ПРИМЕНЕНИЕ ИНГИБИТОРОВ IkB-КИНАЗЫ ПРИ ОБЕЗБОЛИВАЮЩЕМ ЛЕЧЕНИИ

Изобретение относится к области фармакологии и медицины и касается применения ингибиторов IkB-киназы формулы (1а) для получения лекарственных средств для лечения болей, обладающих повышенной эффективностью. 4 з.п. ф-лы, 7 табл.

2,3-ДИГИДРО-1H-ПИРРОЛИЗИН-7-ФОРМАМИДНОЕ ПРОИЗВОДНОЕ И ЕГО ПРИМЕНЕНИЕ

Изобретение относится к 2,3-дигидро-1H-пирролизин-7-формамидному производному в качестве ингибитора нуклеопротеинов. Технический результат: получены новые соединения формулы (II), которые могут найти применение при получении лекарственного средства для лечения заболеваний, связанных с HBV. 4 н. и 16 з.п. ф-лы, 12 табл., 39 пр., 2 ил.

СОЛЬ ИНГИБИТОРА LSD1 И ЕЁ ПОЛИМОРФНАЯ ФОРМА

Изобретение относится к соединению III и его кристаллической форме A, характеризующейся дифрактограммой рентгеновской порошковой дифракции (XPDR), содержащей характеристические дифракционные пики при значениях угла 2θ: 4,72 ± 0,2°, 14,24 ± 0,2°, 16,28 ± 0,2°, 17,14 ± 0,2°, 20,72 ± 0,2°, 21,78 ± 0,2°, 23,98 ± 0,2° и 24,96 ± 0,2°. Соединение III по изобретению или его кристаллическую форму A применяют для получения лекарственного средства для лечения заболевания, связанного с ЛСД1. Также соединение III по изобретению или его кристаллическую форму A применяют для получения лекарственного средства для лечения рака легких. Технический результат – соединение III и его кристаллическая форма в качестве ингибитора ЛСД1. 4 н. и 8 з.п. ф-лы, 6 табл., 4 ил., 7 пр. Соединение III ...

АНИЛИДЫ АМИНОКИСЛОТ В КАЧЕСТВЕ НИЗКОМОЛЕКУЛЯРНЫХ МОДУЛЯТОРОВ IL-17

Изобретение относится к соединению формулы (I) или его фармацевтически приемлемым солям, которые обладают ингибирующей активностью в отношении IL-17. В формуле (I) R1 выбирают из группы, состоящей из 5-членного гетероарила, который содержит от 2 до 3 гетероатомов, выбранных из N, O и S, 9- или 10-членного бициклического гетероарила, который содержит от 2 до 3 гетероатомов, выбранных из N, O и S, фенила, (C1-C6)алкокси, (C3-C7)циклоалкокси, (C1-C6)алкила, фенил-(C1-C4)алкила, (C3-C7)циклоалкила и -NRcRd, где указанный 5-членный гетероарил, 9- или 10-членный бициклический гетероарил, фенил, (C1-C6)алкокси, (C3-C7)циклоалкокси, (C1-C6)алкил, фенил-(C1-C4)алкил и (C3-C7)циклоалкил необязательно замещен одним или более заместителями, независимо выбранными из Ra; Ra представляет собой галоген, гидрокси, -NRcRd, (C1-C6)алкил, (C3-C7)циклоалкил, фенил, 5- или 6-членный гетероарил, который содержит от 1 до 3 гетероатомов, выбранных из N, O и S, или 4-6-членный гетероциклоалкил, который содержит ...

ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ ДЛЯ ИНГИБИРОВАНИЯ АПОПТОЗА НЕЙРОНОВ ИЛИ НЕЙРОДЕГЕНЕРАЦИИ

Группа изобретений относится к медицине и фармации. Предложено применение соединения формулы I для изготовления лекарственного средства для: 1) нейропротекции, 2) для предупреждения или лечения нейродегенеративных заболеваний; предложены способы 1) защиты нейронов введением содержащей указанное соединение фармацевтической композиции и 2) предупреждения или лечения нейродегенеративных заболеваний введением указанной фармацевтической композиции. Технический результат: фармацевтическая композиция соединения формулы I за счёт антиоксидантного действия и стабилизации мембраны митохондрий в нейронах предотвращает их апоптоз и на модели болезни Паркинсона лечит заболевания, связанные с апоптозом или с нейродегенерацией. 4 н. и 4 з.п. ф-лы, 24 ил., 1 табл., 12 пр.

АКТИВАТОР KCNQ2-5 КАНАЛОВ

Изобретение относится к соединению, представленному общей формулой (I), или его фармацевтически приемлемой соли, которые могут найти применение для профилактики и/или лечения заболевания, связанного с KCNQ2-3 каналом. В формуле (I) X1 представляет собой C-R6; X2 представляет собой C-R7; R11 представляет собой (1) OR1 или (2) NH2; R1 представляет собой (1) атом водорода или (2) C1-4 алкильную группу; каждый R2 и R3 независимо представляет собой (1) атом водорода или (2) C1-4 алкильную группу, которая может быть замещена атомом галогена, где R2 и R3 не могут оба одновременно представлять собой атом водорода; каждый R4, R5, R6 и R7 независимо представляет собой (1) атом водорода, (2) атом галогена или (3) C1-4 алкильную группу, где R4 и R5 не могут оба одновременно представлять собой атом водорода; Y представляет собой (1) -NH- или (2) связь; R8 представляет собой (1) атом водорода или (2) C1-4 алкильную группу; R9 представляет собой (1) цикл A, (2) C1-6 алкильную группу, (3) -C1-4 алкилен-цикл ...

ТВЕРДЫЕ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, СОДЕРЖАЩИЕ ИНГИБИТОР ИНТЕГРАЗЫ

Описаны прессованные таблетки для перорального введения, содержащие ралтегравир в форме фармацевтически приемлемой соли. Таблетки содержат: (A) внутригранулярный компонент, содержащий (i) эффективное количество калиевой соли ралтегравира, (ii) первый суперразрыхлитель и (iii) связывающий агент; и (B) внегранулярный компонент, содержащий (i) второй суперразрыхлитель, (ii) наполнитель и (iii) смазывающий агент. Суперразрыхлитель представляет собой кроскармеллозу натрия, наполнитель представляет собой микрокристаллическую целлюлозу или комбинацию микрокристаллической целлюлозы и двухосновного фосфата кальция, смазывающий агент представляет собой стеарат магния. В состав таблетки не входит атазанавир или его фармацевтически приемлемая соль. Прессованные таблетки по изобретению характеризуются высокой нагрузкой по лекарственному веществу при приемлемом размере таблетки. 3 н. и 8 з.п. ф-лы, 1 ил., 3 пр.

СУЛЬФОНАМИДНОЕ СОЕДИНЕНИЕ ИЛИ ЕГО СОЛЬ

Изобретение относится к новому сульфонамидному соединению формулы (I), обладающему ингибирующей рибонуклеотидредуктазy активностью, и к фармацевтическим композициям, содержащим его в качестве активного ингредиента. Технический результат: получены новые соединения, обладающие ингибирующей рибонуклеотидредуктазy активностью, которые могут быть применимы в качестве противоопухолевого агента, где опухоль выбрана из группы, состоящей из рака молочной железы, рака желудка, рака легкого, рака поджелудочной железы, саркомы Юинга, глиобластомы, рака печени, мезотелиомы, рака простаты, рака яичников, рака почки, рака толстой и прямой кишки, меланомы и рака крови. 12 н. и 19 з.п. ф-лы, 4 ил., 21 табл., 354 пр.[Формула 1] ...

Блокаторы рецептора гормона роста при предупреждении заболеваний и лечении

Изобретение относится к способу ингибирования GH, GHR, STAT5, SOCS и с-fos, который включает идентификацию субъекта, имеющего заболевание или состояние с изменениями экспрессии или активности генов/белков, относящихся к GH, GHR, STAT5 и SOCS человека, или на которого изменения экспрессии или активности генов/белков, относящихся к GH, GHR, STAT5 и SOCS человека, могут оказывать благоприятный эффект; и введение терапевтически эффективного количества соединения, выбранного из группы, состоящей из:и их фармацевтически приемлемых солей. Технический результат - выявлена новая активность известных соединений и разработан способ ингибирования на их основе, который может найти применение в медицине для лечения рака, диабета, иммуносупрессии, болезни Альцгеймера и заболеваний и состояний, в отношении которых клеточная и тканевая регенерация оказывает благоприятный эффект. 16 з.п. ф-лы, 23 ил.

1,3,4-ОКСАДИАЗОЛЬНЫЕ ПРОИЗВОДНЫЕ СОЕДИНЕНИЯ В КАЧЕСТВЕ ИНГИБИТОРА ГИСТОНДЕАЦЕТИЛАЗЫ 6 И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СОДЕРЖАЩАЯ ИХ

Изобретение относится к 1,3,4-оксадиазольному производному соединению, представленному следующей формулой I, его стереоизомеру или его фармацевтически приемлемой соли, где L, Lили Lкаждый независимо представляют собой связь или -(C-Cалкилен)-; Rпредставляет собой -CXH или -CX; Rпредставляет собой -NRR, -OR, структуру (а) или структуру (b), где по меньшей мере один Н, входящий в состав структуры (а) или (b), может быть замещен -X, -OH, -NRRили -(C-Cалкил); Rпредставляет собой -(C-Cалкил), -(C-Cциклоалкил), -фенил, -пиридил, -пиримидинил, -тиофенил, -тиазолил, -тиадиазолил, -адамантил, структуру (с) или структуру (d), которые могут быть замещены; Y, Yи Yкаждый независимо представляют собой -CH-, -NR-, -O-, -C(=O)- или -S(=O)-; Yпредставляет собой -CH- или -N-; Z-Zкаждый независимо представляют собой N или CR, где три или четыре из Z-Zкаждый независимо представляют собой CR, и Rпредставляет собой -H, -X или -O(C-Cалкил); Zи Zкаждый независимо представляют собой -CH- или -O-; Zи Zкаждый независимо ...

ПРОИЗВОДНЫЕ (ИНДОЛ-3-ИЛ)ГЕТЕРОЦИКЛИЧЕСКИХ СОЕДИНЕНИЙ В КАЧЕСТВЕ АГОНИСТОВ КАННАБИНОИДНЫХ РЕЦЕПТОРОВ СВ1

Изобретение относится к новым производным (индол-3-ил)гетероциклическим соединениям формулы 1: ! ! где А представляет собой 5-членное ароматическое гетероциклическое кольцо, где ! Х1, Х2 и Х3 независимо выбирают из N, О, S, CR; R означает Н, (С1-4)алкил; или R, когда он присутствует в Х2 или Х3, может вместе с R3 образовывать 5-8-членное кольцо; R1 означает 5-8-членное насыщенное карбоциклическое кольцо, необязательно содержащее гетероатом О; R2 означает Н; или R2 соединен с R7 с образованием 6-членного кольца, необязательно содержащего гетероатом О, и где указанный гетероатом связан с положением 7 индольного кольца; R3 и R4 независимо означают Н, (С1-6)алкил, необязательно замещенный ОН, (С1-4)алкилокси; или R3 вместе с R4 и N, с которым они связаны, образует 4-8-членное кольцо, необязательно содержащее дополнительный гетероатом, выбранный из О и S, и необязательно замещенное ОН, (С1-4)алкилом, (С1-4)алкилокси или (С1-4)алкилокси-(С1-4)алкилом; или R3 вместе с R5 образует 4-8-членное кольцо ...

ГЕТЕРОЦИКЛИЧЕСКОЕ СОЕДИНЕНИЕ

Изобретение относится к группе новых химических соединений или его фармакологически приемлемым солям общей формулы I ! ! где А означает СООН; В означает Н; n равно 0; V означает -СН2-, одинарную связь; W означает 5-7-членную гетероароматическую группу с одним гетероатомом, выбранным из N, О, S, которая необязательно может быть замещена 1-3 заместителями, выбранными из группы заместителей А, в том случае, когда V представляет собой -CH2-группу, при этом в том случае, когда V означает одинарную связь, W означает бициклическую конденсированную кольцевую 9-членную гетероциклическую группу с одним гетероатомом, выбранным из О, S, которая необязательно может быть замещена 1-3 заместителями, выбранными из группы заместителей А; Х означает 5-7-членную гетероароматическую группу с одним атомом О и одним или двумя атомами N, которая необязательно может быть замещена 1-3 заместителями, выбранными из группы заместителей A; Y означает С6-С10 арил, который необязательно может быть замещен 1-3 заместителями ...

ПРОИЗВОДНЫЕ БЕНЗИМИДАЗОЛА В КАЧЕСТВЕ МОДУЛЯТОРОВ ROR-ГАММА

Изобретение относится к области органической химии, а именно к циклическому соединению формулы (I) или к его фармацевтически приемлемой соли, где X представляет собой –C(O)NH- или –NHC(O)-; R1выбран из (C1–C4)алкила, галоген(C1–C4)алкила, циклобутила, тетрагидрофуранила, (C1–C4)алкокси, -N((C1–C3)алкил)2, -(C1–C3)алкил-O-(C1–C2)алкила, -C(O)O(C1–C2)алкила и циклопропила, причем каждый из указанных циклобутила и циклопропила необязательно замещен C(=O)OMe, -CN или 1 галогеном; L2представляет собой CH2или CHMe; Cy1выбран из фенила, пиридила и пиперидинила, каждый из которых необязательно замещен 1-2 группами, которые независимо выбирают из R5; Cy2выбран из гетероциклических структур, указанных в п. 1, каждый из которых необязательно замещен 1-2 группами, которые независимо выбирают из R6; R5выбран из галогена, -CN, -ORc, -S(O)2NRdReи -SO2Rb; R6выбирают из галогена, оксо и (C1–C4)алкила; R7представляет собой водород, ORcили (C1–C3)алкил, необязательно замещенный ORc; R8, при наличии, представляет ...

Применение производного бета-морфолинопропиоамидоксима в качестве противодиабетического средства

Изобретение относится к медицине, а именно к эндокринологии, и касается лечения диабета. Для этого вводят эффективное количество О-пара-толуоил-β-(морфолин-1-ил)пропиоамидоксима. Это обеспечивает эффективное гипогликемическое действие, превышающее гипогликемическое действие препарата сравнения - метформина в 1,2 раза. 1 табл.

ГЕТЕРОЦИКЛИЧЕСКИЕ МОДУЛЯТОРЫ АКТИВНОСТИ HIF ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ

Изобретение относится к соединению структурной Формулы II или его фармацевтически приемлемой соли. В Формуле II два из Х2, Х4 и Х5 представляют собой N; и один из Х2, Х4 и Х5 представляет собой О; или один из Х2, Х4 и Х5 представляет собой N; один из Х2, Х4 и Х5 представляет собой О; и один из Х2, Х4 и Х5 представляет собой СН; Z1 и Z2 независимо выбраны из группы, состоящей из N, NR1, С=O и CR1; по меньшей мере один из Z1 и Z2 представляет собой CR1; Z3 выбран из группы, состоящей из N, и CR12; значения остальных радикалов указаны в формуле изобретения. Изобретение также относится к соединению структурной Формулы III, формула и значения радикалов для которого указаны в формуле изобретения, к индивидуальным соединениям, к фармацевтической композиции, к способу лечения заболеваний, к применению соединения в качестве лекарственного средства. Технический результат: получены новые соединения, которые могут быть полезными в качестве ингибиторов активности каскада HIF. 7 н. и 7 з.п. ф-лы, 11 ...

ПРОИЗВОДНЫЕ ИНДАЗОЛОНА В КАЧЕСТВЕ ИНГИБИТОРОВ 11B-HSD1

Изобретение относится к соединениям формулы (I) и их фармацевтически приемлемым солям, в которой R1-R7 имеют значения, приведенные в описании и формуле изобретения. Соединения формулы (I) являются специфическими ингибиторами 11b-HSD1. Они могут быть использованы для лечения и/или профилактики заболеваний, которые вызваны нарушениями, связанными с ферментом 11b-HSD1, в частности для лечения и/или профилактики метаболических заболеваний, ожирения, дислипидемии, гипертензии и/или диабета, особенно диабета II типа. Объектом изобретения также является фармацевтическая композиция, предназначенная для лечения и/или профилактики указанных выше заболеваний. 2 н. и 19 з.п. ф-лы, 1 табл.

БЕНЗОПИРАНОВЫЕ И БЕНЗОКСЕПИНОВЫЕ ИНГИБИТОРЫ РI3K И ИХ ПРИМЕНЕНИЕ

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ПРОИЗВОДНЫЕ БЕНЗИМИДАЗОЛА И ЕГО ПРИМЕНЕНИЕ

Настоящее изобретение относится к соединению формулы (I) ! ! в которой R1 представляет собой группу формулы ! , или в которой R2, R3, R4, R5, R6, R7 и R8, каждый, независимо представляет собой атом водорода или С1-6алкил или его соль, к способу его получения, к способу антагонистического воздействия на ангиотензин II у млекопитающего, к применению соединений формулы (I), а также к способам предотвращения или лечения заболеваний. Технический результат: получены и описаны новые соединения, которые могут найти свое применение в профилактике или лечении нарушений кровообращения, таких как гипертония и т.п., и нарушений обмена веществ, таких как диабет и т.п. 14 н. и 2 з.п.ф-лы, 2 табл.

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Изобретение относится к медицине. Фармацевтические композиции, включают в себя усилитель чувствительности к инсулину в сочетании с другими антидиабетическими препаратами, отличными от указанного усилителя по механизму действия, которые могут применяться для профилактики и лечения диабета. Предложенные композиции оказывают более сильное подавляющее действие в отношении гипергликемии. 2 с. и 31 з.п. ф-лы, 2 табл.

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Кардиотонические лекарственные средства, используемые в медицине для лечения сердечной недостаточности, содержат в качестве активного компонента по меньшей мере одно из соединений формулы I или их фармакологически приемлемых солей. где n = 0 или 1; А представляет собой OH или Н; В представляет собой атом водорода; X представляет собой атом кислорода, атом азота; R1 и R2 представляют собой атом водорода, C1-C4-алкил; R3 и R4 представляют собой атом водорода, C1-C6-алкил, C2-C6-алкенил, или С(=Y)ZR6, где Z=NH; Y=О,S, N-C≡N, или они вместе образуют 1,4-бутилен или 1,5-пентилен. Эти соединения обладают повышенной активностью по усилению сокращения сердечных мышц и сильной активностью по снижению скорости сердечного сокращения. 4 з.п.ф-лы, 6 табл.

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Изобретение относится к способу получения N-карбэтоксиметилимидазо[4,5-е]бензо[1,2-с;3,4-с’]дифуроксана, отличающемуся тем, что алкилирование имидазо[4,5-е]бензо[1,2-с;3,4-с’]дифуроксана проводят этиловым эфиром бромуксусной кислоты. Технический результат: новый способ позволяет повысить выход целевого продукта.

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СПОСОБ КОРРЕКЦИИ МЕТАБОЛИЧЕСКОГО СИНДРОМА В ЭКСПЕРИМЕНТЕ

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Новые пространственно-затрудненные фенолы, содержащие бензофуроксановые фрагменты, обладающие противоопухолевой активностью

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Изобретение относится к производным соединений 1,3,4-оксадиазола химической формулы I, где K, R1-R4, Z1-Z4, n, кольцо A определены в формуле изобретения, которые обладают ингибирующим действием на гистондеацетилазу 6 (HDAC6), их стереоизомерам или их фармацевтически приемлемым солям, фармацевтической композиции, включающей указанные соединения, и способу ингибирования гистондеацетилазы 6 (HDAC6). 3 н. и 7 з.п. ф-лы, 2 табл., 368 пр.

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... 1. Соединения формулы (I): где R1 представляет собой водород, низший алкил, арил или арил-низший алкил; R2 представляет собой арил, арил-низший алкил, гетероарил, гетероарил-низший алкил, циклоалкил, циклоалкил-низший алкил, фтор-низший алкил или низший алкил, где низший алкил необязательно замещен 1-3 заместителями, выбранными из группы, состоящей из ОН, CN, галогена, низшего алкокси и C(O)NR8R9; R3 представляет собой водород, галоген, низший алкил, фтор-низший алкил, низший алкокси или фтор-низший алкокси; R4 представляет собой водород, галоген, низший алкил, фтор-низший алкил, низший алкокси или фтор-низший алкокси; R5 представляет собой водород, галоген, низший алкил, фтор-низший алкил, низший алкокси или фтор-низший алкокси; R6 представляет собой водород или низший алкил; R7 представляет собой арил, гетероарил, фтор-низший алкил или низший алкил, где низший алкил необязательно замещен 1-3 заместителями, выбранными из группы, состоящей из ОН, CN, галогена, низшего алкокси и циклоалкила ...

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... 1. Лекарственное средство, включающее соединение формулы (I) ! ! в которой R1 представляет собой группу формулы ! ! в которых R2, R3, R4, R5, R6, R7 и R8, каждый, независимо представляет собой атом водорода или C1-6алкил, или его соль. ! 2. Лекарственное средство по п.1, которое является антагонистом ангиотензина II. ! 3. Лекарственное средство по п.1, которое является сенсибилизатором инсулина. ! 4. Лекарственное средство по п.1, которое предназначено для профилактики или лечения нарушений кровообращения. ! 5. Лекарственное средство по п.1, которое представляет собой средство для профилактики или лечения заболеваний, вызванных резистентностью к инсулину. ! 6. Лекарственное средство по п.1, которое представляет собой средство для профилактики или лечения нейродегенеративных заболеваний. ! 7. Лекарственное средство, включающее соединение формулы (I) ! ! в которой R1 представляет собой группу формулы ! ! в которых R2, R3, R4, R5, R6, R7 и R8, каждый, независимо представляет собой атом водорода ...

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Изобретение относится к области ветеринарии, а именно к офтальмологии, и предназначено для лечения и профилактики инфекционных воспалительных заболеваний глаз у домашних и сельскохозяйственных животных. Средство для лечения глазных заболеваний в ветеринарии включает три действующих вещества и фармацевтически приемлемый носитель. Действующими веществами являются н-гексадецилтрибутилфосфоний бромид в концентрации 0.0000001 вес.%, 5,7-дихлор-4,6-динитробензофуроксан в концентрации 0,00001 вес.% и 4,6-дихлор-5-нитробензофуроксан в концентрации 0,0001 вес.%. В качестве фармацевтически приемлемого носителя используют искусственную слезу, которая включает в свой состав гипромеллозу 0,3 вес.%, бензалкония хлорид 0,01 вес.%, динатрия эдетат 0,1 вес.%, натрия хлорид 0,2 вес.%, натрия фосфат однозамещенный двуводный 0,35 вес.%, натрия фосфат двузамещенный 12-водный 2,4 вес.%, остальное вода. Использование изобретения обеспечивает лечение и/или профилактику заболеваний глаз у животных. 1 з.п. ф-лы, ...

ПРОИЗВОДНЫЕ ФЕНИЛ-1,2,4-ОКСАДИАЗОЛОНА, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ФАРМАЦЕВТИЧЕСКИХ СРЕДСТВ

... 1. Соединения формулы I, ! ! где B обозначает C(R4) или N; ! R1 обозначает H, галоген, (C1-C8)алкил, (C0-C4)алкилен-O-(C0-C4)алкилен-H, (C3-C7)циклоалкил, SCH3, CN, где алкил и алкилен являются незамещенными или 1-5-кратно замещенными F; ! R2, R3, R4 независимо обозначают H, галоген, (C1-C8)алкил, (C0-C4)алкилен-O-(C0-C4)алкилен-H, SCH3, CN, где алкил и алкилен являются незамещенными или 1-5-кратно замещенными F; ! R2 и R3 вместе с C-атомами, к которым они присоединены, образуют (C6-C10)арильный или (C5-C10)гетероарильный цикл; ! X обозначает O, S, S(O), S(O)2, O-CH2, S-CH2, CH2-O, CH2-S; ! один из U и V обозначает N, другой обозначает S или O; ! W обозначает связь, (C1-C8)алкилен, (C2-C8)алкенилен, которые являются незамещенными или моно-, ди- или тризамещенными группами OH и F; ! Y обозначает связь, O, S, S(O), S(O)2, N(R6); ! R5 обозначает H, (C1-C8)алкил, (C0-C4)алкилен-(C3-C13)циклоалкил, (C0-C4)алкилен-(C6-C14)арил, (C2-C8)алкенил, (C0-C4)алкилен-(C3-C15)гетероциклоалкил, (C0-C4)алкилен ...

СУЛЬФОНАМИДНОЕ СОЕДИНЕНИЕ ИЛИ ЕГО СОЛЬ

ГРИЗЕОФУЛЬВИНОВОЕ СОЕДИНЕНИЕ

БЕНЗОПИРАНОВЫЕ И БЕНОКСЕПИНОВЫЕ ИНГИБИТОРЫ РI3K И ИХ ПРИМЕНЕНИЕ

... 1. Соединение, выбранное из соединений формулы I: ! ! Z1 представляет собой CR1 или N; ! Z2 представляет собой CR2 или N; ! Z3 представляет собой CR3 или N; ! Z4 представляет собой CR4 или N; ! где (i) X1 представляет собой N и X2 представляет собой S, (ii) X1 представляет собой S и X2 представляет собой N, (iii) X1 представляет собой CR7 и X2 представляет собой S или (iv) X1 представляет собой S и X2 представляет собой CR7; ! R1, R2, R3, R4 и R7 независимо выбраны из Н, F, Cl, Br, I, -CN, -СF3, -CH2OR10, -CH2R10, -(C1-C12 алкилен)NR10R11, -(C1-C12 алкилен)NR12C(=O)R10, -(C1-C12 алкилен)C(=O)NR10, -(C1-C12 алкилен)OR10, -CO2R10, C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, C(=O)NR10R11, -С(=O)NR10(С1-С12 алкилен)NR10R11, -C(=O)NR10(C1-C12 алкилен)NR10C(=O)OR11, -C(=O)NR10(C1-C12 алкилен)R11, -C(=O)NR10(C1-C12 алкилен)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12C(=O)(C1-C12 алкилен)NR10R11, -NR12(C1-C12 алкилен)NR10R11, -NR12(C1-C12 алкилен)OR10, - ...

ПРОИЗВОДНЫЕ 3-ГЕТЕРОАРОИЛАМИНОПРОПИОНОВОЙ КИСЛОТЫ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ

... 1. Соединение формулы I в любой из его стереоизомерных форм или в виде смеси стереоизомерных форм в любом отношении, или его физиологически приемлемая соль, или физиологически приемлемый сольват любого из них,в которой Нt выбран из группы, состоящей изG выбран из группы, состоящей из R-O-C(O)-, R-N(R)-С(O)-, NC- и тетразол-5-ила;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, CF, (С-C)-циклоалкил-CH-, Ar-CH-, Ar-O, (C-C)-алкил-O-, (C-C)-алкил-S(O)- и NC-; где s представляет собойцелое число, выбранное из группы, состоящей из 0, 1, 2 и 3;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, CF, (C-C)-алкил-O-, (C-C)-алкил-S(O)- и NC-;Rвыбран из группы, состоящей из водорода, (C-C)-алкила;Rвыбран из группы, состоящей из (C-C)-алкила, (С-C)-циклоалкил-CH- и Ar-CH-, где s представляет собой целое число, выбранное из группы чисел, состоящей из 0, 1, 2 и 3;Rвыбран из группы, состоящей из водорода, галогена, (C-C)-алкила, (C-C)-алкил-O-, (C-C)-алкил-S(О)- и NC-;Rвыбран ...

Блокаторы рецептора гормона роста при профилактике заболеваний и лечении

ИНГИБИТОРЫ ВАСЕ ДЛЯ ПРИМЕНЕНИЯ В ЛЕЧЕНИИ ДИАБЕТА

... 1. Соединение формулы I,,гдеRвыбран из группы, состоящей изi) арила иii) гетероарила,Rвыбран из группы, состоящей изi) H,ii) C-алкила иiii) -N(R,R);Rвыбран из группы, состоящей изi) H иii) C-алкила,Rвыбран из группы, состоящей изi) -CH-арила иii) -CH-гетероарила;или Rи Rвместе с азотом, к которому они присоединены, образуют пятичленный гетероциклил, возможно замещенный Z, или 3-аза-бицикло[3.2.1]октан-3-ил, возможно замещенный C-алкилом;Rвыбран из группы, состоящей изi) H иii) C-алкила;Rпредставляет собой -SO-C-алкил;n представляет собой 0, 1 или 2;m представляет собой 0, 1 или 2;А независимо выбран из группы, состоящей изi) ацетамидила,ii) ацетила,iii) амидо,iv) амино,v) C-алкокси,vi) C-алкила,vii) карбокси,viii) циано,ix) галогена,x) галоген-C-алкокси,xi) галоген-C-алкила,xii) гидрокси,xiii) -N(C-алкил, C-алкил) иxiv) -N(H, C-алкил),xv) -SO-C-алкила, представляет собой C-алкил;Z независимо выбран из группы, состоящей изi) арила, возможно замещенного 1 или 2 заместителями, независимо выбранными ...

ПРОИЗВОДНОЕ ОКСАДИАЗОЛА, ОБЛАДАЮЩЕЕ ИНГИБИРУЮЩЕЙ АКТИВНОСТЬЮ В ОТНОШЕНИИ ЭНДОТЕЛИАЛЬНОЙ ЛИПАЗЫ

... 1. Соединение формулы (I):,его фармацевтически приемлемая соль или сольват,гдекольцо А представляет собой ароматический карбоцикл или ароматический гетероцикл,Z представляет собой -NR-, -О- или -S-,Rпредставляет собой водород, замещенный или незамещенный алкил, замещенный или незамещенный алкенил, замещенный или незамещенный алкинил, замещенный или незамещенный арил, замещенный или незамещенный гетероарил, замещенный или незамещенный циклоалкил, замещенный или незамещенный циклоалкенил, замещенный или незамещенный гетероциклил, замещенный или незамещенный алкилоксикарбонил, или замещенный или незамещенный ацил,Rпредставляет собой водород, галоген, гидрокси, циано, нитро, карбокси, замещенный или незамещенный алкил, замещенный или незамещенный алкенил, замещенный или незамещенный алкинил, замещенный или незамещенный арил, замещенный или незамещенный гетероарил, замещенный или незамещенный циклоалкил, замещенный или незамещенный циклоалкенил, замещенный или незамещенный гетероциклил, замещенный ...

ПРОИЗВОДНЫЕ ИНДОЛИН-2-ОНА ИЛИ ПИРРОЛОПИРИДИН/ПИРИМИДИН-2-ОНА

СОЕДИНЕНИЕ ГРИЗЕОФУЛЬВИНА И ЕГО ФАРМАЦЕВТИЧЕСКОЕ ПРИМЕНЕНИЕ

КОМБИНИРОВАННАЯ ТЕРАПИЯ ДЛЯ ЛЕЧЕНИЯ СВЯЗАННЫХ С BCMA РАКОВЫХ ЗАБОЛЕВАНИЙ И АУТОИММУННЫХ РАССТРОЙСТВ

1,3,4,-ОКСАДИЗОЛАМИДНОЕ ПРОИЗВОДНОЕ СОЕДИНЕНИЕ В КАЧЕСТВЕ ИНГИБИТОРА ГИСТОНДЕАЦЕТИЛАЗЫ 6 И СОДЕРЖАЩАЯ ЕГО ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ

ПЕСТИЦИДНЫЕ КОМПОЗИЦИИ И СВЯЗАННЫЕ С НИМ СПОСОБЫ

СОЕДИНЕНИЯ ПИРРОЛИДИНИЛМОЧЕВИНЫ И ПИРРОЛИДИНИЛТИОМОЧЕВИНЫ КАК ИНГИБИТОРЫ КИНАЗЫ TRKA

... 1. Соединение Формулы I:или его стереоизомеры, таутомеры или фармацевтически приемлемые соли, сольваты или пролекарства, где:фрагмент Y-B и фрагмент NH-C(=X)-NH находятся в транс-конфигурации;R, R, Rи Rнезависимо выбраны из Н и (1-3С)алкила;X представляет собой О, S или NH;Rпредставляет собой (1-3С алкокси)(1-6С)алкил, (трифторметокси)(1-6С)алкил, (1-3С сульфанил)(1-6С)алкил, монофтор(1-6С)алкил, дифтор(1-6С)алкил, трифтор(1-6С)алкил, тетрафтор(2-6С)алкил, пентафтор(2-6С)алкил, циано(1-6С)алкил, аминокарбонил(1-6С)алкил, гидрокси(1-6С)алкил, дигидрокси(2-6С)алкил, (1-6С)алкил, (1-3С алкиламино)(1-3С)алкил, (1-4С алкоксикарбонил)(1-6С)алкил, амино(1-6С)алкил, гидрокси(1-3С алкокси)(1-6С)алкил, ди(1-3С алкокси)(1-6С)алкил, (1-3С алкокси)трифтор(1-6С)алкил, гидрокситрифтор(1-6С)алкил, (1-4С алкоксикарбонил)(1-3С алкокси)(1-6С)алкил, гидроксикарбонил(1-3С алкокси)(1-6С)алкил, гетAr(СН)или Ar(СН);Rпредставляет собой Н, F или ОН;Y представляет собой связь, -O- или -ОСН-;В представляет собой Ar ...

ПРОФИЛАКТИЧЕСКОЕ ИЛИ ТЕРАПЕВТИЧЕСКОЕ СРЕДСТВО ОТ АЛОПЕЦИИ

... 1. Профилактическое или терапевтическое средство от алопеции, включающее 1-[2-((2S)-2-{5-[(3,4-диметоксифенокси)метил]-1,2,4-оксадиазол-3-ил}пирролидин-1-ил)-1,1-дифтор-2-оксоэтил]-3,3,5,5-тетраметилциклогексанол в качестве активного ингредиента. ! 2. Профилактическое или терапевтическое средство от алопеции по п.1, являющееся препаратом для наружного применения. ! 3. Профилактическое или терапевтическое средство от алопеции по п.1 или 2, в котором от 0,00001 до 4 мг/см2 1-[2-((2S)-2-{5-[(3,4-диметоксифенокси)метил]-1,2,4-оксадиазол-3-ил}пирролидин-1-ил)-1,1-дифтор-2-оксоэтил]-3,3,5,5-тетраметилциклогексанола наносят на кожу головы. ! 4. Профилактический или терапевтический способ борьбы с алопецией, включающий введение млекопитающему 1-[2-((2S)-2-{5-[(3,4-диметоксифенокси)метил]-1,2,4-оксадиазол-3-ил}пирролидин-1-ил)-1,1-дифтор-2-оксоэтил]-3,3,5,5-тетраметилциклогексанола в количестве, эффективном для профилактики или лечения алопеции. ! 5. Профилактический или терапевтический способ борьбы ...

Therapeutic compounds

Chemical compounds

Antiinflammatory heterocyclic sulphones

Compounds of the formula are useful in the treatment of inflammatory processes, where
Het represents a C-bound heterocycle, and A represents an optional substituent on the heterocycle, m being from 0 to 3. D represents an optionally substituted (C 1 -C 4 )-alkandiyl, E represents CH=CH, CH=N or N=CH, and G represents a group of the formula wherein R2 represents H or (C 1 -C 6 )-alkyl,
R1, R3 and R4 are groups selected from hydrogen, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 6 -C 10 )-aryloxy or (C 1 -C 6 )-alkyl, and R5 is optionally substituted (C 6 -C 10 )-aryl, (C 5 -C 10 )-heteroaryl, (C 3 -C 8 )-cycloalkyl or (C 1 -C 7 )-alkyl.

Treatment

Novel compounds, methods for their manufacture, and uses thereof

Synthetic cannabinoid analogue compounds of formula (I), wherein X is a group as defined herein. Also provided is a pharmaceutical composition of compounds of formula (I). Also provided is a compound of formula (I), or pharmaceutical composition, for use in a method of treatment, or for use as a medicament; which may be for use in the treatment of, or for use as a medicament for treating, epilepsy, generalised seizure, tonic-clonic seizure. Also provided is a method of preparing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III), both defined herein. The method may use a palladium catalyst. Also provided is a method of preparing compounds of formula (I), comprising reacting a compound of formula (II) with bis(pinacolato)diboron (B2pin2), and reacting the product of that with a compound of formula (IV). The steps of the method may use a palladium catalyst. Also provided is an intermediate compound of formula (II), for use in the preparation ...

Oxazoline and isoxazoline derivatives as crac modulators

Triazolone compounds as mPGES-1 inhibitors

Heteroaryl compounds as 5-HT4 receptor ligands

Compounds with antiparasitic activity and medicines containing same.

3-Ox (adi) azolylpropanohydroxamic acids useful as procollagen c-proteinase inhibitors

COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS

INDAZOLE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS

Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders

COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS

Compounds with antiparasitic activity and medicines containing same

Haloalkyl heteroaryl benzamide compounds

3-OX(ADI)AZOLYLPROPANOHYDROXAMIC ACIDS USEFUL AS PROCOLLAGEN C-PROTEINASE INHIBITORS

Compound of formula (I): wherein X is C1-6alkylene or C2-6 alkenylene, each of which is optionally substituted by one or more fluorine atoms; R is aryl or C3-8 cycloalkyl optionally substituted by one or more fluorine atoms; W is N or CZ; are procollagen C-proteinase (PCP) inhibitors useful in treating conditions mediated by PCP.

Inhibitors of AKT activity

Compounds with antiparasitic activity and medicines containing same.

Cyclic bridgehead ether DGAT1 inhibitors

Heteroaryl compounds as 5-HT4 receptor ligands

Oxazoline and isoxazoline derivatives as crac modulators

CYCLIC BRIDGEHEAD ETHER DGAT1 INHIBITORS.

AUTOTAXIN INHIBITORS COMPRISING A HETEROAROMATIC RING-BENZYL-AMIDE-CYCLE CORE

HETEROARYL BUTANOIC ACID DERIVATIVES AS LTA4H INHIBITORS

Haloalkyl heteroaryl benzamide compounds.

New indanyloxydihydrobenzofuranylacetic acid derivatives and their use as GPR40 receptor agonists

Oxazoline and isoxazoline derivatives as crac modulators

Combination os azilsartan and chlorthlidone for treating hypertension black patients

Heteroaryl compounds as 5-HT4 receptor ligands

Small molecule inhibitors for the treatment or prevention of denque virus infection.

INDAZOLE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS

3-Ox (adi) azolylpropanohydroxamic acids useful as procollagen c-proteinase inhibitors

Combination os azilsartan and chlorthlidone for treating hypertension black patients

Triazolone compounds as mPGES-1 inhibitors

Composed with pest-destroying activity and drugs containing them.

Use of IKB-kinase inhibitors for the treatment of pain.

Compounds with antiparasitic activity and medicines containing same.

Cyclic bridgehead ether DGAT1 inhibitors

Triazolone compounds as mPGES-1 inhibitors

Heteroaryl compounds as 5-HT4 receptor ligands

Small molecule inhibitors for the treatment or prevention of denque virus infection.

HETEROARYL BUTANOIC ACID DERIVATIVES AS LTA4H INHIBITORS

Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders

AUTOTAXIN INHIBITORS COMPRISING A HETEROAROMATIC RING-BENZYL-AMIDE-CYCLE CORE

Haloalkyl heteroaryl benzamide compounds.

Bicyclic compounds and use as antidiabetics

The present invention relates to novel compounds that are useful in the treatment of metabolic disorders, particularly type II diabetes mellitus and related disorders, and also to the methods for the making and use of such compounds.

Medicinal package

The present invention relates to a medicinal package comprising a medicinal preparation capable of giving out smells, a packaging component and a chemical absorption-type desiccant. According to the present invention, a medicinal package wherein unpleasant smells are reduced is provided.

Nitrogen-containing aromatic heterocyclyl compound

The present invention provides a compound having excellent regulating action on blood lipid level that is represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein, in one embodiment, A represents a 5-membered nitrogen-containing aromatic heterocyclyl group; R 1 represents COOH; each R 2 represents an alkyl; each R 3 represents an optionally substituted phenyl, an optionally substituted phenylalkyl; m represents 0, 1, 2, or 3; n represents 0 or 1; each of R 4 , R 5 , R 6 , and R 7 represents H, an alkyl; and B represents an optionally substituted naphthyl, an optionally substituted aromatic heterocyclyl, or a group represented by the following formula (II) wherein each of B 1 and B 2 represents an optionally substituted phenyl or an optionally substituted aromatic heterocyclyl.

Novel modulators of sphingosine phosphate receptors

Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.

Pharmaceutical composition for inhibiting apoptosis of neuron or neurodegeneration

Provided is a pharmaceutical composition for inhibiting apoptosis of neurons or neurodegeneration. The pharmaceutical composition effectively prevents or treats diseases related to apoptosis of neurons or neurodegeneration.

Compounds and methods

Disclosed are compounds having the formula: wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , Y, A, Z, L and n are as defined herein, and methods of making and using the same.

Antiviral Compounds and Methods of Use Thereof

Inhibitors of retroviral propagation, methods of treatment and prevention of retroviral infections using the inhibitors, and pharmaceutical compositions including the inhibitors, are disclosed. 1. (canceled)34-. (canceled)6. (canceled)7. The composition of claim 5 , wherein at least one of R4 claim 5 , R5 claim 5 , R6 claim 5 , R7 claim 5 , R15 claim 5 , R16 claim 5 , and R17 is other than H.8. (canceled)9. The composition of claim 1 , further comprising an additional antiviral agent.10. The composition of claim 9 , wherein the additional antiviral agent is an entry inhibitor claim 9 , integrase inhibitor claim 9 , reverse transcriptase inhibitor claim 9 , protease inhibitor claim 9 , or an immune-based therapeutic agent.11. A method of treating a retroviral infection claim 1 , comprising administering a composition of .12. The method of claim 11 , wherein the inhibitor inhibits retroviral reverse transcription.13. The method of claim 11 , wherein the inhibitor inhibits viral recruitment of the retroviral primer used in translation claim 11 , human tRNA.14. The method of claim 11 , wherein the inhibitor inhibits the final packaging and assembly of new virions.15. The method of claim 11 , wherein the inhibitor inhibits the binding of a host cell tRNA to a target nucleic acid molecule.16. The method of claim 11 , further comprising the co-administration of a second antiretroviral compound.17. The method of claim 16 , wherein the second antiretroviral agent is selected from the group consisting of NRTIs claim 16 , NNRTIs claim 16 , VAP anti-idiotypic antibodies claim 16 , CD4 and CCR5 receptor inhibitors claim 16 , entry inhibitors claim 16 , antisense oligonucleotides claim 16 , ribozymes claim 16 , protease inhibitors claim 16 , neuraminidase inhibitors claim 16 , tyrosine kinase inhibitors claim 16 , PI-3 kinase inhibitors claim 16 , and Interferons.18. The method of any of claim 11 , wherein the retrovirus is selected from the group consisting of Feline ...

Polycyclic compounds as lysophosphatidic acid receptor antagonists

Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.

INHIBITORS OF JUN N-TERMINAL KINASE

The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula: 3. The compound of claim 1 , wherein ring A is chosen from thiophene claim 1 , thiazole claim 1 , and pyrazole claim 1 , wherein the thiophene claim 1 , the thiazole claim 1 , or the pyrazole is optionally substituted with 1 or 2 substituents chosen from C-C-alkyl claim 1 , C-C-alkenyl claim 1 , C-C-alkynyl claim 1 , C-C-haloalkyl claim 1 , 2- to 4-membered heteroalkyl claim 1 , C-C-cycloalkyl claim 1 , 3- to 6-membered heterocycloalkyl claim 1 , CN claim 1 , and halogen.6. The compound of claim 1 , wherein W is methylene (—CH—).7. The compound of claim 1 , wherein Ris H.8. The compound of claim 1 , wherein Cy is chosen from phenyl claim 1 , naphthyl claim 1 , quinoline claim 1 , isoquinoline claim 1 , quinoxaline claim 1 , quinazoline claim 1 , 3 claim 1 ,4-dihydroquinolin-2-one claim 1 , and 3 claim 1 ,4-dihydro-1 claim 1 ,6-naphthyridin-2-one claim 1 , each optionally substituted with 1-6 substituents independently chosen from C-C-alkyl claim 1 , C-C-alkenyl claim 1 , C-C-alkynyl claim 1 , C-C-haloalkyl claim 1 , 2- to 6-membered heteroalkyl claim 1 , C-C-cycloalkyl claim 1 , 3- to 8-membered heterocycloalkyl claim 1 , aryl claim 1 , 5- or 6-membered heteroaryl claim 1 , CN claim 1 , halogen claim 1 , OR claim 1 , SR claim 1 , NRR claim 1 , C(O)R claim 1 , C(O)NRR claim 1 , OC(O)NRR claim 1 , C(O)OR claim 1 , NRC(O)R claim 1 , NRC(O)OR claim 1 , NRC(O)NRR claim 1 , NRC(S)NRR claim 1 , NRS(O)R claim 1 , S(O)NRR claim 1 , S(O)Rand S(O)R claim 1 ,wherein{'sup': 52', '53', '55', '52', '53, 'sub': 1', '6', '3', '8, 'R, Rand Rare independently chosen from H, acyl, C-C-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C-Ccycloalkyl and 3- to 8-membered heterocycloalkyl, wherein Rand R, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and'}{'sup ...

USES OF SELECTIVE INHIBITORS OF HDAC8 FOR TREATMENT OF INFLAMMATORY CONDITIONS

Described herein are methods for treating a subject suffering from an inflammatory, autoimmune, or heteroimmune condition by administering to the subject a pharmaceutical composition containing a therapeutically effective amount of a compound that is a selective inhibitor of histone deacetylase 8. Also described herein are methods for decreasing secretion of pro-inflammatory cytokines by administering an HDAC8-selective inhibitor compound. Further described herein are methods for predicting responsiveness to treatments for inflammatory conditions. Methods for predicting efficacy of treatments for inflammatory conditions are also described. 1. A method for treating an inflammatory condition in a subject in need thereof , comprising administering to the subject a composition containing a therapeutically effective amount of a selective inhibitor of histone deacetylase 8 activity.2. The method of claim 1 , wherein (a) the secretion of IL-1β in a sample taken from the subject is inhibited by at least 40% claim 1 , and/or (b) the swelling on the skin of the subject decreases by at least 30% after administering the therapeutically effective amount of the selective inhibitor of histone deacetylase 8 activity.3. The method of claim 1 , wherein the inflammatory condition is a skin inflammatory condition claim 1 , autoimmune condition claim 1 , or heteroimmune condition.4. The method of claim 1 , wherein the inflammatory condition is rheumatoid arthritis or psoriasis.5. The method of claim 1 , wherein the subject is refractory or intolerant to at least one other treatment for an inflammatory condition.6. The method of claim 1 , wherein the composition is administered in combination with an additional anti-inflammatory agent.7. The method of claim 6 , wherein the additional anti-inflammatory agent is an immunosuppressant claim 6 , glucocorticoid claim 6 , non-steroidal anti-inflammatory drug claim 6 , Cox-2 specific inhibitor claim 6 , leflunomide claim 6 , gold thioglucose ...

Reversed biaryl spiroaminooxazoline analogues as alpha2c adrenergic receptor modulators

In its many embodiments, the present invention provides a novel class of biaryl spiroaminooxazoline analogues as modulators of α2C adrenergic receptor agonists, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.

Method Of Treating Acute Lung Injury Using Sphingosine 1 Phosphate Analogs Or Sphingosine 1 Phosphate Receptor Agonists

The invention provides methods for treating or reducing the risk of developing acute lung injury manifested by increased vascular permeability. Also provided are pharmaceutical compositions comprising an FTY720 analog or derivative and/or SEW 2871 for use in the disclosed methods. The invention also provides methods for treating or reducing the risk of developing acute lung injury resulting from dysregulation of ceramide/sphingolipid pathway, more specifically, acute lung injury resulting from radiation.

Oxadiazole Diaryl Compounds

The invention relates to compounds of formula (I): 2. The compound according to claim 1 , wherein Rdenotes Ar or Het.5. The compound according to claim 2 , wherein Ar or Het is substituted by methyl claim 2 , trifluoromethyl or methoxy.7. The compound according to claim 1 , wherein said compound has an EC50 in GTPγS for the binding to the S1Preceptor of less than about 5 μM.9. A pharmaceutical composition comprising at least one compound according to and an excipient or adjuvant.10. The pharmaceutical composition according to claim 9 , further comprising at least one further active ingredient.11. A kit consisting of separate packs of:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(a) an effective amount of a compound according to , and'}(b) an effective amount of an additional active ingredient.12. A method for the treatment and/or prophylaxis of a sphingosine 1-phosphate associated disorder comprising the administration of a composition according to to an individual having said disorder.13. The method according to claim 12 , wherein the sphingosine 1-phosphate-(1) associated disorder is an autoimmune disorder or condition associated with an overactive immune response.14. The method according to claim 12 , wherein said disorder is an immunerogulatory abnormality.15. The method according to claim 14 , wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosis claim 14 , chronic rheumatoid arthritis claim 14 , type I diabetes mellitus claim 14 , inflammatory bowel disease claim 14 , biliary cirrhosis claim 14 , uveitis claim 14 , multiple sclerosis claim 14 , amyotrophic lateral sclerosis (ALS) claim 14 , Crohn's disease claim 14 , ulcerative colitis claim 14 , bullous pemphigoid claim 14 , sarcoidosis claim 14 , psoriasis claim 14 , autoimmune myositis claim 14 , Wegener's granulomatosis claim 14 , ichthyosis claim 14 , Graves ophthalmopathy claim 14 , bone marrow ...

Chemical Compounds

The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfon-amide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein X, Ar, R, R, R, Rand Rare as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain. 2. A compound according to wherein X is —OCH—.3. A compound according to wherein X is —CHO—.4. A compound according to wherein Aris phenyl independently substituted by one to three Y.5. A compound according to wherein Arphenyl independently substituted by one or two Y.6. A compound according to wherein Aris phenyl meta-substituted by Y claim 1 , para-substituted by Y claim 1 , or meta- and para-substituted by independent Y.7. A compound according to wherein Y is F; Cl; CN; (C-C)alkyl claim 1 , optionally substituted by (C-C)cycloalkyl or one to three F; (C-C)cycloalkyl claim 1 , optionally substituted by one to three F; (C-C)alkyloxy claim 1 , optionally substituted by one to three F; or (C-C)cycloalkyloxy.8. A compound according to wherein Ris (C-C)alkyl or (C-C)cycloalkyl.9. A compound according to wherein Ris (C-C)alkyl or (C-C)cycloalkyl.10. A compound according to wherein R claim 1 , Rand Rare independently H claim 1 , F or Cl.11. A compound according to wherein Ris H; CN; F; Cl; (C-C)alkyl claim 1 , optionally substituted by one to three F; or (C-C)alkyloxy claim 1 , optionally substituted by one to three F.12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together claim 1 , as defined in claim 1 , with one or more pharmaceutically acceptable excipients.13. A pharmaceutical composition according to including one or more additional therapeutic agents.14. (canceled)15. (canceled)16. (canceled)17. ( ...

MODULATORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF USING THE SAME

The present invention is directed to modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof. 2. The compound of wherein Ring A is heterocyclyl optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.3. The compound of wherein Ring A is 5- or 6-membered heterocyclyl optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.4. The compound of wherein Ring A is 5-membered heterocyclyl optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.5. The compound of wherein Ring A is 5-membered heterocyclyl containing at least one ring-forming N atom and Ring A is optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.6. The compound of wherein Ring A is 5-membered heterocyclyl containing at least one ring-forming O atom and Ring A is optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.7. The compound of wherein Ring A is 5-membered heterocyclyl containing at least one ring-forming O atom and containing at least one ring-forming N atom claim 1 , and Ring A is optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 R.10. The compound of wherein Ris H claim 1 , C(O)R claim 1 , C(O)NRR claim 1 , or C(O)OR.11. The compound of wherein Ris H.12. The compound of wherein Ris H.13. The compound of wherein a and b are both 0.14. The compound of wherein Ris aryl claim 1 , cycloalkyl claim 1 , heteroaryl claim 1 , or heterocycloalkyl claim 1 , each optionally substituted by 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 substituents independently selected from halo claim 1 , Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Chaloalkyl claim 1 , Chydroxyalkyl claim 1 , Cy claim 1 , CN claim 1 , NO claim 1 , OR claim 1 , SR claim 1 , C(O)R claim 1 , C(O)NRR claim 1 , C(O)OR claim 1 , OC(O)R claim 1 , OC(O)NRR claim 1 , NRC(O)NRR claim 1 , NRR claim 1 , NRC(O)R claim 1 , NRC(O)OR claim 1 , C(═NR)NRR claim 1 , NRC(═NR)NRR claim 1 , P(R) claim 1 , P( ...

Methods

The disclosure relates to compounds of formula (I) for use in the treatment or prophylaxis of rhinovirus infection, methods of treating or preventing rhinovirus infection employing said compounds or pharmaceutical composition comprising the same. The disclosure also relates to compounds of formula (I) for use in the treatment or prophylaxis of exacerbation of respiratory disorders (such as asthma, COPD, bronchitis and/or cystic fibrosis) by rhinovirus infection. 2. A compound of formula (I) according to claim 1 , wherein Ar is naphthyl.3. A compound of formula (I) according to or claim 1 , wherein Ris tert-butyl.4. A compound of formula (I) according to any one of to claim 1 , wherein Ris methyl.5. A compound of formula (I) according to any one of to claim 1 , wherein Ris in the para position.6. A compound of formula (I) according to any one of to wherein Ris H.7. A compound of formula (I) according to any one of to claim 1 , wherein NRC(O)Q is selected from: —NRC(O)CHOCalkyl claim 1 , —NRC(O)CHO(CH)OCH claim 1 , —NRC(O)CH(CH)OCH claim 1 , —NRC(O)CHNHCH claim 1 , —NRC(O)CHNHCHCHOCH claim 1 , —NRC(O)CHSCH claim 1 , —NRC(O)NH claim 1 , —NRC(O)CHS(O)CH claim 1 , —NRC(O)NHCalkyl claim 1 , —NRC(O)N(Calkyl)Calkyl claim 1 , and —NRC(O)CHN[(CH)OCH].8. A compound of formula (I) according to claim 7 , wherein NRC(O)Q is selected from: —NHC(O)CHOCH; —NHC(O)CHO(CH)OCH; —NHC(O)CH(CH)OCH; —NHC(O)CHNHCH; —NHC(O)CHNH(CH)OCH claim 7 , —NHC(O)CHSCH; —NHC(O)NH; —NHC(O)CHS(O)CH; —NHC(O)NHCH; —NHC(O)N(CH); and —NHC(O)CHN[(CH)OCH].14. A compound of formula (I) according to claim 1 , wherein the compound is selected from:N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-(2-methoxyethoxy)acetamide;N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-(methylthio)acetamide;N-(4-(4-(3-(3- ...

BENZOPYRAN AND BENZOXEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Benzopyran and benzoxepin compounds of Formulas I and II, and including stereoisomers, geometric isomers, tautomer solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formulas I and II for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. 2. The method of wherein Xis N and Xis S.3. The method of wherein Xis S and Xis CR.6. The method of wherein the compound of formula I is selected from:N2-(2-chlorophenyl)-N2,N8,N8-trimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide;7-acetamido-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N2-(2-chlorophenyl)-N8-(3-(diethylamino)propyl)-N2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide;N-(2-chlorophenyl)-7-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-chlorophenyl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-chloro-4-fluorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2,4-dichlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;2-(4-isopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamide;1-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-3-methylurea;methyl 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-ylcarbamate;7-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide;N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide;N-(4-(3-amino-5-methyl-1H-pyrazole-1-carbonyl)-2-chlorophenyl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d] ...

Modulators of sperm hypermobility and uses thereof

The invention provides novel compositions and compounds that inhibit CatSper channel activity, that preferentially inhibits sperm hyperactivity over sperm motility, or both. The compounds of the invention are useful as contraceptive agents that may be adminstered to males, females, or concurrently to both sexual partners. The invention further provides methods of conducting drug discovery business and of conducting a reproductive medicine business. The invention also provides methods of identifying compounds that modulate sperm hypermotility.

METHOD OF USING DOPAMINE REUPTAKE INHIBITORS AND THEIR ANALOGS FOR TREATING DIABETES SYMPTOMS AND DELAYING OR PREVENTING DIABETES-ASSOCIATED PATHOLOGIC CONDITIONS

Method of using dopamine reuptake inhibitors, e.g., sydnonimine derivatives, for the management of diabetic symptoms and associated complications or conditions, such as hyperglycemia and diabetic neuropathy. 1. A method for treatment of symptoms of Type II diabetes and delay of onset or prevention of occurrence of pathologic conditions associated with Type II diabetes in a patient in need thereof , said method comprising administering an amount of a dopamine reuptake inhibitor that is effective for said treatment and said delay or prevention.3. The method of claim 2 , wherein said dopamine reuptake inhibitor is selected from the group consisting of 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(p-methylbenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(p-carboxybenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-phenethyl-sydnonimine-N-phenylcarbamoyl claim 2 , 3-phenethyl-sydnonimine-N-(3′ claim 2 ,4′-dichloro-phenyl)-carbamoyl claim 2 , 3-(p-nitrophenethyl)-sydnonimine-N-(3′ claim 2 ,4′-dinitro-phenyl)-carbamoyl claim 2 , 3-(p-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-benzyl-sydnonimine-N-phenylcarbamoyl claim 2 , 3-phenethyl-sydnonimine-N-(p-chlorophenyl)-carbamoyl claim 2 , 3-phenethyl-sydnonimine-N-(m-trifluoromethyl)-phenylcarbamoyl claim 2 , 3-(3′ claim 2 ,5′-difluorobenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(m-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(p-trifluoromethyl-benzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(p-tert-butylbenzyl)-sydnonimine-N-phenylcarbamoyl claim 2 , 3-(p-methylbenzyl)-sydnonimine-N-(p′-trifluoromethyl-phenyl)carbamoyl claim 2 , and 3-(p-methylbenzyl)-sydnonimine-N-(p-dimethylamino-phenyl)carbamoyl.4. The method of claim 1 , wherein said dopamine reuptake inhibitor is administered in combination with a therapeutic agent for Type II diabetes selected from the group consisting of glucophage claim 1 , glyburide claim 1 , repaglinide claim 1 , acarbose claim 1 , pramlintide and ...

Di-Substituted Amides for Enhancing Glutamatergic Synaptic Responses

This invention relates to compounds, pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors. These brain networks, which are involved in regulation of breathing, and cognitive abilities related to memory impairment, such as is observed in a variety of dementias, in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as Parkinson's disease, schizophrenia, respiratory depression, sleep apneas, attention deficit hyperactivity disorder and affective or mood disorders, and in disorders wherein a deficiency in neurotrophic factors is implicated, as well as in disorders of respiration such as overdose of an alcohol, an opiate, an opioid, a barbiturate, an anesthetic, or a nerve toxin, or where the respiratory depression results form a medical condition such as central sleep apnea, stroke-induced central sleep apnea, obstructive sleep apnea, congenital hypoventilation syndrome, obesity hypoventilation syndrome, sudden infant death syndrome, Rett syndrome, spinal cord injury, traumatic brain injury, Cheney-Stokes respiration, Ondines curse, Prader-Willi's syndrome and drowning. In a particular aspect, the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment. 138-. (canceled)43. A method of treating respiratory depression in a patient or subject in need comprising administering to said patient or subject an effective amount of a compound according to .44. A method of treating respiratory depression in a patient or subject in need comprising administering to said patient or subject an effective amount of a compound according to .45. A method of treating respiratory depression in a patient or subject in need comprising administering to said patient or subject an effective amount of a ...

Autotaxin inhibitors and uses thereof

Described herein are compounds that are inhibitors of autotaxin. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such inhibitors, alone and in combination with other compounds, for treating autotaxin-dependent or autotaxin-mediated conditions or diseases.

IMMUNOTHERAPY USING REDIRECTED ALLOGENEIC CELLS

A method of treating a disease, such as cancer, by administering to a subject in need of such treatment an effective amount of allogeneic T cells with a MHC unrestricted chimeric receptor short time after partial lymphodepletion. The method also comprises administering one or more agents that delay egression of the allogeneic T cells from lymph nodes of said subject during adoptive transfer of said allogeneic T cells to the subject by trapping the T cells in the lymph nodes. 1. A method of treating cancer , said method comprising subjecting a patient in need of such treatment to partial lymphodepletion , and then administering to the patient an effective amount of allogeneic T cells expressing an MHC unrestricted tumor-directed chimeric receptor , wherein said partial lymphodepletion is to an extent sufficient to delay the host versus graft reaction for a period sufficient to allow said allogeneic T cells to attack the tumor to which they are directed , but to an extent insufficient to require rescue of the host immune system by bone marrow transplantation.2. A method in accordance with claim 1 , further including administration of one or more agents that delay egression of the allogeneic T cells from lymph nodes of said subject claim 1 , after adoptive transfer of said allogeneic T cells to the subject claim 1 , by trapping the T cells in the lymph nodes.3. The method of claim 1 , wherein the agent that traps T cells in the lymph node is selected from the group consisting of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 claim 1 ,3-diol (FTY720) claim 1 , 5-[4-phenyl-5-(trifluoromethyl)thiophen-2-yl]-3-[3-(trifluoromethyl)phenyl]1 claim 1 ,2 claim 1 ,4-oxadiazole (SEW2871) claim 1 , 3-(2-(-hexylphenylamino)-2-oxoethylamino)propanoic acid (W123) claim 1 , and 2-ammonio-4-(2-chloro-4-(3-phenoxyphenylthio)phenyl)-2-(hydroxymethyl)butyl hydrogen phosphate (KRP-203 phosphate).4. The method of claim 1 , wherein the tumor-directed chimeric receptor is antibody-based.5. The ...

Methods for inhibition of cell proliferation, synergistic transcription modules and uses thereof

The invention provides for methods for treating nervous system cancers in a subject. The invention further provides methods for treating nervous system tumor cell invasion, migration, proliferation, and angiogenesis associated with nervous system tumors.

METHODS FOR TREATING HYPERTENSION IN BLACK PATIENTS

The present invention relates to methods of treating hypertension in a black patient using a therapeutically effective amount of a combination of an angiotensin II receptor blocker and chlorthalidone. 1. A method of lowering blood pressure in a black patient in need of treatment thereof , the method comprising the steps of:preferentially selecting a therapeutically effective amount of at least one angiotensin II receptor blocker (ARB) from a class of ARBs to lower the blood pressure in a black patient, wherein the ARB selected is azilsartan medoxomil; andadministering a combination of a therapeutically effective amount of the azilsartan medoxomil and a therapeutically effective amount of chlorthalidone to lower the blood pressure of the black patient.2. The method of claim 1 , wherein the patient is administered 20 mg once per day of azilsartan medoxomil.3. The method of claim 1 , wherein the patient is administered 40 mg once per day of azilsartan medoxomil.4. The method of claim 1 , wherein the patient is administered 80 mg once per day of azilsartan medoxomil.5. The method of claim 1 , wherein the chlorthalidone is administered simultaneously or sequentially with the azilsartan medoxomil.6. The method of claim 1 , wherein the chlorthalidone and azilsartan medoxomil are administered as separate dosage forms.7. The method of claim 1 , wherein the chlorthalidone and azilsartan medoxomil are administered in a single dosage form.8. The method of claim 1 , wherein the patient is administered 12.5 mg once per day of chlorthalidone.9. The method of claim 1 , wherein the patient is administered 25 mg once per day of chlorthalidone.10. The method of claim 1 , wherein the patient is administered 20 mg of azilsartan medoxomil and 25.0 mg of chlorthalidone once per day.11. The method of claim 1 , wherein the patient is administered 40 mg of azilsartan medoxomil and 25.0 mg of chlorthalidone once per day.12. The method of claim 1 , wherein the patient is administered 80 mg of ...

Substituted heterocyclyl benzyl pyrazoles, and use thereof

The present application relates to novel substituted 1-[3-(heterocyclyl)benzyl]-1H-pyrazole derivatives, to processes for preparation thereof, to use thereof for treatment and/or prevention of diseases and to use thereof for production of medicaments for treatment and/or prevention of diseases, more particularly for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be effected in the form of monotherapy or else in combination with other medicaments or further therapeutic measures. 4. A compound according to claim 1 , in which{'sup': '1', 'Ris hydroxyl,'}and{'sup': '2', 'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'm, n and Rare each as defined in ,'}and the salts, solvates and solvates of the salts thereof.9. (canceled)10. (canceled)11. (canceled)12. (canceled)13. (canceled)14. A pharmaceutical composition comprising a compound as defined in combination with one or more inert claim 1 , nontoxic claim 1 , pharmaceutically suitable excipients.15. A pharmaceutical composition comprising a compound as defined in in combination with one or more further active ingredients.16. (canceled)17. (canceled)18. A method for the treatment and/or prevention of a cancer or tumour in a human or animal in need thereof comprising administering to the human or animal an effective amount of at least one compound as defined in .19. A method for the treatment and/or prevention of ischaemic cardiovascular diseases claim 1 , heart failure claim 1 , myocardial infarction claim 1 , arrhythmia claim 1 , stroke claim 1 , pulmonary hypertension claim 1 , fibrotic diseases of the kidney and lung claim 1 , psoriasis claim 1 , diabetic retinopathy claim 1 , macular degeneration claim 1 , rheumatic arthritis or Chuvash polycythaemia in a human or animal in need thereof claim 1 , comprising administering to the human or animal an effective amount of at least one compound as ...

SUBSTITUTED N- [1-CYANO-2- (PHENYL) ETHYL] -2-AZABICYCLO [2.2.1] HEPTANE-3-CARBOXAMIDE INHIBITORS OF CATHEPSIN C

Disclosed are N-1-cyano-2-(phenyl)ethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamides of formula I 2. The compound according to whereinn is 0, 1, 2, 3 or 4;{'sup': '1', 'sub': '2', 'is Ris Me-, F—, HO—, MeO—, HN;'}{'sup': '2', 'sub': 1-6', '2-6', '3-6', '3-6, 'claim-text': [{'sub': '5-7', 'sup': '2.1', 'a monocyclic C-heterocyclyl-, wherein one or two carbon atoms are replaced by heteroatoms selected from —O— or —N— and the ring is fully or partially saturated, optionally substituted independently from each other with one, two, three or four R;'}, {'sub': '8-10', 'sup': '2.1', 'a bicyclic C-heterocyclyl-, wherein one, two, three or four carbon atoms are replaced by heteroatoms selected from —S—, —O— or —N— and the ring is fully or partially saturated, optionally substituted independently from each other with one, two, three or four R;'}, {'sub': '5-10', 'sup': '2.1', 'a C-heteroaryl-, wherein one, two or three carbon atoms are replaced by heteroatoms selected from —O— or —N— and the ring is aromatic, optionally substituted independently from each other with one, two, three or four R;'}, {'sup': '2.1', 'aryl-, optionally substituted independently from each other with one, two, three or four R;'}, {'sup': '2.1', 'aryl-(O)C—HN—, optionally substituted independently from each other with one, two, three or four R;'}], 'Ris selected from the group consisting of halogen, C-alkyl-, C-alkenyl-, C-cycloalkyl-, C-cycloalkenyl- or a ring system selected from the group consisting of'}{'sup': '2.1', 'sub': 1-4', '3-6', '1-4', '1-4', '2', '1-4', '2', '1-4', '2', '1-4', '3-6', '1-4', '1-4', '1-4', '2', '2', '1-4', '2', '1-4', '2', '1-4, 'Ris halogen, C-alkyl-, C-cycloalkyl-, O═, C-alkyl-(O)C—, C-alkyl-(O)S—, C-alkyl-(O)SO—, (C-alkyl)N(O)C—, C-alkyl-HN(O)C—, C-cycloalkyl-(O)C—, phenyl-C-alkyl-, MeO—C-alkyl-, NC—, (C-alkyl)N(O)S—, C-alkyl-HN(O)S—, (C-alkyl)(HO)C— or phenyl-, optionally substituted with C-alkyl-O—;'}or a salt thereof.3. The compounds according to whereinn is 0, 1, 2 or 3 ...

N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase

The present invention is directed to N-hydroxyamidino compounds which are modulators of indoleamine 2,3-dioxygenase (IDO), as well as pharmaceutical compositions thereof and methods of use thereof relating to the treatment of cancer and other diseases.

NOVEL GLP-1 RECEPTOR MODULATORS

The invention relates to compounds that modulate the glucagon-like peptide 1 (GLP-1) receptor, methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds are act as modulators or potentiators of GLP-1 receptor on their own, or with receptor ligands including GLP-1 peptides GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “” represents either or both the R and S form of the compound): 2. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and A is a 5- or 6-membered heteroaryl group.4. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and A is a 5- or 6-membered non-aromatic heterocycyl group.6. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and C is aryl.8. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and C is heterocyclyl.10. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and B is aryl or arylalkyl.12. The compound of wherein Yand Yare null claim 1 , Z is —C(O)— and B is heterocyclyl or heterocyclylalkyl.14. The compound of wherein Yand Yare null claim 1 , Z is —S(O)—.16. The compound of wherein where Yis null claim 1 , Yis —O— and Z is —C(O)—.18. The compound of wherein where Yis NH claim 1 , Yis null and Z is —C(O)—.20. A pharmaceutical composition comprising a compound of together with at least one pharmaceutically acceptable carrier claim 1 , diluent or excipient.21. A pharmaceutical combination comprising the compound of and a second medicament.22. The pharmaceutical combination of wherein the second medicament is an agonist or modulator for glucagon receptor claim 21 , GIP receptor claim 21 , GLP-2 receptor claim 21 , or PTH receptor claim 21 , or glucagon-like peptide 1 (GLP-1) receptor.23. The pharmaceutical combination of wherein the second medicament is exenatide claim 21 , liraglutide claim 21 , taspoglutide claim 21 , albiglutide claim 21 , or ...

Bisaryl-bonded aryltriazolones and use thereof

The present application relates to novel bisaryl-linked 5-aryl-1,2,4-triazolone derivatives, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.

Bicyclic amides for enhancing glutamatergic synaptic responses

This invention relates to bicyclic amide compounds, pharmaceutical compositions and methods for use in the prevention and treatment of a variety of conditions and/or disease states including cerebral insufficiency, through the enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors as defined herein. These brain networks, which are involved in regulation of breathing, and cognitive abilities related to memory impairment, such as is observed in a variety of dementias, in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as Parkinson's disease, schizophrenia, respiratory depression, sleep apneas, attention deficit hyperactivity disorder and affective or mood disorders, and in other disorders wherein a deficiency in neurotrophic factors is implicated, as well as other disorders as described herein.

HETEROCYCLICALLY SUBSTITUTED ARYL COMPOUNDS AS HIF INHIBITORS

The present application relates to novel aryl compounds with heterocyclic substituents, processes for their preparation, their use for treatment and/or prevention of diseases and their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be carried out as monotherapy or also in combination with other medicaments or further therapeutic measures. 12. (canceled)13. (canceled)14. (canceled)15. (canceled)16. (canceled)17. A pharmaceutical composition comprising compound as defined in in combination with one or more inert claim 1 , non-toxic claim 1 , pharmaceutically suitable auxiliary substances.18. A pharmaceutical composition comprising compound as defined in in combination with one or more further active compounds.19. (canceled)20. (canceled)21. Method for the treatment and/or prevention of cancer diseases or tumour diseases comprising administering an effective amount of at least one compound as defined in to a human or animal in need thereof.22. Method for the treatment and/or prevention of ischaemic cardiovascular diseases claim 1 , cardiac insufficiency claim 1 , cardiac infarction claim 1 , arrhythmia claim 1 , stroke claim 1 , pulmonary hypertension claim 1 , fibrotic diseases of the kidney and lung claim 1 , psoriasis claim 1 , diabetic retinopathy claim 1 , macular degeneration claim 1 , rheumatic arthritis and Chugwash polycythaemia comprising administering an effective amount of at least one compound as defined in to a human or animal in need thereof. The present application relates to novel aryl compounds with heterocyclic substituents, processes for their preparation, their use for treatment and/or prevention of diseases and their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular for treatment ...

Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis

Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the S1P receptor. Methods of chiral synthesis of such compounds are provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.

PDE10 INHIBITORS AND RELATED COMPOSITIONS AND METHODS

Compounds that inhibit PDE10 are disclosed that have utility in the treatment of a variety of conditions, including (but not limited to) psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders. Pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs of the compounds are also provided. Also disclosed are compositions containing a compound in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for inhibiting PDE10 in a warm-blooded animal in need of the same. 11. A pharmaceutical composition of wherein Ris hydrogen.12. A pharmaceutical composition of wherein Ris Calkyl.13. A pharmaceutical composition of wherein Ris methyl.14. A pharmaceutical composition of wherein Ris Calkyl.15. A pharmaceutical composition of wherein Ris methyl.16. A pharmaceutical composition of wherein Ris ethyl.17. A pharmaceutical composition of wherein Ris substituted or unsubstituted phenyl.18. A pharmaceutical composition of wherein Ris substituted phenyl.19. A pharmaceutical composition of wherein Ris 4-bromo-3 claim 18 ,5-dimethoxyphenyl.20. A pharmaceutical composition of wherein Ris 4-chloro-3 claim 18 ,5-dimethoxyphenyl.21. A pharmaceutical composition of wherein Ris 3 claim 18 ,4 claim 18 ,5-trimethoxyphenyl.22. A pharmaceutical composition of wherein Ris substituted or unsubstituted aryl.23. A pharmaceutical composition of wherein Ris substituted or unsubstituted phenyl.24. A pharmaceutical composition of wherein Ris substituted phenyl.25. A pharmaceutical composition of wherein Ris phenyl substituted with Calkoxy.26. A pharmaceutical composition of wherein Ris phenyl substituted with substituted or unsubstituted ...

DUAL-ACTING OXAZOLE ANTIHYPERTENSIVE AGENTS

In one aspect, the invention relates to compounds having the formula: 1. (canceled)5. The method of claim 16 , where Ris propyl claim 16 , ethyl claim 16 , butyl claim 16 , or ethoxy.6. The method of claim 16 , where Ris —CHSH claim 16 , —CHN(OH)C(O)H claim 16 , —CHC(O)NH(OH) claim 16 , —CH(OH)C(O)NH(OH) claim 16 , —CH(OH)COOH claim 16 , or —CHCOOH.7. The method of claim 16 , where Ris —CH—S—C(O)CH claim 16 , —CH(OH)COOCH claim 16 , or —CHCOOCH.8. The method of claim 16 , where Ris i-butyl claim 16 , —CH-furan-2-yl claim 16 , —CH-thiophen-3-yl claim 16 , benzyl claim 16 , 2-bromobenzyl claim 16 , 2-chlorobenzyl claim 16 , 2-fluorobenzyl claim 16 , 3-fluorobenzyl claim 16 , 4-fluorobenzyl claim 16 , 2-methylbenzyl claim 16 , or 2-trifluoromethylbenzyl.1215-. (canceled) This application claims the benefit of U.S. Provisional Application No. 61/227,473, filed on Jul. 22, 2009; the entire disclosure of which is incorporated herein by reference.1. Field of the InventionThe present invention relates to novel compounds having angiotensin II type 1 (AT) receptor antagonist activity and neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat diseases such as hypertension.2. State of the ArtThe aim of antihypertensive therapy is to lower blood pressure and prevent hypertension-related complications such as myocardial infarction, stroke, and renal disease. For patients with uncomplicated hypertension (that is, no risk factors, target organ damage, or cardiovascular disease), it is hoped that reducing blood pressure will prevent development of cardiovascular and renal comorbidities, conditions that exist at the same time as the primary condition in the same patient. For those patients with existing risk factors or comorbidities, the therapeutic target is the slowing of comorbid disease progression and reduced ...

SUBSTITUTED 8-ALKOXY-2-AMINOTETRALIN DERIVATIVES, AND USE THEREOF

The present application relates to novel substituted 8-alkoxy-2-aminotetraline derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders. 5. (canceled)6. A method for the treatment and/or prevention of heart failure claim 1 , angina pectoris claim 1 , hypertension claim 1 , pulmonary hypertension claim 1 , ischemias claim 1 , vascular disorders claim 1 , thromboembolic disorders and arteriosclerosis comprising administering and effective amount of a compound of to a human or animal in need thereof.7. (canceled)8. A pharmaceutical composition comprising a compound of in combination with one or more inert claim 1 , non-toxic claim 1 , pharmaceutically suitable excipients.9. The pharmaceutical composition of claim 8 , further comprising an at least one active ingredients selected from the group consisting of an organic nitrate claim 8 , an NO donors claim 8 , a cGMP-PDE inhibitor claim 8 , a stimulator of guanylate cyclase claim 8 , an agent having antithrombotic activity claim 8 , an agent lowering blood pressure claim 8 , and an agent altering lipid metabolism.10. (canceled) The present application relates to novel substituted 8-alkoxy-2-aminotetraline derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO/cGMP system. Guanylate cyclases catalyze the biosynthesis of cGMP from ...

COMPOUND USEFUL FOR THE TREATMENT OF NONSENSE-MUTATION-MEDIATED DISEASES AND PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPOUND

The present invention relates to the compound of formula (I) 112-. (canceled)15. The method according to claim 14 , wherein the compound of formula (I) is administered through injection.16. The method according to claim 14 , further comprising administering to the subject an agent able to enhance readthrough of the mRNA premature stop-codon claim 14 , said mRNA premature stop-codon coming from the translation of the gene comprising thenonsense-mutation.17. The method according to claim 16 , wherein the agent is 3-[5-(2-fluorophenyl)-1 claim 16 ,2 claim 16 ,4-oxadiazol-3-yl]benzoic acid.18. The method according to claim 16 , wherein the compound of formula (I) and the agent are administered simultaneously claim 16 , sequentially or over a period of time.19. (canceled)22. The method according to claim 14 , wherein said genetic disease is selected from: nonsense-mutation-mediated beta-thalassemia claim 14 , nonsense-mutation-mediated Ehlers-Danlos syndrome claim 14 , nonsense-mutation-mediated severe myoclonic epilepsy of infancy claim 14 , nonsense-mutation-mediated achromatopsia claim 14 , nonsense-mutation-mediated retinitis pigmentosa claim 14 , nonsense-mutation-mediated Usher Syndrome Type 1C claim 14 , nonsense-mutation-mediated adducted thumb-clubfoot syndrome claim 14 , nonsense-mutation-mediated Alagille syndrome claim 14 , nonsense-mutation-mediated Alström syndrome claim 14 , nonsense-mutation-mediated antithrombin deficiency claim 14 , nonsense-mutation-mediated Carney complex claim 14 , nonsense-mutation-mediated Currarino syndrome claim 14 , nonsense-mutation-mediated Diamond-Blackfan anemia claim 14 , nonsense-mutation-mediated erythropoietic protoporphyria claim 14 , nonsense-mutation-mediated Fabry disease claim 14 , nonsense-mutation-mediated factor XIII deficiency claim 14 , nonsense-mutation-mediated Fanconi-Bickel syndrome claim 14 , nonsense-mutation-mediated fish odor syndrome claim 14 , nonsense-mutation-mediated Gaucher disease claim 14 , ...

Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis

Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the S1P receptor. Methods of chiral synthesis of such compounds are provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.

Hydroxamate-based inhibitors of deacetylases

The present teachings relate to compounds of Formula (I): and pharmaceutically acceptable salts, hydrates, esters, and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , ring A, and Z are as defined herein. The present teachings also provide methods of preparing compounds of Formula (I) and methods of use compounds of Formula (I) in treating pathologic conditions or disorders mediated wholly or in part by deacetylases.

NEW INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS

The present invention relates to compounds of general formula I, 3. A compound according to claim 2 , wherein{'sup': '1', 'Ris selected from the group consisting of a phenyl ring, a 5-membered heteroaromatic ring which contains 2 or 3 heteroatoms independently of each other selected from ═N—, —NH—, —O— and —S—, and a 6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms;'}{'sup': N', '3, 'wherein in said 5-membered heteroaromatic ring the H-atom in one or more NH groups is replaced with Ror R, and'}{'sup': 3', '4, 'wherein each of said phenyl ring, tetrazolyl ring, and heteroaromatic rings is substituted with one group Rand optionally additionally substituted with 1 or 2 substituents independently selected from R;'}{'sup': N', '3', '4, 'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'wherein R, Rand Rare defined as in ,'}or a salt thereof.6. A compound according to to claim 2 , wherein{'sup': '3', 'sub': 1-4', '1-4', '3-6, 'Ris selected from the group consisting of C-alkyl, C-alkyl-O—, and C-cycloalkyl-O—,'}{'sup': '5', 'wherein each alkyl and cycloalkyl group and each alkyl and cycloalkyl sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from Rand optionally substituted with 1 to 3 F atoms;'}or from{'sub': 3', '2', '3, 'C-alkyl-S(═O)— substituted with 1 HO— or HC—O— group; and'}{'sub': 2', '3', '2', '2', '1-3', '1-4', '3-6', '1-4', '2', '2, 'sup': N', 'N', 'N', 'N', 'N, 'heterocyclyl-C(═O)—, HN—C(═O)—, HO—(HC)O—CH—NH—C(═O)—, C-alkyl-NR—C(═O)—, C-alkyl-C(═O)NR—, C-cycloalkyl-C(═O)NR—, heterocyclyl-O(═O)NR—, C-alkyl-S(═O)NR—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, heterocyclyl-S(═O)—, heterocyclyl, phenyl, and heteroaryl,'}{'sup': '5', 'wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from Rand optionally substituted with 1 or more F atoms; and'}{'sup': '6', 'wherein each phenyl and heteroaryl ...

Nitric oxide donors in therapy of nitric oxide deficiency-induced disturbances of cerebral microcirculation

The present invention relates to nitric oxide releasing compounds and their use in the prevention, amelioration and/or therapy of nitric oxide (NO) deficiency induced disturbances of the cerebral microcirculation. The NO deficiency induced disturbances of the cerebral microcirculation may be due to an intracranial hemorrhage or stroke and can cause cerebrovascular spasms (or cerebral vasospasms) (CVS) and/or malperfusion of brain parenchyma caused by blood vessel and blood flow dysregulation which, in turn, can cause secondary neurological deficiencies (DIND) and/or brain infarction. Particularly, the present invention relates to the prevention, amelioration and/or therapy of delayed cerebral vasospasm-associated disorders after survived subarachnoidal hemorrhage by applying a NO-donor, most preferably Molsidomine.

LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS FOR THE TREATMENT OF CONDITIONS OR DISEASES OF THE EYE

Described herein is the use of LPA1 antagonists in the treatment or prevention of diseases or conditions of the eye of a mammal. Also described are pharmaceutical compositions that include at least one LPA1 antagonist. 1. An ophthalmic formulation comprising an LPA1 receptor antagonist and at least one suitable pharmaceutically acceptable excipient , wherein the formulation is in a form suitable for administration to the eye of a mammal.2. The ophthalmic formulation of claim 1 , wherein the LPA1 receptor antagonist is in an amount effective for the treatment of an ophthalmic disease or condition in a mammal claim 1 , and the ophthalmic formulation is in the form of a solution claim 1 , suspension claim 1 , emulsion claim 1 , ointment claim 1 , cream claim 1 , lotion claim 1 , gel claim 1 , colloidal dispersion claim 1 , or spray.3. (canceled)4. The ophthalmic formulation of claim 1 , wherein the ophthalmic formulation is in the form of a solution that is administered to the mammal in the form of an eye drop or eye ointment.5. (canceled)9. (canceled)10. The ophthalmic formulation of claim 6 , wherein the LPA1 receptor antagonist is:(R)-2-(4′-(3-methyl-4-((1-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A):(R)-1-(4′-(3-methyl-4-((1-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)cyclopropanecarboxylic acid (Compound B):(R)-2-(4′-(4-((1-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound C):{5-[4′-(1-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid (R)-1-phenyl-ethyl ester (Compound D):1-(4′-{4-[(R)-1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound E):1-{4′-[4-((R)-1-Phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound F):(3-Methyl-5-{4′-[1-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl}-isoxazol-4-yl)-carbamic ...

Use in brain degenerative diseases

Disclosed is a new use for sphingosine-1-phosphate (S1P) receptor agonists in the treatment of progressive dementia or brain degenerative diseases.

CYCLIC BRIDGEHEAD ETHER DGAT1 INHIBITORS

The invention relates to compounds of formula (I): 5. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein p is 1.6. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein p is 2.7. The compound according to or a salt or solvate thereof claim 1 , wherein Z claim 1 , Z claim 1 , Zand Zare all CH.8. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein Zis N and Z claim 1 , Zand Zare each CH.9. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein Zis N and Z claim 1 , Zand Zare each CH.10. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein Zand Zare both N and Zand Zare both CH.11. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein L is C(O).12. The compound according to claim 1 , or a salt or solvate thereof claim 1 , wherein L is absent.16. The compound of claim 1 , or a salt or solvate thereof claim 1 , which compound is selected from:2-(4-(4′-((5-cyclobutyl-1,3,4-thiadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(4-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(4-(4-(5-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(4-(4-(5-(2-ethyl-4-methyloxazole-5-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(4-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;2-(1-(4′-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;2-(1-(4-(5-((5-cyclobutyl-1, ...

Composition and Method for Treating a Neurodegenerative Event

Disclosed is an article of manufacture featuring a support with a therapeutically effective amount of at least one fatty acid amide hydrolase (FAAH) inhibitor therein. The article has several uses and advantages including use to increase levels of at least one neurotrophin in a subject in need of such treatment. Also disclosed is a method of increasing levels of the neurotrophin in an animal by administering to a subject in need thereof at least one FAAH inhibitor. 1. An article of manufacture comprising a support comprising a therapeutically effective amount of at least one fatty acid amide hydrolase (FAAH) inhibitor or a physiologically acceptable salt thereof for release into an orifice , wound or surgical site in which each is in need of an increase of at least one neurotrophin.2. The article of manufacture of claim 1 , wherein the support further comprises an adhesive surface adapted to provide contact between the support and the orifice claim 1 , wound or surgical site in need of the increase of the neurotrophin.3. The article of manufacture of claim 1 , wherein the support comprises a stent adapted to elute the FAAH inhibitor into the orifice claim 1 , wound or surgical site.4. The article of manufacture of claim 1 , wherein the support comprises one or more of a surgical dressing or polymer adapted to retain the FAAH inhibitor therein.5. The article of manufacture of claim 2 , wherein the support comprises one or more of a surgical dressing or polymer adapted to retain the FAAH inhibitor therein.6. The article of manufacture of claim 3 , wherein the support comprises one or more of a surgical dressing or polymer adapted to retain the FAAH inhibitor therein.7. A method for preventing claim 3 , treating claim 3 , and/or reducing symptoms of a neurodegenerative event in a subject claim 3 , the method comprising administering a therapeutically effective amount of at least one fatty acid amide hydrolase (FAAH) inhibitor or a physiologically acceptable salt ...

NOVEL FORMULATIONS OF FACTOR VIIa INHIBITORS AND UTILITY

A method for treating a subject, such as a human patient, having a vascular disorder. The treatment method administers a therapeutic effective amount of a nanoparticle or a chemical structure to the subject to treat the disorders. The nanoparticle includes a poly L-arginine polymer and a Factor VIIa inhibitor conjugated to, or encapsulated in, the poly L-arginine polymer. The chemical structure includes a Factor VIIa inhibitor that includes at least one nitric oxide (NO) donor. The disorder may be sickle cell disease; stimulated or pathological angiogenesis associated disorders, cancer, ocular angiogenesis-mediated disorders such as diabetic retinopathy and macular degeneration, coagulation and/or platelet activation-associated disorders, pulmonary hypertension, or combinations thereof. 2. The method of claim 1 , wherein the Factor VIIa inhibitor is encapsulated in the poly L-arginine polymer and is not covalently bonded to the poly L-arginine polymer.3. The method of claim 1 , wherein the Factor VIIa inhibitor is conjugated to the poly L-arginine polymer by being covalently bonded to the poly L-arginine polymer.4. The method of claim 1 , wherein the poly L-arginine polymer is cross-linked with at least one substance selected from the group consisting of chitosan claim 1 , poly (lactic-co-glycolic) acid (PLGA) claim 1 , fatty acids claim 1 , bile acids claim 1 , amino acids claim 1 , hyaluronic acid claim 1 , and combinations thereof.5. The method of claim 1 , wherein the poly L-arginine polymer is cross-linked to chitosan.6. The method of claim 1 , wherein the Factor VIIa inhibitor does not include any nitric oxide (NO) donor.7. The method of claim 1 , wherein the Factor VIIa inhibitor includes at least one nitric oxide (NO) donor.8. The method of claim 1 , wherein said administrating comprises administrating the therapeutic effective amount in the range of 0.1-10 mg per kilogram of body weight of the subject.9. The method of claim 1 , wherein the vascular disorder ...

PYRROLIDINONES AS METAP-2 INHIBITORS

Compounds of the formula I in which R, R, Rand Rhave the meanings indicated in Claim , are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours. 4. Compounds according to in which{'sup': '3', 'sub': 3', '2, 'Rdenotes OH, N, NHor F,'}and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.5. Compounds according to in which{'sub': 2', 'n', '2', '2', 'n', '2', 'n', '2', '2', '2, 'sup': '1', 'Het denotes pyridazinyl, pyrazolyl, benzimidazolyl, pyridyl, dibenzofuranyl, carbazolyl, indolyl, dihydroindolyl, benzofuranyl, dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl, chromanyl, piperazinyl, morpholinyl, tetrahydropyranyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pyrimidinyl, indazolyl, furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazole, benzothiazolyl, imidazo[1,2-a]pyridinyl, 1,3-benzodioxolyl, benzoxazolyl, piperidin-1-yl, pyrrolidin-1-yl, 1,2-oxazinan-2-yl, 1,2,5-oxadiazinan-2-yl, 1,3-oxazinan-3-yl or hexahydropyrimidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OA, COOA, COA, CHO, (CH)CONH, (CH)CONHA, (CH)CONA, SOA, NHSOA, ═O and/or Het,'}and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.10. A pharmaceutical composition comprising at least one compound of the formula I according to and/or pharmaceutically usable salts claim 1 , tautomers and stereoisomers thereof claim 1 , including mixtures thereof in all ratios claim 1 , and one or more excipients and/or adjuvants.11. A method for the treatment of tumours claim 1 , tumour metastases claim 1 , proliferative diseases of the mesangial cells claim 1 , haemangioma claim 1 , proliferative retinopathy claim 1 , ...

SEROTONIN REUPTAKE INHIBITORS

In one aspect, the invention relates to compounds of formula I: 1. (canceled)2. The method of claim 20 , where Y is —CH—.3. The method of claim 20 , where Ris selected from —Calkyl optionally substituted with 1 to 5 fluoro atoms claim 20 , —O—Calkyl optionally substituted with 1 to 5 fluoro atoms claim 20 , and —NO.4. The method of claim 3 , where Ris —Calkyl optionally substituted with 1 to 5 fluoro atoms.5. The method of claim 4 , where Ris —CF.6. The method of claim 20 , where Ris selected from hydrogen and —CN.7. The method of claim 20 , where Ris hydrogen.8. The method of claim 20 , where n is 1.9. The method of claim 20 , where Q is —NRSOR.10. The method of claim 9 , where Ris selected from hydrogen claim 9 , —CH claim 9 , and —C(O)CH.11. The method of claim 9 , where Ris selected from —CH; —CHCH; —CH(CH); cyclopropyl; —NH; —NH(CH); —N(CH); —CHSO—CH; pyrazole; pyrazole substituted with —CH; triazole; morpholine; benzoxadiazole; and phenyl optionally substituted with R; where Ris selected from —CN claim 9 , —COOH claim 9 , —NO claim 9 , —OCH claim 9 , —C(O)NHCH claim 9 , —NHC(O)CH claim 9 , —SO—CH claim 9 , —SO—NH claim 9 , —SO—NHCH claim 9 , oxazole claim 9 , pyrimidine claim 9 , tetrazole claim 9 , pyrazole claim 9 , and pyrazole substituted with two methyl groups.12. The method of claim 20 , where Q is —SONRR.13. The method of claim 12 , where Ris selected from hydrogen and —CH.14. The method of claim 12 , where Ris selected from hydrogen claim 12 , —CH claim 12 , and benzyl.1519-. (canceled)21. The method of claim 20 , where the disease is pulmonary arterial hypertension. This application claims the benefit of U.S. Provisional Application No. 61/419,346, filed on Dec. 3, 2010; the entire disclosure of which is incorporated herein by reference.1. Field of the InventionThe present invention relates to and 2-phenoxy-2-pyrrolidin-3-yl-ethylsulfonamide and 2-phenoxy-2-pyrrolidin-3-ylethanesulfonic acid amide compounds having activity as serotonin (5-HT) reuptake ...

Inhibitors of HIV Infections and uses thereof

The invention relates to compounds which are agonists of at least one receptor selected from S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 receptors, for use in methods for treating HIV infections in humans or animals. 1. A compound which is an agonist of at least one receptor selected from S1PR1 , S1PR2 , S1PR3 , S1PR4 and S1PR5 receptors , for use in a method for treating an HIV infection in humans or animals.2. The compound as claimed in claim 1 , characterized in that said agonist is an S1PR1 receptor agonist.3. The compound as claimed in either one of and claim 1 , characterized in that said agonist is also an agonist of at least one receptor selected from S1PR2 claim 1 , S1PR3 claim 1 , S1PR4 and S1PR5.4. The compound as claimed in either one of and claim 1 , said compound being selected from the group comprising sphingosine-1-phosphate claim 1 , FTY720 claim 1 , FTY720-P claim 1 , AUY954 claim 1 , CYM-5442 claim 1 , CYM-5181 claim 1 , SEW2871 claim 1 , VPC01091 claim 1 , DS-SG-44 claim 1 , KRP-203-P claim 1 , DihydroS1P claim 1 , Compound 26 claim 1 , Compound 12 claim 1 , sphingosylphosphorylcholine and AFD-R.54. The compound as claimed in any one of - claims 1 , said compound being FTY720 or FTY720-P.65. A pharmaceutical composition for use in a method for treating an HIV infection in humans or animals claims 1 , said composition comprising a compound as defined in any one of - and a pharmaceutically acceptable vehicle.75. The compound as claimed in any one of - claims 1 , or the composition as claimed in claims 1 , said HIV infection being an HIV-1 infection.85. The compound as claimed in any one of - claims 1 , or the composition as claimed in claims 1 , said HIV infection being an HIV-2 infection. The invention relates to compounds which are agonists of a receptor selected from S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 receptors, for use in the treatment of HIV infections.The human immunodeficiency virus (HIV) is a retrovirus which infects human beings and is ...

NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF METABOLIC AND INFLAMMATORY DISEASES

Compounds are disclosed that have a formula represented by the following: 3. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Y is Me claim 1 , Et claim 1 , Pr claim 1 , iPr claim 1 , or —CH-Ph.5. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Ris —(CH)—COOH claim 1 , —(CH)—COOH claim 1 , —(CH)—SONH claim 1 , or —(CH)—SONHMe.6. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Cyis phenyl claim 1 , or naphthalene.7. A compound or pharmaceutically acceptable salt thereof claim 1 , according to claim 1 , wherein Cyis thiophenyl claim 1 , benzothiophenyl claim 1 , benzofuranyl claim 1 , benzoisoxazolyl claim 1 , benzoxazolyl or indolyl.8. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 1 or 2.9. A compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein each Rgroup is independently selected from F claim 8 , Cl claim 8 , Br claim 8 , Me claim 8 , CF claim 8 , and OMe.10. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 0.11. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Lis a single bond.12. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Lis —CH—.13. A compound according to claim 1 , wherein the compound is 4-[[(R)-1-(Benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid; or a pharmaceutically acceptable salt claim 1 , or a solvate claim 1 , or a solvate of the pharmaceutically acceptable salt.14. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof claim 1 , according to claim 1 , and a pharmaceutically acceptable carrier.15. The pharmaceutical composition according to comprising a further therapeutic agent.16. (canceled)17. A method for the treatment of inflammatory conditions claim 1 ...

INDOLE DERIVATIVE AND PHARMACOLOGICALLY ACCEPTABLE SALT THEREOF

The present invention provides a compound represented by the general formula (I) of the present invention, which has EPreceptor antagonism: 3. The compound as claimed in or a pharmaceutically acceptable salt thereof claim 2 , wherein Ris a group selected from the group consisting of the following j) claim 2 , x) claim 2 , y) and z):{'sub': 3-6', '1-6, 'j) a Ccycloalkyl group, in which the ring is unsubstituted or substituted with one Calkyl group,'}{'sub': 1-6', '1-6', '1-6, 'x) a phenyl group, in which the ring is unsubstituted or substituted with one group selected from the group consisting of the following: a halogen atom, a Calkyl group, a halo-Calkyl group, and a Calkoxy group,'}{'sub': 1-6', '1-6', '1-6, 'y) a 6-membered aromatic heterocyclic group, in which the ring is unsubstituted or substituted with one group selected from the group consisting of the following: a halogen atom, a Calkyl group, a halo-Calkyl group, and a Calkoxy group, and'}{'sub': 1-6', '1-6', '1-6, 'z) a 5-membered aromatic heterocyclic group, in which the ring is unsubstituted or substituted with one group selected from the group consisting of the following: a halogen atom, a Calkyl group, a halo-Calkyl group, and a Calkoxy group.'}4. The compound as claimed in or a pharmaceutically acceptable salt thereof claim 3 , wherein Ris a phenyl group claim 3 , in which the ring is unsubstituted or substituted with one group selected from the group consisting of the following: a halogen atom claim 3 , a Calkyl group claim 3 , a halo-Calkyl group claim 3 , and a Calkoxy group.5. The compound as claimed in or a pharmaceutically acceptable salt thereof claim 3 , wherein Ris a 5-membered aromatic heterocyclic group claim 3 , in which the ring is unsubstituted or substituted with one group selected from the group consisting of the following: a halogen atom claim 3 , a Calkyl group claim 3 , a halo-Calkyl group claim 3 , and a Calkoxy group.6. The compound as claimed in or a pharmaceutically acceptable ...

NITRIC OXIDE DONOR NEPRILYSIN INHIBITORS

In one aspect, the invention relates to compounds having the formula: 2. The compound of claim 1 , where Ris —Calkyl substituted with 1 or 2 —ONOgroups.3. The compound of claim 2 , where Ris —(CH)(ONO).6. The compound of claim 1 , where Ris —OH and Ris H.7. The compound of claim 1 , where Ris —CHOH and Ris —CH.8. The compound of claim 1 , where X is selected from —COOR claim 1 , pyrazole claim 1 , imidazole claim 1 , triazole claim 1 , benzotriazole claim 1 , furan claim 1 , pyrrole claim 1 , tetrazole claim 1 , pyrazine claim 1 , thiophene claim 1 , oxazole claim 1 , isoxazole claim 1 , thiazole claim 1 , isothiazole claim 1 , oxadiazole claim 1 , thiadiazole claim 1 , pyridazine claim 1 , pyridine claim 1 , pyrimidine claim 1 , pyran claim 1 , benzimidazole claim 1 , benzoxazole claim 1 , benzothiazole claim 1 , pyridylimidazole claim 1 , and pyridyltriazole.10. The compound of claim 8 , where X is —COOR claim 8 , and Ris H.12. The compound of claim 1 , where Ris absent or is selected from H claim 1 , —Calkylene-OH claim 1 , —Calkylene-O—Calkyl claim 1 , —C(O)—Calkyl claim 1 , ═O claim 1 , and phenyl substituted with one halo.13. The compound of claim 1 , where Ris selected from H claim 1 , —OH claim 1 , —Calkyl claim 1 , pyridinyl claim 1 , and phenyl optionally substituted with one halo.14. The compound of claim 1 , where b is 0 or b is 1 and Ris 3′-chloro.15. The compound of claim 1 , where c is 0 claim 1 , or c is 1 and Ris 3′-chloro claim 1 , or c is 0 and Ris 2′-fluoro claim 1 , 5′-chloro or 2′ claim 1 ,5′-dichloro.18. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.19. The pharmaceutical composition of claim 18 , further comprising a therapeutic agent selected from adenosine receptor antagonists claim 18 , α-adrenergic receptor antagonists claim 18 , β-adrenergic receptor antagonists claim 18 , β-adrenergic receptor agonists claim 18 , dual-acting β-adrenergic receptor antagonist/α-receptor antagonists claim ...

METHODS FOR TREATING VASCULAR LEAK SYNDROME

Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, irritable bowel disease. Yet further disclosed are methods for treating renal cell carcinoma and melanoma. Still further disclosed are methods for reducing metastasis of malignant cells and/or preventing the proliferation of carcinoma cells via spreading due to vascular leakage. 2. The method according to claim 1 , wherein the cancer is renal cell carcinoma or malignant melanoma.3. The method according to wherein the cancer is medulloblastoma claim 1 , ependymoma claim 1 , ogliodendroglioma claim 1 , pilocytic asrocytoma claim 1 , diffuse astrocytoma claim 1 , anaplasic astrocytoma claim 1 , or glioblastoma.5. The method according to claim 4 , wherein the cancer is renal cell carcinoma or malignant melanoma.6. The method according to claim 4 , wherein the cancer treatment comprises administering to the subject an effective amount of IL-2.8. The method according to claim 7 , wherein the pathogen is chosen from bacteria claim 7 , viruses claim 7 , yeasts claim 7 , fungi claim 7 , or protozoa.9. The method according to claim 7 , further comprising administering to the subject an effective amount of an antibacterial agent claim 7 , an antiviral agent claim 7 , a fungicide claim 7 , or combination thereof.10. The method according to claim 7 , wherein Ris chosen from methyl claim 7 , ethyl claim 7 , n-propyl claim 7 , iso-propyl claim 7 , n-butyl claim 7 , iso-butyl claim 7 , sec-butyl claim 7 , and tert-butyl; and Ris hydrogen.11. The method according to claim 7 , wherein Ris a heteroaryl unit chosen from 1 claim 7 ,2 claim 7 ,3 claim 7 ,4-tetrazol-1-yl claim 7 , 1 claim 7 ,2 claim 7 ,3 claim 7 ,4-tetrazol-5-yl claim 7 , [1 claim 7 ,2 claim 7 ,3]triazol-4-yl claim 7 , [1 claim 7 ,2 claim 7 ,3]triazol-5-yl claim 7 , [1 claim 7 ,2 claim 7 ,4]triazol-4-yl claim 7 , [1 claim 7 ,2 claim 7 ,4]triazol-5- ...

MINERALOCORTICOID RECEPTOR ANTAGONISTS

Disclosed are the compounds of the Formula (I) as well as pharmaceutically acceptable salts thereof, which are useful for treating aldosterone-mediated diseases. The processes for preparing compounds of the Formula (I), the use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and the pharmaceutical compositions which comprise compounds of the formula (I) are disclosed too. 3. The compound of wherein Ris H.8. The compound of which is(R)—N-{1-[(2R)-2-(4-chlorophenyl)-1-hydroxybutan-2-yl]-1H-indol-4-yl}methanesulfonamide;N-(1-(1-(4-chlorophenyl)-1-(2-cyanocyclopropyl)propyl)-1H-indazol-4-yl)methanesulfonamide;N-(1-(1-(4-chlorophenyl)-1-(3-ethyl-1,2,4-oxadiazol-5-yl)propyl)-1H-indol-4-yl)methanesulfonamide;N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-yl)methanesulfonamide;N-(1-(1-(4-chlorophenyl)-1-(1-hydroxycyclopropyl)propyl)-1H-indol-4-yl)methanesulfonamide;N-(1-(3-(4-chlorophenyl)-2-hydroxypentan-3-yl)-6-fluoro-1H-indol-4-yl)methanesulfonamide;N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)indolin-4-yl)methanesulfonamide;N-{1-[3-(4-chlorophenyl)-2-hydroxypentan-3-yl]-1H-indazol-4-ylmethanesulfonamide;N-(1-(2-amino-3-(4-chlorophenyl)pentan-3-yl)-1H-indol-4-yl)methanesulfonamide;1-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indazol-4-yl)-3-methyl-sulfonylurea;methyl {4-[(methylsulfonyl)amino]-1H-indol-1-yl}(phenyl)acetate;N-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-6-fluoro-1H-indol-4-yl)methane sulfonamide;N-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indol-4-yl)methanesulfonamide;N-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;N-(1-(2-hydroxy-2-methyl-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;N-(1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indol-4-yl)methanesulfonamide;N-(1-(3-(4-chlorophenyl)-2-oxopentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;N-(1-(2-hydroxy-3-(4-( ...

ALPHA-KETOHETEROCYCLES AND METHODS OF MAKING AND USING

Compounds are disclosed that are effective in inhibition of fatty acid amide hydrolase, an enzyme responsible for catabolism of endogenous cannabinoids such as anandamide. The compounds are useful as analgesic compounds and as sleep-inducing compounds, that can be orally administered, and that can have a relatively long duration of effect. Methods of preparation of the compounds are also provided. The compounds are conformationally constrained analogs of heterocyclylketones such as oxazolylketones. 1. (canceled)3. The compound of wherein Ris heteroaryl4. The compound of wherein Ris a 2- claim 2 , 3- claim 2 , or 4-pyridyl claim 2 , wherein the pyridyl is optionally mono- or independently multi-substituted with J claim 2 , and wherein any pyridyl is optionally fused with a 5-7 membered cycloalkyl claim 2 , heterocyclyl claim 2 , aryl claim 2 , or heteroaryl claim 2 , any of which cycloalkyl claim 2 , heterocyclyl claim 2 , aryl claim 2 , or heteroaryl can be further mono- or independently multi-substituted with J.5. The compound of wherein Ris 2-pyridyl claim 2 , optionally mono- or independently multi-substituted with J.6. The compound of wherein the 2-pyridyl is unsubstituted or is substituted with carboxylic acid claim 5 , alkoxycarbonyl or carboxamido group.9. The compound of wherein X is CHor CHCH.10. The compound of wherein Ris aryl claim 2 , aralkyl claim 2 , aryloxy claim 2 , or aralkoxy claim 2 , and of which aryl claim 2 , aralkyl claim 2 , aryloxy claim 2 , or aralkoxy is optionally mono- or independently multi-substituted with J.11. The compound of wherein Ris phenyl claim 10 , phenoxy claim 10 , or benzyloxy claim 10 , any of which optionally mono- or independently multi-substituted with J12. The compound of wherein the chiral center is of the S absolute configuration.14. A compound of wherein the compound inhibits the bioactivity of a fatty acid amide hydrolase (FAAH) at a therapeutically achievable concentration.15. A pharmaceutical composition ...

1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3-Dioxygenase

The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives. 1174-. (canceled)176. The method of claim 175 , wherein the antibody is an anti-CTLA-4 antibody.177. The method of claim 175 , wherein the antibody is an anti-PD-1 antibody.179. The method of claim 178 , wherein Ris NH.180. The method of claim 178 , wherein Ris Br.181. The method of claim 178 , wherein Ris F.182. The method of claim 178 , wherein n is 2.183. The method of claim 178 , wherein said compound is selected from:4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;4-({3-[(aminosulfonyl)amino]propyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl} amino)-1,2,5-oxadiazole-3-carboximidamide;4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;4-({3-[(aminosulfonyl)amino]propyl}amino)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide;4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}-amino)-1,2,5-oxadiazole-3-carboximidamide;4-({3-[(aminosulfonyl)amino]propyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5- ...

USE OF GLU-TUBULIN AS A BIOMARKER OF DRUG RESPONSE TO FURAZANOBENZIMIDAZOLES

Use of glu-tubulin as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject to said compound, wherein the compound is a furazanobenzimidazole compound of general formula (I). 27. The method of claim 26 , wherein said subject is a human or animal claim 26 , said sample is taken from the human or animal body claim 26 , and the level of glu-tubulin proteins in said sample is measured ex vivo.28. The method of claim 27 , wherein the sample is derived from tumour tissue claim 27 , normal tissue claim 27 , circulating tumour cells claim 27 , cell lines claim 27 , plasma claim 27 , whole blood or serum.29. The method of claim 28 , wherein the protein sequence of glu-tubulin is selected from the group consisting of SEQ ID No. 1 claim 28 , SEQ ID 2 claim 28 , SEQ ID 3 claim 28 , SEQ ID 4 and homologues claim 28 , mutant forms claim 28 , allelic variants claim 28 , isoforms claim 28 , splice variants and proteins with sequences having at least 75% identity to SEQ ID 1 claim 28 , SEQ ID 2 claim 28 , SEQ ID 3 or SEQ ID 4 claim 28 , with the proviso that glutamate is the final amino acid at the C terminal of the protein.30. The method of claim 29 , wherein the determination of a higher level of glu-tubulin proteins in the sample from a subject relative to a standard value or values of glu-tubulin protein levels predicts resistance to treating said disease with said compound of formula I.31. The method of claim 30 , wherein the measured glu-tubulin protein levels in said sample is determined by comparing the measured glu-tubulin protein levels in said sample with:i) a standard value or a set of standard values of glu-tubulin protein levels from samples of subjects; orii) a standard value or a set of standard values of glu-tubulin protein levels from normal tissues.32. The method of claim 26 , wherein the compound is a compound of general formula I whereinR represents phenyl or pyridinylwherein phenyl is optionally ...

HEPATITIS C INHIBITORS AND USES THEREOF

This disclosure relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions. 2. The compound or salt of claim 1 , wherein:{'sup': 2', '2A', '2a', '2A, 'Ris L-G, wherein Lis a bond;'}{'sup': 2', '5, 'Wis CR;'}{'sup': 3', '4, 'Wis CR;'}{'sup': 4', '40', '4a, 'sub': '2', 'Ris hydrogen, —N(R)(SOR), or a 5-membered heteroaryl optionally substituted with 1 or 2 halogen or alkyl; and'}{'sup': 5', '5a, 'sub': 3', '6', '1', '6', '3', '6', '1', '3', '1', '3, 'Ris hydrogen, C-Ccycloalkyl, —O—C-Calkyl, or G, wherein the C-Ccycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C-Calkyl, C-Chaloalkyl, and oxo.'}4. The compound or salt of claim 3 , wherein:{'sup': 1', '2', '1', '2', '3', '2, 'Vand Vare each C, or one of Vand Vis N and the other is C; wherein, when Vis O or S or when A is formula (vii), Vis C;'}{'sup': 3', '7', '7, 'when A is formula (vi), Vis CR, NR, N, O, or S;'}{'sup': '3', 'when A is formula (vii), Vis N, O, or S;'}{'sup': 1', '6', '2', '5', '3', '4', '4', '3', '1', '2', '3', '4, 'Wis N or CR, Wis N or CR, Wis N or CR, Wis N or CR, wherein none, one, or two of W, W, Wand Wis N;'}{'sup': 5', '6', '6', '5', '5', '6, 'Wis N or CR, Wis N or CR, wherein none or one of Wand Wis N; and'}{'sup': '7', 'Wis N, O, or S.'}6. The compound or salt of claim 5 , wherein:{'sup': 1', '2', '1', '2', '3', '2, 'Vand Vare each C, or one of Vand Vis N and the other is C; wherein, when Vis O or S or when A is formula (vii), Vis C;'}{'sup': 3', '7', '7, 'when A is formula (vi), Vis CR, NR, N, O, or S;'}{'sup': '3', 'when A is formula (vii), Vis N, O, or S;'}{'sup': 1', '6', '2', ...

RORgammaT INHIBITORS

The present invention relates to compounds according to Formula (I) or a pharmaceutically acceptable salt or solvate thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or condition. 3. The compound of claim 1 , wherein A claim 1 , A claim 1 , A claim 1 , Aare selected from the group consisting of: (i) CR claim 1 , CR claim 1 , CR claim 1 , CR; (ii) N claim 1 , CR claim 1 , CR claim 1 , CR; and (iii) CR claim 1 , N claim 1 , CR claim 1 , CR.4. The compound of claim 3 , wherein A claim 3 , A claim 3 , A claim 3 , Ais (i) CR claim 3 , CR claim 3 , CR claim 3 , CR claim 3 , or (ii) N claim 3 , CR claim 3 , CR claim 3 , CR; and Y is N.5. The compound of claim 4 , wherein{'sub': '2', 'X is C(O) or SO;'}{'sup': '1', 'sub': 3-7', '3-5', '1-4', '2-9', '1-4', '6-14', '1-3', '1-4', '1-3', '1-3', '1-4', '1-3, 'Ris (i) (C)cycloalkyl or (C)heterocycloalkyl, both optionally substituted with one or more groups selected from (C)alkyl or halogen; (ii) (C)heteroaryl, optionally substituted with one or more groups selected from halogen, amino or (C)alkyl; or (iii) (C)aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C)alkoxycarbonyl, (C)alkyl, (C)alkoxy, wherein (C)alkoxycarbonyl, (C)alkyl and (C)alkoxy are optionally substituted with one or more halogens.'}6. The compound of claim 5 , wherein{'sup': '1', 'sub': 2-9', '6-14', '1-3', '1-4', '1-3', '1-3', '1-4', '1-3, 'Ris (C)heteroaryl or (C)aryl, both optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C)alkoxycarbonyl, (C)alkyl or (C)alkoxy, wherein (C)alkoxycarbonyl, (C)alkyl and (C)alkoxy are optionally substituted with one or more halogens.'}7. The compound of claim 6 , wherein Ris phenyl claim 6 , naphthyl claim 6 , pyridinyl claim 6 , quinolinyl claim 6 , benzooxadiazolyl claim 6 , thiophenyl claim 6 , or isoxazolyl claim 6 , each optionally substituted with one or more groups selected from ...

USE OF BUBR1 AS A BIOMARKER OF DRUG RESPONSE TO FURAZANOBENZIMIDAZOLES

Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a furazanobenzimidazole compound of general formula (I). 125-. (canceled)27. The method of wherein said subject is a human or animal and said sample is taken from the human or animal body and the level of BUBR1 proteins in said sample is measured ex vivo.28. The method of claim 27 , wherein the sample is derived from tumour tissue claim 27 , normal tissue claim 27 , circulating tumour cells claim 27 , cell lines claim 27 , plasma claim 27 , whole blood or serum.29. The method of claim 28 , wherein the protein sequence of BUBR1 is selected from the group consisting of SEQ ID No. 1 and homologues claim 28 , mutant forms claim 28 , allelic variants claim 28 , isoforms claim 28 , splice variants and proteins with sequences having at least 75% identity to SEQ ID 1.30. The method of wherein the sample is from a tumour taken from said subject.31. The method of wherein the determination of a lower level of BUBR1 proteins in the sample from subject relative to a standard value or values of BUBR1 protein levels predicts resistance to treating said disease with said compound of formula I.32. The method of wherein the measured BUBR1 protein levels in said sample is determined by comparing the measured BUBR1 protein levels in a said sample with:i) a standard value or a set of standard values of BUBR1 proteins from samples of subjects with the same tumour histotype;ii) a standard value or a set of standard values of BUBR1 proteins from samples of normal tissues; oriii) a value or set of values of a sample or samples of expression levels of BURB1 from samples from the same subject before or after initiation of treatment with the compound of formula.33. The method of claim 26 , wherein the compound is a compound of general formula I whereinR represents phenyl or pyridinylwherein phenyl is optionally substituted by one or two ...

5-membered ring heteroaromatic derivatives having npy y5 receptor antagonistic activity

This invention provides new compounds having NPY Y5 antagonistic activity. The present inventors found that a compound of the formula (I): wherein R 1 is substituted or unsubstituted alkyl or the like; p, q and r are each independently 0 or 1; ring A is oxadiazole; and R 2 is substituted or unsubstituted alkyl or the like, has NPY Y5 antagonistic activity.

HETEROCYCLIC MODULATORS OF HIF ACTIVITY FOR TREATMENT OF DISEASE

The present invention relates to compounds and methods which may be useful as inhibitors of HIF pathway activity for the treatment or prevention of cancer and other hypoxia-mediated diseases. 5. The compound as recited in wherein:n is 1;p is 1; and{'sub': '23', 'Ris selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, hydroxy, and cyclopropyl.'}7. The compound as recited in wherein:{'sub': 2', '4', '5', '2', '4', '5, 'two of X, X, and Xare N, and one of X, X, and Xis O; or'}{'sub': 2', '4', '5', '2', '4', '5', '2', '4', '5, 'one of X, X, and Xis N; one of X, X, and Xis O; and one of X, X, and Xis CH; and'}{'sub': '23', 'Ris selected from the group consisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to 6-membered cycloalkyl.'}11. The compound as recited in wherein two of X claim 9 , X claim 9 , and Xare N; and one of X claim 9 , X claim 9 , and Xis O.12. The compound as recited in wherein one of X claim 9 , X claim 9 , and Xis N; one of X claim 9 , X claim 9 , and Xis O; and one of X claim 9 , X claim 9 , and Xis CH.14. The compound as recited in wherein Ris hydrogen.18. The compound as recited in wherein Ris hydrogen.19. A compound selected from the group consisting of Examples 1 to 14 claim 16 , or a salt thereof.20. A pharmaceutical composition comprising a compound as recited in together with a pharmaceutically acceptable carrier.21. A method of treatment of a HIF pathway-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in to a patient in need thereof.22. The method as recited in wherein said disease is cancer.23. The method as recited in wherein said cancer is selected from the group consisting of colon cancer claim 22 , breast cancer claim 22 , ovarian cancer claim 22 , lung cancer claim 22 , prostrate cancer; cancers of the oral cavity and pharynx (lip claim 22 , tongue claim 22 , mouth claim 22 , larynx claim 22 , pharynx) claim 22 , ...

COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRIDAE VIRAL INFECTIONS

A compound is selected from the structural formulae depicted in FIG. or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound selected from the structural formulae depicted in FIG. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of selected from the structural formulae depicted in FIG. or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of selected from the structural formulae depicted in FIG. or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition , comprising a compound of or , and a pharmaceutically acceptable carrier or excipient.5. A pharmaceutical composition claim 3 , comprising a compound of and a pharmaceutically acceptable carrier or excipient.63. A method of inhibiting or reducing the activity of HCV polymerase in a biological in vitro sample claims 1 , comprising administering to the sample an effective amount of a compound of any one of -.73. A method of treating a HCV infection in a subject claims 1 , comprising administering to the subject a therapeutically effective amount of a compound of any one of -.83. A method of inhibiting or reducing the activity of HCV polymerase in a subject claims 1 , comprising administering to the subject a therapeutically effective amount of a compound of any one of -.9. The method of or claims 1 , further comprising co-administering one or more additional therapeutic agents to the subject.10. The method of claim 9 , wherein the additional therapeutic agents include an anti-HCV drug.11. The method of claim 10 , wherein the anti-HCV drug is an HCV protease inhibitor.12. The method of ...

S1P Receptors Modulators and Their Use Thereof

The invention relates to novel compounds that have SIP receptor modulating activity. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate SIP receptor modulating activity or expression, for example, autoimmune response. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate SIP receptor modulating activity or expression such as autoimmune response.

Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

INHIBITORS OF THE PLASMODIAL SURFACE ANION CHANNEL AS ANTIMALARIALS

Disclosed are inhibitors of the plasmodial surface anion channel (PSAC) inhibitors and the use thereof in treating or preventing malaria in an animal such as a human, comprising administering an effective amount of an inhibitor or a combination of inhibitors. An example of such an inhibitor is a compound of formula I, 232-. (canceled)33. The method of claim 1 , comprising administering a compound of formula (V) claim 1 , wherein Ris alkyl or alkoxy and Rand Rare hydrogen.34. The method of claim 33 , wherein Ris methyl or methoxy.35. The method of claim 33 , wherein Ris alkyl and Ris alkyl claim 33 , cycloalkyl claim 33 , or aryl claim 33 , wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of alkyl claim 33 , alkoxy claim 33 , halo claim 33 , hydroxy claim 33 , nitro claim 33 , cyano claim 33 , amino claim 33 , alkylamino claim 33 , aminoalkyl claim 33 , alkylcarbonyl claim 33 , alkoxycarbonyl claim 33 , aminocarbonyl claim 33 , and formyl.36. The method of claim 35 , wherein Ris alkyl claim 35 , cycloalkyl claim 35 , or aryl claim 35 , wherein said aryl is optionally substituted with one or more alkyl and/or alkoxy substituents.38. The method of claim 33 , wherein Ris hydrogen and Ris cycloalkyl or aryl claim 33 , which is optionally substituted with one or more alkyl and/or alkoxy substituents.40. The method of claim 1 , wherein an effective amount of a combination of compounds of formulas I and IV claim 1 , or pharmaceutically acceptable salts thereof claim 1 , is administered.41. The method of claim 1 , wherein an effective amount of a combination of compounds of formulas I and V claim 1 , or pharmaceutically acceptable salts thereof claim 1 , is administered.42. The method of claim 1 , wherein an effective amount of a combination of compounds of formulas IV and V claim 1 , or pharmaceutically acceptable salts thereof claim 1 , is administered.43. The method of claim 1 , wherein an effective amount of a ...

Mitotic kinesin inhibitors and methods of use thereof

This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders.

SULFUR (VI) FLUORIDE COMPOUNDS AND METHODS FOR THE PREPARATION THEREOF

This application describes modified amino acids and polypeptides comprising a SOF or CHCHSOF group bound to the side chain of an amono acid or amino acid residue of a polypeptide in place of a hydrogen of a hydroxyl or amino substituent thereof. Methods of covalently binding the polypeptides to receptot sites of receptor proteins are also described herein. 1. A modified amino acid comprising an amino acid core group bound to a SOF or CHCHSOF group; wherein the amino acid core group has a side chain comprising a hydroxyl or amino substituent , and the SOF or CHCHSOF group is bound to the side chain in place of a hydrogen of the hydroxyl or amino substituent thereof.2. The modified amino acid of claim 1 , wherein the amino acid core group is tyrosine.3. The modified amino acid of claim 1 , wherein the amino acid core group is 2 claim 1 ,6-dimethyltyrosine.4. The modified amino acid of claim 1 , wherein the amino acid core group is histidine.5. The modified amino acid of claim 1 , wherein the amino acid core group is lysine.6. The modified amino acid of claim 1 , wherein the amino acid core group is arginine.7. A polypeptide comprising a modified amino acid residue bearing a SOF or CHCHSOF group; wherein the a modified amino acid residue comprises an amino acid residue core group having a side chain comprising a hydroxyl or amino substituent claim 1 , and the SOF or CHCHSOF group is bound to the side chain in place of a hydrogen of the hydroxyl or amino substituent thereof.8. The polypeptide of claim 7 , wherein the amino acid residue core group is a tyrosine residue.9. The polypeptide of claim 7 , wherein the amino acid residue core group is a 2 claim 7 ,6-dimethyltyrosine residue.10. The polypeptide of claim 7 , wherein the amino acid residue core group is a histidine residue.11. The polypeptide of claim 7 , wherein the amino acid residue core group is a lysine residue.12. The polypeptide of claim 7 , wherein the amino acid residue core group is an arginine residue. ...

METHODS FOR INDUCING AN IMMUNE RESPONSE

Provided herein, inter alia, are compositions and methods for generating a immune response in an individual and/or inducing the expression of neoantigens on the surface of abnormal (such as proliferative) cells via promotion of premature termination codon (PTC) read-through and inhibition of nonsense-mediated decay (NMD) of messenger RNAs (mRNAs) bearing PTCs. 153.-. (canceled)54. A method of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a composition comprising atuluren and a compound that inhibits one or more immune checkpoint molecules.55. The method of claim 54 , wherein the cancer is selected from the group consisting of colon carcinoma claim 54 , breast cancer claim 54 , pancreatic cancer claim 54 , ovarian cancer claim 54 , prostate cancer claim 54 , fibrosarcoma claim 54 , myxosarcoma claim 54 , liposarcoma claim 54 , chondrosarcoma claim 54 , osteogenic sarcoma claim 54 , chordoma claim 54 , angiosarcoma claim 54 , endotheliosarcoma claim 54 , lymphangiosarcoma claim 54 , lymphangioendotheliosarcoma claim 54 , synovioma claim 54 , mesothelioma claim 54 , Ewing's tumor claim 54 , leiomyosarcoma claim 54 , rhabdomyosarcoma claim 54 , squamous cell carcinoma claim 54 , basal cell carcinoma claim 54 , adenocarcinoma claim 54 , sweat gland carcinoma claim 54 , sebaceous gland carcinoma claim 54 , papillary carcinoma claim 54 , papillary adenocarcinomas claim 54 , cystadenocarcinoma claim 54 , medullary carcinoma claim 54 , bronchogenic arcinoma claim 54 , renal cell carcinoma claim 54 , hepatoma claim 54 , bile duct carcinoma claim 54 , choriocarcinoma claim 54 , seminoma claim 54 , embryonal carcinoma claim 54 , Wilms' tumor claim 54 , cervical cancer claim 54 , testicular tumor claim 54 , lung carcinoma claim 54 , small cell lung carcinoma claim 54 , bladder carcinoma claim 54 , epithelial carcinoma claim 54 , glioma claim 54 , astrocytoma claim 54 , meduloblastoma claim 54 , merkel cell ...

SPHINGOSINE PATHWAY MODULATING COMPOUNDS FOR THE TREATMENT OF CANCERS

The invention provides methods and compositions for treating cancers and myeloproliferative disorders using sphingosine kinase-1 inhibitors, such as SK1-I, and selective sphingosine-1-phosphate receptor agonists, such as ozanimod. 1. A method for treating prostate cancer in a mammalian subject , comprising the step of:administering to a mammalian subject in need of treatment for prostate cancer an effective amount of ozanimod or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the administering step comprises administering the hydrochloride salt of ozanimod to the mammalian subject.3. The method of claim 1 , wherein the mammalian subject is a human.4. The method of claim 3 , wherein the administering step comprises administering the hydrochloride salt of ozanimod to the mammalian subject. This application is a continuation of U.S. patent application Ser. No. 16/830,357 filed Mar. 26, 2020, which is a continuation of U.S. patent application Ser. No. 16/287,201 filed Feb. 27, 2019 (now U.S. patent no. 10,646,459), which is a divisional of U.S. patent application Ser. No. 16/017,345 filed June 25, 2018 (now U.S. Pat. No. 10,278,960), which claims the benefit of U.S. provisional patent application Ser. No. 62/524,221 filed Jun. 23, 2017, each of which is hereby incorporated by reference in its entirety.The invention relates to the field of pharmaceutical treatment of cancers.Sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule over 20 years ago. Studies have since identified two related kinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I” and “type II” respectively, and SphK1 and SphK2 respectively), which catalyze the phosphorylation of sphingosine to S1P. Extracellular S1P can bind to and activate each of five S1P-specific, G protein-coupled receptors (designated S1PR) to regulate cellular and physiological processes in an autocrine or paracrine manner. Selective inhibitors of each of ...

N-HETEROARYL SUBSTITUTED ANILINE DERIVATIVES AS HCV-ANTIVIRALS

The present invention discloses compounds of Formula (I): wherein the variables in Formula I are defined as described herein. Also disclosed are pharmaceutical compositions containing such compounds and methods for using the compounds of Formula I in the prevention or treatment of HCV infection. 2. The compound of claim 1 , wherein Ris Cl.3. The compound of claim 2 , wherein Ris Cl.4. The compound of claim 3 , wherein Ris H or halo.5. The compound of claim 1 , wherein Xis N.6. The compound of claim 1 , wherein X is N and Xis O.7. The compound of claim 1 , wherein X is O and Xis N.8. The compound of claim 1 , wherein Xis CH.9. The compound of claim 8 , wherein X is NH and Xis N.10. The compound of claim 1 , wherein Xis O.11. The compound of claim 10 , wherein X is N and Xis CH or N.13. A method for preventing a Hepatitis C Virus (HCV) infection claim 1 , comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of or a pharmaceutically acceptable salt thereof.14. The method of claim 13 , further comprising the step of administering to a patient in need thereof a therapeutically effective amount of an immune system suppressant.15. A method for treating a Hepatitis C Virus (HCV) infection claim 1 , comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of or a pharmaceutically acceptable salt thereof.16. The method of claim 13 , further comprising the step of administering a combination of antiviral agents that inhibits replication of HCV.17. The method of claim 13 , further comprising the step of administering an immune system modulator or an antiviral agent that inhibits replication of HCV claim 13 , or a combination thereof.18. The method of claim 17 , wherein the immune system modulator is an interferon or a chemically derivatized interferon.19. The method of claim 17 , wherein the antiviral agent is selected from the group consisting of a HCV ...

METHODS FOR DECREASING INFLUENZA-INDUCED LETHALITY USING GASTRIN-RELEASING PEPTIDE (GRP) INHIBITORS OR GASTRIN-RELEASING PEPTIDE RECEPTOR (GRPR) ANTAGONISTS

Gastrin-releasing peptide (GRP) is a neuroendocrine peptide that acts as a novel contributor to the inflammatory response to influenza infection. Thus, inhibition of GRP or antagonizing the GRP receptor (GRPR) during influenza infection represents a novel therapeutic approach to mitigating lung damage. The present invention encompasses methods of treatment based on these novel findings and observations. 1. A method for reducing GRP-induced pulmonary inflammation in a subject , comprising administering a therapeutically effective amount of a GRP inhibitor or a GRPR antagonist , or a combination thereof , to a subject having GRP-induced pulmonary inflammation.2. A method for reducing GRP-induced lung pathology in a subject , comprising administering a therapeutically effective amount of a GRP inhibitor or a GRPR antagonist , or a combination thereof , to a subject at risk for GRP-induced lung pathology.3. The method of claim 2 , wherein the lung pathology is one or more of increased numbers of mononuclear cell masses surrounding conducting airways; increased numbers of neutrophil masses in alveoli; increased numbers of PNEC; degradation of airway parenchyma at bronchiole/alveoli foci due claim 2 , for example claim 2 , to infiltrating inflammatory cells; breakdown of pulmonary capillary integrity; and leaky vasculature.48-. (canceled)9. A method for treating a viral infection in a subject claim 2 , comprising administering a therapeutically effective amount of a GRP inhibitor or a GRPR antagonist claim 2 , or a combination thereof claim 2 , to a subject infected with a virus.10. The method of claim 9 , wherein said treatment is a reduction in one or more of pulmonary inflammation claim 9 , lung damage claim 9 , decreased PNECs claim 9 , GRP gene expression claim 9 , GRP protein production claim 9 , GRPR activation claim 9 , GRPR signaling claim 9 , inflammatory cytokine and/or chemokine production claim 9 , and HMGB1 release in the subject in comparison to a subject ...

COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY

The invention encompasses compounds such as compounds having the Formula (I) or (II), compositions thereof, and methods of modulating CFTR activity. The invention also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of or claim 1 , wherein Ris hydrogen.4. The compound of or claim 1 , wherein Ris fluoro.5. The compound of any one of to claim 1 , wherein Ris selected from the group consisting of hydrogen claim 1 , optionally substituted C-Calkyl claim 1 , optionally substituted C-Calkenyl claim 1 , optionally substituted C-Calkynyl claim 1 , optionally substituted C-Ccycloalkyl claim 1 , optionally substituted C-Ccycloalkenyl claim 1 , halo claim 1 , OR claim 1 , NRR claim 1 , S(O)R claim 1 , C(O)OR claim 1 , NO claim 1 , CN and C(O)R.6. The compound of claim 5 , wherein Ris selected from the group consisting of optionally substituted C-Calkyl claim 5 , optionally substituted C-Ccycloalkyl claim 5 , and OR claim 5 , wherein Ris an optionally substituted C-Calkyl.7. The compound of claim 6 , wherein Ris C-Calkyl or C-Ccycloalkyl claim 6 , where the C-Calkyl and C-Ccycloalkyl are each optionally substituted with one or more groups selected from OR claim 6 , NRR claim 6 , and SR claim 6 ,{'sub': f', 'h', '1', '10', '2', '10', '2', '10', '3', '12', '3', '12, 'wherein each of Rand Ris independently selected from the group consisting of hydrogen, optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, optionally substituted C-Ccycloalkyl, optionally substituted C-Ccycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and'}{'sub': g', '1', '10', '2', '10', '2', '10', '3', '12', '3', '12', 'g, 'each Ris independently selected from the ...

Tetrazolones as a Carboxylic Acid Bioisosteres

The present disclosure provides compounds that include a tetrazolone derivative of a carboxyl group of an active agent. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds. 1. A compound comprising a tetrazolone derivative of a carboxyl group of an active agent.2. The compound of claim 1 , wherein the tetrazolone derivative comprises a tetrazolone or a substituted tetrazolone.4. The compound of claim 3 , wherein Ris hydrogen or alkyl.5. The compound of claim 1 , wherein the active agent is a therapeutically effective active agent.6. The compound of claim 1 , wherein the tetrazolone derivative is produced from the carboxyl group of the active agent.8. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.9. The pharmaceutical composition of claim 8 , further comprising a second active agent.10. A compound comprising a tetrazolone or substituted tetrazolone produced from a carboxyl group of an active agent.11. A method of treating a disease or disorder in a subject in need of treatment claim 8 , the method comprising administering to the subject a compound comprising a tetrazolone derivative of a carboxyl group of an active agent.12. The method of claim 11 , wherein the tetrazolone derivative comprises a tetrazolone or a substituted tetrazolone.14. The method of claim 13 , wherein Ris hydrogen or alkyl.15. The method of claim 11 , wherein the active agent is a therapeutically effective active agent.16. The method of claim 11 , wherein the tetrazolone derivative is produced from the carboxyl group of the active agent. This application claims priority pursuant to 35 U.S.C. §119(e) to the filing date of U.S. Provisional Application No. 62/107,948, filed Jan. 26, 2015, the disclosure of which is herein incorporated by reference.Tetrazole is an organic heterocyclic ...

ADENYLYL CYCLASE INHIBITORS FOR CHRONIC PAIN AND OPIOID DEPENDENCE

This present application disclosed a series of selective adenylyl cyclase 1 (AC1) inhibitors as a pain therapeutic. Those compounds may provide an effective method of treatment for chronic/inflammatory pain. Those compounds may also prevent opioid dependence and/or reduce opioid dependence. Both method and composition matters are within the scope of this invention. 2. The compound according to claim 1 , wherein Ris a C-Calkyl claim 1 , cycloalkyl claim 1 , or an optionally substituted C-Caryl or heteroaryl.3. The compound according to claim 2 , wherein Ris an optionally substituted C-Caryl or heteroaryl.4. The compound according to claim 2 , wherein Ris a C-Calkyl or cycloalkyl claim 2 , which is optionally substituted.5. The compound according to claim 1 , wherein one or more of the five Rsubstituents are an alkylsulfide claim 1 , sulfonamide claim 1 , or alkylsulfonamide claim 1 , and the other substituents are hydrogen.6. The compound according to claim 1 , wherein one or more of the five Rsubstituents are a halo or haloalkyl claim 1 , and the other substituents are hydrogen.8. A pharmaceutical composition comprising one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , together with one or more diluents claim 1 , excipients or carriers.9. A pharmaceutical composition comprising one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , in combination with one or more other compounds by the same or different mode of action claim 1 , together with one or more diluents claim 1 , excipients or carriers.11. The method of claim 10 , wherein the pain is chronic pain.12. The method of claim 10 , wherein the treatment is for reducing pain and opioid dependence.13. The method of claim 10 , wherein Ris a C-Calkyl claim 10 , cycloalkyl claim 10 , or an optionally substituted C-Caryl or heteroaryl.14. The method of claim 10 , wherein one of the five Rsubstituents is an alkylsulfide claim 10 , sulfonamide ...

TRICYCLIC SPIRO COMPOUND

A medicinal agent for the prevention and/or treatment of diseases caused by EPreceptor activation. A compound having antagonistic activity against the EPreceptor is contained as an active ingredient in the medicinal agent. The compound represented by the following general formula (I) as defined in the specification, a salt, an N-oxide, or a solvate thereof, or a prodrug of these is useful as a medicinal component having antagonistic activity against the EPreceptor for the prevention and/or treatment of diseases caused by EPreceptor activation. 3. The compound according to claim 1 , wherein at least one Ris —CONHR.4. The compound according to claim 1 , wherein Lis —NHCO— claim 1 , or —CONH—.6. The compound according to claim 1 , which is any one of the following:(1) 4-[4-cyano-2-({[(2′R,4S)-6-(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(2) 4-{4-cyano-2-[({(2′R,4S)-6-[(cyclopropylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(3) 4-{4-cyano-2-[({(2′R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(4) 4-{4-cyano-2-[({(2′R,4S)-6-[(2-methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(5) 4-[4-cyano-2-({[(2′R,4S)-6-{[(2S)-1-methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(6) 4-{4-cyano-2-[({(2′R,4S)-6-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl}carbonyl)amino]phenyl}butanoic acid,(7) 4-[4-cyano-2-({[(2′R,4S)-6-(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene-4, 1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(8) 4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid,(9) 4-[4-cyano-2-({[(2′R,4S)-6-(cyclopentylcarbamoyl)-2,3- ...

INDAZOLE DERIVATIVES

Disclosed are compounds of Formula 1, 2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein Ris selected from phenyl claim 1 , naphthalenyl claim 1 , fluorenyl claim 1 , pyrrolyl claim 1 , furanyl claim 1 , thiopheneyl claim 1 , pyrazolyl claim 1 , imidazolyl claim 1 , isoxazolyl claim 1 , oxazolyl claim 1 , isothiazolyl claim 1 , thiazolyl claim 1 , 1 claim 1 ,2 claim 1 ,3-triazolyl claim 1 , 1 claim 1 ,3 claim 1 ,4-triazolyl claim 1 , 1-oxa-2 claim 1 ,3-diazolyl claim 1 , 1-oxa-2 claim 1 ,4-diazolyl claim 1 , 1-oxa-2 claim 1 ,5-diazolyl claim 1 , 1-oxa-3 claim 1 ,4-diazolyl claim 1 , 1-thia-2 claim 1 ,3-diazolyl claim 1 , 1-thia-2 claim 1 ,4-diazolyl claim 1 , 1-thia-2 claim 1 ,5-diazolyl claim 1 , 1-thia-3 claim 1 ,4-diazolyl claim 1 , tetrazolyl claim 1 , pyridinyl claim 1 , pyridazinyl claim 1 , pyrimidinyl claim 1 , pyrazinyl claim 1 , benzofuranyl claim 1 , isobenzofuranyl claim 1 , benzothiopheneyl claim 1 , benzo[c]thiopheneyl claim 1 , 1H-indolyl claim 1 , 3H-indolyl claim 1 , isoindolyl claim 1 , 1H-isoindolyl claim 1 , indolinyl claim 1 , isoindolinyl claim 1 , benzimidazolyl claim 1 , indazolyl claim 1 , benzotriazolyl claim 1 , 1H-pyrrolo[2 claim 1 ,3-b]pyridinyl claim 1 , 1H-pyrrolo[2 claim 1 ,3-c]pyridinyl claim 1 , 1H-pyrrolo[3 claim 1 ,2-c]pyridinyl claim 1 , 1H-pyrrolo[3 claim 1 ,2-b]pyridinyl claim 1 , 3H-imidazo[4 claim 1 ,5-b]pyridinyl claim 1 , 3H-imidazo[4 claim 1 ,5-c]pyridinyl claim 1 , 1H-pyrazolo[4 claim 1 ,3-b]pyridinyl claim 1 , 1H-pyrazolo[4 claim 1 ,3-c]pyridinyl claim 1 , 1H-pyrazolo[3 claim 1 ,4-c]pyridinyl claim 1 , 1H-pyrazolo[3 claim 1 ,4-b]pyridinyl claim 1 , 7H-purinyl claim 1 , indolizinyl claim 1 , imidazo[1 claim 1 ,2-a]pyridinyl claim 1 , imidazo[1 claim 1 ,5-a]pyridinyl claim 1 , pyrazolo[1 claim 1 ,5-a]pyridinyl claim 1 , pyrrolo[1 claim 1 ,2-b]pyridazinyl claim 1 , imidazo[1 claim 1 ,2-c]pyrimidinyl claim 1 , quinolinyl claim 1 , isoquinolinyl claim 1 , cinnolinyl claim 1 , quinazolinyl claim 1 ...

Stable Pharmaceutical Package Comprising Azilsartan Medoxomil

The present invention relates to pharmaceutical package comprising a pharmaceutical preparation comprising azilsartan medoxomil and salts thereof, and a desiccant. Also, relates to a pharmaceutical preparation comprising azilsartan medoxomil and salts thereof and a pH modifier, wherein pH modifier provides a pH range of about 5.5 to about 6.5 when dissolved or suspended in water at a concentration of 1% at 25° C. The invention also relates to processes for the preparation of such pharmaceutical preparation and use thereof for prophylaxis or treatment of circulatory diseases. 1. A pharmaceutical package comprising a pharmaceutical preparation comprising azilsartan medoxomil and salts thereof , and a desiccant.2. The pharmaceutical package as claimed in claim 1 , the pharmaceutical preparation comprising azilsartan medoxomil and salts thereof claim 1 , a pH modifier claim 1 , and a desiccant claim 1 , wherein pH modifier provides a pH range of about 5.5 to about 6.5 when dissolved or suspended in water at a concentration of 1% at 25° C.3. The pharmaceutical package as claimed in claim 1 , the pharmaceutical preparation comprising azilsartan medoxomil and salts thereof claim 1 , pH modifier and a desiccant claim 1 , wherein the composition is free of odor produced by hydrolysis of (5-methyl-2-oxo-1 claim 1 ,3-dioxol-4-yl)methyl group (i.e. claim 1 , a medoxomil group) in azilsartan.4. The pharmaceutical package as claimed in claim 1 , the pharmaceutical preparation comprising azilsartan medoxomil and salts thereof claim 1 , pH modifier and a desiccant claim 1 , wherein the said pharmaceutical preparation retains at least 80% of the potency of azilsartan medoxomil and salts thereof in the pharmaceutical composition after storage at 40° C. and 75% relative humidity for three months.5. The pharmaceutical package as claimed in claim 1 , the pharmaceutical preparation comprising azilsartan medoxomil and salts thereof claim 1 , pH modifier and a desiccant claim 1 , wherein ...

Promoting sleep using at1 receptor blockers

The present invention relates to the use of an Angiotensin II type 1 (AT1) receptor blocker for promoting sleep and/or the treatment of insomnia. It is based, at least in part, on the results of experiments performed using a validated rat model of stress-induced insomnia in which candesartan was found to ameliorate sleep disturbances induced by stress. Further, it was observed that this effect seems to be caused by blockade of AT1 receptors located in several brain regions that are key components of the neural circuitry activated during insomnia. In contrast to currently marketed treatments for insomnia, the AT1 receptor blocker was found to restore normal sleep without inhibiting REM sleep and/or inducing atypical wave components in the EEG.

Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid for the treatment of disease

The present invention relates to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, pharmaceutical compositions and dosage forms comprising the crystalline forms, methods of making the crystalline forms and methods for their use for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay.

Regulators of the endoplasmic reticulum proteostasis network

The invention provides compounds for activating the activating transcription factor 6 (ATF6) arm of the unfolded protein response (UPR), or activating the transcriptional targets of ATF6, in the endoplasmic reticulum of a cell, the compounds being of any of formulas (I) through (IX) as described herein. The compounds can be used for treatment of conditions involving gain-of-toxic-function and loss-of-function folding disorders including lysosomal storage diseases, antitrypsin-associated emphysema and similar diseases. These molecules are also expected to have disease-ameliorating effects in Alzheimer's disease and diabetes.

HETEROCYCLIC COMPOUND

The present invention provide a heterocyclic compound having a HDAC inhibitory action, and useful for the treatment of autoimmune diseases and/or inflammatory diseases, graft versus host disease, cancers, central nervous diseases including neurodegenerative diseases, Charcot-Marie-Tooth disease and the like, and a medicament comprising the compound. 2. The compound or salt according to claim 1 , wherein{'sup': '1', 'sub': '6-14', 'Ris an optionally substituted Caromatic hydrocarbon ring or an optionally substituted 5- to 6-membered monocyclic aromatic heterocycle;'}{'sup': 2', '3, 'sub': '1-6', 'Rand Rare independently a hydrogen atom, an optionally substituted Calkyl group or an optionally substituted carbamoyl group; and'}{'sup': 4', '5, 'sub': '1-6', 'Rand Rare independently a hydrogen atom or an optionally substituted Calkyl group.'}3. The compound or salt according to claim 1 , wherein{'sup': '1', 'sub': '6-14', 'Ris a Caromatic hydrocarbon ring or a 5- to 6-membered monocyclic aromatic heterocycle, each of which is optionally substituted by 1 to 3 substituents selected from'}(a) a halogen atom,(b) a cyano group,{'sub': '1-6', 'claim-text': [{'sub': '1-6', '(i) a mono- or di-Calkyl-carbamoyl group, and'}, '(ii) a halogen atom,, '(c) a Calkyl group optionally substituted by 1 to 3 substituents selected from'}{'sub': '1-6', 'claim-text': (i) a halogen atom, and', '(ii) a 3- to 14-membered non-aromatic heterocyclic group,, '(d) a Calkoxy group optionally substituted by 1 to 3 substituents selected from'}{'sub': '6-14', '(e) a Caryloxy group,'}{'sub': '1-6', '(f) a Calkylsulfonyl group,'}{'sub': 1-6', '1-6, '(g) a (Calkyl) (Calkylsulfonyl)amino group,'}{'sub': '1-6', '(h) a mono- or di-Calkyl-carbamoyl group,'}{'sub': '6-14', '(i) a Caryl group, and'}(j) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups;{'sup': 2', '3, 'Rand Rare independently'}(1) a hydrogen atom,{'sub': '1-6', 'claim-text': [{'sub': '1-6', '(a) a ...

NOVEL MODULATORS OF SPHINGOSINE PHOSPHATE RECEPTORS

Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphingosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided. 165.-. (canceled)67. The compound of wherein the phenyl moiety is substituted with 1 J group.68. The compound of wherein the phenyl moiety is substituted with 2 J groups.69. The compound of wherein the phenyl moiety is substituted with a J group at both the meta and para positions of the phenyl moiety.70. The compound of wherein the phenyl moiety is substituted with 3 J groups.71. The compound of any one of - wherein J is independently at each occurrence F claim 66 , Cl claim 66 , Br claim 66 , I claim 66 , OR′ claim 66 , CN claim 66 , CF claim 66 , OCF claim 66 , CHF claim 66 , or NO.72. The compound of wherein J is independently at each occurrence OR′ claim 71 , CN claim 71 , or CF claim 71 , and R′ is alkyl.73. The compound of wherein R′ is ethyl.74. The compound of wherein R′ is iso-propyl.75. The compound of or wherein both J groups are OR′ claim 72 , and R′ is independently at each occurrence ethyl or iso-propyl.76. The compound of or wherein one J is OR′ and the other J is CN claim 72 , and wherein R′ is ethyl or iso-propyl.77. The compound of wherein R′ is ethyl.78. The compound of wherein R′ is iso-propyl.79. The compound or wherein one J is OR′ and the other J is CF claim 76 , and wherein R′ is ethyl or iso-propyl.80. The compound of wherein R′ is ethyl.81. The compound of wherein R′ is iso-propyl. This application is a continuation of and claims the benefit of priority to U.S. patent application Ser. No. 14/311,825, filed Jun. 23, 2014, which is a divisional of and claims the benefit of priority to U.S. patent application Ser. No. 12/465,767, filed May 14, 2009 (which ...

LUPANE TRITERPENOID DERIVATIVES AND PHARMACEUTICAL USE THEREOF

The present invention relates to a lupane triterpenoid derivatives and pharmaceutical use thereof, specifically relates to a lupane triterpenoid derivatives of formula (I)˜(III), a pharmaceutical composition and a combination preparation comprising a lupane triterpenoid derivatives or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose, particularly relates to the use in preparation of a medicament for the treatment of HIV-1/AIDS. 113-. (canceled)23. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 14 , or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose claim 14 , as well as a pharmaceutical acceptable carrier claim 14 , adjuvant claim 14 , excipient claim 14 , or vehicle.24. A pharmaceutical composition comprising a compound of formula (II) as defined in claim 15 , or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose claim 15 , as well as a pharmaceutical acceptable carrier claim 15 , adjuvant claim 15 , excipient claim 15 , or vehicle.25. A pharmaceutical composition comprising a compound of formula (III) as defined in claim 17 , or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose claim 17 , as well as a pharmaceutical acceptable carrier claim 17 , adjuvant claim 17 , excipient claim 17 , or vehicle.26. A compound of formula (I) as defined in claim 14 , or a pharmaceutically acceptable salt thereof for the use in preparation of a medicament for preventing or treating HIV-1 infections in a subject in need of a therapeutically-effective amount.27. A compound of formula (II) as defined in claim 15 , or a pharmaceutically acceptable salt thereof for the use in preparation of a medicament for preventing or treating HIV-1 infections in a subject in need of a therapeutically-effective amount.28. A compound of formula (III) as defined in claim 17 , or a pharmaceutically acceptable salt thereof for the use in preparation ...

BIN1 EXPRESSION AS A MARKER OF CANCER

Provided are methods for screening a subject for cancer. The methods involve obtaining a blood sample from the subject and determining a level of Bridging Integrator 1 (BIND isoforms comprising exon 12a in the sample. Optionally, the method involves determining a level of 12a+/13− BIN isoform (comprising exon 12a but lacking exon 13) in the sample. An elevated level of 12a+ (e.g., 12a+/13−) BIN1 isoforms in the blood sample indicates the subject has cancer. Also provided are methods for determining efficacy of a cancer therapy in a subject and methods of treating cancer. Isolated antibodies that selectively bind human 12a+ BIN1 are also provided as well as kits for determining 12a+/13− BIN1 isoforms. 1. A method of screening for cancer in a subject comprising:(a) obtaining a blood sample from the subject;(b) detecting a level of 12a+Bridging Integrator 1 (BIN1) polypeptide in the sample;(c) detecting a level of 12a+/13+ BIN1 polypeptide in the sample;(d) comparing the detected level of step (b) to the detected level of step (c) to determine a 12a+/13− BIN1 value for the sample;(e) comparing the 12a+/13− BIN1 value from step (d) to one or more control values, wherein an elevated 12a+/13− BIN1 value indicates the subject has a cancer; and(f) obtaining a tissue sample from the subject identified in step (e).2. The method of claim 1 , wherein an elevated 12a+/13− BIN1 value is based on a threshold value determined by comparing a negative control value to one or more positive control values claim 1 , wherein an 12a+/13− BIN1 value greater than the threshold value indicates the subject has a cancer.3. The method of claim 2 , wherein the threshold value is set at least one standard deviation above a mean negative control value.4. (canceled)5. The method of claim 2 , wherein the threshold value shows no statistically significant difference as compared to a positive control value.69-. (canceled)10. The method of claim 1 , wherein the subject is at risk of developing cancer. ...

Bicycloheteroaryl-Heteroaryl-Benzoic Acid Compounds as Retinoic Acid Receptor Beta (RARBeta) Agonists

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicycloheteroaryl-heteroaryl-benzoic acid compounds of the following formula (for convenience, collectively referred to herein as “BHBA compounds”), which, inter alia, are (selective) retinoic acid receptor beta (RARβ) (e.g., RARβ2) agonists. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to (selectively) activate RARβ (e.g., RARPβ2), to cause or promote neurite development, neurite outgrowth, and/or neurite regeneration, and in the treatment of diseases and conditions that are mediated by RARβ (e.g., RARβ2), that are ameliorated by the activation of RARβ (e.g., RARβ2), etc., including, e.g., neurological injuries such as spinal cord injuries.

PHARMACEUTICAL COMBINATIONS FOR USE IN THE TREATMENT OF NEOPLASTIC DISEASES

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a compound of Formula (II) (gemcitabine) or a pharmaceutically acceptable salt thereof and the use of the pharmaceutical combinations in the treatment of neoplastic diseases. 3. The pharmaceutical combination according to claim 2 , wherein the compound of formula I or pharmaceutically acceptable derivative thereof is the dihydrochloride salt of the compound of formula I-B and wherein the compound of formula II or a pharmaceutically acceptable salt thereof is gemcitabine hydrochloride.4. The pharmaceutical combination according to claim 1 , wherein the mole ratio of the mole amount of the compound of formula II or pharmaceutically acceptable salt thereof to the mole amount of the compound of formula II or pharmaceutically acceptable derivative thereof is 2:1 to 340:1.5. A method for the treatment of a neoplastic disease in a subject in need thereof claim 1 , comprising the step of administering the pharmaceutical combination according to to said subject.6. The method according to claim 5 , wherein the compound of formula I or pharmaceutically acceptable derivative thereof and of the compound of formula II or pharmaceutically acceptable salt thereof are administered to the subject according to cyclic treatment schedules;wherein when the treatment cycles are of the same duration the mole ratio of the total mole amount of the doses of the compound of ...

PREPARATION AND USE OF 7A-HETEROCYCLE SUBSTITUTED- 6,6-DIFLUORO BICYCLIC HIMBACINE DERIVATIVES AS PAR-1 RECEPTOR ANTAGONISTS

The present invention relates to bicyclic himbacine derivatives of the formula 4. A pharmaceutical composition comprising an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.5. The pharmaceutical composition as defined in claim 4 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.6. The pharmaceutical composition as defined in claim 5 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel claim 5 , wherein clopidogrel is a free base or pharmaceutically acceptable salt.7. A pharmaceutical composition comprising an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.8. The pharmaceutical composition as defined in claim 7 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.9. The pharmaceutical composition as defined in claim 8 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel claim 8 , wherein clopidogrel is a free base or pharmaceutically acceptable salt.11. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in or a pharmaceutically acceptable salt thereof. The present invention relates to 7a-heterocycle substituted 6,6-difluro bicyclic himbacine derivatives, which are useful as protease activated receptor-1 (PAR-1) antagonists and might be expected to be cannabinoid (CB) receptor inhibitors. PAR-1 receptors are also known in the art as thrombin receptor antagonists (TRA). The inventive compounds have utility in treating disease states such as acute coronary syndrome (ACS) (unstable angina, non-ST-segment elevation [NSTE] myocardial infarction [MI], and ST segment-elevation myocardial infarction [STEMI]), secondary prevention of myocardial infarction or ...

NOVEL HETEROARYL BUTANOIC ACID DERIVATIVES

The present invention describes novel heteroaryl butanoic acid derivatives that are good drug candidates especially with regard to leukotriene A4 hydrolase (LTA4H). The present invention also relates to pharmaceutical compositions comprising said novel heteroaryl butanoic acid derivatives, methods of using said compounds in the treatment of various diseases and disorders, and processes for preparing the said novel compounds. 2. The compound of or a pharmaceutically acceptable salt thereof; wherein{'sub': '2', 'R1 is OH or NH;'}Y is O;X1, X2, X3 and X4 are selected from N, NH, C, CH and O with the proviso that at least two of X1, X2, X3 or X4 are N or NH; and{'sub': 1', '6', '1', '6, 'R2 is phenyl optionally being substituted by halogen, cyano, C-Calkyl optionally substituted by halogen, C-Calkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or'}{'sub': 1', '6, 'R2 is a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by C-Calkyl optionally substituted by halogen, cyano or halogen.'}3. The compound of or a pharmaceutically acceptable salt thereof claim 1 , wherein Y is attached in the para-position of the phenyl moiety.4. The compound of or a pharmaceutically acceptable salt thereof claim 1 , wherein Y is attached in the meta-position of the phenyl moiety.5. The compound of or a pharmaceutically acceptable salt thereof; wherein{'sub': '2', 'R1 is OH or NH;'}{'sub': '2', 'Y is CH; X1, X2, X3 and X4 are N; and'}{'sub': 1', '6', '3', '6, 'R2 is C-Calkyl optionally substituted by phenyl; or C-Ccycloalkyl.'}10. The compound in accordance to claim 9 , or a pharmaceutically acceptable salt thereof; whereinR1 is OH;Y is O; andR2 is a pyridyl ring being optionally substituted by cyano or halogen.11. The compound of or a pharmaceutically acceptable salt thereof claim 1 , wherein the compound is selected from:(R)-3-amino-4-(5-(4-(benzo[d] ...

Compositions for Use in Treating Pulmonary Arterial Hypertension

The present disclosure provides methods of treating pulmonary arterial hypertension (PAH) in a subject in need thereof. Compositions for use in these methods are also provided. 2. The compound of claim 1 , wherein Z is O.3. The compound of claim 1 , wherein Ris phenyl substituted with at least one substituent selected from the group consisting of halo claim 1 , C-Calkyl claim 1 , C-Calkoxy claim 1 , and cyano.4. The compound of claim 3 , wherein the halo is fluoro.5. The compound of claim 1 , wherein the 5-membered heterocycle contains an oxygen atom.6. The compound of claim 5 , wherein the 5-membered heterocycle is substituted with at least one substituent selected from the group consisting of halo claim 5 , hydroxy claim 5 , C-Calkoxy claim 5 , alkyl claim 5 , heteroalkyl claim 5 , and cyano.7. The compound of claim 1 , wherein Z is O claim 1 , Ris phenyl claim 1 , and the 5-membered heterocycle contains an oxygen atom.8. The compound of claim 7 , wherein said 5-membered heterocycle is substituted with at least one substituent selected from the group consisting of halo and hydroxy.9. The compound of claim 8 , wherein said 5-membered heterocycle is substituted with fluoro.10. The compound of claim 8 , wherein Ris selected from the group consisting of sulfonyl claim 8 , fluoroalkyl sulfonyl claim 8 , fluoroalkyl claim 8 , and trifluoromethyl.12. The compound of claim 11 , wherein Z is O.13. The compound of claim 11 , wherein Ris phenyl substituted with at least one substituent selected from the group consisting of halo claim 11 , C-Calkyl claim 11 , C-Calkoxy claim 11 , and cyano.14. The compound of claim 13 , wherein the halo is fluoro.15. The compound of claim 11 , wherein Rand Rtaken together form a 5- or 6-membered carbocycle with at least one sphybridized carbon.16. The compound of claim 15 , wherein the carbocycle is substituted with at least one substituent selected from the group consisting of halo claim 15 , hydroxy claim 15 , alkyl claim 15 , heteroalkyl ...

BICYCLO [2.2.1] ACID GPR120 MODULATORS

The present invention provides compounds of Formula (I): (I) or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR120 G protein-coupled receptor modulators which may be used as medicaments.

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula: where R 1 -R 6 , a, b, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

HUMAN HELICASE DDX3 INHIBITORS AS THERAPEUTIC AGENTS

The present invention refers to compounds endowed with RNA helicase DDX3 inhibitory activity of formula I and II and their therapeutic use, in particular for the treatment of viral diseases. 2. The compound according to wherein X and Y are C.3. The compound according to or wherein A is substituted aryl.4. The compound according to wherein the substituted aryl is phenyl.5. The compound according to wherein the phenyl is substituted by one claim 4 , two or more groups independently selected from methyl claim 4 , isopropyl claim 4 , CF claim 4 , F claim 4 , Cl claim 4 , OH claim 4 , OMe.6. The compound according to or wherein A is unsubstituted or substituted heteroaryl.7. The compound according to wherein the substituted heteroaryl is pyridinyl or isoquinolinyl.10. The compound or pharmaceutical acceptable salt claim 6 , solvate claim 6 , stereoisomer thereof according to any one of previous claim being an inhibitor of DDX3.11. The compound or pharmaceutical acceptable salt claim 6 , solvate claim 6 , stereoisomer thereof according to any one of previous claim for medical use.12. The compound or pharmaceutical acceptable salt claim 11 , solvate claim 11 , stereoisomer thereof according to for use in the treatment of a viral disease.13. The compound for use according to wherein the viral disease is modulated by DDX3.14. The compound for use according to or wherein the viral disease is caused by a virus that is resistant to at least one compound selected from the group consisting of: protease inhibitor; nucleoside reverse transcriptase inhibitor claim 12 , non-nucleoside reverse transcriptase inhibitor or integrase inhibitor.15. The compound according to to for use in the treatment of a viral disease is caused by a virus selected from the group consisting of: Human Immunodeficiency Virus 1 (HIV-1) claim 12 , Hepatitis C Virus claim 12 , Hepatitis B Virus claim 12 , Eastern Equine Encephalitis Virus claim 12 , Western Equine Encephalitis Virus claim 12 , Venezuelan ...

PYRIDAZINONE COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS

The invention relates to a compound of having the following formulae and methods of treating cystic fibrosis: 251-. (canceled) This application is a continuation of U.S. application Ser. No. 15/726,813, filed on Oct. 6, 2017, which is a divisional of U.S. application Ser. No. 14/210,277, filed on Mar. 13, 2014 (now U.S. Pat. No. 9,783,529), which claims the benefit of U.S. Provisional Application No. 61/778,870, filed on Mar. 13, 2013. The entire teachings of the above applications are incorporated herein by reference.Cystic fibrosis (CF) is a lethal, recessive, genetic disease affecting approximately 1 in 2500 live births among Caucasians. (Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med (2011); 183: 1463-1471; Boat T F, Welsh M J and Beaudet A L. Cystic fibrosis. (1989) IN “The Metabolic Basis of Inherited Disease” (C L Scriver, A L Beaudet, W S Sly and D Valee, eds.), 6Ed., pp. 2649-2680. McGraw-Hill, New York. Approximately 1 in 25 persons are carriers of the genetic defect associated with disease. The major symptoms of cystic fibrosis include chronic pulmonary disease, pancreatic exocrine insufficiency, infertility in males, and elevated sweat electrolyte levels. The symptoms are consistent with cystic fibrosis being an exocrine disorder. (Hantash F: U.S. Patent Application No. 20060057593. Method for detecting cystic fibrosis).The CF gene codes for a cAMP/PKA-dependent, ATP-requiring, membrane-bound chloride ion channel known as CFTR (cystic fibrosis transmembrane conductance regulator), and is, generally localized to the apical membranes of many secreting. There are currently over 1700 known mutations affecting CFTR, many of which give rise to a disease phenotype. Around 75% of CF alleles contain the ΔF508 mutation in which a triplet codon has been lost, leading to a missing phenylalanine at position 508 in the protein. This altered protein fails ...

INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE (IDO)

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention. 9. The compound according to wherein the ICin the HEK Human IDO-1 assay is <10 nM.10. A pharmaceutical composition comprising one or more compounds according to and a pharmaceutically acceptable carrier or diluent.11. (canceled)12. (canceled)13. (canceled)14. A method for the treatment of a disease selected from the group consisting of cancer claim 1 , viral infections claim 1 , depression claim 1 , organ transplant rejection and autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to .15. The method according to further comprising administering to the patient a therapeutically effective amount of at least one of an anti-viral agent claim 14 , a chemotherapeutic agent claim 14 , an immunosuppressant claim 14 , radiation claim 14 , an anti-tumor vaccine claim 14 , an antiviral vaccine claim 14 , cytokine therapy or a tyrosine kinase inhibitor prior to claim 14 , simultaneously with or after administration of the compound.16. A method of inhibiting the activity of indoleamine 2 claim 1 ,3-dioxygenase comprising contacting said indoleamine 2 claim 1 ,3-dioxygenase with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.17. The method of claim 14 , wherein said disease is cancer.18. The method of wherein said cancer is selected from the group consisting of colon claim 17 , glioblastoma claim 17 , pancreatic claim 17 , breast claim 17 , prostate claim 17 , lung claim 17 , ovarian claim 17 , cervical claim 17 , renal claim 17 , head and neck claim 17 , lymphoma claim 17 , leukemia and melanoma.19. A ...

OXAZOLE AND ISOXAZOLE CRAC MODULATORS

The present invention relates to compounds of Formula (I) along with processes for their preparation that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions associated with the modulation of CRAC. The invention further relates to methods of treating, preventing managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of CRAC of Formula (I). 118.-. (canceled)20. The method of for treating a disease or disorder by administering a therapeutically effective amount of a compound which is selected from:N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-2,6-difluorobenzamide,N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide,N-(5′-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2′-methyl-[1,1′-biphenyl]-4-yl-2,6-difluorobenzamide,N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-2,6-difluorobenzamide,N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyrazin-2-yl)-2,6-difluorobenzamide,N-(5′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2′-ethyl-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,N-(6-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyridin-3-yl)-2,6-difluorobenzamide,N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isopropylphenyl)pyrazin-2-yl)-2,6-difluorobenzamide,N-(5′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2′-isopropyl-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,N-(2′-(tert-butyl)-5′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,N-(2′-chloro-5′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-fluorophenyl)pyrazin-2-yl)-2,6-difluorobenzamide,N-(5′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide, ...

BKCA CHANNEL ACTIVATOR FOR TREATING MUSCULAR DISORDER

The present invention relates to BKCa activators for use in the treatment of a muscular disorder, or for controlling spasticity or tremors, for example, spasticity in MS. 1. A method of treating a muscular disorder in a subject in need thereof , comprising administering to the subject a BKCa channel activator.2. The method according to wherein the muscular disorder is a disorder of skeletal muscle.3. The method according to wherein the muscular disorder is a neuromuscular disorder.4. A method of treating or controlling spasticity or tremors in a subject in need thereof claim 1 , comprising administering to the subject a BKCa channel activator.5. The method according to claim 4 , for treating spasticity in multiple sclerosis (MS).6. The method according to claim 4 , for treating spinal cord spasticity.9. The method according to wherein the BKCa channel activator is in admixture with a pharmaceutically acceptable diluent claim 1 , excipient or carrier.1012-. (canceled)1415-. (canceled)17. The method according to wherein the BKCa channel activator is in admixture with a pharmaceutically acceptable diluent claim 13 , excipient or carrier. The present invention relates to compounds useful in the treatment of muscular disorders, or for controlling spasticity or tremors.Spasticity is a motor disorder clinically defined as a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms and hypersensitivity to normally innocuous sensory stimulations. The intermittent or sustained involuntary muscle hyperactivity that characterises spasticity is associated with upper motor neurone lesions that can be located anywhere along the path of the corticospinal (pyramidal) tracts. This includes the motor pathways of the cortex, basal ganglia, thalamus, cerebellum, brainstem or spinal cord.The aetiology of spasticity in MS has been relatively little studied. This is in contrast to spasticity caused by spinal cord injury, where the control of chloride ...

AUTOTAXIN INHIBITORS

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin. 15-. (canceled)8. A pharmaceutical composition comprising a compound according to claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , and a pharmaceutically acceptable carrier.9. A pharmaceutical combination comprising a therapeutically effective amount of the compound according to claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , and one or more therapeutically active co-agent.1015-. (canceled)16. A method of treating an autotaxin dependent or an autotaxin mediated disease or condition wherein the disease or condition is idiopathic pulmonary fibrosis comprising administering to a subject a therapeutically effective amount of a compound according to . This application is a continuation of U.S. patent application Ser. No. 14/906,161, filed Jan. 19, 2016, which is a U.S. National Phase filing of International Application No. PCT/IB2014/063143 filed 16 Jul. 2014, which claims priority to EP Application No. EP13177061.2 filed 18 Jul. 2013, the contents of which are incorporated herein by reference in their entirety.The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase (ENPP2), is a secreted ectoenzyme known to possess lysophospholipase D activity (Umezu-Goto et al., 2002), and is responsible for producing the bioactive lipid mediator lysophosphatidic acid (LPA) by the hydrolysis of lysophosphatidylcholine (LPC) (Tokumura et al., 2002). LPA is highly implicated in the pathogenesis of a number of physio-pathological diseases, including cancer (Liu ...

Novel glp-1 receptor modulators

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “ ” represents either or both the R and S form of the compound): where A, B, C, Y 1 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , W 1 , n, p and q are as defined herein.

Hepatitis C Virus Inhibitors

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein. 3. A composition comprising a combination of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.4. The composition of further comprising one or two additional compounds having anti-HCV activity.5. The composition of wherein at least one of the additional compounds is an interferon or a ribavirin.6. A method of treating an HCV infection in a patient claim 1 , comprising administering to the patient a therapeutically effective amount of a combination of claim 1 , or a pharmaceutically acceptable salt thereof.7. The method of further comprising administering one or two additional compounds having anti-HCV activity prior to claim 6 , after or simultaneously with the combination claim 6 , or a pharmaceutically acceptable salt thereof. The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.HCV is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.Over the past decade the standard of care for the treatment of chronic HCV employed a combination of pegylated-interferon and ribavirin. The treatment has a non-optimal success rate in achieving sustained viral response (SVR) against the six major HCV ...

COMPOSITIONS AND METHODS OF TREATMENT FOR NEUROLOGICAL DISORDERS COMPRISING DEPRESSION

This invention, in at least some embodiments, relates to an inventive molecule, compositions comprising same, and methods of use thereof for treatment of a neurological disorder. 114.-. (canceled)15. The method of claim 26 , wherein said subtype includes one or more of disruptive mood dysregulation disorder (in children up to the age of 18) claim 26 , major depressive disorder (including major depressive episode) claim 26 , persistent depressive disorder (dysthymia) claim 26 , premenstrual dysphoric disorder claim 26 , substance/medication-induced depressive disorder claim 26 , depressive disorder due to another medical condition claim 26 , other specified depressive disorder claim 26 , unspecified depressive disorder; depression with another feature claim 26 , including but not limited to anxious distress; mixed features; melancholic features; atypical features (depression that includes the ability to temporarily be cheered by happy events claim 26 , increased appetite claim 26 , excessive need for sleep claim 26 , sensitivity to rejection claim 26 , and a heavy feeling in the arms or legs); psychotic features; catatonia; seasonal pattern depression (also referred to as seasonal affective disorder); or treatment-resistant depression (TRD).16. The method of claim 26 , further comprising delaying disease onset in individuals at risk for disease development according to one or more predictive markers.17. The method of claim 26 , further comprising administering a drug selected from the group consisting of tricyclic antidepressant compounds (TCAs) claim 26 , selective serotonin re-uptake inhibitors (SSRIs) claim 26 , monoamine oxidase inhibitors (MAOIs) claim 26 , serotonin-norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants.18. The method of claim 17 , wherein said:a. TCA is selected from the group consisting of imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline;b. SSR1 is selected from the group ...