ГЕТЕРОЦИКЛИЧЕСКИЕ ПРОИЗВОДНЫЕ ПЕРВИЧНЫХ АМИНДИАЗЕНИУМДИОЛАТОВ

Изобретение относится к соединениям формулы I или их фармацевтически приемлемым солям, которые обладают антигипертензивным действием. В формуле I X представляет собой О или NR; группаприсоединена к любому атому углерода кольца, отличному от атома углерода, к которому присоединены Rи R; Rпредставляет собой водород или вместе с Rобразует =O; Rпредставляет собой водород или вместе с Rобразует =O; Rпредставляет собой -Салкил; Rи R, которые присоединены к любому доступному атому углерода кольца, независимо представляют собой водород или Rи Rв тех случаях, когда они присоединены к одному и тому же атому углерода, вместе образуют =O; Rпредставляет собой -Салкил, -С(О)O-Cалкил, -С(О)O-Cалкилен-CRRR, -С(О)Салкил, -С(О)ОСкарбоцикл, -С(О)арил, -С(О)гетероарил, где гетероарил представляет собой ненасыщенное 5- или 6-членное кольцо, содержащее 1-4 гетероатома, выбранных из N, -С(О)NHCалкил, -С(О)NH-адамантил, -SOCалкил, арил или ненасыщенное 5- или 6-членное гетероарильное кольцо, содержащее 1-4 гетероатома ...

СОЕДИНЕНИЯ И СПОСОБЫ ИНГИБИРОВАНИЯ ВЗАИМОДЕЙСТВИЯ БЕЛКОВ BCL С КОМПОНЕНТАМИ СВЯЗЫВАНИЯ

Настоящее изобретение относится к гетероциклическим соединениям формулы I ! ! где Y означает -(С=O)-, Х означает -N(R10)-, А означает -C(A1)(A2)-, В означает О, S, -(С=O)- или характеризуется формулой ! ! где D означает N или СR10 и где значения остальных заместителей раскрыты в формуле изобретения. Соединения формулы 1, а также композиции на его основе обладают способностью ингибировать белки семейства bcl-2, что обуславливает возможность применения таких соединений и композиций при лечении или модулировании нарушений, ассоциированных с гиперпролиферацией, таких как рак. 7 н. и 13 з.п. ф-лы.

N-МЕТИЛ-N-/(1S-)-1-ФЕНИЛ-2-((3S)-3-ГИДРОКСИПИРРОЛИДИН-1-ИЛ)-ЭТИЛ/-2,2-ДИФЕНИЛАЦЕТАМИД

Изобретение относится к N-метил-N-/(1S-)-1-фенил-2-((3S)-3-гидроксипирролидин-1-ил)-этил/-2,2-дифенилацетамиду, который может быть использован при лечении воспалительных заболеваний кишечника. Соединение получают взаимодействием охлажденного от - 5 до 10oC раствора 1-/(1S)-3-гидроксипирролидин-1-ил-(2-S)-2-метиламино-2-фенилэтана в растворителе с дифенилацетилхлоридом при молярном соотношении исходных реагентов 1:0,75-1:1,65 соответственно и при молярном соотношении исходных реагентов и растворителя (0,8-1,2): (0,9-1,3): (14-22). Полученный после реакции сырой продукт перекристаллизовывают в теплом состоянии из растворителя. Тпл 221-226oC. Соединение, полученное таким образом, является термодинамически устойчивым. 2 с. п. ф-лы.

ПРОИЗВОДНОЕ ФЕНИЛА

Изобретение относится к соединению общей формулы (I), обладающему высокой антагонистической активностью по отношению к S1Pчеловека, и может применяться для приготовления лекарственного средства для лечения заболевания, опосредованного S1P, такого как заболевание, обусловленное сужением сосудов, фиброз и респираторное заболевание. 4 н. и 10 з.п. ф-лы, 2 табл., 9 пр.

ПРОИЗВОДНЫЕ БЕНЗАМИДА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ

Изобретение относится к производным бензамида формулы I где R3 представляет собой (1-6С)алкил или галоген; Q - арил или гетероарил, который необязательно несет 1, 2, 3 или 4 заместителя, выбранных из гидрокси, галогена, циано, нитро, амино, карбокси, (1-6С)алкила, (2-6С)алкенила, (2-6С)алкинила, (1-6С)алкокси, (1-3С)алкилендиокси, (1-6С)алкиламино и т.д.; R2 - (1-6С)алкил, (2-6С)алкенил, (2-6С)алкинил, (1-6С)алкокси, (1-6С)алкиламино или ди-[(1-6С)алкил]амино; p = 0, 1 или 2; q = 0, 1, 2, 3 или 4; R4 - арил, арил-(1-6С)алкокси, арилокси, ариламино, циклоалкил или гетероарил и R4 необязательно несет 1, 2, 3 или 4 заместителя, выбранных из галогена, циано, (1-6С)алкила, (2-6С)алкенила, (2-6С)алкинила, (1-6С)алкокси, (1-6С)алкиламино и т.д., или его фармацевтически приемлемая соль, или расщепляемый in vivo сложный эфир. Предложены способы получения производных бензамида формулы (I). Также предложена фармацевтическая композиция, обладающая ингибирующей цитокины активностью, содержащая активный ...

НЕПРЕРЫВНЫЙ СПОСОБ АЛКИЛИРОВАНИЯ ЦИКЛИЧЕСКИХ ТРЕТИЧНЫХ АМИНОВ

Изобретение относится к непрерывному способу алкилирования третичных аминов и, в частности, к непрерывному способу кватернизации циклических третичных аминов. Способ позволяет получить циклические соли четвертичного аммония с высокой степенью превращения и высокой степенью чистоты. 18 з.п. ф-лы, 1 табл., 6 пр.

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Изобретение относится к новым производным нафталина формулы I , а также к их фармацевтически приемлемым солям, которые могут найти применение для лечения и/или профилактики заболеваний, связанных с модулированием Н-3 рецепторов. В формуле I R1 выбран из водорода, низшего алкила, фенила, фенила-низшего алкила и низшего алкоксиалкила; R2 выбран из водорода, низшего алкила, С3-С7-циклоалкила, низшего алкоксиалкила или низшего алкилсульфанилалкила (все значения R1 и R2 приведены в формуле изобретения); или R1 и R2 вместе с атомом азота, к которому они присоединены, образуют 4-7-членное насыщенное или частично ненасыщенное гетероциклическое кольцо, которое может содержать еще один гетероатом, выбранный из атомов азота, кислорода и серы, где указанное гетероциклическое кольцо может быть незамещенным или замещенным 1-2 группами, либо оно может быть конденсировано с незамещенным фенильным кольцом; ! А выбран из ! или ! (значения R3-R7, R9, R10, X, m, n, t, p, q и s приведены в формуле изобретения ...

ИОНИЗИРУЕМЫЕ СОЕДИНЕНИЯ И КОМПОЗИЦИИ И ИХ ПРИМЕНЕНИЯ

Изобретение относится к области биофармацевтических и терапевтических средств. Предложены ионизируемые соединения, а также фармацевтическая композиция на основе ионизируемых соединений. Технический результат – получение ионизируемых соединений, которые используются для доставки и распределения действующих агентов или лекарственных средств. 12 н. и 16 з.п. ф-лы, 32 ил., 10 табл., 40 пр.

ИНГИБИТОРЫ МЕТАЛЛО-β-ЛАКТАМАЗЫ

Изобретение относится к новому ингибитору металло-β-лактамазы, который действует как лекарственное средство для ингибирования инактивации β-лактамовых антибиотиков и восстановления антибактериальных активностей. Производные малеиновой кислоты, имеющие общую формулу (I), имеют металло-β-лактамаза-ингибирующую активность. Возможно восстанавливать антибактериальные активности β-лактамовых антибиотиков в отношении бактерий, продуцирующих металло-β-лактамазу, комбинируя соединение общей формулы (I) с β-лактамовыми антибиотиками. Ингибитор металло-β-лактамазы представляет собой соединение формулы (I) или его фармацевтически приемлемую соль, в которой R1 обозначает С2-6-алкил; С3-7-циклоалкил, где указанный цикл может быть замещен гидроксильной группой или может быть конденсирован с арилом; гидроксиметил; - С1-3-алкиленфенил, где указанная фенильная группа может быть замещена гидроксильной группой, С1-6-алкильной группой, гидроксиметильной группой, группой -СООМ, где М обозначает атом водорода ...

КРИСТАЛЛИЧЕСКИЕ ФОРМЫ КОМПЛЕКСОВ, ПОЛЕЗНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ SGLT2, И СПОСОБЫ ИХ ПОЛУЧЕНИЯ

Изобретение относится к кристаллической форме комплекса (2S,3R,4R,5S,6R)-2-(4-хлор-3-(4-(2-иклопропоксиэтокси)бензил)фенил)-6-(гидроксиметил)тетрагидро-2Н-пиран-3,4,5-триол, бис(L-пролин), характеризующаяся паттерном дифракции рентгеновских лучей на порошке, включающим пики при 4,08, 17,19 и 21,12 градусов 2θ (±0.05 градусов 2θ), где указанный паттерн дифракции рентгеновских лучей на порошке получают с применением излучения CuK. Предоставленный комплекс обладает ингибиторным действием на зависимый от натрия транспортер SGLT. 4 н. и 3 з.п. ф-лы, 1 табл., 3 ил., 7 пр.

ПРОИЗВОДНЫЕ 3-(ПИПЕРИДИНИЛ-1)-ХРОМАН-4,7-ДИОЛА И 1-(4-ГИДРОКСИФЕНИЛ)-2-(ПИПЕРИДИНИЛ-1)-АЛКАНОЛА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ СВЯЗЫВАНИЯ NMDA РЕЦЕПТОРА

Изобретение относится к производным 3-(пиперидинил-1)-хромана-5,7-диола и 1-(4-гидроксифенил)-2-(пиперидинил-1)алканола общей формулы I или их фармацевтически приемлемым солям присоединения кислот, в которой (a) R2 и R5 взяты в отдельности и R1, R2, R3 и R4 независимо представляют собой водород, (C1-C6)-алкил, галоген, ОН или OR7, а R5 представляет собой метил; или (b) R2 и R5, взятые вместе, образуют кольцо хроман-4-ола, a R1, R3 и R4 каждый независимо представляют собой водород, (C1 -C6)-алкил, галоген, OН или OR7; R7 представляет собой метил; а R6 представляет собой замещенный пиперидинил или 8-азабицикло[3,2,1]октанильное производное; при условии, что (a) если R2 и R5 взяты в отдельности, то по крайней мере один из R1, R2, R3 и R4 не является водородом; и (b) если R2 и R5 взяты вместе, то по крайней мере один из R1, R3 и R4 не является водородом, обладающие свойством NMDA антагониста. Предложены также фармацевтическая композиция на их основе и способ связывания NMDA рецептора. 8 с.

СПОСОБ ПОЛУЧЕНИЯ СОЕДИНЕНИЙ ПИРРОЛИДИНИЛГИДРОКСАМОВОЙ КИСЛОТЫ

Описывается способ получения соединений пирролидинил гидроксамовой кислоты, которые используются в качестве анестезирующих противовоспалительных или нейропротекторных средств. Описываются также новые промежуточные соединения, которые полезны для получения целевых продуктов. 9 с. и 9 з.п. ф-лы.

ПРОИЗВОДНЫЕ ГУАНИДИНА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ОБЛАДАЮЩАЯ ГИПОГЛИКЕМИЧЕСКОЙ АКТИВНОСТЬЮ

Предложены производные гуанидина формулы I, представленной в описании, и их фармацевтически приемлемые соли, где R1 является необязательно замещенным фенилом, R2 является необязательно замещенным амином, R3 - H или (C1-C4) алкил, R4-H1(C1-C6) алкил, карбоциклическое кольцо с 3-7 атомами углерода и др. R5-H1, галоид, (C1-C4) алкил, (C1-C3 )алкокси, S(O)m R8 и др., предложен также способ их получения, а также фармацевтическая композиция, обладающая гипогликемической активностью. 3 с. и 11 з.п. ф-лы, 2 табл.

ЛИГАНДЫ МЕЛАНОКОРТИНОВЫХ РЕЦЕПТОРОВ

... 1. Соединение, включая все его энантиомерные и диастереомерные формы и фармацевтически приемлемые соли, причем указанное соединение имеет формулу: где А представляет конформационно ограниченную кольцевую систему, выбранную из группы, включающей: a) неароматические карбоциклические кольца; b) ароматические карбоциклические кольца; c) неароматические гетероциклические кольца; d) ароматические гетероциклические кольца; где указанные кольца содержат от 5 до 8 атомов; W представляет боковой фрагмент, имеющий формулу: где R выбран из группы, включающей: a) неароматические карбоциклические кольца; b) ароматические карбоциклические кольца; c) неароматические гетероциклические кольца; d) ароматические гетероциклические кольца; указанные кольца содержат от 3 до 12 атомов; J выбран из группы, включающей: i) -[C(R”)d]k-, где каждый R” независимо представляет водород, C1-C12 линейный или разветвленный алкил, -SUB, два фрагмента R”, взятые вместе с атомом кислорода, могут образовывать карбонильный фрагмент ...

ПРОИЗВОДНЫЕ 2-ФЕНОКСИ И 2-ФЕНИЛСУЛЬФОНАМИДА С ССR3 АНТАГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ ДЛЯ ЛЕЧЕНИЯ АСТМЫ И ДРУГИХ ВОСПАЛИТЕЛЬНЫХ ИЛИ ИММУНОЛОГИЧЕСКИХ ЗАБОЛЕВАНИЙ

... 1. Производное бензолсульфонамида, имеющее формулу (I), его таутомерные и стереоизомерные формы и его соли где Х представляет О или S; R1 представляет водород, галоген, гидрокси, нитро, циано, С1-6алкоксикарбонил, амино, С1-6алкиламино, ди(С1-6алкил)амино, С1-6алканоил, фенил, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами, или С1-6алкокси, необязательно замещенный одним, двумя или тремя галогенами; R2 представляет водород, галоген, гидрокси, нитро, циано, С1-6алкоксикарбонил, С1-6алкиламино, ди(С1-6алкил)амино, С1-6 алканоил, фенил, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами, или С1-6алкокси, необязательно замещенный одним, двумя или тремя галогенами; R3 представляет водород, галоген, гидрокси, нитро, циано, амино, карбокси, тетразолил, С1-6алкокси, С1-6алкоксикарбонил, С1-6алканоил, С1-6 алканоиламино, С1-6алкил, необязательно замещенный одним, двумя или тремя галогенами или гидрокси; R4 представляет или где R40 представляет С1-6алкил, ...

ИНГИБИТОРЫ ФЕРМЕНТАТИВНОЙ АКТИВНОСТИ РОТАМАЗЫ, ЯВЛЯЮЩИЕСЯ МАЛЫМИ МОЛЕКУЛАМИ

... 1. Фармацевтический состав, содержащий соединение формулы: где R1 является С1-С9алкильной или алкенильной группой с прямой или разветвленной цепью, возможно замещенной С3 -С8циклоалкилом, С3 или С5циклоалкилом, С5-С7циклоалкенилом или Ar1, где указанные алкильная, алкенильная, циклоалкильная или циклоалкенильная группы возможно могут иметь один или более чем один атом водорода, замещенный С1-С4алкилом, С1-С4алкенилом или гидроксилом, и где Ar1 выбран из группы, состоящей из 1-нафтила, 2-нафтила, 2-индолила, 3-индолила, 2-фурила, 3-фурила, 2-тиазолила, 2-тиенила, 3-тиенила, 2-, 3- или 4-пиридила и фенила, имеющих от одного до трех заместителей, которые независимо выбраны из группы, состоящей из водорода, галогена, гидроксила, нитрогруппы, трифторметила, прямого или разветвленного C1-С6алкила или алкенила, С1-С4алкоксила или C1-С4алкенилоксила, феноксигруппы, бензилоксигруппы и аминогруппы; Х является кислородом, серой, метиленом (СН2) или Н2; Y является кислородом или NR2, где R2 является ...

БЕНЗИЛЭФИРАМИНЫ, ПОЛЕЗНЫЕ КАК АНТАГОНИСТЫ CCR-5

... 1. Соединение общей формулы I его энантиомеры, диастереомеры, соли и сольваты, в которой Х представляет собой связь или кислород; m представляет собой 0, 1, 2, 3 или 4; n представляет собой 0, 1 или 2; R1 представляет собой необязательный заместитель, независимо выбираемый в каждом случае из галогена, алкила, галоалкила, нитро или -NR5R6; R2 представляет собой a) водород; или b) алкил, циклоалкил, алкенил, арил или гетероарил, любой из которых может быть, необязательно, замещен группой Y; Y представляет собой a) арил или гетероарил, каждый из которых может быть, необязательно, замещен одним или несколькими Z1, Z2, Z3; b) циклоалкил или гетероцикло, каждый из которых может быть, необязательно, замещен одним или несколькими Z1, Z2, Z3; c) -COOR7; d) -NR8R9; e) CHR10(OR11); f) -C(=O)-NR8R9; g) -NR12-(C=O)-NR8 R9; h) -CN; i) -C(=N-OR13); j) алкокси; R3 и R4 независимо выбирают из a)водорода; b) алкила, циклоалкила, (циклоалкил)алкила, арила, (арил)алкила, гетероцикло, (гетероцикло)алкила, гетероарила ...

АРИДЗАМЕЩЕННЫЕ ПИПЕРАЗИНОВЫЕ ПРОИЗВОДНЫЕ

... 1. Соединение формулы или его фармацевтически приемлемая соль, где V отсутствует или представляет собой -(С=O)-; W представляет собой N, СН или С-ОН; Y1, Y3, Y4, и Y5 независимо представляют собой CR1 или азот; Z представляет собой азот или CR2; каждый R1 независимо представляет собой (i) водород, галоген, гидрокси, нитро, циано, амино, аминокарбонил, C1-С6алкил, С2-С6алкенил, С3-С6алкинил, C1-С6алкокси, галогенС1-С6алкил, галогенС1-С6алкокси, гидроксиС1-С6алкил, (С1-С4алкокси)С1-С4алкил, C1-С6алкилтио, аминоС1-С6алкил, моно- или ди-(С1-С6алкил)аминоС0-С6алкил, моно- или ди-(С1-С6алкил)аминокарбонил, (С3-С7циклоалкил)С0-С6алкил, или (от 4- до 7-членный гетероциклоалкил)С0-С6алкил; или (ii) взятый вместе с R2 образует конденсированный 5- или 6-членный карбоцикл или гетероцикл, каждый из которых является замещенным 0-3 заместителями, независимо выбранными из галогена, гидрокси, нитро, циано, амино, С1-С4алкил, С1-С4 алкокси, галогенС1-С4алкил и галогенС1-С4алкокси; R2 представляет собой галоген ...

ИНГИБИТОРЫ ФАРНЕЗИЛТРАНСФЕРАЗЫ

... 1. Соединение формулы (I) где R1 и R2 независимо выбраны из Н или фрагмента пролекарства; R3 представляет водород или галоген; R4 представляет водород или галоген; L представляет -СН=СН или -CH2-Z-, где Z представляет NH или О; Y представляет S, S(O) или S(O)2; или его соль. 2. Соединение формулы (I) по п.1, где группа R1 представляет водород или группу пролекарства формулы R5C(О)-, где R5представляет необязательно замещенную арильную или гетероциклильную группу. 3. Соединение формулы (I) по п.2, где R5 представляет необязательно замещенный фенил, необязательно замещенный пиридил, необязательно замещенный фурил, необязательно замещенный изоксазол, необязательно замещенный тетрагидропиридил или необязательно замещенный тетрагидрофурил. 4. Соединение формулы (I) по п.3, где R5 представляет фенил, пиридил или N-метилпиперидин. 5. Соединение формулы (I) по пп.2, 3 или 4, где R5 необязательно замещен алкилом, галоидалкилом, гидрокси, алкокси или циано. 6. Соединение формулы (I) по любому из ...

ПРОИЗВОДНОЕ ВИТАМИНА D, СОДЕРЖАЩЕЕ ЦИКЛИЧЕСКИЙ АМИН В БОКОВОЙ ЦЕПИ

Изобретение относится к производному витамина D формулы (1), фармацевтической композиции, стимулятору ремиелинизации, терапевтическому средству на его основе. Технический результат: получены новые производные витамина D, обладающие прекрасной миграцией в центральную нервную систему, которые стимулируют дифференциацию клеток-предшественников олигодендроцитов или нервных стволовых клеток в олигодендроциты и тем самым стимулируют регенерацию миелиновой оболочки. 4 н. и 18 з.п. ф-лы, 11 табл., 359 пр.

ПРОИЗВОДНЫЕ УКСУСНОЙ КИСЛОТЫ

Производные уксусной кислоты формулы I, где L, M, Q и Т имеют значения, указанные в описании, могут находить применение для лечения или профилактики заболеваний, обусловленных связыванием адгезивных протеинов с тромбоцитами, а также агрегацией тромбоцитов и адгезией клетка-клетка. Их получают путем отщепления защитных групп в соответствующих защищенных соединения или переводом циановой группы в амидиновую группу в соответствующих нитрилах.

НОВЫЕ СУЛЬФОНАМИДКАРБОКСАМИДНЫЕ СОЕДИНЕНИЯ

АМИНОТЕТРАЛИНОВЫЕ ПРОИЗВОДНЫЕ, СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ И ИХ ПРИМЕНЕНИЕ В ТЕРАПИИ

... 1. Аминотетралиновые производные формулы (I)гдеA обозначает 5- или 6-членное кольцо;R обозначает R-W-A-Q-Y-A-X-;Rобозначает водород, C-C-алкил, C-C-циклоалкил-C-C-алкил, галогенированный C-C-алкил, три-(C-C-алкил)-силил-C-C-алкил, гидрокси-C-C-алкил, C-C-алкокси-C-C-алкил, амино-C-C-алкил, C-C-алкиламино-C-C-алкил, ди-C-C-алкиламино-C-C-алкил, C-C-алкилкарбониламино-C-C-алкил, C-C-алкилоксикарбониламино-C-C-алкил, C-C-алкиламинокарбониламино-C-C-алкил, ди-C-C-алкиламинокарбониламино-C-C-алкил, C-C-алкилсульфониламино-C-C-алкил, (необязательно замещенный C-C-арил-C-C-алкил)амино-C-C-алкил, необязательно замещенный C-C-арил-C-C-алкил, необязательно замещенный C-C-гетероциклил-C-C-алкил, C-C-циклоалкил, C-C-алкилкарбонил, C-C-алкоксикарбонил, галогенированный C-C-алкоксикарбонил, C-C-арилоксикарбонил, аминокарбонил, C-C-алкиламинокарбонил, (галогенированный C-C-алкил)аминокарбонил, C-C-ариламинокарбонил, C-C-алкенил, C-C-алкинил, необязательно замещенный C-C-арил, гидрокси, C-C-алкокси, галогенированный ...

ЭФИРЫ ТРИСКАРБАМИНОВОЙ КИСЛОТЫ: ИНГИБИТОРЫ АБСОРБЦИИ ХОЛЕСТЕРИНА

Ингибирование ферментов гидролазы эфиров холестерина (ГЭХ) и/или ацил-софермента А: ацилтрансферазу холестерина (АТАХ) приводит к ингибированию этерификации холестерина и посредством этого к ингибированию абсорбции холестерина. В результате может быть понижено содержание сывороточного холестерина. Соединение, имеющее формулузаместитель Z представляет собой, а А представляет собой связующую группу ингибирует ферменты ГЭХ и/или АТАХ (in vitro) и ингибирует абсорбцию холестерина.

N-ФЕНИЛ-ФЕНИЛАЦЕТАМИДНЫЕ НЕНУКЛЕОЗИДНЫЕ ИНГИБИТОРЫ ОБРАТНОЙ ТРАНСКРИПТАЗЫ

... 1. Соединение формулы I ! , ! где R1 обозначает галоген, C1-6алкил, С3-7циклоалкил, C1-6алкоксигруппу, нитрогруппу или аминогруппу; ! R2 обозначает водород или фтор; ! R3 обозначает фенил, замещенный от одного до трех заместителями, независимо выбранными из группы, включающей C1-6алкил, C1-6галоалкил, С3-8циклоалкил, галоген, цианогруппу или нитрогруппу; ! R4 обозначает водород, C1-6алкил или галоген; ! R5 обозначает водород, C1-6алкил, С3-7циклоалкил или галоген; ! R6 и R7 обозначают водород, C1-6алкил, SO2C1-6алкил или C1-3ацил; ! Х обозначает ОН, C1-6алкоксигруппу или NRaRb; ! один из Ra или Rb обозначает водород, C1-6алкил, С3-6циклоалкил или C1-6гидроксиалкил, а другой из Ra или Rb выбирают из группы, включающей ! (а) водород, ! (б) C1-6алкил, ! (в) C1-6гидроксиалкил, ! (г) C1-6карбоксиалкил, ! (д) (алкилен)rNRcRd, ! (е) SO2-С1-6алкил, и ! (ж) пиридинилметил, ! (з) гетероциклилалкил, где названный гетероциклил обозначает группу А1, А2, A3, А4 или А5: ! ! при этом названная гетероциклильная ...

ПРОТИВОМАЛЯРИЙНЫЕ СОЕДИНЕНИЯ

... 1. Соединение формулы III: ! ! где Z представляет собой ! или фенил; ! каждый Q независимо представляет собой или -C(=O)-(CH2)b-NH-C(=NH)-NH2, где каждый b независимо представляет собой 1-4; ! каждый X независимо представляет собой O, S или N; ! каждый R1 независимо представляет собой H, CF3, C(CH3)3, галоген или OH; ! каждый R3 независимо представляет собой H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2, или , где каждый r независимо представляет собой 1 или 2, каждый w независимо представляет собой 1-3, и каждый y независимо представляет собой 1 или 2; каждый R2 независимо представляет собой H, или свободное основание или солевую форму группы -(CH2)n-NH2 или -(CH2)n-NH-C(=NH)NH2, в которых каждый n независимо представляет собой 1-4; каждый R4 независимо представляет собой H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2 или , где каждый p независимо представляет собой 1-6, и каждый q независимо представляет собой 1 или 2; и ! каждый R5 независимо представляет собой H или CF3; !или его фармацевтически ...

ГЕТЕРОЦИКЛИЧЕСКИЕ ПРОИЗВОДНЫЕ ПЕРВИЧНЫХ АМИНДИАЗЕНИУМДИОЛАТОВ

... 1. Соединение формулы I:или его фармацевтически приемлемая соль, гдеХ представляет собой O или NR;группаприсоединена к любому атому углерода кольца, отличному от атома углерода, к которому присоединены Rи R;Rпредставляет собой водород, -C(O)OCалкил или -C(O)OH, или вместе с Rобразует =O;Rпредставляет собой водород или вместе с Rобразует =O;Rпредставляет собой-Cалкил,-CDCалкил,-Cалкилен-OH,-Cалкилен-O-C(O)Cалкил,-Cалкилен-арил или-CHCH=CH;Rи R, которые присоединены к любому доступному атому углерода кольца, независимо представляют собойводород,дейтерий,-Cалкил,-C(O)OCалкил,-C(O)OH,арил,или Rи Rв тех случаях, когда они присоединены к одному и тому же атому углерода, вместе образуют =O;Rпредставляет собойводород,-Cалкил,-Cалкилен-арил,-CалкиленС(O)O-Cалкил,-Cалкилен-CRRR,-CN,-C(O)O-Cалкил,-C(O)O-Cалкилен-CRRR,-C(O)Cалкил,-C(O)OCкарбоцикл,-C(O)CHF,-C(O)CF,-C(O)CHOH,-C(O)арил,-C(O)гетероарил, где гетероарил представляет собой ненасыщенное 5- или 6-членное кольцо, содержащее 1-4 гетероатома, ...

НОВЫЕ ЦИКЛИЧЕСКИЕ УГЛЕВОДОРОДНЫЕ СОЕДИНЕНИЯ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ

... 1. Соединение общей формулы I ! ! где ! группа представляет циклоалкил, содержащий 4-7 атомов углерода, необязательно замещенный одним или несколькими, одинаковыми или разными заместителями, выбранными из R2, R3, R4 или R5; ! A представляет С1-10 гетероарил, С6-14 арил или C6-10 гетероциклоалкиларил, каждый из которых необязательно замещен одним или несколькими, одинаковыми или разными заместителями, такими как галоген, гидрокси, меркапто, трифторметил, циано, карбокси, -NH2, -C(О)MHZ, нитро, оксо, -S(О)2NH2, C1-4 алкил, C2-4 алкенил, C2-4 алкинил, C1-4 гидроксиалкил, C1-6 галогеналкил, C1-4 алкокси, C1-4 алкоксикарбонил, C1-4 алкилкарбонилокси, C1-4 алкоксикарбонилокси, C1-4 алкоксисульфонилокси, C1-4 алкоксикарбамоил, C1-4 аминокарбонил, C1-4 алкилтио, C3-8 циклоалкил, C3-8 циклоалкенил, C1-6 амино, иминометил, C1-4 аминосульфонил, C1-4 аминокарбонилокси, C1-4 алкилсульфониламино, гидроксииминометил, C1-4 алкилкарбониламино, C1-4 алкилсульфонил, C1-6 гетероциклоалкил, C1-6 гетероциклоалкенил ...

АРИЛАМИНЫ ДЛЯ ЛЕЧЕНИЯ СОСТОЯНИЙ, АССОЦИИРОВАННЫХ С КИНАЗОЙ-3 ГЛИКОГЕНСИНТАЗЫ (GSK-3)

... 1. Соединение, имеющее формулу I где Z представляет собой СН или N; Y представляет собой CONR5, NR5CO, SO2NR5, NR5SO2, CH2NR5, NR5CH2, NR5CONR5, С1-6алкилен, CH2CO, СОСН2, СН=СН, ОСН2 или СН2O; Х представляет собой СН или N; Р представляет собой фенильное кольцо или 5- либо 6-членное гетероароматическое кольцо, содержащее один или более чем один гетероатом, выбранный из N, О или S, и указанное фенильное кольцо или 5- либо 6-членное гетероароматическое кольцо возможно может быть конденсированным с 5- либо 6-членным насыщенным, частично насыщенным или ненасыщенным кольцом, содержащим один или более чем один атом, выбранный из С, N, О или S; Q представляет собой фенил или 5- либо 6-членное гетероароматическое кольцо, содержащее один или более чем один гетероатом, выбранный из N, О или S, из которых по меньшей мере один атом выбран из азота; R представляет собой СНО, фторметокси, дифторметокси, трифторметокси, С0-6 алкил(SO2)NR1R2, ОС0-6алкил(SO2)NR1R2, OC1-6алкил(SO)NR1R2, С1-6 алкил(SO)NR1R2 ...

Способ получения гетероциклических производных циклобутиламинометана

Изобретение касается гетероциклических производных, в частности циклобутйламинометана общей формулы I Я2ЯзЯ1 СбН2- с- СН2- СН2- СН2 GH(R01S1H2 где f2-фурил , 5-метилфурил-2; тиенил; 1метилЬиррол-2-ил; 1-метилимидазол-2ил; пиридил; 4-метилтиазол-2-ил; 1метилпиразол-5-ил; 1,3-дитиан-2-ил В бензольном кольце R, .а К зависимо друг от друга Н, С1, С , (СН , ОСИ,,, SCH, и Клвместе взятые с соседними атомами углерода, с которыми они связаны, образуют второе бензольное кольцо, которое может быть незамещенным или замещенным хлором, которые, как обладающие антйдепрессантной активностью, могут-использоваться в медицине. Для выявления физиологической активности в указанном ряду соединений получены новые соединения I. Процесс ведут восстановлением соответствующей группы C(R)NY при X - углеродном атоме, где Y - литий или группа MgBr или i MgCl. Восстановление ведут с помощью СО боргидрида натрия в среде оганического растворителя, например этанола, пропан-2-ола, диэтиленгликольдиметилового эфира при температуре ...

BRADYKININ TYPISCHE PEPTIDE

TACE INHIBITOREN

AZAHETEROZYKLISCHEDERIVATE ZUR BEHANDLUNG VON HAARAUSFALL UND NEUROLOGISCHER KRANKHEITEN

3- oder 4-substituierte Oxotremorin-Derivate.

AZACYCLOALKANE, AZACYCLOALKENE UND IHRE DERIVATE

PHENOXYPROPYL AMINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

SULFONAMIDE

NEUE DERIVATE VON N-SUBSTITUIERTEN PYRROLIDIN DERIVATEN UND DEREN HERSTELLUNGSVERFAHREN

Compounds

PREPARATION OF 1-ALKYL-2-AMINOMETHYL-PYRROLIDINES

... 1374818 1 - Alkyl - 2 - aminomethylpyrrolidines FRATMANN SA 4 Nov 1971 [10 Nov 1970] 51225/71 Heading C2C 1 - Alkyl - 2 - aminomethylpyrrolidines are prepared by reacting a 1-alkyl-2-pyrrolidine in a solvent, e.g. benzene, toluene or xylene, with phosgene at - 5‹ to + 10‹ C.; reacting the resultant product, optionally after isolation and purification of the same, with an alkali metal alcoholate at 0‹ to -20‹C. and then with nitromethane at room temperature; and finally reducing the resultant nitromethylene group to an aminoethyl group. The 1-alkyl-2-nitromethylenepyrrolidine may also be isolated and purified before the reduction and the latter is preferably carried out (i) by catalytic hydrogenation in an inert solvent, e.g. Pt black, Rh on Al 2 O 3 , Pd on charcoal and Raney Ni in water, methanol, ethanol, isopropanol, butanol, tetrahydrofuran or dioxane or (ii) by hydrogen produced in situ by the reaction of an acid on a metal. In the first step of the process the phosgene may be first ...

3-PYRROLIDINYLTHIO-1-AZABICYCLO(3.2.0)HEPT-2-ENE-2-CARBOXYLIC ACID DERIVATIVES

Substituted 3-Aminopyrrolidines

... 1,173,372. Substituted 3-aminopyrrolidines. A. H. ROBINS CO. Inc. 20 March, 1967 [22 March, 1966], No. 12973/67. Heading C2C. Novel pyrrolidines I (including salts thereof) wherein R represents a phenyl, alkylphenyl, alkoxyphenyl, halophenyl or trifluoromethylphenyl group, and R1 represents an alkyl group, wherein the alkyl and alkoxy groups have up to 8 carbon atoms are obtained: (a) by reacting an amine R1NH2 with a maleimide II (prepared by the interaction of an amide, R.NH.CO.CH: CH.CO 2 H, and acetic anhydride in the presence of sodium acetate, the amide itself is obtained by reacting maleic anhydride with an amine, RNH 2 ) and subsequently reducing the resulting aspartimide compound III so obtained with lithium aluminium hydride; or (b) by reacting an amine, R1NH 2 , with a I - -R-substituted- 3 -pyrrolidinol -aryl -sulphonate. 1 -Phenyl-3-pyrrolidinol, obtained by the interaction of 1,4-dichloro-2-butanol and aniline, is converted into its p-methylbenzene ...

Therapeutic N-(2-biphenylyl)guanidine derivatives

THERAPEUTIC AGENTS

PENEM DERIVATIVES

Pharmaceutical composition

A pharmaceutical composition suitable for use with a metered dose inhaler (MDI) comprises; (i) a drug component comprising at least one pharmaceutically acceptable salt of glycopyrrolate; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a). Preferably, the glycopyrrolate is present as the bromide salt. Preferably, the composition further comprises at least one long acting beta-2-agoinst (LABA) (e.g. indacaterol, olodaterol, formoterol, vilanterol). Preferably, the composition additionally comprises at least one corticosteroid (e.g. budesonide, mometasone, beclomethasone, fluticasone). Preferably, the composition additionally comprises at least one surfactant compound (e.g. polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), oleic acid, lecithin). Preferably, the composition contains less than 5 ppm water. In preferred embodiments the propellant is entirely HFA-152a. The composition may contain ethanol as a polar excipient. Also claimed is a method of improving the ...

Process for preparing organic compounds containing one or more nitrile groups

Organic compounds containing one or more nitrile groups are made by reacting a compound containing one or more carbonamide-N-sulphonic halide groups, -CO.NH.SO2X, where X is halogen, with a compound containing one or more carboxylic amide groups. As the reaction proceeds with elimination of the halosulphonic acid which is bound by the amide, it is preferred to use at least one equivalent of amide per -CO.NH.SO2X group. The reaction can be effected at temperatures in the range - 30 DEG C. to 120 DEG C. optionally in the presence of solvents or excess of the amide compound. The amides can be recovered by treatment with water and neutralizing the separated acid. The carboxylic amide compounds include cyclic amides, polyamides, ureas and carbamic acids. The radical to which the -CO.NH.SO2X group is attached can be saturated or unsaturated aliphatic, cycloaliphate, e.g. cyclohexyl, aromatic, e.g. phenyl, pyrenyl, anthracenyl, or heterocyclic e.g. thiophene, pyran or pyrrole, and may be substituted ...

Pyrrolidinyl hydroxamic acid compounds and their production process

Pyrrolidinyl hydroxamic acid compounds and their production process

Pyrrolidinyl and pyrrolinyl ethylamine compounds as opioid kappa receptor agonists.

A compound of the formula:and the salts thereof, wherein A is halo, hydroxy or the like; the broken line represents an optional double bond with proviso that if the broken line is a .double bond, then A is absent; Ar1 is optionally substituted phenyl or the like; Ar2 is aryl or heteroaryl^selected from phenyl, naphthyl, pyridyl and the like, the aryl or heteroaryl being optionally substituted; R is hydrogen, hydroxy, Ci-C4 alkyl or the like; and R2 and R3 are independently selected from optionally substituted Ci-C? alkyl Cs-Ce cycloalkyl, C2-Cs alkenyl, Ci-Cg alkynyl and the like or R2 and R3, together with the nitrogen atom to which they are attached, form an optionally substituted pyrrolidine, piperidine or morpholine ring. These compounds are useful as kappa agonists.

COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN

Estrogen agonist metabolites.

This invention relates to compounds that are mammalian metabolites of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yI- ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. The compounds of the invention can be used as standards for analytical assays or as intermediates for the further chemical synthesis or biosynthesis of chemical entities. The invention also relates to pharmaceutical compositions for the treatment of disease and methods of treating disease.

3- or 4-monosubstituted phenol and thiophenol derivatives useful as H3 ligands.

Pyrrolidinyl hydroxamic acid compounds and their production process.

A compound of the formula: ...

Pyrrolidinyl hydroxamic acid compounds and their production process

Heterocyclic inhibitors of P38.

The present invention relates to inhibitors of p38, a mammlian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

3-OR 4-Monosubstituted phenol and thiophenolderivatives useful as H3 ligands

Proline derivatives having affinity for the calcium channel alpha-2-delta subunit

Substituted aryl thioureas and related compounds; inhibitors of viral replication

Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

Carboxamide derivatives as muscarinic receptor antagonists

Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

Arylthio compounds as antibacterial and antiviral agents

Acids 3-pyrrolidinylthio-1-azabicyclo [3.2.0] - hept-2-ène-2-carboxylic and processes for their preparation.

Substituted aryl thioureas and related compounds, inhibitors of viral replication.

Estrogen agonist/antagonist metabolites.

Process of inhibition of a virus.

Method of preparation of 1-alkyl-2-aminométhylpyrrolidines.

Derived from the acid 3-pyrrolidinylthio-1-azabicyclo (3.2.0.) - hept-2-ene-2-carboxylic and their preparation.

“New derivatives with naphthalenic structure, their method of preparation and the compositions pharmaceutical which contain them”.

Estrogen angonist/antagonis metabolites

Substituted aryl thioureas and related compounds; inhibitors of viral replication

Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

3-OR 4-Monosubstituted phenol and thiophenolderivatives useful as H3 ligands

Substituted aryl thioureas and related compounds; inhibitors of viral replication

Estrogen angonist/antagonis metabolites

3-OR 4-Monosubstituted phenol and thiophenolderivatives useful as H3 ligands

VERFAHREN ZUR HERSTELLUNG VON NEUEN SUBSTITUIERTEN 1,3-DIHYDRO-SPIRO- (ISOBENZOFURAN) UND IHREN SALZEN

PROCEDURE AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF PYRROLIDINEN

NPYY5-ANTAGONISTEN

CYCLOHEXYL CONNECTIONS AS CCR5-ANTAGONISTEN

N-ARYL-N' ARYLCYCLOALKYL UREA AS MCH ANTAGONIST FOR the TREATMENT OF OBESITY

AMIN-1,2 AND -1,3-DIOLVERBINDUNGEN AND THEIR USE FOR THE TREATMENT OF ALZHEIMER ILLNESS

ALKYLETHERDERIVATE OR THEIR SALTS

1 (2-AMINO-BENZOYL) - PIPERAZIN DERIVATIVES AS GLYCINE AUFNAHMEHEMMER FOR the TREATMENT OF PSYCHOSEN

TACE INHIBITORS

PROLINDERIVATE WITH AFFINITY FOR THE ALPHA-2DELTA SUBUNIT OF THE CALCIUM CHANNEL

INHIBITORS BINDUNGDER CHEMOKINE I-TAC AND/OR SDF-1 TO THE CCXCKR2-REZEPTOR

AS H3-LIGANDEN APTITUDE 3ODER 4MONOSUBSTITUIERTE PHENOLUND of THIOPHENOL DERIVATIVES

N-PHENYL-PHENYLACETAMID-NICHTNUKLEOSIDINHIBITOR N OF REVERSER TRANSKRIPTASE

PROCEDURE FOR THE PREPARATION OF INHIBITORS OF THE NUCLEOSIDE METABOLISM

VERFAHREN ZUR HERSTELLUNG VON NEUEN PYRROLIDINUND PIPERIDIN-DERIVARTEN

VERFAHREN ZUR HERSTELLUNG VON NEUEN DERIVATEN VON PERHYDRO-AZA-HETEROCYCLEN UND IHREN SAEURE- ADDITIONSSALZEN

ASIMADOLIN FOR THE TREATMENT IRRITABLE BOWEL OF THE SYNDROME

AMINOCYCLOHEXYLETHER CONNECTIONS AND THEIR USE

PROCEDURE FOR THE PRODUCTION OF NEW PYRROLIDINUND PIPERIDIN DERIVARTEN

PROCEDURE FOR the PRODUCTION OF NEW ONES 5-SULFAMYLBENZOESÄUREDERIVATEN AND THEIR AMIDES, LOW ONES ALKYL ESTER AND SALTS

PLEUROMUTILINDERIVATE AS ANTIMICROBIAL MEANS

Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and other diseases and conditions that are mediated by excessive glucocorticoid action.

Acid-free quaternized nitrogen compounds and use thereof as additives in fuels and lubricants

The present invention relates to novel acid-free quaternized nitrogen compounds, to the preparation thereof and to the use thereof as a fuel and lubricant additive, more particularly as a detergent additive, as a wax antisettling additive (WASA) or as an additive for reducing internal diesel injector deposits (IDID); to additive packages which comprise these compounds; and to fuels and lubricants thus additized. The present invention further relates to the use of these acid-free quaternized nitrogen compounds as a fuel additive for reducing or preventing deposits in the injection systems of direct-injection diesel engines, especially in common-rail injection systems, for reducing the fuel consumption of direct-injection diesel engines, especially of diesel engines with common-rail injection systems, and for minimizing power loss in direct-injection diesel engines, especially in diesel engines with common-rail injection systems.

11-Beta-Hydroxysteroid Dehydrogenase Type 1 Active Compounds

The use of substituted amides for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, of the general formula I. Their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11βHSDI and may be useful in the treatment of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Pyrrolidine triple reuptake inhibitors

In various embodiments, the present invention provides cycloalkyl pyrrolidine compounds and methods for their use in the treatment and/or prevention of various diseases, conditions and syndromes, including central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter.

Novel method for producing optically active pyrrolidine compound

[Object] A novel method for producing an optically active pyrrolidine compound, which is useful as a production intermediate of a pharmaceutical, and a production intermediate thereof, is provided. [Means for Solution] According to the production method of the present invention, a chloro compound that is a key intermediate can be produced efficiently industrially by subjecting a mixture of regioisomers obtained by reacting an optically active epoxy compound substituted with aryl, which is easily available, with an amine compound, to chlorination. Furthermore, an optically active pyrrolidine compound can be produced industrially efficiently with the key intermediate. [Selected Figure] None

Synthetic processes for the preparation of aminocyclohexyl ether compounds

This invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II): or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R 3 , R 4 and R 5 are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.

Metallo-beta-lactamase inhibitors

A new metallo-β-lactamase inhibitor which acts as a medicament for inhibiting the inactivation of β-lactam antibiotics and recovering anti-bacterial activities is disclosed. The maleic acid derivatives having the general formula (I) have metallo-β-lactamase inhibiting activities. It is possible to recover the anti-bacterial activities of β-lactam antibiotics against metallo-β-lactamase producing bacteria by combining the compound of the general formula (I) with β-lactam antibiotics.

New compounds, pharmaceutical compositions and uses thereof

The invention relates to new compounds of the formula I to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Novel heterocyclic acrylamides and their use as pharmaceuticals

The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.

Cyclic amine bace-1 inhibitors having a benzamide substituent

Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R is —C(O)—N(R 27 )(R 28 ) or and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.

Chemoselective enrichment for compound isolation

Chemoselective isolation of hydroxyl group-containing and carboxyl group-containing compounds is accomplished via formation of polymeric silyl ethers and polymeric siloxyl esters, respectively. Preparation of chemoselective polymeric reagents for capture of hydroxyl group containing compounds and carboxyl group containing compounds is described.

Synthetic processes for the preparation of aminocyclohexyl ether compounds

This invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II): or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R 3 , R 4 and R 5 are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.

SYNTHETIC PROCESS FOR AMINOCYCLOHEXYL ETHER COMPOUNDS

Methods for the preparation of stereoisomerically substantially aminocyclohexyl ether compounds such as trans-(1R,2R)-aminocyclohexyl ether compounds and/or trans-(1S,2S)-aminocyclohexyl ether compounds as well as various intermediates and substrates are disclosed. 15.-. (canceled)7. The method of further comprising optionally protecting the compound of formula (4) and/or the compound of formula (6) before the reaction of compound of formula (4) with the compound of formula (6) and optionally deprotecting the compound of formula (8) after the reaction.9. The method of wherein the suitable conditions comprise activating Q in the presence of a catalytic amount of an acid in an aprotic solvent.12. The method of further comprising optionally protecting the compound of formula (71) and/or the compound of formula (6) before the reaction of compound of formula (71) with the compound of formula (6) and optionally deprotecting the compound of formula (73) after the reaction.14. The method of wherein the suitable conditions comprise activating Q in the presence of a catalytic amount of an acid in an aprotic solvent.17. The method of further comprising optionally protecting the compound of formula (72) and/or the compound of formula (6) before the reaction of compound of formula (72) with the compound of formula (6) and optionally deprotecting the compound of formula (74) after the reaction.19. The method of wherein the suitable conditions comprise activating Q in the presence of a catalytic amount of an acid in an aprotic solvent.2120. The method of any one of claim 16 , claim 16 , and claim 16 , wherein the separation step comprises crystallization claim 16 , kinetic resolution claim 16 , chemical separation claim 16 , enzymatic resolution claim 16 , and/or chromatographic resolution.22. The method of wherein said optional functionalization step comprises formation of acid addition salts of the mixture of the compound of formula (4a) and the compound of formula (5a) or the ...

C7-Fluoro Substituted Tetracycline Compounds

The present invention is directed to a compound represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

SALACINOL AND PONKORANOL HOMOLOGUES, DERIVATIVES THEREOF, AND METHODS OF SYNTHESIZING SAME

Salacinol and ponkoranol homologues, derivatives thereof and methods of synthesizing and using said homologies and derivatives. The derivatives include stereoisomers, de-O-sulfonated compounds and congeners of the naturally occurring homologues. Some of the derivatives exhibit enhanced glucosidase inhibitory bioactivity in comparison to the naturally occurring compounds which have been isolated from 5. (canceled)8. (canceled)9. (canceled)13. A method of using a compound as defined in as a glycosidase inhibitor claim 1 , comprising administering said compound to a patient.14. A method for treating diabetes in an affected patient comprising the step of administering to the patient a therapeutically effective amount of a compound as defined in .15. (canceled)16. (canceled) This application claims priority to, and the benefit under 35 U.S.C. §119 of, U.S. provisional patent application No. 61/265,695 filed 1 Dec. 2009 and entitled SALACINOL HOMOLOGUES, DERIVATIVES THEREOF AND METHODS OF SYNTHESIZING SAME, the entirety of which is hereby incorporated by reference.This application relates to salacinol and ponkoranol homologues, derivatives thereof and methods of synthesizing and using same.Glycosidases are enzymes that are involved in the catabolism of glycoproteins and glycoconjugates and the biosynthesis of oligosaccharides. Disruption in regulation of glycosidases can lead to diseases.Over the years, glycosidase inhibitors have received considerable attention in the field of chemical and medicinal researchbecause of their effects on quality control, maturation, transport, secretion of glycoproteins, and cell-cell or cell-virus recognition processes. This principle has potential for many therapeutic applications, such as in the treatment of diabetes, cancer and other viral infections.Bioactive components isolated from medicinal plants that are used in traditional medicine or folk medicine often provide the lead structures for modern drug-discovery programs. For example, ...

CATIONIC LIPID

The present invention provides a cationic lipid, which allow nucleic acids to be easily introduced into cells, represented by formula (I) 2. The cationic lipid according to claim 1 , wherein Xand Xare combined together to form a single bond or alkylene.3. The cationic lipid according to claim 1 , wherein Lis a single bond claim 1 , Ris a hydrogen atom claim 1 , methyl claim 1 , pyrrolidin-3-yl claim 1 , piperidin-3-yl claim 1 , piperidin-4-yl claim 1 , or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s) claim 1 , which is(are) claim 1 , the same or different claim 1 , amino claim 1 , monoalkylamino claim 1 , dialkylamino claim 1 , trialkylammonio claim 1 , hydroxy claim 1 , alkoxy claim 1 , carbamoyl claim 1 , monoalkylcarbamoyl claim 1 , dialkylcarbamoyl claim 1 , pyrrolidinyl claim 1 , piperidyl or morpholinyl claim 1 , and Land Lare —O—.4. The cationic lipid according to claim 1 , wherein Lis —CO— or —CO—O— claim 1 , Ris pyrrolidin-3-yl claim 1 , piperidin-3-yl claim 1 , piperidin-4-yl claim 1 , or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s) claim 1 , which is(are) claim 1 , the same or different claim 1 , amino claim 1 , monoalkylamino claim 1 , dialkylamino claim 1 , trialkylammonio claim 1 , hydroxy claim 1 , alkoxy claim 1 , carbamoyl claim 1 , monoalkylcarbamoyl claim 1 , dialkylcarbamoyl claim 1 , pyrrolidinyl claim 1 , piperidyl or morpholinyl claim 1 , wherein at least one of the substituents is amino claim 1 , monoalkylamino claim 1 , dialkylamino claim 1 , trialkylammonio claim 1 , pyrrolidinyl claim 1 , piperidyl or morpholinyl claim 1 , and Land Lare identically —CO—O— or —O—CO—.5. The cationic lipid according to any one of to claim 1 , wherein Xis absent claim 1 , or is methyl.64. The cationic lipid according to any one of to claims 1 , wherein Land Lare —O— or —O—CO— claims 1 , and Rand Rare (Z)-hexadec-6-enyl or (Z)-hexadec ...

PYRROLIDINE TRIPLE REUPTAKE INHIBITORS

In various embodiments, the present invention provides cycloalkyl pyrrolidine compounds and methods for their use in the treatment and/or prevention of various diseases, conditions and syndromes, including central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter. 131-. (canceled)44. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.45. A method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter claim 32 , comprising contacting the monoamine transporter with a compound of .46. The method of claim 45 , wherein the monoamine transporter is selected from serotonin transporter (SERT) claim 45 , dopamine transporter (DAT) claim 45 , norepinephrine transporter (NET) and combinations thereof.47. A method of inhibiting the activity of at least one monoamine transporter claim 32 , comprising contacting the monoamine transporter with a compound of .48. The method of claim 47 , wherein the monoamine transporter is selected from serotonin transporter (SERT) claim 47 , dopamine transporter (DAT) claim 47 , norepinephrine transporter (NET) and combinations thereof.49. A method of inhibiting uptake of at least one monoamine by a cell claim 32 , comprising contacting said cell with a compound of .50. The method of claim 49 , wherein the monoamine is selected from serotonin claim 49 , dopamine claim 49 , norepinephrine and combinations thereof.51. The method of claim 49 , wherein the cell is a neuronal cell.52. A method of treating a central nervous system disorder claim 32 , comprising administering to a subject in need thereof ...

Novel hydroxamates as therapeutic agents

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

COMPOUNDS AND THEIR USE AS IKACH BLOCKERS

The invention relates to compounds according to Formula I: 111-. (canceled)1516-. (canceled) The present invention relates to a novel class of compounds which are pharmacologically effective as potassium channel inhibitors, in particular inhibitors of the acetylcholine operated inward rectifying potassium channel current, i.e. IKACh blockers.The invention also relates to processes for preparing such compounds, to pharmaceutical compositions containing them, to the use of such compounds and to methods for their therapeutic use, particularly in the treatment of cardiac arrhythmias.The normal electrophysiologic behaviour of the heart is determined by ordered propagation of excitatory stimuli that result in rapid depolarization of the cardiac cell, followed by a slower repolarization. The sum of these events creates the cardiac action potential in individual myocytes. Cardiac rhythm disturbances can be caused by abnormalities of impulse generation, propagation or the duration and configuration of such individual cardiac action potentials. The action potentials are generated by the integrated activity of specific ion currents through various transmembrane spanning ion channels with specific selectivity for individual ions (e.g. potassium, sodium, calcium, see Grant AO. Circ. Arrhythmia Electrophysiol. 2009; 2:185-194). The majority of these ion channels have been cloned and thus, their molecular components are known. This knowledge has enabled a more effective search for selective ion channel blockers, as specific ion channel targets can be recombinantly over-expressed in mammalian cells and be used for high capacity screening.Electrophysiological studies in the early 1950s showed the importance of the movement of K out of the cell to produce repolarization after the rapid depolarizing spike. Over the last 60 years, the introduction of single channel recording techniques and molecular cloning has resulted in a deeper understanding of cardiac repolarization and of the ...

HEXAFLUOROISOPROPYL CARBAMATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The disclosure relates to hexafluoroisopropyl carbamate derivatives of general formula (I): 2. The compound of formula (I) according to claim 1 , wherein:{'sup': '1', 'Rrepresents a phenyl, naphthyl, indanyl, benzoxazole, benzisoxazole, benzimidazole, benzotriazole, oxadiazole, indazole, isoxazole, pyridine, pyrazine, pyrimidine, thienyl, thiazole, benzothiophene, indole, dihydrobenzodioxane, benzothiadiazole, pyrazole, dihydrobenzoxazine or indoline group;'}{'sup': '2', 'sub': 3', '3', '2', '2', '2', '2', '2, 'Rrepresents one or more groups chosen from a halogen atom or a methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, oxo, CHNHCO, CHSO, NHCO, NHSOand pyrrolidine-SOgroup;'}{'sup': '3', 'Rrepresents a group chosen from a phenyl and an oxazole; and also the compound 2,2,2-trifluoro-1-(trifluoromethyl)ethyl 4-{[3-(2-methylpyrimidin-4-yl)benzenesulphonylamino]methyl}piperidine-1-carboxylate,'}in the form of the base or of an addition salt with an acid.3. The compound of formula (I) according to claim 1 , wherein:{'sub': 2', '2', '2', '2', '3', '2, 'Z represents a bond or a CH, (CH), CH═CH, C≡C, OCHor OC(CH)group,'}in the form of the base or of an addition salt with an acid.4. The compound of formula (I) according to claim 1 , wherein:{'sub': 2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '3', '2', '2', '2', '3', '2', '2', '2', '3', '2, 'A represents a bond, an oxygen atom, a sulphur atom, an OCHgroup, an O—(CH)group, an NH, NHCHor NH(CH)group, an SOor CO group, a CONH group, a CONHCHor CONH(CH)group, an SONH group, an SONHCHor SONH(CH)group, an SONHCO, SONHCONH or SONHCONHCHgroup, an OCONH group, an NHCONH group, an NHCONHCHgroup, an N(CH)CONHCH, NHCONH(CH)or N(CH)CONH(CH)group or an SON(CH)CHgroup,'}in the form of the base or of an addition salt with an acid.5. The compound of formula (I) according claim 1 , wherein m and n represent 1 claim 1 , in the form of the base or of an addition salt with an ...

Continuous process for the alkylation of cyclic tertiary amines

A continuous process for the alkylation of tertiary amines and, in particular, to a continuous process for the quaternization of cyclic tertiary amines useful for the preparation of cyclic quaternary ammonium salts with high purity is described.

ION CHANNEL MODULATING COMPOUNDS AND USES THEREOF

Ion channel modulating compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses a variety of in vitro and in vivo uses for the compounds and compositions, including the treatment of arrhythmia and the production of analgesia and local anesthesia. 2. The method of wherein administration is by a route selected from the group consisting of oral claim 1 , topical claim 1 , parenteral claim 1 , sublingual claim 1 , rectal claim 1 , vaginal claim 1 , and intranasal.3. The method of wherein the parenteral administration is selected from the group consisting of subcutaneous injection claim 2 , intravenous injection claim 2 , intramuscular injection claim 2 , epidural injection claim 2 , intrasternal injection claim 2 , and infusion.4. The method of wherein the oral administration comprises administering an oral dosage form selected from the group consisting of a powder claim 2 , a granule claim 2 , a compressed tablet claim 2 , a pill claim 2 , a capsule claim 2 , a cachet claim 2 , a chewing gum claim 2 , a wafer claim 2 , and a lozenge.5. The method of wherein the arrhythmia is atrial arrhythmia.6. The method of wherein the atrial arrhythmia is atrial fibrillation.7. (canceled)8. The method of wherein the arrhythmia is ventricular arrhythmia.9. The method of wherein the ventricular arrhythmia is ventricular fibrillation.10. The method of wherein the ventricular fibrillation occurs during acute ischemia.1117.-. (canceled)18. The method of wherein the compound is a mixture of isomers.21. The method of wherein the compound is an isolated isomer.26. The method of wherein the pharmaceutically acceptable salt is a monohydrochloride salt. This application is a continuation of U.S. patent application Ser. No. 11/619,136 filed Jan. 2, 2007, now pending; which is a continuation of U.S. patent application Ser. No. 11/342,270 filed Jan. 27, 2006 (U.S. Pat. No. 7,259,184); which is a continuation ...

Combined Acetylcholinesterase Inhibitor and Quaternary Ammonium Antimuscarinic Therapy to Alter Progression of Cognitive Diseases

A method administers quaternary ammonium anti-cholinergic muscarinic receptor antagonists in combination with acetyl-cholinesterase inhibitors to treat either cognitive impairment or acute delirium. This therapy results in a modification of a cognitive disorder or disease, namely a slow down in the disease progression. In one preferred embodiment, the disease is dementia with Lewy Bodies. New formulations for quaternary ammonium anti-cholinergic muscarinic receptor antagonists are also disclosed. 1. A method for altering a disease progression of a cognitive disorder comprising the step of administering to the patient a therapeutic amount of a quaternary ammonium anti-cholinergic muscarinic receptor antagonist and a therapeutic amount of an acetyl-cholinesterase inhibitor.2. The method of claim 1 , wherein the disease progression is altered by slowing the progression of the disease compared to disease progression in patients not treated with the quaternary ammonium anti-cholinergic muscarinic receptor antagonist and the acetyl-cholinesterase inhibitor.3. The method of claim 1 , wherein the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is glycopyrrolate and the acetyl-cholinesterase inhibitor is rivastigmine.4. The method of claim 3 , comprising administering a minimum of about 2-4 mg/day of glycopyrrolate and a minimum of about 12-48 mg/day of rivastigmine to the patient.5. The method of claim 3 , comprising administering a minimum of about 12 mg/day orally or a minimum of about 9.5 mg/day transdermally of rivastigmine to the patient.6. The method of claim 3 , comprising administering between about 24 and about 48 mg/day orally or administering between about 19 mg and 54 mg transdermally of rivastigmine to the patient.7. The method of claim 1 , wherein the cognitive disorder is dementia with Lewy bodies.8. The method of claim 7 , wherein the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is glycopyrrolate and the acetyl- ...

CHIRAL AUXILIARIES

Chiral auxiliaries useful for efficiently producing a phosphorus atom-modified nucleic acid derivative with high stereoregularity, and compounds represented by the following the general formula (I) or the general formula (XI) for introducing the chiral auxiliaries. 2. The compound or a salt thereof according to claim 1 , wherein Rand Rare hydrogen atom or an alkyl group claim 1 , Ris phenyl group claim 1 , Rand Rare hydrogen atom or an alkyl group claim 1 , and Y is —C(R)(R)— (Rand Rare independently hydrogen atom or an alkyl group claim 1 , and when Rrepresents an alkyl group claim 1 , Rmay bind with the phenyl group represented by Rto form a ring) claim 1 , o-phenylene group claim 1 , or naphthalene-1 claim 1 ,2-diyl group.8. The method according to claim 7 , wherein 3% dichloroacetic acid (DCA) in dichloromethane is used for the acidic condition in the step (c).9. The method according to claim 7 , wherein claim 7 , as the modification of phosphorus atom claim 7 , a group represented by X (X represents an alkylthio group which may have a substituent claim 7 , an alkenylthio group which may have a substituent claim 7 , an alkynylthio group which may have a substituent claim 7 , an arylthio group which may have a substituent claim 7 , thiol group claim 7 , an alkoxy group which may have a substituent claim 7 , —BH claim 7 , —Se claim 7 , an alkyl group which may have a substituent claim 7 , an alkenyl group which may have a substituent claim 7 , an alkynyl group which may have a substituent claim 7 , an aryl group which may have a substituent claim 7 , an acyl group which may have a substituent claim 7 , or —N(R)(R) (Rand Rindependently represent hydrogen atom claim 7 , an alkyl group which may have a substituent claim 7 , an alkenyl group which may have a substituent claim 7 , an alkynyl group which may have a substituent claim 7 , or an aryl group which may have a substituent) is introduced on the phosphorus atom.11. The compound or a salt thereof according to ...

Alkaloid aminoester derivatives and medicinal composition thereof

Alkaloid aminoester compounds which act as muscarinic receptor antagonists are useful for the prevention and/or treatment of a broncho-obstructive or inflammatory diseases.

Crystalline Glycopyrrolate Tosylate

Salts of glycopyrrolate, including solid forms thereof are herein disclosed. Methods of making glycopyrrolate salts and methods of treating hyperhidrosis with salts of glycopyrrolate are disclosed.

NOVEL LOW MOLECULAR WEIGHT CYCLIC AMINE CONTAINING CATIONIC LIPIDS FOR OLIGONUCLEOTIDE DELIVERY

The instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver. The present invention employs low molecular weight cationic lipids comprising at least one short lipid chain to enhance the efficiency and tolerability of in vivo delivery of siRNA. 2. A cationic lipid of Formula A according to claim 1 , wherein:{'sup': '1', 'Ris H or methyl;'}n and m are 1;X is 0;{'sub': 1', '12', '24', '12', '24, 'Lis selected from C-Calkyl and C-Calkenyl; and'}{'sub': 2', '3', '9', '3', '9, 'Lis selected from C-Calkyl and C-Calkenyl;'}or any pharmaceutically acceptable salt or stereoisomer thereof.3. A cationic lipid which is:trans-1 -Methyl-3-[((9Z, 12Z)-octadeca-9,12-dienyl)oxy]-4-octyloxy-pyrrolidine (Compound 4);trans-1-methyl-3-[(9Z)-octadec-9-en-1-yloxy]-4-(octyloxy)pyrrolidine (Compound 5);trans-1-methyl-3-[(12Z)-octadec-12-en-1-yloxy]-4-(octyloxy)pyrrolidine (Compound 6);trans-3-[(3,7-dimethyloctyl)oxy]-1-methyl-4-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]pyrrolidine (Compound 7);cis-1-methyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-4-(octyloxy)pyrrolidine (Compound 11) or any pharmaceutically acceptable salt or stereoisomer thereof.4. The use of a cationic lipid according to for the preparation of lipid nanoparticles.5. The use of a cationic lipid according to as a component in a lipid nanoparticle for the delivery of oligonucleotides.6. The use according to wherein the oligonucleotides are siRNA or miRNA.7. The use according to wherein the oligonucleotides are siRNA. The present invention relates to novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with ...

Bridged Spiro[2.4]heptane Ester Derivatives

The invention relates to a method for preparing linear polymers having an amide end or having a star architecture comprising an amide core, by means of a ring opening using lactide and glycolide monomers or a lactide monomer ring in the presence of a catalyst, wherein the method includes the steps of: (i) reacting the excess monomer(s) with an initiator in a solvent, said initiator being selected from among an amine and an amino alcohol, given that the initiator has at least one primary or secondary amine function; (ii) adding a catalyst, said catalyst being a non-nucleophilic base and including at least one neutral sp2 nitrogen atom; and (iii) neutralizing the reaction mixture. Said novel method is particularly advantageous in that it can be easily monitored and enables better modulation of the polymers, and thus of the properties thereof, than the methods of the prior art. The invention also relates to novel polymers that are obtainable by means of said method. 2. The compound according to claim 1 , whereinY represents a bond or a methandiyl group;{'sup': '1', 'sub': 1', '4', '1', '4', '1', '2, 'Rrepresents an aryl- or a heteroaryl-group, wherein the groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently halogen, (C-C)alkyl, (C-C)alkoxy or (C-C)fluoroalkyl;'}{'sup': '2', 'claim-text': [{'sup': 3', '4, 'sub': '2', 'cyclopentyl or cyclohexyl, which are independently unsubstituted or mono-substituted with RRN—CH— or heterocyclyl-methyl;'}, {'sub': 2', '6', '1', '4, 'sup': 3', '4', '5', '6, '(C-C)alkyl, which is mono-substituted with —NRR, —C(O)NRR, or (C-C)alkoxy which is mono-substituted with heterocyclyl, wherein the heterocyclyl is unsubstituted or mono- or di-substituted at one of the carbon atoms with fluoro; or'}, {'sub': 1', '6, 'claim-text': [{'sub': 1', '4, 'with heterocyclyl, wherein the heterocyclyl is unsubstituted, or mono-substituted at a nitrogen atom with (C-C)alkyl and/or mono- or di-substituted at ...

PROCESS FOR PREPARATION OF AMINOCYCLOHEXYL ETHERS AND INTERMEDIATE PRODUCTS USED IN THE PROCESS

A process for preparation of a compound of formula (I) or or a pharmaceutically acceptable salt, ester, or prodrug thereof, is disclosed. The process involves hydrogenating, in the presence of a catalyst, a compound of formula (II). The different substituents are as described in the specification. Also disclosed are intermediates and processes for their preparation. Further, the process can provide an alternate route for the synthesis of Vernakalant from starting materials that can be readily available. 2. The process according to claim 1 , wherein the catalyst is Pd/C.3. The process according to claim 1 , wherein the catalyst is Pd/C (10 mole %).4. The process according to claim 1 , wherein Z is —CHAr claim 1 , wherein Ar is an aryl group.5. The process according to claim 1 , wherein Z is —CHPh.7. The process according to claim 6 , wherein the reaction is carried out in the presence of a base.8. The process according to claim 7 , wherein the base is sodium hydride.12. (canceled)13. (canceled)14. (canceled)15. (canceled) The specification relates to a process for preparation of aminocyclohexyl ethers and intermediate products used in the process.WO 99/50225 and WO 2004/099137 disclose aminocyclohexyl ether compounds as being useful in the treatment of arrhythmias. Some of the compounds disclosed therein have been found to be effective in the treatment and/or prevention of atrial fibrillation (AF). The process for the preparation of the compounds disclosed can involve a complex synthetic route, including multiple protection and deprotection steps.Among the aminocyclohexyl ether compounds, the compound (1R, 2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethyoxyphenethoxy)-cyclohexane, which has also been named as (3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}pyrrolidin-3-ol, and known as Vernakalant, shown below, has been taught to be useful for the treatment of atrial fibrillation.WO 2006/138673 discloses a process for the preparation of compounds of ...

CATIONIC LIPID

The present invention provides a cationic lipid, which allow nucleic acids to be easily introduced into cells, represented by formula (I) 2. The cationic lipid according to claim 1 , wherein Land Lare —O— or —O—CO— claim 1 , and Rand Rare dodecyl claim 1 , tetradecyl claim 1 , hexadecyl claim 1 , octadecyl claim 1 , icosyl claim 1 , docosyl claim 1 , tetracosyl claim 1 , (Z)-tetradec-9-enyl claim 1 , (Z)-hexadec-9-enyl claim 1 , (Z)-octadec-6-enyl claim 1 , (Z)-octadec-9-enyl claim 1 , (E)-octadec-9-enyl claim 1 , (Z)-octadec-11-enyl claim 1 , (9Z claim 1 ,12Z)-octadec-9 claim 1 ,12-dienyl claim 1 , (9Z claim 1 ,12Z claim 1 ,15Z)-octadec-9 claim 1 ,12 claim 1 ,15-trienyl claim 1 , (Z)-icos-11-enyl claim 1 , (11Z claim 1 ,14Z)-icos-11 claim 1 ,14-dienyl claim 1 , 3 claim 1 ,7 claim 1 ,11-trimethyldodeca-2 claim 1 ,6 claim 1 ,10-trienyl or 3 claim 1 ,7 claim 1 ,11 claim 1 ,15-tetramethylhexadec-2-enyl.3. The cationic lipid according to claim 1 , wherein Land Lare —CO—O— claim 1 , and Rand Rare tridecyl claim 1 , pentadecyl claim 1 , heptadecyl claim 1 , nonadecyl claim 1 , heneicosyl claim 1 , tricosyl claim 1 , (Z)-tridec-8-enyl claim 1 , (Z)-pentadec-8-enyl claim 1 , (Z)-heptadec-5-enyl claim 1 , (Z)-heptadec-8-enyl claim 1 , (E)-heptadec-8-enyl claim 1 , (Z)-heptadec-10-enyl claim 1 , (8Z claim 1 ,11Z)-heptadec-8 claim 1 ,11-dienyl claim 1 , (8Z claim 1 ,11Z claim 1 ,14Z)-octadec-8 claim 1 ,11 claim 1 ,14-trienyl claim 1 , (Z)-nonadec-10-enyl claim 1 , (10Z claim 1 ,13Z)-nonadec-10 claim 1 ,13-dienyl claim 1 , (11Z claim 1 ,14Z)-icos-11 claim 1 ,14-dienyl claim 1 , 2 claim 1 ,6 claim 1 ,10-trimethylundec-1 claim 1 ,5 claim 1 ,9-trienyl or 2 claim 1 ,6 claim 1 ,10 claim 1 ,14-tetramethylpentadec-1-enyl.4. The cationic lipid according to claim 1 , wherein a and b are both 0 or 1.5. The cationic lipid according to claim 1 , wherein Lis a single bond claim 1 , Ris a hydrogen atom claim 1 , methyl claim 1 , pyrrolidin-3-yl claim 1 , piperidin-3-yl claim 1 , piperidin-4- ...

Psyllid Attractants and Their Uses

The present specification discloses psyllid attractants, compositions comprising such attractants, lures, traps and other devices using such attractants, methods and uses to attract, capture and/or kill psyllids using such attractants, compositions and/or lures, traps and/or other devices, and methods and uses for monitoring a psyllid population using such attractants, compositions and/or lures, traps and/or other devices. 156-. (canceled)62. The compound of claim 57 , wherein the compound has a binding affinity for a psyllid OBP or SAP having an equilibrium dissociation constant of less than 0.500 nM claim 57 , less than 0.450 nM claim 57 , less than 0.400 nM claim 57 , less than 0.350 nM claim 57 , less than 0.300 nM claim 57 , less than 0.250 nM claim 57 , less than 0.200 nM claim 57 , less than 0.150 nM claim 57 , less than 0.100 nM claim 57 , or less than 0.050 nM.63. A composition comprising one or more of the compounds as defined in .64. The composition of claim 57 , wherein the composition is a liquid composition claim 57 , a semi-solid composition claim 57 , or a solid composition.65. A device comprising one or more of the compounds as defined in .66. A method of capturing psyllids claim 57 , the method comprising using one or more of the compounds as defined in to attract the psyllids to a device claim 57 , thereby capturing the psyllids.67. A method of killing psyllids claim 57 , the method comprising using one or more of the compounds as defined in to attract the psyllids to a device claim 57 , thereby killing the psyllids.68. A method of monitoring a psyllid population claim 57 , the method comprising a) using one or more of the compounds as defined in to attract psyllids to a device claim 57 , thereby capturing the psyllids; b) counting the psyllids to determine a number of captured psyllids; and c) performing a statistical analysis on the number of captured psyllids in order to determine the psyllid population claim 57 , thereby monitoring the psyllid ...

DIAZENIUMDIOLATE HETEROCYCLIC DERIVATIVES

A compound having the structure: useful for treating hypertension, Pulmonary Arterial Hypertension (PAH), congestive heart failure, conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy. 4. A compound of claim 1 , wherein Ris hydrogen claim 1 , —C(O)OH claim 1 , or —C(O)OCH claim 1 , or a pharmaceutically acceptable salt thereof.5. A compound of claim 1 , wherein Ris hydrogen claim 1 , or a pharmaceutically acceptable salt thereof.6. A compound of claim 1 , wherein Ris —CDCalkyl claim 1 , —C(CH) claim 1 , —CHCH claim 1 , or —CH(CH).8. A compound of claim 1 , wherein Ris hydrogen claim 1 , —CH claim 1 , C(O)OCH claim 1 , —C(O)OH claim 1 , phenyl claim 1 , or a pharmaceutically acceptable salt thereof.9. A compound of claim 1 , wherein Ris hydrogen or —CH claim 1 , or a pharmaceutically acceptable salt thereof.10. A compound of claim 1 , wherein Rand Rare attached to the same carbon atom and together form ═O claim 1 , or a pharmaceutically acceptable salt thereof.16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —CHor —CH.17. A compound of claim 1 , wherein Rand R claim 1 , together with the N atom to which they are attached claim 1 , form a 5- or 6-membered heterocyclic ring containing 1 N atom claim 1 , which ring is unsubstituted or substituted with —CHOH.18. A compound of claim 1 , wherein Rtogether with R claim 1 , forms ═O.19. A compound of claim 1 , which is{'sup': '2', 'O-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,'}{'sup': '2', 'O-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,'}{'sup': '2', 'O-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,'}{'sup': '2', 'O-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N- ...

DITERPENOID DERIVATIVES ENDOWED OF BIOLOGICAL PROPERTIES

The present invention relates to new diterpenoid derivatives of formula (I), processes for their preparation, and to pharmaceutical compositions containing them for the treatment of cardiovascular disorders, urinary incontinence, asthma, or Alzheimer's disease and/or to prevent obstructive vascular lesions consequently to arteriotomy and/or angioplasty, and to prevent organ damage in hypertensive patients. 2. The compound according to claim 1 , wherein Rrepresents —CH═NOR.3. The compound according to claim 1 , wherein Ris amino-(Ci-C6)alkyl or heterocycloalkyl.4. A medicament comprising an effective amount of the compound according to .5. (canceled)6. A method according to wherein cardiovascular disorder is hypertension.7. The method according to wherein hypertension is caused by the effects of endogenous ouabain.8. A method of treatment of a patient affected by cardiovascular disorder claim 1 , hypertension claim 1 , heart failure claim 1 , cardiac hypertrophy claim 1 , renal failure claim 1 , glomerulosclerosis claim 1 , proteinuria and vascular stenosis after vascular surgery claim 1 , comprising administering to said patient an effective amount of a compound according to .9. A pharmaceutical composition comprising a compound according to together with a pharmaceutically acceptable excipient.11. The medicament according to claim 4 , wherein said effective amount comprises from about 0.1 to about 50% by weight.12. The medicament according to claim 4 , wherein said effective amount comprises from about 1 to about 40% by weight.13. The method according to claim 8 , wherein said effective amount comprises from 0.001 mg/kg to 10 mg/kg.14. The method according to claim 8 , wherein said effective amount comprises from 0.05 mg/kg to 50 mg/kg. The present invention relates to new diterpenoid derivatives, process for their preparation, and to pharmaceutical compositions containing them for the prevention and/or treatment of cardiovascular disorders, obstructive vascular ...

AMINOTETRALINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR USE IN THERAPY

The present invention relates to aminotetraline derivatives of the formula (I) 234.-. (canceled)35. A method for inhibiting the glycine transporter GlyT1 in a mammal in need thereof which comprises the administration of an effective amount of a compound of .36. (canceled)37. A method for treating a neurologic or psychiatric disorder or pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of .38. (canceled)39. The compound of for use in a method of treating a neurologic or psychiatric disorder or pain.40. The method as claimed in claim 37 , wherein the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.41. The method as claimed in claim 37 , wherein the neurologic disorder is selected from the group consisting of dementia claim 37 , cognitive impairment claim 37 , and attention deficit disorder.42. The method as claimed in claim 41 , wherein the attention deficit disorder is an attention deficit disorder with hyperactivity.43. The method as claimed in claim 37 , wherein the psychiatric disorder is selected from the group consisting of anxiety disorder claim 37 , depression claim 37 , bipolar disorder claim 37 , schizophrenia claim 37 , and psychosis.44. (canceled) This claims the benefit of U.S. Provisional Application No. 61/152,825, which was filed on Feb. 16, 2009, the contents of which are incorporated herein by reference.The present invention relates to aminotetraline derivatives, pharmaceutical compositions comprising such aminotetraline derivatives, and the use of such aminotetraline derivatives for therapeutic purposes. The aminotetraline derivatives are GlyT1 inhibitors.Dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease and bipolar disorder. A large ...

Serotonin receptor modulator

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

Phenoxy-Pyrrolidine Derivative and Its Use and Compositions

The present invention is directed to the compound 2-(4-(hydroxymethyl)phenoxy)-1-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)ethanone, its use as an inhibitor of stearoyl CoA desaturase and to pharmaceutical compositions containing this compound. 2. The method of claim 1 , wherein said subject is a human.3. The method of claim 1 , wherein said compound is administered topically claim 1 , orally or parenterally.46-. (canceled)8. The method of claim 7 , wherein said subject is a human.9. The method of claim 7 , wherein said compound is administered topically claim 7 , orally or parenterally.11. The method of claim 10 , wherein said subject is a human.12. The method of claim 10 , wherein said compound is administered topically claim 10 , orally or parenterally. This application is a continuation of U.S. patent application Ser. No. 12/670,010, filed May 17, 2010, which is the U.S. National Stage of International Application No. PCT/IB2008/002028, filed Jul. 28, 2008 and published in English, which claims the benefit of U.S. Provisional Patent Application No. 60/954,593, filed Aug. 8, 2007. Each of these applications is incorporated herein by reference in its entirety.The present invention relates to phenoxy-pyrrolidine derivatives and compositions and uses thereof, in particular phenoxy-pyrrolidine derivatives for use as stearoyl-CoA desaturase (SCD1) inhibitors.Stearoyl-CoA desaturase (SCD1) is a microsomal, enzyme that catalyzes the de novo biosynthesis of monounsaturated fatty acids from saturated fatty acyl-CoA substrates in mammals. Specifically, SCD1 introduces a cis-double bond in the C9-C10 position of saturated fatty acids such as palmitoyl-CoA (16:0) and stearolyl-CoA (18:0). The resulting monounsaturated fatty acids, palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), are in turn substrates for incorporation into a variety of lipids, such as phospholipids, cholesterol esters, and triglycerides. Monounsaturated fatty acids are also mediators of several other ...

HETEROCYCLIC COMPOUND

The present invention relates to 2. The compound according to claim 1 , wherein ring A is benzene optionally further substituted;{'sup': '1', 'sub': '3-6', 'Ris an optionally substituted branched Calkyl group;'}{'sup': '1', 'sub': '2', 'Xis O, S, SO, SOor NH;'}{'sup': '2', 'sub': '1-3', 'Xis a bond or a Calkylene group;'}ring B is piperidine;{'sup': '3', 'Xis CO; and'}{'sup': '2', 'Ris an acyl group or an optionally substituted hydrocarbon group.'}3. The compound according to claim 1 , wherein ring A is benzene optionally further substituted by 1 to 3 substituents selected from the group consisting of (1) a halogen atom claim 1 , (2) an optionally halogenated Calkyl group and (3) an optionally halogenated Calkoxy group.4. The compound according to claim 1 , wherein Ris an isopropyl group or a tert-butyl group.5. The compound according to claim 1 , wherein Xis O.6. The compound according to claim 1 , wherein Xis a bond or methylene.8. The compound according to claim 1 , wherein Xis CO.9. The compound according to claim 1 , wherein Ris an acyl group or an optionally substituted hydrocarbon group.1126-. (canceled)27. {4-[(2-tert-Butyl-4-chlorophenoxy)methyl]piperidin-1-yl}(oxo)acetic acid or a salt thereof.28. [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid or a salt thereof.29. {4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}(oxo)acetic acid or a salt thereof.30. A pharmaceutical composition comprising the compound according to and a pharmacologically acceptable carrier. The present invention relates to a novel heterocyclic compound, which is useful as an agent for the prophylaxis or treatment of diabetes and the like; and the like.Retinol binding protein 4 (hereinafter sometimes to be abbreviated as “RBP4”) is known to be a sole blood retinol transport protein mainly produced in the liver. In recent years, moreover, RBP4 is suggested to be an insulin resistance-inducing factor from the following literatures and the like.(1) Since RBP4 expression increases in ...

PYRROLIDINE TRIPLE REUPTAKE INHIBITORS

In various embodiments, the present invention provides cycloalkyl pyrrolidine compounds and methods for their use in the treatment and/or prevention of various diseases, conditions and syndromes, including central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter. 130-. (canceled)32. The compound of or a pharmaceutically acceptable salt claim 31 , solvate claim 31 , enantiomer claim 31 , diastereomer claim 31 , racemic mixture claim 31 , enantiomerically enriched mixture claim 31 , or enantiomerically pure form thereof claim 31 , wherein Ar is phenyl substituted with at least one chloro.34. The compound according to or a pharmaceutically acceptable salt claim 33 , solvate enantiomer claim 33 , diastereomer claim 33 , racemic mixture claim 33 , enantiomerically enriched mixture claim 33 , or enantiomerically pure form thereof claim 33 , wherein each of Xand Xis independently halogen.35. The compound according to or a pharmaceutically acceptable salt claim 34 , solvate enantiomer claim 34 , diastereomer claim 34 , racemic mixture claim 34 , enantiomerically enriched mixture claim 34 , or enantiomerically pure form thereof claim 34 , wherein each of Xand Xis Cl.42. A pharmaceutical composition comprising a compound of claim 31 , or a pharmaceutically acceptable salt claim 31 , solvate enantiomer claim 31 , diastereomer claim 31 , racemic mixture claim 31 , enantiomerically enriched mixture claim 31 , or enantiomerically pure form thereof claim 31 , and a pharmaceutically acceptable carrier.43. A method of inhibiting the activity of at least one monoamine transporter claim 31 , the method ...

PYRROLIDINE DERIVATIVES AS SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF

Disclosed are compounds of formula (I): 2. The compound of wherein Rrepresents C1-15 alkyl claim 1 , C1-15 alkenyl or C1-15 alkynyl substituted with one or more R.3. The compound of wherein Ris selected from carbocyclyl or aryl claim 2 , either of which is optionally substituted with one or more OH claim 2 , OR claim 2 , ═O claim 2 , NH claim 2 , N claim 2 , SH claim 2 , SOR claim 2 , halo claim 2 , CN claim 2 , NO claim 2 , NRR claim 2 , (NR)NRR claim 2 , NH(NR)NRR claim 2 , COR claim 2 , OC(O)R claim 2 , P(O)(OR) claim 2 , C1-9 alkyl optionally substituted with one or more OH claim 2 , OR claim 2 , ═O claim 2 , NH claim 2 , N claim 2 , halo claim 2 , CN claim 2 , NO claim 2 , NRR claim 2 , COR claim 2 , aryl or carbocyclyl groups.4. The compound of wherein Rrepresents C1-9 alkyl substituted with one or more aryl groups.5. The compound of wherein Rrepresents propyl phenyl or propyl methoxyphenyl.6. The compound of wherein Rrepresents a substituent selected from:hydrogenmethyl hexyl4-methyl pentylethylethyl cyclohexylpropylpropyl phenylpropyl methoxyphenylpropyl chlorphenylpropyl (bis)phenylpropanoyl phenylpropyl (p-ethylsulfamoyl)phenylpropyl (p-phenylthio)phenylbutylbutyl phenylhexyl6-hydroxy hexylhexyldansylhexyltosylamidehexyl biphenylsulfonamidehexyl phenoxyphenyl sulfonamideN-Boc propylaminenonylhydroxynonylmethoxyethoxyethylethylphenylbenzylbenzyl phenylphenoxy ethylethoxy dichlorophenyl.7. The compound of wherein Rrepresents C(O)NRR; CRRC(O)NRR; NRC(O)NRRor CRRNRC(O)NRR.8. The compound of wherein Rrepresents a substituent selected from:methylethylhydroxyethylpropylisopropylcyclopropylbutylisobutylallylmethylcyclohexylethyl ureaglycolamide.9. The compound of wherein one from R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , Ris connected to Rto form an additional ring structure.10. The compound of wherein one from R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , Ris connected to Rto form an additional ring ...

PYRROLIDINONE DERIVATIVES AS GPR119 MODULATORS FOR THE TREATMENT OF DIABETES, OBESITY, DYSLIPIDEMIA AND RELATED DISORDERS

The present invention relates to pyrrolidinone derivatives. The pyrrolidinone derivatives are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of pyrrolidinone derivatives as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them. 2. The compound of claim 1 , whereinthe 3-position of the pyrrolidinone ring has (R)-configuration.3. The compound of claim 1 , wherein{'sub': '2', 'X is CH.'}4. The compound of claim 1 , wherein{'sup': '1a', 'Ris selected from the group consisting of H, F, Cl, methyl and CN;'}{'sup': '1b', 'Ris H and'}{'sup': '1c', 'Ris selected from the group consisting of H, F and methyl.'}5. The compound of claim 1 , wherein{'sup': '2a', 'Ris selected from the group consisting of H, F, Cl, methyl and CN;'}{'sup': '2b', 'Ris H and'}{'sup': '2c', 'Ris H.'}7. The compound of claim 1 , wherein{'sub': 2', '2', '2, 'X is selected from the group consisting of CHand CH—CH;'}{'sup': '1a', 'sub': 1', '4, 'Ris selected from the group consisting of H, F, Cl, Br, (C-C)-alkyl and CN;'}{'sup': '1b', 'Ris H;'}{'sup': '1c', 'Ris selected from the group consisting of H, F and methyl;'}{'sup': '2a', 'sub': 1', '4, 'Ris selected from the group consisting of H, F and (C-C)-alkyl;'}{'sup': '2b', 'Ris H;'}{'sup': '2c', 'Ris H;'}{'sup': 1', '2', '2d', '3', '4, 'one of the groups Yand Yis N, N-oxide or CR, the other is C—Z—R—R;'}{'sup': '2d', 'Ris H;'}Z is selected from the group consisting of a bond, O, CO, COO, S and SO;{'sup': 3', '6', '6′, 'sub': 'n', 'Ris selected from the group consisting of a bond and (CRR);'}n is selected from the group consisting of 1, 2, 3, 4 and 5;{'sup': 6', '6', '6', '6′, 'sub': 'n', 'R, Rare independently of each other selected from the group consisting of H, methyl, ethyl and 2-fluoro-ethyl, and the overall number of carbon atoms in a (CRR)group is below or equal to eight (8);'}{'sup': 4', '5', '7 ...

New pyrrolidine derivatives, pharmaceutical compositions and uses thereof

Pyrrolidine derivatives of the formula 4. A compound according to claim 1 , wherein{'sub': '3', 'L is —CH(CH)—; and'}{'sup': '2', 'Ris H.'}5. A compound according to claim 1 , wherein Ris selected from a group consisting of:{'sub': 1-4', '3-5', '1-4', '3-5', '2', '3-5', '2, 'claim-text': wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl,', 'wherein aryl is phenyl or naphthyl,', {'sub': '3', 'wherein each alkyl is optionally substituted with 1 to 3 F or with one —O—CH, and'}, {'sub': 3', '3', '2', '3, 'wherein each cycloalkyl is optionally substituted with 1 to 2 F or with one CH, CFor —COCH;'}], 'F, Cl, Br, CN, C-alkyl, C-cycloalkyl, —O—(C-alkyl), —O—(C-cycloalkyl), —O—CH—(C-cycloalkyl), —O—CH-aryl, —O-tetrahydrofuranyl and —O-heteroaryl,'}{'sup': '1', 'sub': 2', '2', '2', '2', '2', '2', '3', '3, 'or two Rgroups attached to adjacent C-atoms together may form a —(CH)—O—, —O—CH—O—, —O—(CH)—O— or —O—(CH)—O— bridge that is optionally substituted with one or two F or CH.'}7. A compound according to claim 1 , wherein T is selected from a group consisting of:{'sub': 1-3', '3, 'C-alkyl which is optionally substituted with one to three F or with one CN, OH or —OCH;'}{'sub': 3', '3', '3', '2, 'cyclopropyl which is optionally substituted with one or two F or with one CN, CH, OH, —OCHor —(C═O)—N(CH);'}{'sub': '3', '—OCH;'}{'sub': 2', '1-3', '2, '—NH, wherein each H is optionally independently replaced with C-alkyl or wherein one H is optionally replaced by isoxazolyl or by —CH-pyrimidyl; and'}a 5-membered heteroaryl group selected from imidazolyl, oxazolyl, pyrazolyl, isoxoazolyl, thioazolyl and isothiazolyl,wherein said 5-membered heteroaryl group is optionally substituted with one or two substituents selected independently from the group consisting of:{'sub': 2', '1-3', '2', '3', '2', '3', '2', '2', '3', '1-2, 'claim-text': 'wherein each alkyl is optionally substituted with one to three F.', 'Cl, CN, NH, —NH—C(═O)—C- ...

C17-ALKANEDIYL AND ALKENEDIYL DERIVATIVES OF OLEANOLIC ACID AND METHODS OF USE THEREOF

Disclosed herein are novel C17-alkanediyl and alkenediyl derivatives of oleanolic acid, including those of the formula: 5. The compound of claim 1 , wherein the bond between carbon atoms a and b is a single bond.6. The compound of claim 1 , wherein the bond between carbon atoms a and b is a double bond.7. The compound of claim 1 , wherein Y is a covalent bond.8. The compound of claim 1 , wherein Y is —CH—.9. The compound of claim 1 , wherein Y is —C(O)—.10. The compound of claim 1 , wherein Y is —O—.11. The compound of claim 1 , wherein Ris —H.12. The compound of claim 1 , wherein Ris methyl.13. The compound of claim 1 , wherein Ris —H.14. The compound of claim 1 , wherein Ris —OH.15. The compound of claim 1 , wherein Ris amino.16. The compound of claim 1 , wherein Ris alkyl.17. (canceled)18. The compound of claim 1 , wherein Ris heterocycloalkyl.19. (canceled)20. The compound of claim 1 , wherein Ris substituted heterocycloalkyl.21. (canceled)22. The compound of claim 1 , wherein Ris acyl.23. (canceled)24. The compound of claim 1 , wherein Ris substituted acyl.25. (canceled)26. The compound of claim 1 , wherein Ris alkoxy.27. (canceled)28. The compound of claim 1 , wherein Ris aryloxy.29. (canceled)30. The compound of claim 1 , wherein Ris aralkoxy.31. (canceled)32. The compound of claim 1 , wherein Ris substituted acyloxy.33. The compound of claim 32 , wherein Ris —OC(O)NHCHCH.34. The compound of claim 1 , wherein Ris heterocycloalkoxy.35. (canceled)36. The compound of claim 1 , wherein Ris alkylamino.37. (canceled)38. The compound of claim 1 , wherein Ris substituted alkylamino.39. The compound of claim 38 , wherein Ris 2 claim 38 ,2 claim 38 ,2-trifluoroethylamino claim 38 , —NHCHC(O)OCHor —NHCHC(O)OH.40. The compound of claim 1 , wherein Ris dialkylamino.41. (canceled)42. The compound of claim 1 , wherein Ris alkoxyamino.43. (canceled)44. The compound of claim 1 , wherein Ris arylamino.45. (canceled)46. The compound of claim 1 , wherein Ris aralkylamino.47. ( ...

C7-FLUORO SUBSTITUTED TETRACYCLINE COMPOUNDS

The present invention is directed to a compound represented by Structural Formula (A): 4. The compound of claim 3 , wherein Ris hydrogen or a (C-C)alkyl.5. The compound of claim 3 , wherein Ris selected from (C-C)alkyl claim 3 , (C-C)cycloalkyl(C-C)alkyl claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , phenyl claim 3 , phenyl(C-C)alkyl claim 3 , (C-C)cycloalkyl and halo(C-C)alkyl claim 3 , wherein each alkyl claim 3 , alkoxy and cycloalkyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl and halo; and each phenyl moiety in the groups represented by Ris optionally substituted with one or more substituents independently selected from the group consisting of (C-C)alkyl claim 3 , halo claim 3 , (C-C)alkoxy claim 3 , (C-C)alkoxy(C-C)alkyl claim 3 , —CN claim 3 , halo(C-C)alkyl claim 3 , and halo(C-C)alkoxy.6. The compound of any one of claim 3 , wherein Ris selected from hydrogen claim 3 , methyl and ethyl.7. The compound of claim 6 , wherein Ris selected from the group consisting of cyclopropyl claim 6 , cyclobutyl claim 6 , cyclopentyl claim 6 , cyclopropylmethyl claim 6 , cyclobutylmethyl claim 6 , phenyl claim 6 , benzyl claim 6 , —(CH)—O—CH claim 6 , —(CH)—OCH claim 6 , —C(CH) claim 6 , —CH(CH) claim 6 , —CHC(CH) claim 6 , —CHCH(CH) claim 6 , —CH—CF claim 6 , —(CH)—CHF claim 6 , and —(CH)CH; n is 0 claim 6 , 1 claim 6 , 2 claim 6 , 3 claim 6 , 4 claim 6 , 5 or 6; and wherein the phenyl or benzyl group represented by Ris optionally substituted with one or two substituents independently selected from the group consisting of (C-C)alkyl claim 6 , halogen claim 6 , (C-C)alkoxy claim 6 , (C-C)alkoxy(C-C)alkyl claim 6 , —CN claim 6 , halo(C-C)alkyl claim 6 , and halo(C-C)alkoxy.8. The compound of claim 7 , wherein Ris selected from cyclopropyl claim 7 , cyclopropylmethyl claim 7 , cyclobutyl claim 7 , cyclopentyl claim 7 , cyclohexyl claim 7 , —(CH)—O—CH claim 7 , —C(CH) ...

PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis. 119-. (canceled)20. A glycopyrrolate base composition comprising threo-glycopyrrolate base and erythro-glycopyrrolate base , wherein the threo-glycopyrrolate base is at least 95% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 5% of the total glycopyrrolate base content of the composition.21. The glycopyrrolate base composition of claim 20 , wherein the threo-glycopyrrolate base is at least 96% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 4% of the total glycopyrrolate base content of the composition.22. The glycopyrrolate base composition of claim 20 , wherein the threo-glycopyrrolate base is at least 97% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 3% of the total glycopyrrolate base content of the composition.24. A glycopyrronium tosylate composition comprising threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate claim 20 , wherein the threo glycopyrronium tosylate is at least 95% of the total glycopyrrolate tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 5% of the total glycopyrronium tosylate content of the composition.25. The glycopyrronium tosylate composition of claim 24 , wherein the threo-glycopyrronium tosylate is at least 96% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 4% of the total glycopyrronium tosylate content of the composition.26. The glycopyrronium tosylate composition ...

HISTONE DEACETYLASE INHIBITORS

Provided herein are compounds and methods for inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3). 2. The compound of claim 1 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom or a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom; Z is O claim 1 , NR claim 1 , S claim 1 , or SO; Ris Calkyl claim 1 , Chydroxyalkyl claim 1 , or Calkylene-Ccycloalkyl; Ris H claim 1 , F claim 1 , Cl claim 1 , or CH; Ris H claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , C(O)Calkyl claim 1 , or C(O)Calkylene-Ccycloalkyl; and Ris H or Calkyl.3. The compound of or claim 1 , wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom.4. The compound of or claim 1 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom.5. The compound of any one of to claim 1 , wherein Z is O or NR.6. The compound of any one of to claim 1 , wherein Ris Calkyl claim 1 , Chydroxyalkyl claim 1 , C(O)Calkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 1 , S claim 1 , N claim 1 , and N(Calkyl).7. The compound of any one of to claim 1 , wherein Ris H claim 1 , Calkyl claim 1 , Chydroxyalkyl claim 1 , Calkylene-Ccycloalkyl claim 1 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 1 , S claim 1 , N claim 1 , and N(Calkyl).8. The compound of claim 7 , wherein Ris Calkyl claim 7 , Chydroxyalkyl claim 7 , Calkylene-Ccycloalkyl claim 7 , or Calkylene-Cheterocycloalkyl having 1 or 2 heteroatoms selected from O claim 7 , S claim 7 , N claim 7 , and N(Calkyl).9. The compound of claim 7 , wherein Ris Calkyl claim 7 , Chydroxyalkyl claim 7 , or Calkylene-Ccycloalkyl.10. The compound of claim 7 , wherein Ris H.11. The compound of claim 7 , wherein Ris a Calkyl.12. The compound of claim 7 , wherein Ris methyl claim 7 , ...

Benzamide compounds

Compounds of Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including conditions characterized by excessive cellular proliferation, such as cancer and tumors, as well as viral infections such as HIV.

AMIDE COMPOUND

The present invention relates to compound (I) or a salt thereof which has a RORγt inhibitory action. In the formula (I), each symbol is as defined in the specification. 116-. (canceled)18. The method of claim 17 , wherein the substituent that Ring A optionally further has is a fluorine atom or a chlorine atom.19. The method of claim 17 , wherein Ris a tert-butyl group claim 17 , a neopentyl group or a trimethylsilyl group.21. The method of claim 17 , wherein Ris a hydrogen atom or a methyl group.22. The method of claim 17 , wherein the compound is (3S)—N-((1R)-2-((4-tert-Butyl-3-fluorophenyl)amino)-1-(4 claim 17 ,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide or a salt thereof.23. The method of claim 17 , wherein the compound is N-((1R)-2-((3 claim 17 ,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1 claim 17 ,2-oxazole-5-carboxamide or a salt thereof.24. The method of claim 17 , wherein the compound is (2R)—N-(4-tert-Butyl-3 claim 17 ,5-difluorophenyl)-2-(((3-hydroxy-1 claim 17 ,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide or a salt thereof.25. The method of claim 17 , wherein the compound is (3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide or a salt thereof.26. The method of claim 17 , wherein the compound is selected from the group consisting of(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide,N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,(2R)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide,(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4 ...

Process for the synthesis of difluoromethyl ether-based compounds

The present application relates to a novel process for the preparation of difluoromethyl ether-based derivatives from, for example, aliphatic and aromatic hydroxyl precursors, compositions comprising these compounds and their use, in particular as precursors for medicines for the treatment of diseases, disorders or conditions. In particular, the present application includes the process of preparing compounds of Formula (I), and compositions and uses thereof:

KAPPA OPIOID AGONISTS AND USES THEREOF

Provided are compounds of Formula I: 2. The compound of claim 1 , wherein Ris a phenyl substituted with 1 claim 1 , 2 claim 1 , or 3 halogen atoms.3. The compound of claim 1 , wherein Ris methyl.4. The compound of claim 1 , wherein Ris phenyl substituted with —X-POLY.5. The compound of claim 1 , wherein Rand Rare taken together to form an optionally substituted pyrrolidinyl.6. The compound of claim 1 , wherein X is:{'sub': 2', '2', '2', '2', '2', '2', '2', '2, 'a covalent bond; —C(O)NH—; —C(O)NHCH—; —C(O)NHCHCH—; —OC(O)NH—; —C(O)NH—; —O—; —NHC(O)—; —NHC(O)CH—; —NHC(O)CHO—; —NHC(O)CHCH—; —NH—; or —NHS(O)—.'}7. The compound of claim 1 , wherein POLY is a poly(alkylene oxide) oligomer.8. The compound claim 1 , wherein POLY is a poly(ethylene oxide) oligomer.9. The compound of claim 1 , wherein POLY is end-capped with a hydroxyl group claim 1 , a lower alkoxy group claim 1 , or a trifluoromethoxy group.15. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable excipient.16. A method of treating pain or inflammation comprising administering a compound of to a patient in need thereof. This application a Continuation of U.S. application Ser. No. 14/900,039, filed 18 Dec. 2015, which is a 35 U.S.C. §371 application of International Application No. PCT/US2014/044535, filed 27 Jun. 2014, designating the United States, which claims the benefit of priority under 35 U.S.C. §119(e) to both U.S. Provisional Patent Application Ser. No. 61/929,685, filed 21 Jan. 2014, and U.S. Provisional Patent Application Ser. No. 61/841,042, filed 28 Jun. 2013, the disclosures of which are incorporated herein by reference in their entireties.The present disclosure relates to novel compounds and to their use as agonists of the kappa opioid receptor. The disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions containing such compounds. The compounds described herein relate to and/or have application(s) in ( ...

4-PYRIDONE COMPOUND OR SALT THEREOF, AND PHARMACEUTICAL COMPOSITION AND FORMULATION INCLUDING SAME

An object of the present invention is to provide a compound or a salt thereof having anti-HBV activity, a pharmaceutical composition, an anti-hepatitis B virus agent, a production inhibitor of DNA of a hepatitis B virus, and a production or secretion inhibitor of a hepatitis B surface antigen. According to the present invention, provided are a compound represented by General Formula [1] or a salt thereof: 3. The compound or a salt thereof according to claim 2 ,{'sup': 'a1', 'sub': 1-6', '1-6, "wherein m R's are each independently the same as or different from each other, and are each a halogen atom, a Calkyl group which may be substituted, or a Calkoxy group which may be substituted; and"}m is an integer of 0 or 1.4. The compound or a salt thereof according to claim 2 ,{'sup': 'b1', 'sub': 1-6', '1-6', '1-6', '1-6, 'wherein Ris a hydrogen atom, a halogen atom, a Calkyl group which may be substituted, a Calkoxy group which may be substituted, a Calkylamino group which may be substituted, a di(Calkyl)amino group which may be substituted, or a heterocyclic group which may be substituted.'}5. The compound or a salt thereof according to claim 1 ,{'sup': '2', 'wherein Ris a phenyl group which may be substituted, a thienyl group which may be substituted, a thiazolyl group which may be substituted, or a benzoxazinyl group which may be substituted.'}7. The compound or a salt thereof according to claim 6 ,{'sub': '1', 'wherein the substituent group Aisa halogen atom,a cyano group,{'sub': 1-6', '2, 'a Calkyl group which may have one or more substituents selected from the substituent group A,'}{'sub': 1-6', '2, 'a Calkoxy group which may have one or more substituents selected from the substituent group A,'}{'sub': 1-6', '2, 'a Calkylamino group which may have one or more substituents selected from the substituent group A,'}{'sub': 1-6', '2, 'a di(Calkyl)amino group which may have one or more substituents selected from the substituent group A, or'}{'sub': '2', 'a heterocyclic ...

ADAMANTANE DERIVATIVES FOR THE TREATMENT OF FILOVIRUS INFECTION

Compounds of structural Formula I were developed for the treatment of infections by filoviruses including Ebolavirus and Marburgvirus, wherein, R, R, R, X and Y are defined in the specification. 119-. (canceled)21. The compound of claim 20 , wherein:{'sup': 4', '5, 'X is C-A-D and Y is CRR.'}23. The compound of claim 22 , wherein:{'sup': 2', '11a', '11b', '12, 'sub': 1', '10', '1', '10', '1', '10', '3', '10', '5', '10', '1', '10', '2', 'n, 'Ris selected from hydrogen, (Cto C) alkyl, (Cto C) alkenyl, (Cto C) alkynyl, (Cto C) cycloalkyl, (Cto C) cycloalkenyl, (Cto C) alkoxy, —(CH)C(O)N(RR), and —C(O)R, wherein'}{'sub': 1', '10', '1', '10', '1', '10', '3', '10', '5', '10', '1', '10, 'sup': '13', 'each of the said (Cto C) alkyl, (Cto C) alkenyl, (Cto C) alkynyl, (Cto C) cycloalkyl, (Cto C) cycloalkenyl, and (Cto C) alkoxy is optionally substituted with at least one Rgroup;'}{'sup': '3', 'sub': 1', '10', '1', '10', '1', '10', '3', '10', '5', '10, 'Ris selected from hydrogen, (Cto C) alkyl, (Cto C) alkenyl, (Cto C) alkynyl, (Cto C) cycloalkyl, and (Cto C) cycloalkenyl, wherein'}{'sub': 1', '10', '1', '10', '1', '10', '6', '10', '5', '10, 'sup': '13', 'each of the said (Cto C) alkyl, (Cto C) alkenyl, (Cto C) alkynyl, (Cto C) cycloalkyl, (Cto C) cycloalkenyl is optionally substituted with at least one Rgroup.'}24. The compound of claim 23 , wherein:{'sup': '3', 'Ris hydrogen.'}31. The method of claim 30 , wherein the infection is associated with filovirus selected from the group consisting of Ebolavirus and Marburgvirus.32. The method of claim 31 , where the filovirus is Ebolavirus.33. The method of claim 31 , including administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin claim 31 , viral RNA-dependent-RNA polymeras inhibitors including favipiravir claim 31 , Triazavirin claim 31 , Remdesivir (GS-5734) claim 31 , monoclonal antibody therapies including claim 31 , ZMapp claim 31 , REGN3470-3471-3479 claim 31 , mAb 114 ...

INHIBITING NEUROTRANSMITTER REUPTAKE

This document relates to compounds as well as methods and materials involved in modulating neurotransmitter reuptake. For example, compounds, methods for synthesizing compounds, and methods for inhibiting neurotransmitter reuptake are provided. Specifically gamma-amino alcohol derivatives that inhibit the reuptake of neurotransmitters such as dopamine, serotonin, epinephrine or norepinephrine are provided as therapeutic agents for the treatment of depression or anxiety in a mammalian subject. 17-. (canceled)9. The compound of claim 8 , wherein Ris optionally substituted with one or two substituents.11. The compound of claim 10 , wherein at least two of R claim 10 , R claim 10 , R claim 10 , R claim 10 , and Rare hydrogen.12. The compound of claim 11 , wherein the remaining R claim 11 , R claim 11 , R claim 11 , R claim 11 , and Rare independently selected from ethyl claim 11 , chloro claim 11 , and bromo.13. The compound of claim 10 , wherein R claim 10 , R claim 10 , and Rare hydrogen; and Rand Rare independently selected from ethyl claim 10 , chloro claim 10 , and bromo.15. The compound of claim 14 , wherein each of Rand Ris not hydrogen.17. The compound of claim 16 , wherein Ris selected from hydrogen claim 16 , lower alkyl claim 16 , halo claim 16 , hydroxyl claim 16 , lower alkoxy claim 16 , methylsulfanyl claim 16 , and methsulfonyl; and Ris selected from hydrogen claim 16 , lower alkyl claim 16 , halo claim 16 , dimethylamino claim 16 , methylsulfanyl claim 16 , and 1 claim 16 ,1 claim 16 ,1-trifluoromethanesulfonamide.1826-. (canceled) This application claims the benefit of U.S. Provisional Application Ser. No. 61/783,122, filed Mar. 14, 2013. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application.1. Technical FieldThis document relates to compounds as well as methods and materials involved in modulating neurotransmitter reuptake.2. Background InformationNeuronal signals are ...

PESTICIDAL ARYLPYRROLIDINES

Arylpyrrolidines of formula (I): 2. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris hydroxy;'}n is 1;{'sup': 1', '1, 'Bis C—Y;'}{'sup': 3', '3, 'Bis C—Y;'}{'sup': 4', '4, 'Bis C—Y; and'}{'sub': 1-3', '1', '6, 'E E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups.'}3. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris hydroxy;'}n is 1;{'sup': '1', 'Bis nitrogen;'}{'sup': 3', '3, 'Bis C—Y;'}{'sup': 4', '4, 'Bis C—Y; and'}{'sub': 1-3', '1', '6, 'E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups.'}4. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris hydroxy;'}n is 1;{'sup': 1', '1, 'Bis C—Y;'}{'sup': '3', 'Bis nitrogen;'}{'sup': 4', '4, 'Bis C—Y; and'}{'sub': 1-3', '1', '6, 'E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups.'}5. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris hydroxy;'}n is 1;{'sup': 1', '1, 'Bis C—Y;'}{'sup': 3', '3, 'Bis C—Y;'}{'sup': '4', 'Bis nitrogen; and'}{'sub': 1-3', '1', '6, 'E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups.'}6. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris an oxo group;'}n is 1;{'sup': 1', '1, 'Bis C—Y;'}{'sup': 3', '3, 'Bis C—Y;'}{'sup': 4', '4, 'Bis C—Y; and'}{'sub': 1-3', '1', '6, 'E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups.'}7. Compound according to claim 1 , wherein{'sup': '1', 'sub': '3', 'Ris CF;'}{'sup': '2', 'Ris an oxo group;'}n is 1;{'sup': '1', 'Bis nitrogen;'}{'sup': 3', '3, 'Bis C—Y;'}{'sup': 4', '4, 'Bis C—Y; and'}{'sub': 1-3', '1', '6, 'E is oxygen or a Calkandiyl-group which group can be optionally substituted by 1 or 2 C-Calkyl groups ...

PROCESSES FOR THE PREPARATION OF ARGINASE INHIBITORS AND THEIR SYNTHETIC INTERMEDIATES

Provided herein are processes and intermediates useful for the preparation of certain compounds, including a compound of formula 21 or formula 22 2. (canceled)4. (canceled)6. (canceled)8. (canceled)10. (canceled)12. (canceled)14. (canceled)16. (canceled)18. (canceled)20. (canceled)22. (canceled)24. (canceled)26. (canceled)28. (canceled)30. (canceled)32. (canceled)34. (canceled)36. (canceled)38. (canceled)39. A process for preparing a compound of formula 2 as defined in claim 37 , the process comprising esterifying L-malic acid under suitable conditions to form the compound of formula 2 or a salt thereof.40. (canceled)42. (canceled)4463-. (canceled)65. (canceled)67. (canceled)69. (canceled)71. (canceled)73. (canceled)75. (canceled)7783-. (canceled)8594-. (canceled) Compounds of general formula 21 and formula 22including pharmaceutically acceptable salts thereof, exhibit potent arginase inhibition.U.S. Pat. Nos. 10,065,974 and 10,494,339 describe benchtop preparation of compounds of the general formula 21. U.S. Pat. No. 10,287,303 describes preparation of compounds of the general formula 22. A need exists for economical synthetic procedures and intermediate compounds for the preparation of the compounds of formula 21 and formula 22 including pharmaceutically acceptable salts thereof for batch process scale-up. Such alternative synthetic procedures and intermediate compounds are provided herein.Provided herein is a process for preparing a compound of formula 21:or a pharmaceutically acceptable salt thereof, wherein:Also provided herein is a process for preparing a compound of formula 22:or a pharmaceutically acceptable salt thereof, wherein:In some embodiments, the process for preparing a compound of formula 21 or formula 22 comprises treating a compound of formula 20or a salt thereof, wherein:In some embodiments, the suitable conditions to deprotect the compound of formula 20 comprise treating with hydrogen and a palladium catalyst.In some embodiments, the process for ...

(+)-3-(2,3-DIFLUOROPHENYL)-3-METHOXYPYRROLIDINE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, A PROCESS FOR PREPARATION THEREOF AND USES THEREOF

The disclosure provides a process for manufacturing thereof a salt of Formula IIb: 115.-. (canceled)17. The process according to claim 16 , wherein the (−)-dibenzoyl-L-tartaric acid is removed from the salt of Formula IIa by treating the salt of Formula IIa with a base thereby providing the compound of Formula II.18. The process according to claim 16 , wherein the resolution comprises:a) dissolving the (−)-dibenzoyl-L-tartaric acid in the at least one solvent, optionally by heating, to provide a first solution,b) adding a solution comprising the compound of Formula I and at least one further solvent to said first solution thereby providing a second solution, andc) precipitating the salt of Formula IIa, optionally by cooling, from said second solution.19. The process according to claim 16 , wherein the at least one solvent and/or the at least one further solvent is/are selected from the group consisting of: methanol claim 16 , ethanol claim 16 , 1-propanol claim 16 , 2-propanol claim 16 , 1-butanol claim 16 , and 2-butanol claim 16 , and any combination thereof.20. The process according to claim 16 , wherein the at least one solvent and/or the at least one further solvent comprise(s) ethanol.21. The process according to claim 16 , wherein said treatment with the base comprises the steps of:mixing the salt of Formula IIa with a mixture of a first water-insoluble solvent and an aqueous solution comprising a base, thereby forming:(i) a solvent phase comprising the first water-insoluble solvent, and(ii) an aqueous phase comprising the aqueous solution comprising the base,extracting (ii) with a second water-insoluble solvent to provide:(iii) at least one phase comprising the second water-insoluble solvent,combining the phases (i) and (iii),evaporating the first and second water-insoluble solvents from the combined phases (i) and (iii) thereby providing the compound of Formula II,optionally converting the compound of Formula II into a pharmaceutically acceptable salt ...

ROR GAMMA MODULATORS

There are described RORγ modulators of the formula (I), 2. A compound of claim 1 , wherein{'sup': 1', '1a', '1a, 'sub': '1-6', 'Ris halo, phenyl substituted with 0-3 R, or Calkyl substituted with 0-3 R;'}{'sup': 1a', 'a', 'b', 'a, 'sub': 3', '1-6', '2', 'r', '2', 'r, 'Ris, independently at each occurrence, hydrogen, CF, halo, Calkyl substituted with 0-3 R, —(CH)OR, and (CH)-phenyl substituted with 0-3 R,'}or a stereoisomer or pharmaceutically-acceptable salt thereof.3. The compound of claim 1 , wherein:{'sup': 2', '2c', '2a', '2b', '2d', '11', '11', 'a, 'sub': 2', '1-6', '2', 'p, 'Ris hydrogen, SOR, Calkyl substituted with 0-3 R, COR, —C(O)R, —C(O)NRR; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)substituted with 0-3 R,'}{'sup': 2a', 'a, 'sub': '1-6', 'Ris hydrogen or Calkyl substituted with 0-3 R;'}{'sup': 2b', 'a', 'a', 'a', 'a, 'sub': 1-6', '3-6', '2', 'r', 'p', '2', 'r, 'Ris hydrogen, Calkyl substituted with 0-3 R, Ccycloalkyl substituted with 0-3 R, or —(CH)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)substituted with 0-3 R, or (CH)-phenyl substituted with 0-3 R;'}{'sup': 2c', 'a', 'a', 'a', 'a', 'a, 'sub': 1-6', '2-6', '3-10', '6-10', '2', 'r, 'Ris, independently at each occurrence, hydrogen, Calkyl substituted with 0-3 R, Calkenyl substituted with 0-3 R, Ccycloalkyl substituted with 0-3 R, Caryl substituted with 0-3 R, or a —(CH)5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R; and'}{'sup': 2d', 'd', '11', '11', 'd', 'a', 'a, 'sub': 1-6', '1-6', '3-6', '2', 'r, 'Ris, independently at each occurrence, hydrogen, Calkyl substituted with 0-3 R, Chaloalkyl, C(O)NRR, Ccycloalkyl substituted with 0-2 R, (CH)-phenyl substituted with 0-2 R, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R'}or a stereoisomer or pharmaceutically-acceptable salt ...

CYCLIC AMIDES AS METAP-2 INHIBITORS

Compounds of the formula (I), in which R, R, R, R, R, R, X and Y have the meanings indicated in Claim , are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours. 2. Compounds according to in which{'sub': 2', '2', '2', '2', 'n', '2', '2', 'n', '2', 'n', '2', '2', '2', '2', '2', '2', '2', '2, 'sup': 1', '3', '3, 'Het denotes pyrazinyl, pyrazolyl, benzimidazolyl, pyridyl, indolyl, dihydroindolyl, benzofuranyl, tetrahydropyranyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indazolyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, benzothiazolyl, piperidin-1-yl, pyrrolidin-1-yl, 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazinyl, 3,4-dihydro-2H-benzo-1,4-oxazinyl, benzofuranyl, azetidinyl, 3-azabicylo[3.2.0]hexyl, pyrrolo[2,3-b]pyridinyl, tetrahydrofuranyl, tetrahydro-1,8-naphthyridinyl, 2,3-dihydrobenzoisothiazolyl, 1,2,3,4-tetrahydrobenzothiazinyl or hexahydrobenzo-1,3-dioxolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, CN, NH, NHA, NA, NO, CN, COOH, COOA, (CH)CONH, (CH)CONHA, (CH)CONA, NHCOA, COA, CHO, Het, SOA, SONH, SONHA, SONA, CONHNH, CONHAr, ═O and/or Ar,'}and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.3. Compounds according to in which{'sup': '1', 'Hetdenotes pyridazinyl, pyrazolyl, pyridyl, piperazinyl, morpholinyl, pyrimidinyl, furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazole, piperidin-1-yl, pyrrolidin-1-yl, tetrahydropyranyl, 1,2-oxazinan-2-yl, 1,2,5-oxadiazinan-2-yl, 1,3-oxazinan-3-yl or hexahydropyrimidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A and/or OA,'}and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.4. Compounds according to in which{'sup': 2', '4', '4', '2', '2', '4', '2, 'sub': 2', '2', 'n', '2', 'n, 'R ...

Lactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated diseases and conditions

Disclosed herein are compounds of formula (I) wherein L 1 , L 2 , L 3 , R 1 , R 4 , R 5 , and R 6 are as defined in the specification. Compounds of formula (I) are EP 4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.

Compounds for their use as drugs for the treatment and/or the prevention of infection(s) caused by biofilm-forming bacteria

Disclosed are compounds of the following formula I: wherein: m represents an integer being equal to 0, 1, 2, 3, 4, 5 or 6, X represents a simple bond or a radical —CHR 1 — wherein R 1 represents: a hydrogen atom, or a linear or branched, possibly interrupted by up to 3 heteroatoms selected from O, S or N and/or possibly substituted, (C 1 -C 12 )-alkyl, R 2 , R 3 and R 4 represent independently from each other: a hydrogen atom, or a linear or branched (C 1 -C 12 )-alkyl or (C 1 -C 12 )-acyl R 5 represents: a hydrogen atom, or a linear or branched, possibly substituted, (C 1 -C 13 )-alkyl possibly interrupted by up to 3 heteroatoms selected from O, S or N, R 6 represents: a hydrogen atom, or a linear or branched possibly substituted (C 1 -C 12 )-alkyl, possibly substituted and possibly interrupted by up to 3 heteroatoms selected from O, S or N, for their use as antibacterial drugs.

Prodrugs of fumarates and their use in treating various diseases

The present invention provides compounds of formula (I), wherein: R 1 is unsubstituted C 1 -C 6 alkyl; L a is substituted or unsubstituted C 1 -C 6 alkyl linker, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R 2 and R 3 are each, independently, H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 6 -C 10 aryl; or alternatively, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. The invention also provides pharmaceutical compositions and methods for treating neurological diseases, such as multiple sclerosis.

PHENYL DERIVATIVE

The compound of the formula (I-1): 2. The method according to claim 1 , wherein the ring 1 and the ring 2 each independently are (1) a benzene claim 1 , (2) cyclohexane or (3) pyridine ring.3. The method according to claim 1 , wherein the compound of formula (I-A) is 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid or a salt thereof.4. The method according to claim 1 , wherein the protecting group T comprises a carbonyl group.5. The method according to claim 4 , wherein the protecting group T is a 2 claim 4 ,2 claim 4 ,2-trichloroethoxycarbonyl (Troc) group claim 4 , a phenoxycarbonyl group claim 4 , or a p-nitrophenoxycarbonyl group.6. The method according to claim 2 , wherein the compound of formula (I-A) is 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid or a salt thereof.7. The method according to claim 1 , wherein the ring 1 and the ring 2 each independently are a benzene.8. The method according to claim 2 , wherein the ring 1 and the ring 2 each independently are a benzene.9. The method according to claim 1 , wherein the base is selected from the group consisting of pyridine claim 1 , triethylamine claim 1 , dimethylaniline claim 1 , dimethylaminopyridine claim 1 , diisopropylethylamine claim 1 , or a mixture thereof.10. The method according to claim 1 , wherein the organic solvent is selected from N claim 1 ,N-dimethylacetamide claim 1 , chloroform claim 1 , dichloromethane claim 1 , diethyl ether claim 1 , tetrahydrofuran claim 1 , and a mixture thereof.11. The method according to claim 2 , wherein the base is selected from the group consisting of pyridine claim 2 , triethylamine claim 2 , dimethylaniline claim 2 , dimethylaminopyridine claim 2 , diisopropylethylamine claim 2 , or a mixture thereof.12. The method according to claim 2 , wherein the organic solvent is selected from N claim 2 ,N-dimethylacetamide claim 2 ...

MICROORGANISMS AND METHODS FOR ENHANCING THE AVAILABILITY OF REDUCING EQUIVALENTS IN THE PRESENCE OF METHANOL, AND FOR PRODUCING 1,4-BUTANEDIOL RELATED THERETO

Provided herein is a non-naturally occurring microbial organism having a methanol metabolic pathway that can enhance the availability of reducing equivalents in the presence of methanol. Such reducing equivalents can be used to increase the product yield of organic compounds produced by the microbial organism, such as 1,4-butanediol (BDO). Also provided herein are methods for using such an organism to produce BDO. 167-. (canceled)68. A method of producing an intermediate of a metabolic pathway that can be used in the formation of biomass , comprising culturing a non-naturally occurring microbial organism under conditions and for a sufficient period of time to produce the intermediate , (i) a methanol methyltransferase and a methylenetetrahydrofolate reductase;', '(ii) a methanol dehydrogenase; or', '(iii) a methanol dehydrogenase and a formaldehyde activating enzyme; and, 'wherein the non-naturally occurring microbial organism has a methanol metabolic pathway and comprises at least one exogenous nucleic acid encoding a methanol metabolic pathway enzyme expressed in a sufficient amount to enhance the availability of reducing equivalents in the presence of methanol, wherein said methanol metabolic pathway compriseswherein the non-naturally occurring microbial organism has a formaldehyde assimilation pathway and comprises at least one exogenous nucleic acid encoding a formaldehyde assimilation pathway enzyme expressed in a sufficient amount to produce an intermediate of a metabolic pathway that can be used in the formation of biomass.69. The method of claim 68 , wherein the formaldehyde assimilation pathway comprises(i) a hexulose-6-phosphate synthase and a 6-phospho-3-hexuloisomerase; or(ii) a dihydroxyacetone synthase and a dihydroxyacetone kinase.70. The method of claim 68 , wherein the intermediate of a metabolic pathway is:(i) a hexulose-6-phosphate, a fructose-6-phosphate, or a combination thereof; or(ii) a dihydroxyacetone, a dihydroxyacetone phosphate, or a ...

FARNESOID X RECEPTOR AGONISTS AND USES THEREOF

Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity. 1131-. (canceled)134. The compound of claim 132 , or a pharmaceutically acceptable salt or solvate thereof claim 132 , wherein:ring B is phenyl; orring B is monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.136. The compound of claim 134 , or a pharmaceutically acceptable salt or solvate thereof claim 134 , wherein:ring D is phenyl; orring D is monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; or{'sub': 2', '8, 'ring D is a monocyclic heterocycle that is a monocyclic C-Cheterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidine-2,5-dionyl, piperidinyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl.'}138. The compound of claim 136 , or a pharmaceutically acceptable salt or solvate thereof claim 136 , wherein:{'sup': 3', '10, 'Lis absent, —O—, —S—, —CH═CH—, —C≡C—, or —NR—.'}139. The compound of claim 132 , or a pharmaceutically acceptable salt or solvate thereof claim 132 , wherein:{'sub': 3', '8, 'ring A is C-Ccycloalkyl'}140. The compound of claim 132 , or a pharmaceutically acceptable salt or solvate thereof claim 132 , wherein:{'sub': 2', '8, 'ring A is C-Cheterocycloalkyl.'}141. The compound of claim 140 , or a pharmaceutically acceptable salt or solvate thereof claim 140 , wherein:{'sub': 2', '8', '5', '8', '5', '8', '5', '8', '5', '8, 'ring A is a monocyclic C-Cheterocycloalkyl or a bicyclic C-Cheterocycloalkyl ...

PHENYL DERIVATIVE

An object of the present invention is to provide a compound having strong human S1Pantagonistic activity in order to develop a useful medicament for therapy of a S1P-mediated disease such as a disease resulting from vascular constriction, fibrosis and respiratory disease. The compound represented by the general formula (I), wherein all the symbols have the same meanings as described in the specification, has a halogen atom or a haloalkyl group and a phenoxy group at certain substitution sites, and thus has strong human S1Pantagonistic activity. Therefore, the compound can be a therapeutic agent for a S1P-mediated disease, such as a disease resulting from vascular constriction, fibrosis and respiratory disease. 2. The compound according to claim 1 , wherein Ris (1) a C1-8 alkyl group which may be substituted with 1 to 5 Rgroups claim 1 , or (2) a C3-7 carbocycle which may be substituted with 1 to 5 substituents selected from the group consisting of a C1-4 alkyl group claim 1 , a C1-4 haloalkyl group claim 1 , a C1-4 alkoxy group and a halogen atom.3. The compound according to or claim 1 , wherein Mis (1) —O— or (2) —C(O)O—.5. The compound according to claim 4 , wherein Ris a hydrogen atom.6. The compound according to or claim 4 , wherein the ring 1 is (1) a benzene claim 4 , (2) cyclohexane or (3) pyridine ring.7. The compound according to claim 4 , which is 2-{3-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(trifluoromethyl)phenoxy]phenyl}-2-methylpropanoic acid claim 4 , 4-cyclopentyl-4-hydroxy-N-[3-{4-[(methylsulphonyl)carbamoyl]phenoxy}-5-(trifluoromethyl)phenyl]-1-piperidine carboxamide claim 4 , 4-cyclopentyl-N-[3-{4-[(ethylsulphonyl)carbamoyl]phenoxy}-5-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidine carboxamide claim 4 , 1-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(trifluoromethyl)phenoxy]phenyl}cyclopropanecarboxylic acid claim 4 , 2-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(trifluoromethyl) ...

Opsin-Binding Ligands, Compositions and Methods of Use

Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described. 3. The compound of claim 2 , wherein Rand Rare each independently hydrogen or methyl.4. The compound of claim 2 , wherein Rand Rare each independently hydrogen or lower alkyl.6. The compound of claim 5 , wherein a and b are each 1 claim 5 , X is hydrogen claim 5 , Y is C—C(O)NRRor N—C(O)NRRwherein R claim 5 , Rand Rare all hydrogen.7. The compound of claim 1 , wherein X is H claim 1 , lower alkyl or —C≡CR.8. The compound of claim 1 , wherein Y is O or N—C(O)—NRR.920-. (canceled)21. A method of reducing or inhibiting mislocalization of an opsin protein claim 1 , comprising contacting an opsin protein with a compound of .22. The method of claim 21 , wherein said opsin protein is pressent in a rod cell or a cone cell.23. (canceled)24. The method of claim 22 , wherein said cell is present in a mammalian eye.25. A method of inhibiting the formation or accumulation of a visual cycle product claim 1 , comprising contacting an opsin protein with a compound of .26. The method of claim 25 , wherein said visual cycle product is lipofuscin or N-retinylidene-N-retinylethanolamine (A2E).27. A method of treating or preventing an ophthalmic condition in a subject at risk thereof claim 1 , comprising administering to the subject an effective amount of a compound of .28. The method of claim 27 , wherein said ophthalmic condition is an ocular protein mislocalization disorder.29. The method of claim 27 , wherein said ophthalmic condition is selected from the group consisting of wet or dry age related macular degeneration (ARMD) claim 27 , retinitis pigmentosa ...

NOVEL LOW MOLECULAR WEIGHT CYCLIC AMINE CONTAINING CATIONIC LIPIDS FOR OLIGONUCLEOTIDE DELIVERY

The instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver. The present invention employs low molecular weight cationic lipids comprising at least one short lipid chain to enhance the efficiency and tolerability of in vivo delivery of siRNA. 2. A lipid nanoparticle comprising a cationic lipid according to .3. The lipid nanoparticle according to further comprises an oligonucleotide.4. The lipid nanoparticle according to wherein the oligonucleotide is siRNA or miRNA.5. The lipid nanoparticle according to wherein the oligonucleotide is siRNA. This application is a Continuation of U.S. patent application Ser. No. 14/719,513 filed, May 22, 2015, which is a Continuation of U.S. patent application Ser. No. 13/883,487 filed May 3, 2013, now U.S. Pat. No. 9,0678,82 issued Jun. 30, 2015, which is 371 National Phase Entry of International Patent Application No. PCT/US2011/058498 filed on Oct. 31, 2011, which claims benefit under 35 U.S.C. § 119(e) of the U.S. Provisional Application No. 61/410,472, filed Nov. 5, 2010, the contents of each of which are incorporated herein by reference in their entirety.The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 26, 2017 is named MRLMIS00047WOPCTSEQ.txt and is 3,671 bytes.The present invention relates to novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides, to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in ...

Necrosis Inhibitors

The invention provides amides that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition. 2. The compound of claim 1 , wherein:{'sub': '1', 'Ris substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole;'}{'sub': '2', 'Ris substituted or unsubstituted: aziridine, azetidine, pyrrolidine, piperidine, oxazolidine, oxazinane; diazolidine, diazinane, pyrrole, dihydropyrrole, dihydropyridine, or tetrahydropyridine; and'}{'sub': '3', 'Ris 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or'}a corresponding sulfonamide of the amide compound, ora pharmaceutically acceptable salt, hydrate or stereoisomer of the compound or corresponding sulfonamide.3. The compound of claim 1 , wherein:{'sub': '1', 'Ris substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole;'}{'sub': '2', 'Ris substituted or unsubstituted: azetidine, pyrrolidine, piperidine, oxazolidine, diazolidine, or diazinane; and'}{'sub': '3', 'Ris 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or'}a corresponding sulfonamide of the amide compound, ora pharmaceutically acceptable salt, hydrate or stereoisomer of the compound or corresponding sulfonamide.4. The compound of claim 1 , wherein:{'sub': '1', 'Ris substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole;'}{'sub': '2', 'Ris substituted or unsubstituted: azetidine or pyrrolidine; and'}{'sub': '3', 'Ris 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop- ...

PRODRUGS OF GAMMA-HYDROXYBUTYRIC ACID, COMPOSITIONS AND USES THEREOF

The present disclosure discloses prodrugs of gamma-hydroxybutyric acid as well as compositions and uses thereof. 2. The composition of claim 1 , wherein the composition is a solid.3. The composition of claim 1 , wherein the composition further comprises a solvent for dissolving or dispersing the compound.4. The composition of claim 3 , wherein the solvent comprises water.5. The composition of claim 1 , wherein the composition is in a liquid dosage form.6. The composition of claim 1 , wherein the composition further comprises a flavoring agent claim 1 , sucrose claim 1 , lactose claim 1 , cellulose sugar claim 1 , mannitol claim 1 , maltitol claim 1 , dextran claim 1 , sorbitol claim 1 , starch claim 1 , agar claim 1 , alginates claim 1 , chitins claim 1 , chitosans claim 1 , pectins claim 1 , tragacanth gum claim 1 , gum arabic claim 1 , gelatins claim 1 , collagens claim 1 , casein claim 1 , albumin claim 1 , synthetic or semi-synthetic polymers or glycerides claim 1 , methyl cellulose claim 1 , hydroxypropylmethyl-cellulose claim 1 , or polyvinylpyrrolidone.7. The composition of claim 1 , wherein the composition further comprises a polymeric excipient.8. The composition of claim 1 , wherein the composition comprises a tablet claim 1 , a caplet claim 1 , a capsule claim 1 , a gel cap claim 1 , granules claim 1 , a pill claim 1 , a powder claim 1 , a lozenge claim 1 , a sachet claim 1 , a cachet claim 1 , a suspension claim 1 , an emulsion claim 1 , a solution claim 1 , a slurry claim 1 , or a syrup.9. The composition of claim 1 , wherein the composition is formulated in a unit dosage form.10. The composition of claim 9 , wherein the unit dosage form has a weight from 0.5 grams to 30 grams.11. The composition of claim 10 , wherein the composition is in a liquid dosage form.12. The composition of claim 11 , further comprising a pH adjusting agent selected from sodium hydroxide claim 11 , hydrochloric acid claim 11 , or malic acid.13. The composition of claim 1 , ...

NOVEL CITRIC ACID DERIVATIVE

Compounds (citric acid derivatives) represented by formulas (1) and (2) below are novel compounds having an inhibitory effect against liver disorder and can be used as liver disorder inhibitors and food additives (wherein Rrepresents a C1 to C3 alkyl group optionally having a carboxyl group or a hydroxyl group, and Rrepresents a hydrogen atom, or Rand Roptionally form a cyclic structure together to represent a C2 to C3 alkylene chain). 4. The method for inhibiting liver disorder according to claim 3 , wherein the liver disorder is nonalcoholic steatohepatitis (NASH).6. The method according to claim 3 , wherein the compound represented by formula (1) is allowed to react in an aqueous solution having a pH of 6.0 to 12.0 to which the alkaline substance for generating hydroxide ions is added claim 3 , at 80 to 130° C. for 20 minutes to 240 minutes. This application is a divisional of U.S. application Ser. No. 15/770,300 filed Apr. 23, 2018, which is a U.S. National Phase of PCT/JP2016/004789, filed on Nov. 1, 2016, which claims priority to Japanese Application No. 2015-216000, filed Nov. 2, 2015. The disclosure of each of these applications is herein incorporated by reference in its entirety.The present invention relates to a novel citric acid derivative, and more specifically, to a citric acid derivative having an inhibitory effect against liver disorder.Ume (Japanese apricot) () belongs to the subgenus of the genus of the subfamily Amygdaloideae of the family Rosaceae and is eaten in the form of processed products of ume such as pickled ume, ume wine, and ume extract (ume flesh extract). Further, ume extract has advantageous effects such as sterilization, treatment from fatigue, and stomach protection action, and thus ume extract has been taken for health. Further, ume extract is known to have an effect of improving bloodstream (see Non-patent Documents 1 and 2). It is known that the effect of improving bloodstream is derived from Mumefural which is produced by ...

PHENYL DERIVATIVE

The compound of the formula (I-1): 1. A method of preventing and/or treating a S1P2-mediated disease , comprising administering to a mammal an effective amount of 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid , or a salt thereof.2. The method according to claim 1 , wherein the S1P2-mediated disease is a disease resulting from vascular constriction claim 1 , fibrosis claim 1 , peripheral arterial occlusive disease claim 1 , hepatitis claim 1 , hepatic cirrhosis claim 1 , or hepatic failure.3. The method according to claim 2 , wherein the disease resulting from vascular constriction is cerebral vasospastic disease claim 2 , cardiac vasospastic disease claim 2 , coronary vasospastic disease claim 2 , hypertension claim 2 , pulmonary hypertension claim 2 , myocardial infarction claim 2 , angina claim 2 , arrhythmia claim 2 , portal hypertension claim 2 , varix claim 2 , or ischemia-reperfusion injury.4. The method according to claim 2 , wherein the fibrosis is pulmonary fibrosis claim 2 , hepatic fibrosis claim 2 , kidney fibrosis claim 2 , myocardial fibrosis claim 2 , or skin fibrosis. This is a Divisional of U.S. patent application Ser. No. 15/089,690 filed Apr. 4, 2016 (allowed), which is a Divisional of U.S. patent application Ser. No. 14/592,100 filed Jan. 8, 2015 (issued as U.S. Pat. No. 9,340,499 on May 17, 2016), which is a Continuation of U.S. application Ser. No. 14/347,178 filed Mar. 25, 2014 (issued as U.S. Pat. No. 8,975,409 on Mar. 10, 2015), which is a National Stage Entry of PCT International Application No. PCT/JP2012/074968 filed Sep. 27, 2012, which claims benefit of Japanese Patent Application No. 2011-213987 filed Sep. 29, 2011 of which disclosures are incorporated herein by reference in their entirety.The present invention relates to a compound represented by the formula (I-1):wherein all the symbols have the same meanings as described hereinbelow, and a salt thereof, a ...

SEROTONIN RECEPTOR MODULATORS

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases. 2. A compound as defined in claim 1 , wherein Ris —H claim 1 , —CH claim 1 , —CHCH claim 1 , —CHCHCH claim 1 , —CH(CH) claim 1 , —C(CH) claim 1 , cyclopropyl claim 1 , cyclobutyl claim 1 , or benzyl.3. A compound as defined in claim 2 , wherein Ris —H.4. (canceled)5. (canceled)6. (canceled)7. (canceled)8. A compound as defined in claim 1 , wherein Ris —H or —CH.9. A compound as defined in claim 1 , wherein Ris —H or —CH.10. A compound as defined in claim 1 , wherein Rand Rare each —H.11. A compound as defined in claim 1 , wherein Ris —H.12. A compound as defined in claim 1 , wherein L is —O— claim 1 , —CH— claim 1 , —OCH— claim 1 , —OCH(CH)— claim 1 , —CHO— claim 1 , —CHF— claim 1 , or —CF—.13. A compound as defined in claim 1 , wherein L is —O—.15. A compound as defined in claim 1 , wherein Z is —O— claim 1 , —OCH— claim 1 , —OCHCH— claim 1 , or —OCH(CH)—.16. A compound as defined in claim 1 , wherein Ris phenyl claim 1 , optionally substituted with halo claim 1 , —OCH claim 1 , —OSOCH claim 1 , CF claim 1 ,17. A compound as defined in claim 1 , wherein Ris cyclohexyl claim 1 , 2-indanyl claim 1 , or furanyl optionally substituted with one or more substituents individually selected from halo claim 1 , —CH claim 1 , —CF claim 1 , —OCF claim 1 , or —CN.19. A compound as defined in claim 1 , wherein Rand Rare each independently —H claim 1 , halo claim 1 , —CF claim 1 , thiophene-3-yl claim 1 , or N claim 1 ,N-dimethyl-formamidyl.20. A compound as defined in claim 1 , wherein Ris —H or halo.21. A compound as defined in claim 1 , wherein Ris —H or halo and Ris —H claim 1 , halo claim 1 , —CF claim 1 , thiophene-3-yl claim 1 , or N claim 1 ,N-dimethyl-formamidyl.22. (canceled)23. (canceled)27. A pharmaceutical composition according to claim 25 , further comprising: an active ingredient selected from the group consisting of an additional active ingredient selected ...

PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis. 2. The method of claim 1 , wherein the glycopyrrolate base contacted with methyl tosylate is contacted with an organic solvent.3. The method of claim 2 , wherein the organic solvent is acetone or ethyl acetate.4. The method of claim 1 , wherein the glycopyrronium tosylate is purified by one or more crystallizations in an aqueous solvent.5. The method of claim 4 , wherein the purified glycopyrronium tosylate is in the form of glycopyrronium tosylate monohydrate.6. The method of claim 4 , wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate claim 4 , and the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate in the mixture.7. The method of claim 6 , wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate in the mixture.8. The method of claim 6 , wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.10. The method of claim 9 , wherein the glycopyrrolate base claim 9 , 5-nitroisophthalate salt and inorganic base are contacted with an organic solvent.11. The method of claim 10 , wherein the organic solvent is toluene.12. The method of claim 9 , wherein the inorganic base is aqueous ...

Novel compounds

The present invention relates to substituted N-biphenyl-3-acetylamino-benzamides and N-[3-(acetylamino)phenyl]-biphenyl-carboxamides of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative disorder, as a sole agent or in combination with other active ingredients.

SUBSTITUTED BENZAMIDES

The invention relates to compounds of formula 2. The compound of claim 1 , wherein X is NR′ and R′ is hydrogen.3. The compound of claim 2 , selected from the group consisting of(RS)-1-(4-Butyl-2-methyl-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;1-(3,4-Dichloro-phenyl)-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea;(RS)-1-(3,4-Dichloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(4-Chloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-Phenyl-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(2,4-Dichloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(3-Chloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(4-Pyrrolidin-3-yl-phenyl)-3-(4-trifluoromethyl-phenyl)-urea;(RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(6-Chlor-pyridin-3-yl)-3-(4-piperidin-3-yl-phenyl)-urea;(RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-piperidin-3-yl-phenyl)-urea; and(RS)-1-(5-Chloro-pyridin-2-yl)-3-[4-(2-pyrrolidin-3-yl-ethyl)-phenyl]-urea.4. The compound of claim 2 , selected form the group consisting of(RS)-1-(4-Chloro-phenyl)-3-[4-(2-pyrrolidin-3-yl-ethyl)-phenyl]-urea;(RS)-1-(4-Chloro-phenyl)-3-[4 (2-piperidin-3-yl-ethyl)-phenyl]-urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;(RS)-1-(4-Chiorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-p-tolylurea;(RS)-1-(6-Chloropyridin-3-yl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(3-Chlorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-m-tolylurea;(RS)-1-(2-Chlorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-Methylbenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;(R)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea; and(S)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.5. The compound of claim 1 , wherein X is a bond.6. The compound of claim 5 , selected from the group consisting of(RS)—N-(4-Pyrrolidin-3-yl-phenyl)-benzamide;(RS)-4-Chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide;(RS)—N-(4-Pyrrolidin-3-yl-phenyl)-4- ...

2-Methylthiopyrrolidines and Their Use for Modulating Bacterial Quorum Sensing

Compounds of Formula (I) are disclosed herein and their use in inhibiting quorum sensing in bacteria. 2. The compound of claim 1 , wherein Ris OH and Ris H.3. The compound of claim 1 , wherein Rand Rtogether are oxo.43. The compound of any one of - claims 1 , wherein at least one of Rand Ris OH.5. The compound of claim 4 , wherein both Rand Rare OH.63. The compound of any one of - claims 1 , wherein both Rand Rare H.76. The compound of any one of - claims 1 , wherein X is S.86. The compound of any one of - claims 1 , wherein X is NR.9. The compound of claim 8 , wherein Ris H.10. The compound of claim 8 , wherein Ris C(O)alkyl.1110. The compound of any one of - claims 1 , wherein Ris C-Calkyl.1210. The compound of any one of - claims 1 , wherein Ris C-CalkyleneCOH.1310. The compound of any one of - claims 1 , wherein Ris C-CalkyleneCO—C-Calkyl.1410. The compound of any one of - claims 1 , wherein Ris C-CalkyleneCO-amino.1615. A pharmaceutical composition comprising the compound of any one of - and a pharmaceutically acceptable excipient.1715. A method of inhibiting bacterial quorum sensing comprising contacting bacteria with the compound of any one of - or the composition of .18Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas salmonicida, Agrobacterium tumefaciens, Brucella melitensis, Burkholderia cenocepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia vietnamiensis, Chromobacterium violaceum, Enterobacter agglomeran, Erwinia carotovora, Erwinia chrysanthemi, Escherichia coli, Nitrosomas europaea, Obesumbacterium proteus, Pantoea agglomerans, Pantoea stewartii, Pseudomonas aureofaciens, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas fuscovaginae, Pseudomonas syringae, Ralstonia solanacearum, Rhizobium etli, Rhizobium leguminosarum, Rhodobacter sphaeroides, Serratia liquefaciens, Serratia marcescens, Vibrio anguillarum, Vibrio fischeri, Vibrio parahaemolyticus, Vibrio salmonicida, Xanthomonas campestris, Xenorhabdus ...

Novel Substituted 6,7-Dihydro-5H-Benzo[7]Annulene Compounds, Processes for their Preparation and Therapeutic Uses Thereof

Compounds of formula (I): 2. The compound of formula (I) according to claim 1 , wherein R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C-C)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a —OH group; a (C-C)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C-C)-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C-C)-alkyl group wherein said (C-C)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C-C)-alkyl groups; an amine group unsubstituted or substituted with one or more (C-C)-alkyl groups; an amide group unsubstituted or substituted with one or more (C-C)-alkyl groups; a heterocycloalkyl group saturated or partially saturated claim 1 , comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen claim 1 , nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen claim 1 , nitrogen and sulphur and being unsubstituted or substituted with an oxo group;or a pharmaceutically acceptable salt thereof.3. The compound of formula (I) according to claim 1 , wherein R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from: a methyl group; an ethyl group; an isopropyl group; a tert-butyl group; a —CHFgroup; a —CFgroup; a —CFCHgroup; a chlorine atom; a fluorine atom; a —OH group; a —OCHgroup; a —OCHCHgroup; a —OCHCHF group; a —OCHFgroup; a —OCHCFgroup; a —OCFgroup; a —OCHCFgroup; a cyano group; a —SCHF2 group; a —SCFgroup; a —SFgroup; a —SOCHgroup; a —SOCFgroup; a —Si(CH)group; an oxetane group; a piperidine group; a morpholine group; a pyrrolidine group; and a triazolone group;or a pharmaceutically acceptable salt thereof.4. The compound of ...

PROCESS FOR PREPARING BETA 3 AGONISTS AND INTERMEDIATES

The application is directed to efficient and economical processes as described in more detail below for the preparation of the beta 3 agonists of the formula of I-7 and intermediate compounds that can be used for making these agonists. The present disclosure relates to a process for making beta-3 agonists and intermediates using ketoreductase (KRED) biocatalyst enzymes and methods of using the biocatalysts. 118.-. (canceled)20. The process of claim 19 , wherein Catalyst D in step (a) is selected from the group consisting of Pd(PPh) claim 19 , PdCl claim 19 , (PPh)PdCl claim 19 , Pd(dppe)Cl claim 19 , Pd(dppp)Cl claim 19 , Pd(dppf)Cl claim 19 , and Pd(OAc)/PhP claim 19 , in the presence or absence of a catalytic amount of material selected from the group consisting of CuI claim 19 , CuBr claim 19 , and CuCl.21. The process of claim 19 , wherein the reaction in step (a) is carried out in the presence of a solvent selected from the group consisting of THF claim 19 , IPA claim 19 , MeOH claim 19 , EtOH claim 19 , n-PrOH claim 19 , NMP claim 19 , DMAc claim 19 , MTBE claim 19 , CHCl claim 19 , MeCN claim 19 , Me-THF claim 19 , methyl cyclopentyl ether claim 19 , toluene claim 19 , and combinations thereof.22. The process of claim 19 , wherein the reaction product in step (a) is isolated as an HCl salt.23. The process of claim 19 , wherein step (b) is conducted in the presence of a base selected from the group consisting of EtN claim 19 , i-PrNEt claim 19 , i-PrNH claim 19 , pyridine claim 19 , lutidine claim 19 , N-methyl morpholine claim 19 , t-BuOK claim 19 , t-BuONa claim 19 , t-BuOLi claim 19 , NaH claim 19 , NaHMDS claim 19 , LiHMDS claim 19 , and KHMDS.24. The process of claim 19 , wherein Compound I-6-1 is not isolated.25. The process of claim 19 , wherein step (c) is conducted in the presence of hydrogen gas.26. The process of claim 19 , wherein Catalyst E in step (c) is selected from the group consisting of Pt/AlO claim 19 , Pd/AlO claim 19 , Rh/AlO claim 19 , ...

LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS

Disclosed herein are compounds of formula (I) 3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein:{'sup': '2', 'Lis a bond;'}{'sup': 4', '2', '3, 'Lis —C(R)═C(R)—;'}{'sup': 2', '3, 'Rand Rare each hydrogen;'}{'sup': 4', '5, 'sub': 1', '4, 'Rand Rare independently H or C-Calkyl;'}{'sup': '3', 'sub': 2', '6', '2', '6, 'Lis C-Calkynylene; wherein the C-Calkynylene is optionally substituted with 1, 2, 3, or 4 fluoro substituents; and'}{'sup': '6', 'sub': 1', '10', '1', '4', '1', '3', '1', '3', '1', '3', '1', '3', '1', '3, 'Ris aryl or C-Calkyl, wherein the aryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C-Calkyl, C-Chaloalkyl, cyano, halogen, C-Calkoxy, C-Chaloalkoxy; and —C-Calkylene-C-Calkoxy.'}8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein:{'sup': '3', 'sub': '2', 'Lis —CH—C≡C—; and'}s is 1.9. The compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein:{'sup': '3', 'Lis —C≡C—; and'}s is 0.10. The compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein:{'sup': '1', 'sub': 3', '7', '3', '7, 'Lis C-Calkylene, wherein the C-Calkylene is optionally substituted with 1, 2, 3, or 4 fluoro substituents.'}12. The compound of claim 8 , or a pharmaceutically acceptable salt thereof claim 8 , wherein:{'sup': '1', 'sub': 3', '7', '3', '7, 'Lis C-Calkylene, wherein the C-Calkylene is optionally substituted with 1, 2, 3, or 4 fluoro substituents.'}14. The compound of claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , wherein:{'sup': '1', 'sub': 3', '7', '3', '7, 'Lis C-Calkylene, wherein the C-Calkylene is optionally substituted with 1, 2, 3, or 4 fluoro substituents.'}16. The compound of claim 7 , or a pharmaceutically acceptable salt thereof claim 7 , wherein:{'sup': '3', 'sub': '2', 'Lis —CH—C≡C—; and'}s is 1.17. The compound of claim 7 , or a pharmaceutically ...

COMPOUNDS USEFUL AS IMMUNOMODULATORS

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases. 2. A compound of wherein Ris hydrogen.3. A compound of wherein Rand Rare selected from —CHand halo.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein:{'sup': 2', '3', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', '1', '3', '3', '6', '2', 'm', '2', '2, 'one of Rand Ris hydrogen and the other is selected from —O(CH)Ph, —(CH)OPh, —O(CH)NRR, —S(O)NH(CH)NRR, —S(O)NH(CH)COH, —O(CH)pyridinyl, —(CH)NH(CH)NRR, —C(O)NH(CH)NRR, —NHC(O)(CH)NRR, —NHC(O)NH(CH)NRR; and —NHC(O)NH(CH)COH; wherein each piperidinyl group is optionally substituted with a C-Calkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C-Calkoxy, C-Calkyl, C-Calkylcarbonyl, amino, carboxy, (C-Ccycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, —CHO, —C(O)NRR, —(CH)NRR, —OCHphenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCHpyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; and'}{'sup': 6', '7', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', ...

3-PHENYL-3-METHOXY-PYRROLIDINE DERIVATIVES USEFUL AS MODULATORS OF CORTICAL CATECHOLAMINERGIC NEUROTRANSMISSION

The present invention relates to novel 3-phenyl-3-methoxy-pyrrolidine derivatives, useful for modulating extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders. In other aspects the invention relates to pharmaceutical compositions comprising the 3-phenyl-3-methoxy-pyrrolidine derivatives of the invention and to the use of these compounds for therapeutic applications. 1. A 3-phenyl-3-methoxy-pyrrolidine derivative which is (+)-3-(2 ,3-difluorophenyl)-3-methoxypyrrolidine , any of its stereoisomers or any mixture of its stereoisomers , or an N-oxide thereof , or a deuterated analog thereof , or a pharmaceutically acceptable salt thereof.2. (+)-3-(2 ,3-Difluorophenyl)-3-methoxypyrrolidine. The present application is a 37 C.F.R. §1.53(b) continuation of U.S. application Ser. No. 13/130,438 filed Jul. 11, 2011, which is the National Phase of PCT/EP2009/065676 filed on Nov. 24, 2009, which claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/117,822 filed on Nov. 25, 2008, and under U.S.C. 119(a) to Patent Application No. PA 2008 01657 filed in Denmark on Nov. 24, 2008, all of which are hereby expressly incorporated by reference into the present application.The present invention relates to novel 3-phenyl-3-methoxy-pyrrolidine derivatives, useful for modulating extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders.In other aspects the invention relates to pharmaceutical compositions comprising the 3-phenyl-3-methoxy-pyrrolidine derivatives of the invention and to the use of these compounds for therapeutic applications.The cerebral cortex encompasses several major regions that are involved in higher functions such as thought, feelings, memory and planning. Biogenic amines ...

SUBSTITUTED BENZAMIDES

The invention relates to compounds of formula 132-. (canceled)34. The method according to claim 33 , wherein X is NR′ and R′ is hydrogen.35. The method according to claim 33 , wherein X is a bond.36. The method according to claim 33 , wherein X is —(CH)—O—.37. The method according to claim 33 , wherein X is —O(CHR″)—.38. The method according to claim 33 , wherein X is —CHR″—.39. The method according to claim 33 , wherein X is —CHCH—.40. The method according to claim 33 , wherein said compound is selected from the group consisting of:(RS)-1-(4-Butyl-2-methyl-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;1-(3,4-Dichloro-phenyl)-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea;(RS)-1-(3,4-Dichloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(4-Chloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-Phenyl-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(2,4-Dichloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(3-Chloro-phenyl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(4-Pyrrolidin-3-yl-phenyl)-3-(4-trifluoromethyl-phenyl)-urea;(RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-urea;(RS)-1-(6-Chloro-pyridin-3-yl)-3-(4-piperidin-3-yl-phenyl)-urea;(RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-piperidin-3-yl-phenyl)-urea;(RS)-1-(5-Chloro-pyridin-2-yl)-3-[4-(2-pyrrolidin-3-yl-ethyl)-phenyl]-urea;(RS)-1-(4-Chloro-phenyl)-3-[4-(2-pyrrolidin-3-yl-ethyl)-phenyl]-urea;(RS)-1-(4-Chloro-phenyl)-3-[4-(2-piperidin-3-yl-ethyl)-phenyl]-urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;(RS)-1-(4-Chlorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-p-tolylurea;(RS)-1-(6-Chloropyridin-3-yl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(3-Chlorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-(Morpholin-2-yl)phenyl)-3-m-tolylurea;(RS)-1-(2-Chlorophenyl)-3-(4-(morpholin-2-yl)phenyl)urea;(RS)-1-(4-Methylbenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;(R)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;(S)-1-(4-(Morpholin-2-yl)phenyl)-3-(4-( ...

C7-fluoro substituted tetracycline compounds

The present invention is directed to a compound represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

METAL OXIDE-ORGANIC HYBRID MATERIALS FOR HETEROGENEOUS CATALYSIS AND METHODS OF MAKING AND USING THEREOF

Catalysts prepared from abundant, cost effective metals, such as cobalt, nickel, chromium, manganese, iron, and copper, and containing one or more neutrally charged ligands (e.g., monodentate, bidentate, and/or polydentate ligands) and methods of making and using thereof are described herein. Exemplary ligands include, but are not limited to, phosphine ligands, nitrogen-based ligands, sulfur-based ligands, and/or arsenic-based ligands. In some embodiments, the catalyst is a cobalt-based catalyst or a nickel-based catalyst. The catalysts described herein are stable and active at neutral pH and in a wide range of buffers that are both weak and strong proton acceptors. While its activity is slightly lower than state of the art cobalt-based water oxidation catalysts under some conditions, it is capable of sustaining electrolysis at high applied potentials without a significant degradation in catalytic current. This enhanced robustness gives it an advantage in industrial and large-scale water electrolysis schemes. 1. A heterogeneous catalyst having the chemical formula{'br': None, 'sub': a', 'b', 'c', 'd', '2', 'e, 'MY(CO)O(OH)(HO)'} M is a d-block transition metal;', 'Y is a monodentate ligand, bidentate ligand, polydentate ligand, or combinations thereof;', 'a is any value from about 0 to about 3;', 'b is any value from about 0 to about 3;', 'c is any value from about 1 to about 4; and', 'd is any value from about 0 to about 4; and', 'e is any value from about 0 to about 6., 'wherein'}2. The catalyst of claim 1 , wherein M is selected from the group consisting of Cr claim 1 , Mn claim 1 , Fe claim 1 , Co claim 1 , Ni claim 1 , Cu claim 1 , Rh claim 1 , Ir claim 1 , or combinations thereof.3. The catalyst of claim 1 , wherein M is cobalt.4. The catalyst of claim 1 , wherein M is nickel.5. The catalyst of claim 1 , wherein the M is chromium.6. The catalyst of claim 1 , wherein the M is copper.7. The catalyst claim 1 , wherein the M is iron.8. The catalyst of claim 1 , ...

FARNESOID X RECEPTOR AGONISTS AND USES THEREOF

Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity. 4. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:ring B is phenyl.5. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:ring B is monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.7. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:ring D is phenyl.8. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:ring D is monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.11. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:{'sub': 2', '8, 'ring D is a monocyclic heterocycle that is a monocyclic C-Cheterocycloalkyl containing at least 1 N atom in the ring that is selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidine-2,5-dionyl, piperidinyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl.'}12. The compound of any one of - , or a pharmaceutically acceptable salt or solvate thereof , wherein:{'sup': 3', '2', '4', '4', '2, 'Lis —X-L- or -L-X—;'}{'sup': 2', '10', '10', '10', '10', '10, 'sub': 2', '2', '2', '2, 'Xis absent, —O—, —S—, —S(═O)—, —S(═O)—, —S(═O)NR—, —CH—, —CH═CH—, —C≡C—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NR—, —NRC(═O)—, —NRS(═O)—, or —NR—;'}{'sup': '4', 'sub': '2', 'Lis absent or —CH—.'}13. The compound of any one of - , or a pharmaceutically ...

Lipids and lipid compositions for the delivery of active agents

or a pharmaceutically acceptable salt thereof, wherein R1-R4, L1, n and p are defined herein. The compounds of formula (X) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.

FORMULATION FOR SOFT ANTICHOLINERGIC ANALOGS

Topical formulations comprising soft glycopyrrolates are useful for treating excessive sweating conditions in subjects, such as humans suffering from hyperhidrosis. Preferably, at least one soft anticholinergic agent is provided in an effective amount or concentration in an anhydrous formulation that can inhibit excessive perspiration resulting from a condition such as hyperhidrosis. 113.-. (canceled)15. The anhydrous topical gel composition of claim 14 , wherein said anhydrous topical gel composition comprises at least about 70% w/w anhydrous ethanol.16. The anhydrous topical gel composition of claim 14 , wherein said anhydrous topical gel composition comprises from about 70% to about 99.99% w/w anhydrous ethanol.17. The anhydrous topical gel composition of claim 14 , wherein said anhydrous topical gel composition comprises at least one additional carrier or excipient.18. The anhydrous topical gel composition of claim 14 , wherein the compound of formula (2) is selected from the group consisting of:(a) (2R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(b) (2R,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(c) (2R,1′R,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(d) (2R,1'S,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(e) (2R,1′R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(f) (2R,1'S,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(g) (2R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1-methoxycarbonylmethylpyrrolidinium bromide;(h) (2R, 3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1-methoxycarbonylmethylpyrrolidinium bromide;(i) (2R,1′R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1- ...

INHIBITORS OF INDOLEAMINE-2,3-DIOXYGENASE FOR THE TREATMENT OF CANCER

There are disclosed compounds of formula (I) that modulate or inhibit the enzymatic activity of indoleamine-2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention. 2. The compound of claim 1 , wherein Y and V are each CH.3. The compound of or claim 1 , wherein Ris —COOH.4. The compound of any one of the preceding claims claim 1 , wherein one of Rand Ris H and the other is optionally substituted C-Calkyl claim 1 , optionally substituted Ccycloalkyl claim 1 , optionally substituted heterocyclyl claim 1 , or optionally substituted aryl.5. The compound of any one of to claim 1 , wherein Rand Rare each independently optionally substituted C-Calkyl.6. The compound of any one of the preceding claims claim 1 , wherein Rand Rare each H.7. The compound of any one of the preceding claims claim 1 , wherein Ris optionally substituted heterocyclyl and Ris optionally substituted C-Calkyl.8. The compound of any one of to claim 1 , wherein Rand Rare taken together with the nitrogen to which they are attached to form a 4- to 8-membered optionally substituted heterocyclic ring containing 0-3 additional heteroatoms selected from —N— claim 1 , —S— and —O—.9. The compound of any one of the preceding claims claim 1 , wherein Ris optionally substituted aryl.10. The compound of any one of to claim 1 , wherein Ris optionally substituted heteroaryl.11. The compound of any one of to claim 1 , wherein Ris optionally substituted heterocyclyl.12. A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.13. A compound of any one of to for use in therapy.14. A method of treating cancer is a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound according to any one of to .15. The method ...

Novel substituted 6,7-dihydro-5h-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

Compounds of formula (I): wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a —COOH, a —OH or a —OPO(OH) 2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a —OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a —COOH, —OH or —OPO(OH) 2 group, then R5 represents a hydrogen atom; when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl and heterocycloalkyl group; and the preparation and the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in the treatment of cancer.

MONOCYCLIC COMPOUND

The present invention relates to a compound which may be useful as an agent for the prophylaxis or treatment of cancer, hepatitis, hepatic fibrosis, fatty liver and the like. 2. The compound or salt according to claim 1 , wherein{'sup': 3', '4, 'Rand Rare each independently a hydrogen atom or an optionally substituted hydroxy group;'}{'sup': 5', '6, 'Rand Rare both hydrogen atoms;'}{'sup': 7', '8, 'sub': '1-6', 'Rand Rare each independently a hydrogen atom or an optionally substituted Calkyl group;'}{'sup': 9', '10, 'Rand Rare both hydrogen atoms; and'}{'sup': '11', 'sub': '1-6', 'Ris a hydrogen atom or an optionally substituted Calkyl group; or'}{'sup': 8', '10', '8', '10, 'sub': '3-4', 'Rand Rin combination optionally form, together with the adjacent carbon atoms, an optionally further substituted Ccycloalkane, or Rand Rin combination optionally form a bond.'}3. The compound or salt according to claim 1 , wherein{'sup': '1', 'sub': '1-6', 'Ris a Calkyl group or an amino group;'}{'sup': '2', 'sub': '1-6', 'Ris a Calkyl group;'}{'sup': 3', '4, 'Rand Rare each independently a hydrogen atom or a hydroxy group;'}{'sup': 5', '6, 'Rand Rare both hydrogen atoms;'}{'sup': 7', '8, 'sub': '1-6', 'Rand Rare each independently a hydrogen atom or a Calkyl group;'}{'sup': 9', '10, 'Rand Rare both hydrogen atoms;'}{'sup': '11', 'sub': '1-6', 'Ris a hydrogen atom or a Calkyl group; or'}{'sup': 8', '10', '8', '10, 'sub': '3-4', 'Rand Rin combination optionally form, together with the adjacent carbon atoms, a Ccycloalkane, or Rand Rin combination optionally form a bond;'}{'sub': '1-6', 'Ring Q is a 5- or 6-membered ring optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a cyano group and (c) a Calkyl group;'} (a) a halogen atom,', '(b) an oxo group,', {'sub': '1-6', '(c) a Calkyl group, and'}, {'sub': 1-6', '3-10, '(d) a Calkoxy group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom and (ii) a Ccycloalkyl group ...

PYRROLIDINE GPR40 MODULATORS

The present invention provides compounds of Formula (I): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments. 4. A compound of Formula (I) or (II) according to claim 3 , or a stereoisomer claim 3 , a tautomer claim 3 , a pharmaceutically acceptable salt claim 3 , or a solvate thereof claim 3 , wherein:{'sup': 1', '6', '6, 'Ris independently phenyl substituted with 0-3 Ror a heteroaryl substituted with 0-2 R; wherein said heteroaryl is selected from: thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl.'}5. A compound of Formula (I) according to claim 1 , or a stereoisomer claim 1 , a tautomer claim 1 , a pharmaceutically acceptable salt claim 1 , or a solvate thereof claim 1 , wherein:{'sup': 1', '6', '6', '6', '6', '6, 'R, at each occurrence, is independently phenyl substituted with 0-3 R, pyridinyl substituted with 0-2 R, pyrazinyl substituted with 0-2 R, pyrimidinyl substituted with 0-2 R, or thiazolyl substituted with 0-2 R;'}{'sup': '2', 'sub': 1-6', '1-6, 'R, at each occurrence, is independently selected from: OH, halogen, Calkyl substituted with 0-1 CN, Calkoxy, benzyl, and tetrazolylmethyl;'}{'sup': '6', 'sub': 1-8', '1-4', '1-4', '1-4', '3-6', '1-4', '5-6', '1-4', '3-6, 'R, at each occurrence, is independently selected from: halogen, CN, Calkyl, Calkoxy, Chaloalkyl, Chaloalkoxy, Ccycloalkyl substituted with 0-2 Calkyl, Ccycloalkenyl substituted with 0-2 Calkyl, —O—Ccycloalkyl, benzyl, and oxazolyl; and'}{'sup': '10', 'sub': 1-4', '1-4', '1-4', '1-4', '2', '1-2, 'R, at each occurrence, is independently selected from: halogen, CN, Calkyl, Calkoxy, Chaloalkyl, Chaloalkoxy, and CO(Calkyl).'}6. A compound of Formula (I) according to claim 1 , or a stereoisomer claim 1 , a tautomer claim 1 , a pharmaceutically acceptable salt claim 1 , or a solvate thereof claim 1 , ...

FORMULATION FOR SOFT ANTICHOLINERGIC ANALOGS

Topical formulations comprising soft glycopyrrolates are useful for treating excessive sweating conditions in subjects, such as humans suffering from hyperhidrosis. Preferably, at least one soft anticholinergic agent is provided in an effective amount or concentration in an anhydrous formulation that can inhibit excessive perspiration resulting from a condition such as hyperhidrosis. 126.-. (canceled)28. The anhydrous topical gel composition of claim 27 , wherein said anhydrous topical gel composition further comprises at least one additional carrier or excipient.29. The anhydrous topical gel composition of claim 27 , wherein the compound of formula (2) is selected from the group consisting of:(i) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(ii) (2R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(iii) (2R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(iv) (2R,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(v) (2R,1′R,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(vi) (2R,1'S,3'S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(vii) (2R,1′R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and(viii) (2R,1'S,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide.30. The anhydrous topical gel composition of claim 27 , wherein the anhydrous topical gel composition comprises the compound of formula (2) at a concentration of from about 1% to about 20%.31. The anhydrous topical gel composition of claim 27 , wherein the anhydrous topical gel composition comprises the compound of formula (2) at a concentration of from about 2% to about 10%.32. ...

MICROORGANISMS AND METHODS FOR ENHANCING THE AVAILABILITY OF REDUCING EQUIVALENTS IN THE PRESENCE OF METHANOL, AND FOR PRODUCING 1.4-BUTANEDIOL RELATED THERETO

Provided herein is a non-naturally occurring microbial organism having a methanol metabolic pathway (MMP) that can enhance the availability of reducing equivalents in the presence of methanol. Such reducing equivalents can be used to increase the product yield of organic compounds produced by the microbial organism, such as 1,4-butanediol (BDO). Also provided herein are methods for using such an organism to produce BDO. 1. A non-naturally occurring microbial organism (NNOMO) having a methanol metabolic pathway (MMP) , wherein said organism comprises at least one exogenous nucleic acid encoding a MMP enzyme (MMPE) expressed in a sufficient amount to enhance the availability of reducing equivalents in the presence of methanol , wherein said MMP comprises:(i) a methanol dehydrogenase (EM9);(ii) an EM9 and a formaldehyde activating enzyme (EM10); or(iii) a methanol methyltransferase (EM1) and a methylenetetrahydrofolate reductase (EM2).2. The organism of claim 1 , wherein: (i) (a) an EM9, a methylenetetrahydrofolate dehydrogenase (EM3), a methenyltetrahydrofolate cyclohydrolase (EM4) and a formyltetrahydrofolate deformylase (EM5); (b) an EM9, an EM3, an EM4 and a formyltetrahydrofolate synthetase (EM6); (c) an EM9 and a formaldehyde dehydrogenase (EM11); (d) an EM9, a S-(hydroxymethyl)glutathione synthase (EM12), a glutathione-dependent formaldehyde dehydrogenase (EM13) and a S-formylglutathione hydrolase (EM14); or (e) an EM9, an EM13 and an EM14;', '(ii) (a) an EM9, an EM10, an EM3, an EM4 and an EM5; or (b) an EM9, an EM10, an EM3, an EM4 and an EM6; or', '(iii) (a) an EM1, an EM2, an EM3, an EM4, and an EM5; or (b) an EM1, an EM2, an EM3, an EM4 and an EM6;, '(a) the MMP compriseswherein the MMP optionally further comprises a formate dehydrogenase (EM8), a formate hydrogen lyase (EM15) or a hydrogenase (EM16); and/orwherein said organism optionally comprises two, three, four, five, six or seven exogenous nucleic acids, each encoding a MMPE.3. The organism of or ...

EBNA1 INHIBITORS AND THEIR METHOD OF USE

Pharmaceutical compositions of the invention comprise EBNA1 inhibitors useful for the treatment of diseases caused by EBNA1 activity such as cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by lytic Epstein-Barr Virus (EBV) infection. 4. The method of claim 1 , wherein the compound is at least one selected from the group consisting of:3-{2-[3-(methylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid;3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoic acid;3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;3-{2-[2-( ...

ANTIBACTERIAL AGENTS

Antibacterial compounds of formula (I) are provided: 2. A compound of wherein G is selected from the group consisting of:(1) —C≡C—,(2) —C≡C—C≡C—,{'sup': 3G', '3G, '(3) —CR═CR—C≡C—, and'}{'sup': 3G', '3G, '(4) —C≡C—CR═CR—.'}3. A compound of wherein G is selected from the group consisting of:(1) —C≡C—,(2) —C≡C—C≡C—,(3) —CH═CH—C≡C—, and(4) —C≡C—CH═CH—.4. A compound of wherein G is —C≡C—.5. A compound of wherein G is —C≡C—C≡C—.6. A compound of wherein G is —CH═CH—C≡C—.8. A compound of wherein G is —C≡C—CH═CH—.10. A compound of any one of - wherein X is —(C═O)NR—.11. A compound of wherein X is —(C═O)NH—.12. A compound of any one of - wherein Q is —(C═O)N(R claim 10 ,R).13. A compound of wherein Q is —(C═O)NHOH.14. A compound of any one of - wherein n is 0.15. A compound of any one of - wherein Ris H.16. A compound of any one of - wherein Y is substituted or unsubstituted aryl.17. A compound of wherein Y is substituted or unsubstituted phenyl.18. A compound of wherein Y is unsubstituted phenyl.19. A compound of any one of - wherein A is selected from the group consisting of:{'sub': 2', '0-4', '2', '0-4, 'sup': 1a', '2a', '3a, '(1) —(CH)C(R,R)(CH)OR,'}{'sub': 2', '0-4, 'sup': 1a', '2a', '4a', '5a, '(2) —(CH)C(R,R)N(R,R), and'}{'sup': 1a', '2a, '(3) —CH(R,R).'}20. A compound of wherein A is selected from the group consisting of —CH(CH) claim 19 , —CHOH claim 19 , —CHNH claim 19 , —CHCHOH claim 19 , —CHCHNHand —C(CH)OH.21. A compound of wherein A is —C(CH)NH.22. A compound of any one of - wherein A is selected from the group consisting of:{'sub': 3', '10, '(1) substituted or unsubstituted C-C-cycloalkyl,'}(2) substituted or unsubstituted aryl,(3) substituted or unsubstituted heterocyclyl, and(4) substituted or unsubstituted heteroaryl.26. A compound of any one of - wherein D is present.27. A compound of wherein D is substituted or unsubstituted heteroaryl.29. A compound of wherein D is substituted or unsubstituted aryl.30. A compound of wherein D is substituted or ...

Hybrid Compounds And Methods Of Making And Using The Same

The present disclosure provides compounds, or pharmaceutically acceptable salts thereof, for inhibiting the growth of a microbe; treating a mammal having a microbial infection, malaria, mucositis, an ophthalmic infection, an otic infection, a cancer, or a Mycobacterium infection; killing or inhibiting the growth of a Plasmodium species; inhibiting the growth of a Mycobacterium species; modulating an immune response in a mammal; or antagonizing unfractionated heparin, low molecular weight heparin, or a heparin/low molecular weight heparin derivative.

SUBSTITUTED BENZAMIDES AND METHODS OF USE THEREOF

The invention provides compounds having the general formula I: 24-. (canceled)713-. (canceled)14. The compound of claim 1 , wherein Ris Ccycloalkyl.1517-. (canceled)18. The compound of claim 1 , wherein Xis —O—; the subscript m is 1 and -(L)- is —CH— or —CH—CH—.19. The compound of claim 1 , wherein Xis absent; Xis —O— or —N(H)—; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H)— claim 1 , —C(═O)— claim 1 , —C(H)(CH)— claim 1 , —CH—CH— claim 1 , —CH—C(H)(CH)— claim 1 , —C(H)(CH)—C(H)— claim 1 , —CHCHCH— claim 1 , —CH—C(H)(CH)—CH— or —CHCHCHCH—.20. The compound of claim 1 , wherein Xand Xis absent; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H)— claim 1 , —C(═O)— claim 1 , —C(H)(CH)— claim 1 , —CH—CH— claim 1 , —CH—C(H)(CH)— claim 1 , —C(H)(CH)—C(H)— claim 1 , —CHCHCH— claim 1 , —CH—C(H)(CH)—CH— or —CHCHCHCH—.2122-. (canceled)2530-. (canceled)3236-. (canceled)38. The compound of wherein Ris methyl claim 37 , ethyl claim 37 , cyclopropyl claim 37 , or 1-azetidinyl.39. The compound of claim 37 , wherein —X-(L)-X— is —O— claim 37 , —CH— claim 37 , —CH—O— claim 37 , or —CHCH—O—.42. The compound of claim 37 , wherein A is optionally substituted azetidine claim 37 , pyrrolidine claim 37 , piperidine claim 37 , morpholine claim 37 , homopiperazine claim 37 , and piperazine.4344-. (canceled)4749-. (canceled)51. (canceled)52. A method of treating a disease or condition in a mammal selected from the group consisting of pain claim 1 , depression claim 1 , cardiovascular diseases claim 1 , respiratory diseases claim 1 , and psychiatric diseases claim 1 , and combinations thereof claim 1 , wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.5364-. (canceled) The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in ...

Chemical Compounds as ATF-4 Pathway Inhibitors

The invention is directed to substituted bridged cycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula IIIQ: 8. A pharmaceutical composition comprising the compound according to or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.9. A method of treating a disease selected from: cancer claim 1 , pre-cancerous syndromes claim 1 , Alzheimer's disease claim 1 , spinal cord injury claim 1 , traumatic brain injury claim 1 , ischemic stroke claim 1 , stroke claim 1 , diabetes claim 1 , Parkinson disease claim 1 , Huntington's disease claim 1 , Creutzfeldt-Jakob Disease claim 1 , prion diseases claim 1 , progressive supranuclear palsy claim 1 , amyotrophic lateral sclerosis claim 1 , myocardial infarction claim 1 , cardiovascular disease claim 1 , inflammation claim 1 , fibrosis claim 1 , chronic and acute diseases of the liver claim 1 , chronic and acute diseases of the lung claim 1 , chronic and acute diseases of the kidney claim 1 , chronic traumatic encephalopathy (CTE) claim 1 , neurodegeneration claim 1 , dementia claim 1 , cognitive impairment claim 1 , atherosclerosis claim 1 , ocular diseases claim 1 , neurological disorders claim 1 , pain claim 1 , in organ transplantation and arrhythmias claim 1 , in a human in need thereof claim 1 , which comprises administering to such human a therapeutically effective amount of the compound as described in or a pharmaceutically acceptable salt thereof.10. (canceled)11. A method of treating a disease selected from: cancer claim 7 , pre-cancerous syndromes claim 7 , Alzheimer's disease claim 7 , spinal cord injury claim 7 , traumatic brain injury claim 7 , ischemic stroke claim 7 , stroke claim 7 , diabetes claim 7 , Parkinson disease claim 7 , Huntington's disease claim 7 , Creutzfeldt-Jakob Disease claim 7 , and related prion diseases claim 7 , progressive supranuclear palsy claim 7 , amyotrophic lateral sclerosis claim 7 , myocardial infarction ...

FORMULATION FOR SOFT ANTICHOLINERGIC ANALOGS

Topical formulations comprising soft glycopyrrolates are useful for treating excessive sweating conditions in subjects, such as humans suffering from hyperhidrosis. Preferably, at least one soft anticholinergic agent is provided in an effective amount or concentration in an anhydrous formulation that can inhibit excessive perspiration resulting from a condition such as hyperhidrosis. 126.-. (canceled)28. The method of claim 27 , wherein said composition comprises at least one gelling or viscosity-controlling ingredient.29. The method of claim 27 , wherein said composition comprises at least one additional carrier or excipient.30. The method of claim 28 , wherein said composition comprises at least one additional carrier or excipient.31. The method of claim 27 , wherein the compound of formula (2) is selected from the group consisting of:(i) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(ii) (2R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(iii) (2R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(iv) (2R,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(v) (2R,1′R,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(vi) (2R,1′S,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide;(vii) (2R,1′R,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and(viii) (2R,1′S,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide.32. The method of claim 27 , wherein the composition comprises the compound of formula (2) at a concentration of from about 1% to about 20%.33. The method of claim 27 , wherein the composition comprises the compound of formula (2) at a ...

PROLINE AUXOTROPHS

The present disclosure provides compositions and methods for making and using methanotrophic proline auxotrophs. 1. A non-naturally occurring proline auxotroph , wherein the proline auxotroph is a methanotrophic microorganism comprising an altered endogenous proC gene , wherein the proline auxotroph exhibits a growth phenotype of no growth when cultured in a proline-free culture medium and in the presence of a Csubstrate.2. The non-naturally occurring proline auxotroph of claim 1 , wherein the proline auxotroph exhibits a growth phenotype of growth when cultured in a proline-containing medium claim 1 , the proline-containing culture medium comprising from about 10 μg/mL to about 500 μg/mL of proline.3. The non-naturally occurring proline auxotroph of claim 1 , wherein the auxotroph is a ΔproC mutant of a parental methanotrophic microorganism.4. The non-naturally occurring proline auxotroph of claim 1 , wherein the auxotroph is an obligate methanotroph.5. The non-naturally occurring proline auxotroph of claim 1 , wherein the auxotroph is a facultative methanotroph.6. The non-naturally occurring proline auxotroph of claim 1 , wherein the auxotroph further comprises a recombinant polynucleotide claim 1 , wherein the recombinant polynucleotide encodes a desired protein or the recombinant polynucleotide modifies expression of an endogenous protein.7. The non-naturally occurring proline auxotroph of claim 6 , wherein the recombinant polynucleotide encodes a desired protein.8. The non-naturally occurring proline auxotroph of claim 7 , wherein the desired protein is a metabolic pathway enzyme involved in the biosynthesis of a metabolite.9. The non-naturally occurring proline auxotroph of claim 4 , wherein the recombinant polynucleotide is incorporated in a nucleic acid construct.10. The non-naturally occurring proline auxotroph of claim 4 , wherein the recombinant polynucleotide is integrated in a chromosome.11. A plasmid-addicted methanotrophic expression system claim 1 , ...

COMPOUNDS USEFUL AS IMMUNOMODULATORS

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases. 3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein m is 1 and Ris halo.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein A is —CHO—.6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris —(CH)Ar claim 5 , wherein n is 1 and Ar is pyridinyl optionally substituted with one or two groups independently selected from C-Calkyl claim 5 , C-Calkylsulfonyl claim 5 , amido claim 5 , cyano claim 5 , and halo.7. A compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Y and Rare independently selected from —CHand halo.17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.18. A method of enhancing claim 1 , stimulating claim 1 , modulating and/or increasing the immune response in a subject in need thereof claim 1 , said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.19. The method of further comprising administering an additional agent prior to claim 1 , after claim 1 , or simultaneously with the compound of claim 1 , or the pharmaceutically acceptable salt thereof.20. The method of wherein the additional agent is an antimicrobial agent claim 17 , an antiviral agent claim 17 , a cytotoxic agent claim 17 , a gene expression modulatory agent claim 17 , and/or an immune response modifier.21. A method of inhibiting growth ...