Hz)
Example 65
(1) 1-tert-Butoxycarbonylmethyl-4-nitro-2-trifluoromethyl- 1H-benzimidazole was obtained by reacting 4-nitro-2- trifluoromethyl-1H-benzimidazole with tert-butyl bromoacetate according to a similar manner to that of Example 5.
mp : 163-168°C
NMR (CDCl3, δ) : 1.42 (9H, s), 5.01 (2H, s), 7.60 (1H, t, J=8Hz), 7.71 (1H, d, J=8Hz), 8.27 (1H, d,
J=8Hz)
(2) 1-Carboxymethyl-4-nitro-2-trifluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 9.
mp : 223-224°C
NMR (DMSO-d6, δ) : 5.43 (2H, s), 7.72 (1H, t, J=8Hz), 8.28 (1H, d, J=8Hz), 8.39 (1H, d, J=8Hz)
(3) 1-(Morpholinocarbonyl)methyl-4-nitro-2-trifluoromethyl- 1H-benzimidazole was obtained according to a similar manner to that of Example 14
mp : 212-214°C
NMR (CDCl3, δ) : 3.58-3.69 (4H, m), 3.69-3.86 (4H, m),
5.17 (2H, s), 7.56 (1H, t, J=8Hz), 7.68 (1H, d, J=8Hz), 8.23 (1H, d, J=8Hz)
(4) 4-Amino-1-(morpholinocarbonyl)methyl-2-trifluoromethyl- 1H-benzimidazole was obtained according to a similar manner to that of Example 59-(3).
mp : 202-205°C
NMR (CDCl3, δ) : 3.52-3.69 (4H, m), 3.69-3.81 (4H, m), 4.47 (2H, br s), 5.00 (2H, s), 6.58 (1H, d, J=8Hz), 6.52 (1H, d, J=8Hz), 7.20 (1H, t, J=8Hz)
(5) A mixture of 2,6-dichloro-3-formylbenzoic acid (63 mg) and thionyl chloride (725 mg) in toluene (1 ml) was refluxed for 1.5 hours. After concentration of the mixture, the residue was dissolved in dichloromethane (1 ml) and to the solution was added 4-amino-1-(morpholinocarbonyl)methyl-2- trifluoromethyl-1H-benzimidazole (80 mg) and triethylamine (57 mg) with ice cooling. After stirring for 3 hours at ambient temperature, the resulting mixture was purified by column chromatography on silica gel (1% methanol in
dichloromethane). The obtained solid was triturated with diethyl ether to give 4-(2,6-dichloro-3-formylbenzoylamino)- 1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazoie (56 mg).
mp : 189-192°C
NMR (CDCl3, δ) : 3.57-3.70 (4H, m), 3.70-3.85 (4H, m), 5.11 (2H, s), 7.20-7.29 (2H, m), 7.44-7.51 (2H, m), 8.48 (1H, d, J=8Kz), 9.65 (1H, s) (6) A mixture of 4-(2,6-dichloro-3-formylbenzoylamino)-1-morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (100 mg) and sodium borohydride (11 mg) in ethanol (2 ml) and tetrahydrofuran (1 ml) was stirred for 6 hours at ambient temperature. To the resulting mixture was added water and the separated solid was collected to give 4-(2,6-dichloro-3-hydroxymethylbenzoylamino)-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (87 mg).
mp : >260°C
NMR (DMSO-d6, δ) : 3.41-3.49 (2H, m), 3.55-3.67 (4K, m), 3.67-3.73 (2H, m), 4.59 (2H, d, J=6Hz), 5.50
(2H, s), 5.60 (1H, d, J=6Hz), 7.47 (1H, t, J=8Hz), 7.50 (1H, d, J=8Hz), 7.53 (1H, d, J=8Hz), 7.61 (1H, d, J=8Hz), 8.22 (1H, d, J=8Hz) (7) A mixture of 4-(2,6-dichloro-3-formyylbenzoylamino)-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (100 mg) and ethyl (triphenylphosphoranylidene) acetate (79 mg) was stirred for 1.5 hour at ambient temperature. The resulting mixture was purified by column chromatography on silica gel (0.5%-1% methanol in dichloromethane). The obtained oil was crystallized from a mixture of ethanol and water to give (E)-4-[2,6-dichloro-3-(2- ethoxycarbcnylethenyl)benzoylamino]-1-(morpholinocarbonyl)- methyl-2-trifluoromethyl-1H-benzimidazole (96 mg).
mp : 258-260°C
NMR (CDCl3, δ) : 1.24 (0.75H, t, J=7Hz), 1.37 (2.25H, t, J=7Hz), 3.57-3.70 (4H, m), 3.70-3.86 (4H, m), 4.19 (0.5H, q, J=7Hz), 4.30 (1.5H, q, J=7Hz), 5.10 (2H, s), 6.17 (0.25H, d, J=15Hz), 6.48 (0.75H, d, J=15Hz), 7.05-7.13 (1H, m), 7.36-7.53 (2H, m), 7.60
(0.25H, d, J=8Hz), 8.02 (0.75H, d, J=15Hz), 7.54- 8.69 (2.25H, m)
Example 66
(1) A mixture of 4-ethoxycarbonyl-2-trifluoromethyl-1H- benzimidazole (258 mg), 2-benzyloxyethyl bromide (301 mg), potassium iodide (33 mg) and potassium carbonate (345 mg) in N,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. The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1/4- 1/3) to give 4-ethoxycarbonyl-1-(2-benzyioxyethyl)-2-trifluoromethyl-1H-benzimidazole (333 mg) as oil.
NMR (CDCl3, δ) : 1.48 (3H, t, J=7Hz), 3.82 (2H, t,
J=6Hz), 4.41 (2H, s), 4.51 (2H, q, J=7Hz), 4.56 (2H, t, J=6Hz), 7.07-7.12 (2H, m), 7.22-7.29 (3H, m), 7.44 (1H, t, J=9Hz), 7.79 (1H, d, J=8Hz), 8.04 (1H, d, J=8Hz)
(2) A mixture of 4-ethoxycarbonyl-1-(2-benzyloxyethyl)-2-trifluorcmethyl-1H-benzimidazole (325 mg) and 1N aqueous sodium hydroxide (1.5 ml) in ethanol (1.5 ml) was stirred for 8 hours at ambient temperature. The mixture was acidified with 1N aqueous hydrochlolic acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from a mixture of diethyl ether and ethanol to give 4-carboxy-1-(2- benzyloxyethyl)-2-trifluoromethyl-1H-benzimidazole (174 mg). mp : 117-118°C
NMR (DMSO-d6, δ) : 3.80 (2H, t, J=6Hz), 4.40 (2H, s), 4.69 (2H, t, J=6Hz), 7.01-7.09 (2H, m), 7.18-7.24 (3H, m), 7.52 (1H, t, J=8Hz), 7.91 (1H, d, J=8Hz), 8.07 (1H, d, J=8Hz)
(3) A mixture of 4-carboxy-1-(2-benzyloxyethyl)-2- trifluoromethyl-1H-benzimidazole (260 mg), oxalyl chloride (136 mg) and N,N-dimethylformamide (one drop) in
dichloromethane (3 ml) was stirred for 1 hour at ambient temperature. The mixture was concentrated and the residue was dissolved in dichloromethane (3 ml). To this solution was added 2,6-dichloroaniline (173 mg) and triethylamine (144 mg) with ice cooling. After stirring for 2 hours with ice cooling, the mixture was stirred for 1 hour at ambient temperature. The resulting mixture was washed successively with water and brine, dried over sodium sulfate and
concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/5-1/4) to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2-benzyloxyethyl)-2-trifluoromethyl-1H-benzimidazole (298 mg) as solid after crystallization from diethyl ether,
mp : 143-144ºC
NMR (CDCl3, δ) : 3.87 (2H, t, J=6Hz), 4.45 (2H, s),
4.59 (2H, t, J=6Hz), 7.04-7.11 (2H, m), 7.19-7.29 (4H, m), 7.45 (2H, d, J=8Hz), 7.56 (1H, t, J=8Hz),
7.79 (1H, d, J=8Hz), 8.38 (1H, d, J=8Hz)
(4) A mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2-benzyloxyethyl)-2-trifluoromethyl-1H-benzimidazole (100 mg) and 10% palladium on activated carbon (15 mg) in methanol (0.5 ml) and dioxane (1 ml) was stirred under a hydrogen atmosphere (1 atm) for 1 hour at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give 4-[N-(2,6-dichlorophenyl)- carbamoyl]-1-(2-hydroxyethyl)-2-trifluoromethyl-1H- benzimidazole (69 mg) as solid after crystallization from diethyl ether.
mp : 234-238°C
NMR (CDCl3, δ) : 1.93 (1H, t, J=6Hz), 4.10 (2H, q,
J=6Hz), 4.59 (2H, t, J=6Hz), 7.21 (1H, t, J=8Hz),
7.43 (2H, d, J=8Hz), 7.60 (1H, t, J=8Hz), 7.84 (1H, d, J=8Hz), 8.33 (1H, d, J=8Hz)
(5) To a mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1- (2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (148 mg) and N-bromosuccinimide (82 mg) in dichloromethane (2 ml) was added triphenylphosphine (121 mg) in dichloromethane (0.5 ml) with ice cooling. After stirring for 1 hour, the resulting solution was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/3). The obtained oil was
crystallized from a mixture of diethyl ether and n-hexane to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2-bromoethyl)-2- trifluoromethyl-1H-benzimidazole (123 mg) as solid,
mp : 170-171°C
NMR (CDCl3, δ) : 3.71 (2H, t, J=7Hz), 4.80 (2H, t,
J=7Hz), 7.22 (1H, t, J=8Hz), 7.44 (2H, d, J=8Hz), 7.66 (1H, t, J=8Hz), 7.78 (1H, d, J=8Hz), 8.42 (1H, d, J=8Hz) (6) A mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2-bromoethyl)-2-trifluoromethyl-1H-benzimidazole (115 mg), 2-mercaptoimidazole (31 mg) and potassium carbonate (50 mg) was stirred for 3 hours at ambient temperature. To the resulting mixture was added a mixture of water and ethanol (2/1) and the separated solid was collected to give 4-[N-(2,6- dichlorophenyl)carbamoyl]-1-[2-(2-imidazolylthio)ethyl]-2- trifluoromethyl-1H-benzimidazole (110 mg).
mp : 202-204ºC
NMR (DMSO-d6, δ) : 3.49 (2H, t, J=7Hz), 4.82 (2H, t, J=7Hz), 7.11 (2H, s), 7.43 (1H, t, J=8Hz), 7.63
(2H, d, J=8Hz), 7.70 (1H, d, J=8Hz), 8.12 (1H, d, J=8Hz), 8.27 (1H, d, J=8Hz)
(7) A mixture of 4- [N-(2,6-dichlorophenyl)carbamoyl]-1-[2- (2-imidazolylthio)ethyl]-2-trifluoromethyl-1H-benzimidazole (100 mg) in methanol was treated with excess of 10% hydrogen chloride in methanol. The resulting solution was
concentrated and the obtained oil was crystallized from diethyl ether to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-1- [2-(2-imidazolylthio)ethyl]-2-trifluoromethyl-1H-benzimidazole hydrochloride (100 mg).
mp : I56°C
NMR (DMSO-d6, δ) : 3.73 (2H, t, J=7Hz), 4.70 (2H, t, J=7Hz), 7.43 (1H, t, J=8Hz), 7.60 (2H, s), 7.64 (2H, d, J=8Kz), 7.70 (1H, t, J=8Hz), 8.13 (1H, d,
J=8Hz), 8.21 (1H, d, J=8Hz)
Example 67
(1) To a solution of 4-(2,6-dichlorobenzoylamino)-1-(2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (126 mg) 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 1-(2-bromoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (99 mg).
mp : 175-176°C
NMR (CDCl3, δ) : 3.67 (2H, t, J=8Hz), 4.70 (2H, t,
J=8Hz), 7.28 (1H, d, J=8Hz), 7.30-7.42 (3H, m), 7.52 (1H, t, J=8Hz), 8.60 (1H, d, J=8Hz), 8.60 (1H, s)
(2) 4-(2,6-Dichlorobenzoylamino)-1-[2-(imidazol-2-ylthio)- ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 66-(6). NMR (DMSO-d6, δ) : 3.42 (2H, t, J=8Hz), 4.70 (2H, t,
J=8Hz), 7.13 (2H, s), 7.40-7.55 (4H, m), 7.61 (1H, d, J=8Hz), 8.22 (1H, d, J=8Hz)
(3) 4-(2,6-Dichlorobenzoylamino)-1-[2-(imidazol-2- yithio)ethyl]-2-trifluoromethyl-1H-benzimidazole
hydrochloride was obtained from a similar manner to that of Example 66-(7).
mp : 158-168°C
NMR (DMSO-d6, δ) : 3.73 (2H, t, J=8Hz), 4.68 (2H, t,
J=2Hz), 7.40-7.62 (5K, m), 7.65 (2H, s), 8.22 (1H, d, J=8Hz) Example 68
The following compounds were obtained according to a similar manner to that of Example 66-(6).
(1) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-[2-(2- pyridylthio)ethyl]-2-trifluoromethyl-1H-benzimidazole mp : 176-178°C
NMR (CDCl3, δ) : 3.55-3.61 (2H, m), 4.64 (2H, m), 7.08 (1H, t, J=8Hz), 7.19 (1H, d, J=8Hz), 7.31-7.42 (3H, m), 7.49-7.57 (2H, n), 7.67 (1H, d, J=8Hz), 3.52- 8.60 (3H, m)
(2) 4-(2,6-Dichlorobenzoylamino)-1-[2-(5-methyl-1,3,4- thiadiazol-2-ylthio)ethyl]-2-trifluoromethyl-1H- benzimidazole
mp : 206-208°C NMR (CDCl3, δ) : 2.78 (3H, s), 3.70 (2H, t, J=7Hz),
4.33 (2H, t, J=7Hz), 7.29-7.42 (3H, m), 7.53 (1H, t, J=8Hz), 7.63 (1H, d, J=8Hz), 8.67 (1H, d,
J=8Hz), 8.69 (1H, br s)
(3) 4-(2,6-Dichlorobenzoylamino)-1-[2-(1H-imidazo[4,5-b]- pyridin-2-ylthio)ethyl]-2-trifluoromethyl-1H- benzimidazole
mp : >250°C
NMR (DMSO-d6, δ) : 3.27 (2H, t, J=7Hz), 4.34 (2H, t,
J=7Hz), 7.18 (1H, dd, J=5, 8Hz), 7.42-7.58 (4H, m), 7.87 (2H, d, J=8Hz), 8.23 (2H, d, J=8Hz) its hydrochloride
mp : 246-254°C
NMR (DMSO-d6, δ) : 3.83 (2H, t, J=7Hz), 4.84 (2H, t, J=7Hz), 7.40-7.60 (5H, m), 7.82 (1H, d, J=8Hz), 8.22 (2H, d, J=8Hz), 8.42 (1H, d, J=8Hz) Example 69
(1) A mixture of 2-(2,4-dichlorophenyl)ethanol (5.12 g), tert-butylchlorodiphenylsilane (7.37 g) and imidazole (2.37 g) in N,N-dimethylformamide (15 ml) was stirred for 66 hours at ambient temperature. The resulting mixture was
partitioned between diethyl ether and water. The organic phase was concentrated in vacuo to give 2-(2,4-dichlorophenyl)-1-(tert-butyldiphenylsilyloxy)ethane (11.8 g) as oil.
NMR (CDCl3, δ) : 1.01 (9H, s), 2.96 (2H, t, J=6Hz),
3.84 (2H, t, J=6Hz), 7.15 (2H, s), 7.29 (1H, s),
7.29-7.43 (6H, m) , 7.56 (4H, d, J=8Hz)
(2) To a solution of 2-(2,4-dichlorophenyl)-1-tert-butyldiphenylsilyloxy)ethane (11.8 g) in dry tetrahydrofuran (40 ml) was added 15% n-butyllithium in n-hexane (20.1 ml) dropwise in a dry ice-acetone bath while the resulting solution was maintained at -55~60°C. After the addition was complete, the mixture was stirred for 1 hour under the same condition and then stirred for 30 minutes at -50°C. The resulting solution was poured into a powder of dry ice (67 g) and the mixture was stood for 3 hours at ambient temperature. The resulting mixture was partitioned between diethyl ether (30 ml) and 2N aqueous sodium hydroxide (70 ml). The
separated ether layer was concentrated in vacuo to give 2,6- dichloro-3-[2-(tert-butyldiphenylsilyloxy)ethyl]benzoic acid (11.3 g) as amorphous.
NMR (CDCl3, δ) : 0.99 (9H, s), 2.80 (2H, t, J=6Hz),
3.73 (2H, t, J=6Kz), 6.88 (2H, s), 7.22-7.34 (6H, m), 7.51-7.59 (4H, m)
(3) 4-{2,6-Dichloro-3-[2-(tert-butyldiphenylsilyloxy)ethyl]-benzoylamino}-1-(morpholinocarbonyl)methyl-2-trifluoromethyl- 1H-benzimidazole was obtained from 2,6-dichloro-3-[2-(tert-butyldiphenylsilyloxy)ethyl]benzoic acid and 4-amino-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 66-(3)(
NMR (CDCl3, δ) : 1.05 (9H, s), 3.00 (2H, t, J=6Hz),
3.57-3.70 (4H, m), 3.70-3.86 (4H, m), 3.91 (1H, t, J=6Hz), 5.10 (2H, s), 7.10 (1H d, J=8Hz), 7.27 (2H, s), 7.35-7.51 (6H, m), 7.61 (4H, d, J=8Hz), 8.51- 8.60 (2H, m)
(4) A mixture of 4-{2,6-dichloro-3-[2-(tert-butyldiphenylsilyloxy)ethyl]benzoylamino}-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (595 mg) and tetrabutylammonium fluoride (0.9 ml, 1M in tetrahydrofuran) was stirred for 3 hours at ambient
temperature. The resulting mixture was concentrated in vacuo and the obtained oil was crystallized from a mixture of ethyl acetate and diethyl ether to give a solid. The crude product was purified by washing with hot ethanol to give 4-[2,6- dichloro-3-(2-hydroxyethyl)benzoylamino]-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (186 mg). mp : 240-241ºC
NMR (CDCl3, δ) : 3.03 (2H, t, J=7Hz), 3.58-3.70 (4H, m), 3.70-3.91 (6H, m), 5.10 (2H, s), 7.11 (1H, d, J=8Hz), 7.33 (2H, s), 7.50 (1H, t, J=8Hz), 8.60 (1H, d, J=8Hz) Example 70
(1) A mixture of 2,2-dimethyl-5-hydroxy-4-oxo-1,3-benzodioxane (2.00 g), 2-iodopropane (2.80 g) and potassium carbonate (2.85 g) in acetone (20 ml) was refluxed for 24 hours. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/8-1/4) to give 2,2-dimethyl-4-oxo-5-isopropoxy-1,3-benzodioxane (1.88 g) as oil.
NMR (CDCl3, δ) : 1.44 (6H, d, J=7Hz), 1.70 (6H, s), 4.64 (1H, quint., J=7Hz), 6.51 (1H, d, J=8Hz), 6.62
(1H, d, J=8Hz), 7.40 (1H, t, J=8Hz)
(2) To a solution of 2,2-dimethyl-4-oxo-5-isopropoxy-1,3-benzodioxane (1.00 g) in methanol (5 ml) was added sodium methoxide (252 mg) in one portion at ambient temperature.
After stirring for 1 hour, the mixture was acidified with IN hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated in vacuo to give methyl
2-hydroxy-6-isopropoxybenzoate (816 mg) as oil.
NMR (CDCl3, δ) : 1.35 (6H, d, J=7Hz), 3.92 (3H, s),
4.56 (1H, quint., J=7Hz), 6.41 (1H, d, J=8Hz), 6.56 (1H, d, J=8Hz), 7.29 (1H, t, J=8Hz)
(3) A mixture of methyl 2-hydroxy-6-isopropoxybenzoate (810 mg) and sodium hydride (97 mg, 60% in oil) in 1,3-dimethyl-2- imidazolidinone (6.5 ml) was stirred for 30 minutes with ice cooling. Additionally, the mixture was stirred for 1 hour at ambient temperature, and to the mixture was added 2,2,2- trifluoroethyl p-toluenesulfonate (1.03 g) and the mixture was stirred for 18 hours at 120°C. The resulting mixture was partitioned between ethyl acetate and 3% aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/8-1/6) to give methyl 2-isopropoxy-6- (2,2,2-trifluoroethoxy)benzoate (1.16 g) as oil.
NMR (CDCl3, δ) : 1.31 (6H, d, J=7Hz), 3.90 (3H, s),
4.36 (2H, q, J=8Hz), 4.55 (1H, quint., J=7Hz), 6.50 (1H, d, J=8Hz), 6.68 (1H, d, J=8Hz), 7.28 (1H, m)
(4) A mixture of 2-isopropoxy-6-(2,2,2-trifluoroethoxy)-benzoate (1.13 g) and 1N aqueous sodium hydroxide (5 ml) in ethanol (5 ml) was refluxed for 8 hours. After concentration in vacuo, the mixture was partitioned between dichloromethane and 1N hydrochloric acid. The organic phase was concentrated in vacuo and the residue was crystallized from n-hexane to give 2-isopropoxy-6-(2,2,2-trifluoroethoxy)benzoic acid (728 mg).
mp : 117-118°C
NMR (CDCl3, δ) : 1.38 (6H, d, J=7Hz), 4.40 (2H, q,
J=8Hz), 4.63 (1H, quint., J=7Hz), 6.59 (1H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 7.33 (1H, t, J=8Hz)
(5) 1-(Morpholinocarbonyl)methyl-4-[2-isopropoxy-6-(2,2,2-trifluoroethoxy)benzoylamino]-2-trifluoromethyl-1H-benzimidazole was obtained from 2-isopropoxy-6-(2,2,2-trifluoroethoxy)benzoic acid and 4-amino-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 66-( ).
mp : 243-244°C NMR (CDCl3, δ) : 1.35 (6H, d, J=7Hz), 3.57-3.70 (4H, m), 3.70-3.84 (4H, m) , 4.43 (2H, q, J=8Hz), 4.63 (1H, quint., J=7Hz), 5.08 (2H, s), 6.62 (1H, d, J=8Hz), 6.74 (1H, d, J=8Hz), 7.01 (1H, d, J=8Hz), 7.35 (1H, t, J=8Hz), 7.56 (1H, t, J=8Hz), 8.51 (1H, d, J=8Hz), 8.82 (1H, br s)
Example 71
(1) Methyl 2-chloro-6-(2,2,2-trifluoroethoxy)benzoate was obtained from methyl 2-chloro-6-hydroxybenzoate and
2,2,2-trifluoroethyl p-toluenesulfonate according to a similar manner to that of Example 70-(3).
NMR (CDCl3, δ) : 3.95 (3H, s), 4.39 (2H, q, J=8Hz),
6.84 (1H, d, J=8Hz), 7.12 (1H, d, J=8Hz), 7.31 (1H, t, J=8Hz)
(2) 2-Chloro-6-(2,2,2-trifluoroethoxy)benzoic acid was
obtained according to a similar manner to that of
Example 70-(4).
mp : 98-100°C
NMR (DMSO-d6, δ) : 4.87 (2H, q, J=8Hz), 7.19 (1H, d, J=8Hz), 7.22 (1H, d, J=8Hz), 7.43 (1H, t, J=8Hz)
(3) 4-[2-Chloro-6-(2,2,2-trifluoroethoxy)benzoylamino]-1- (morpholinocarbonyl) methyl-2-trifluoromethyl-1H- benzimidazole was obtained from 2-chloro-6-(2,2,2- trifluoroethoxy)benzoic acid and 4-amino-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 66-(3). mp : 242-243°C
NMR (CDCl3, δ) : 3.58-3.70 (4H, m), 3.70-3.83 (4H, m), 5.09 (2H, s), 6.91 (1H, d, J=8Hz), 7.06 (1H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.38 (1H, t, J=8Hz), 7.47 (1H, t, J=8Hz), 8.54 (1H, d, J=8Hz), 8.51 (1H, s) Example 72
(1) 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).
NMR (CDCl3, δ) : 3.41 (3H, s), 3.71 (2H, t, J=6Hz),
3.93 (3H, s), 4.15 (2H, t, J=6Hz), 6.87 (1H, d, J=8Hz), 7.00 (1H, d, J=8Hz), 7.26 (1H, t, J=8Hz) (2) 2-Chloro-6-(2-methoxyethoxy)benzoic acid was obtained according to a similar manner to that of Example 70- (4). NMR (CDCl3, δ) : 3.43 (3H, s), 3.75 (2H, t, J=6Hz),
4.23 (2H, t, J=6Hz), 6.89 (1H, d, J=8Hz), 7.07 (1H, d, J=8Hz), 7.30 (1H, t, J=8Hz)
(3) 4-[2-Chloro-6-(2-methoxyethoxy)benzoylamino]-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole was obtained from 2-chloro-6-(2- methoxyethoxy)benzoic acid and 4-amino-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 66-(3). mp : 229-230°C
NMR (CDCl3, δ) : 2.25 (3H, s), 3.57-3.83 (12H, m),
4.20 (2H, t, J=6Hz), 5.08 (2H, s), 6.92 (1H, d, J=8Hz), 7.03 (1H, d, J=8Hz), 7.07 (1H, d, J=8Hz),
7.30 (1H, t, J=8Hz), 7.43 (1H, t, J=8Hz), 8.55 (1H, d, J=8Hz), 8.71 (1H, br s)
Example 73
The following compounds were obtained according to a similar manner to that of Example 66-(3).
(1) 4-(2,6-Dimethoxybenzoylamino)-1-(morpholinocarbonyl)- methyl-2-trifluoromethyl-1H-benzimidazole
(from 1,2-dimethoxybenzoic acid and 4-amino-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole)
mp : 225-229°C
NMR (CDCl3, δ) : 3.55-3.69 (4H, m), 3.69-3.81 (4H, m), 3.84 (2H, s), 6.62 (2H, d, J=8Hz), 6.98 (1H, d,
J=8Hz), 7.35 (1H, t, J=8Hz), 7.40 (1H, t, J=8Hz), 8.58 (1H, d, J=8Hz), 8.73 (1H, br s)
(2) 4-(2,6-Dichloro-3-methoxybenzoylamino)-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole
(from 2,6-dichloro-3-methoxybenzoic acid and 4-amino-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole)
mp : 236-238°C
NMR (CDCl3, δ) : 3.54-3.70 (4H, m), 3.70-3.83 (4H, m), 3.95 (3H, s), 5.08 (2H, s), 6.97 (1H, d, J=8Hz), 7.07 (1H, d, J=8Hz), 7.33 (1H, d, J=8Hz), 7.47 (1H, t, J=8Hz), 8.53-8.61 (2H, m)
(3) 4-(2-Chloro-6-methoxybenzoylamino)-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole
(from 2-chloro-6-methoxybenzoic acid and 4-amino-1- (morpholinocarbonyl)methyl-2-trifluoromethyl-1H- benzimidazole)
mp : 218-219°C
NMR (CDCl3, δ) : 3.56-3.69 (4H, m), 3.69-3.72 (4H, m), 3.86 (3H, s), 5.06 (2H, s), 6.89 (1H, d, J=8Hz), 7.04 (1H, t, J=8Hz), 7.33 (1H, t, J=8Hz), 7.45 (1H, t, J=8Hz), 8.58 (1H, d, J=8Hz), 8.64 (1H, br s)
Example 74
A mixture of 1-carboxymethyl-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (98 mg) and 1-hydroxybenzotriazole (69 mg) in N,N-dimethylformamide (2 ml) was stirred for 30 minutes at room temperature. To the solution was added 2-(N- hydroxyamidino)pyridine (70 mg), and the mixture was stirred for 2 hours at room temperature. To the mixture was added water and the separated solid was collected. A mixture of the solid in a mixture of acetic acid (1 ml) and N,N- dimethylformamide (1.5 ml) was stirred for 2 hours at 100°C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate solution and brine, and
concentrated in vacuo. The residue was crystallized from ethanol to give 4-(2,6-dichlorobenzoylamino)-1-[3-(2- pyridyl)-1,2,4-oxadiazol-5-yl]methyl-2-trifluoromethyl-1H- benzimidazole. The product was dissolved in 10% methanolic hydrogen chloride, and the solution was concentrated in vacuo to give 4-(2,6-dichlorobenzoylamino)-1-[3-(2-pyridyl)-1,2,4- oxadiazol-5-yl]methyl-2-trifluoromethyl-1H-benzimidazole hydrochloride (129 mg).
mp : 248-250°C
NMR (DMSO-d6, δ) : 6.30 (2H, s), 7.43-7.63 (5H, m),
7.70 (1H, d, J=8Hz), 7.92-8.00 (2H, m), 8.29 (1H, d, J=8Hz), 8.72 (1H, d, J=6Hz)
Example 75
4-(2,6-Dichlorobenzoylamino)-1-{2-[(pyridin-3-yl)carbonylamino]ethyl}-2-trifluoromethyl-1H-benzimidazole hydrochloride was obtained from 1-(2-aminoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole and nicotinoyl chloride hydrochloride according to a similar manner to that of Example 1-(2).
mp : 204-213ºC
NMR (DMSO-d6, δ) : 3.76 (2H, q, J=5Hz), 4.62 (2H, t, J=5Hz), 7.40-7.70 (6H, m), 4.18-8.25 (2H, m), 8.78 ( 1H, d, J=5Hz ) , 8 . 93 ( 1H, s ) , 9 . 07 ( 1H, t , J=5Hz )
Example 76
To a mixture of 4-(2,6-dichlorobenzoylamino)-1H- benzimidazole (100 mg), 2-(3-pyridyloxy)ethanol (48 mg), triphenylphosphine (112 mg) in dichloromethane (2 ml) was added diethyl azodicarboxylate (51 mg) with ice cooling. The reaction mixture was stirred for 18 hours at ambient
temperature. The separated solid was collected and the solid was purified by preparative TLC (eluted with 1% methanol in dichloromethane). The obtained solid was triturated with diethyl ether and collected to give 4-(2,6- dichlorobenzoylamino)-1-[2-(3-pyridyloxy)ethyl]-2- trifluoromethyl-1H-benzimidazole (25 mg).
mp : 166-167°C
NMR (DMSO-d6, δ) : 4.46 (2H, t, J=5Hz), 4.86 (2H, t,
J=5Hz), 7.26-7.32 (2H, m), 7.44-7.58 (3H, m), 7.70 (1H, d, J=8Hz), 8.14-8.20 (2H, m), 8.24 (1H, d, J=8Hz), 11.16 (1H, s) its hydrochloride
mp : 215-218°C
NMR (DMSO-d6, δ) : 4.58 (2H, t, J=6Hz), 4.90 (2H, t,
J=6Hz), 7.44-7.57 (4H, m), 7.66 (1H, m), 7.70 (1H, d, J=8Hz), 7.76 (1H, dd, J=2Hz, 8Hz), 8.23 (1H, d,
J=8Hz), 8.37 (1H, d, J=6Hz), 8.43 (1H, d, J=2Hz)
Example 77
A mixture of 4-(2,6-dichlorobenzoylamino)-1-(2-methylsulfonyloxyethyl)-2-trifluoromethyl-1H-benzimidazole
(50 mg) and potassium iodide (19 mg) in N,N-dimethylformamide (0.5 ml) was stirred for 2 hours at 60°C. After cooling to ambient temperature, to the mixture was added 1-methyl-2-mercaptoimidazole (13 mg). The resulting mixture was stirred for 2 hours at ambient temperature and to the mixture was added water. The separated solid was purified by preparative TLC (5% methanol in dichloromethane). The separated oil was crystallized from a mixture of ethanol and water to give 4-(2,6-dichlorobenzoylamino)-1-[2-(1-methylimidazol-2- ylthio)ethyl]-2-trifluoromethyl-1H-benzimidazole (30 mg). mp : 177-178°C
NMR (CDCl3, δ) : 3.48 (2H, t, J=7Hz), 3.53 (3H, s),
4.75 (2H, t, J=7Hz), 6.99 (1H, s), 7.18 (1H, s), 7.30-7.42 (4H, m), 7.48 (1H, t, J=8Hz), 8.56 (1H, d, J=8Hz), 8.60 (1H, br s) its hydrochloride
mp : 223-226°C
NMR (DMSO-d6, δ) : 3.60-3.70 (5H, m), 4.69 (2H, t,
J=7Hz), 7.46-7.62 (5H, m), 7.65 (1H, s), 7.70 (1H, s), 8.22 (1H, d, J=8Hz)
Example 78
4-(2,6-Dichlorobenzoylamino)-1-[2-(thiazolin-2-ylthio)ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 77.
mp : 175-183°C
NMR (CDCl3, δ) : 3.38-3.52 (4H, m), 4.21-4.35 (2H, m), 4.60-4.77 (2H, m), 7.20-7.30 (1H, m), 7.30-7.43 (2H, m), 7.43-7.61 (2H, m), 8.58 (1H, m)
Example 79
(1) To a mixture of 4-(2,6-dichlorobenzoylamino)-1-(N-hydroxyamidino)methyl-2-trifluoromethyl-1H-benzimidazole (150 mg) and triethylamine (51 mg) in dichloromethane (2 ml) was added ethyl chloroformate (44 mg) with ice cooling. The mixture was stirred for 1 hour at ambient temperature. The resulting mixture was washed successively with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluted with 1% methanol in dichloromethane) to give 4-(2,6-dichlorobenzoylamino)-1-[(N-ethoxycarbonyloxy)- amidinomethyl]-2-trifluoromethyl-1H-benzimidazole (128 mg) as amorphous.
NMR (CDCl3, δ) : 1.38 (3H, t, J=7Hz), 4.33 (2H, q,
J=7Hz), 4.70-4.90 (2H, m), 5.10 (2H, s), 7.31-7.45 (3H, m), 7.45-7.59 (2H, m), 8.54-8.67 (2H, m)
(2) A mixture of 4-(2,6-dichlorobenzoylamino)-1-[(N- ethoxycarbonyloxy)amidinomethyl]-2-trifluoromethyl-1H-benzimidazole (125 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 ml) in toluene (1.5 ml) was stirred for 30 minutes at ambient temperature. After dilution with ethyl acetate, the resulting mixture was washed successively with IN
hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo. The obtained oil was crystallized from a mixture of ether and n-hexane (1:1) to give 4-(2,6-dichlorobenzoylamino)-1-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)methyl-2-trifluoromethyl-1H-benzimidazole (77 mg).
mp : 242-244°C
NMR (CDCl3, δ) : 5.43 (2H, s), 7.24-7.32 (1H, m),
7.36-7.45 (3H, m), 7.56 (1H, t, J=8Hz), 8.61 (1H, d, J=8Hz) Example 80
To a mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1- (2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (100 mg), hydantoin (31 mg) and triphenylphosphine (113 mg) in N,N-dimethylformamide (1 ml) was added diethyl azodicarboxylate (75 mg) at ambient temperature. The mixture was stirred for 30 minutes at 80°C. The resulting mixture was partitioned between ethyl acetate and 3% aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/1 then ethyl acetate only) and the obtained oil was purified by preparative thin layer chromatography (TLC) (ethyl acetate/n-hexane = 2/1). The obtained oil was crystallized from a mixture of ethanol and water to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-[2-(2,4- dioxoimidazolidin-3-yl)ethyl]-2-trifluoromethyl-1H- benzimidazole (25 mg).
mp : 212-214°C
NMR (CDCl3, δ) : 3.83 (2H, s), 4.05 (2H, t, J=7Hz),
4.65 (2H, t, J=7Hz), 5.38 (1H, br s), 7.21 (1H, t,
J=8Hz), 7.43 (2H, d, J=8Hz), 7.62 (1H, t, J=8Hz), 7.78 (1H, d, J=8Hz), 8.38 (1H, d, J=8Hz)
Example 81
(1) 4-Ethoxycarbonyl-1-methoxymethyl-2-trifluoromethyl-1H-benzimidazole was obtained by reacting 4-ethoxycarbonyl-2-trifluoromethyl-1H-benzimidazole with chloromethyl methyl ether according to a similar manner to that of Example 5. mp : 54-56°C
NMR (CDCl3, δ) : 1.48 (3H, t, J=6Hz), 3.32 (3H, s),
4.52 (2H, q, J=6Hz), 5.69 (2H, s), 7.52 (1H, t, J=8Hz), 7.85 (1H, d, J=8Hz), 8.08 (1H, d, J=8Hz)
(2) 4-Carboxy-1-methoxymethyl-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 51-(4).
mp : 127-129°C
NMR (CDCl3, δ) : 3.39 (3H, s), 5.75 (2H, s), 7.66 (1H, t, J=8Hz), 7.92 (1H, d, J=8Hz), 8.28 (1H, d, J=8Hz)
(3) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-methoxymethyl-2-trifluoromethyl-1H-benzimidazole was obtained according to a similar manner to that of Example 45.
mp : 122-123°C
NMR (CDCl3, δ) : 3.40 (3H, s), 5.74 (2H, s), 7.22 (1H, t , J=8Hz ) , 7 . 45 ( 2H, d, J=8Hz ) , 7 . 64 ( 1H, t ,
J=8Hz ) , 7 . 87 ( 1H, d, J=8Hz ) , 8 . 42 ( 1H, d, J=8Hz )
(4) A mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1- methoxymethyl-2-trifluoromethyl-1H-benzimidazole (35 mg) and concentrated hydrochloric acid (0.042 ml) in tetrahydrofuran (0.46 ml) was stirred for 1 hour at ambient temperature. To the mixture was added 8N hydrogen chloride in ethanol (0.2 ml) and refluxed for 5 hours, and the mixture was poured into sodium bicarbonate - ethyl acetate solution. The organic layer was dried and concentrated in vacuo. The residue was crystallized from isopropyl ether to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-2-trifluoromethyl-1H-benzimidazole (24 mg).
mp : >250°C
NMR (CDCl3, δ) : 7.22 (1H, t, J=8Hz), 7.45 (2H, d,
J=8Hz), 7.53 (1H, t, J=8HZ), 7.72 (1H, d, J=8Hz), 8.32 (1H, d, J=8Hz) (5) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-[2-(4-methylthiazol-5-yl)ethyl]-2-trifluoromethyl-1H-benzimidazole was obtained from 4- [N-(2,6-dichlorophenyl)carbamoyl]-2-trifluoromethyl-1H-benzimidazole and 4-methyl-5-thiazoleethanol according to a similar manner to that of Example 80.
mp : 205-206°C
NMR (CDCl3, δ) : 2.30 (3H, s), 3.38 (2H, t, J=7Hz),
7.44 (2H, d, J=8Hz), 7.49 (1H, d, J=8Hz), 7.59 (1H, t, J=8Hz), 8.39 (1H, d, J=8Hz), 8.62 (1H, s)
Example 82
(1) 4-Ethoxycarbonyl-1-(2-phenoxyethyl)-2-trifluoromethyl-1H-benzimidazole was obtained from 4-ethoxycarbonyl-2-trifluoromethyl-1H-benzimidazole and 2-bromoethyl phenyl ether according to a similar manner to that of Example 5. NMR (CDCI3, δ) : 1.46 (3H, t, J=8Hz), 4.33 (2H, t,
J=7Hz), 4.50 (2H, q, J=8Hz), 4.78 (2H, t, J=7Hz), 6.77 (2H, d, J=8Hz), 6.96 (1H, t, J=8Hz), 7.24 (2H, t, J=8Hz), 7.52 (1H, t, J=8Hz), 7.90 (1H, d,
J=8Hz), 8.07 (1H, d, J=8Hz)
(2) 4-Carboxy-1-(2-phenoxyethyl)-2-trifluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 51-(4).
mp : 133-134ºC
NMR (DMSO-d6, δ) : 4.36 (2H, t, J=7Hz), 4.90 (2H, t, J=8Hz), 6.80 (2H, d, J=8Hz), 6.90 (1H, t, J=8Hz), 7.22 (2H, t, J=8Hz), 7.60 (1H, t, J=8Hz), 7.92 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz)
(3) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(2-phenoxyethyl)- 2-trifluoromethyl-1H-benzimidazole was obtained
according to a similar manner to that of Example 45.
mp : 184-185°C
NMR (CDCl3, δ) : 4.39 (2H, t, J=7Hz), 4.83 (2H, t,
J=7Hz), 6.80 (2H, d, J=8Hz), 6.98 (1H, t, J=8Hz), 7.19-7.30 (3H, m), 7.43 (2H, d, J=8Hz), 7.66 (1H, t, J=8Hz), 7.92 (1H, d, J=8Hz), 8.40 (1H, d, J=8Hz) Example 83
(1) 4-Ethoxycarbonyl-1-(4-methoxybenzyl)-2-trifluoromethyl-1H-benzimidazole was obtained from 4-ethoxycarbonyl-2-trifluoromethyl-1H-benzimidazole and 4-methoxybenzyl chloride according to a similar manner to that of Example 5.
NMR (CDCI3, δ) : 1.48 (3H, t, J=7Hz), 3.78 (3H, s),
5.51 (2H, s), 6.84 (2H, d, J=8Hz), 7.04 (2H, d, J=8Hz), 7.40 (1H, t, J=8Hz), 7.50 (1H, d, J=8Hz), 8.03 (1H, d, J=8Hz) (2) 4-Carboxy-1-(4-methoxybenzyl)-2-trifluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 51- (4).
mp : 134-135°C
NMR (DMSO-d6, δ) : 3.70 (3H, s), 5.67 (2H, s), 6.90 (2H, d, J=8Hz), 7.09 (2H, d, J=8Hz), 7.53 (1H, t,
J=8Hz), 7.91 (1H, d, J=8Hz), 7.96 (1H, d, J=8Hz)
(3) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(4-methoxybenzyl)- 2-trifluoromethyl-1H-benzimidazole was obtained
according to a similar manner to that of Example 45. mp : 158-159°C
NMR (CDCl3, δ) : 3.79 (3H, s), 5.56 (2H, s), 6.89 (2H, d, J=8Hz), 7.12 (2H, d, J=8Hz), 7.19-7.27 (1H, m), 7.43 (2H, d, J=8Hz), 7.49-7.53 (2H, m), 8.36 (1H, m)
Example 84
(1) 4-[N-(2-Methyl-6-methoxyphenyl)carbamoyl]-1-(4-methoxybenzyl)-2-trifluoromethyl-1H-benzimidazole was
obtained from 4-carboxy-1-(4-methoxybenzyl)-2-trifluoromethyl-1H-benzimidazole and 2-methoxy-6-methylaniline
according to a similar manner to that of Example 45.
mp : 172-173°C
NMR (CDCl3, δ) : 2.36 (3H, s), 3.80 (3H, s), 3.87 (3H, s), 5.54 (2H, s), 6.83-6.95 (4H, m), 7.11 (2H, d,
J=8Hz), 7.20 (1H, t, J=8Hz), 7.56-7.52 (2H, m), 8.34 (1H, m)
(2) A mixture of 4- [N-(2-methyl-6-methoxyphenyl)carbamoyl]-1-(4-methoxybenzyl)-2-trifluoromethyl-1H-benzimidazole (380 mg) in trifluoroacetic acid (3 ml) was stirred for 2 hours at 70°C. The resulting mixture was concentrated followed by azeotropic removal of the residual trifluoroacetic acid with toluene. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/4-1/3). The obtained oil was crystallized from ethyl acetate to give 4-[N-(2-methyl-6-methoxyphenyl)carbamoyl]-2-trifluoromethyl- 1H-benzimidazole (78 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.21 (3H, s), 3.76 (3H, s), 6.91
(1H, d, J=8Hz), 6.97 (1H, d, J=8Hz), 7.61 (1H, m), 7.96 (1H, m), 8.11 (1H, d, J=8Hz)
(3) 4-[N-(2-Methyl-6-methoxyphenyl)carbamoyl]-1-(2- acetoxyethyl)-2-trifluoromethyl-1H-benzimidazole was obtained from 4-[N-(2-methyl-6-methoxyphenyl)carbamoyl]-2- trifluoromethyl-1H-benzimidazole and 2-bromoethyl acetate according to a similar manner to that of Example 5.
NMR (CDCl3, δ) : 2.00 (3H, s), 2.37 (3H, s), 3.83 (3H, s), 4.49 (2H, t, J=6Hz), 4.67 (2H, t, J=6Hz), 6.83
(2H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 7.20 (1H, t, J=8Hz), 7.61 (1H, t, J=8Hz), 7.71 (1H, d, J=8Hz), 8.39 (1H, d, J=8Hz) (4) 4-[N-(2-Methyl-6-methoxyphenyl)carbamoyl]-1-(2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole was obtained from 4-[N-(2-methyl-6-methoxyphenyl)carbamoyl]-1-(2-acetoxyethyl-2-trifluoromethyl-1H-benzimidazole according to a similar manner to that of Example 51-(4) .
mp : 184-185°C
NMR (CDCl3, δ) : 2.05 (1H, t, J=7Hz), 2.35 (3H, s),
3.83 (3H, s), 4.06 (2H, q, J=7Hz), 4.54 (2H, t, J=7Hz), 6.83 (1H, d, J=8Hz), 6.92 (1H, d, J=8Hz), 7.20 (1H, t, J=8Hz), 7.57 (1H, t, J=8Hz), 7.79 (1H, d, J=8Hz), 8.30 (1H, d, J=8Hz)
Example 85
(1) 4-Ethoxycarbonyl-1-(pyridin-2-yl)methyl-2-trifluoromethyl-1H-benzimidazole was obtained from
4-ethoxycarbonyl-2-trifluoromethyl-1H-benzimidazole and 2-picolyl chloride hydrochloride according to a similar manner to that of Example 5.
mp : 96-98°C
NMR (CDCl3, δ) : 1.48 (3H, t, J=6Hz), 4.52 (2H, q,
J=6Hz), 5.60 (2H, s), 7.20-7.32 (2H, m), 7.40-7.50
(2H, m), 8.07 (1H, d, J=8Hz), 8.56 (1H, s), 8.59 (1H, d, J=5Hz)
(2) 4-Carboxy-1-(pyridin-2-yl)methyl-2-trifluoromethyl-1H- benzimidazole was obtained according to a similar manner to that of Example 51-(4).
mp : 169-172°C
NMR (DMSO-d6, δ) : 5.82 (2H, s), 7.31-7.47 (2H, m),
7.57 (1H, t, J=8Hz), 8.95 (1H, d, J=8Hz), 8.02 (1H, d, J=8Hz), 8.48 (1H, s), 8.50 (1H, d, J=5Hz)
(3) 4-[N-(2,6-Dichlorophenyl)carbamoyl]-1-(pyridin-2- yl)methyl-2-trifluoromethyl-1H-benzimidazole
hydrochloride was obtained according to a similar manner to that of Example 45.
mp : 190-202ºC
NMR (DMSO-d6, δ) : 5.98 (2H, s), 7.35 (1H, dd, J=5Hz, 3Hz), 7.40-7.51 (2H, m), 7.87 (1H, t, J=8Hz), 8.10 (1H, d, J=8Hz), 8.13 (1H, d, J=8Hz), 8.43 (1H, d, J=5Hz)
Example 86
A mixture of 4-amino-2-trifluoromethyl-1H-benzimidazole (7.68 g), 2,6-dichlorobenzoyl chloride (8.80 g) and
triethylamine (5.80 g) in 1,3-dimethyl-2-imidazolidinone (61 ml) was stirred for 12 hours at ambient temperature. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed successively with 3% aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (4% ethyl acetate in dichloromethane). The obtained first fraction was crystallized from a mixture of ethyl acetate and n-hexane to give 4-(2,6-dichlorobenzoylamino)-1-(2,6- dichlorobenzoyl)-2-trifluoromethyl-1H-benzimidazole (3.20 g). mp : 210-212°C
NMR (CDCl3, δ) : 6.13 (1H, m), 7.32 (1H, t, J=8Hz),
7.37-7.43 (3H, m), 7.50-7.60 (3H, m), 8.58-8.64 (2H, m)
Example 87
(1) A mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2- hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (400 mg), acetic anhydride (117 mg) and 4-dimethylaminopyridine (117 mg) in dichloromethane (4 ml) was stirred for 1 hour at ambient temperature. The resulting solution was washed with saturated aqueous sodium bicarbonate and concentrated in vacuo to give 4-[N-(2,6-dichlorophenyl)carbamoyl]-1-(2-acetoxyethyl)-2-trifluoromethyl-1H-benzimidazole (375 mg) as oil.
NMR (CDCl3, δ) : 2.00 (3H, s), 2.37 (3H, s), 3.83 (3H, s), 4.49 (2H, t, J=7Hz), 4.67 (2H, t, J=7Hz), 6.83 (1H, d, J=8Hz), 6.92 (1H, d, J=8Hz), 7.20 (1H, t, J=8Hz), 7.61 (1H, t, J=8Hz), 7.71 (1H, d, J=8Hz), 8.39 (1H, d, J=8Hz)
(2) To a solution of 4-[N-(2,6-dichlorophenyl)carbamoyl]-1- (2-acetoxyethyl)-2-trifluoromethyl-1H-benzimidazole (365 mg) in N,N-dimethylformamide (3.5 ml) was added 60% sodium
hydride in oil (20 mg) with ice cooling. After stirring for 15 minutes, the mixture was stirred for 30 minutes at ambient temperature. The mixture was recooled on an ice bath, and to the mixture was added iodomethane (135 mg). After stirring for 12 hours at ambient temperature, to the mixture was added excess of 1N aqueous sodium hydroxide and the mixture was stirred for 4 hours at ambient temperature. The resulting solution was partitioned between ethyl acetate and 3% aqueous sodium bicarbonate. The organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1% methanol in dichloromethane). The obtained oil was crystallized from a mixture of ethanol and water to give 4-[N-(2,6-dichlorophenyl)-N-methylcarbamoyl]-1-(2-hydroxyethyl)-2-trifluoromethyl-1H-benzimidazole (167 mg) . mp : 156-158°C
NMR (CDCl3, δ) : 1.79 (0.8H, t, J=7Hz), 1.95 (0.2H, t,
J=7Hz), 3.18 (0.6H, s), 3.47 (2.4H, s), 3.86-3.99 (1.6H, m), 4.00-4.09 (0.4H, m), 4.40 (1.6H, t, J=7Hz), 4.51 (0.4H, t, J=7Hz), 7.00 (1H, t, J=8Hz), 7.10-7.20 (2H, m), 7.10-7.33 (1H, m), 7.48 (1.6H, t, J=8Hz), 7.53-7.70 (0.4H, m)
Example 88
A mixture of 1-(2-bromoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (170 mg), dimethylamine hydrochloride (288 mg) and potassium carbonate (586 mg) in N,N-dimethylformamide (2 ml) was stirred for 1 hour at 85°C. To the mixture was added water and the separated solid was collected and dried. The crude product was purified by column chromatography on silica gel and the obtained oil was crystallized from hexane to give 4-(2,6-dichlorobenzoylamino)-1-vinyl-2-trifluoromethyl-1H-benzimidazole (85 mg).
mp : 160-162°C
NMR (CDCl3, δ) : 5.54 (1H, d, J=8Hz), 5.76 (1H, d,
J=15Hz), 7.14 (1H, dd, J=8Hz, 15Hz), 7.27-7.45 (4H, m), 7.52 (1H, t, J=8Hz), 8.55-8.63 (2H, m)
Example 89
1-(2-Aminoethyl)-4-(2,6-dichlorobenzoylamino)-2-trifluoromethyl-1H-benzimidazole hydrochloride was obtained by treating the object compound of Example 28 according to a similar manner to that of Example 66-(7).
mp : 197-207°C
NMR (DMSO-d6, δ) : 3.20-3.30 (2H, m), 4.66-4.73 (2H, m), 7.45-7.58 (4H, m), 7.22 (1H, d, J=8Hz), 8.18- 8.30 (4H, m)
Example 90
A mixture of 4-[N-(2,6-dichlorophenyl)carbamoyl]-2-trifluoromethyl-1H-benzimidazole (374 mg), ethyl bromoacetate (184 mg) and potassium carbonate (414 mg) in N,N-dimethylformamide (3 ml) was stirred for 3 days at ambient temperature. The resulting mixture was partitioned between ethyl acetate and 3% aqueous sodium bicarbonate and the separated organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1/3). (1) The first fraction was crystallized from a mixture of ethanol and water to give 4-[N-(2,6-dichlorophenyl)- carbamoyl]-1-ethoxycarbonylmethyl-2-trifluoromethyl-1H- benzimidazole (184 mg).
mp : 193-194°C
NMR (CDCl3, δ) : 1.30 (3H, t, J=7Hz), 4.30 (2H, q,
J=7Hz), 5.11 (2H, s), 7.22 (1H, t, J=8Hz), 7.44 (2H, d, J=8Hz), 7.58-7.69 (2H, m), 8.41 (1H, d, J=8Hz) (2) The second fraction was crystallized from a mixture of ethanol and water to give 4-[N-(2,6-dichlorophenyl)-N- (ethoxycarbonylmethyl)carbamoyl]-1-ethoxycarbonylmethyl- 2-trifluoromethyl-1H-benzimidazole (167 mg).
mp : 193-194°C
NMR (CDCl3, δ) : 1.20 (3H, t, J=7Hz), 1.32 (3H, t, J=7Hz), 4.15-4.31 (4H, m), 4.60 (2H, s), 4.93 (2H, s), 7.00 (1H, t, J=8Hz), 7.17 (2H, d, J=8Hz), 7.22- 7.30 (3H, m), 7.50 (1H, m) Example 91
A mixture of 4-amino-1-(morpholinocarbonyl)methyl-2-trifluoromethyl-1H-benzimidazole (200 mg) and 2-nitrobenzoyl chloride (136 mg) in dichloromethane (1.5 ml) was stirred at ambient temperature overnight. The mixture was diluted with CH2Cl2 (1 ml) and washed with water. The organic phase was dried, filtered and concentrated in vacuo. The residual solid was washed with hot ethanol (5 ml) and allowed to cool to ambient temperature. The precipitate was filtered and air-dried to give 1-(morpholinocarbonyl)methyl-4-(2-nitrobenzoylamino)-2-trifluoromethyl-1H-benzimidazole (280 mg).
mp : 237-245°C
NMR (CDCl3, δ) : 3.50-3.67 (4H, m), 3.70-3.84 (4H, m), 5.07 (2H, s), 7.01 (1H, d, J=8Hz), 7.38 (1H, t, J=8Hz), 7.61-7.81 (3H, m) , 8.18 (1H, d, J=8Hz), 8.40 (1H, d, J=9Hz), 8.78 (1H, br s)

Claims

C L A I M S
1. A compound of the formula :
Figure imgf000131_0001
wherein
R1 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, amino, substituted amino, acyl, mercapto, substituted mercapto,
hydroxyamidino, substituted hydroxyamidino and
substituted hydrazono, and
R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl,
halo(lower)alkyl, lower alkoxy, lower alkylthio, acyl or cyano, or
R1 and R2 are taken together to form lower alkylene or lower alkenylene, each of which may include O, S or N-R5 in the chain, in which R5 is hydrogen or lower alkyl, R3 is hydrogen or halogen,
R4 is a heterocyclic group or aryl, each of which may be
substituted with suitable substituent(s), and
A is
Figure imgf000131_0002
, in which R9 is hydrogen, lower alkyl or substituted
lower alkyl, and
R10 is hydrogen, lower alkyl or substituted lower alkyl,
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1, wherein
R1 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 lower alkanoyl, hydroxy substituted with carboxy(lower)alkanoyl, hydroxy substituted with succinimidooxycarbonyl(lower)alkanoyl, hydroxy
substituted with diphosphono(lower)alkylcarbamoyl- (lower)alkanoyl, hydroxy substituted with aryl, hydroxy substituted with ar(lower)alkyl, hydroxy substituted with a heterocyclic group, cyano, halogen, amino, lower alkanoylamino, lower alkylsulfonylamino,
heterocycliccarbonylamino, lower alkanoyl, aroyl, carboxy, lower alkoxycarbonyl, heterocycliccarbonyl, heterocycliccarbonyl substituted with lower alkyl, heterocycliccarbonyl substituted with lower alkanoyl, heterocycliccarbonyl substituted with halogen,
heterocycliccarbonyl substituted with aryl, carbamoyl, lower alkylcarbamoyl, carboxy(lower)alkylcarbamoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl,
cyclo(lower)alkylcarbamoyl, halo(lower)alkylcarbamoyl, cyano(lower)alkylcarbamoyl, hydroxy(lower)- alkylcarbamoyl, lower alkoxy(lower)alkylcarbamoyl, lower alkanoyloxy(lower)alkylcarbamoyl, lower
alkoxycarbamoyl, aminocarbamoyl,
tert-butoxycarbonylaminocarbamoyl,
carbamoyl(lower)alkylcarbamoyl,
hydroxy(lower)alkylcarbamoyl(lower)alkylcarbamoyl, arylsulfonylcarbamoyl, arylcarbamoyl, lower alkoxyarylcarbamoyl, halo(lower)alkyl-arylcarbamoyl, lower alkylamino-arylcarbamoyl, ar(lower)alkylcarbamoyl, halo(lower) alkyl-ar(lower)alkylcarbamoyl, heterocyclic- (lower)alkylcarbamoyl, lower alkyl-heterocyclic(lower)- alkylcarbamoyl, heterocycliccarbamoyl,
lower alkyl-heterocycliccarbamoyl,
halo(lower)alkyl-heterocycliccarbamoyl,
lower alkoxy-heterocycliccarbamoyl,
lower alkylthio-heterocycliccarbamoyl,
sulfamoyl-heterocycliccarbamoyl, N-heterocyclic-N-(lower alkyl)carbamoyl, phthaloyl, mercapto, mercapto
substituted with a heterocyclic group, mercapto
substituted with a heterocyclic group substituted with lower alkyl, hydroxyamidino, hydroxyamidino substituted with lower alkoxycarbonyl, and hydrazono substituted with a heterocyclic group; and
R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl,
halo(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, carbamoyl or cyano, or
R1 and R2 are taken together to form a group of the formula :
-CH2-CH2-CH2-S-,
Figure imgf000133_0001
,
,
Figure imgf000133_0002
in which R5 and R8 are each hydrogen or lower alkyl,
R3 is hydrogen or halogen,
R4 is aryl substituted with substituent(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- (lower)alkyl, and
A is
Figure imgf000134_0001
or
Figure imgf000134_0002
, in which R9 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl, and
R10 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl.
3. A compound of claim 2, wherein
R1 is lower alkanoyl; dichlorobenzoyl; lower alkenyl;
lower alkyl; or lower alkyl substituted with
substituent(s) selected from the group consisting of phenyl, phenyl substituted with nitro, phenyl
substituted with cyano, phenyl substituted with lower alkoxy, morpholinyl, piperazinyl, pyridyl, furyl, thiazolyl, oxadiazolyl, dihydrooxadiazolyl, tetrazolyl, imidazolyl, imidazolidinyl, pyrrolidinyl, oxiranyl, benzodioxolyl, phthalimido, oxadiazolyl substituted with pyridyl, piperazinyl substituted with lower alkyl, oxadiazolyl substituted with lower alkyl, imidazolyl, substituted with lower alkyl, thiazolyl substituted with lower alkyl, benzodioxolyl substituted with halogen,
4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, imidazolidinyl substituted with two oxos, hydroxy, hydroxy substituted with lower alkyl, hydroxy substituted with lower
alkanoyl, hydroxy substituted with
carboxy(lower)alkanoyl, hydroxy substituted with succinimidooxycarbonyl(lower)alkanoyl, hydroxy
substituted with diphosphono(lower)alkylcarbamoyl- (lower)alkanoyl, hydroxy substituted with phenyl, hydroxy substituted with phenyl(lower)alkyl, hydroxy substituted with pyridyl, cyano, halogen, amino, lower alkanoylamino, lower alkylsulfonylamino,
morpholinylcarbonylamino, pyridylcarbonylamino, lower alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, morpholinylcarbonyl, pyridylcarbonyl,
pyrrolidinylcarbonyl, piperazinylcarbonyl,
thienylcarbonyl, morpholinylcarbonyl substituted with lower alkyl, piperazinylcarbonyl substituted with lower alkanoyl, thienylcarbonyl substituted with halogen, piperazinylcarbonyl substituted with phenyl, carbamoyl, lower alkylcarbamoyl, carboxy(lower)alkylcarbamoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl,
cyclo(lower)alkylcarbamoyl, halo(lower)alkylcarbamoyl, cyano(lower)alkylcarbamoyl, hydroxy(lower)-alkylcarbamoyl, lower alkoxy(lower)alkylcarbamoyl, lower alkanoyloxy(lower)alkylcarbamoyl, lower
alkoxycarbamoyl, aminocarbamoyl,
tert-butoxycarbonylaminocarbamoyl,
carbamoyl(lower)alkylcarbamoyl,
hydroxy(lower)alkylcarbamoyl(lower)alkylcarbamoyl, phenylsulfonylcarbamoyl, phenylcarbamoyl, lower alkoxyphenylcarbamoyl, halo(lower)alkyl-phenylcarbamoyl, lower alkylamino-phenylcarbamoyl, phenyl(lower)alkylcarbamoyl, halo(lower)alkyl-phenyl(lower)alkylcarbamoyl, pyridyl- (lower)alkylcarbamoyl, furyl(lower)alkylcarbamoyl, tetrahydrofuryl(lower)alkylcarbamoyl,
oxadiazolyl(lower)alkylcarbamoyl,
indolyl(lower)alkylcarbamoyl,
benzodioxolyl(lower)alkylcarbamoyl,
imidazolyl(lower)alkylcarbamoyl,
lower alkyl-oxadiazolyl(lower)alkylcarbamoyl. pyridylcarbamoyl, morpholinylcarbamoyl,
thiazolylcarbamoyl, thiadiazolylcarbamoyl,
oxazolylcarbamoyl, isoxazolylcarbamoyl, lower alkyloxazolylcarbamoyl, lower alkyl-isoxazolylcarbamoyl, lower alkyl-thiadiazolylcarbamoyl, halo(lower)alkylthiadiazolylcarbamoyl, lower alkoxy-pyridylcarbamoyl, lower alkylthio-thiadiazolylcarbamoyl,
sulfamoyl-thiadiazolylcarbamoyl, N-pyridyl-N-(lower alkyl)carbamoyl, phthaloyl, mercapto, pyridylthio, imidazolylthio, thiazolinylthio, thiadiazolylthio, imidazopyridylthio, lower alkylimidazolylthio, lower alkylthiadiazolylthio, hydroxyamidino, hydroxyamidino substituted with lower alkoxycarbonyl, and hydrazono substituted with pyridyl; and
R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl,
halo(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, carbamoyl or cyano, or
R1 and R2 are taken together to form a group of the formula
-CH2-CH2-CH2-S-,
Figure imgf000136_0002
,
Figure imgf000136_0001
,
in which R5 and R8 are each hydrogen or lower alkyl,
R3 is hydrogen or halogen,
R4 is phenyl substituted with substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkoxy(lowero alkoxy, halo(lower)alkoxy, lower alkanoyl, lower alkoxycarbonyl(lower)alkenyl, hydroxy(lower)alkyl and lower alkyldiarylsilyloxy- (lower)alkyl, and is
Figure imgf000137_0002
or
Figure imgf000137_0003
, in which R9 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl, and
R10 is hydrogen, lower alkyl or lower
alkoxycarbonyl(lower)alkyl.
4. A process for preparing a compound of the formula
Figure imgf000137_0001
wherein
R1 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, amino, substituted amino, acyl, mercapto, substituted mercapto,
hydroxyamidino, substituted hydroxyamidino and
substituted hydrazono, and
R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl,
halo(lower)alkyl, lower alkoxy, lower alkylthio, acyl or cyano, or
R1 and R2 are taken together to form lower alkylene or lower alkenylene, each of which may include O, S or N-R5 in the chain, in which R5 is hydrogen or lower alkyl,
R3 is hydrogen or halogen,
R4 is a heterocyclic group or aryl, each of which may be
substituted with suitable substituent(s), and
A is
Figure imgf000138_0002
or
Figure imgf000138_0003
, in which R9 is hydrogen, lower alkyl or substituted
alkyl, and
R10 is hydrogen, lower alkyl or substituted alkyl,
or its salt, which comprises a) reacting a compound of the formula
Figure imgf000138_0001
wherein R2, R3, R4 and A are each as defined above, or its salt with a compound of the formula :
R1 - X wherein X is a leaving group, and
R1 is as defined above,
or its salt to give a compound of the formula
Figure imgf000139_0001
wherein R1, R2, R , R4 and A are each as defined above, or its salt, or b) reacting a compound of the formula
Figure imgf000139_0002
wherein R1, R2, R3 and R10 are each as defined above, or its reactive derivative at the amino group
or a salt thereof with a compound of the formula :
R 4 - COOH wherein R4 is as defined above,
or its reactive derivative at the carboxy group
or a salt thereof to give a compound of the formula
Figure imgf000140_0001
wherein R1, R2, R3, R4 and R10 are each as defined above,
or its salt, or c) reacting a compound of the formula :
Figure imgf000140_0002
wherein R1, R2 and R3 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula
Figure imgf000140_0003
wherein R4 and R9 are each as defined above,
or its reactive derivative at the amino group
or a salt thereof to give a compound of the formula
Figure imgf000141_0001
wherein R1, R2, R3, R4 and R9 are each as defined above, or its salt, or reacting a compound of the formula
Figure imgf000141_0002
wherein Q is lower alkylene, and
R2, R3, R4 and A are each as defined above, or its reactive derivative at the carboxy group
or a salt thereof with a compound of the formula :
Figure imgf000142_0001
wherein R6 is hydrogen or lower alkyl optionally
substituted with a substituent selected from the group consisting of hydroxy and lower alkoxy, and
R7 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
R6 and R7 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with a substituent selected from the group consisting of lower alkyl, halogen, aryl and acyl,
or its reacting derivative at the amino group
or a salt thereof to give a compound of the formula :
Figure imgf000143_0001
wherein R2, R3, R4, R6, R7, A and Q are each as defined above,
cr its salt.
5. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.
6. A compound of claim 1 for use as a medicament.
7. A method for the prevention and/or the treatment of bone diseases caused by abnormal bone metabolism which comprises administering a compound of claim 1 to human being or animals.
8. Use of a compound of claim 1 for manufacture of a
medicament for the prevention and/or the treatment of bone diseases caused by abnormal bone metabolism.
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US7943622B2 (en) 2006-06-06 2011-05-17 Cornerstone Therapeutics, Inc. Piperazines, pharmaceutical compositions and methods of use thereof
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1646614A4 (en) * 2003-07-01 2008-09-10 Merck & Co Inc Ophthalmic compositions for treating ocular hypertension
CN100415721C (en) * 2005-11-10 2008-09-03 上海大学 Method for preparing nitrobenzimidazole of containing fluorin

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003833A1 (en) * 1987-10-30 1989-05-05 Aktiebolaget Hässle IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS
EP0574174A2 (en) * 1992-06-03 1993-12-15 Eli Lilly And Company Angiotensin II antagonists
WO1995003298A1 (en) * 1993-07-19 1995-02-02 Fujisawa Pharmaceutical Co., Ltd. BENZIMIDAZOLE DERIVATIVES USEFUL AS DOPAMINE RECEPTOR ANTAGONIST, 5-HT RECEPTOR AGONIST OR α1 RECEPTOR ANTAGONIST
JPH08143525A (en) * 1994-11-21 1996-06-04 Banyu Pharmaceut Co Ltd Prophylactic and therapeutic agent for bone diseases containing hydroxybenzoic acid amide derivative as active agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003833A1 (en) * 1987-10-30 1989-05-05 Aktiebolaget Hässle IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS
EP0574174A2 (en) * 1992-06-03 1993-12-15 Eli Lilly And Company Angiotensin II antagonists
WO1995003298A1 (en) * 1993-07-19 1995-02-02 Fujisawa Pharmaceutical Co., Ltd. BENZIMIDAZOLE DERIVATIVES USEFUL AS DOPAMINE RECEPTOR ANTAGONIST, 5-HT RECEPTOR AGONIST OR α1 RECEPTOR ANTAGONIST
JPH08143525A (en) * 1994-11-21 1996-06-04 Banyu Pharmaceut Co Ltd Prophylactic and therapeutic agent for bone diseases containing hydroxybenzoic acid amide derivative as active agent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOORG. MED. CHEM. LETT., vol. 6, no. 4, 1996, pages 477 - 480 *
CHEMICAL ABSTRACTS, vol. 124, no. 21, 20 May 1996, Columbus, Ohio, US; abstract no. 289350a, L.A. FLIPPIN ET AL.: "(R)-3-(6-chloro-1-isopropylbenzimidazole-4-carboxamido)quinuclidine; a high affinity ligand for the (R)-zacopride binding site." page 1326; column 2; XP002022316 *
DATABASE WPI Section Ch Week 9632, Derwent World Patents Index; Class B05, AN 96-318905, XP002022317 *

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CN113185447A (en) * 2021-05-06 2021-07-30 四川大学 Phthaloyl cysteamine compound, preparation method and use thereof
CN113185447B (en) * 2021-05-06 2023-07-21 四川大学 Phthaloyl cysteamine compound, preparation method and application thereof

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