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    • 专利摘要:
    The present invention relates to novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide derivatives of formula 1 useful as histamine receptor antagonists and tachykinin receptor antagonists , Stereoisomers thereof, and pharmaceutically acceptable salts thereof. Such antagonists include allergic rhinitis including seasonal rhinitis and sinusitis; Inflammatory bowel disease including Crohn's disease and ulcerative colitis; Asthma, bronchitis and vomiting.
    公开号:KR19990087055A
    申请号:KR1019980706440
    申请日:1997-01-27
    公开日:1999-12-15
    发明作者:조지 디 메이나드；존 엠 케인；래리 디 브래튼；엘리자베스 엠 쿠들라츠
    申请人:게리 디. 스트리트, 스티븐 엘. 네스비트；훽스트 마리온 로우셀, 인크.；
    IPC主号:
    专利说明:

    Methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide useful for the treatment of allergic diseases
    The present invention relates to novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide derivatives (herein referred to as compounds or compounds of formula Histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful for treating allergic rhinitis, allergies and vomiting, including inflammatory bowel disease, seasonal rhinitis and sinusitis, including asthma, bronchitis, Crohn's disease and ulcerative colitis.
    The compounds of the present invention are useful in their pharmacological activity, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of the histamine response can be induced by blocking histamine receptors. The antagonism of the tachykinin response can be induced by blocking the tachykinin receptor. One object of the present invention is to provide novel, useful antagonists of histamine. It is a further object of the present invention to provide novel, useful antagonists of tachycinin. Particular object of the present invention is a compound exhibiting both the H 1 and NK 1 receptor antagonism.
    The present invention relates to novel substituted N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide derivatives of formula 1, stereoisomers thereof and pharmaceutically acceptable salts thereof Salt.
    In this formula,
    R 'is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    R " is hydrogen or And Wherein R 20 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and -CF 3 ,
    Ar 1 is , , And Wherein R 1 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and , R 2 is 1 to 2 substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    X 1 and X 2 are as defined in one of parts A), B) or C).
    A) X < 1 > is hydrogen,
    X 2 is , , , And Lt; / RTI > is a radical selected from the group consisting of &
    Wherein p is 1 or 2,
    R 3 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    R 4 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy, R 5 is hydrogen or hydroxy,
    Ar 2 is , , , And Wherein R 6 is selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and -CO 2 R 9 wherein R 9 is hydrogen and C 1 -C And R 7 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, each of which is independently selected from the group consisting of And R 8 is selected from the group consisting of hydrogen, -CH 3 and -CH 2 OH, and R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and benzyl,
    Z is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, - (CH 2 ) w -O- (CH 2 ) t -Y, - (CH 2 ) f A, - (CH 2 ) u CO 2 R 11 , 2) u C (O) NR 12 R 13, - (CH 2) g C (O) (CH 2) h CH 3, - (CH 2) w -O-Ar 3, -CH 2 CH 2 OCF 3, -CH 2 CF 3, -CH 2 CH 2 CH 2 CF 3, - (CH 2) 2 CH = CH 2, -CH 2 CH = CH 2, -CH 2 CH = CHCH 3, -CH 2 CH = CHCH 2 and CH 3, -CH 2 CH = C (CH 3) 2 and -CH 2 OCH 2 CH 2 Si ( CH 3) 3 , wherein, w is an integer from 2 to 5, t is an integer of 1 to 3, f is 2 or 3, u is an integer from 1 to 4, g is an integer from 1 to 3, h is an integer from 0 to 3, w is an integer from 2 to 4, Y is hydrogen, -CF 3 , -CH = CH 2 , -CH = C (CH 3 ) 2 and -CO 2 R 14 wherein R 14 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, A is -NR 15 R 16 (R 15 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, R 16 is C 1 -C 4 alkyl), acetylamino, and morpholino group consisting of furnace coming Is selected from, R 11 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, R 12 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and benzyl, R 13 is hydrogen and C 1 - C 4 alkyl, Ar 3 is selected from the group consisting of And Wherein v is an integer from 1 to 3 and R 17 is selected from the group consisting of hydrogen and -COR 18 where R 18 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl. ];
    B) X < 1 > is hydroxy,
    X 2 is And , Wherein p, R 3 , Z and Ar 2 are as defined above;
    C) X < 2 > Wherein R < 3 > and R < 4 > are as defined above,
    X 1 and Z 1 together form a double bond between carbon atoms containing X 1 and Z 1 .
    As is known to those skilled in the art, the compound of formula 1 is present as a stereoisomer of N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide . Specifically, the N-methyl-N- (4- (piperidin-1-yl) -2- (aryl) butyl) benzamide of the present invention has a stereoisomer Lt; / RTI > Any reference to one of the compounds of formula (I) means that the particular stereoisomer or mixture of stereoisomers is included.
    Certain stereoisomers may be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. Specific enantiomers of starting materials or products can be separated by known techniques in the art, such as chromatography on a chiral stationary phase, enzymatic degradation or fractional re-crystallization of the addition salts formed by the reagents used for such purposes , Can be recovered. Useful methods for isolating and recovering specific stereoisomers are well known in the art and described in the literature (see EL Eliel and SH Wilen, Stereochemistry of organic compounds , Wiley (1994), J. Jacque, A. Collet, and SH Willen, Enantiomers, Racemates, and Resolution , Wiley (1981).
    As described herein:
    a) the term " halogen " means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
    b) The term "C 1 -C 6 alkyl" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and the like,
    c) The term "C 1 -C 6 alkoxy" refers to straight or branched chain alkoxy groups containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Propoxy, tert-butoxy, pentoxy, hexoxy, cyclopentoxy, cyclohexoxy and the like,
    d) -C (O) - or - (O) C- Carbonyl < / RTI > group,
    e) " Quot; means a bond in which stereochemistry is not present,
    f) The following terms used in the examples and preparations, "kg" are kilograms, "g" is grams, "mg" is milligrams, "μg" is micrograms, "mol""is a millimolar and," nmole "is nanomolar," l "is liters, and," mL "or" ㎖ "it is milliliters, and" ㎕ "is microliter,""and are Celsius," ℃ R f " Bp "is the boiling point," mmHg "is the millimeter mercury pressure," cm "is the centimeter," nm "is the nanometer, "[α] 2 D 0 " is the specific rotation of the sodium D line obtained at 1 square cell at 20 ° C, "C" is the concentration in g / ml, "THF" is the tetrahydrofuran, "DMF"Quot; nM " is nano-molal, " psi " is < / RTI > a monomolecular < RTI ID = 0.0 & Pounds / inch 2 , " TLC ""Ip" is intraperitoneal, "iv" is intravenous, and "DPM" is high resolution liquid chromatography, "HRMS" is high resolution mass spectrum, "μCi" is microcurie, Quot; is decomposition / minute,
    g) Is a phenyl or substituted phenyl wherein the radical is bonded at position 1 and the substituent or substituent represented by R is believed to be able to be attached at any position 2, 3, 4, 5 or 6,
    h) Is a pyridine, substituted pyridine, pyridyl or substituted pyridyl, the radical may be attached at both the 2-position, the 3-position or the 4-position and further when the radical is bonded at the 2- The substituent represented by R may be bonded at any position of 3, 4, 5, or 6, and when the radical is bonded at the 4-position, the substituent or the substituent represented by R may be substituted at any position of 2, 3, It is believed that they can be combined,
    i) Lt; / RTI > is thienyl or thiophene and the radical is considered to be attached at the 2- or 3-
    j) Is a naphthyl or substituted naphthyl radical and the radical may be attached at the 1- or 2-position and when the radical is bonded at the 1- position, the substituent or substituent represented by R is 2, 3, 4, 5, 6, 7 or 8, and when the radical is bonded at the 2-position, the substituent or the substituent represented by R may be bonded at any position of 1, 3, 4, 5, 6, 7 or 8 It is supposed to be possible,
    k) The term "enantiomeric excess" or "ee" means one enantiomer such as ee = {(E1-E2) ÷ (E1 + E2)} × 100%, E1 is a mixture of two ethanethiomers (+) - " means + enantiomer, " (-) - " means enantiomer,
    l) " C 1 -C 4 alkyl " means a saturated straight or branched chain aralkyl group having 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
    m) -CO 2 R and -C (O) OR is formula , ≪ / RTI >
    n) -C (O) NRR < / RTI > , ≪ / RTI >
    o) Quot; is < / RTI > furyl or furan, and the radical is considered to be attached at the 2- or 3-
    p) The term " pharmaceutically acceptable salts thereof " means an acid addition salt or a base addition salt.
    The expression " pharmaceutically acceptable acid addition salt " means that it applies to all non-toxic organic acids or inorganic acid addition salts of base compounds of formula (I) or intermediates thereof. Examples of inorganic acids which form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and acid metal salts such as sodium monohydrogenphosphate, orthophosphoric acid and potassium hydrogen sulphate. Examples of organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, , Phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may be present in the hydrate or substantially anhydrous form. Generally, the acid addition salts of such compounds are soluble in water and various hydrophilic organic solvents and generally exhibit a higher melting point than their free base forms.
    The expression " pharmaceutically acceptable base addition salt " means that the compound is applied to the non-toxic organic acid or mineral acid addition salt of the compound of formula (I) or any of its intermediates. Examples of bases which form suitable salts are alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides, ammonia and aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, dimethylamine, Trimethylamine and picoline.
    Preferred embodiments of formula (1) are as follows:
    1) a compound wherein X < 1 > is hydrogen,
    2) when X < 2 & Lt; / RTI > are preferred,
    3) when X < 2 & Wherein p is 1 and Ar 2 is 4-fluorophenyl, pyrid-2-yl, fur-2-yl or fur-3-yl,
    4) when X < 2 & Lt; / RTI > are preferred,
    5) when X < 2 & Wherein Z is - (CH 2 ) w -O- (CH 2 ) t -Y (where w is 2), and Z is 2-ethoxyethyl is most preferred.
    Examples of compounds included in the present invention include the following. Examples include (+) - isomers and (-) - isomers of the compounds, and mixtures thereof. This list is meant to be representative only and does not limit the scope of the invention in any way:
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    2-phenylbutyl) -3,4,5-trimethoxybenzamide (prepared according to the method described in < RTI ID = 0.0 >;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;
    2- (4-fluorophenyl) butyl) -3,4,5-dihydro-2H-benzoimidazol-2- -Trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) benzamide;
    Yl) -2- (3,4-difluorophenyl) butyl) -3, 7-dihydro- 4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;
    2- (3-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-1,5-benzodiazepin- Trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;
    2- (4-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-pyran-2- Trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    2- (3,4-dichlorophenyl) butyl) -3,4-dihydro-2H-pyran-2- 5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;
    Yl) -2- (4-methoxyphenyl) butyl) -3,4,5-dihydro-2H-benzoimidazol- -Trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;
    Yl) -2- (3-methoxyphenyl) butyl) -3,4,5-dihydro-2H-benzoimidazol- -Trimethoxybenzamide;
    N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-dimethoxyphenyl) butyl) benzamide;
    2- (3,4-dimethoxyphenyl) butyl) -3, 4-dimethoxyphenyl) -3,4- , 5-trimethoxybenzamide;
    Benzoimidazol-2-yl) -4-hydroxypiperidin-1-yl) -2-phenylbutyl) benzene amides;
    4-hydroxypiperidin-1-yl) -2-phenylbutyl) - (4-fluorobenzyl) 3,4,5-trimethoxybenzamide;
    4-hydroxypiperidin-1-yl) -2- (4-fluoro-4-fluoro-benzoimidazol- Phenyl) butyl) benzamide;
    4-Hydroxypiperidin-1-yl) -2- (3,4 < RTI ID = 0.0 & - < / RTI > dichlorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- -Phenylbutyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- -Phenylbutyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-fluorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-difluorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3-fluorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-chlorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-dichlorophenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-methoxyphenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3-methoxyphenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-methoxyphenyl) butyl) benzamide;
    2-yl) -2-methyl-N- (4- (4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (3,4-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (4-fluorophenoxy) -Phenylbutyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (4-fluorophenoxy) - (3-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (4-fluorophenoxy) - (3,4-dichlorophenyl) butyl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide ;
    1-yl) -2-phenylbutyl) -3 < RTI ID = 0.0 > (3-ethoxyethyl) , 4,5-trimethoxybenzamide;
    (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin- Phenyl) butyl) benzamide;
    (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2-carbonyl) piperidin- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Difluorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-l-yl) -2- (3-chlorophenyl) ) Butyl) benzamide;
    2-carbonyl) piperidin-l-yl) -2- (3-chlorophenyl) ) Butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-l-yl) -2- (4-chlorophenyl) ) Butyl) benzamide;
    2-carbonyl) piperidin-l-yl) -2- (4-chlorophenyl) ) Butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dimethoxyphenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dimethoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-phenylbutyl) -2 < RTI ID = 0.0 > (2-ethoxyethyl) -Methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Phenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-phenylbutyl) -2 < RTI ID = 0.0 > (2-ethoxyethyl) -Methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Phenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzene amides;
    Yl) -2-phenylbutyl) - < / RTI > (4-fluoro- 3,4,5-trimethoxybenzamide;
    1-yl) -2- (4-fluoro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin- Phenyl) butyl) benzamide;
    1-yl) -2- (4-fluoro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- - difluorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- - difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-l-yl) -2- (3-chloro-benzoimidazol- Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-l-yl) -2- (3-chloro-benzoimidazol- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    Yl) -2- (4-chloro-benzoimidazol-2-yl) -piperidine- Phenyl) butyl) benzamide;
    Yl) -2- (4-chloro-benzoimidazol-2-yl) -piperidine- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- - < / RTI > dichlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- -Dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (4-methyl-N- (4- (4- Butylphenyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (3-methoxy-benzyl) -2-methyl-N- Lt; / RTI > phenyl) butyl) benzamide;
    1-yl) -2- (3-methoxy-benzyl) -2-methyl-N- Butylphenyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- - dimethoxyphenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin- -Dimethoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzene amides;
    2-phenylbutyl) - < / RTI > < RTI ID = 0.0 &3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluoro-phenyl) Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluoro-phenyl) Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- - difluorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- - difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-chloro-benzoimidazol- Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-chloro-benzoimidazol- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-chloro-benzoimidazol- Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-chloro-benzoimidazol- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- - < / RTI > dichlorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- -Dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) Butylphenyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Lt; / RTI > phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) Butylphenyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- - dimethoxyphenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- -Dimethoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- phenylbutyl) Benzamide;
    2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- phenylbutyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Fluorophenyl) butyl) benzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-difluorophenyl) butyl) benzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-ylmethyl) -2- (3-methyl-pyridin-2-ylmethyl) Chlorophenyl) butyl) benzamide;
    2-ylmethyl) -2- (3-methyl-pyridin-2-ylmethyl) Chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Chlorophenyl) butyl) benzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-dichlorophenyl) butyl) benzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Methoxyphenyl) butyl) benzamide;
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-ylmethyl) -2- (3-methyl-pyridin-2-ylmethyl) Methoxyphenyl) butyl) benzamide;
    2-ylmethyl) -2- (3-methyl-pyridin-2-ylmethyl) Methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-dimethoxyphenyl) butyl) benzamide;
    2- (3, < / RTI > < RTI ID = 0.0 & 4-dimethoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (2-oxobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    1-yl) -2-phenylbutyl) -3, 3-dihydroxy-N- (4- 4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloro-benzoimidazol- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) ) Butyl) benzamide;
    N-methyl-N- (4- (4- (1- (1-methyl-1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    Methyl-N- (4- (4- (1-methyl-1H-benzimidazole-2-carbonyl) piperidin- 4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1-methyl-1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (4-methoxyphenyl) ;
    (4-carboxyphenyl) propyl) -1 H-benzimidazole-2-carbonyl) piperidin- 3-chlorophenyl) butyl) -3,4,5-methoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) , 4-dichlorophenyl) butyl) benzamide;
    (4-carboxyphenyl) propyl-1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- -Methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (2-oxopropyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    1-yl) -2-phenylbutyl) -3, < RTI ID = 0.0 >4,5-trimethoxybenzamide;
    Yl) -2- (3-chlorophenyl) -lH-pyrrolo [2,3-d] pyrimidin- Butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloro-benzoimidazol- Phenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (5-methylpur-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- 4-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (5-methylpur-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- 3-chlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (5-methylpur-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- 3-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (5-methylpur-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- 4-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (1 H) -quinolinone -Phenylbutyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2 (1 H) -quinolinone -Phenylbutyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (1 H) -quinolinone - (3-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (1 H) -quinolinone - (3,4-dichlorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2 (1 H) -quinolinone - (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (4-carboxybenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorobenzyl) ) Butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorobenzyl) ) Butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) Butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloro-benzoimidazol- Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloro-benzoimidazol- Phenyl) butyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    (4-methoxycarbonylbenzyl) -1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- Fluorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1 -yl) -2- (3- (4-methoxycarbonylbenzyl) Chlorophenyl) butyl) benzamide;
    (4-methoxycarbonylbenzyl) -1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- Methoxyphenyl) butyl) benzamide;
    1-yl) -2-phenylbutyl) piperidine-1-carboxylic acid methyl ester, Benzamide;
    (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzimidazole-2-carbonyl) piperidin- Fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzimidazole-2-carbonyl) piperidin- Methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2 (4-fluorophenyl) - (4-methoxyphenyl) butyl) benzamide;
    N-methyl-N- (4- (4-benzhydrylidipiperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4-benzhydrylidipiperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-phenylbutyl) - < / RTI > < RTI ID = 0.0 &3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (3, 4-dihydroxy- -Dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1-ethyl-1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (4- fluorophenyl) ;
    Yl) -2- (3,4-dichlorophenyl) butyl) benzene (hereinafter referred to as "amides;
    2- (3,4-dichlorophenyl) butyl) - (4-methyl-N- 3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (2-carboxyethyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    1-yl) -2- (4-fluoro-pyridin-2-yl) Phenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3- (4-fluorophenyl) Chlorophenyl) butyl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) benzamide;
    2-ylmethyl) -2- (3-methoxy-benzyl) -piperidin-l- Chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) - (4-methyl- 2- (4-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide ;
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3-chlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-l-yl) -2- (3-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-chlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (4-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3-methoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-dimethoxyphenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2- (3,4-dimethoxyphenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2-carbonyl) piperidin-1-yl) -2-phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- -Yl) -2- (3,4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- Yl) -2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- - yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- -Yl) -2-phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- Yl) -2- (3,4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- -Yl) -2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- -Yl) -2- (3-methoxyphenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    N-methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2- carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2-phenylbutyl) benzamide;
    N-methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2- carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2- carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    N-methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2- carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    N-methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2- carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) Phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) (3,4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) (3,4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) Phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) (3,4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) (3,4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Methyl-N- (4- (4- (1- (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2-phenylbutyl) benzamide;
    Methyl-N- (4- (4- (1- (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Phenylbutyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Methyl-N- (4- (4- (1- (2- (4,4,4-trifluorobutyl) -1H-benzimidazole-2- carbonyl) piperidin- -2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Phenylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-difluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    (4,4,4-trifluorobutyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) - < / RTI & -2-phenylbutyl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) - < / RTI & -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) - < / RTI & -2- (3,4-dichlorophenyl) butyl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) - < / RTI & -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    1-yl) -2- (3,4-dichlorophenyl) butyl (2-methylphenyl) ) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    1-yl) -2- (3,4-dichlorophenyl) butyl (2-methylphenyl) ) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Benzimidazole-2-carbonyl) -lH-benzimidazole-2-carbonyl) -lH- Piperidin-1-yl) -2-phenylbutyl) benzamide;
    Benzimidazole-2-carbonyl) -lH-benzimidazole-2-carbonyl) -lH- Piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) -lH-benzimidazole-2-carbonyl) -lH- Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    Benzimidazole-2-carbonyl) -lH-benzimidazole-2-carbonyl) -lH- Piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2- ( Dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2- ( Dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide;
    Methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) Carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide;
    Methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) Carbonyl) piperidin-1-yl) -2-phenylbutyl) -3,4,5-trimethoxybenzamide;
    Methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) Carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) benzamide;
    Methyl-N- (4- (4- (1- (3-methylbut-2-en-1-yl) -1H-benzimidazole-2-carbonyl) Carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide;
    1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - 2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide;
    1-yl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) - 2- (3,4-dichlorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide.
    A general synthetic method for preparing compounds of formula (1) is described in scheme A. The reagents and starting materials can be readily used by those skilled in the art. All substituents in Scheme A are as defined above unless otherwise indicated.
    In step 1 of Scheme A, the hydroxy group of the appropriate alcohol of formula 2 is converted to the appropriate leaving group to give the compound of formula 2a. Suitable alcohols of formula 2 are those in which the stereochemistry is as desired in the final product of formula 1 and R ', R "and Ar 1 are as intended in the final product of formula 1. Alternatively, The alcohol may be as desired in the final product of formula 1 after the stereochemistry is decomposed, and R ', R "and Ar 1 may be alcohols as desired in the final product. Suitable alcohols of formula 2 are those in which the stereochemistry, R 'and R ", are as desired in the final product of formula 1 and Ar 1 is deprotection as desired in the final product of formula 1. Alternatively, , A suitable alcohol of formula 2 may be an alcohol in which the stereochemistry is as desired in the final product of formula 1 after resolution and Ar 1 is deprotected as desired in the final product of formula 1.
    Suitable alcohols of formula 2 include those described herein and methods known and recognized in the art, such as those described in U.S. Patent Nos. 5,317, 020 and 5,236,921; European Patent Application No. 0 428 434, published May 22, 1991, No. 0 630 887, December 12, 1994, and No. 0 559 538, September 8, 1993, 1994 PCT Patent Application No. WO 9417045, published Aug. 4, and WO 95415061, published June 15, 1995, and Bioorganic & Medicinal Chemistry Letters , 3 , 925-930 (1993) .
    Suitable leaving groups L 1 is substituted by piperidine of formula 3 is a group that can give a compound of formula (I). Suitable leaving groups L < 1 > include, but are not limited to, chlorine, bromine, iodine, mesylate, tosylate, benzenesulfonate and the like. Conversion to a leaving group of a hydroxy group, such as chlorine, bromine, iodine, mesylate, tosylate, benzenesulfonate, etc., is well known in the art.
    For example, a compound wherein L < 1 > is bromine can be formed by contacting a suitable alcohol of formula 2 with 1.0 to 1.5 molar equivalents of carbon tetrabromide and 1.0 to 1.75 molar equivalents of triphenyl phosphine . Org. Chem. , 42 , 353-355 (1997)]. The reaction is carried out by combining the appropriate alcohol of formula 2 with carbon tetrabromide in a suitable solvent such as dichloromethane or chloroform and then adding a solution of triphenylphosphine in a suitable solvent such as dichloromethane or chloroform. In general, the reaction is carried out at a temperature of -10 ° C to ambient temperature. In general, the reaction requires from 5 minutes to 24 hours. The product can be isolated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    Alternatively, compounds wherein L < 1 > is bromine are formed by contacting a suitable alcohol of formula 2 with a slight excess of moles of triphenylphosphine dibromide (see RF Borch et al., J. Am. Chem. Soc. , ≪ / RTI > 99 , 1612-1619 (1977)). The reaction can be carried out by contacting a suitable alcohol of formula 2 with a preformed triphenylphosphine dibromide. The reaction is carried out in a suitable solvent such as tetrahydrofuran and diethyl ether. The reaction is carried out in the presence of a suitable base such as pyridine. Generally, the reaction is carried out at a temperature of 0 to 50 ° C. In general, the reaction requires from 5 minutes to 24 hours. The product can be isolated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    Alternatively, for example, compounds wherein L < 1 > is bromine are formed by contacting the appropriate alcohol of formula 2 with a slight excess of moles of methanesulfonyl chloride. The reaction is carried out in a suitable solvent, for example dichloromethane, chloroform, toluene, benzene or pyridine. The reaction is carried out in the presence of a suitable base, for example triethylamine, diisopropylethylamine or pyridine. In general, the reaction is carried out at a temperature of from -20 캜 to 50 캜. In general, the reaction requires 1 to 24 hours. The product can be isolated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    The compound of formula 2a wherein L < 1 > is iodine can be prepared by an exchange reaction, for example a Finkelstein reaction, from a compound of formula 2a wherein L < 1 > is mesylate, chloro or bromine.
    For example, the compound of formula 2a wherein L < 1 > is mesylate, chloro or bromine is contacted with 1.0 to 10.0 molar equivalents of an iodide salt such as sodium iodide or potassium iodide. The reaction is carried out in a suitable solvent, for example acetone, butanone, tetrahydrofuran, tetrahydrofuran / water mixture, toluene and acetonitrile. In general, the reaction is carried out at ambient temperature to the reflux temperature of the solvent. Generally, 1 to 24 hours are required for the reaction. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    In Step 2 of Scheme A, the compound of formula 2a is reacted with the piperidine compound of formula 3 or a salt thereof to give the protected compound of formula 1 or the compound of formula 1.
    Suitable piperidines or salts thereof of formula 3 are those wherein X 1 and X 2 are as intended in the final product of formula 1 or X 1 and X 2 are modified or deprotected and then reacted with the desired product X 1 and X 2 are obtained. Suitable piperidines of structural formula 3 are known and appreciated in the art and are described in International Patent Application No. PCT WO 92/06086, U.S. Patent No. 4,908,372, filed March 3, 1990, 1981 3 U.S. Patent No. 4,254,129 filed on March 3, U.S. Patent No. 4,254,130 filed on March 3, 1981, U.S. Patent No. 4,285,958 filed on Apr. 25, 1981, filed on October 29, 1985 U.S. Pat. No. 4,550,116, published on Mar. 24, 1993, European Patent Application No. 0 533 344, and in a similar manner to this method, in the order necessary for the formation of the appropriate piperidines of formula 3, Protection, and alkylation as is known in the art. Appropriate piperidine of formula 3 to X 1 forms a double bond between the carbon atoms contained in X 1 and Z 1 together with Z 1 is, X 1 known in the hydroxy of the corresponding general, the art of a compound For example, by refluxing in a strong acid solution. Alternatively, suitable piperidines of structural formula 3 can be prepared as described in GD Maynard et al. , Bioorg. and Med. Chem. Lets. , 3 , 753-756 (1993)), or a suitably protected isonipecotate derivative, which is suitably protected, by suitably protecting the organometallic reagent by methods known in the art Can be produced. Alternatively, suitable piperidines of formula 3 can be readily prepared from the starting materials or prepared according to the methods of CG wahlgren and AW Addison, J. Heterocyclic Chem. , 26 , 541 (1989), R. Iemura and H. Ohtka, Chem. Pharm. Bull. , 37, 967-972 (1989), and K. Ito and G. Tsukamoto, J. Heterocyclic Chem. , 24 , 31 (1987)] in a manner necessary for the formation of the appropriate piperidines of structure 3 by methods analogous to those known in the art, such as deprotection, protection and Alkylation.
    For example, a compound of formula 2a is contacted with a suitable piperidine compound of formula 3 or a salt thereof to give a protected compound of formula 1 or a compound of formula 1. The reaction may be carried out in a suitable solvent such as dioxane, tetrahydrofuran, tetrahydrofuran / water mixture, acetone, acetone / water mixture, ethyl acetate, ethyl acetate / water mixture, pyridine, acetonitrile, toluene, Is carried out in chlorobenzene or dimethylformamide. The reaction is carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, 1.0 to 6.0 molar equivalents of pyridine or diisopropylethylamine. If a suitable salt of piperidine of structure 3 is used, excess moles of the appropriate base may be necessary. The reaction may be facilitated by adding an iodide salt such as sodium iodide, potassium iodide or tetrabutylammonium iodide in an amount of 0.1 to 0.5 molar equivalent of the catalyst. The reaction is generally carried out at ambient temperature to the reflux temperature of the solvent. Generally, 1 to 72 hours are required for the reaction. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    In optional step 3 of Scheme A, the compound of formula (I) wherein Z is hydrogen or the protected compound of formula (I) is modified to provide a compound of formula (I) or a protected compound of formula (I) wherein Z is not hydrogen. Step 3 of Scheme A also includes deprotecting the protected compound of formula 1 to obtain the compound of formula 1.
    Deformation reactions include the formation of amides and the alkylation of benzimidazole nitrogen. Alkylation of benzimidazole nitrogen using suitable alkylating agents is well known in the art. The reaction is carried out in a suitable solvent, for example dioxane, tetrahydrofuran, tetrahydrofuran / water mixture, acetone or acetonitrile. Suitable alkylating agents are a group Z or (CH 2) to the p Ar 2 transition or protecting group Z or (CH 2) p Ar 2 by a deprotection desired in the final compound of formula (I) as bar desired in the final compound of formula (I) Is an alkylating agent which results in a group Z or (CH 2 ) p Ar 2 as defined herein. The reaction may be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3 -0.0] non-5-ene, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide or diisopropylethylamine. The reaction is generally carried out at ambient temperature to the reflux temperature of the solvent. Generally, 1 to 72 hours are required for the reaction. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    Alternatively, the compound of formula (I) or the protected compound of formula (I) wherein Z is hydrogen and the benzimidazole-2-carbonyl can be alkylated by a Mitsnobu reaction using a suitable alcohol. Suitable alcohols is the purpose in the final compound of formula (I) after object bar in the group Z or (CH 2) to transfer a p Ar 2 or protecting group Z or (CH 2) deprotecting the p Ar 2 which in the final compound of formula (I) It is to be obtained in the Z or (CH 2) p Ar 2 as bar alcohol.
    Using a suitable protecting group as described for example in T. Greene, Protecting Groups in Organic Synthesis , for example, deprotection reactions which remove a hydroxy protecting group or hydrolyze an ester are known in the art It is acknowledged.
    A general synthetic method for preparing alcohols of formula (2) is described in scheme B. Reagents and starting materials are readily available to those of ordinary skill in the art. Unless otherwise stated in Scheme B, all substituents are as defined above.
    In step 1 of Scheme B, the appropriate nitrile of formula 5 is alkylated with a suitable protecting group of formula 4 to give 4- (protected-hydroxy) butyronitrile of formula 6. [
    Suitable nitriles of formula 5 are those wherein Ar 1 is as desired in the desired compound of formula 1 or is isothyryl as desired in the final product of formula 1 after deprotection of Ar 1 . Suitable protective alcohols of formula 4 are escape groups, alcohols in which L < 2 > can be substituted with an anion derived from the appropriate nitrile of formula 5. Suitable leaving groups include, but are not limited to, chlorine, bromine, iodine and mesylate, preferably bromine and iodine. The selection and use of a suitable protecting group, Pg 1 , as described in T. Greene, Protecting Groups in Organic Synthesis , is well known in the art. The use of tetrahydropyran-2-yl and tert-butyldimethylsilylhydroxy protecting groups is generally preferred.
    For example, suitable nitriles of formula 5 are contacted with 0.8 to 1.2 molar equivalents of a suitable protective alcohol of formula 4 under phase transfer catalytic conditions. The reaction is carried out in a molar amount of 2 to 10 times excess of a suitable base, such as sodium hydroxide or potassium hydroxide. The reaction is carried out in a solvent, for example water, an ethyl acetate / water mixture, a dichloromethane / water mixture or a tetrahydrofuran / water mixture. The reaction may be carried out in the presence of a suitable phase transfer catalyst such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium iodide, Monohydrogen sulfate, and the like. The reaction is generally carried out at -20 캜 to 60 캜. Generally, the reaction requires 1 to 762 hours. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    Alternatively, for example, a suitable nitrile of formula 5 is contacted with 1.0 to 1.2 molar equivalents of a suitable protective alcohol of formula 4. The reaction is carried out in the presence of equimolar amounts of a suitable base such as sodium hydride, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, potassium 3-hept-butoxide, s-butyl lithium and lithium diisopropylamide . The reaction is generally carried out in a solvent such as dimethylformamide and tetrahydrofuran. The reaction is generally carried out at -78 ° C to 0 ° C. Generally, 1 to 72 hours are required for the reaction. The product can be separated and purified by techniques known in the art, such as extraction, evaporation, distillation, grinding, chromatography and recrystallization.
    In step 2 of Scheme B, the 4- (protected-hydroxy) butyronitrile of formula 6 is reduced to give the amino compound of formula 7.
    4- (protected-hydroxy) butyronitrile of formula 6 is reacted in the presence of a suitable catalyst, such as Raney nickel or platinum, in the presence of cobalt (II) hexahydrate or hydrogen in the presence of an excess of a suitable reducing agent, For example sodium borohydride. Ar 1 is preferably thienyl or pyridyl, sodium borohydride in the presence of cobalt (II) hexahydrate.
    When sodium borohydride is used in the presence of cobalt chloride, the reaction is carried out in a suitable solvent, for example methanol or ethanol. The reaction is generally carried out at 0 캜 to 50 캜. Generally, 1 to 72 hours are required for the reaction. The product can be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, distillation, chromatography and recrystallization.
    When Raney nickel is used, the reaction is carried out in a suitable solvent containing ammonia, for example, an aqueous solution of ethanol / ammonium hydroxide or a solution of methanol / ammonium hydroxide. The reaction is generally carried out at ambient temperature to 70 ° C. The reaction is carried out at a hydrogen pressure of 15 psi to 120 psi in a device designed to carry out the reaction under pressure, for example a Parr hydrogenation unit. The product can be separated by filtration, evaporation and careful removal of the catalyst. The product can be purified by extraction, evaporation, grinding, chromatography and recrystallization.
    If platinum oxide is used, the reaction is carried out in a suitable solvent, for example ethanol, methanol, chloroform, ethanol / chloroform mixture or methanol / chloroform mixture. The reaction is generally carried out at ambient temperature to 50 < 0 > C. The reaction is carried out at a hydrogen pressure of 15 psi to 120 psi in a device designed to carry out the reaction under pressure, for example a Parr hydrogenation unit. Generally, 8 to 48 hours are required for the reaction. The product can be purified by extraction, evaporation, grinding, chromatography and recrystallization.
    In step 3 of Scheme B, the amino compound of formula 7 is benzoylated with a suitable benzoylating agent to give the benzamide of formula 8. Suitable benzoylating agents are obtained by the transfer of benzoyl groups or substituted benzoyl groups such as benzoyl halides, substituted benzoyl halides, benzoyl anhydrides, substituted benzoyl anhydrides, benzoyl mixed anhydrides or substituted benzoyl mixed anhydrides to give the benzamide of formula 8 It is a substance that can be made. Suitable benzoylating agents provide the benzamide of formula 8 wherein R ' and R " are as desired in the final product of formula (1).
    For example, the amino compound of formula 7 is contacted with 1 to 1.5 molar equivalents of a suitable benzoylating agent. The reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide or pyridine. The reaction is carried out in the presence of a base, for example sodium carbonate, sodium bicarbonate, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine. The reaction is generally carried out at -20 캜 to 50 캜. In general, the reaction requires 1 to 6 hours. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    Alternatively, for example, the amino compound of formula 7 is contacted with 1 to 1.5 molar equivalents of a suitable benzoylating agent under Schotten-Baumann conditions. The reaction is carried out in a suitable solvent, for example an ethyl acetate / water mixture, an acetone / water mixture, a tetrahydrofuran / water mixture or a dichloromethane / water mixture. The reaction is carried out in the presence of a base, for example sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or sodium hydroxide. The reaction is generally carried out at a temperature of 0 ° C to the reflux temperature of the solvent. In general, the reaction requires 1 to 6 hours. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    In step 4 of Scheme B, the benzamide of formula 8 is methylated with a suitable methylating agent to give the N-methylbenzamide of formula 9. Suitable methylating agents are those which transfer methyl to the benzamide of formula 8 and include iodomethane, bromomethane, dimethyl sulfate, trimethyloxonium, tetrafluoroborate, and the like.
    For example, the benzamide of formula 8 is contacted with 1 to 4 molar equivalents of a suitable methylating agent. The reaction is carried out in the presence of a suitable base such as n-butyllithium, sec-butyllithium, sodium hydride, sodium bis (trimethylsilyl) amide, potassium tert-butoxide and lithium diisopropylamide, preferably sodium hydride , Sodium bis (trimethylsilyl) amide and 1 to 4 molar equivalents of sec-butyllithium. The reaction is generally carried out at -20 캜 to 60 캜. Generally, 1 to 72 hours are required for the reaction. The product may be separated and purified by techniques known in the art, such as extraction, evaporation, grinding, chromatography and recrystallization.
    In step 5 of scheme B, the N-methyl benzamide of formula 9 is deprotected to give the alcohol of formula 2. < Desc / For example, deprotection reactions using a suitable protecting group to remove the hydroxy protecting group, as described in T. Greene, Protecting Groups in Organic Synthesis , are well known.
    The following examples and preparations are typical synthetic methods for the compounds of formula (I). It is to be understood that these examples are illustrative only and are not in any way limited to the scope of the present invention.
    Recipe 1
    Synthesis of 4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt
    Piperidine-4-carboxylic acid (500 g), water (4.2 L), tertiary-butanol (4 L) and 50% aqueous sodium hydroxide solution (386 g). Di-tert-butyl dicarbonate (930 g) is added. After 20 hours, the reaction mixture is concentrated in vacuo to about 1/2 volume. Add a 10% aqueous hydrochloric acid solution slowly until the pH is about 4. Extract with diethyl ether (3 x 4 L). The organic layer is dried over MgSO 4 , filtered and evaporated in a volume of about 4 L in a steam bath. Ethyl acetate (4 L) is added and evaporated to about 4 L volume in a steam bath. Filter and continue to evaporate in a volume of about 2 liters in a steam bath. Cool filtration affords 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid.
    4-carboxylic acid (813.7 g) and dichloromethane (6 L) are combined. Carbodiimidazole (633.1 g). After 1 hour, N-methyl-O-methylhydroxylamine hydrochloride (380.5 g) was added. After 56 hours, the reaction mixture is extracted with a 5% aqueous hydrochloric acid solution and a 5% aqueous sodium bicarbonate solution. The organic layer was dried in MgSO 4, filtered, and evaporated in vacuo 1- (tert-butoxycarbonyl) piperidine -4- (N- methyl -O- methyl) to give the hydroxyl samin acid.
    Benzimidazole (57.8 g, 490 mmol) and dimethylformamide (570 ml) are combined. Cool to about 20 캜 using an ice bath. Sodium hydride (20.2 g, 60% in oil, 500 mmol) is added at a similar rate and the temperature of the reaction mixture is maintained at about 20 ° C. After the addition of sodium hydride is completed, stirring is carried out for about 1 hour. A solution of 2- (trimethylsilyl) ethoxymethyl chloride (60 g, 360 mmol) in dimethylformamide (60 ml) is added at a similar rate and the temperature of the reaction mixture is kept below 20 ° C. After 18 hours, water (50 ml) is added dropwise. When addition is complete, pour the reaction mixture into water (2 L). It is extracted repeatedly with diethyl ether. The organic layers are combined and extracted with water. The organic layer is dried over MgSO 4 , filtered and concentrated in vacuo to give 1 - ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole.
    1 - ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole (91.2 g, 367 mmol) and tetrahydrofuran (500 ml). Cool to -78 ° C using a dry ice / acetone bath. A solution of n-butyllithium (146 mL, 2.5 M in hexanes, 367 mmol) was added at a similar rate and the temperature of the reaction mixture was kept at -70 < 0 > C. After addition of n-butyllithium is complete, it is stirred for 30 minutes and brought to -78 ° C. A solution of 1- (tert-butoxycarbonyl) piperidine-4- (N-methyl-O-methyl) hydroxamic acid (99.9 g, 367 mmol) in tetrahydrofuran (100 mL) is added dropwise. Allow to warm to ambient temperature. After 18 hours, a saturated aqueous ammonium chloride solution (100 ml) is added dropwise. Water (300 ml) is added and extracted with diethyl ether. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel eluting with 10% ethyl acetate / hexanes to give a residue. Recrystallization of the residue from ethanol / water gave (1- (tert-butoxycarbonyl) -4- (1 - ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole- ) Piperidine. ≪ / RTI >
    (20.0 g, 43.5 mmol) was added to a solution of 1- (tert-butoxycarbonyl) -4- (1 - ((2-trimethylsilyl) ethoxymethyl) -1H-benzimidazole-2-carbonyl) piperidine After the addition was completed, the mixture was heated to 50 DEG C. After 1.5 hours, the mixture was cooled to ambient temperature, and after 2.5 hours, the mixture was extracted twice with diethyl ether. Ethyl ether (300 mL) and isopropanol (60 mL) were added to the aqueous layer to obtain a solid. The solid was collected by filtration, washed with diethyl ether and dried to give the title compound.
    Elemental analysis of C 13 H 15 N 3 O · 2 HI
    Found C 32.19; H 3.53; N 8.66
    Calculated C 32.34; H 3.37; N 8.48
    Recipe 2
    Synthesis of 1- (tert-butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine
    4- (1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt (9.17 g, 18.9 mmol) and tert-butanol (100 mL) are combined. Aqueous sodium bicarbonate solution (40 mL, 1M, 40 mmol) was added. Di-tert-butyl dicarbonate (5.2 g, 23.9 mmol) is added. After 72 hours, it is concentrated in vacuo to give a residue. The residue and ethyl acetate are combined. Aqueous 1M hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, aqueous 0.5M sodium thiosulfate solution and brine. The separated organic layer was dried over Na 2 SO 4, filtered, and concentrated in vacuo to give a solid. The solid was triturated with ethyl acetate and the solid was collected by filtration, recrystallized from ethyl acetate, and recovered to dryness to give the title compound. Melting point; 226-228 [deg.] C. Rf = 0.30 (silica gel, 20% ethyl acetate / hexanes).
    Recipe 3
    Synthesis of 4- (1- (pyrid-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt
    To a solution of l- (tert-butoxycarbonyl) -4- (lH-benzimidazole-2-carbonyl) piperidine (2.0 g, 6.1 mmol) and 2 (Chloromethyl) pyridine (2.32 g, 18.2 mmol) was obtained by combining 2- (chloromethyl) pyridine hydrochloride, sodium carbonate and dichloromethane with stirring, followed by filtration and evaporation and potassium carbonate (4.2 g, 30.4 mmol) . Reflux is heated. After 24 hours, cool to ambient temperature and dilute with ethyl acetate. Extract with water and brine. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 50% ethyl acetate / hexanes, and then dried to give 1- (tert-butoxycarbonyl) -4- (1-pyrid- Benzimidazole-2-carbonyl) piperidine. ≪ / RTI > Melting point 45-50 캜. Rf = 0.24 (silica gel, 40% ethyl acetate / hexanes).
    Elemental analysis of C 24 H 28 N 4 O 3
    Found C 68.08; H 6.74; N 13.23
    Calcd. C 67.88; H 6.68; N 13.00
    Benzimidazole-2-carbonyl) piperidine (1.96 g, 4.7 mmol) and dichloro (4-fluorobenzyl) Methane (150 ml) is added. Cool to 0 캜 using an ice bath. The hydric acid (gas) is added until the solution is saturated and stirred. After 30 minutes, the hydride acid (gas) is added again until the solution is saturated. After 2 h evaporation in vacuo and drying gave the title compound. Melting point 165-167 [deg.] C.
    Recipe 4
    Synthesis of 1- (tert-butyldimethylsilyloxy) -2-bromoethane
    Add imidazole (59.9 g, 880 mmol), tert-butyldimethylsilyl chloride (60.3 g, 400 mmol) and dimethylformamide (300 mL). Cool in a salt-water bath to 0 < 0 > C. 2-Bromoethanol (50.0 g, 400 mmol) is added dropwise at a similar rate so that the temperature of the reaction mixture does not rise above 0 ° C. After 2 hours, warm to ambient temperature. After 18 h, the reaction mixture is extracted three times with hexane. The hexane layers are combined, extracted three times with saturated aqueous ammonium chloride solution, three times with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over Na 2 SO 4, and evaporated in vacuo to give the title compound.
    Recipe 5
    Synthesis of 1- (tert-butylmethylsilyloxy) -2-iodoethane
    Using 2-iodoethanol and by the method of Preparation 4, the title compound is obtained.
    Example 1
    1-yl) -2- (4- (4-fluorophenyl) -1H-benzimidazole-2-carbonyl) Fluorophenyl) butyl) -3,4,5-trimethoxybenzamide

    1.1.1 Synthesis of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    See Org. Syn. Collective Volume Ⅳ, 897-900 (1988) ] of the method by applying the phenyl acetonitrile in a 4-in water (100㎖) (56.5g, 418mmol) , 50% sodium hydroxide aqueous solution (106.3g, 1330mmol) and benzyltriethylammonium Add ethyl ammonium chloride (0.95 g). The mixture is heated to about 30 DEG C and vigorously stirred. 1- (tert-Butyldimethylsilyloxy) -2-bromoethane (50 g, 209 mmol) is added dropwise over about 30 minutes. When the dropwise addition is completed, the mixture is heated to about 40 DEG C and stirred vigorously. After 18 h, the reaction mixture is diluted with ethyl acetate and stirred. After 30 minutes, the organic layer was separated, extracted three times with saturated aqueous ammonium chloride solution, twice with aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over Na 2 SO 4, filtered, and evaporated in vacuo to give a residue. Evaporation of the residue affords the title compound. Melting point: 100-115 ° C at 0.2 mm Hg. Rf = 0.35 (silica gel, 1/1 dichloromethane / hexane).
    1.1.2 Synthesis of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    4-Fluorophenylacetonitrile (5.0 g, 37.0 mmol) and tetrahydrofuran (45 ml) are combined. Cool to about -65 C using a dry ice / acetone bath. A solution of 1- (tert-butyldimethylsilyloxy) -2 (1 H) -dione in tetrahydrofuran (10 mL) was added to a solution of potassium bis- (trimethylsilyl) amide (89 mL, 0.5 M in toluene, 44.5 mmol) Iodoethane (12.7 g, 44.4 mmol) is added. After the addition of 1- (tert-butyldimethylsilyloxy) -2-iodoethane is complete, the mixture is warmed to ambient temperature. After 18 h, the reaction mixture is diluted with tetrahydrofuran, extracted three times with saturated aqueous ammonium chloride solution and then twice with brine. The organic layer was dried in Na 2 SO 4, filtered and concentrated in vacuo to thereby obtain a residue. The residue was subjected to silica gel chromatography eluting with 1/1 dichloromethane / hexane to give the title compound.
    1.1.3 Synthesis of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butylonitrile
    4-Fluorophenylacetonitrile (1.0 g, 7.4 mmol) and tetrahydrofuran (9 mL) are combined. Cool to about -70 C using a dry ice / acetone bath. A solution of potassium bis- (trimethylsilyl) amide (14.8 mL, 0.5 M in toluene, 7.4 mmol) was added. After 2 h, the solution prepared above via cannula was added to a cold (25 [deg.] C) solution of l- (tert-butyldimethylsilyloxy) -2-iodoethane (2.1 g, 7.4 mmol) in tetrahydrofuran Lt; / RTI > solution. After the addition of 1- (tert-butyldimethylsilyloxy) -2-iodoethane is complete, the mixture is warmed to ambient temperature. After 18 h, the reaction mixture is diluted with tetrahydrofuran, extracted three times with saturated aqueous ammonium chloride solution and then twice with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography eluting with 1/1 dichloromethane / hexane to give the title compound.
    1.1.4 Synthesis of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    4-Fluoroacetonitrile (1.0 g, 7.4 mmol) and tetrahydrofuran (20 mL) are combined. Cool to about -70 C using a dry ice / acetone bath. S-Butyl lithium (6.3 mL, 1.3 M in cyclohexane, 8.1 mmol) is added. After 1 hour, a solution of 1- (tert-butyldimethylsilyloxy) -2-iodoethane (2.1 g, 7.4 mmol) in tetrahydrofuran (4 ml) was added. After 2 hours, warm to ambient temperature. After 18 h, the reaction mixture is diluted with ethyl acetate, extracted twice with saturated aqueous ammonium chloride solution and then twice with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography eluting with 1/1 dichloromethane / hexane to give the title compound.
    1.2 Synthesis of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile (43.0 g, 146.5 mmol) and ethanol (200 mL) were combined in a dropping funnel. Raney nickel (129 g) is added to the reaction mixture. A concentrated ammonium hydroxide (40 ml) solution is added. Hydrogenated at 50 psi in a wave shaker. After 24 hours, filter through a celite pad and wash the solid with ethanol. The filtrate is concentrated in vacuo to give the title compound.
    1.3 Synthesis of N- (2-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl-3,4,5-trimethoxybenzamide
    To a solution of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine (7.33 g, 24.6 mmol) and sodium carbonate (2.61 g, 24.6 mmol) in ethyl acetate / water (400 mL) ). The reaction mixture is cooled to 0 < 0 > C using a salt-ice bath. A solution of 3,4,5-trimethoxybenzoyl chloride (5.96 g, 25.9 mmol) in ethyl acetate (50 mL) is slowly added at a similar rate so that the temperature of the reaction mixture does not rise above 5 ° C. After 2 hours, warm to ambient temperature. After 18 h the layers are separated and the organic layer is extracted twice with saturated aqueous ammonium chloride solution, twice with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel eluting with 50% ethyl acetate / hexanes and dried to give the title compound. Melting point: 113-114 캜. Rf = 0.30 (silica gel, 50% ethyl acetate / hexanes).
    Elemental analysis of C 26 H 38 FNO 3 Si
    Found: C 63.51; H 7.79; N 2.85
    Calculated: C 63.43; H 7.51; N 2.66
    1.4 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Combine the hexane washed with sodium hydride (0.48 g, 50% in oil, 10.0 mmol) and dimethylformamide (5 mL). The reaction mixture is cooled to 0 < 0 > C using a salt-ice bath. To a solution of N-2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide (4.0 g, 8.1%) in dimethylformamide mmol) is added slowly. Stir until gas evolution stops. Iodomethane (0.62 ml, 10.0 mmol) was added. After 16 hours, the reaction mixture is diluted with ethyl acetate, extracted with water three times, then with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel eluting with 1/1 ethyl acetate / hexanes and dried to give the title compound. Rf = 0.15 (silica gel, 1/1 ethyl acetate / hexanes).
    Elemental analysis of C 27 H 40 FNO 3 Si
    Found: C 64.13; H 7.97; N 2.77
    Calculated: C 63.73; H 7.90; N 2.88
    1.5 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    -3,4,5-trimethoxybenzamide (3.9 g, 7.65 mmol) and N-methyl-N- (2- (4- fluorophenyl) -4- (tert- butyldimethylsilyloxy) Add methanol (40 ml). Ammonium fluoride (1.71 g, 46.0 mmol) is added. Reflux is heated. After 20 h, it is concentrated in vacuo to give a residue. The residue is combined with water and dichloromethane. The layers are separated and the aqueous layer is extracted with dichloromethane. The organic layers are combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound. Melting point: 30-35 占 폚. Rf = 0.30 (silica gel, 10/1 ethyl acetate / methanol).
    1.6 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4- (methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide (2.5 g, 6.36 mmol) in N, N-dimethylformamide And diisopropylethylamine (2.4 mL, 14.0 mmol) and anhydrous dichloromethane (25 mL). The reaction mixture is cooled to 0 < 0 > C in an ice bath. Methanesulfonyl chloride (0.69 ml, 8.9 mmol) is slowly added. After 1 h, the reaction mixture is diluted with dichloromethane, extracted three times with 1 M aqueous hydrochloric acid solution, twice with aqueous sodium bicarbonate solution and then with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give the title compound. Rf = 0.43 (silica gel, 10/1 ethyl acetate / methanol).
    1.7 Preparation of N-Methyl-N- (4- (4- (1- (pyrid-2-ylmethyl) -1H- benzimidazole- 2-carbonyl) piperidin- -Fluorophenyl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    To a solution of N-methyl-N- (2- (4-fluorophenyl) -4- (methanesulfonylbutyl) -3,4,5-trimethoxybenzamide (0.37 g, 0.79 mmol ), Diisopropylethylamine (1.23 ml, 7.1 mmol) and 4- (1-pyrid-2-ylmethyl) -1H-benzimidazole-2- carbonyl) piperidine hydroiodic acid salt g, 1.2 mmol). Reflux is heated. After 18 h, the reaction mixture is cooled, diluted with ethyl acetate, extracted with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried in Na 2 SO 4, filtered, and concentrated in vacuo to give a residue. The title compound is obtained after chromatography on silica gel, eluting with 10 / 0.3 / 89.7 methanol / concentrated aqueous ammonia solution / dichloromethane, and drying.
    Recipe 6
    Synthesis of 1- (tetrahydropyran-2-yloxy) -2-bromomethane
    2-Bromoethanol (14.2 ml, 200 mmol) and dihydropyran (18.25 ml, 200 mmol) in dichloromethane (20 ml) are combined. Pyridinium p-toluenesulfonic acid (5 g, 20 mmol) was added. After 2.5 hours, the reaction mixture is diluted with diethyl ether and extracted with water, 1/1 water / brine, water then brine. The organic layer was dried in MgSO 4, filtered, and evaporated in vacuo to give a residue. Evaporation of the residue affords the title compound. Boiling point: 80-90 ° C at 15-20 mm Hg.
    Example 2
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorobenzyl) Dichlorophenyl) butyl) benzamide

    2.1 Synthesis of 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyronitrile
    Sodium hydride (1.2 g, 50 mmol) and tetrahydrofuran (20 mL) are combined. A solution of 3,4-dichlorophenylacetonitrile (8.9 g, 47.8 mmol) in tetrahydrofuran (50 ml) is added dropwise at about 0 ° C. After the addition is complete, the mixture is warmed to ambient temperature and stirred. After 2.5 hours, the mixture was cooled to 0 占 폚 and 1- (tetrahydropyran-2-yloxy) -2-bromoethane (10.0 g, 47.9 mmol) was added. Allow to warm to ambient temperature. After 16 h, the reaction mixture is poured into saturated ammonium chloride solution and extracted with diethyl ether. The organic layer is separated and extracted with water and brine. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography to obtain the title compound with successive elution with 5% ethyl acetate / hexanes, 10% ethyl acetate / hexanes and 20% ethyl acetate in hexanes.
    2.2 Synthesis of 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine
    2- (3,4-Dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyronitrile (7 g) and ethanol (20 ml) were combined in a wave funnel. Raney nickel (1 g) is added to the reaction mixture. A concentrated ammonium hydroxide solution (3.5 ml) is added. The paddle stirrer is hydrogenated at 50 psi. After 24 hours, filtrate through a celite pad and wash the solid with ethanol. The filtrate is concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography in vacuo, eluting successively with 50% ethyl acetate / hexanes and 10% methanol / dichloromethane to give the title compound.
    2.3 Synthesis of N- (2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide
    2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine (3.05 g, 9.6 mmol) and N-methylmorpholine (2.2 ml, 20 mmol). The reaction mixture is cooled to 0 < 0 > C in a salt-water bath. Benzoyl chloride (1.2 mL, 10.3 mmol) is slowly added. After 1 h, the reaction mixture is extracted with saturated sodium bicarbonate solution followed by water. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography with successive elution with 35% ethyl acetate / hexanes and 50% ethyl acetate / hexanes to give the title compound.
    2.4 N-Methyl-N- (2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2- yloxy) butyl)
    N-2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butyl) benzamide (3.84 g) and tetrahydrofuran (20 ml). Sodium hydride (0.28 g, 11.5 mmol) was added and stirred until gas evolution ceased. Iodomethane (1.5 mL, 24.1 mmol) was added. After 6 hours, the reaction mixture is diluted with diethyl ether and extracted with saturated ammonium chloride solution. The organic layer is separated and extracted with sodium bisulfite solution, water and brine. The organic layer is dried over MgSO 4 , filtered and concentrated in vacuo to give the title compound.
    2.5 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) benzamide
    (3.7 g) and methanol (30 ml) were combined. The mixture was stirred at room temperature for 2 hours. p-Toluenesulfonic acid hydrate (0.73 g) was added and stirred. After 18 hours, it is concentrated in vacuo to give a residue. The residue and dichloromethane are combined and extracted with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography with successive elution with 50% ethyl acetate / hexanes and ethyl acetate to give the title compound.
    2.6 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide
    (0.5 g), diisopropylethylamine (0.3 mL, 1.7 mmol) and anhydrous dichloromethane (8 mL) was added dropwise to a solution of N- (2- (3,4- dichlorophenyl) ). The reaction mixture is cooled to 0 < 0 > C in an ice bath. Methanesulfonyl chloride (0.13 ml, 1.7 mmol) is slowly added. Allow to warm to ambient temperature. After 18 h, the reaction mixture was quenched by ice. The organic layer is separated and extracted three times with 1 M hydrochloric acid solution and twice with saturated sodium bicarbonate solution. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound.
    2.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2- carbonyl) piperidin- Dichlorophenyl) butyl) benzamide Synthesis of
    A solution of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide (0.6 g, 1.4 mmol), sodium bicarbonate (0.23 g, 2.8 mmol) in tetrahydrofuran mmol) and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine trifluoroacetic acid salt (0.63 g, 1.4 mmol) Sum. Reflux is heated. After 3 days, the reaction mixture is cooled, diluted with ethyl acetate, and then extracted with water and brine. The organic layer was dried in MgSO 4, filtered, and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography with successive elution with 10% toluene / ethyl acetate and 10% ethanol / 10% toluene / ethyl acetate to give the title compound, after drying, the title compound was obtained. Melting point: 65-70 DEG C
    2.8 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2- carbonyl) piperidin- -Dichlorophenyl) butyl) benzamide hydrochloride salt Synthesis of
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorobenzyl) Dichlorobenzyl) butyl) benzamide (0.71 g, 1.4 mmol) and methanol (10 ml). A saturated solution of hydrochloric acid in diethyl ether (3 ml) is added. Evaporation in vacuo yields a residue. The residue and butanone (5 mL) are combined and diethyl ether is slowly added to give a solid. The solid was collected and dried to give the title compound.
    Example 3
    (4-fluorobenzyl) -1H-benzoimidazol-2-yl) -4-hydroxypiperidin- 4-methoxybenzyl) butyl) benzamide

    3.1 Synthesis of 2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Prepared by the method of Example 1.1.1 using 4-methoxyphenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, the title compound was obtained.
    3.2 Synthesis of 2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2, using 2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    3.3 Synthesis of N- (2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide
    The title compound is prepared by the method of Example 1.3 using 2- (4-methoxyphenyl) -4- (tert-butylmethylsilyloxy) butylamine and benzoyl chloride.
    3.4 Synthesis of N-methyl-N- (2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl)
    The title compound is prepared by the method of Example 1.4, using N- (2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide.
    3.5 Synthesis of N-methyl-N- (2- (4-methoxyphenyl) -4-hydroxybutyl) benzamide
    The title compound is prepared by the method of Example 1.5 using N-methyl-N- (2- (4-methoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide.
    3.6 Synthesis of N-methyl-N- (2- (4-methoxyphenyl) -4-methanesulfonylbutyl) benzamide
    The title compound was prepared by the method of Example 1.6 using N-methyl-N- (2- (4-methoxyphenyl) -4- (tert-butylbutyl) benzamide and methanesulfonyl chloride. do.
    3.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzoimidazol- (4-methoxyphenyl) butyl) benzamide Synthesis of
    (4-methoxyphenyl) -4-methanesulfonylbutyl) benzamide and 4- (1- (4-fluorobenzyl) -1H-benzoimidazol- -4-hydroxy-piperidine and by the method of Example 1.7, the title compound is obtained.
    Recipe 7
    Synthesis of 4- (1- (2- (5-hydroxymethylpur-2-ylmethyl) -4- (1H-benzimidazole-2-carbonyl) piperidine
    PG McDougal, et al., J. Org. Chem. , 51 , 3388-3390 (1986)], hexane washed with sodium hydride (20 mmol) and tetrahydrofuran (40 ml) is combined. 2,5-Furandimethanol (20 mmol) is slowly added. After gas evolution ceased, tert-butyldimethylsilyl chloride (20 mmol) was added and vigorously stirred. After 1 hour, the reaction mixture is poured into diethyl ether and extracted with saturated aqueous sodium bicarbonate solution, water and then brine. The organic layer is dried over Na 2 SO 4 , filtered and evaporated in vacuo to give 5- (tert-butyldimethylsilyloxy) methyl-2-hydroxymethylfuran.
    (Tert-Butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (10 mmol), 5- (tert- butyldimethylsilyl Oxy) methyl-2-hydroxymethylfuran (10 mmol) and triphenylphosphine (10 mmol). Diethyl azodicarboxylate (10 mmol) is added. After 18 h, the reaction mixture is evaporated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic layer is separated and extracted with water and brine. The organic layer was dried over Na 2 SO 4, filtered off and evaporated in vacuo to give a residue. The residue was subjected to silica gel chromatography to obtain 1- (tert-butoxycarbonyl) -4- (1-5- (tert-butyldimethylsilyloxy) methylfur-2-ylmethyl) -1H-benzimidazole -2-carbonyl) piperidine. ≪ / RTI >
    1- (tert-Butoxycarbonyl) -4- (1-5- (tert-butyldimethylsilyloxy) methylfur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine (7 mmol) and methanol. Ammonium fluoride (42 mmol) is added. Reflux is heated. After 20 h, it is concentrated in vacuo to give a residue. The residue is combined with water and dichloromethane. The layers are separated and the aqueous layer is extracted twice with dichloromethane. The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 1- (tert-butoxycarbonyl) -4- (1- (5-hydroxymethylpur-2-ylmethyl) Benzimidazole-2-carbonyl) piperidine. ≪ / RTI >
    Benzimidazole-2-carbonyl) piperidine (5 mmol) and di (tert-butoxycarbonyl) -4- (25 ml). Add a hydrochloric acid solution in dioxane (1.25 mL, 4M, 5 mmol) slowly. After 45 minutes, diethyl ether was added and evaporated in vacuo to give a residue. The residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer is separated and extracted with brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated in vacuo to give the title compound.
    Example 4
    Methyl-N- (4- (4- (1- (5-hydroxymethylpur-2-ylmethyl) -1H-benzimidazole) -4-hydroxypiperidin- - phenylbutyl) benzamide

    4.1. Preparation of N-methyl-N- (4- (4- (1- (5-hydroxymethylpur-2-ylmethyl) -1H-benzimidazole) -4-hydroxypiperidin- Synthesis of 2-phenylbutyl) benzamide
    Methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1- (5-hydroxymethylpur -2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine, and by the method of Example 1.7, the title compound was obtained.
    Example 5
    2- (3,4-dichlorophenyl) butyl) benzamide < / RTI >

    5.1 Synthesis of N-methyl-N- (4- (4- (benzthiazole-2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl)
    (Benzothiazole-2-carbonyl) piperidine was used instead of N-methyl-N- (2- (3,4- dichlorophenyl) -4- methanesulfonylbutyl) To give the title compound.
    Example 6
    Methyl-N- (4- (4-hydroxydiphenylmethyl) piperidin-1-yl) -2-phenylbutyl) benzamide

    6.1 Synthesis of 2-phenyl-4- (tert-butyldimethylsilyloxy) butyronitrile
    Prepared by the method of Example 1.1.1, using phenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, the title compound is obtained.
    6.2 Synthesis of 2-phenyl-4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2 using 2-phenyl-4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    6.3 Synthesis of N- (2-phenyl-4- (tert-butyldimethylsilyloxy) butyl) benzamide
    The title compound was prepared by the method of Example 1.3 using 2-phenyl-4- (tert-butyldimethylsilyloxy) butylamine and benzoyl chloride.
    6.4 Synthesis of N-methyl-N- (2-phenyl-4- (tert-butyldimethylsilyloxy) butyl)
    Prepared by the method of Example 1.4, using N- (2-phenyl-4- (tert-butyldimethylsilyloxy) butyl) benzamide, the title compound was obtained.
    6.5 Synthesis of N-methyl-N- (2-phenyl-4-hydroxybutyl) benzamide
    Prepared by the method of Example 1.5 using N-methyl-N- (2-phenyl-4- (tert-butyldimethylsilyloxy) butyl) benzamide, the title compound was obtained.
    6.6 Synthesis of N-methyl-N- (2-phenyl-4- (methanesulfonylbutyl) benzamide
    Methyl-N- (2-phenyl-4-hydroxybutyl) benzamide and methanesulfonyl chloride, the title compound is obtained.
    6.7 Synthesis of N-methyl-N- (4- (4- (hydroxydiphenylmethyl) piperidin-1-yl) -2-phenylbutyl) benzamide
    The title compound was prepared by the method of Example 1.7 using N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (hydroxyphenylmethyl) piperidine.
    Example 7
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorobenzyl) Dimethoxyphenyl) butyl) benzamide

    7.1 Synthesis of 2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Dimethoxyphenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound was obtained.
    7.2 Synthesis of 2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2, using 2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    7.3 Synthesis of N- (2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide
    Prepared by the method of Example 1.3, using 2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butylamine and benzoyl chloride, the title compound was obtained.
    7.4 Synthesis of N-methyl-N- (2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl)
    The title compound is prepared by the method of Example 1.4, using N- (2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide.
    7.5 Synthesis of N-methyl-N- (2- (3,4-dimethoxyphenyl) -4-hydroxybutyl) benzamide
    The title compound was obtained by the method of Example 1.5 using 2- (3,4-dimethoxyphenyl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide.
    7.6 Synthesis of N-methyl-N- (2- (3,4-dimethoxyphenyl) -4- (methanesulfonylbutyl) benzamide
    The title compound is prepared by the method of Example 1.6 using N-methyl-N- (2- (3,4-dimethoxyphenyl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride.
    7.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- - dimethoxyphenyl) butyl) benzamide Synthesis of
    Benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazol-2-ylmethyl) Carbonyl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Example 8
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2- (benzo [1, 3] dioxol-5-yl) butyl) benzamide

    8.1 Synthesis of 2- (benzo [1,3] dioxol-5-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Benzo [1,3] dioxol-5-yl acetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromomethane as starting materials and by the method of Example 1.1.1, the title compound was obtained do.
    8.2 Synthesis of 2- (benzo [1,3] dioxol-5-yl) -4- (tert-butyldimethylsilyloxy) butylamine
    The title compound is prepared by the method of Example 1.2 using 2- (benzo [1,3] dioxol-5-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile.
    8.3 Synthesis of N- (2- (benzo [1,3] dioxol-5-yl) -4- (tert-butyldimethylsilyloxy) butyl)
    The title compound is prepared by the method of Example 1.3 using 2- (benzo [1,3] dioxol-5-yl) -4- (tert-butyldimethylsilyloxy) butylamine and benzoyl chloride .
    8.4 Synthesis of N-methyl-N- (2- (benzo [1,3] dioxol-5-yl) -4- (tert- butyldimethylsilyloxy)
    The title compound was prepared using the method of Example 1.4, using N-2- (benzo [1,3] dioxol-5-yl) -4- (tert- butyldimethylsilyloxy) do.
    8.5 Synthesis of N-methyl-N- (2- (benzo [1,3] dioxol-5-yl) -4-hydroxybutyl) benzamide
    Using the method of Example 1.5 and using N-methyl-N- (2- (benzo [1,3] dioxol-5-yl) -4- (tert- butyldimethylsilyloxy) To give the title compound.
    8.6 Synthesis of N-methyl-N- (2- (benzo [1,3] dioxol-5-yl) -4-methanesulfonylbutyl)
    The title compound was prepared according to the method of Example 1.6, using N-methyl-N- (2- (benzo [1,3] dioxol-5-yl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride. Compound.
    8.7 Preparation of N-methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- , 3] dioxol-5-yl) butyl) benzamide
    Benzamide and 4- (1- (4-fluorobenzyl) -1H-benzo [b] thiophene) Imidazole-2-carbonyl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Example 9
    (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- Yl) butyl) benzamide

    9.1 Synthesis of 2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Naphth-2-yl acetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound is obtained.
    9.2 Synthesis of 2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butylamine
    The title compound is prepared by the method of Example 1.2 using 2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile.
    9.3 Synthesis of N- (2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide
    The title compound is prepared by the method of Example 1.3 using 2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butylamine and benzoyl chloride.
    9.4 Synthesis of N-methyl-N- (2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butyl)
    (Tert-butyldimethylsilyloxy) butyl) benzamide was used in place of N-2- (naphth-2-yl) -4-
    9.5 Synthesis of N-methyl-N- (2- (naphth-2-yl) -4-hydroxybutyl) benzamide
    The title compound was prepared by the method of Example 1.5 using N-methyl-N- (2- (naphth-2-yl) -4- (tert-butyldimethylsilyloxy) butyl) benzamide .
    9.6 Synthesis of N-methyl-N- (2- (naphth-2-yl) -4-methanesulfonylbutyl)
    The title compound was prepared by the method of Example 1.6 using N-methyl-N- (2- (naphth-2-yl) -4-hydroxybutyl) benzamide and methanesulfonyl chloride.
    9.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2- carbonyl) piperidin- Yl) butyl) benzamide < / RTI >
    Benzamide and 4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbo Yl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Example 10
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorobenzyl) Dichlorophenyl) butyl) -3,5-bis (trifluoromethyl) benzamide

    10.1 Synthesis of N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,5-bis (trifluoromethyl) benzamide
    The title compound was prepared according to the method of Example 1.3, using 2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,5-bis (trifluoromethyl) benzoyl chloride The title compound is obtained.
    10.2 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,5-bis (trifluoromethyl)
    (Trifluoromethyl) benzamide was used in place of N-2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,5-bis ≪ / RTI > to give the title compound.
    10.3 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -3,5-bis (trifluoromethyl)
    (Trifluoromethyl) benzamide was used instead of N-methyl-N- (2- (3,4-dichlorophenyl) -4- (tert- butyldimethylsilyloxy) butyl) -3,5-bis Prepared by the method of Example 1.5 to give the title compound.
    10.4 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -3,5-bis (trifluoromethyl) benzamide
    (Trifluoromethyl) benzamide and methanesulfonyl chloride was used instead of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -3,5- To give the title compound.
    10.5 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- -Dichlorophenyl) butyl) -3,5-bis (trifluoromethyl) benzamide Synthesis of
    (Trifluoromethyl) benzamide and 4- (1- (4-fluoro-phenyl) -4-methanesulfonylbutyl) -3,5- Benzyl) -1H-benzimidazole-2-carbonyl) piperidine, and according to the method of Example 1.7, the title compound is obtained.
    Example 11
    2-ylmethyl) -2- (3-methyl-pyridin-2-ylmethyl) Trifluoromethylphenyl) butyl) -3,4,5-trimethoxybenzamide

    11.1 Synthesis of 2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    3-trifluoromethylphenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound was obtained.
    11.2 Synthesis of 2- (3-trifluorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2, using 2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    11.3 Synthesis of N- (2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Using the method of Example 1.3, using 2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride, the title compound ≪ / RTI >
    11.4 Synthesis of N-methyl-N- (2- (3-trifluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl-3,4,5-trimethoxybenzamide
    Using the procedure of Example 1.4 and using N- (2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    11.5 Synthesis of N-methyl-N- (2- (3-trifluorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    Using 1.5 g of N-methyl-N- (2- (3-trifluoromethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    11.6 Synthesis of N-methyl-N- (2- (3-trifluorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    Using the method of Example 1.6 and using N-methyl-N- (2- (3-trifluoromethylphenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide, the title compound ≪ / RTI >
    11.7 N-Methyl-N- (4- (4- (1- (pyrid-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- -Trifluoromethylphenyl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    Methyl-N- (2- (3-trifluoromethylphenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1- (pyrid- ) Butyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt as the starting material, the compound was prepared by the method of Example 1.7.
    Example 12
    Yl) -2- (thien-2- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- Yl) butyl) -3,4,5-trimethoxybenzamide

    12.1 Synthesis of 2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    2-yl acetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound is obtained.
    12.2 Synthesis of 2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butylamine
    (3.24 mmol) of 2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile and 1.5 g (6.48 mmol) of cobald (II) hexahydrate in methanol (50 ml) . Sodium borohydride (2.17 g, 57 mmol) is added in the ice bath while maintaining the temperature at or below 20 ° C. After the addition is complete, the reaction mixture is allowed to stand at ambient temperature for 18 hours. The reaction mixture is evaporated in vacuo and the residue is obtained. The residue is partitioned between dichloromethane and a saturated aqueous ammonium chloride solution. The pH of the aqueous layer is adjusted to about 8 using a 1 M aqueous hydrochloric acid solution. The layers were separated, the aqueous layer was extracted several times with dichloromethane, the organic layers were combined and the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound.
    12.3 Synthesis of N- (2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.3, using 2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride. .
    12.4 Synthesis of N-methyl-N- (2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Using the procedure of Example 1.4 and using N- (2- (thien-2-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, The title compound is obtained.
    12.5 Synthesis of N-methyl-N- (2- (thien-2-yl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    The procedure of Example 1.5 was repeated except that N-methyl-N- (2- (thien-2-yl) -4- (tert- butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide was used, ≪ / RTI > to give the title compound.
    12.6 Synthesis of N-methyl-N- (2- (thien-2-yl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.6 using N-methyl-N- (2- (thien-2-yl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide .
    12.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- Yl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    Methyl-N- (2- (thien-2-yl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1- (4- fluorobenzyl) Benzimidazole-2-carbonyl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Example 13
    (4-fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- Yl) butyl) -3,4,5-trimethoxybenzamide

    13.1 Synthesis of 2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Pyrid-3-yl acetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane and using the method of Example 1.1.2 to give the title compound.
    13.2 Synthesis of 2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butylamine
    The title compound is prepared by the method of Example 12.2 using 2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyronitrile.
    13.3 Synthesis of N- (2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.3, using 2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride. ≪ / RTI >
    13.4 Synthesis of N-methyl-N- (2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Using the method of Example 1.4 and using N- (2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    13.5 Synthesis of N-methyl-N- (2- (pyrid-3-yl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    Butyl-3-methyl-N- (2- (pyrid-3-yl) -4- (tert- butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    13.6 Synthesis of N-methyl-N- (2- (pyrid-3-yl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    Using the method of Example 1.6, using N-methyl-N- (2- (pyrid-3-yl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide and methanesulfonyl chloride, . Separation by extraction using a saturated aqueous sodium bicarbonate solution yielded the title compound.
    13.7 N-Methyl-N- (4- (4- (1- (4-fluorobenzyl) -1H-benzimidazole-2- carbonyl) piperidin- 3-yl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    Methyl-N- (2- (pyrid-3-yl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1- (4- fluorobenzyl) -1H-benzimidazole-2-carbonyl) piperidine, and by the method of Example 1.7, the title compound is obtained.
    Example 14
    Methyl-N- (4- (4- (4-benzhydrylidipiperidin-1-yl) -2- (3,4-dichlorophenyl) butyl)

    14.1 Synthesis of N-methyl-N- (4- (4- (4- (benzhydrylidene) piperidin-1-yl) -2- (3,4-dichlorophenyl)
    The title compound was prepared according to the method of Example 2.7, using N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide and 4-benzhydrylidenepiperidine Compound.
    Example 15
    2- (3,4-dichlorophenyl) butyl) -3,4-dihydro-2H-pyran-2- 5-trimethoxybenzamide

    15.1 Synthesis of N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared using the method of Example 1.3, using 2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride. ≪ / RTI >
    15.2 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Using the procedure of Example 1.4 and using N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    15.3 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    Except that N-methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide was used, To give the title compound.
    15.4 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    Using the method of Example 1.6, using N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide and methanesulfonyl chloride, To give the title compound.
    15.5 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4- dichlorophenyl) , Synthesis of 5-trimethoxybenzamide
    Methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1H-benzimidazole- Yl) piperidine hydrochloride, and by the method of Example 1.7, the title compound is obtained.
    Example 16
    2- (3,4-dichlorophenyl) butyl) benzamide < / RTI >

    16.1 Synthesis of N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin-1-yl) -2- (3,4-dichlorophenyl)
    Methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) benzamide and 4- (1H-benzimidazole-2- carbonyl) piperidine hydroiodic acid salt , And by the method of Example 1.7, the title compound is obtained.
    Example 17
    2-carbonyl) piperidin-1-yl) -2 (4-fluorophenyl) - (3,4-dichlorophenyl) butyl) -3,4,5-trimethoxybenzamide

    17.1 N-Methyl-N- (4- (4- (1- (2- (morpholin-4-yl) ethyl) -1H-benzimidazole-2- carbonyl) piperidin- Synthesis of 2- (3,4-dichlorophenyl) butyl) -3,4,5-dimethoxybenzamide
    To a solution of N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4-dichlorophenyl) butyl ), 3,4,5-trimethoxybenzamide (0.70 mmol) and 4- (2-chloroethyl) morpholine hydrochloride (0.84 mmol) and potassium carbonate (3.36 mmol) (5 ml). Reflux is heated. After 20 hours, it is cooled to ambient temperature and the reaction mixture is concentrated in vacuo and diluted with ethyl acetate. Aqueous saturated sodium chloride solution, water, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic layer was dried over Mg 2 SO 4 , filtered and concentrated in vacuo to give the title compound.
    Example 18
    (3, < RTI ID = 0.0 > 3-ethoxycarbonylpropyl) -lH-benzimidazole-2-carbonyl) piperidin- 4-dichlorophenyl) butyl) benzamide

    18.1 N-Methyl-N- (4- (4- (1- (3-ethoxycarbonylpropyl) -1H-benzimidazole-2- carbonyl) piperidin- , 4-dichlorophenyl) butyl) benzamide Synthesis of
    To a solution of N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- (1.35 mmol), ethyl 4-bromobutyrate (5.4 mmol) and potassium carbonate (2.24 g, 16.2 mmol) were combined. Reflux is heated. After 38 hours, cool to ambient temperature and dilute with ethyl acetate. And extracted with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over Mg 2 SO 4 , filtered and concentrated in vacuo to give the title compound.
    Example 19
    (3, < RTI ID = 0.0 > 4-methoxycarbonylbenzyl) -lH-benzimidazole-2-carbonyl) piperidin- 4-dichlorophenyl) butyl) benzamide

    19.1 N-Methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzimidazole-2- carbonyl) piperidin- , 4-dichlorophenyl) butyl) benzamide Synthesis of
    To a solution of N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4- dichlorophenyl) (1.69mmol), methyl (4-bromomethyl) benzoate (1.55g, 6.76mmol) and 1,8-diazabicyclo [5.4.0] undec-7- ene (2.06g, 13.52mmol ). Reflux is heated. After 72 hours, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and extracted three times with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound.
    Example 20
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloro-benzoimidazol- Phenyl) butyl) benzamide

    20.1 N-Methyl-N- (4- (4- (1- (4-carboxybenzyl) -lH-benzimidazole- 2-carbonyl) piperidin- Dichlorophenyl) butyl) benzamide Synthesis of
    To a solution of N-methyl-N- (4- (4- (1- (4-methoxycarbonylbenzyl) -1H-benzimidazole- 2-carbonyl) piperidine in 4/1 tetrahydrofuran / water 2- (3,4-dichlorophenyl) butyl) benzamide (0.92 mmol) and lithium hydroxide hydrate (0.12 g, 2.75 mmol) were combined. After 72 hours, the reaction mixture is diluted with water and concentrated in vacuo to remove most of the tetrahydrofuran. Acidify to pH 2 using 1 M aqueous hydrochloric acid solution. Extract three times with ethyl acetate. The combined organic layers were dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound.
    Example 21
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) benzamide

    21.1 N-Methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2- carbonyl) piperidin- - < / RTI > dichlorophenyl) butyl) benzamide
    To a solution of N-methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4- dichlorophenyl) (1.36 mmol), 2-chloroethyl ethyl ether (0.59 g, 5.44 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.66 g, 10.9 mmol). Reflux is heated. After 18 hours, it is cooled to ambient temperature and the reaction mixture is diluted with ethyl acetate. Extracted twice with a saturated aqueous ammonium chloride solution, with a 5% aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound.
    Recipe 8
    Synthesis of 4- (1- (fur-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine
    (1.16 mmol), furfuryl alcohol (0.10 ml, 1.16 mmol) in tetrahydrofuran (5 ml) was added dropwise to a solution of 1- (tert-butoxycarbonyl) -4- mmol) and triphenylphosphine (0.33 g, 1.28 mmol). Diethyl azodicarboxylate (0.20 ml, 1.28 mmol) is added. After 18 h, the reaction mixture is evaporated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic layer is separated and extracted with a saturated aqueous solution of water and sodium chloride. The organic layer was dried over Na 2 SO 4, filtered and evaporated in vacuo to give the title compound. The residue was subjected to silica gel chromatography eluting with 5% acetone / dichloromethane to give 1- (tert-butoxycarbonyl) -4- (1- (fur-2-ylmethyl) -1H-benzimadazol- -Carbonyl) piperidine. ≪ / RTI >
    Benzimidazole-2-carbonyl) piperidine (1.0 ml) and dichloromethane (5 ml) were added to a solution of 1- (tert-butoxycarbonyl) -4- ). A cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 ml) is slowly added. After 15 min, the reaction mixture is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer is separated and extracted with brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated in vacuo to give the title compound.
    Example 22
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzene amides

    22.1 N-Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- Synthesis of benzamide
    Methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (fur-2-ylmethyl) -1H-benzimidazole- , And by the method of Example 1.7, the title compound is obtained.
    Recipe 9
    Synthesis of 4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine
    Puppuryl alcohol (1 ml, 11.6 mmol) and tetrahydrofuran (20 ml) are combined. Sodium hydride (0.57 g, 60% in oil, 14 mmol) is added. After gas evolution ceased, ethyl bromoacetate (1.3 mL, 11.7 mmol) was added. Reflux is heated. After 2.5 hours, cool to ambient temperature. After 18 h, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is separated and extracted twice with ethyl acetate. The organic layers are combined, extracted with saturated aqueous sodium chloride, dried over Na 2 SO 4, filtered and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography, eluting with 1% ethyl acetate / dichloromethane to give ethyl-fur-2-ylmethoxyacetate. Rf = 0.62 (silica gel, 5% ethyl acetate / dichloromethane).
    Ethyl 2-fur-2-ylmethoxyacetate (1.2 g, 6.5 mmol) and tetrahydrofuran (10 ml) are combined. Cool in ice bath. Lithium aluminum hydride solution (8.0 mL, 1.0 M in THF, 8.0 mmol) is added dropwise. After 2 hours, water (0.3 ml) was added, 15% sodium hydroxide solution (0.3 ml) was added, and water (0.9 ml) was added. Stir vigorously. After 15 minutes, the reaction mixture was filtered, dried and the filtrate from the Na 2 SO 4, filtered off and concentrated in vacuo to give a residue. The residue was subjected to silica gel chromatography, eluting with 2% ethyl acetate / dichloromethane to give fur-2-ylmethyl 2-hydroxyethyl ether. Rf = 0.22 (silica gel, 5% acetone / dichloromethane).
    To a solution of 1- (tert-butoxycarbonyl) -4- (1H-benzimidazole-2-carbonyl) piperidine (1.71 g, 5.2 mmol), fur- Add methyl 2-hydroxyethyl ether (0.74 g, 5.2 mmol) and triphenylphosphine (1.67 g, 6.4 mmol). Diethyl azodicarboxylate (1.0 mL, 6.35 mmol) was added. After 21 hours, the reaction mixture is evaporated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 5% acetone / dichloromethane to give 1- (tert-butoxycarbonyl) -4- (1- (2-fur-2-ylmethoxy-ethyl) Imidazole-2-carbonyl) piperidine. ≪ / RTI > Rf = 0.30 (silica gel, 5% acetone / dichloromethane).
    Benzimidazole-2-carbonyl) piperidine (1.0 mmol) and di (tert-butoxycarbonyl) -4- (1- (10 ml). Cool in ice bath. The hydrochloric acid solution in dioxane (0.25 mL, 4M, 1.0 mmol) is slowly added. After 45 minutes, the reaction mixture is diluted with dichloromethane and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer is separated and extracted with brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated in vacuo to give the title compound.
    Example 23
    Methyl-N- (4- (4- (1- (2-furyl-2-ylmethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- Phenylbutyl) benzamide

    23.1 N-Methyl-N- (4- (4- (1- (fur-2-ylmethyl) -1 H- benzimidazole- 2- carbonyl) piperidin- Synthesis of benzamide
    Methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (fur-2-ylmethoxy) ethyl) -1H-benzimidazole- ) Piperidine and by the method of Example 1.7, the title compound is obtained.
    Recipe 10
    Synthesis of 4- (1- (2-allyloxyethyl) -1H-bendimidazole-2-carbonyl) piperidine
    Allyl hydroxyethyl ether (1.02 g, 10 mmol), diisopropylethylamine (4.0 mL, 23 mmol) and dichloromethane (20 mL) are combined. Cool in ice bath. Methanesulfonyl chloride (1.0 ml, 13 mmol) is added dropwise. After 1.5 h, the reaction mixture is extracted with a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried in Na 2 SO 4 and filtered, to afford the methanesulfonyl allyl ether and evaporated under reduced pressure. Rf = 0.80 (silica gel, 20% ethyl acetate / dichloromethane).
    (1.87 g, 5.68 mmol), allyl methanesulfonyl ethyl ether (1.83 g, 5.68 mmol), and triethylamine were added to a solution of 1- (tert-butoxycarbonyl) -4- g, 10.1 mmol), potassium carbonate (1.60 g, 11.5 mmol) and water (7 ml). Reflux is heated. After 18 hours, the reaction mixture is concentrated under reduced pressure and most of the acetone is removed. Concentrate The reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is separated and extracted three times with ethyl acetate. The combined organic layers are extracted with saturated aqueous sodium chloride solution. The organic layer is dried over Na 2 SO 4, filtered and evaporated in vacuo to thereby obtain a residue. Chromatography of the residue on silica gel eluting with 15% ethyl acetate / dichloromethane gave 1- (tert-butoxycarbonyl) -4- (1- (2-allyloxyethyl) -1H-benzimidazol- 2-carbonyl) piperidine. ≪ / RTI > Rf = 0.48 (silica gel, 20% ethyl acetate / dichloromethane).
    Benzimidazole-2-carbonyl) piperidine (1.0 mmol) and dioxane (3 ml) were added to a solution of 1- (tert-butoxycarbonyl) -4- . A solution of hydrochloric acid in dioxane (4 mL, 4M, 16 mmol) was added. After 30 minutes, the residue is partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer is separated and extracted with a saturated aqueous sodium chloride solution. The organic layer is dried over Na 2 SO 4, filtered and evaporated in vacuo to give the title compound.
    Example 24
    Benzimidazole-2-carbonyl) piperidin-1-yl) -2-phenylbutyl) benzamide

    24.1 Preparation of N-methyl-N- (4- (4- (1- (2-allyloxyethyl) -1H-benzimidazole-2-carbonyl) piperidin- Synthesis of amide
    (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (allyloxyethyl) -1H-benzimidazole- , And by the method of Example 1.7, the title compound is obtained.
    Recipe 11
    Synthesis of 4- (1- (2- (3,3-dimethylallyloxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine
    3-methyl-2-butene < / RTI > hydroxyethyl ether.
    Example 25
    Benzimidazole-2-carbonyl) piperidin-1-yl) - (4-methyl- 2-phenylbutyl) benzamide

    25.1 N-Methyl-N- (4- (4- (1- (2- (3,3-Dimethylallyloxy) ethyl) -1H-benzimidazole-2- carbonyl) piperidin- -2-phenylbutyl) benzamide
    N-methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2- (3,3- dimethylallyloxy) ethyl) -1H-benzimidazole- Yl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Example 26
    2- (3-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-1,5-benzodiazepin- Trimethoxybenzamide

    26.1 Synthesis of 2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    3-chlorophenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound is obtained.
    26.2 Synthesis of 2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2, using 2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    26.3 Synthesis of N- (2- (pyrid-3-yl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.3 using 2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride. do.
    26.4 Synthesis of N-methyl-N- (2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.4, using N- (2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, Compound.
    26.5 Synthesis of N-methyl-N- (2- (3-chlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    The procedure of Example 1.5 was repeated except for using N-methyl-N- (2- (3-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide. To give the title compound.
    26.6 Synthesis of N-methyl-N- (2- (3-chlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.6, using N-methyl-N- (2- (3-chlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide do.
    26.7 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3- chlorophenyl) Synthesis of trimethoxybenzamide
    Methyl-N- (2- (3-chlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (lH-benzimidazole- Piperidine hydroiodic acid salt as the starting material and by the method of Example 1.7, the title compound is obtained.
    Example 27
    2-carbonyl) piperidin-l-yl) -2- (3-chlorophenyl) ) Butyl) -3,4,5-trimethoxybenzamide

    27.1 N-Methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2- carbonyl) piperidin- Phenyl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    2- (3-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-1,5-benzodiazepin- The title compound was obtained by the method of Example 21.1, using trimethoxybenzamide and 2-chloroethylethylether.
    Example 28
    2- (4-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-pyran-2- Trimethoxybenzamide

    28.1 Synthesis of 2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Prepared by the method of Example 1.1.1 using 4-chlorophenylacetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, the title compound was obtained.
    28.2 Synthesis of 2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2, using 2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    28.3 Synthesis of N- (2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared by the method of Example 1.3 using 2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride. do.
    28.4 Synthesis of N-methyl-N- (2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    The title compound was prepared according to the method of Example 1.4, using N- (2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, Compound.
    28.5 Synthesis of N-methyl-N- (2- (4-chlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    The procedure of Example 1.5 was repeated except that N-methyl-N- (2- (4-chlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide was used. To give the title compound.
    28.6 Synthesis of N-methyl-N- (2- (4-chlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    The title compound was obtained by the method of Example 1.6, using N-methyl-N- (2- (4-chlorophenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide do.
    28.7 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (4- chlorophenyl) Synthesis of trimethoxybenzamide
    Methyl-N- (2- (4-chlorophenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (lH-benzimidazole- Piperidine hydroiodic acid salt as the starting material and by the method of Example 1.7, the title compound is obtained.
    Example 29
    2-carbonyl) piperidin-l-yl) -2- (4-chlorophenyl) ) Butyl) -3,4,5-trimethoxybenzamide

    29.1 N-Methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2- carbonyl) piperidin- Phenyl) butyl) -3,4,5-trimethoxybenzamide Synthesis of
    2- (4-chlorophenyl) butyl) -3,4,5-tetrahydro-2H-pyran-2- The title compound was obtained by the method of Example 21.1, using trimethoxybenzamide and 2-chloroethylethylether.
    Example 30
    Yl) -2- (3,4-dimethylphenyl) butyl) -3, 4-dihydro- 5-trimethoxybenzamide

    30.1 Synthesis of 2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile
    Dimethylphenyl acetonitrile and 1- (tert-butyldimethylsilyloxy) -2-bromoethane, and by the method of Example 1.1.1, the title compound was obtained.
    30.2 Synthesis of 2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butylamine
    Prepared by the method of Example 1.2 using 2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyronitrile, the title compound was obtained.
    30.3 Synthesis of N- (2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    (Tert-butyldimethylsilyloxy) butylamine and 3,4,5-trimethoxybenzoyl chloride, and by the method of Example 1.3, the title compound ≪ / RTI >
    30.4 Synthesis of N-methyl-N- (2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide
    Using the procedure of Example 1.4 and using N- (2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide, To give the title compound.
    30.5 Synthesis of N-methyl-N- (2- (3,4-dimethylphenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide
    The same procedure as in Example 1.5 was repeated except that N-methyl-N- (2- (3,4-dimethylphenyl) -4- (tert-butyldimethylsilyloxy) butyl) -3,4,5-trimethoxybenzamide was used. To give the title compound.
    30.6 Synthesis of N-methyl-N- (2- (3,4-dimethylphenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide
    Prepared by the method of Example 1.6, using N-methyl-N- (2- (3,4-dimethylphenyl) -4-hydroxybutyl) -3,4,5-trimethoxybenzamide, ≪ / RTI >
    30.7 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4-dimethylphenyl) , Synthesis of 5-trimethoxybenzamide
    Methyl-N- (2- (3,4-dimethylphenyl) -4-methanesulfonylbutyl) -3,4,5-trimethoxybenzamide and 4- (1H-benzimidazole- Yl) piperidine hydrochloride, and by the method of Example 1.7, the title compound is obtained.
    Example 31
    1-yl) -2-phenylbutyl (4-methyl-N- (4- ) Benzamide

    31.1 N-Methyl-N- (4- (4- (1- (benzylimidazol-2-ylmethyl) -1H-benzimidazole-2- carbonyl) piperidin- Phenylbutyl) benzamide
    2-phenylbutyl) benzamide and 1-benzyl-1-imidazol-2-yl) Prepared by the method of Example 21.1 using 2-ylmethyl chloride hydrochloride, the title compound is obtained.
    31.2 Preparation of N-methyl-N- (4- (4- (1- (imidazol-2-ylmethyl) -1H-benzimidazole- 2- carbonyl) piperidin- ) ≪ / RTI > benzamide
    To a solution of N-methyl-N- (4- (4- (1-benzylimidazol-2-ylmethyl) -1H-benzimidazole- 2-carbonyl) piperidin- ) -2-phenylbutyl) benzamide (5 mmol) and 10% palladium on carbon (1.5 g). Anhydrous ammonium formate (25 mmol) was added. Reflux is heated. After 18 h the filtrate was washed with dichloromethane and the filtrate was evaporated in vacuo to give the title compound.
    Recipe 12
    Synthesis of 4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine
    1- (2-ethoxyethyl) -1H-benzimidazole (2.0 g, 10.51 mmol) and tetrahydrofuran (20 ml) are combined. Cool to -78 ° C using a dry ice / acetone bath. A solution of lithium diisopropylamide (4.62 mL, 2.5 M in hexanes, 11.56 mmol) is added dropwise. After 1 hour, a solution of 1- (tert-butoxycarbonyl) piperidin-4-one (2.09 g, 10.51 mmol) in tetrahydrofuran (10 ml) was added dropwise. Allow to warm to ambient temperature for more than 3 hours. Water is added and the layers are separated. The aqueous layer is extracted three times with ethyl acetate. Dry the combined organic layers of the filtrate from the Na 2 SO 4, filtered and evaporated in vacuo to give a residue. The residue was subjected to silica gel chromatography eluting with 1/1 ethyl acetate / hexane to give 1- (tert-butoxycarbonyl) -4- (1- (2-ethoxyethyl) -1H-benzimidazole) 4-hydroxypiperidine is obtained. Rf = 0.25 (silica gel, 1/1 ethyl acetate / hexane).
    4-hydroxypiperidine (2.05 g) was cooled in an ice bath, and the resulting residue was purified by silica gel column chromatography . Trifluoroacetic acid (25 ml) is added dropwise. After 1 hour, diethyl ether (100 ml) was added and evaporated in vacuo to give a residue. Dichloromethane and 5% potassium carbonate solution are added. Stir vigorously. After 3 hours the layers were separated and the aqueous layer was washed three times with dichloromethane. The organic layers were combined, dried in a K 2 CO 3, filtered and evaporated in vacuo to give the title compound. Rf = 0.18 (silica gel, 2% triethylamine / ethyl acetate).
    Example 32
    Benzimidazole) -4-hydroxypiperidin-1-yl) -2-phenylbutyl) benzamide < EMI ID =

    32.1 N-Methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-4-hydroxypiperidin- Synthesis of
    Methyl-N- (2-phenyl-4-methanesulfonylbutyl) benzamide and 4- (1- (2-ethoxyethyl) -1H-benzimidazole) -4-hydroxypiperidine And by the method of Example 1.7, the title compound is obtained.
    Recipe 13
    Synthesis of 2-methoxy-5- (1H-tetrazol-1-yl) benzoyl chloride
    A solution of 2-hydroxy-5-nitrobenzoic acid (21.5 g, 117 mmol), potassium carbonate (162.3 g, 1.174 mmol) and methyl iodide (136.8 g, 96.4 mmol) in acetone (500 mL) Reflux is heated. After 18 hours, the reaction mixture is heated to ambient temperature and methyl iodide (136.8 g, 96.4 mmol) is added. And then heated to reflux again. After 56 hours, the reaction mixture is cooled to ambient temperature, filtered, washed with acetone and the filtrate is evaporated in vacuo to give a residue. The residue is recrystallized from ethanol to give a secondary residue. The secondary residue is combined with chloroform (approximately 100 mL), filtered and the filtrate is evaporated in vacuo to give methyl 2-methoxy-5-nitrobenzoate. Rf = 0.38 (silica gel, ethyl acetate / hexane 1/1).
    Methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol are combined. 5% Palladium on carbon (0.66 g) is added. Hydrogenated at 50 psi pressure. After 17 h, the mixture is filtered through celite, the catalyst is removed and the filtrate is evaporated in vacuo to give a residue. The residue and dichloromethane are combined and extracted with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to give methyl 2-methoxy-5-aminobenzoate. Rf = 0.18 (silica gel, ethyl acetate / methanol 1/1).
    Elemental analysis for C 9 H 11 NO 3 :
    Theoretical value: C 59.66; H 6.12; N 7.73
    Found: C 59.44; H 6.04; N 7.62
    Methyl 2-methoxy-5-aminobenzoate (3.94 g, 21.7 mmol) and triethylorthoformate (12.8 g, 86.7 mmol) in anhydrous acetic acid (20 mL) are combined. After 20 h, the reaction mixture is concentrated in vacuo to remove ethanol. Acetic anhydride (20 ml) and sodium azide (5.64 g, 86.7 mmol) were added. Heat to 70 ° C. After 1 hour, acetic anhydride (10 ml) was added and heating was continued at 70 ° C. After an additional hour, the reaction mixture is cooled to ambient temperature and diluted with water (500 mL). The solid is collected by filtration and washed with water to give methyl 2-methoxy-5- (1H-tetrazol-1-yl) benzoate.
    Methoxy-5- (1H-tetrazol-1-yl) benzoate (2.86 g, 12.2 mmol) and 1 M aqueous sodium hydroxide solution (13.43 ml, 12.2 mmol) in methanol / water (100 ml, 13.43 mmol). Reflux is heated. After 4 hours, it is concentrated in vacuo to remove most of the methanol, add water (50 ml) and adjust to a pH of about 4 using a 1 M aqueous hydrochloric acid solution. Evaporation in vacuo yielded a solid, the solid was slurried with water, filtered and dried to give 2-methoxy-5- (1H-tetrazol-1-yl) benzoic acid.
    Alternatively, methyl 2-methoxy-5- (1H-tetrazol-1-yl) benzoate (13.3 g, 56.8 mmol) and methanol (150 mL) are combined. 1 M sodium hydroxide (62.5 ml, 62.5 mmol) is added. Reflux is heated. After 30 minutes, methanol (50 ml) and water (50 ml) were added and the mixture was heated under reflux. After 1 hour, it is concentrated in vacuo to remove most of the solvent. The pH is adjusted to about 1-2 using a 1 M aqueous hydrochloric acid solution to give a solid. The solid is collected by filtration, washed with water and dried to give 2-methoxy-5- (1H-tetrazol-1-yl) benzoic acid.
    (1.2 g, 5.5 mmol) and dichloromethane (40 ml) were combined. Oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops) is added dropwise. After 4 h, it was evaporated in vacuo and dried to give the title compound.
    Example 33
    2- (4-fluorophenyl) butyl) -2-methoxy-isoquinolin-2- 5- (1H-tetrazol-1-yl) benzamide

    33.1 Synthesis of N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-
    A solution of 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine (5.0 g, 16.8 mmol) and sodium bicarbonate (7.0 g, 83 mmol) in water (50 ml) ). Methoxy-5- (1H-tetrazol-1-yl) benzoyl chloride (3.3 g, 14.55 mmol). After 18 h, the reaction mixture is diluted with ethyl acetate and the layers are separated and the organic layer is extracted with saturated aqueous sodium bicarbonate solution, water, then brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel eluting with 50% ethyl acetate / hexanes, 75% acetate / hexanes and dried to give the title compound. Rf = 0.58 (silica gel, ethyl acetate).
    33.2 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4- (tert- butyldimethylsilyloxy) butyl) -2-methoxy- Synthesis of amide
    To a solution of N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (1H-tetrazol- Yl) benzamide (3.57 g, 7.13 mmol). Cool in a dry ice / acetone bath. A solution of sec-butyllithium (7.2 ml, 1.3 M in cyclohexane, 9.5 mmol) is added. Iodomethane (2.0 mL, 32.1 mmol) was added after 30 minutes. Warmed to ambient temperature, and then heated to reflux. After 18 hours the reaction mixture is cooled and the reaction mixture is diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over Na 2 SO 4, filtered off and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel eluting with 3/7 ethyl acetate / hexanes to give the title compound after drying. Rf = 0.63 (silica gel, ethyl acetate).
    33.3 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-
    Methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (1H-tetrazol- And according to the method of Example 1.5, the title compound is obtained. Rf = 0.18 (silica gel, ethyl acetate).
    33.4 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-
    Using 1.6 mmol of N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol- To give the title compound.
    33.5 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (4-fluorophenyl) -5- (1H-tetrazol-1-yl) benzamide Synthesis of
    Methyl-N- (2- (4-fluorophenyl) -4-methanesulfonylbutyl) -2-methoxy- Benzimidazole-2-carbonyl) piperidine hydroiodic acid salt as the starting material, the compound was prepared by the method of Example 1.7.
    Example 34
    2- (3,4-dichlorophenyl) butyl) -2-methoxy-N-methyl-N- (4- (4- (1H- benzimidazole- 2- carbonyl) piperidin- -5- (1H-tetrazol-1-yl) benzamide

    34.1 Synthesis of N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (1H-tetrazol-
    The title compound was prepared by the method of Example 33.1, using 2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine (5.0 g, 16.8 mmol).
    34.2 N-Methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) Synthesis of benzamide
    (1H-tetrazol-1-yl) benzamide was used instead of N-2- (3,4-dichlorophenyl) -4- (tert- butyldimethylsilyloxy) The title compound is prepared by the method of Example 1.4.
    34.3 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-
    Methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy- Amide and by the method of Example 1.5, the title compound is obtained.
    34.4 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-
    Methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5- (1H-tetrazol-1-yl) 1.6, < / RTI > to give the title compound.
    2- (3,4-dichlorophenyl) butyl) -2-methyl-N- (4- (4- (1H-tetrazol-1-yl) benzamide
    Methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1H) -quinolinone -Benzimidazole-2-carbonyl) piperidine hydroiodic acid salt as the starting material, the compound was prepared by the method of Example 1.7.
    Recipe 14
    Synthesis of 2,2,2-trifluoroethyl trifluoromethanesulfonate
    2,2,2-Trifluoroethanol (12.4 ml, 170 mmol), pyridine (13.6 ml, 170 mmol) and dichloromethane (40 ml) are combined. Cool in ice bath. Trifluoromethanesulfonic anhydride (50 g, 196 mmol) is added over about 45 minutes. After 15 minutes, water is added and the layers are separated and the organic layer is extracted with water. Dry the organic layer with MgSO 4 and concentrate through a short tube distillation apparatus to give the title compound. Melting point 89-91 [deg.] C.
    Example 35
    2-carbonyl) piperidin-1-yl) -2- (4-fluorophenyl) (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide

    35.1 N-Methyl-N- (4- (4- (1- (2,2,2-trifluoroethyl) -1H-benzimidazole-2-carbonyl) piperidin- - (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide
    Prepared by the method of Example 21.1 using trifluoroethyl trifluoromethanesulfonate, the title compound is obtained.
    Recipe 15
    Synthesis of 4- (1-allyl-1H-benzimidazole-2-carbonyl) piperidine
    Using the allyl alcohol, and by the method of Preparation 8, the title compound is obtained.
    Example 36
    Yl) -2- (3,4-dichlorophenyl) butyl) - (4-methyl- Methoxy-5- (1H-tetrazol-1-yl) benzamide

    36.1 N-Methyl-N- (4- (4- (1-allyl-lH-benzimidazole-2- carbonyl) piperidin- -2-methoxy-5- (1H-tetrazol-1-yl) benzamide Synthesis of
    Methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (1H- -Allyl-lH-benzimidazole-2-carbonyl) piperidine and by the method of Example 1.7, the title compound is obtained.
    Recipe 16
    Synthesis of 2-methoxy-5- (4H-triazol-4-yl) benzoyl chloride
    J. Chem. soc. Methoxy-5-aminobenzoate (2.0 g, 11 mmol) and N, N-dimethylformamide azine (1.56 g, 11 mmol) were added to toluene (25 ml) 11 mmol) and p-toluenesulfonic acid (190 mg). Headspace of the vessel Fit the inlet of the vessel to the gas to be filled with argon and wash the effluent with diluted aqueous hydrochloric acid solution. Reflux is heated. After 20 h, the reaction mixture is concentrated in vacuo and the residue is obtained. The residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer is extracted twice with dichloromethane. The organic layers were combined, dried over MgSO 4, filtered and concentrated in vacuo to thereby obtain a residue. The residue is chromatographed on silica gel with successive elution with 70% ethyl acetate / dichloromethane, 5% methanol / dichloromethane to give a residue. The residue is recrystallized from ethyl acetate / hexane to give methyl 2-methoxy-5- (4H-triazol-4-yl) benzoate. Melting point 191 to 195.5 [deg.] C.
    Or, see J. Med. Chem. 21, 1100 (1978) method, the methyl 2-methoxy-5-aminobenzoate (1.8g, 10mmol), di-formyl hydrazine (0.97g, 11mmol) and phosphorus pentoxide (1.84g, 13mmol) in accordance with the Sum. Heat to 160 ° C. After 1.5 h, the reaction mixture is cooled and a saturated aqueous sodium bicarbonate solution is added. Extract three times with dichloromethane. The combined organic layers were dried in MgSO 4, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel with successive elution with 40% ethyl acetate / dichloromethane, 5% methanol / dichloromethane to give methyl 2-methoxy-5- (4H-triazol- do. Melting point 179-182 占 폚.
    Combine methyl 2-methoxy-5- (4H-triazol-4-yl) benzoate (56 mmol), methanol (200 mL) and water (50 mL). A 1 M aqueous sodium hydroxide solution (62.5 ml, 62.5 mmol) was added. Reflux is heated. After 8 hours, it is concentrated in vacuo to remove most of the solvent. The pH is adjusted to about 1-2 with 1 M aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried in MgSO 4, filtered and evaporated to afford the vacuum 2-methoxy -5- (4H- triazol-4-yl) benzoic acid.
    Methoxy-5- (4H-triazol-4-yl) benzoic acid (5 mmol) and dichloromethane (40 ml). Oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops) is added dropwise. After 4 h, it was evaporated in vacuo and dried to give the title compound.
    Example 37
    2-yl) -2- (4-fluoro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin- - fluorophenyl) butyl) -2-methoxy-5- (4H-triazol-4-yl) benzamide

    37.1 Synthesis of N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (4H-triazol-
    The title compound was synthesized in analogy to example 33, using 2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butylamine and 2-methoxy-5- (4H- To give the title compound.
    37.2 N-Methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) Synthesis of amide
    (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5- (4H- The title compound is prepared by the method of Example 1.4.
    37.3 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl) -2-methoxy-5- (4H-triazol-
    Methyl-N- (2- (4-fluorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy- And according to the method of Example 1.5, the title compound is obtained.
    37.4 Synthesis of N-methyl-N- (2- (4-fluorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5- (4H-triazol-
    Using the N-methyl-N- (2- (4-fluorophenyl) -4-hydroxybutyl-2-methoxy-5- (4H-triazol- ≪ / RTI > to give the title compound.
    2-ylmethyl) -1H-benzimidazole-2-carbonyl) pyrrolidin-1 -yl) -2- (4- Fluorophenyl) butyl-2-methoxy-5- (4H-triazol-4-yl) benzamide
    Methoxy-5- (4H-triazol-4-yl) benzamide and 4- (l- (Pyrid-2-ylmethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt as the starting material, the compound was prepared by the method of Example 1.7.
    Recipe 18
    Synthesis of 2-methoxy-5-trifluoromethoxybenzoyl chloride
    Methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) and trifluoroacetic acid (200 mL) were combined. Hexamethylenetetramine (26 g, 185.7 mmol) is slowly added. Heat to 60 캜. After 24 hours, the reaction mixture was cooled to ambient temperature and the reaction mixture was poured into 2 M aqueous sulfuric acid (500 mL). Cool and extract 10 times with diethyl ether. The combined organic layers are dried over Na2SO4, filtered and evaporated in vacuo to give a residue. The residue is chromatographed on silica gel with 1/4 ethyl acetate / hexanes to give 2-methoxy-5-trifluoromethoxybenzaldehyde.
    According to the method of Heterocycles, 16, 2091 (1981), 2-methoxy-5-trifluoromethoxybenzaldehyde (0.58 g, 2.65 mmol) and 2-methyl But-2-ene (37 ml) are combined. A solution of sodium dihydrogenphosphate hydrate (0.92 g) and sodium chlorite (0.42 g, 4.7 mmol) in water (10 ml) is added dropwise. After 4 hours, the reaction mixture is adjusted to a pH of about 8-9 using a 1 M aqueous sodium hydroxide solution. Most of the tertiary-butanol is removed by evaporating the reaction mixture at about ambient temperature and vacuum. Water (40 ml) is added and extracted three times with hexane (10 ml). The aqueous layer is adjusted to a pH of about 1 with a 1 M aqueous hydrochloric acid solution and extracted five times with diethyl ether. The organisms are combined, dried over Na 2 SO 4 , filtered and evaporated in vacuo to give a residue. The residue was subjected to silica gel chromatography, eluting with 1/1 ethyl acetate / hexane containing 0.5% acetic acid to give 2-methoxy-5-trifluoromethoxybenzoic acid. Rf = 0.34 (silica gel, 1/1 ethyl acetate / hexane containing 0.5% acetic acid).
    Methoxy-5-trifluoromethoxybenzoic acid (0.6 g, 2.53 mmol) and dichloromethane (10 mL). Cool in ice bath. Oxalyl chloride (0.64 ml, 5.0 mmol) was added dropwise followed by dimethylformamide (1 drop). Allow to warm to ambient temperature. After 3 h, it was evaporated in vacuo and dried to give the title compound.
    Example 38
    2- (3,4-dichlorophenyl) butyl) -2-methoxy-N-methyl-N- (4- (4- (1H- benzimidazole- 2- carbonyl) piperidin- -5-trifluoromethoxybenzamide

    38.1 Synthesis of N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide
    Using tert-butyldimethylsilyloxy) butylamine (5.0 g, 16.8 mmol) and 2-methoxy-5-trifluoromethoxybenzoyl chloride, Prepared by the method of Example 33.1 to give the title compound.
    38.2 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide
    The procedure of Example 1.4 was repeated except that N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide was used, To give the title compound.
    38.3 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5-trifluoromethoxybenzamide
    Methyl-N- (2- (3,4-dichlorophenyl) -4- (tert-butyldimethylsilyloxy) butyl) -2-methoxy-5-trifluoromethoxybenzamide was used, Prepared by the method of Example 1.5 to give the title compound.
    38.4 Synthesis of N-methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5-trifluoromethoxybenzamide
    Using the method of Example 1.6 and using N-methyl-N- (2- (3,4-dichlorophenyl) -4-hydroxybutyl) -2-methoxy-5-trifluoromethoxybenzamide, The title compound is obtained.
    38.5 N-Methyl-N- (4- (4- (1H-benzimidazole-2-carbonyl) piperidin- 1 -yl) -2- (3,4- dichlorophenyl) butyl- -5-trifluoromethoxybenzamide < / RTI >
    Methyl-N- (2- (3,4-dichlorophenyl) -4-methanesulfonylbutyl) -2-methoxy-5-trifluoromethoxybenzamide and 4- (1H- - carbonyl) piperidine hydroiodic acid salt as the starting material and by the method of Example 1.7, the title compound is obtained.
    Example 39
    2-carbonyl) piperidin-1-yl) -2- (3,4-dichloropyrimidin- Dichlorophenyl) butyl) -2-methoxy-5-trifluoromethoxybenzamide

    39.1 N-Methyl-N- (4- (4- (1- (2-ethoxyethyl) -1H-benzimidazole-2- carbonyl) piperidin- -Dichlorophenyl) butyl) -2-methoxy-5-trifluoromethoxybenzamide Synthesis of
    2- (3,4-dichlorophenyl) butyl) -2-methoxy-N-methyl-N- (4- (4- (1H- benzimidazole- 2- carbonyl) piperidin- -5-trifluoromethoxybenzamide and 2-chloroethyl ethyl ether, and by the method of Example 21.1, the title compound is obtained.
    Recipe 17
    Synthesis of 4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt
    References: Tet. Let. , 35 , 5997-6000 (1994)] in 1 -hydroxy-2-tetrahydropyran-2-yloxyethane [ J. Chem. Soc. Chem. Commun. , 1766 (1990)] (5.0 mmol), 1,1-diethyl azodicarboxylate (10 mmol), 2,2,2-trifluoroethanol (100 mmol) and tributylphosphine (10 mmol). After 6 h, it is concentrated in vacuo to give a residue. Silica gel chromatography afforded 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluoroethyl ether.
    2-yloxypyr-2-yloxyethylbut-2-en-1-yl ether (2 mmol) and magnesium bromide (6 mmol) in diethyl ether (10 ml). After 24 hours, it is extracted with water and then with brine. The organic layer was dried in Na 2 SO 4, filtered, washed with ether to obtain ethyl 2-hydroxyethyl 2,2,2-trifluoroethyl and concentrated in vacuo.
    2-hydroxyethyl 2,2,2-trifluoroethyl ether and l- (tert-butoxycarbonyl) -4- (lH-benzimidazole-2-carbonyl) piperidine (2.0 g, (Tert-butoxycarbonyl) -4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) - Benzimidazole-2-carbonyl) piperidine. ≪ / RTI >
    1- (tert-Butoxycarbonyl) -4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1 H- benzimidazole-2-carbonyl) piperidine (5.0 mmol) and dichloromethane (150 ml). Cool to 0 < 0 > C using an ice bath. The hydric acid (gas) is added and stirred until the solution is saturated. After 30 minutes, the hydronic acid (gas) is added again when the solution is saturated. After evaporation to dryness in vacuo for 2 hours, the title compound is obtained.
    Example 40
    Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidin- Yl) -2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-

    40.1 N-Methyl-N- (4- (4- (1- (2- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole- 2- carbonyl) piperidine- Yl) -2- (4-fluorophenyl) butyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide
    Methanesulfonylbutyl) -2-methoxy-5- (1H-tetrazol-1-yl) benzamide and 4- (1- (2,2,2-trifluoroethoxy) ethyl) -1H-benzimidazole-2-carbonyl) piperidine hydroiodic acid salt was used in place of The title compound is obtained.
    Tachykinins are generally C- terminal sequence, is a class of neuronal proteins that share Phe-Xaa-Gly-Leu- Met-NH 2. Tachycinins are distributed in the peripheral and central nervous system, where they bind to more than three receptor types. The NK 1 , NK 2 , and NK 3 receptors in the tachykinin receptor are defined by the preferred binding affinities of substrate P, neurokinin A (NKA) and neurokinin B (NKB), respectively.
    The use of a tachykinin antagonist is hypersensitive; Immunological side effects; asthma; Bronchitis, allergic rhinitis including seasonal rhinitis and sinusitis; allergy; Contact dermatitis; Atopic dermatitis; Inflammatory bowel disease including Crohn's disease and ulcerative colitis; ≪ / RTI > and vomiting. ≪ Desc / Clms Page number 2 >
    Tachycinin-mediated diseases and conditions are known to be diseases and conditions in which tachycinins are involved in all or part of the clinical symptoms thereof. Moreover, the involvement of tachycinin is not essential for causing certain tachykinin-mediated diseases and conditions. Tachykinin antagonists are useful for modulating or providing the therapeutic relief of such tachycinin-mediated diseases and conditions.
    The present invention provides novel and useful tachykinin antagonists or stereoisomers or pharmaceutically acceptable salts thereof.
    In a further aspect, the present invention provides a method of treating a subject suffering from a hypersensitivity reaction as a tachykinin antagonist; Immunological side effects; asthma; bronchitis; Allergic rhinitis including seasonal rhinitis and sinusitis; allergy; Contact dermatitis; Atopic dermatitis; Inflammatory bowel disease including Crohn's disease and ulcerative colitis; Comprising administering to a person in need of treatment of a tachycinin-mediated disease and condition comprising a therapeutically effective amount of a compound of formula I, do.
    The hypersensitivity reaction may occur when the IgE antibody response is directed against non-toxic antigens such as pollen. During this reaction, pharmacological mediators such as histamine are continuously released by IgE-photosensitive oily cells, and acute inflammatory reactions generally occur. A characteristic of the reaction is that allergic rhinitis, in which reactions occur, including seasonal rhinitis and sinusitis; Lung diseases such as asthma; Allergic dermatitis, such as ulcers, vascular edema, eczema, atopic dermatitis and contact dermatitis; Gastrointestinal allergies such as allergies caused by food and drugs; convulsion; Motion Sickness; throw up; Diarrhea, and allergic diseases, including allergic allergies.
    Histamine, an effect of which is activated through the activation of H 1 receptors, is an important mediator of the response involved in vasoactive hypersensitivity. In the acute state of allergic rhinitis, histamine H 1 receptor antagonists effectively inhibit itching, runny nose and sneezing of the nose associated with this condition. However, histamine H 1 receptor antagonists are less effective at removing nasal bleeding. Acute reactions to allergens in rhinitis often involve a chronic inflammatory response while hemorrhagic mucosa becomes sensitive to both antigenic and nonspecific stimulants. In addition, histamine H 1 receptor antagonists are ineffective in attenuating the symptoms of the chronic condition of the response.
    The present invention provides novel and useful histamine antagonists, stereoisomers or pharmaceutically acceptable salts thereof of formula (I).
    In a further aspect, the invention provides an allergic rhinitis comprising seasonal rhinitis and sinusitis as histamine antagonists; Lung diseases such as asthma; Allergic dermatitis, such as ulcers, vascular edema, eczema, atopic dermatitis, contact dermatitis; Gastrointestinal allergies such as allergies caused by food and drugs; convulsion; Motion Sickness; throw up; There is provided a method of treating such an allergic disease, comprising administering to a person in need of such treatment an allergic disease including diarrhea and an allergic disease a therapeutically effective amount of a compound of formula (I).
    In addition to histamine, tachykinin, particularly substrate P, is also an important contributor to allergic reactions and exhibits some symptoms that are different from those caused by histamine reactions. This is caused by the release of tachycinin from the sensory neurons of the tertiary origin located in the peri-vascular and nasal mucosal lines promoted by stimulants such as histamine or inflammatory mediators.
    The presence of rhinitis symptoms in patients with allergic rhinitis has been known to have a high level of substrate P in the nasal cavity (Mosimann et al. , J. Allergy Clin. Immunol. 92 , 95 (1993); Takeyama et al. , J. Pharma. Pharmacol. 46,41 (1994); And Watanabe et al. , Ann. Otol. Rhinol. and Laryngol. , 102 , 16 (1993)]. Administration of tachycinin locally or intravenously to humans induces nasal congestion, recovery of inflammatory cells, secretion, and capillary damage in allergic rhinitis. Nasal plugging caused by substrate P has been shown to be NK 1 receptor mediated [Braunstein et al. , Am. Rev. Respir. Dis. , ≪ / RTI > 144 , 630 (1991); Devillier et al. , Eur. Respir. J. 1 , 356 (1988)]. In addition, the sensory neuro-mediated effects, such as nasal irritation and hypersensitivity, in the terminal states of allergic reactions are also a consequence of tachycinin release [Anggard, Acta Otolaryngol. 113 , 394 (1993)). The release of tachycinin from the nerve of the nose after chronic capsaicin administration improves the person's rhinitis symptoms [Lacroix et al. , Clin. and Exper. Allergy, 21, 595 (1991) ].
    The antagonistic effect of histamine on H 1 receptors is useful for the treatment of allergic diseases such as rhinitis. Similarly, the antagonism of tachykinin, particularly substrate P, to its receptor of interest is useful for the treatment of symptoms that occur simultaneously with allergic diseases. The potential advantage of antagonists with affinity at the H 1 and NK 1 receptors is therefore that they can reduce or prevent clinically prevalent allergic diseases mediated through both of these receptors.
    More particularly, the present invention provides novel, useful compounds of formula 1, stereoisomers or pharmaceutically acceptable salts thereof, which are tachykinin antagonists and histamine antagonists.
    In a further embodiment, the tachykinin antagonist and histamine antagonist of the present invention are selected from allergic rhinitis including seasonal allergies and sinusitis; And a therapeutically effective amount of a compound of formula (I) for the treatment of an allergic disease, including inflammatory bowel disease, including Clonorchis sinensis and western colitis.
    The various diseases and conditions that are to be treated are well known to those skilled in the art. It will also be appreciated by those skilled in the art that by treating a patient currently suffering from a disease with a therapeutically effective amount of a compound of formula 1 or by prophylactically treating a patient suffering from a disease with a therapeutically effective amount of a compound of formula 1, It is known that it can influence.
    The term " patient " herein refers to a warm-blooded animal, such as a mammal, particularly suffering from an allergic disease. Guinea pigs, dogs, cats, rats, mice, horses, cows, sheep, and humans are examples of animals within the scope of the term meaning.
    The term " therapeutically effective amount " of a compound of formula (1) herein means an amount effective to treat a disease described herein. The term " treatment " refers to any process that can alleviate, block, inhibit or halt progression of the disease described herein, but does not mean the complete elimination of all symptoms of the disease, .
    The therapeutically effective amount can be easily determined by a practitioner skilled in the art by using a conventional technique and observing the obtained result under the same environment. In determining a therapeutically effective amount, the dose, the species of mammal; Its size, age and general health status; Specific disease progressed; The progression or severity of the disease; Individual patient response; The particular compound administered; Methods of administration; The bioavailability of the administered formulation, the selected dose regimen; Many factors, including but not limited to the use of the accompanying medicament and other appropriate circumstances, are contemplated by the attending physician.
    The therapeutically effective amount of the compound of formula I varies from about 0.1 to about 100 mg / kg / day. Preferred amounts can be determined by those skilled in the art.
    In carrying out the treatment of a patient suffering from the above-described diseases, the compound of formula (I) may be administered in any form or method including oral, inhalation, and parenteral routes such that an effective amount of the compound is followed by a biologically useful compound . For example, the compound of formula (I) may be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, anal, topically, by inhalation of an aerosol or anhydrous powder. Oral or inhalation administration is generally preferred for the treatment of allergic diseases. Those skilled in the art of formulating can readily choose the appropriate dosage form and method depending on the particular characteristics of the selected compound, the disease or condition to be treated, the stage of the disease or condition, and other appropriate circumstances. [Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).
    The compounds of the present invention may be administered alone or in the form of pharmaceutical compositions in combination with pharmaceutically acceptable carriers or excipients, the ratios and properties of which will depend on a variety of factors including the solubility and chemical characteristics of the selected compound, ≪ / RTI > The compounds of the present invention which are effective per se may be formulated and administered in the form of a pharmaceutically acceptable salt such as an acid addition salt or a base addition salt for stability, convenient crystallization, increase in solubility, and the like.
    In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) in admixture or association with one or more pharmaceutically acceptable carriers or excipients.
    The pharmaceutical compositions are prepared by methods known in the pharmaceutical arts. The carrier or excipient may be a solid, semi-solid or liquid material provided as a vehicle or medium for the active ingredient. Suitable carriers or excipients may be employed for oral, inhalation, parenteral or local application and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, and the like.
    The compounds of the present invention may be administered orally, for example, with an inert carrier or an edible carrier. They can be compressed into gelatin capsules or tablets. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such formulations contain at least 4% of the compounds of the invention, but the active ingredient may vary depending on the particular form and may conveniently be between 4% and 70% of the unit dose. The amount of the compound in the composition is that amount at which a suitable dose is obtained. The preferred compositions and formulations according to the present invention can be determined by those skilled in the art.
    In addition, tablets, pills, capsules, troches and the like may contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid, Primogel, corn starch and the like; Lubricants such as magnesium stearate or stearothex; Such as colloidal silicon dioxide, and sweeteners such as sucrose or saccharin, or peptides such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, in addition to the above types of materials, a weak carrier such as polyethylene glycol or fatty oil may also be included. Tablets or pills may also be coated with sugar, shellac or other enteric coating agents. Syrups contain sucrose as a sweetening agent in addition to the compounds of the present invention and may contain specific preservatives, dyes, coloring agents and flavoring agents. The materials used to make these various compositions are pharmaceutically pure and used in a toxic amount.
    For parenteral therapeutic administration, the compounds of the present invention may be incorporated as a solution or suspension. Such formulations contain 0.1% or more of the compound of the present invention, but may vary from 0.1% to about 50% by weight of the compound. The amount of the compound of formula (I) of the present invention in such compositions is such that a suitable dose is obtained. Preferred compositions and formulations can be determined by those skilled in the art.
    The compounds of the present invention may also be administered by inhalation of aerosols and anhydrous powders. By a liquefied or compressed gas, or by a suitable pump system for dispensing the compounds of the invention or formulations thereof. Formulations for administration by inhalation of the compound of formula (I) may be delivered in a single, double or triple system. A variety of systems may be useful for administration by aerosol of the compound of formula (I). A dry powder formulation may be prepared by pelleting or pulverizing the compound of formula (I) into a suitable particle size or by blending the pelleted or ground compound of formula (I) with a suitable carrier material such as lactose. Delivery by inhalation includes required containers, activators, valves, subcontainers, and the like. Aerosol and anhydrous powder formulations suitable for administration by inhalation may be measured by those skilled in the art.
    The compounds of the present invention may also be administered locally, where the carrier may suitably comprise a solution, ointment or gel base. The substrate can include, for example, one or more of the following materials: diluents such as petroleum, lanolin, polyethylene glycol, bee wax, mineral oil, water and alcohols, and emulsifiers and stabilizers. The topical formulations may contain a concentration of from about 0.1 to about 10% w / v of the compound of formula (I) or a pharmaceutical salt thereof (weight per unit dose).
    The solution or solution may also contain one or more of the following auxiliaries: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antimicrobial agents such as Bell alcohol or methyl paraben; Antioxidants such as ascorbic acid or sodium diasulfate; Chelating agents such as ethylenediaminetetraacetic acid; A buffer such as acetate, citrate or phosphate, and a toxic modulator such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic.
    Example A
    Histamine H < RTI ID = 0.0 > OneLt; RTI ID = 0.0 > [ 3H] -pyrylamine < / RTI >
    Skilled artisans will be able to evaluate the H 1 receptor affinity of the proposed histamine antagonist in rat brain or Chinese hamster ovary cells infected with the human histamine H 1 receptor gene (CHOpcDNA3H1R cells).
    For study in the rat brain, young male rats are beheaded and the brain is immediately removed. The cortex is incised, immediately used or stored at -20 ° C. Chinese hamsters For study in ovarian cells, fusion cells are collected from culture flasks. Tissue or cells are homogenized with 20 mM polytron (Polytron, no. 6, set at 15 seconds) in 20 ml of 50 mM potassium sodium phosphate (pH 7.4, 4 ° C). Centrifuge the homogenate at 4 ° C and 48,000 x g for 12 minutes. The pellet was resuspended in culture buffer (50 mM potassium sodium phosphate with 0.1% bovine serum albumin, pH 7.4, ambient temperature) using a polytron (set at no. 6, 15 seconds) to a concentration of 40 mg / , Immediately add to the tube and start the assay. The protein concentration of the crude membrane suspension is determined by the method of OH Lowery et al., J. Biol. Chem. , ≪ / RTI > 193 265 (1951).
    Binding assays are performed twice in 50 mM potassium sodium phosphate (pH 7.4, ambient temperature) containing 0.1% bovine serum albumin in a 12 x 75 mm polypropylene tube. The radioligand and [ 3 H] -pyrylamine are diluted in culture buffer to a concentration of 2 nM and added to each tube (50 μl). The test compound is diluted with culture buffer (10 -10 M to 10 -5 M) and added to a suitable tube (50.). Assay is started by adding 250 μL of mixed tissue suspension to the wells. The final culture volume is 0.5 ml. The assay is carried out at ambient temperature for 30 minutes. The culture is terminated by adding 3.5 ml (0.9 캜) of 0.9% sodium chloride solution and filtering through a GF / B filter pre-infiltrated overnight in 0.1% polyethyleneimine using a Brandel cell harvester. The filter is quickly washed twice with 3.5 ml of culture buffer and transferred to a scintillation vial. Add this column (Ecolume, 9 ml) to the vial. The vials are shaken and fixed for 4 hours before counting in a liquid scintillation spectrometer. The specific binding is measured as the difference between the tube containing no test compound and the tube containing 10 [mu] M promethazine. Total membrane bound radioactivity is generally about 5% of the amount applied to the tub. Specific binding is generally described by MD DeBacker et al., Biochem. and Biophys. Res. Commun. , 197 (3) 1601 (1991)].
    The molar concentration of the compound causing 50% inhibition of ligand binding at the screening dose (10 μM) is the IC 50 value, expressed as cumulative averages (± SEM) for n experiments.
    Example B
    NK OneAntagonism of tachycin iodide binding to the receptor
    One skilled in the art can evaluate the NK 1 receptor affinity of the proposed tachykinin antagonist by evaluating it in Keystone Bioligicals, Cleveland, Ohio. Tissue is homogenized with polytron in 15 volumes of 50 mM Tris-HCl buffer (pH 7.4, 4 占 폚) and centrifuged. The pellet is resuspended in Tris-HCl buffer and centrifuged. The pellet is washed twice with ash suspension. The final pellet is resuspended in culture buffer at a concentration of 40 mg / ml and left at room temperature for at least 15 minutes before use.
    Receptor binding was determined by incubating the cells with 50 mM Tris-HCl (pH 7.4, room temperature), 0.1% bovine serum albumin, 2 mM manganese chloride, 40 μg / ml bacitracin, 4 μg / ml leupeptin and chymostatin, Start by adding 250 μl of the membrane preparation twice to 0.1 nM 125 I-Bolton Hunter Lys-3 labeled substrate P in a final volume of 500 μl of buffer containing the estimated tachykinin antagonist. The incubation is carried out at room temperature for 90 minutes and the binding is terminated by adding 50 mM Tris-HCl buffer (pH 7.4, 4 ° C) and filtration under reduced pressure through a GF / B filter pre-infiltrated with 0.1% polyethyleneimine. The radioactivity bound to the filter is quantified in a gamma counter. Non-specific binding is measured as binding in the presence of 1 [mu] M substrate P.
    Specific binding is calculated by subtracting non-specific binding from total binding. Competition of iodinated substrate P bonds by test compounds or standards is expressed as a percentage of maximum competition. IC 50 values (concentration required to inhibit 50% of receptor binding) are determined by nonlinear regression using a repetitive curve fitting program (GraphPAD Inplot, San Diego, Calif.) For each test compound.
    Example C
    Histamine at the Guinea Pig One) Antagonism
    One of skill in the art will assess the ability of the compounds to inhibit histamine-mediated smooth muscle contraction to determine whether the compounds of the invention are antagonists to H 1 receptors in vitro. A male Hartley guinea pig weighing 200-450 g is sacrificed by suffocation with CO 2 . Remove one 20 cm long chair and cut into 2 cm pieces. Each sculpture piece is placed in a 37 ° C bath containing Tyrode's solution and immediately ventilated with 95% O 2 /5% CO 2 . The tea rod solution has a composition of 136.9 mM sodium chloride, 2.68 nM potassium chloride, 1.8 mM calcium chloride, 0.42 mM sodium dihydrogenphosphate, 11.9 mM sodium bicarbonate, and 5.55 mM Dextrose. The shrinkage is measured with a static transducer (Grass FTO3C) and recorded on a polygraph recorder and / or a computer. The plaque fragments are loaded at 1.0 g and equilibrated for at least 30 minutes before starting the experiment. Tissue is preincubated with vehicle or test compound at various concentrations and histamine challenge is performed.
    Competitive H 1 receptor antagonists equilibrate the histamine dose-response curve to the right without diminishing the maximal response.
    The efficacy of the antagonism is measured by the magnitude of migration and is expressed as the negative log-pA 2 value of the molar concentration of the antagonist that shifts the dose response curve to the right by two folds. The pA 2 value is calculated using a Schild analysis (reference: O. Arunlakshana and HO Schild, Br. J. Pharmacol Chemother. 14 , 48-58 (1958)). If the slope of the line obtained by the shield analysis is significantly different from (1), the compound acts as a competitive antagonist.
    Example D
    Antagonism of in vitro Tachycinin-induced phosphatidylinositol (PI) conversion by putative antagonists
    One skilled in the art can measure NK 1 receptor antagonism by measuring accumulation of substance P-induced phosphatidylinositol (PI, inositol phosphate) in UC11 cells in the presence and absence of NK 1 receptor antagonists. Cells are seeded in 24-well plates at 125,000 cells / well 2 or 3 days before assay. Before the test cells 20 to 24 hours 0.2μM myo- [2- 3 H (N )] inositol (American Radiolabeled Chemicals Inc., specific activity ; 20μCi / mmol) loads the 0.5㎖. The cultured cells are maintained at 37 ° C under a 5% CO 2 environment.
    On the day of the challenge, the medium was aspirated and cells were resuspended in RPMI-1640 medium containing 40 μg / ml bacthitracin, 4 μg / ml leupeptin and chimostatin, 0.1% bovine serum albumin, 10 μM thiorbine and 10 mM lithium chloride, Lt; / RTI > After 15 minutes, the test compound is added to the cells in a volume of 0.1 ml. After 15 minutes, the substrate P is added to various concentrations of UC11 cells to start the reaction, followed by incubation at 37 DEG C for 60 minutes in a final volume of 1 mL in a 5% CO 2 environment. The medium is aspirated to terminate the reaction, and methanol (0.1 ml) is added to each well. Two aliquots of methanol (0.5 ml) are added to the wells and the cells are recovered in chloroform-resistant tubes. Chloroform (1 ml) is added to each tube, followed by twice distilled water (0.5 ml). Samples are vortexed for 15 seconds and centrifuged at 1700 x g for 10 minutes. Aliquots (0.9 ml) on the aqueous (upper) phase are removed and double distilled water (2 ml) is added. The mixture is vortexed and loaded onto a 50% Bio-Rad AG 1-X8 (formate form, 100-200 mesh) exchange column (Bio-Rad Laboratories, Hercules, Calif.). The column is washed with 1) twice 10 ml of distilled water, 2) 5 ml of sodium tetraborate / 60 mM sodium formate, and 5 ml of 3M ammonium formate / 0.1M formic acid. The third eluate is recovered and counted in a 9 ml scintillation liquid. An aliquot of 50 [mu] l on top of the organic (lower) was removed, dried in a scintillation vial and counted in 7 ml of scintillation liquid.
    The ratio of DPM in an aqueous phase aliquot (total inositol phosphate) to DPM in a 50 ul organic phase aliquot (total [ 3 H] inositol incorporated) is calculated for each sample. The data represent the antagonist-induced accumulation of [< 3 > H] -inositol phosphate to baseline levels in%. The ratio in the presence of the test compound and / or standard is compared to the ratio for the control sample (i. E., Without any facilitating antagonist).
    The capacity-response graph is shown and the ability of test compounds to inhibit tachykinin-induced phosphopetaine inositol exchange is measured with the aid of a computer program. The data represent the% stimulation of total inositol phosphate accumulation to the baseline level and normalize to the maximum response exhibited by the substrate P. Shield assays are performed using a dose response curve to obtain a value indicative of the intensity of the competitive antagonist, which is a negative logarithm of the antagonist molarity that reduces the effect of the agonist dose to one half the expected effect of the agonist dose value, expressed in pA 2. The slope of the line obtained by shield analysis is not significantly different from (1), and the compound acts as a competitive antagonist.
    Example E
    In vivo, H One(Or NK One) Evaluation of antagonism
    One of skill in the art will be able to assess the ability of a compound to inhibit the formation of histamine (or substrate P) induced wheal in guinea pigs to determine whether the compounds of the present invention mediate the direct mediation of the hypersensitivity reaction in vivo Can be measured. Animals are anesthetized with pentobarbital (ip). Shake the skin, inject the histamine (or the substrate P) into the skin of the shaving site an appropriate number of times after administration of the test compound. The dose, route and frequency of administration may vary according to the method of the experiment. Such experimental methods are well known in the art. Immediately after the in-skin challenge, animals are given intravenous 1% Evan's blue dye to reveal the gauze. After challenging, the animals are inhaled by sucking CO 2 at an appropriate number of times. The skin is removed and the diameter of each well is measured in two vertical directions.
    Gastric reactions use an index of edema response. Percent inhibition of the pore response is calculated by comparing the drug-treatment group with the Beckl-treatment group. The linear regression curve of dose-response inhibition is used to determine the ED 50 value (mg / kg) as a dose of a compound that inhibits histamine-induced skin ganglia by 50%.
    Example F
    In vivo, NK OneAssessment of antagonism
    One of skill in the art will be able to determine whether a compound of the present invention is an NK 1 receptor antagonist in vivo by evaluating the ability of the compound to inhibit the extravasation of p-induced plasma proteins in guinea pig organs . The amount of substrate P-induced protein leakage through postcapillary venules is assessed by measuring the Evan blue dye accumulation in guinea pig organs.
    When the putative antagonist is administered intravenously, the animal is anesthetized with pentobarbitol and then an evan blue dye (20 mg / kg, i.v., prepared in 0.9% sodium chloride solution) is injected. One minute after the dye administration, the antagonist was administered (iv), followed by administration of the substrate P (0.3 nmole / kg), and after 5 minutes, 50 ml of 0.9% sodium chloride solution was used to circulate the cardiac transition perfusion to remove excess dye do. The engine and main bronchial tubes are removed, blotted, dried and weighed.
    If the putative antagonist is administered orally, the animal is anesthetized with pentobarbitol 1 hour after administration and infused with an evan blue dye (20 mg / kg, i.v., prepared in 0.9% sodium chloride solution). One minute after the administration of the dye, the substrate P (0.3 nmole / kg, i.v.) is administered, and after 5 minutes, 50 ml of 0.9% sodium chloride solution is used to circulate the cardiac transition perfusion to remove excess dye. The engine and main bronchial tubes are removed, blotted, dried and weighed.
    After extracting the tissue from the formamide at 50 ° C for 24 hours, the dye amount is measured with a spectrophotometer at 620 nm. The value is subtracted from the background value (dye only without antagonist). The ED 50 (the amount of compound that inhibits the sunrise of the substrate P-induced plasma protein by 50%) is calculated by linear regression analysis.
    权利要求:
    Claims (22)
    [1" claim-type="Currently amended] A compound of formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof.
    Formula 1

    In this formula,
    R 'is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    R " is hydrogen or And Wherein R 20 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and -CF 3 ,
    Ar 1 is , , And Wherein R 1 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and , R 2 is 1 to 2 substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    X 1 and X 2 are as defined in one of parts A), B) or C)
    A) X < 1 > is hydrogen,
    X 2 is , , , And Lt; / RTI > is a radical selected from the group consisting of &
    p is 1 or 2,
    R 3 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    R 4 is 1 to 3 substituents each independently selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy,
    R < 5 > is hydrogen or hydroxy,
    Ar 2 is , , , And Wherein R 6 is selected from the group consisting of hydrogen, halogen, -CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and -CO 2 R 9 wherein R 9 is hydrogen and C 1 -C 4 Alkyl, and R 7 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, each of which is independently selected from the group consisting of R 1 is selected from the group consisting of hydrogen, -CH 3 and -CH 2 OH, R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and benzyl,
    Z is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, - (CH 2 ) w -O- (CH 2 ) t -Y, - (CH 2 ) f A, - (CH 2 ) u CO 2 R 11 , 2) u C (O) NR 12 R 13, - (CH 2) g C (O) (CH 2) h CH 3, - (CH 2) w -O-Ar 3, -CH 2 CH 2 OCF 3, -CH 2 CF 3, -CH 2 CH 2 CH 2 CF 3, - (CH 2) 2 CH = CH 2, -CH 2 CH = CH 2, -CH 2 CH = CHCH 3, -CH 2 CH = CHCH 2 and CH 3, -CH 2 CH = C (CH 3) 2 and -CH 2 OCH 2 CH 2 and Si (CH 3) 3, where w is an integer from 2 to 5, t is an integer of 1 to 3, f is 2 or 3, u is an integer from 1 to 4, g is an integer from 1 to 3, h is an integer from 0 to 3, w is an integer from 2 to 4, Y is a hydrogen, -CF 3, -CH = CH 2 , -CH = C (CH 3 ) 2 and -CO 2 R 14 wherein R 14 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, A is - NR 15 R 16 (R 15 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, R 16 is C 1 -C 4 alkyl), acetylamino, and morpholino group consisting of furnace coming Is selected from, R 11 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, R 12 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and benzyl, R 13 is hydrogen and C 1 - C 4 alkyl, Ar 3 is selected from the group consisting of And Wherein v is an integer from 1 to 3 and R 17 is selected from the group consisting of hydrogen and -COR 18 where R 18 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, Selected;
    B) X < 1 > is hydroxy,
    X 2 is And , Wherein p, R 3 , Z and Ar 2 are as defined above;
    C) X < 2 > Wherein R < 3 > and R < 4 > are as defined above,
    X 1 and Z 1 together form a double bond between carbon atoms containing X 1 and Z 1 .
    [2" claim-type="Currently amended] 2. The compound according to claim 1, wherein X < 1 > is hydrogen.
    [3" claim-type="Currently amended] 3. The compound according to claim 2, wherein X < 2 & (Wherein R < 3 >, Ar < 2 > and p are as defined in claim 1).
    [4" claim-type="Currently amended] 4. A compound according to claim 3, wherein R < 3 > is hydrogen, p is 1 and Ar < 2 > is 4-fluorophenyl.
    [5" claim-type="Currently amended] 4. A compound according to claim 3, wherein R < 3 > is hydrogen, p is 1 and Ar < 2 >
    [6" claim-type="Currently amended] The compound according to claim 3, wherein R 3 is hydrogen, p is 1, and Ar 2 is fur- 2 -yl.
    [7" claim-type="Currently amended] The compound according to claim 3, wherein R 3 is hydrogen, p is 1, and Ar 2 is fur-3-yl.
    [8" claim-type="Currently amended] 3. The compound according to claim 2, wherein X < 2 & (Wherein R < 3 > and Z are as defined in claim 1).
    [9" claim-type="Currently amended] 9. Compounds according to claim 8, wherein Z is - (CH 2 ) w -O- (CH 2 ) t -Y, wherein w, t and Y are as defined in claim 1.
    [10" claim-type="Currently amended] 10. The compound of claim 9, wherein w is 2.
    [11" claim-type="Currently amended] 11. Compounds according to claim 10, wherein Z is 2-ethoxyethyl.
    [12" claim-type="Currently amended] 2. The compound according to claim 1, wherein X < 1 > is hydroxy.
    [13" claim-type="Currently amended] 13. The compound of claim 12, wherein X < 2 & (Wherein R < 3 >, Ar < 2 > and p are as defined in claim 1).
    [14" claim-type="Currently amended] 14. The compound of claim 13, wherein R < 3 > is hydrogen, p is 1 and Ar < 2 > is 4-fluorophenyl.
    [15" claim-type="Currently amended] 2. The compound of claim 1 which is (+) - or (-) - N-methyl-N- (4- (4- (1- (pyrid-2- ylmethyl) -1H-benzimidazole- ) Piperidin-1-yl) -2- (4-fluorophenyl) butyl) -3,4,5-trimethoxybenzamide.
    [16" claim-type="Currently amended] 2. The method according to claim 1, which comprises reacting (+) - or (-) - N- methyl- N- (4- (4- (1- (4- fluorobenzyl) -1H- benzimidazole- Yl) -2- (3,4-dichlorophenyl) butyl) benzamide, or a mixture thereof.
    [17" claim-type="Currently amended] A pharmaceutical composition comprising a compound of claim 1.
    [18" claim-type="Currently amended] A pharmaceutical composition comprising a compound of claim 1 mixed or associated with one or more inert carriers.
    [19" claim-type="Currently amended] A method of treating an allergic rhinitis, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
    [20" claim-type="Currently amended] A method of treating asthma, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
    [21" claim-type="Currently amended] A method of treating vomiting comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of vomiting treatment.
    [22" claim-type="Currently amended] A method of treating inflammatory bowel disease, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
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    同族专利:
    公开号 | 公开日
    ES2184992T3|2003-04-16|
    EP0882038A1|1998-12-09|
    EP0882038B1|2002-12-18|
    NZ330910A|2001-05-25|
    BR9707643A|1999-07-27|
    AU2270797A|1997-09-10|
    JP2002504082A|2002-02-05|
    CN1096460C|2002-12-18|
    IL125577A|2004-03-28|
    WO1997030990A1|1997-08-28|
    NO983831L|1998-10-20|
    DE69717969D1|2003-01-30|
    AT229952T|2003-01-15|
    CA2246727C|2002-04-23|
    TW375610B|1999-12-01|
    DK882038T3|
    NO983831D0|1998-08-20|
    AU709215B2|1999-08-26|
    HU9901751A3|2004-09-28|
    CN1211247A|1999-03-17|
    CA2246727A1|1997-08-28|
    PT882038E|2003-04-30|
    DE69717969T2|2003-08-28|
    HU9901751A2|1999-08-30|
    DK0882038T3|2003-04-14|
    IL125577D0|1999-03-12|
    SI0882038T1|2003-06-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-02-21|Priority to US60420296A
    1996-02-21|Priority to US8/604,202
    1996-12-23|Priority to US77154496A
    1996-12-23|Priority to US8/771,544
    1997-01-27|Application filed by 게리 디. 스트리트, 스티븐 엘. 네스비트, 훽스트 마리온 로우셀, 인크.
    1999-12-15|Publication of KR19990087055A
    优先权:
    申请号 | 申请日 | 专利标题
    US60420296A| true| 1996-02-21|1996-02-21|
    US8/604,202|1996-02-21|
    US77154496A| true| 1996-12-23|1996-12-23|
    US8/771,544|1996-12-23|
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