BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES

FIELD: chemistry. ^ SUBSTANCE: invention relates to novel benzimidazole derivatives of formula ^ ^ and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alky...

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Hauptverfasser: GRETER UVE, MARTIN RAJNER EH, KUN BERND, JAN MIN'MIN', RIKHTER KHANS, RAJT MATT'JU, PANDAJ NARENDRA, DEMLOV KHENIRIETTA, VARO AV'ER MARI, NIZOR EHRIK J, BENSON GREGORI MARTIN, SHULER FRANTS, CHUCHOLOVSKI ALEKSANDER, BLAJKHER KONRAD
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creator GRETER UVE
MARTIN RAJNER EH
KUN BERND
JAN MIN'MIN'
RIKHTER KHANS
RAJT MATT'JU
PANDAJ NARENDRA
DEMLOV KHENIRIETTA
VARO AV'ER MARI
NIZOR EHRIK J
BENSON GREGORI MARTIN
SHULER FRANTS
CHUCHOLOVSKI ALEKSANDER
BLAJKHER KONRAD
description FIELD: chemistry. ^ SUBSTANCE: invention relates to novel benzimidazole derivatives of formula ^ ^ and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compo
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fullrecord <record><control><sourceid>epo_EVB</sourceid><recordid>TN_cdi_epo_espacenet_RU2424233C2</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>RU2424233C2</sourcerecordid><originalsourceid>FETCH-epo_espacenet_RU2424233C23</originalsourceid><addsrcrecordid>eNqNjsFqAkEQRPeSg2j-oY4R9OL6A-1Mr9vg9izds2K8iMh4EiOYP8qPZg8J5BjqUDwoqmpSfW1Yj9JJpGPaMSKb7CnLnn0Bf9fcsouj49ym6BjRODULDM6_AHI0ZMqeJOIA48B9Toa35mBz0DapeAZpRN-SdRR4yBJoh964JxvXkjpC0kyiols4jUV_nsyql-v59iyvPz6t0HAO7bI8Pk7l-Thfyr18nmxYrUfVdVjV_4h8AwbjRdQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>patent</recordtype></control><display><type>patent</type><title>BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES</title><source>esp@cenet</source><creator>GRETER UVE ; MARTIN RAJNER EH ; KUN BERND ; JAN MIN'MIN' ; RIKHTER KHANS ; RAJT MATT'JU ; PANDAJ NARENDRA ; DEMLOV KHENIRIETTA ; VARO AV'ER MARI ; NIZOR EHRIK J ; BENSON GREGORI MARTIN ; SHULER FRANTS ; CHUCHOLOVSKI ALEKSANDER ; BLAJKHER KONRAD</creator><creatorcontrib>GRETER UVE ; MARTIN RAJNER EH ; KUN BERND ; JAN MIN'MIN' ; RIKHTER KHANS ; RAJT MATT'JU ; PANDAJ NARENDRA ; DEMLOV KHENIRIETTA ; VARO AV'ER MARI ; NIZOR EHRIK J ; BENSON GREGORI MARTIN ; SHULER FRANTS ; CHUCHOLOVSKI ALEKSANDER ; BLAJKHER KONRAD</creatorcontrib><description>FIELD: chemistry. ^ SUBSTANCE: invention relates to novel benzimidazole derivatives of formula ^ ^ and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound. ^ EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained. ^ 30 cl, 379 ex Настоящее изобретение относится к новым производным бензимидазола формулы (I) и к их фармацевтически приемлемым солям и сложным эфирам, где R1 обозначает C1-10алкил, низшую алкоксигруппу-низший алкил, низшую алкоксигруппу-карбонил-низший алкил, С3-6циклоалкил, С3-6циклоалкил-низший алкил, фенил, фенил-низший алкил, ди(фенил)-низший алкил, гетероциклил, такой как пиперидинил, тетрагидропиранил, 2-оксо-пирролидинил-низший алкил, где циклоалкильная, фенильная или гетероциклильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, низшую алкоксигруппу, низшую алкоксигруппу-карбонил, морфолинил, формиламиногруппу и галоген; R2 обозначает водород или низший алкил; R3 обозначает низший алкил, С3-6циклоалкил, частично ненасыщенный циклогексил, фенил, фенил-низший алкил, пиридинил, бензодиоксолил, тетрагидропиранил, где фенильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей галоген, низший алкил, низшую алкоксигруппу, фтор-низший алкил, фтор- низшую алкоксигруппу, N(низший алкил)2; R4 обозначает: а) гетероарил, который представляет собой ароматическое 5-6-членное моноциклическое кольцо или 9-10-членное бициклическое кольцо, содержащее 1 или 2 гетероатома, выбранных из азота, кислорода и/или серы, который является необязательно замещенным 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, фенил, низшую алкоксигруппу, -N(низший алкил)2, оксогруппу, NH2, галоген, цианогруппу и морфолинил; б) незамещенный нафтил, или нафтил, или фенил, которые замещены от 1 до 3 заместителями, независимо выбранными из группы, включа</description><language>eng ; rus</language><subject>CHEMISTRY ; HETEROCYCLIC COMPOUNDS ; HUMAN NECESSITIES ; HYGIENE ; MEDICAL OR VETERINARY SCIENCE ; METALLURGY ; ORGANIC CHEMISTRY ; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES ; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS</subject><creationdate>2011</creationdate><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://worldwide.espacenet.com/publicationDetails/biblio?FT=D&amp;date=20110720&amp;DB=EPODOC&amp;CC=RU&amp;NR=2424233C2$$EHTML$$P50$$Gepo$$Hfree_for_read</linktohtml><link.rule.ids>230,308,780,885,25562,76317</link.rule.ids><linktorsrc>$$Uhttps://worldwide.espacenet.com/publicationDetails/biblio?FT=D&amp;date=20110720&amp;DB=EPODOC&amp;CC=RU&amp;NR=2424233C2$$EView_record_in_European_Patent_Office$$FView_record_in_$$GEuropean_Patent_Office$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>GRETER UVE</creatorcontrib><creatorcontrib>MARTIN RAJNER EH</creatorcontrib><creatorcontrib>KUN BERND</creatorcontrib><creatorcontrib>JAN MIN'MIN'</creatorcontrib><creatorcontrib>RIKHTER KHANS</creatorcontrib><creatorcontrib>RAJT MATT'JU</creatorcontrib><creatorcontrib>PANDAJ NARENDRA</creatorcontrib><creatorcontrib>DEMLOV KHENIRIETTA</creatorcontrib><creatorcontrib>VARO AV'ER MARI</creatorcontrib><creatorcontrib>NIZOR EHRIK J</creatorcontrib><creatorcontrib>BENSON GREGORI MARTIN</creatorcontrib><creatorcontrib>SHULER FRANTS</creatorcontrib><creatorcontrib>CHUCHOLOVSKI ALEKSANDER</creatorcontrib><creatorcontrib>BLAJKHER KONRAD</creatorcontrib><title>BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES</title><description>FIELD: chemistry. ^ SUBSTANCE: invention relates to novel benzimidazole derivatives of formula ^ ^ and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound. ^ EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained. ^ 30 cl, 379 ex Настоящее изобретение относится к новым производным бензимидазола формулы (I) и к их фармацевтически приемлемым солям и сложным эфирам, где R1 обозначает C1-10алкил, низшую алкоксигруппу-низший алкил, низшую алкоксигруппу-карбонил-низший алкил, С3-6циклоалкил, С3-6циклоалкил-низший алкил, фенил, фенил-низший алкил, ди(фенил)-низший алкил, гетероциклил, такой как пиперидинил, тетрагидропиранил, 2-оксо-пирролидинил-низший алкил, где циклоалкильная, фенильная или гетероциклильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, низшую алкоксигруппу, низшую алкоксигруппу-карбонил, морфолинил, формиламиногруппу и галоген; R2 обозначает водород или низший алкил; R3 обозначает низший алкил, С3-6циклоалкил, частично ненасыщенный циклогексил, фенил, фенил-низший алкил, пиридинил, бензодиоксолил, тетрагидропиранил, где фенильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей галоген, низший алкил, низшую алкоксигруппу, фтор-низший алкил, фтор- низшую алкоксигруппу, N(низший алкил)2; R4 обозначает: а) гетероарил, который представляет собой ароматическое 5-6-членное моноциклическое кольцо или 9-10-членное бициклическое кольцо, содержащее 1 или 2 гетероатома, выбранных из азота, кислорода и/или серы, который является необязательно замещенным 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, фенил, низшую алкоксигруппу, -N(низший алкил)2, оксогруппу, NH2, галоген, цианогруппу и морфолинил; б) незамещенный нафтил, или нафтил, или фенил, которые замещены от 1 до 3 заместителями, независимо выбранными из группы, включа</description><subject>CHEMISTRY</subject><subject>HETEROCYCLIC COMPOUNDS</subject><subject>HUMAN NECESSITIES</subject><subject>HYGIENE</subject><subject>MEDICAL OR VETERINARY SCIENCE</subject><subject>METALLURGY</subject><subject>ORGANIC CHEMISTRY</subject><subject>PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES</subject><subject>SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS</subject><fulltext>true</fulltext><rsrctype>patent</rsrctype><creationdate>2011</creationdate><recordtype>patent</recordtype><sourceid>EVB</sourceid><recordid>eNqNjsFqAkEQRPeSg2j-oY4R9OL6A-1Mr9vg9izds2K8iMh4EiOYP8qPZg8J5BjqUDwoqmpSfW1Yj9JJpGPaMSKb7CnLnn0Bf9fcsouj49ym6BjRODULDM6_AHI0ZMqeJOIA48B9Toa35mBz0DapeAZpRN-SdRR4yBJoh964JxvXkjpC0kyiols4jUV_nsyql-v59iyvPz6t0HAO7bI8Pk7l-Thfyr18nmxYrUfVdVjV_4h8AwbjRdQ</recordid><startdate>20110720</startdate><enddate>20110720</enddate><creator>GRETER UVE</creator><creator>MARTIN RAJNER EH</creator><creator>KUN BERND</creator><creator>JAN MIN'MIN'</creator><creator>RIKHTER KHANS</creator><creator>RAJT MATT'JU</creator><creator>PANDAJ NARENDRA</creator><creator>DEMLOV KHENIRIETTA</creator><creator>VARO AV'ER MARI</creator><creator>NIZOR EHRIK J</creator><creator>BENSON GREGORI MARTIN</creator><creator>SHULER FRANTS</creator><creator>CHUCHOLOVSKI ALEKSANDER</creator><creator>BLAJKHER KONRAD</creator><scope>EVB</scope></search><sort><creationdate>20110720</creationdate><title>BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES</title><author>GRETER UVE ; MARTIN RAJNER EH ; KUN BERND ; JAN MIN'MIN' ; RIKHTER KHANS ; RAJT MATT'JU ; PANDAJ NARENDRA ; DEMLOV KHENIRIETTA ; VARO AV'ER MARI ; NIZOR EHRIK J ; BENSON GREGORI MARTIN ; SHULER FRANTS ; CHUCHOLOVSKI ALEKSANDER ; BLAJKHER KONRAD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-epo_espacenet_RU2424233C23</frbrgroupid><rsrctype>patents</rsrctype><prefilter>patents</prefilter><language>eng ; rus</language><creationdate>2011</creationdate><topic>CHEMISTRY</topic><topic>HETEROCYCLIC COMPOUNDS</topic><topic>HUMAN NECESSITIES</topic><topic>HYGIENE</topic><topic>MEDICAL OR VETERINARY SCIENCE</topic><topic>METALLURGY</topic><topic>ORGANIC CHEMISTRY</topic><topic>PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES</topic><topic>SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS</topic><toplevel>online_resources</toplevel><creatorcontrib>GRETER UVE</creatorcontrib><creatorcontrib>MARTIN RAJNER EH</creatorcontrib><creatorcontrib>KUN BERND</creatorcontrib><creatorcontrib>JAN MIN'MIN'</creatorcontrib><creatorcontrib>RIKHTER KHANS</creatorcontrib><creatorcontrib>RAJT MATT'JU</creatorcontrib><creatorcontrib>PANDAJ NARENDRA</creatorcontrib><creatorcontrib>DEMLOV KHENIRIETTA</creatorcontrib><creatorcontrib>VARO AV'ER MARI</creatorcontrib><creatorcontrib>NIZOR EHRIK J</creatorcontrib><creatorcontrib>BENSON GREGORI MARTIN</creatorcontrib><creatorcontrib>SHULER FRANTS</creatorcontrib><creatorcontrib>CHUCHOLOVSKI ALEKSANDER</creatorcontrib><creatorcontrib>BLAJKHER KONRAD</creatorcontrib><collection>esp@cenet</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>GRETER UVE</au><au>MARTIN RAJNER EH</au><au>KUN BERND</au><au>JAN MIN'MIN'</au><au>RIKHTER KHANS</au><au>RAJT MATT'JU</au><au>PANDAJ NARENDRA</au><au>DEMLOV KHENIRIETTA</au><au>VARO AV'ER MARI</au><au>NIZOR EHRIK J</au><au>BENSON GREGORI MARTIN</au><au>SHULER FRANTS</au><au>CHUCHOLOVSKI ALEKSANDER</au><au>BLAJKHER KONRAD</au><format>patent</format><genre>patent</genre><ristype>GEN</ristype><title>BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES</title><date>2011-07-20</date><risdate>2011</risdate><abstract>FIELD: chemistry. ^ SUBSTANCE: invention relates to novel benzimidazole derivatives of formula ^ ^ and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound. ^ EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained. ^ 30 cl, 379 ex Настоящее изобретение относится к новым производным бензимидазола формулы (I) и к их фармацевтически приемлемым солям и сложным эфирам, где R1 обозначает C1-10алкил, низшую алкоксигруппу-низший алкил, низшую алкоксигруппу-карбонил-низший алкил, С3-6циклоалкил, С3-6циклоалкил-низший алкил, фенил, фенил-низший алкил, ди(фенил)-низший алкил, гетероциклил, такой как пиперидинил, тетрагидропиранил, 2-оксо-пирролидинил-низший алкил, где циклоалкильная, фенильная или гетероциклильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, низшую алкоксигруппу, низшую алкоксигруппу-карбонил, морфолинил, формиламиногруппу и галоген; R2 обозначает водород или низший алкил; R3 обозначает низший алкил, С3-6циклоалкил, частично ненасыщенный циклогексил, фенил, фенил-низший алкил, пиридинил, бензодиоксолил, тетрагидропиранил, где фенильная группа необязательно замещена 1-2 заместителями, независимо выбранными из группы, включающей галоген, низший алкил, низшую алкоксигруппу, фтор-низший алкил, фтор- низшую алкоксигруппу, N(низший алкил)2; R4 обозначает: а) гетероарил, который представляет собой ароматическое 5-6-членное моноциклическое кольцо или 9-10-членное бициклическое кольцо, содержащее 1 или 2 гетероатома, выбранных из азота, кислорода и/или серы, который является необязательно замещенным 1-2 заместителями, независимо выбранными из группы, включающей низший алкил, фенил, низшую алкоксигруппу, -N(низший алкил)2, оксогруппу, NH2, галоген, цианогруппу и морфолинил; б) незамещенный нафтил, или нафтил, или фенил, которые замещены от 1 до 3 заместителями, независимо выбранными из группы, включа</abstract><oa>free_for_read</oa></addata></record>
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subjects CHEMISTRY
HETEROCYCLIC COMPOUNDS
HUMAN NECESSITIES
HYGIENE
MEDICAL OR VETERINARY SCIENCE
METALLURGY
ORGANIC CHEMISTRY
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS
title BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES
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