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 ...

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 ...

АНАЛОГИ ПРОСТАГЛАНДИНОВ, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ОБЛАДАЮЩАЯ СЕЛЕКТИВНОЙ АГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ В ОТНОШЕНИИ РЕЦЕПТОРА EP4

Изобретение относится к аналогам простагландина формулы I: где А означает -СН2-СН2 или -СН=СН-, В отсутствует или означает фенил, Z означает -C(O)OR' или тетразол-5-ил, где R' означает водород или C1-С6алкил, m равно 1, 2, 3, 4, 5 или 6, R1 означает C1-С6 алкил, незамещенный фенил или фенил, замещенный по меньшей мере одним заместителем, выбранным из группы, включающей трифторметил, галоген, -Y-Ra, -Y-ORa и -Y-C(O)Ra, где Y означает химическую связь или C1-С3алкиленовую группу, a Ra означает C1-С6алкил, незамещенный фенил или фенил, замещенный по меньшей мере одним заместителем, выбранным из группы, включающей C1-С6алкил, C1-С6алкокси, трифторметил и галоген, при условии, что В означает фенил, a R3, R4, R5 и R6 одновременно не означают водород, или R1 означает незамещенный фенил или фенил, замещенный по меньшей мере одним заместителем, выбранным из группы, включающей трифторметил, галоген, -Y-Ra, -Y-ORa и -Y-C(O)Ra, где Y означает химическую связь или C1-С3алкиленовую группу, a Ra означает ...

НАФТИЛПРОИЗВОДНЫЕ ИЛИ ИХ ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМЫЕ СОЛИ, СПОСОБ ИХ ПОЛУЧЕНИЯ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И ПРОМЕЖУТОЧНЫЕ ВЕЩЕСТВА

Изобретение относится к новым нафтилпроизводным ф-лы (I), где R1 и R2 - Н, -ОН или -O(С1-С4-алкил); R3 - 1-пиперидинил, 1-пирролидинил, метил-1-пирролидинил, диметил-1-пирролидинил, 4-морфолинил, диалкиламино- или 1-гексаметилен-иминогруппа; n = 2 или 3, или их фармацевтически приемлемым солям. Соединения ф-лы (I) ингибируют проявление симптомов постклимактерического синдрома и могут найти применение в качестве средства для облегчения симптомов постклимактерического синдрома, представляющих собой остеопороз, сердечно-сосудистые заболевания, гиперлипидемию или гормонально зависимое раковое заболевание. Описываются также промежуточные соединения ф-лы (II), где R1a - Н или OR5, R2a - Н или OR6, R5 и R6 - гидроксизащитная группа, R4 - -ОН или - СНО. 4 с. и 9 з.п. ф-лы, 6 табл.

СОЕДИНЕНИЯ, СВЯЗЫВАЮЩИЕ ДОМЕН BIR БЕЛКОВ IAP

Изобретение относится к соединениям формулы (I) или (II) включая его энантиомер или диастереомер, где значения R1, R2, R3, R100, R200, R300, A, A1, BG, Q и Q1 приведены в пункте 1 формулы. Соединения могут быть использованы для лечения пролиферативных расстройств, например рака. 13 н. и 29 з.п. ф-лы, 29 схем, 7 ил., 7 табл.

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.

ПРОИЗВОДНЫЕ НАФТАЛИНА, ПРИГОДНЫЕ В КАЧЕСТВЕ ЛИГАНДОВ РЕЦЕПТОРОВ 3 ГИСТАМИНА

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 ...

СРЕДСТВО ДЛЯ ЛЕЧЕНИЯ ВОСПАЛИТЕЛЬНЫХ ЗАБОЛЕВАНИЙ КИШЕЧНИКА

Изобретение относится к медицине, конкретно к фармакологии. Предложено: применение каппа-агониста опиатных рецепторов N-метил-N[(1S)-1-фенил-2-((3S)-3-оксипирролидин-1-ил)-этил]-2,2-дифенил-ацетамид гидрохлорида для лечения воспалительных заболеваний кишечника. Соединение не только лечит боль и снимает дискомфорт, связанные с нарушенной моторикой кишечника, но и оказывает непосредственно противовоспалительное действие. Изобретение расширяет арсенал средств указанного назначения.

СУЛЬФОНАМИДНЫЕ ИНГИБИТОРЫ HIY - АСПАРТИЛ-ПРОТЕАЗЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБ ЛЕЧЕНИЯ, СПОСОБ ИДЕНТИФИКАЦИИ ИНГИБИТОРА

Изобретение относится к новому классу сульфонамидов, которые являются ингибиторами аспартил-протеазы формулы I. Изобретение относится к новому классу H1У аспартил-протеазных ингибиторов, отличающемуся специфическими структурными и физико-химическими характеристиками. Изобретение относится также к фармацевтическим композициям, содержащим эти соединения. Соединения и фармацевтические композиции изобретения особенно подходят для ингибирования Н1У-1 и Н1У-2 протеазной активности, и, соответственно, их можно с выгодой использовать в качестве вирусных агентов против Н1У-1 и Н1У-2 вирусов. Изобретение относится также к способам ингибирования активности Н1У аспартил-протеазы, за счет использования соединений настоящего изобретения, и способам скринирования соединений по их анти-HIУ активности. 5 с. и 21 з.п. ф-лы, 3 ил., 8 табл.

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 (±) 6-ЦИАНО -3,4-ДИГИДРО -2,2- ДИМЕТИЛ -ТРАНС -4- (2- ОКСИ -1- ПИРРОЛИДИНИЛ) -2H-1- БЕНЗОПИРАН -3-ОЛА

Использование: в медицине в качестве антигипертензивного средства. Сущность изобретения: продукт (±) -6-циано-3, 4-дигидро-2, 2- диметилтранс-4-(2-оксо-1- пирролидинил)- 2H-1- бензопиран-3-ол (кромакалим). Реагент 1: 4-цианофенол. Реагент 2: изопрен. Условия процесса: при 30-120°С в среде растворителя в присутствии щелочного металла и/или катализатора. Реагент 3: 6-циано-3,4- дигидро-2,2- диметил-2H- 1-бензопиран при 40-150°С бромируют в 4-положение бензольпиранового кольца. Реагент 4: (±) 4- бром- 6циано- 3, 4-дигидро- 2,2-диметил -2H-1- бензопиран подвергают дигидробромированию. Реагент 5: 6-циано-3,4-дигидро-2,2- диметил-2H-1- бензопиран. Реагент 6: N-бромсукцианимид. Условия процесса: в среде растворителя при 20-120°С. Реагент 7: 6-циано-3,4- дигидро-2,2- диметил- транс-3- бром-4-окси-2H- бензопиран. Реагент 8: 2-пирралидон. Условия процесса: в присутствии щелочного металла или алкоголята щелочного металла при 20-100°С. Выход целевого продукта до 55-65%. 10 з.п. ф-лы.

СПОСОБ ПОЛУЧЕНИЯ (±)6-ЦИАНО-3,4-ДИГИДРО-2,2- ДИМЕТИЛ-ТРАНС-4-(2-ОКСО-1-ПИРРОЛИДИНИЛ) -2Н-1-БЕНЗОПИРАН-3-ОЛА

Использование: в медицине в качестве анти-гипертензивного средства (кромакалима). Сущность изобретения: продукт (+)-6 циано-3,4-дигидро-2,2- диметил-транс-4-(2-оксо-1-пирролидинил) -2Н-1 -бен зопиран-3-ол:кромакалим. Б.Ф. C16H18N2O2 т.пл. 229-230°С. Выход 90 Реагент 1: 4-циано-фенол. Реагент: изопрен. Условия процесса: при 30-120°С в среде растворителя в присутствии щелочного металла и/или катализатора. Реагент 3:6-циано-3,4-дигидро-2,2-диметил-2Н-1-бензопиран, который превращают в 6-циано-2,2-диметил-2Н-1-бензопиран при 40-150°С в среде растворителя в присутствии катализатора и/или оксилителя или путем бромирования в бензильную часть молекулы и дегидробромированием полученного 6-циано-3,4-дигидро-2,2-диметил-4-бром-2Н-1-бензопирана. Из 6-циано-2,2-диметил-2Н-1-бензопирана получают в одну стадию 6-циано-3,4-дигидро-2,2-диметил-3,4-эпокси-2Н-1-бензопирана действием надкислоты в среде растворителя с последующим взаимодействием этого соединения с 2-пирролидоном в присутствии щелочного металла ...

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.

СПОСОБ ПОЛУЧЕНИЯ N-КАРБЭТОКСИМЕТИЛПИРРОЛИДОНА-2

Использование: в качестве промежуточного продукта для производства пирацетама. Сущность изобретения: продукт: N-карбэтоксиметилпирролидон-2, который получают взаимодействием пирролидона-2 с металлическим натрием в растворе толуола при температуре плавления натрия и молярном соотношении пирролидона - 2: Na: толуола (1,0 - 1,5) : (1,0 - 1,1) : (8 - 15), на полученную реакционную смесь, содержащую Na-соль пирролидона-2, действуют этиловым эфиром монохлоруксусной кислоты при их молярном соотношении (1,0 - 1,1) : (1,0 - 1,5) при комнатной температуре. Выход продукта 60 - 69%. 2 табл.

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, ...

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 ...

СОЕДИНЕНИЯ С ПРОКОНВЕРТИН-ОПИАТАГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ, СОДЕРЖАЩИЕ ИХ КОМПОЗИЦИИ, СПОСОБ ИХ ПОЛУЧЕНИЯ, СПОСОБ ЛЕЧЕНИЯ

... 1. Соединения общей формулы I где R1 обозначает Ar, циклоалкил с 3 - 7 C-атомами или циклоалкилалкил с 4 - 8 C-атомами, R2 обозначает Ar; R1 и R2 обозначают вместе также R3 обозначает H, OH, OA или A, R4 обозначает A или фенил, который в случае необходимости однократно или двукратно может быть замещен через Hal, OH, OA, CF3, NO2, NH2, NHA, NHCOA, NHSO2A или NA2 , R5 обозначает OH, CH2OH, R6 и R7 каждый независимо друг от друга означает H, Hal, OH, OA, CF3, NH2, NHA, NA2, NHCOA, NHCONH2, NO2 или метилендиокси, A обозначает алкил с 1 - 7 C-атомами, Ar обозначает моно- или бициклический ароматический остаток, который в случае необходимости может содержать N-, O- или S-атом и может быть замещен однократно, двукратно или трехкратно через A, Hal, OH, OA, CF3, NH2, NA2, NHCOA, и/или NHCONH2, NHA, D обозначает CH3, O, S, NH, NA, -CH2-CH2-, -CH= CH-, -CH2NH-, -CH2-NA- или связь и Hal обозначает F, Cl, Br или I, за исключением N-метил-N-[(1S)-1-фенил-2-((3S)-3-гидроксипирролидин-1-ил-)-этил]-2,2 ...

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.

СПОСОБ ПОЛУЧЕНИЯ МЕТИЛ-6-(2,4-ДИХЛОРФЕНИЛ)-5-[4-[(3S)-1-(3-ФТОРПРОПИЛ)ПИРРОЛИДИН-3-ИЛ]ОКСИФЕНИЛ]-8,9-ДИГИДРО-7H-БЕНЗО[7]АННУЛЕН-2-КАРБОКСИЛАТА

СПОСОБ СТЕРЕОХИМИЧЕСКИ КОНТРОЛИРУЕМОГО ПОЛУЧЕНИЯ ИЗОМЕРНО ЧИСТЫХ ВЫСОКОЗАМЕЩЕННЫХ АЗАЦИКЛИЧЕСКИХ СОЕДИНЕНИЙ

... 1. Способ стереохимически контролируемого получения соединений общей формулы Iа' где R1R2CH-группа в 5-положении циклического фрагмента и гидроксигруппа в 3-положении циклического элемента находятся в транс-положении относительно друг друга и где заместитель R4 в 4-положении и гидроксигруппа в 3-положении циклического фрагмента находятся в цис-положении относительно друг друга и где n означает 0 или 1; R1 означает водород, C1-С6-алкил или фенил-С1-С6-алкил, в случае необходимости, однократно до трехкратно замещенный в фенильном кольце низшим алкилом, низшим галогеналкилом, низшей алкокси- или низшей галогеналкоксигруппой, и R2 означает водород, или R1 и R2 вместе означают метиленовую группу, связанную двойной связью, которая может быть замещена C1-C5-алкилом или фенил-С1-С5-алкилом, в случае необходимости, однократно до трехкратно замещенным в фенильном кольце низшим алкилом, низшим галогеналкилом, низшей алкокси- или низшей галогеналкоксигруппой; R3 означает водород и R4 означает водород ...

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 ПЯТИЧЛЕННЫЕ ГЕТЕРОЦИКЛЫ, ИХ ПОЛУЧЕНИЕ, ИХ ПРИМЕНЕНИЕ И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ ПРЕПАРАТЫ

... 1. Соединения формулы I в которой W обозначает R1 -А - С(R13) или R1 - А - СН = С; Y обозначает карбонильную группу, тиокарбонильную группу или метиленовую группу; Z обозначает N(R0), кислород, серу или метиленовую группу; А обозначает двухвалентный остаток из группы, включающей (С1 - С6)-алкилен, (С3 - С7)-циклоалкилен, фенилен, фенилен-(С1 - С6)-алкил, (С1 - С6)-алкиленфенил, фенилен-(С2 - С6)-алкенил или двухвалентный остаток 5-членного или 6-членного насыщенного или ненасыщенного гетероцикла, который может содержать один или два атома азота и может быть одно- или двукратно замещен (С1 - С6)-алкилом или связанными двойной связью кислородом или серой; В обозначает двухвалентный остаток (С1 - С6)-алкилена, который может быть незамещенным или замещенным (С1 - С6)-алкилом, (С2 - С8)-алкенилом, (С2 - С8)-алкинилом, (С3 - С10)-циклоалкилом, (С3 - С10)-циклоалкил-(С1 - С6)-алкилом, возможно замещенным (С6 - С14)-арилом, возможно замещенным в арильном остатке (С6 - С14)-арил-(С1 - С6)-алкилом ...

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, ...

СПОСОБ ПОЛУЧЕНИЯ N-(ФЕНИЛАМИНОФЕНИЛ)МАЛЕИНИМИДА

Способ получения N-(4-фениламинофенил)малеинимида формулы,включающий взаимодействие малеинового ангидрида с соответствующим амином, в среде ацетона с образованием амида малеиновой кислоты, последующую дегидроциклизацию раствора амида при кипячении в смеси толуола и диметилформамида в присутствии n-толуолсульфокислоты, отличающийся тем, что в качестве амина используют 4-аминофениланилин.

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 ...

CПOCOБ ПOЛУЧEHИЯ ПИPOГЛУTAMИЛCOДEPЖAЩИX CУБCTPATOB

Способ получения пирролидиновых спиртов

СПОСОБ ПОЛУЧЕНИЯ ПИРРОЛИДИНОВЫХ СПИРТОВ .общей форму}ш RI NX гСНгСНгОН R гае R - водород, метил, фенил, т-толил, h -метокси-илиг гэтоксифенил; R - водород, метил или изобутил, гидрированием аминоалкилфуранов обшей формулы Оч о CHzCfljCHRi . где и R имеют указанные значения, в кислом водном или водно-диоксановом раствора при рН 4,0, температуре 80- и давлении 4О-50 атм в присут ствии никельсодержащего катализатора, отличающийся тем, что, с целью повышения выхода целевых продуктов и упрощения процесса, в качестве катализатора используют борид никеля.

Способ получения галоидзамещенных меркаптоациламинокислот

Способ получения производных 2-аминоэтанола

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 ...

Способ получения оптически чистых моноэфиров винной кислоты и оптически активных алканоламинов или их солей

Изобретение касается производных оксикислот, в частности моноэфи- ров винной кислоты и алканоламинов общей формулы (1)А - С (OR,) - CH,j - - NHR,, где А - 4 нитрофенШ1, 1-наф- тилок симе тил, 4-индолилоксиметнл феноксильный остаток 4-R,, 2-R -CgHj- -O-CBj-, где R - метоксиэтил, -NHK; К - алканоил С,-С, в котором алкил С,-С 7 или дикарбамоил, в котором алкил С,-Сг; R4-H, СН,-С(0)-; RZ-, водород или разветвленный С,-С -алкил; R,- остаток дизамещенной (R, R)- или ...

Способ получения @ -(1-аллил-2-пирролидинилметил)-2-метокси-4-амино-5-метилсульфамилбензамида

СПОСОБ ПОЛУЧЕНИЯ Н- ...

Способ получения производных -метил-3,4 диоксифенилаланина или их солей

Harnstoff-Derivate.

ANTIARRYTHMISCHE DERIVATE 2.

BRADYKININ TYPISCHE PEPTIDE

TACE INHIBITOREN

AZAHETEROZYKLISCHEDERIVATE ZUR BEHANDLUNG VON HAARAUSFALL UND NEUROLOGISCHER KRANKHEITEN

3- oder 4-substituierte Oxotremorin-Derivate.

Hydantoinverbindungen

Sulfonamid inhibitoren von Hiv-aspartyl Protease

AZACYCLOALKANE, AZACYCLOALKENE UND IHRE DERIVATE

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

1,3-DISUBSTITUIERTE HARNSTOFFE UND 2-THIOHARNSTOFFE

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

CCR-3 receptor antagonists III

THERAPEUTIC AGENTS

Chemical compounds

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 ...

Optically active materials

Inhibiting hydrocarbon hydrate agglomeration

A process for inhibiting the formation of gas hydrates in a hydrocarbon fluid comprising adding to the hydrocarbon fluid, a gas hydrate anti-agglomerate which is a biodegradable anti-agglomerant derived from a naturally occurring substance.

Pyrrolidinyl hydroxamic acid compounds and their production process

Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to ppar-gamma

Pyrrolidinyl hydroxamic acid compounds and their production process

Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as antidiabetic agents

Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist to PPAR-gamma.

A compound having formula (I), wherein A is selected from the group consisting of: (i) phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms, C1-6alkyl, C1-3alkoxy, C1-3fluoroalkoxy, nitrile, or -NR7R8 where R7 and R8 are independently hydrogen or C1-3alkyl; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ring (a), wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) C1-6alkylene; (v) -MC1-6alkyiene or C1-6alkyleneMC1-6alkylene, wherein M is O, S, or-NR2 wherein R2 represents hydrogen or C1-3 alkyi; (vi) a 5-or 6-membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C1-3 alkyl; and ( ...

Heterecyclic compounds useful as inhibitors of cysteine protease.

Heterocyclic compounds useful as inhibitors of cysteine protease. A group of compounds of the formula (I) which are inhibitors of cysteine proteases particularly cathepsin K, and are useful in the treatment of excessive bone or cartilege loss.

Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia.

This invention relates to a series of arylsubstituted piperazines, of formula (i), pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the alpha-1a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this and other diseases.

Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as antidiabetic agents.

Amino derivatives of glycine wherein the aride group is substituted by an indole, indoline, benzimidazole or benzimidazoline group and wherein the alpha carbon atom of the glycine moiety may also be substituted are useful as glycogen phosphorylase inhibitors which may be employed in the treatment of diabetes, hyperlipidemia, atherosclerosis and myocardial ischemia. The invention provides novel compounds of this type and pharmaceutical compositions comprising such compounds.

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.

Diphenyl ether compounds useful in therapy.

A compound of general formula (1), or pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R3 is independently CF3, OCF3, C1-C4alkylthio or C1-C4alkoxy, N is 1,2 or 3; and the other valuables are as defined in the claims. These compounds inhibit monoamine re-uptake inhibitors. They are useful in disorders such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substances abuse disorders and sexual dysfunction including premature ejaculation.

Diphenyl ether compound as useful in therpay

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: ...

Novel sulfonamide inhibitors aspartyl protease.

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of hiv aspartyl protease inhibitors characterized by specific structural and characterized by specific structural and physicochemical features this invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting hiv-1 and hiv-2 protease activity and consequently, may be advantageously used as anti-viral agents against the hiv-1 and hiv-2 viruses. This invention also relates to methods for inhibiting the activity of hiv aspartly protease using the compounds of this invention and methods for screening compounds for ant-hiv activity ...

Pyrrolidinyl hydroxamic acid compounds and their production process

Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as antidiabetic agents

Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia

Inhibitors of cycteine protease

NOVEL SULFONAMIDE INHIBITORS OF ASPARTYL PROTEASE

Chemical compounds

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

Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

Carboxamide derivatives as muscarinic receptor antagonists

Substituted n-(indole-2-carbonyl)-glycinamides andderivatives as antidiabetic agents

Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

NR (1 allyl 2 pyrrolidinyl methyl) 2 méthoxy 4 amino 5 méthylsulfamoyl benzamide and its method of preparation.

Arylthio compounds as antibacterial and antiviral agents

Inhibitors of cysteine protease

Diphenyl ether compounds useful in therapy.

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

(2-thio) ureas, 1,3-disubstituted.

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.

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.

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 ...

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 ...

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- ...

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- ...

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 ...

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 ...

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 ...

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 ...

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 ...

(+)-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 ...

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.

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) ...

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 ...

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 ...

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 ...

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 ...

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 ...

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 ...

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- ...

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. ...

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 , ...

Prodrugs of Fumarates and Their Use in Treating Various Diseases

The present invention provides compounds of formula (I), 2. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.3. A method of treating multiple sclerosis in a subject in need thereof claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of .4. A method of treating multiple sclerosis in a subject in need thereof claim 2 , comprising administering to the subject a therapeutically effective amount of a composition of . This application is a continuation of U.S. application Ser. No. 16/221,884, filed Dec. 17, 2018, which is a continuation of U.S. application Ser. No. 15/683,189, filed Aug. 22, 2017, now U.S. Pat. No. 10,189,855, issued Jan. 29, 2019, which is a divisional of U.S. application Ser. No. 14/744,325, filed Jun. 19, 2015, now abandoned, which is a continuation of U.S. application Ser. No. 14/180,687, filed Feb. 14, 2014, now U.S. Pat. No. 9,090,558, issued Jul. 28, 2015, which claims the benefit of U.S. Provisional Application No. 61/782,445, filed on Mar. 14, 2013. The entire teachings of the above applications are incorporated herein by reference.The present invention relates to various prodrugs of monomethyl fumarate. In particular, the present invention relates to derivatives of monomethyl fumarate which offer improved properties relative to dimethyl fumarate. The invention also relates to methods of treating various diseases.Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/ ...

PEGYLATED LIPIDS AND THEIR USE FOR DRUG DELIVERY

The invention provides poly(ethylene glycol)-lipid conjugates for use in drug delivery. 2. The compound of claim 1 , wherein X is —(CH)—.3. The compound of claim 1 , wherein X is —CH— and Y is —O— claim 1 , —S— claim 1 , —OC(O)— claim 1 , —C(O)O— claim 1 , —OC(O)N(R)— claim 1 , —N(R)C(O)O— claim 1 , —SC(O)N(R)— claim 1 , or —N(R)C(O)S—.4. The compound of claim 1 , wherein X is not —CH—; and Y is —(CRR)— claim 1 , —C(O)— claim 1 , —N(R)— claim 1 , —C(O)N(R)— claim 1 , —N(R)C(O)— claim 1 , —OC(O)N(R)— claim 1 , —N(R)C(O)O— claim 1 , —N(R)C(O)N(R)— claim 1 , —SC(O)N(R)— claim 1 , or —N(R)C(O)S—.5. The compound of claim 4 , wherein Zis —C(O)O— or —C(O)N(R)—.6. The compound of claim 1 , wherein X is —N(R)— claim 1 , —C(O)N(R)— claim 1 , —N(R)C(O)— claim 1 , —OC(O)N(R)— claim 1 , —N(R)C(O)O— claim 1 , —N(R)C(O)N(R)— claim 1 , —SC(O)N(R)— claim 1 , or —N(R)C(O)S—.7. The compound of claim 1 , wherein Y is —N(R)— claim 1 , —C(O)N(R)— claim 1 , —N(R)C(O)— claim 1 , —OC(O)N(R)— claim 1 , —N(R)C(O)O— claim 1 , —N(R)C(O)N(R)— claim 1 , —SC(O)N(R)— claim 1 , or —N(R)C(O)S—.8. The compound of claim 1 , wherein each A is Land each L claim 1 , independently claim 1 , is —OCHCH— claim 1 , —OCHCHCH— claim 1 , or —OCHCH(CH)—.9. The compound of claim 1 , wherein Ris alkoxy.10. The compound of claim 1 , wherein the molecular weight of the compound is between 500 g/mol and 5 claim 1 ,000 g/mol.11. The compound of claim 1 , wherein each of Rand R claim 1 , independently claim 1 , is a Cto Calkyl or a Cto Calkenyl group.12. The compound of claim 1 , wherein the variables q and s are each independently 1 claim 1 , 2 claim 1 , 3 claim 1 , or 4.13. The compound of claim 1 , wherein:{'sub': 1', '2', '12', '20', '12', '20, 'each of Rand R, independently, is a Cto Calkyl or a Cto Calkenyl group;'}{'sub': '2', 'X is —CH—, —O—, —OC(O)—, —C(O)O—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, or —NHC(O)NH—;'}Y is —O—, —S—, —OC(O)—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —SC(O)NH—;a is 1;{'sup': ' ...

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. 112-. (canceled)14: The process according to claim 13 , wherein the polycarboxylic anhydride compound is a di- claim 13 , tri- or tetracarboxylic anhydride comprising a hydrophobic hydrocarbyl radical having a number-average molecular weight (M) of 85 to 20 claim 13 ,000.16: The process according to claim 13 , wherein the quaternized nitrogen compound is free of protic solvent and protic acid.17: The process according to claim 15 , wherein Ris H or an alkyl group of 1 to 10 carbon atoms.18: The process according to claim 15 , wherein Ris an alkyl group of 1 to 10 carbon atoms.19: The process according to claim 15 , wherein Ris a hydrocarbyl group having a number-average molecular weight (M) of 85 to 20 claim 15 ,000.20: The process according to claim 15 , wherein Ris a polyalkylene radical.21: The process according to claim 15 , where at least one of the R claim 15 , Rand Rradicals is a hydrocarbyl radical or hydroxyl-substituted hydrocarbyl radical. This application is a continuation application of prior U.S. application Ser. No. 15/423,240, ...

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 method of claim 14 , said anhydrous topical gel composition comprises at least about 70% w/w anhydrous ethanol.16. The method of claim 14 , said anhydrous topical gel composition comprises from about 70% to about 99.99% w/w anhydrous ethanol.17. The method of claim 14 , wherein said anhydrous topical gel composition comprises at least one gelling or viscosity-controlling ingredient.18. The method of claim 14 , wherein said anhydrous topical gel composition comprises at least one additional carrier or excipient.19. The method of claim 17 , wherein said anhydrous topical gel composition further comprises at least one additional carrier or excipient.20. The method 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- ...

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.4. The compound of any one of - claim 1 , wherein at least one of Rand Ris OH.5. The compound of claim 4 , wherein both Rand Rare OH.6. The compound of any one of - claim 4 , wherein both Rand Rare H.7. The compound of any one of - claim 4 , wherein X is S.8. The compound of any one of - claim 4 , wherein X is NR.9. The compound of claim 8 , wherein Ris H.10. The compound of claim 8 , wherein Ris C(O)alkyl.11. The compound of any one of - claim 8 , wherein Ris C-Calkyl.12. The compound of any one of - claim 8 , wherein Ris C-CalkyleneCOH.13. The compound of any one of - claim 8 , wherein Ris C-CalkyleneCO—C-Calkyl.14. The compound of any one of - claim 8 , wherein Ris C-CalkyleneCO-amino.16. A pharmaceutical composition comprising the compound of any one of - and a pharmaceutically acceptable excipient.17. 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 nemalophilus, Yersinia ...

GLYCOPYRROLATE SALTS

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, are disclosed. 1. A racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate.2239.-. (canceled)240. An absorbent pad comprising a pharmaceutically acceptable solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and at least one pharmaceutically acceptable additive.241. The absorbent pad of claim 240 , wherein one pharmaceutically acceptable additive is ethanol.242. The absorbent pad of claim 241 , wherein the weight percent of said racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 claim 241 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 claim 241 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate in said pharmaceutically acceptable solution is between 1% and 6%; and the pH of said pharmaceutically acceptable solution is between 3.5 and 5.5.243. The absorbent pad of claim 240 , wherein the absorbent pad comprises polypropylene.244. The absorbent pad of claim 240 , wherein the absorbent pad is nonwoven 100% polypropylene.245. The absorbent pad of claim 240 , wherein the absorbent pad is sealed in a pouch.246. The absorbent pad of claim 245 , wherein the pouch is a laminate containing aluminum foil as a layer.247. A pharmaceutically acceptable solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2- ...

CARBOHYDRATE CONJUGATED RNA AGENTS AND PROCESS FOR THEIR PREPARATION

This disclosure relates to an improved process for the preparation of carbohydrate conjugates. The disclosure also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents. 2. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 0.5% of any individual urea side product or saccharide compound.3. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 0.2% of any individual urea side product or saccharide compound.4. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 1000 ppm of any individual metal.5. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 100 ppm of any individual metal.6. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 10 ppm of any individual metal.7. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 1 ppm of any individual metal.821-. (canceled)23. The process of claim 22 , wherein X is Bz or Ac.24. The process of claim 22 , wherein Y is Ac.25. The process of claim 22 , wherein n is 7; and q claim 22 , r claim 22 , and s are each 1.26. The process of claim 22 , wherein Prt is a 4 claim 22 ,4′-Dimethoxytrityl protecting group. This application claims the benefit of U.S. Provisional Application Nos. 61/680,069, filed Aug. 6, 2012, and 61/794,114, filed Mar. 15, 2013, each of which is incorporated by reference in its entirety.The present invention relates to an improved process for the preparation of carbohydrate conjugates. The present invention also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents.Efficient delivery to cells in vivo requires specific ...

CRYSTALLINE FORM OF SOFPIRONIUM BROMIDE AND PREPARATION METHOD THEREOF

A cocrystal containing the 1′R-diastereomer and the 1'S-diastereomer of sofpironium bromide at a ratio of 1:3 (Form CO), a crystal mixture (for example, Form B) containing Form CO and a crystalline form of the 1′R-diastereomer (Form MN), and a method for preparing sofpironium bromide, which is suitable for manufacture of the crystal mixture are provided. Form CO and a crystalline form of sofpironium bromide containing Form CO (for example, Form B) have superior stability without hygroscopic property, and accordingly they can be preferably used as a raw material of medicaments. 2. The co-crystal Form CO of claim 1 , said co-crystal Form CO characterized by showing peaks at 5.9±0.2 claim 1 , 7.6±0.2 claim 1 , 11.0±0.2 claim 1 , and 22.2±0.2 degrees as diffraction angles 2θ in a powder X-ray diffraction spectrum.3. The co-crystal Form CO of claim 1 , wherein the crystal form is not hygroscopic.4. The co-crystal Form CO of claim 1 , wherein the crystal form is a physicochemically stable crystalline form.9. The crystal Form MN of claim 8 , wherein the crystal is not hygroscopic.10. The crystal Form MN of claim 8 , wherein the crystal form is a physicochemically stable crystalline form.14. A crystal Form B being a mixture of crystal Form CO and crystal From MN claim 8 , and characterized by showing peaks at 5.9±0.2 claim 8 , 7.2±0.2 claim 8 , 7.7±0.2 claim 8 , 11.1±0.2 claim 8 , 22.3±0.2 claim 8 , and 24.6±0.2 as diffraction angles 2θ in a powder X-ray diffraction spectrum.15. The crystal Form B of claim 14 , wherein the crystal Form B is not hygroscopic.16. The crystal Form B of claim 14 , wherein the crystal form is a physicochemically stable crystalline form.21. The crystal Form B of claim 14 , wherein the crystal Form B is prepared by the steps of: 'filtering the suspension to obtain the crystalline Form B.', 'preparing a suspension of sofpironium bromide in a solvent comprising ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour, ...

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 1-7 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.

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. 1. A process for preparing quaternized nitrogen compounds , whereina. a compound comprising at least one oxygen- or nitrogen-containing group reactive with the anhydride and additionally comprising at least one quaternizable amino group is added onto a polycarboxylic anhydride compound, andb. the product from stage a) is quaternized.2. The process according to claim 1 , wherein the polycarboxylic anhydride compound is a di- claim 1 , tri- or tetracarboxylic anhydride.4. A quaternized nitrogen compound according to which is essentially H donor-free claim 3 , and comprises no inorganic acids or short-chain organic acids.5. A fuel additive or lubricant additive comprising a quaternized nitrogen compound according to .6. A detergent additive for diesel fuels comprising a quaternized nitrogen compound according to .7. A wax antisettling additive (WASA) for middle distillate fuels comprising a quaternized nitrogen compound according to .8. An additive for reducing or preventing deposits in injection systems of direct-injection diesel engines ...

GLYCOPYRROLATE SALTS

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, are disclosed. 1. A racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate.2239.-. (canceled) This application is a continuation of U.S. patent application Ser. No. 14/643,553 filed Mar. 10, 2015 (pending, which is a continuation application of U.S. patent application Ser. No. 14/473,537 filed Aug. 29, 2014 (allowed), which is a continuation of International Patent Application No. PCT/US2014/019552 filed Feb. 28, 2014, which claims priority to U.S. Provisional Patent Application No. 61/770,920 filed Feb. 28, 2013 (expired); U.S. Provisional Patent Application No. 61/770,925 filed Feb. 28, 2013 (expired); U.S. patent application Ser. No. 14/024,480 filed Sep. 11, 2013; and U.S. patent application Ser. No. 14/024,484 filed Sep. 11, 2013 (now U.S. Pat. No. 8,859,610). U.S. patent application Ser. Nos. 14/024,480 and 14/024,484 are each a continuation application of U.S. patent application Ser. No. 13/781,390, filed Feb. 28, 2013 (now U.S. Pat. No. 8,558,008). The entirety of each of these applications is hereby incorporated by reference.Glycopyrrolate is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrrolate, typically as a bromide salt, has been used in the treatment of a variety of conditions including diarrhea (U.S. Pat. Nos. 6,214,792 and 5,919,760), urinary incontinence (U.S. Pat. Nos. 6,204,285 and 6,063,808), and anxiety (U.S. Pat. No. 5,525,347). Additionally, U.S. Pat. No. 5,976,499 discloses a method for diagnosing cystic fibrosis in a patient by, in part, ...

METHOD FOR PRODUCING 1-METHYLPYRROLIDIN-3-OL

The invention relates to a method of producing compound (I) 2. The method according to claim 1 , wherein the amount of the secondary amine to be used is (X-1) to (10X-10) mol when the amount of the formaldehyde to be used is X mol per 1 mol of the compound represented by the formula (II).3. The method according to claim 1 , wherein the amount of the formaldehyde to be used is 1.05 to 2.0 mol per 1 mol of the compound represented by the formula (II).4. The method according to claim 1 , wherein the metal catalyst is palladium on carbon or platinum on carbon. The present invention relates to production of 1-methylpyrrolidin-3-ol.1-Methylpyrrolidin-3-ol is useful as an intermediate for producing a medicament (e.g., Patent Document 1). Patent Document 1 describes in Example 1 that (S)-3-hydroxypyrrolidine and 37% aqueous formaldehyde solution were reacted in the presence of 10% palladium on carbon and hydrogen, in water, and the palladium on carbon was removed by filtration, and the filtrate was distilled to obtain (S)-1-methyl-3-hydroxypyrrolidine in 31% yield.Patent Document 1: WO 03/091209The aim of the present invention is to provide a production method of 1-methylpyrrolidin-3-ol on an industrial scale.The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problem, and resulted in the completion of the present invention.Accordingly, the present invention provides the following.which comprisesformaldehyde and hydrogen in the presence of a metal catalyst, in a solvent, wherein the amount of the formaldehyde to be used is exceeding 1 mol and not exceeding 5 mol per 1 mol of the compound represented by the formula (II), to obtain a mixture containing the formaldehyde and the compound represented by the formula (I), andAccording to the present invention, 1-methylpyrrolidin-3-ol can be produced on an industrial scale.Step A and Step B are explained in detail in the following.In Step A, compound (II), formaldehyde and hydrogen are ...

AZACYCLIC CONSTRAINED ANALOGS OF FTY720

Small molecules comprised of azacyclic constrained analogs of FTY720 are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, leukemia, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration. 2. The compound claim 1 , as described in claim 1 , wherein the benzyl group is linked to the pyrrolidine ring at position 3.3. The compound claim 1 , as described in claim 1 , wherein the compound has a method of activation selected from down-regulating cellular nutrient transport and stimulating PP2A activity.4. The compound claim 1 , as described in claim 1 , wherein the stereochemistry of the compound is selected from the group consisting of S at position 2 and R at position 4 claim 1 , R at position 2 and S at position 4 claim 1 , R at position 2 and R at position 4 claim 1 , and S at position 2 and S at position 4.5. The compound claim 1 , as described in claim 1 , wherein the functional groups attached to the pyrrolidine group are in one of either a cis or trans relative orientation.6. The compound claim 1 , as described in claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.7. The compound claim 1 , as described in claim 1 , wherein the compound is phosphorylated.8. The compound claim 1 , as described in claim 1 , wherein the compound shows reduced activity against binding at least one of either S1P and S1P3 receptors when compared to FTY720.9. The compound claim 1 , as described in claim 1 , wherein Ris CHand Ris CHOH.11. The medicament of claim 10 , wherein the benzyl group is linked to the pyrrolidine ring at position 3.12. The medicament of claim 10 , wherein the stereochemistry of the compound is selected from the group ...

CRYSTALLINE FORM OF SOFPIRONIUM BROMIDE AND PREPARATION METHOD THEREOF

A cocrystal containing the 1′R-diastereomer and the 1′S-diastereomer of sofpironium bromide at a ratio of 1:3 (Form CO), a crystal mixture (for example, Form B) containing Form CO and a crystalline form of the 1′R-diastereomer (Form MN), and a method for preparing sofpironium bromide, which is suitable for manufacture of the crystal mixture are provided. Form CO and a crystalline form of sofpironium bromide containing Form CO (for example, Form B) have superior stability without hygroscopic property, and accordingly they can be preferably used as a raw material of medicaments. 126-. (canceled)28. The co-crystal Form CO of claim 27 , said co-crystal Form CO characterized by showing peaks at 5.9±0.2 claim 27 , 7.6±0.2 claim 27 , 11.0±0.2 claim 27 , and 22.2±0.2 degrees as diffraction angles 2θ in a powder X-ray diffraction spectrum.29. The co-crystal Form CO of claim 27 , wherein the crystal form is not hygroscopic.30. The co-crystal Form CO of claim 27 , wherein the crystal form is a physicochemically stable crystalline form.35. The crystal Form MN of claim 34 , wherein the crystal is not hygroscopic.36. The crystal Form MN of claim 34 , wherein the crystal form is a physicochemically stable crystalline form.401. A crystal Form B of sofpironium bromide being a mixture of co-crystal Form CO of claim and crystal Form MN of .41. The crystal Form B of claim 40 , characterized by showing peaks at 5.9±0.2 claim 40 , 7.2±0.2 claim 40 , 7.7±0.2 claim 40 , 11.1±0.2 claim 40 , 22.3±0.2 claim 40 , and 24.6±0.2 as diffraction angles 2θ in a powder X-ray diffraction spectrum.42. The crystal Form B of claim 40 , wherein the crystal Form B is not hygroscopic.43. The crystal Form B of claim 40 , wherein the crystal form is a physicochemically stable crystalline form.48. The crystal Form B of claim 40 , wherein the crystal Form B is prepared by the steps of:preparing a suspension of sofpironium bromide in a solvent comprising ethyl acetate and methyl t-butyl ether, and stirring the ...

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. 120-. (canceled)21. (canceled)22. (canceled)23. (canceled)24. (canceled)25. (canceled)26. An absorbent pad comprising a pharmaceutically acceptable solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate or a solvate thereof and one or more pharmaceutically acceptable additives.27. A pharmaceutically acceptable solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate or a solvate thereof and one or more pharmaceutically acceptable additives for topical administration.28. A method of treating hyperhidrosis comprising topically administering a therapeutically effective amount of a pharmaceutically acceptable solution of a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate or solvate thereof to the skin of a mammal.29. The method of claim 28 , wherein said mammal is human.30. The method of claim 29 , wherein said solution is applied to the axilla.31. The method of claim 29 , wherein said solution is applied to the hands.32. The method of claim 29 , wherein said solution is applied to the feet.33. The method of claim 29 , wherein said solution is applied to the groin claim 29 , face claim 29 , back claim 29 , or abdomen.34. The method of claim 28 , where the administration is with an absorbent pad comprising an ...

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. 120-. (canceled)21. Form D crystalline glycopyrrolate tosylate monohydrate characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 6.9 °2θ and about 12.6 °2θ , prepared by treating glycopyrrolate bromide with a metal salt in a suitable solvent to form a glycopyrrolate salt slurry; removing the solids in the slurry to form a solution; lyophilizing the solution to form a solid; dissolving the solid in a crystallization solvent; and removing the crystallization solvent to form Form D.22. The crystalline glycopyrrolate tosylate monohydrate of claim 21 , further characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 10.3 claim 21 , 13.7 claim 21 , 14.9 claim 21 , 15.3 claim 21 , 15.7 claim 21 , 16.4 claim 21 , 17.7 claim 21 , or 18.2 °2θ.23. The crystalline glycopyrrolate tosylate monohydrate of claim 21 , wherein the metal salt is a silver salt24. The crystalline glycopyrrolate tosylate monohydrate of claim 22 , wherein the metal salt is a silver salt.25. The crystalline glycopyrrolate tosylate monohydrate of claim 24 , wherein the suitable solvent is an alcohol.26. The crystalline glycopyrrolate tosylate monohydrate of claim 25 , wherein the alcohol is isopropanol.27. The crystalline glycopyrrolate tosylate monohydrate of claim 22 , wherein the crystallization solvent comprises acetonitrile and water.28. The crystalline glycopyrrolate tosylate monohydrate of claim 23 , wherein the crystallization solvent comprises acetonitrile and water.29. The crystalline glycopyrrolate tosylate monohydrate of claim 25 , wherein the crystallization solvent comprises acetonitrile and water.30. The crystalline glycopyrrolate tosylate monohydrate of claim 26 , wherein the crystallization solvent comprises acetonitrile and ...

Process for the Preparation of Methyl 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-Fluoropropyl)Pyrrolidin-3-yl]Oxyphenyl]-8,9-Dihydro-7H-Benzo[7]Annulene-2-Carboxylate

Herein is provided a novel process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate by a Suzuki coupling of compound (3), wherein LG represents a leaving group, with an organoboron reagent: 2. The process according to claim 1 , wherein said organoboron reagent is (3S)-1-(3-fluoropropyl)-3-[4-(4 claim 1 ,4 claim 1 ,5 claim 1 ,5-tetramethyl-1 claim 1 ,3 claim 1 ,2-dioxaborolan-2-yl)phenoxy]pyrrolidine claim 1 , the corresponding acid or a salt thereof.4. The process according to any of to claim 1 , wherein the Suzuki coupling is carried out in the presence of a palladium complex.5. The process according to claim 4 , wherein said palladium complex is bis(triphenylphosphine)palladium(II) dichloride.6. The process according to any of to claim 4 , wherein the Suzuki coupling is carried out in the presence of bis(triphenylphosphine)palladium(II) dichloride and of cesium carbonate claim 4 , in an organic solvent.7. The process according to any of to claim 4 , wherein the leaving group LG in compound (3) represents a triflate group.8. The process according to any of to claim 4 , wherein compound (2) is prepared in the form of an oxalate salt claim 4 , by a salification reaction performed after the Suzuki coupling.9. The process according to claim 8 , wherein the oxalate salt of compound (2) is obtained using oxalic acid in isopropylacetate.12. The process according to claim 11 , wherein sodium hydride is used as strong base and DBU as catalyst.13. The process according to or claim 11 , wherein N-phenylbistriflimide is used as triflation reagent claim 11 , in Me-THF as organic solvent.14. The process according to any of to claim 11 , wherein compound (4) is obtained by alpha-arylation of methyl 5-oxo-6 claim 11 ,7 claim 11 ,8 claim 11 ,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate with 1-LG′-2 claim 11 ,4-dichlorobenzene claim 11 , wherein LG′ represents a leaving group. ...

Salts of Methyl 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-Fluoropropyl)Pyrrolidin-3-yl]Oxyphenyl]-8,9-Dihydro-7H-Benzo[7]Annulene-2-Carboxylate and Preparation Process Thereof

Herein are provided novel salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate namely the oxalate salt 4. The process according to claim 3 , wherein the ester-type solvent is an acetate solvent claim 3 , in particular ethyl acetate or isopropyl acetate.5. The process according to claim 3 , wherein the ether-type solvent is chosen from methyl-tertbutyl ether and diisopropyl ether.6. The process according to any of or claim 3 , wherein the ester-type solvent is isopropyl acetate.7. The process according to claim 6 , wherein the process is carried out in isopropyl acetate claim 6 , under heating claim 6 , in particular between 60° C. and 80° C. claim 6 , and more particularly at 70° C. The present application is a continuation of International Application No. PCT/EP2019/073823, filed Sep. 6, 2019, which claims priority from European Patent Application No. 18306177.9, filed Sep. 7, 2018, each of which is incorporated by reference herein in its entirety for any purpose.Herein are provided novel salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate.Methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate, also named as 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester and hereafter designated as “compound (2)”, is the N-1 intermediate in the synthesis of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (hereafter “compound (1)”). Indeed, compound (1) can be obtained by saponification of compound (2).Compound (1), depicted below, is a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal ...

PROCESSES FOR MAKING, AND METHODS OF USING, GLYCOPYRRONIUM COMPOUNDS

Provided herein are processes for making and methods of using salts of glycopyrronium, including solid forms and forms suitable for use as topicals. Disclosed here are processes for making salts of glycopyrronium, also processes for making compositions comprising salts of glycopyrronium, and methods of treating hyperhidrosis with salts of glycopyrronium as well as with compositions comprising salts of glycopyrronium such as, but not limited to, topical compositions. Disclosed herein are methods of treating hyperhidrosis including administering salts of glycopyrronium to subjects in need thereof. 2. The process of claim 1 , further comprising:step (3) isolating a stereomerically pure stereoisomer of a compound of Formula (I).3. The process of claim 2 , wherein isolating a stereomerically pure stereoisomer of a compound of Formula (I) is by column chromatography or by simulated moving bed (SMB) separation.4. (canceled)5. (canceled)6. The process of claim 1 , wherein Ris alkyl.7. The process of claim 6 , wherein Ris methyl claim 6 , ethyl claim 6 , n-propyl claim 6 , propyl claim 6 , n-butyl claim 6 , t-butyl claim 6 , i-butyl claim 6 , n-pentyl claim 6 , or i-pentyl.8. The process of claim 7 , wherein Ris methyl or ethyl.9. (canceled)10. (canceled)11. The process of claim 1 , wherein Ris alkyl.12. The process of claim 11 , wherein Ris methyl claim 11 , ethyl claim 11 , n-propyl claim 11 , propyl claim 11 , n-butyl claim 11 , t-butyl claim 11 , i-butyl claim 11 , n-pentyl claim 11 , or i-pentyl.13. The process of claim 12 , wherein Ris methyl or ethyl.14. (canceled)15. (canceled)16. The process of claim 1 , wherein Ris alkyl substituted with alkoxycarbonyl.17. (canceled)18. The process of claim 16 , wherein R—CHC(O)OCHCH.19. (canceled)20. (canceled)21. The process of claim 18 , wherein Ris methyl.22. (canceled)23. The process of claim 1 , wherein in step (1) claim 1 , compounds of Formula (Ia) and Formula (Ib) are stereomerically pure.27. (canceled)28. (canceled)33. ( ...

NOVEL PYRROLIDINE DERIVATIVES

The present invention relates to novel pyrrolidine derivatives of formula (I): 2. The pyrrolidine derivatives according to characterized in that X represents —CHR , with Ras defined in .5. The pyrrolidine derivatives according to claim 2 , characterized in that R=OH.6. The pyrrolidine derivatives according to claim 1 , characterized in that Ris a hydrogen atom.7. The pyrrolidine derivatives according to characterized in that R=H and Rrepresents a hydrogen atom or a methyl or —C(O)CHgroup.8. The pyrrolidine derivatives according to characterized in that Rrepresents —COOH claim 1 , —C(O)NHCHor —CHNH.9. The pyrrolidine derivatives according to claim 1 , characterized in that Ris a hydrogen atom.10. The pyrrolidine derivatives according to claim 1 , characterized in that it appears in a salified or zwitterionic form including a quaternary ammonium.1215-. (canceled)16. Pharmaceutical compositions containing a derivative of pyrrolidine according to claim 1 , with at least one pharmaceutically acceptable excipient. The present invention relates to the technical field for treating diseases of the central nervous system. More specifically, the object of the invention is novel pyrrolidine derivatives, pharmaceutical compositions containing such compounds, and such compounds, as a drug, and notably for their use in treating, in particular in humans, epilepsy, ischemia, a neurodegenerative disease such as Parkinson's disease or Huntington's chorea, multiple sclerosis, Devic's disease (NMO), Alzheimer's disease, a psychiatric disease such as schizophrenia, depression, addiction, allodynia, hyperalgia, pain (analgesia), cancer of an organ or of a peripheral tissue, obesity, musculoskeletal disorder, cardio-vascular disease or a disease of the digestive tracts or for controlling food intake.Glutamic acid (Glu) and to a lesser extent, aspartic acid (Asp) are the major neurotransmitters of the central nervous system [1-2]. Both of these neurotransmitter amino adds are present in all ...

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. 2. The composition of claim 1 , wherein at least one additional carrier or excipient is present.3. The composition of claim 1 , wherein the compound of formula (2A) 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-methoxycarbonylmethylpyrrolidinium bromide;(j) (2 R, 1′R,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1-methoxycarbonylmethylpyrrolidinium bromide;(k) (2R,1′S,3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1-methoxycarbonylmethylpyrrolidinium bromide; and(l) (2R,1′S,3′S) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-methyl-1-methoxycarbonylmethylpyrrolidinium bromide.4. The composition of claim 1 , ...

Process for the preparation of DL-proline co-crystal of Dapagliflozin

The present invention relates to a process For the preparation of Dapagliflozin DL—Proline co-crystal and its use in the preparation/purification of Dapagliflozin. The invention also provides a process for the preparation of Dapagliflozin (R,S)-1.2-propanediol monohydrate. 1. A process for the preparation of crystalline Dapagliflozin DL-proline co-crystals , comprising the steps of:a) providing a solution or suspension of Dapagliflozin and DL-proline in a solvent or mixture of solvents;b) optionally heating and concentrating the reaction mass; andc) isolating Dapagliflozin DL-proline co-crystals.2. The process according to claim 1 , wherein the solvent used in step (a) is selected from the group consisting of esters selected from ethyl acetate claim 1 , and isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane claim 1 , n-hexane claim 1 , n-heptane claim 1 , and pentane; aromatic hydrocarbons selected from toluene claim 1 , xylene claim 1 , and naphthalene; halogenated aliphatic hydrocarbons selected from dichloromethane claim 1 , chloroform claim 1 , and ethylene dichloride; dialkyl formamides selected from dimethyl formamide; ethers selected from methyl tertiary butyl ether claim 1 , di-isopropyl ether claim 1 , di-ethyl ether claim 1 , dimethyl ether claim 1 , and methyl butyl ether; cyclic ethers selected from tetrahydrofuran claim 1 , and 1 claim 1 ,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran; alcohols selected from methanol claim 1 , ethanol claim 1 , n-propanol claim 1 , iso-propanol claim 1 , n-butanol claim 1 , iso-butanol claim 1 , n-pentanol claim 1 , ethylene glycol claim 1 , and diethylene glycol; ketones selected from acetone claim 1 , methyl ethyl ketone claim 1 , and methyl isobutyl ketone; dialkylsulfoxides selected from dimethyl sulfoxide; dialkylacetamides selected from N claim 1 ,N-dimethyl acetamide; nitrites selected from acetonitrile claim 1 , and propionitrile; ionic liquids claim 1 , ...

Glycopyrronium Fatty Acid Salts and Methods of Making Same

Novel glycopyrronium fatty acid salts have been developed. Bi-phasic reaction conditions enable the desired counterion exchange reactions between glycopyrronium bromide and fatty acid salts of alkali metals and alkaline earth metals in methods to form glycopyrronium fatty acid salts. In preferred embodiments, an excess of the free fatty acid in the reaction mixture stabilizes the glycopyrronium fatty acid salt and reduces the formation of the impurity, Acid A. In some preferred embodiments, between 0.2 and 1.2 molar equivalent of excess free fatty acid is added to the reaction mixture. In another embodiment, approximately 1.2 molar equivalent of excess free fatty acid is added to the reaction mixture. 1. A method of synthesizing at least one glycopyrronium fatty acid salt product comprising the step of mixing glycopyrronium bromide with a fatty acid salt in a biphasic reaction mixture , wherein at least a 0.2 molar equivalent of excess free fatty acid is added to the reaction mixture.2. The method of claim 1 , wherein the mixing step comprises the substep of:i) mixing a fatty acid with water, 2-methyl-tetrahydrofuran, and a metal hydroxide selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide, until all solids are dissolved to form the fatty acid salt.3. The method of claim 2 , wherein the mixing step further comprises the substeps of:ii) adding glycopyrronium bromide and mixing until solids dissolve;iii) removing a lower aqueous phase of the reaction mixture and retaining an upper organic phase;iv) washing the upper organic phase with water;v) repeating steps iii) and iv) at least once;vi) performing vacuum distillation on the upper organic phase;vii) adding new 2-methyl-tetrahydrofuran;viii) repeating step vi) until no distillate is observed;ix) adding a non-polar hydrocarbon solvent and filtering the resulting mixture to remove any suspended solids; andx) performing vacuum distillation of a filtrate from step ix) to ...

CARBOHYDRATE CONJUGATED RNA AGENTS AND PROCESS FOR THEIR PREPARATION

This disclosure relates to an improved process for the preparation of carbohydrate conjugates. The disclosure also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents. 2. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 0.5% of any individual urea side product or saccharide compound.3. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 0.2% of any individual urea side product or saccharide compound.4. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 1000 ppm of any individual metal.5. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 100 ppm of any individual metal.6. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 10 ppm of any individual metal.7. The compound according to claim 1 , wherein the compound of formula (A) contains no more than 1 ppm of any individual metal.9. The process of claim 8 , wherein the base is a metal alkoxide.10. The process of claim 8 , wherein the base is sodium methoxide claim 8 , step (ii) involves reacting the product of step (i) with sodium borohydride claim 8 , and the acid is hydrochloric acid.13. The process of claim 12 , wherein R is t-butyl claim 12 , Hal is Cl and A is a Calkylene linker.14. The process of claim 12 , wherein the reaction is conducted in the presence of N claim 12 ,N-diisopropylethylamine.17. The process of claim 16 , wherein the sulfonic acid is p-toluene sulfonic acid or methanesulfonic acid.20. The process of claim 19 , wherein the tertiary amine is triethylamine or pyridine.23. The process of claim 22 , wherein X is Bz or Ac.24. The process of claim 22 , wherein Y is Ac.25. The process of claim 22 , wherein n is 7; and q claim 22 , r claim 22 , and s are each 1.26. ...

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. 130.-. (canceled)31. A method of producing purified glycopyrronium tosylate comprising:purifying glycopyrronium tosylate by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate, wherein the aqueous solvent consists essentially of water.32. The method of claim 31 , wherein the aqueous solvent consists of water.33. The method of claim 31 , wherein the glycopyrronium tosylate is purified by at least two crystallizations in the aqueous solvent.34. The method of claim 31 , wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate claim 31 , 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.35. The method of claim 34 , 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.36. The method of claim 34 , 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.38. The method of claim 37 , wherein the water-miscible organic solvent is a water-miscible aldehyde claim 37 , organic acid claim 37 , ketone claim 37 , nitrile claim 37 , diol claim 37 , alcohol claim 37 , aminoalcohol claim 37 , glycol claim 37 , ...

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.

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. 112-. (canceled)14: The process according to claim 13 , wherein the polycarboxyl c anhydride compound is a di- claim 13 , tri- or tetracarboxylic anhydride.15: A quaternized nitrogen compound obtained according to the process which is H donor-free claim 13 , and comprises no inorganic acids or short-chain organic acids.16: A fuel additive or lubricant additive comprising the quaternized nitrogen compound according to .17: A detergent additive for diesel fuels comprising the quaternized nitrogen compound according to .18: A wax antisettling additive (WASA) for middle distillate fuels comprising the quaternized nitrogen compound according to .19: An additive for reducing or preventing deposits in injection systems of direct-injection diesel engines comprising a quaternized nitrogen compound according to .20: An additive for controlling or reducing internal diesel injector deposits (IDID) comprising a quaternized nitrogen compound according to .21: An additive concentrate comprising claim 15 , in combination with further diesel fuel additives ...

PROCESSES FOR THE PREPARATION OF PYRROLIDINE INTERMEDIATES

The present invention relates to processes for the enantio-selective preparation of spyrrolidine derivatives useful in the manufacture of pesticidally active compounds, as well as to intermediates in the processes. The processes include those comprising 8. A process according to any one of to comprisingreducing a compound of formula III to a compound of formula IX with a suitable reducing agent; orreducing a compound of formula IV to a compound of formula III with a suitable reducing agent; orreducing a compound of formula IV to a compound of formula IX with a suitable reducing agent; orreducing a compound of formula XII to a compound of formula XVII with a suitable reducing agent; orreducing a compound of formula XII to a compound of formula XVI with a suitable reducing agent; orreducing a compound of formula XVII to a compound of formula XVI with a suitable reducing agent.26. A process according to any one of to , wherein the chiral catalyst is a chiral cinchona alkaloid derivative.30. A process , compound of mixture as defined in any one of to , wherein{'sup': 2', '70', '70', '7', '70', '71', '71', '71, 'sub': 1', '8', '1', '8', '2', '8', '2', '8', '2', '8', '2', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8', '1', '8, 'Ris aryl or aryl substituted by one to five R, or heteroaryl or heteroaryl substituted by one to five R, preferably phenyl or phenyl substituted by one to five R; each Ris independently halogen, cyano, nitro, C-Calkyl, C-Chaloalkyl, C-Calkenyl, C-Chaloalkenyl, C-Calkynyl, C-Chaloalkynyl, hydroxy, C-Calkoxy-, C-Chaloalkoxy-, mercapto, C-Calkylthio-, C-Chaloalkylthio-, C-Calkylsulfinyl-, C-Chaloalkylsulfinyl-, C-Calkylsulfonyl-, C-Chaloalkylsulfonyl-, C-Calkylcarbonyl-, C-Calkoxycarbonyl-, aryl or aryl substituted by one to five R, or heterocyclyl or heterocyclyl substituted by one to five R; each Ris independently halogen, cyano, nitro, C-Calkyl, C- ...

CRYSTALLINE FORMS OF A LYSYL OXIDASE-LIKE 2 INHIBITOR AND METHODS OF MAKING

Described herein are crystalline forms of pharmaceutically acceptable salts of the lysyl oxidase-like 2 (LOXL2) inhibitor (3-(4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yloxy)phenyl)((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methanone. Also described are methods of making the LOXL2 inhibitor, pharmaceutical compositions and medicaments comprising the LOXL2 inhibitor, and methods of using the LOXL2 inhibitor in the treatment of conditions, diseases, or disorders associated with LOXL2 activity. 1. A pharmaceutically acceptable salt of (R ,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone , wherein the pharmaceutically acceptable salt is a mesylate salt , hydrochloride salt , sulfate salt , maleate salt , phosphate salt , L-tartrate salt , fumarate salt , succinate salt , or acetate salt.3. The pharmaceutically acceptable salt of claim 2 , wherein:Compound 2 is amorphous4. The pharmaceutically acceptable salt of claim 2 , wherein:Compound 2 is crystalline.5. The pharmaceutically acceptable salt of claim 4 , wherein:Compound 2 is crystalline and has at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 13.6° 2-Theta, 16.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.3° 2-Theta, 20.6° 2-Theta, 23.1° 2-Theta, and 23.6° 2-Theta;{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, '(b) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in ;'}(c) a DSC thermogram with endotherms at about 231° C. and about 236° C.; or{'figref': {'@idref': 'DRAWINGS', 'FIG. 2'}, '(d) a DSC thermogram substantially the same as shown in ;'}(e) reversible water uptake of about 2% w/w between 0 and 90% RH; or(f) an unchanged XRPD pattern after a GVS analysis.6. The pharmaceutically acceptable salt of claim 4 , wherein:Compound 2 is crystalline and has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 13.6° 2-Theta, 16.9° 2-Theta, ...

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. The method of wherein the atrial arrhythmia is atrial flutter.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. This application is a continuation of U.S. patent application Ser. No. 13/678,299 filed Nov. 15, 2012 (now pending); which is a continuation of U.S. patent application Ser. No. 11/619,136 filed Jan. 2, 2007 (now abandoned); which is a continuation of U.S. patent application Ser. No. 11/342,270 ...

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. 130.-. (canceled)31. A glycopyrronium tosylate composition produced by a method comprising:purifying glycopyrronium tosylate by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate, wherein the aqueous solvent consists essentially of water;the composition comprises threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein the threo-glycopyrronium tosylate is at least 98% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 2% of the total glycopyrronium tosylate content of the composition.32. The glycopyrronium tosylate composition of claim 31 , wherein the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate content of the composition.33. The glycopyrronium tosylate composition of claim 31 , wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate content of the composition.34. The glycopyrronium tosylate composition of claim 31 , wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate content of the composition.35. A glycopyrronium tosylate composition comprising threo-glycopyrronium tosylate and erythro- ...

Synthetic Cytotoxic Molecules, Drugs, Methods of Their Synthesis and Methods of Treatment

Small molecules compounds and methods of their synthesis are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, neoplasms, cancers, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration. 3. (canceled)4. (canceled)5. (canceled)6. The compound of claim 1 , wherein the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells claim 1 , and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.7. The compound of claim 6 , wherein the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC) of less than twenty micromolar claim 6 , wherein the local ICis defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.8. The compound of claim 6 , wherein the human neoplastic cells are at least one of the following:derived from at least one neoplasm, and wherein the at least one neoplasm is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, ...

USE OF SELECTED ANTICHOLINERGIC ZWITTERIONS

Selected anticholinergic zwittehons are administered to slow the progression of myopia in children and to treat myopia generally. 2. Use according to claim 1 , wherein said composition is administered once or twice per day claim 1 , for from one to seven days per week.3. Use according to or claim 1 , carried out for a time period of at least two years.4. Use according to any one of to claim 1 , wherein the at least one compound is (2R claim 1 , 3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium inner salt.5. Use according to any one of to claim 1 , wherein said compound is present in said composition in an amount of from about 0.2% w/v to about 1% w/v.7. Use according to claim 6 , wherein said composition is administered once or twice per day claim 6 , for from one to seven days per week.8. Use according to or claim 6 , wherein the at least one compound is (2R claim 6 , 3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium inner salt.9. Use according to any one of to claim 6 , wherein said compound is present in said composition in an amount of from about 0.2% w/v to about 1% w/v.11. The method according to claim 10 , wherein said compound is administered once or twice per day claim 10 , for from one to seven days per week.12. The method according to or claim 10 , carried out for a time period of at least two years.13. The method according to any one of to claim 10 , wherein the at least one compound is (2R claim 10 , 3′R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium inner salt.14. The method according to any one of to claim 10 , wherein said compound is present in said composition in an amount of from about 0.2% w/v to about 1% w/v.16. The method according to claim 15 , wherein said compound is administered once or twice per day claim 15 , for from one to seven days per week.17. The method according to or claim 15 , wherein the at least one compound is ( ...

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. 3. The composition of claim 1 , wherein R is ethyl.4. The composition of wherein R is methyl.5. The composition of wherein the compound has a stereoisomeric configuration at the 2 position and the 1′ and 3′ positions selected from R claim 1 , S and RS claim 1 , or a mixture thereof.6. The composition of wherein the compound has R-stereoisomeric configuration at the 2 position claim 2 , and stereoisomeric configuration at the 1′ and 3′ positions selected from R claim 2 , S and RS claim 2 , or a mixture thereof.7. The composition of wherein the compound is selected from the group consisting of:(i) 3-[2-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-methoxycarbonylmethyl-pyrrolidinium bromide;(ii) 3-[2-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-ethoxycarbonylmethyl-pyrrolidinium bromide;(iii) 3-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-methoxycarbonylmethyl-pyrrolidinium bromide;(iv) 3-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-ethoxycarbonylmethyl-pyrrolidinium bromide;(v) 3′(R)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-methoxycarbonylmethyl-pyrrolidinium bromide;(vi) 3′(S)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-methoxycarbonylmethyl-pyrrolidinium bromide;(vii) 3′(R)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-ethoxycarbonylmethyl-pyrrolidinium bromide;(viii) 3′(S)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-ethoxycarbonylmethyl-pyrrolidinium bromide;(ix) 1′(R)-3′(R)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′-ethoxycarbonylmethyl-pyrrolidinium bromide;(x) 1′(R)-3′(S)-[2(R)-cyclopentylphenylhydroxyacetoxy]-1′-methyl-1′- ...

PROCESS FOR PREPARING AMINOCYCLOHEXYL ETHER COMPOUNDS

The present invention relates to a process for preparing aminocyclohexyl ether compounds of Formula I: 219-. (canceled)21. The salt of which is in crystalline form.25. The process of further comprising the steps:b) adding a second solvent and a basic aqueous solution to the mixture, to thereby obtain a biphasic mixture of an aqueous layer and an organic layer;c) discarding the aqueous layer; andd) adding an acid to the organic layer to obtain a salt of a compound of Formula (I).26. The process of wherein the activated leaving group X is selected from the group consisting of chloride claim 24 , bromide claim 24 , iodide claim 24 , mesylate claim 24 , tosylate claim 24 , and triflate.27. The process of wherein the 1 claim 24 ,4-dielectrophile is a compound of formula vii-a where R2 is hydrogen and X is bromide claim 24 , mesylate or tosylate.28. The process of wherein the 1 claim 24 ,4-dielectrophile is a compound of formula vii-b.28. The process of wherein the 1 claim 24 ,4-dielectrophile is (R)-1 claim 24 ,4-dibromo-butan-2-ol.30. The process of claim 29 , where a transaminase polypeptide having an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 206 is used.31. The process of claim 29 , where a transaminase polypeptide having a polynucleotide sequence of SEQ ID NO: 17 or SEQ ID NO: 205 is used.34. The process of wherein HW is selected from HCl claim 33 , H2SO4 claim 33 , oxalic acid claim 33 , pivalic acid claim 33 , malic acid and maleic acid.38. The process of claim 32 , where a transaminase polypeptide having an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 206 is used.39. The process of claim 32 , where a transaminase polypeptide having a polynucleotide sequence of SEQ ID NO: 17 or SEQ ID NO: 205 is used. This application is a continuation of U.S. application Ser. No. 13/817,274 filed Feb. 15, 2013, which was filed as a national phase application under 35 U.S.C. §371 of International Application No. PCT/US2011/046885 filed Aug. 8, 2011, which claims the ...

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. 125-. (canceled)26. A method for reducing or preventing deposits in an injection system of a diesel engine , the method comprising adding a deposit reducing or deposit preventing effective amount of a quaternized nitrogen compound to a diesel engine in need thereof , wherein said quaternized nitrogen compound is a quaternized nitrogen compound prepared by a process comprising:a) reacting an anhydride compound derived from a polycarboxylic acid, or a dimeric form thereof having two acid anhydride groups, with a compound comprising (i) a group comprising oxygen or nitrogen wherein the group is reactive with an anhydride, and (ii) a quaternizable amino group, to form a product, andb) quaternizing the product from a) to obtain the quaternized nitrogen compound,wherein the anhydride compound comprises a hydrocarbyl substituent having a number-average molecular weight (Mn) in a range from about 200 to 20 000;wherein said method prevents or reduces internal diesel injector deposits of a direct injection diesel engine; andwherein said method prevents ...

Pyrrolidine derivatives, pharmaceutical compositions and uses thereof

Pyrrolidine derivatives which are inhibitors of acetyl-CoA carboxylase(s) and their use in the treatment of obesity and type-2 diabetes. An exemplary compound is 2-(4-(1-[5-Chloro-6-(2-hydroxy-2-methyl-propoxy)-pyrimidin-4-yl]-(R)-pyrrolidin-3-yloxy)-phenyl)-N-cyclopropyl-propionamide. 3. A compound of formula (I) according to claim 1 , wherein{'sup': '1', 'Aris selected from the group consisting of: phenylene, pyridinylene and pyrimidinylene.'}4. A compound of formula (I) according to claim 1 , wherein Ris selected from the group consisting of:{'sub': 1-4', '3-7', '1-6', '3-7', '1-3', '3-7', '2', '1-3', '2', '1-2, 'claim-text': wherein each alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from F and OH;', {'sub': 2', '1-6', '3-7', '1-6', '3-7, 'wherein in the NH-group, one or both hydrogen atoms may independently of each other be replaced by a group selected from C-alkyl and C-cycloalkyl, wherein said C-alkyl and C-cycloalkyl groups may each be substituted by one or more F or OH, wherein said substituents are the same or different; and'}, 'wherein each heterocyclyl group is selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl and may be substituted with one or more F or OH;, 'F, Cl, Br, CN, OH, C-alkyl, C-cycloalkyl, —O—(C-alkyl), —O—(C-cycloalkyl), —O—(C-alkyl)-(C-cycloalkyl), —NH, heterocyclyl, —O—(C-alkyl)-(heterocyclyl), —O-phenyl and —O—(OH)-phenyl,'}{'sup': 1', '1, 'sub': 3-5', '2', '1-4', '1-3, 'or, if two R-groups are attached to adjacent C-atoms of Ar, they may be linked with each other and together form a C-alkylene bridging group in which 1, 2 or 3-CH-groups may independently of each be replaced by —O—, —C(═O)—, —S—, —NH— or —N(C-alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two C-alkyl groups.'}5. A compound of formula (I) according to claim 1 , wherein Ris selected from the group consisting of:{'sub': 1-3', '3-5', '1-6 ...

Crystalline Pharmaceutical Co-Crystals of Glycopyrronium Bromide with Lactose

The present invention provides co-crystals of glycopyrronium bromide with lactose. The glycopyrronium bromide and lactose in the novel co-crystals are present in a stoichiometric ratio of from about 1:2 to 2:1. These are characterized by XRD and DSC. Processes for preparing the novel co-crystals are also provided. The co-crystals are also disclosed for use as a medicament, in particular, for treatment of respiratory complaints, such as chronic pulmonary obstructive disease (COPD), bronchitis and asthma. Pharmaceutical compositions comprising the co-crystals as active ingredient are also presented. 1. A co-crystal of glycopyrronium bromide comprising glycopyrronium bromide and lactose , wherein the glycopyrronium bromide and lactose are present in a stoichiometric ratio of from about 1:2 to 2:1.2. The co-crystal according to claim 1 , wherein the lactose is selected from monohydrate lactose claim 1 , anhydrous lactose or amorphous lactose.3. The co-crystal according to claim 1 , wherein the lactose is a crystalline lactose monohydrate.4. The co-crystal according to claim 1 , wherein the stoichiometric ratio of glycopyrronium bromide and lactose in the co-crystal is 1:1.5. The co-crystal according to claim 1 , wherein the stoichiometric ratio of glycopyrronium bromide and lactose in the co-crystal is 1:2.6. The co-crystal according to claim 1 , wherein the stoichiometric ratio of glycopyrronium bromide and lactose in the co-crystal is 2:1.7. The co-crystal according to claim 1 , characterized by X-Ray spectrum with characteristic 2theta values at: 5.50; 9.12; 9.78; 10.84; 12.48; 13.7; 14.28; 14.38; 15.80; 16.18; 16.90; 18.16; 18.62; 19.36; 19.40; 19.54; 20.06; 21.06; 21.56; 21.92; 22.72; 23.38; 24.34; 24.64; 25.14; 25.76; 26.20; 27.02; 27.34; 28.52; 29.50; 29.98; 30.76; 32.52; 33.28; 34.64; 36.10; 37.06; 38.08; 39.18; 42.66 43.26; and 45.38; ±0.2° 2θ.8. The co-crystal according to claim 1 , characterized by X-Ray spectrum with characteristic 2theta values at: 5.58; 10 ...

PROCESS FOR THE PREPARATION OF GLYCOPYRRONIUM CHLORIDE

The invention concerns a method for preparing glycopyrronium chloride, and its use in pharmaceutical applications. 1. A method for the preparation of glycopyrronium chloride from glycopyrronium acetate , comprising:reacting glycopyrronium acetate with hydrogen chloride to obtain glycopyrronium chloride.2. A method according to claim 1 , wherein said glycopyrronium acetate is prepared from glycopyrronium bromide by reacting the glycopyrronium bromide with silver acetate to obtain said glycopyrronium acetate.3. A method according to claim 2 , wherein said reacting said glycopyrronium bromide with silver acetate is performed in methanol.4. A method according to claim 1 , wherein said glycopyrronium acetate is dissolved in ethyl acetate before addition of said hydrogen chloride to obtain glycopyrronium chloride.5. A method according to claim 2 , wherein said glycopyrronium acetate is dissolved in ethyl acetate before addition of said hydrogen chloride to obtain glycopyrronium chloride.6. A method according to claim 3 , wherein said glycopyrronium acetate is dissolved in ethyl acetate before addition of said hydrogen chloride to obtain glycopyrronium chloride.7. A method for the preparation of glycopyrronium chloride from glycopyrronium bromide claim 3 , comprising:contacting glycopyrronium bromide with an ion exchange resin.8. A method according to claim 7 , wherein said ion exchange resin is preconditioned with sodium chloride.9. A method according to claim 7 , wherein said glycopyrronium chloride is eluted from said ion exchange resin with ethanol or an ethanol/water mixture.10. A method according to claim 8 , wherein said glycopyrronium chloride is eluted from said ion exchange resin with ethanol or an ethanol/water mixture.11. A method for the preparation of glycopyrronium chloride claim 8 , comprising:{'b': '3', '(a) treating -[(cyclopentylhydroxyphenylacetyl)oxy]-1-methylpyrrolidine in the form of a mixture of (R,S), (S,R), (S,S), (R,R) isomers with at least one ...

GLYCOPYRROLATE SALTS

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, are disclosed. 1239.-. (canceled)240. A pharmaceutically acceptable aqueous solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate , and at least one pharmaceutically acceptable additive.241. The pharmaceutically acceptable solution of claim 240 , further comprising ethanol.242240. The pharmaceutically acceptable solution of claim claim 240 , claim 240 , wherein the pH of said pharmaceutically acceptable solution is between 3.5 and 5.5.243. The pharmaceutically acceptable solution of claim 242 , wherein the pH of said pharmaceutically acceptable solution is between about 4.0 and 5.0 claim 242 , between about 4.0 and 4.7 claim 242 , or between about 4.1 and 4.6.244. The pharmaceutically acceptable solution of claim 243 , wherein said pharmaceutically acceptable solution is clear and colorless or pale yellow at a pH of between about 4.0 and about 5.0 at 25° C.245. The pharmaceutically acceptable solution of claim 241 , wherein said additive is citric acid claim 241 , sodium citrate claim 241 , or a combination thereof as a buffer.246. The pharmaceutically acceptable solution of claim 242 , further comprising at least one pharmaceutically acceptable excipient.247. The pharmaceutically acceptable solution of or claim 242 , further comprising povidone as a binding agent and a butyl ester of a polyvinylmethylether/maleic anhydride acid copolymer as a film-forming agent.248. The pharmaceutically acceptable solution of any one of to claim 242 , wherein the solution comprises 0.15% ...

Glycopyrrolate Salts

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, are disclosed. 1239.-. (canceled)240. A pharmaceutically acceptable solution comprising a racemic mixture of (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate and (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1 ,1-dimethylpyrrolidinium 4-methylbenzenesulfonate or a solvate thereof , and at least one pharmaceutically acceptable additive , wherein the pH of said pharmaceutically acceptable solution is between 3.5 and 5.5.241. The pharmaceutically acceptable solution of claim 240 , wherein the pH of said pharmaceutically acceptable solution is between about 4.0 and 5.0 claim 240 , between about 4.0 and 4.7 claim 240 , or between about 4.1 and 4.6.242. The pharmaceutically acceptable solution of claim 241 , wherein said pharmaceutically acceptable solution is clear and colorless or pale yellow at a pH of between about 4.0 and about 5.0 at 25° C.243. The pharmaceutically acceptable solution of claim 242 , wherein said additive is citric acid claim 242 , sodium citrate claim 242 , or a combination thereof as a buffer.244. The pharmaceutically acceptable solution of claim 243 , further comprising ethanol.245. The pharmaceutically acceptable solution of claim 244 , further comprising at least one pharmaceutically acceptable excipient.246. The pharmaceutically acceptable solution of claim 245 , further comprising povidone as a binding agent and a butyl ester of a polyvinylmethylether/maleic anhydride acid copolymer as a film-forming agent247. The pharmaceutically acceptable solution of claim 240 , wherein said pH is between about 4.0 and about 5.0 at 25° C. and further comprises ethanol and a buffer comprising citric ...

CATIONIC LIPID

The present invention provides a cationic lipid, which allow nucleic acids to be easily introduced into cells, represented by formula (I) 127-. (canceled)29. The cationic lipid according to claim 28 , wherein Land Lare —O— or —O—CO— claim 28 , and Rand Rare dodecyl claim 28 , tetradecyl claim 28 , hexadecyl claim 28 , octadecyl claim 28 , icosyl claim 28 , docosyl claim 28 , tetracosyl claim 28 , (Z)-tetradec-9-enyl claim 28 , (Z)-hexadec-9-enyl claim 28 , (Z)-octadec-6-enyl claim 28 , (Z)-octadec-9-enyl claim 28 , (E)-octadec-9-enyl claim 28 , (Z)-octadec-11-enyl claim 28 , (9Z claim 28 ,12Z)-octadec-9 claim 28 ,12-dienyl claim 28 , (9Z claim 28 ,12Z claim 28 ,15Z)-octadec-9 claim 28 ,12 claim 28 ,15-trienyl claim 28 , (Z)-icos-11-enyl claim 28 , (11Z claim 28 ,14Z)-icos-11 claim 28 ,14-dienyl claim 28 , 3 claim 28 ,7 claim 28 ,11-trimethyldodeca-2 claim 28 ,6 claim 28 ,10-trienyl or 3 claim 28 ,7 claim 28 ,11 claim 28 ,15-tetramethylhexadec-2-enyl.30. The cationic lipid according to claim 28 , wherein Land Lare —CO—O— claim 28 , and Rand Rare tridecyl claim 28 , pentadecyl claim 28 , heptadecyl claim 28 , nonadecyl claim 28 , heneicosyl claim 28 , tricosyl claim 28 , (Z)-tridec-8-enyl claim 28 , (Z)-pentadec-8-enyl claim 28 , (Z)-heptadec-5-enyl claim 28 , (Z)-heptadec-8-enyl claim 28 , (E)-heptadec-8-enyl claim 28 , (Z)-heptadec-10-enyl claim 28 , (8Z claim 28 ,11Z)-heptadec-8 claim 28 ,11-dienyl claim 28 , (8Z claim 28 ,11Z claim 28 ,14Z)-octadec-8 claim 28 ,11 claim 28 ,14-trienyl claim 28 , (Z)-nonadec-10-enyl claim 28 , (10Z claim 28 ,13 Z)-nonadec-10 claim 28 ,13-dienyl claim 28 , (11Z claim 28 ,14Z)-icos-11 claim 28 ,14-dienyl claim 28 , 2 claim 28 ,6 claim 28 ,10-trimethylundec-1 claim 28 ,5 claim 28 ,9-trienyl or 2 claim 28 ,6 claim 28 ,10 claim 28 ,14-tetramethylpentadec-1-enyl.31. The cationic lipid according to any one of to claim 28 , wherein a and b are both 0 or 1.32. The cationic lipid according to any one of or claim 28 , wherein Lis a single bond ...

IAP Binding Compounds

IAP binding molecules and compositions including these are disclosed. The IAP binding molecules interact with IAPs (inhibitor of apoptosis proteins) in cells and may be used to modify apoptosis in cells treated with such molecules. Embodiments of these compounds have a Kof less than 0.1 micromolar. Methods of using these IAP binding molecules for therapeutic, diagnostic, and assay purposed are also disclosed. 212.-. (canceled)13. A method of treating cancerous cells comprising administering to the cells an IAP binding compound of .14. A method of treating cells comprising:{'claim-ref': {'@idref': 'CLM-00024', 'claim 24'}, 'administering to cells that have a proliferation disorder, wherein the disorder is selected from the group consisting of a cancer or an autoimmune disorder, an amount of the IAP binding compound of or a pharmaceutically acceptable salt thereof that reduces the cellular proliferation disorder in the sample of cells.'}15. A method of treating cells comprising:{'claim-ref': {'@idref': 'CLM-00024', 'claim 24'}, 'administering to cells that have a proliferation disorder, wherein the disorder is selected from the group consisting of a cancer or an autoimmune disorder, an amount of the IAP binding compound of or a pharmaceutically acceptable salt thereof that reduces the cellular proliferation disorder in the sample of cells.'}16. A method of treating a cellular proliferative disorder in a patient claim 1 , wherein the proliferative disorder is selected from the group consisting of a cancer or an autoimmune disorder claim 1 , the method comprising administering to the patient an IAP binding compound of in an amount that ameliorates the cellular proliferative disorder.17. The method of wherein the IAP binding compound is an IAP binding compound of .18. The method of wherein the IAP binding compound is an IAP binding compound of .19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a ...

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.

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. 2. The method of wherein R claim 1 , Rand Rare independently hydrogen claim 1 , hydroxy or C-Calkoxy claim 1 , with the proviso that R claim 1 , Rand Rcannot all be hydrogen at the same time.3. The method of wherein Ris hydrogen claim 2 , and Rand Rare each C-Calkoxy.4. The method of wherein Rand Rare each Calkoxy at the S- and 4-carbon position of the phenyl group claim 3 , respectively.5. The method of wherein each Lg is independently chloro or bromo; Ris C-Calkyl; Ris C-Cacyl; and Ris C-Cacyl.6. The method of wherein the reducing reagent for step (b) is Red-Al.8. The method of wherein R claim 7 , Rand Rare independently hydrogen claim 7 , hydroxy or C-Calkoxy claim 7 , with the proviso that R claim 7 , Rand Rcannot all be hydrogen at the same time.9. The method of wherein Ris hydrogen claim 8 , and Rand Rare each C-Calkoxy.10. The method of wherein Rand Rare each Calkoxy at the S- and 4-carbon position of the phenyl group claim 9 , respectively.11. The method of wherein each Lg is independently chloro or bromo; Ris C-Calkyl; Ris C-Cacyl; and Ris C-Cacyl.12. The method of wherein the reducing reagent for step (b) is Red-Al.14. The method of wherein R claim 13 , Rand Rare independently hydrogen claim 13 , hydroxy or C-Calkoxy claim 13 , with the proviso that R claim 13 , Rand Rcannot all be hydrogen at the same time.15. The method of wherein Ris hydrogen claim 14 , and Rand Rare each C-Calkoxy.16. The method of wherein Rand Rare each Calkoxy at the S- and 4-carbon position of the phenyl group claim 15 , respectively.17. The method of wherein each Lg is independently chloro or bromo; Ris C-Calkyl; Ris C-Cacyl; and Ris C-Cacyl.18. The method of wherein the reducing reagent for step (b) is Red-Al.20. The ...

COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. 2. A compound of wherein n is 2.3. A compound of or wherein L is a polyalkylene glycol linker.43. A compound of any of - wherein L is a polyethylene glycol is linker.8. A compound of wherein Rand R claim 7 , taken together with the nitrogen to which they are bonded claim 7 , form an optionally substituted 5 or 6 membered heterocyclyl.9. A compound of wherein the optionally substituted 5 or 6 membered heterocyclyl is pyrrolidinyl or piperidinyl.10. A compound of wherein the optionally substituted 5 or 6 membered heterocyclyl is pyrrolidinyl or piperidinyl claim 8 , each substituted with at least one amino or hydroxyl.11. A compound of wherein Rand Rare independently Calkyl.12. A compound of wherein Rand Rare methyl.1312. A compound of any of - wherein each Ris independently selected from the group consisting of hydrogen or halogen.14. A compound of wherein each Ris independently selected from the group consisting of hydrogen claim 13 , F and Cl.1514. A pharmaceutical composition comprising a compound of any of - claims 1 , or a stereoisomer claims 1 , pharmaceutically acceptable salt or prodrug thereof claims 1 , and a pharmaceutically acceptable carrier claims 1 , diluent or excipient.16. A pharmaceutical composition of claim 15 , further comprising a fluid-absorbing polymer.17. A pharmaceutical ...

PROCESS FOR PREPARING (3RS)-3-[(2SR)-(2-CYCLOPENTYL-2-HYDROXY-2-PHENYLACETYL)OXY]-1,1-DIMETHYLPYRROLIDINIUM BROMIDE

The present invention relates to an efficient and environmentally friendly process for preparing (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide with high yield and purity suitable for industrial scale applications. 114.-. (canceled)15. A process for preparing glycopyrronium bromide , or another pharmaceutically acceptable salt of glycopirronium , wherein the process comprises at least the following steps:a) Contacting 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate with 5-nitroisophthalic acid in a mixture of organic solvent/water to yield (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate-5-nitroisophthalic acid salt (compound III);wherein the ratio of organic solvent to water is at most 10:1 (V/V) and the quantity of 5-nitroisophthalic acid is at least 0.5 mol per 1 mol of 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate;b) Isolating the (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate 5-nitroisophthalic acid salt obtained in step a) by filtration;c) Optionally, purifying the (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate 5-nitroisophthalic acid salt of step b) by means of conventional purification techniques;d) Treating the (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate 5-nitroisophthalic acid salt of step b) or c) with a base to yield (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate (compound II);e) Contacting the (RS/SR) 1-methylpyrrolidin-3-yl-2-cyclopentyl-2-hydroxy-2-phenylacetate of step d) with methyl bromide to yield glycopyrronium bromide (compound I);f) Optionally, purifying the glycopyrronium bromide of step d) by means of conventional purification techniques;g) Optionally, converting the glycopyrronium bromide obtained in step d) or e) into another pharmaceutically acceptable salt or co-crystal.16. The process for preparing glycopyrronium bromide according to ...

Glycopyrrolate salts

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, 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 O;{'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.37.-. (canceled)8. A lipid nanoparticle comprising a cationic lipid according to .9. The lipid nanoparticle according to further comprises an oligonucleotide.10. The lipid nanoparticle according to wherein the oligonucleotide is siRNA or miRNA.11. The lipid nanoparticle according to wherein the oligonucleotide is 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 oligonucleotides, to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in vitro and in vivo.Cationic lipids and the use of cationic lipids in lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA, have been previously disclosed. Lipid nanoparticles and use of lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA, has been previously disclosed. Oligonucleotides (including siRNA and miRNA) and the synthesis of oligonucleotides has been previously disclosed. (See US ...

CRYSTALLINE FORMS OF A LYSYL OXIDASE-LIKE 2 INHIBITOR AND METHODS OF MAKING

Described herein are crystalline forms of pharmaceutically acceptable salts of the lysyl oxidase-like 2 (LOXL2) inhibitor (3-(4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yloxy)phenyl)((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methanone. Also described are methods of making the LOXL2 inhibitor, pharmaceutical compositions and medicaments comprising the LOXL2 inhibitor, and methods of using the LOXL2 inhibitor in the treatment of conditions, diseases, or disorders associated with LOXL2 activity. 1. A pharmaceutically acceptable salt of (R ,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone , wherein the pharmaceutically acceptable salt is a mesylate salt , hydrochloride salt , sulfate salt , maleate salt , phosphate salt , L-tartrate salt , fumarate salt , succinate salt , or acetate salt.3. The pharmaceutically acceptable salt of claim 2 , wherein:Compound 2 is amorphous4. The pharmaceutically acceptable salt of claim 2 , wherein:Compound 2 is crystalline.5. The pharmaceutically acceptable salt of claim 4 , wherein:Compound 2 is crystalline and has at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 13.6° 2-Theta, 16.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.3° 2-Theta, 20.6° 2-Theta, 23.1° 2-Theta, and 23.6° 2-Theta;{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, '(b) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in ;'}(c) a DSC thermogram with endotherms at about 231° C. and about 236° C.; or{'figref': {'@idref': 'DRAWINGS', 'FIG. 2'}, '(d) a DSC thermogram substantially the same as shown in ;'}(e) reversible water uptake of about 2% w/w between 0 and 90% RH; or(f) an unchanged XRPD pattern after a GVS analysis.6. The pharmaceutically acceptable salt of claim 4 , wherein:Compound 2 is crystalline and has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 13.6° 2-Theta, 16.9° 2-Theta, ...

PROCESS FOR THE PREPARATION OF GLYCOPYRROLATE TOSYLATE

The present application provides novel process for the preparation of glycopyrrolate tosylate. 3. A process according to claim 1 , wherein said bi-phasic system comprises at least one aqueous solution comprising said tosylic acid or salt thereof.4. A process according to claim 1 , wherein said bi-phasic system comprises at least one non-aqueous solution comprising said halogen salt of glycopyrrolate.5. A process according to claim 2 , wherein said at least one aqueous solution further comprises said at least one phase transfer catalyst.6. A process according to claim 2 , wherein said at least one non-aqueous solution further comprises said at least one phase transfer catalyst.7. A process according to claim 4 , wherein said non-aqueous solution comprises at least one of cyclohexane claim 4 , toluene claim 4 , methylene chloride claim 4 , chloroform and any combinations thereof.8. A process according to claim 2 , wherein said non-aqueous solution comprises at least one of cyclohexane claim 2 , toluene claim 2 , methylene chloride claim 2 , chloroform claim 2 , and any combinations thereof.9. A process according to claim 1 , wherein said halogen salt of glycopyrrolate is a bromide salt.10. A process according to claim 1 , wherein said at least one phase transfer catalyst is selected from tetra-butyl ammonium bromide (TBAB) claim 1 , N-Methyl-N claim 1 ,N claim 1 ,N-trioctylammonium chloride (aliquat-336) claim 1 , 1 claim 1 ,4 claim 1 ,7 claim 1 ,10 claim 1 ,13 claim 1 ,16-hexaoxacyclooctadecane (18-Crown-6) claim 1 , hexadecyltrimethylammonium bromide claim 1 , tetrabutylammonium iodide (TBAI) claim 1 , and any combination thereof.11. A process according to claim 2 , wherein said aqueous solution further comprises a base.12. A process according to claim 1 , wherein said at least one phase transfer catalyst is added to said biphasic system prior to or during the reaction.13. A process according to claim 1 , wherein the glycopyrrolate tosylate product comprises less ...

PROCESS FOR THE PREPARATION OF GLYCOPYRROLATE TOSYLATE

This invention is directed to a process for the preparation of glycopyrrolate tosylate comprising the step of reacting a halogen salt of glycopyrrolate with tosylic acid or a salt thereof in the presence of hydrogen peroxide and at least one unsaturated organic agent. 1. A process for the preparation of glycopyrrolate tosylate comprising the step of reacting a halogen salt of glycopyrrolate with tosylic acid or a salt thereof in the presence of hydrogen peroxide and at least one unsaturated organic agent.2. The process according to claim 1 , wherein said process is performed in the presence of a mixture of at least one saturated organic agent and at least one unsaturated organic agent.3. The process according to claim 1 , wherein said at least one unsaturated organic agent is selected from cyclopentene claim 1 , butene claim 1 , pentene claim 1 , cyclohexene claim 1 , styrene claim 1 , phenol and any combinations thereof.4. The process according to claim 2 , wherein said at least one saturated organic agent is selected from cyclohexane claim 2 , n-hexane claim 2 , dichloromethane claim 2 , heptane claim 2 , and any combinations thereof.5. The process according to claim 1 , wherein said halogen salt of glycopyrrolate is mixed with said at least one unsaturated organic agent prior to addition of said hydrogen peroxide.6. The process according to claim 1 , wherein said halogen salt of glycopyrrolate is mixed with said tosylic acid or salt thereof prior to addition of said hydrogen peroxide7. The process according to claim 1 , wherein said halogen salt of glycopyrrolate is mixed with said tosylic acid or salt thereof and said at least one unsaturated organic agent prior to addition of said hydrogen peroxide.8. The process according to claim 1 , wherein said halogen salt of glycopyrrolate is mixed with said at least one unsaturated organic agent prior to reacting with said tosylic acid or salt thereof.9. The process according to claim 1 , wherein said hydrogen peroxide ...

PRODRUGS OF FUMARATES AND THEIR USE IN TREATING VARIOUS DISEASES

The present invention provides compounds of formula (I), 2. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.3. A method of treating multiple sclerosis in a subject in need thereof claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of .4. A method of treating multiple sclerosis in a subject in need thereof claim 2 , comprising administering to the subject a therapeutically effective amount of a composition of . This application is a continuation of U.S. application Ser. No. 15/683,189, filed Aug. 22, 2017, which is a divisional of U.S. application Ser. No. 14/744,325, filed Jun. 19, 2015, now abandoned, which is a continuation of U.S. application Ser. No. 14/180,687, filed Feb. 14, 2014, now U.S. Pat. No. 9,090,558, issued Jul. 28, 2015, which claims the benefit of U.S. Provisional Application No. 61/782,445, filed on Mar. 14, 2013. The entire teachings of the above applications are incorporated herein by reference.The present invention relates to various prodrugs of monomethyl fumarate. In particular, the present invention relates to derivatives of monomethyl fumarate which offer improved properties relative to dimethyl fumarate. The invention also relates to methods of treating various diseases.Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, 2005, 111(1), 43-48; and Yazdi and Mrowietz, 2008, 26, 522-526); asthma and chronic ...

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.

Prodrugs of Fumarates and Their Use in Treating Various Diseases

The present invention provides compounds of formula (I), 2. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof.3. A method of treating multiple sclerosis in a subject in need thereof claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of .4. A method of treating multiple sclerosis in a subject in need thereof claim 2 , comprising administering to the subject a therapeutically effective amount of the composition of . This application is a continuation of U.S. application Ser. No. 16/987,581, filed Aug. 7, 2020, which is a continuation of U.S. application Ser. No. 16/221,884, filed Dec. 17, 2018, now abandoned, which is a continuation of U.S. application Ser. No. 15/683,189, filed Aug. 22, 2017, now U.S. Pat. No. 10,189,855, issued Jan. 29, 2019, which is a divisional of U.S. application Ser. No. 14/744,325, filed Jun. 19, 2015, now abandoned, which is a continuation of U.S. application Ser. No. 14/180,687, filed Feb. 14, 2014, now U.S. Pat. No. 9,090,558, issued Jul. 28, 2015, which claims the benefit of U.S. Provisional Application No. 61/782,445, filed on Mar. 14, 2013. The entire teachings of the above applications are incorporated herein by reference.The present invention relates to various prodrugs of monomethyl fumarate. In particular, the present invention relates to derivatives of monomethyl fumarate which offer improved properties relative to dimethyl fumarate. The invention also relates to methods of treating various diseases.Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions ...

Synthetic Lubricity Additives for Hydrocarbon Fuels

Lubricity additives for hydrocarbon fuels are presented according to formula I:

6-(2,4-二氯苯基)-5-[4-[(3s)-1-(3-氟丙基)吡咯烷-3-基]氧基苯基]-8,9-二氢-7h-苯并[7]轮烯-2-甲酸甲酯的盐及其制备方法

本文提供了6‑(2,4‑二氯苯基)‑5‑[4‑[(3S)‑1‑(3‑氟丙基)吡咯烷‑3‑基]氧基苯基]‑8,9‑二氢‑7H‑苯并[7]轮烯‑2‑甲酸甲酯的新型盐，即草酸盐(I)和二苯甲酰基酒石酸盐(II)。

Novel quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-fluoroalkyloxime)pyrrolidine substituent and process for preparing thereof

본 발명은 탁월한 항균력을 나타내는 퀴놀론계 화합물 특히, 퀴놀론 모핵의 7-번 위치에 4-아미노메틸-4-알킬-3-알킬옥심피롤리딘 치환체를 갖는 화합물로서, 우수한 항균작용과 광범위한 항균스펙트럼을 가질뿐만 아니라 기존의 퀴놀론계 항생제보다 월등히 뛰어난 흡수 및 약물동력학적 특성을 갖는 다음 일반식 (I)로 표시되는 신규한 퀴놀린(나프티리딘) 카르복실산 유도체, 약제학적으로 허용되는 그의 무독성염, 생리학적으로 가수분해 가능한 에스테르, 용매화물 및 이성체에 관한 것이다. The present invention is a quinolone compound exhibiting excellent antimicrobial activity, in particular, a compound having a 4-aminomethyl-4-alkyl-3-alkyloximepyrrolidine substituent at the 7-position of the quinolone mother nucleus, which has excellent antibacterial activity and broad spectrum antibacterial spectrum. Novel quinoline (naphthyridine) carboxylic acid derivatives represented by the following general formula (I), as well as having superior absorption and pharmacokinetic properties over conventional quinolone antibiotics, pharmaceutically acceptable nontoxic salts thereof, physiology Academically hydrolysable esters, solvates and isomers. 상기식에서, Q, R, R 1 , R 2 , R 3 , R 4 및 R 5 는 명세서중에 정의된 바와 같다. Wherein Q, R, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the specification.

Novel quinoline carboxylic acid derivatives having 7- (4-aminomethyl-4-alkyl-3-alkyloxime) pyrrolidine substituents and methods for their preparation

본 발명은 탁월한 항균력을 나타내는 퀴놀론계 화합물 특히, 퀴놀론 모핵의 7번 위치에 4-아미노메틸-4-알킬-3-알킬옥심피롤리딘 치환체를 갖는 화합물로서, 우수한 항균작용과 광범위한 항균스펙트럼을 가질 뿐만 아니라, 기존의 퀴놀론계 항생제보다 월등히 뛰어난 흡수 및 약물동력학적 특성을 갖는 다음 일반식(Ⅰ)로 표시되는 신규한 퀴놀린(나프티리딘) 카르복실산 유도체, 약제학적으로 허용되는 그의 무독성 염, 생리학적으로 가수분해 가능한 에스테르, 용매화물 및 이성체에 관한 것이다. 상기 식에서, Q, R, R 1 , R 2 , R 3 , R 4 및 R 5 은 명세서중에 정의된 바와 같다.

Pesticidal arylpyrrolidines

Arylpyrrolidines of formula (I) wherein each substituent is as defined in the specification, and use thereof as pesticides and animal parasite-controlling agents.

Process for preparing enantiomerically pure diarylprolinols

The present invention relates to a new process for preparing enantiomerically pure diarylprolinols, especially (R)-(+)- or (S)-(-)-2-(diphenylhydroxymethyl)-pyrrolidine (R)-(+)- or (S)-(-)-α,α-diphenyl-(2-pyrrolidinyl)-methanol) starting from proline.

New synthetic method of glycopyrrolate and pharmaceutical formulations containing this active ingredient

본발명은 구조식 3의 α-사이클로펜틸만델릭산의 라세미체(R/S racemic)를 구조식 5의 1-메틸-3-피롤리디도놀 메틸브로마이드와 반응시켜서 구조식 I의 RS, SR의 라세미 글리코피롤레이트를 제조하는 방법에 관한 것이며. 본 발명의 새로운 글리코피롤레이트의 합성 방법은 반응시 생성하는 부산물이 결정화를 통해 쉽게 제거되고 정제 과장을 용이하게 하고 합성공정 시간을 단축 할 수 있었으며 미국약전 35개정 규격에 적합한 글리코피롤레이트를 합성 할 수 있었다. 또한 미 반응 물질의 회수가 용이 하고 RR체 또는 SS체의 글리코피롤레이트를 재이용함으로써 RS체 또는 SR체의 글리코피롤레이트의 수율을 증가 시킬 수 있는 계기가 되어 앞으로 그 수율은 회수 방식에 의하여 더욱 증가될 것으로 예상되는 우수한 제조 방법이다. The present invention The R / S racemic of? -Cyclopentylmandelic acid of formula 3 is reacted with 1-methyl-3-pyrrolididonol methyl bromide of formula 5 to give the RS of formula I, racemic glycopyrrol of SR ≪ / RTI > The new method of synthesizing glycopyrrolate of the present invention can easily remove the byproducts produced during the reaction by crystallization, facilitate purification and shorten the synthesis process time, and synthesize glycopyrrolate suitable for the US Pharmacopoeia 35 standard I could. In addition, recovery of the unreacted material is easy and the glycopyrrolate of the RR form or the SS form is reused to increase the yield of the glyceropyrrolate of the RS form or the SR form, and the yield is further increased by the recovery method It is an excellent manufacturing method that is expected to be.

Pegylated lipids and their use for drug delivery

The invention provides poly(ethylene glycol)-lipid conjugates for use in drug delivery.

11substituted 33pyrolidine and acid addition salt threof process for preparing same and blood pressure depressant