СОЕДИНЕНИЯ И СПОСОБЫ ИНГИБИРОВАНИЯ ВЗАИМОДЕЙСТВИЯ БЕЛКОВ BCL С КОМПОНЕНТАМИ СВЯЗЫВАНИЯ

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

КАРБОКСАМИДНЫЕ ПРОИЗВОДНЫЕ ПИРРОЛИДИНА ИЛИ ПИПЕРИДИНА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И СПОСОБ ИНГИБИРОВАНИЯ АГРЕГАЦИИ ТРОМБОЦИТОВ

Изобретение относится к новым производным пирролидина или пиперидина ф-лы (I), их энантиомерам и фармацевтически приемлемым солям где R10 - Н или C(O)N(R1)YZ, R1 - Н, Y - (СН2)р, (CH2)qCH(R3) или CH(R3)(CH2)q, R3 - арил, аралкил или гетероарил, q = 1-3, р = 2 или 3, Z - CO2H, СО2-алкил или 5-тетразол, Х-С(O), М-(СН2)n, или пиперидин-1-ил, m = 2, n = 2, R5 - Н, А выбирают из пиперидин-2-ила, пиперидин-3-ила, пиперидин-4-ила или N-замещенного пиперидина. Соединения ф-лы (I) ингибируют агрегацию тромбоцитов и могут найти применение в медицине. 3 с. и 2 з.п. ф-лы, 6 табл.

ИНГИБИТОРЫ ТРОМБИНА И ПРОМЕЖУТОЧНЫЕ СОЕДИНЕНИЯ ДЛЯ ИХ ПОЛУЧЕНИЯ

Описываются соединения формулы (I), а также их соли с физиологически приемлемыми кислотами и их стереоизомеры, где заместители имеют указанные в описании значения. Также в изобретении описываются промежуточные продукты формулы (II) для их получения. Соединения пригодны для борьбы с заболеваниями в системе свертывания крови, а также могут служить для профилактики тромбоза, например после хирургических вмешательств. 2 с.п. ф-лы.

АЛЛОСТЕРИЧЕСКИЕ МОДУЛЯТОРЫ МЕТАБОТРОПНЫХ ГЛУТАМАТНЫХ РЕЦЕПТОРОВ

Изобретение относится к новым соединениям общей формулы I и их фармацевтически приемлемым солям. Соединения настоящего изобретения обладают свойствами положительного аллостерического модулятора mGluR5. В общей формуле I ! ! W представляет собой 6-членное гетероциклоалкильное кольцо с 1-2 гетероатомами, выбранными из N, О; R1 и R2 независимо представляют собой водород, C1-С6-алкил; Р и Q, каждый независимо, выбран из: ! ! R3, R4, R5, R6 и R7 независимо представляют собой водород; галоген; -CN; нитро; C1-С6-алкил; С3-С6-циклоалкил; галоген-С1-С6-алкил; 5-6-членный гетероарил с 1-2 атомами N в качестве гетероатомов; 6-членный гетероцикл с 2 гетероатомами, представляющими собой N, О; фенил, необязательно замещенный галогеном; нафтил; -OR8; где необязательно два заместителя вместе с находящимися между ними атомами образуют 9-10-членное бициклическое арильное или гетероарильное кольцо с 1-2 гетероатомами, выбранными из N, S; R8 представляет собой водород, C1-С6-алкил; D, Е, F, G и Н независимо ...

БИЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ В КАЧЕСТВЕ ИНГИБИТОРОВ ВЗАИМОДЕЙСТВИЯ/АКТИВАЦИИ PD1/PD-L1

Изобретение относится к соединениям формулы I, их стереоизомерам и фармацевтически приемлемым солям, которые являются ингибиторами активации PD-1/PD-L1. В формуле (I) X1 выбирают из -CH2O-; R4 выбирают из водорода; X выбирают из CR3 или N; R1, R2, R3, R6 и R7 независимо выбирают из водорода, галогена, C1-6 алкила, (4-10-членный гетероциклоалкил)-C1-4 алкила-, ORa или C(O)ORa, где C1-6 алкил и (4-10-членный гетероциклоалкил)-C1-4 алкил- независимо необязательно замещены 1, 2 или 3 Rb заместителями, и 4-10-членный гетероциклоалкил имеет 1-3 гетероатома, выбранных из азота и кислорода, и является моно- или бициклическим; Ra выбирают из C1-6 алкила, C1-4 галоалкила, C6-10 арил-C1-4 алкила-, C3-10 циклоалкил-C1-4 алкила-, (5-10-членный гетероарил)-C1-4 алкила- или (4-10-членный гетероциклоалкил)-C1-4 алкила-, где C1-6 алкил, C6-10 арил-C1-4 алкил-, C3-10 циклоалкил-C1-4 алкил-, (5-10-членный гетероарил)-C1-4 алкил- и (4-10-членный гетероциклоалкил)-C1-4 алкил- независимо необязательно замещены ...

РАСТВОРИМЫЕ С5аR АНТАГОНИСТЫ

FIELD: biochemistry.SUBSTANCE: invention relates to compounds of Formula (I):in which R1is selected from a group consisting of H,R2is selected from a group consisting of H,R3is H,or; wherein two of R1, R2and R3are H, and one of R1, R2and R3differs from H, or its pharmacologically acceptable salts modulating C5a receptor. Pharmaceutical compositions containing such compounds and treatment methods are also described.EFFECT: compounds and pharmaceutical compositions containing such compounds can be used in medicine.25 cl, 2 dwg, 25 ex ...

ОПТИЧЕСКИ АКТИВНОЕ ПРОИЗВОДНОЕ ДИАЗАБИЦИКЛООКТАНА И СПОСОБ ЕГО ПОЛУЧЕНИЯ

Изобретение относится к оптически активному диазабициклооктановому производному формулы (F), где Rобозначает COR, COM или CONH, причем R обозначает метильную группу, трет-бутильную группу, аллильную группу, бензильную группу или 2,5-диоксопирролидин-1-ильную группу, и М обозначает атом водорода, неорганический катион, выбранный из лития, калия, натрия, или органический катион, причем органическим катионом является соль аммония, образованная из амина, выбранного из циклогексиламина; и Rобозначает бензильную группу или аллильную группу. Также изобретение относится к способу получения соединения формулы (F) и промежуточных соединений, к промежуточным соединениям, кристаллическим формам соединения формулы (F), а также применению соединения формулы (F) в качестве фармацевтического промежуточного соединения для получения ингибитора β-лактамазы, и к способу его получения. Технический результат: получены новые производные (2S,5R)-7-оксо-1,6-диазабицикло[3.2.1]октан-2-карбоновой кислоты, а также ...

КОМБИНАЦИЯ ИНГИБИТОРА ВИЧ-ПРОТЕАЗЫ С ДРУГИМИ АНТИВИРУСНЫМИ СОЕДИНЕНИЯМИ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И СПОСОБ ПОЛУЧЕНИЯ ФАРМАЦЕВТИЧЕСКОЙ КОМПОЗИЦИИ

Изобретение относится к медицине. Комбинация соединений включает N-(2(R)-гидрокси-1(S)-инданил-2(R)-фенилметил-4(S)-гидрокси-5-(1-(4-(3-пиридилметил)-2(S)-N'(трет-бутилкарбамоил) пиперазинил)пентанамид или его фармацевтически приемлемую соль и любое из соединений, выбранных из 3'-азидо-3'-деокситимидина, 2',3'-дидеоксиинозина и 2',3'-дидеоксицитидина. Указанная комбинация соединений может быть использована как таковая либо в виде фармацевтической композиции в сочетании с фармацевтически приемлемым носителем для ингибирования ВИЧ-протеазы. Технический результат заключается в реализации указанного назначения. 3 с. и 2 з.п.ф-лы, 6 табл.

3,4-ДИЗАМЕЩЕННЫЕ ЦИКЛОБУТЕН-1,2-ДИОНЫ КАК ЛИГАНДЫ СХС- ХЕМОКИНОВОГО РЕЦЕПТОРА

... 1. Соединение формулы или его фармацевтически приемлемая соль или сольват, в котором А выбран из группы, включающей , , , , , , , , , , , , , , , , , n=0-6 , , , X=-O-, -NH-, -S- , , , , , , , , , , , , , , , и В выбран из группы, включающей , , , , , , , , , , , , , , и ; R2 означает водород, ОН, -С(O)ОН, -SH, -SO2NR13R14, -NHC(O)R13, -NHSO2NR13R14, -NHSO2R13, -NR13R14, -C(O)NR13R14, -C(O)NHOR13, -C(O)NR13OH, -S(O2)OH, -OC(O)R13 или незамещенную или замещенную гетероциклическую кислотную функциональную группу, где заместители в замещенных группах R2 являются одинаковыми или разными и независимо выбраны из группы, включающей 1-6 групп R9; R3 и R4 являются одинаковыми или разными и независимо выбраны из группы, включающей водород, цианогруппу, галоген, алкил, алкоксил, -ОН, -CF3, -OCF3, -NO2, -C(O)R13, -C(O)OR13 , -C(O)NHR17, -C(O)NR13R14, -SO(t)NR13R14, -SO(t)R13, -C(O)NR13OR14, , , , -NHC(O)R17, незамещенную или замещенную арильную или незамещенную или замещенную гетероарильную группу, ...

ПРОИЗВОДНЫЕ 1-ПРОПАНОЛА И 1-ПРОПИЛАМИНА И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ГЛЮКОКОРТИКОИДНЫХ ЛИГАНДОВ

... 1. Соединение формулы (IA) где R1 означает арил, гетероарил или С5-С15циклоалкил, каждый из которых необязательно и независимо содержит от одного до трех заместителей, причем каждый заместитель группы R1 независимо означает C1-С5алкил, С2 -С5алкенил, С2-С5алкинил, С3-С8циклоалкил, гетероциклил, арил, гетероарил, C1-C5алкокси, С2-С5 алкенилокси, С2-С5алкинилокси, арилокси, ацил, С1-С5алкоксикарбонил, С1-С5алканоилокси, С1-С5алканоил, ароил, аминокарбонил, алкиламинокарбонил, диалкиламинокарбонил, аминокарбонилокси, С1-С5алкиламинокарбонилокси, С1-С5диалкиламинокарбонилокси, С3-С5циклоалкиламинокарбонилокси, С1-С5алканоиламино, С1-С5алкоксикарбониламино, С1-С5алкилсульфониламино, аминосульфонил, С1-С5алкиламиносульфонил, С1-С5диалкиламиносульфонил, галоген, гидрокси, оксо, карбокси, циано, трифторметил, трифторметокси, нитро или амино, причем атом азота необязательно независимо моно- или дизамещен группой С1-С5алкил или арил; или уреидо, причем каждый атом азота необязательно независимо замещен ...

СПОСОБ ПОЛУЧЕНИЯ 5R-[(БЕНЗИЛОКСИ)АМИНО]ПИПЕРИДИН-2S-КАРБОНОВОЙ КИСЛОТЫ ИЛИ ЕЁ ПРОИЗВОДНОГО

Настоящая заявка относится к способам получения 5R-[(бензилокси)амино]пиперидин-2S-карбоновой кислоты или ее производных безвредным для окружающей среды путем. В способе применяют L-глутаминовую кислоту в качестве исходного вещества, причем ее сначала подвергают реакции эстерификации в присутствии кислотного реагента, а затем последовательно осуществляют реакцию с 2-галогенацетатом и средством для введения защитной группы для атома N или со средством для введения защитной группы для атома N и 2-галогенацетатом в основных условиях с получением соединения IV; затем полученное соединение IV подвергают внутримолекулярной конденсации с образованием кольца при воздействии сильного основания с получением защитная-группа-для-атома-пиперидин-5-он-2S-карбоксилата (V). Полученное соединение V применяют для получения 5R-[(бензилокси)амино]пиперидин-2S-карбоновой кислоты (или ее сложного эфира) посредством одного из нижеследующих путей. Путь 1: соединение V подвергают удалению защитной группы, конденсации ...

СПОСОБ ПОЛУЧЕНИЯ 5R-[(БЕНЗИЛОКСИ)АМИНО]ПИПЕРИДИН-2S-КАРБОКСИЛАТА И ЕГО ОКСАЛАТОВ

Изобретение относится к способам получения 5R-[(бензилокси)амино]пиперидин-2S-карбоксилата и его оксалата, где L-глутаминовую кислоту или натриевую соль L-глутаминовой кислоты в качестве исходного материала вводят в реакцию с монохлоруксусной кислотой в щелочных условиях посредством реакции замещения с получением N-карбоксиметил-L-глутаминовой кислоты (соединение III), затем соединение III вводят в реакцию со спиртом в присутствии кислотного реагента посредством реакции этерификации с получением сложного диэфира N-алкоксикарбонилметил-L-глутаминовой кислоты (соединения IV), под действием сильного основания соединение IV подвергают внутримолекулярной конденсации с образованием кольца, гидролизу с декарбоксилированием и этерификации с получением пиперидин-5-он-2S-карбоксилата (соединения V), соединение V подвергают конденсации с гидрохлоридной солью бензилоксиамина в присутствии щелочи с получением 5-[(бензилокси)имино]пиперидин-2S-карбоксилата (соединения VI), соединение VI подвергают восстановлению ...

3-МОНО- И 3,5-ДИЗАМЕЩЕННЫЕ ПИПЕРИДИНОВЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ РЕНИНА

... 1. Соединение формулы I ! ! где R1 каждый независимо от других (присутствует, если р>0) означает заместитель, выбираемый из группы, состоящей из заместителя формулы -(С0-С7)алкилен)-(Х)r-((С1-С7)-алкилен)-(Y)s-(С0-С7)алкилен)-Н, где C0-алкилен означает, что присутствует связь вместо связанного алкилена, r и s каждый независимо от другого означают 0 или 1, и каждый из Х и Y, если присутствует и независимо от других, означает -O-, -NV-, -S-, -С(=O)-, -C(=S), -O-СО-, -СО-O-, -NV-CO-; -CO-NV-; -NV-SO2-, -SO2-NV; -NV-CO-NV-, -NV-CO-O-, -O-CO-NV-, -NV-SO2-NV-, где V означает водород или незамещенный или замещенный алкил, как определено ниже; (С2-С7)алкенил, (С2-С7)алкинил, фенил, нафтил, гетероциклил, фенил- или нафтил- или гетероциклил(С1-С7)алкил или (С1-С7)алкилокси, ди(нафтил- или фенил)амино(С1-С7)алкил, ди(нафтил- или фенил(С1-С7)алкил)амино(С1-С7)алкил, бензоил- или нафтоиламино(С1-С7)алкил, фенил- или нафтилсульфониламино(С1-С7)алкил, где фенил или нафтил является незамещенным или замещенным ...

ЗАМЕЩЕННЫЕ НИТРИРОВАННЫЕ КАТЕХОЛЫ, ИХ ПРИМЕНЕНИЕ В ЛЕЧЕНИИ НЕКОТОРЫХ РАССТРОЙСТВ ЦЕНТРАЛЬНОЙ И ПЕРИФЕРИЧЕСКОЙ НЕРВНОЙ СИСТЕМЫ И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ

... 1. Соединение формулы I где R1 и R2, одинаковые или отличные друг от друга, обозначают водород, необязательно замещенный низший алканоил или ароил, необязательно замещенный низший алкоксикарбонил, или необязательно замещенный низший алкилкарбамоил; R3 обозначает водород или необязательно замещенную алканоильную или ароильную группу; R4 обозначает необязательно замещенную насыщенную или частично ненасыщенную низшую алкильную или арильную группу, или, взятый вместе с R3, образует необязательно замещенное насыщенное или частично ненасыщенное карбоциклическое кольцо; A обозначает кислород или группу NR5, где R5 обозначает NHR6, где R6 обозначает необязательно замещенную низшую алкильную или арильную группу, или группу OR7, где R7 обозначает водород, низший алкил или низший алканоил, или A обозначает необязательно замещенный алкилиден, когда R4 обозначает группу OR8, где R8 обозначает необязательно замещенную низшую алканоильную или ароильную группу, и его фармацевтически приемлемые соли. 2.

СПОСОБ ПОЛУЧЕНИЯ МОНОГИДРАТА РОПИВАКАИНА ГИДРОХЛОРИДА И МОНОГИДРАТ РОПИВАКАИНА ГИДРОХЛОРИДА, ПОЛУЧЕННЫЙ ЭТИМ СПОСОБОМ

... 1. Способ получения моногидрата ропивакаина гидрохлорида формулы I •HCl•H2O отличающийся тем, что он включает следующие стадии реакции: стадия 1 (i) рацемическое исходное вещество - пипеколоксилидид гидрохлорид формулы II освобождают от НСl, образующий с ним соль, путем экстракции в органическом растворителе, содержащем разбавленное основание; (ii) пипеколоксилидид разделяют путем кристаллизации с разделяющим реагентом, образующим стабильную кристаллизационную систему с водой, и кристаллический продукт выделяют из его соли путем экстракции и органическом растворителе, который растворяет минимум около 1 мас.% воды, с разбавленным основанием, и получают соединение (S)- пипеколоксилидид формулы III стадия 2 (i) (S) - пипеколоксилидид формулы (III) алкилируют 1-галогенпропаном в присутствии основания и, необязательно, в присутствии катализатора, причем реакция проводится при нагревании, после чего неорганические соли удаляют путем экстракции водой; (ii) раствор, полученный на стадии 2 (i), ...

НОВЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ

... 1. Соединение формулы I в которой R1 и R2 независимо представляют собой атом водорода, атом галогена, трифторметил, C1-C6-алкил или C1-C6-алкокси; Y - это группы >N-CH2-, > CH-CH2- или >C=CH-, в которых только подчеркнутый атом участвует в циклической системе; Х - это группы -О-, -S-, -CR7R8-, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH= CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C=O)-, -O-CH2-, -(C=O)- или -(S= O)-, где R7, R8 и R9 независимо представляют собой атом водорода или C1-C6-алкил; r = 1, 2 или 3; m = 1 или 2, n = 1, когда m = 1, и n = 0, когда m = 2; R4 и R5 каждый представляет собой атом водорода или, когда m = 2, могут оба вместе составлять связь; и R6 является гидроксилом или C1-C8-алкокси-группой; или его фармацевтически приемлемая соль, при условии, что не включены соединения 10-(3-(3-карбометокси-1-пиперидил)пропил)фенотиазин и 10-(3-(3-карбогексокси-1-пиперидил)пропил)фенотиазин. 2. Соединение по п.1, отличающееся тем, что его выбирают из следующих: (R)-1-(3-(10,11-дигидро-5Н-дибензо[a, d] ...

Способ получения нитрила 1-бензил4-фенилпиперидинкарбоновой кислоты

Производные R- и S-2-аминоалкилкарбонил-2-аминобензальдегида в качестве реагента для получения оптически активных аминокислот

Способ получения этилового эфира 1-метилпиперидин-3-карбоновой кислоты

Способ получения энантиомеров @ -аминокислот

СПОСОБ ПОЛУЧЕНИЯ ЭНАНТЙОМЕРОВ ct - АМИНОКИСЛОТ взаимодействием d - (R,S)- аминокислоты хирального реагента общей формулы CH JipCH-C-K- S) iM- о Н IQ ; I СН2-СбН5 R где-п - 3,4, и Солей двухвалентных металлов в щелочной среде с образованием диастереоизомерных смесей комплексов, включающий разложение комплексов в кислой среде и вьщеление энантиоме (Л ров cL- аминокислот, отличающийся тем, что, с целью упрощения процесса и увеличения выхода целевого продукта, комплекс непосредственно разделяют на диастереомбры путем жидкостной распределительной хроматографии, которые далее обраба;о тывают кислотой. 00 о О) 00 ...

Способ получения галоидзамещенных меркаптоациламинокислот

Способ получения производныхпРОлиНА

SULFONAMIDDERIVATE ALS ASPARTYLPROTEASE-INHIBITOREN

NEUARTIGE ANTIKOAGULIERENDE PEPTIDDERIVATE UND ARZNEIMITTEL DIE SOLCHE ENTHALTEN SO WIE ENTSPRECHENDES HERSTELLUNGSVERFAHREN

Substituierte Pipecoline-Säurederivate als HIV-Protease-Hemmer.

Verfahren zur Herstellung von Aminocarbonsaeureamiden, welche die Atomgruppierung ? enthalten

Verfahren zur Herstellung von neuen N-substituierten 5-Cyan-pyrrolidin- und 6-Cyan-piperidin-verbindungen

AZAHETEROZYKLISCHEDERIVATE ZUR BEHANDLUNG VON HAARAUSFALL UND NEUROLOGISCHER KRANKHEITEN

Hydantoinverbindungen

FKBP INHIBITOREN

SUBSTITUIERTE ZYKLISCHE AMINE ALS METALLOPROTEASEINHIBITOREN

HYDROXYPIPECOLATE-HYDROXAMSÄURE-DERIVATIVE ALS MMP INHIBITOREN

HERBIZIDE MITTEL

VERFAHREN ZUR HERSTELLUNG VON 3-AMIDINOPHENYLALANIN-DERIVATEN

DERIVATE DES 2-HYDROXYMETHYL-3,4,5- TRIHYDROXY-PIPERIDINS, IHRE HERSTELLUNG UND VERWENDUNG ZUR BEEINFLUSSUNG DES KOHLENHYDRAT- UND FETTSTOFFWECHSELS

Hydrogenation of unsaturated heterocyclic compounds, especially pyridine compounds, uses a catalyst containing a Subgroup VIII metal on a macroporous support

A macroporous support is used in a process for the hydrogenation of unsaturated heterocyclic compounds with hydrogen in presence of a supported catalyst containing at least one Subgroup VIII metal as the active metal.

SUBSTITUIERTE HETEROCYCLISCHE VERBINDUNGEN UND DEREN VERWENDUNG ZUR BEHANDLUNG MULTIPLER MEDIKAMENTENRESISTENZ

MOLEKÜLMODELL FÜR VLA-4-INHIBITOREN

Neuroleptische Perhydro-1H-pyrido/1,2-a/pyrazine

Levobupivacaine and its use

ANALGESTIC AGENT AND ITS USE

PHARMACEUTICALS

AMINOALKYLBENZENE DERIVATIVES

Condensation products of tetracycline

Water-soluble aminomethyl derivatives of tetracycline having a low content of epitetra-cycline are prepared by reacting 1 mole of tetracycline, 1 to 2 moles of formaldehyde and 1 mole of an aliphatic or aromatic amino-acid, or a compound havin the general Formula I wherein n represents an integer from 1 to 3 inclusive, in a a lower aliphatic alcohol of 1 to 8 carbon atoms inclusive (e.g. EtOH or MeOH) and in the presence of sufficient amount of tertiary organic base (e.g. triethylamine, trimethylamine or pyridine) to impart to the mixture a pH from 7.5 to 8.5 at a temperature of 10 DEG to 50 DEG C. for 5 to 15 mins. Novel tetracycline derivatives of the Formula II wherein n is as above defined are prepared when one of the reactants is the compound of general Formula I. The derivatives are precipitated from the reaction mixture by cooling and acidification to pH 4-5. Examples of compounds prepared by this Mannich reaction are 3 - (carboxymethyl - 1 ...

Novel levo-1-n-butyl-2',6'-pipecoloxylidide and the Preparation Thereof

... 1,180,712. Levo - -1 - n - Butyl - 21,61 - pipecoloxylidide. STERLING DRUG Inc. 10 May, 1968 [18 May, 1967], No. 22420/68. Heading C2C. Novel levo - 1 - n - butyl - 21,61- pipecoloxylidide, free or substantially free from its optical antipode, and acid addition salts thereof are prepared (a) by reacting dl-21,61-pipecoloxylidide with O,O-dibenzoyl-d-tartaric acid to form a mixture of the diastereoisomeric O,O-dibenzoyl-d-tartrates, treating said mixture with boiling acetone, separating the acetone-insoluble dextro - 21,61 - pipecoloxylidide O,O - dibenzoyl - d-tartrate, isolating the levo-21,61-pipecoloxylidide O,O-dibenzoyl-d-tartrate from the acetone solution thereof, generating the levo-21,61- pipecoloxylidide base, e.g. with an inorganic base, from its O,O-dibenzoyl-d-tartrate and N- butylating said base, e.g. with n-butyraldehyde under catalytically hydrogenating conditions or with an n-butyl ...

Treatment

6,7-Di(lower alkoxy)-4-amino-2-(substituted piperidino) quinazolines

The title compounds wherein the substituent on the piperidino group is in, the 3- or 4-position and has the formula -(CH2)nCONR<1>R<2>,- O(CH2)nCONR<1>R<2> or - OCH(phenyl)CONR<1>R<2> wherein n is 0, 1 or 2; R<1> is hydrogen or lower alkyl; and R<2> is lower alkyl, phenyl, cycloalkyl, or lower alkyl substituted by certain stated substituents, with the proviso that any O, N or halogen atom in R<2> is separated by at least 2 carbon atoms from the nitrogen atom to which R<2> is attached; or R<1> and R<2> taken together with the nitrogen atom to which they are attached from a morpholino group optionally substituted by 1 or 2 lower alkyl groups, or a 1,2,3,4-tetrahydroiso -quinolyl group optionally substituted on the benzene ring portion by 1 or 2 lower alkoxy groups wherein phenyl groups are optional substituted are antihypertensives. Also claimed are the compounds' pharmaceutically acceptable bioprecursors and acid addition salts, processes for the preparation of the compounds, and pharmaceutical ...

AMINO ACID DERIVATIVES

Method of preparing amides of n-alkyl piperidine mono-carboxylic acid and n-alkyl pyrrolidine -a-monocarboxylic acid

Amides of the general formul and wherein R1 is an alkyl group, R2 an alkyl group of 1-5 carbon atoms or chlorine, R3 a hydrogen atom, an alkyl group of 1-5 carbon atoms, an alkoxy or a hydroxy group, and R4 a hydrogen atom, chlorine, an alkyl group of 1-5 carbon atoms or an alkoxy group, or in which R2, R3 and R4 are all hydrogen, are prepared by reacting an appropriately substituted aniline magnesium halide with the appropriate pyridine, piperidine, pyrrole or pyrrolidine monocarboxylic acid ester, which may or may not be N-alkylated, hydrolysing the reaction product and, where required, hydrogenating the heterocyclic ring and alkylating the nitrogen atom thereof. In the examples: (1) ethyl magnesium bromide and 2 : 6-dimethylaniline give 2 : 6-dimethylaniline magnesium bromide, this is refluxed with N-methylpipecolic acid ethyl ester and the product on hydrolysis with dilute Hcl gives N-methylpipecolic acid 2 : 6-dimethylanilide; (2) nipecotic ...

2-Adrenergic receptor agonists

Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

New carbonylated (AZA) cyclohexanes as dopamine D3 receptor ligands

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

Hydroxy pipecolate hydroxamic acid derivatives as mmp inhibitors

Fkbp inhibitors

Process for stereospecific hydrolysis oof piperidinedione. derivatives.

A process for stereospecifically hydrolysing a mixture of the (+)and (-)isomers of a compound of formula (ii)in which r is c1-6 alkyl using a carboxyl esterase enzyme (i)ro form a compound of formula (iiia), ane thereafter separating the resulting compound of formula (iiia)from the remaining (-)isomer of formula (ii); or (ii)to form a compound of formula (iiib): and thereafter separating the resulting compound of formula (iiib)from the remaining (=)isomer of formula (ii).

"Diborane reduction of certain aryl piperidines".

A process for the preparation of a compound of formula (1); in which r3 is hydrogen, c1-6alkul or c1-6 alkylaryl, by reduction using diborane, of a compound of formula (11): in which r3 is as defined in relation to formula (1)and r4 is c1-6 alkyl.

HIV Protease inhibitors.

Hiv protease inhibitors, obtainable by chemical systhesis, inhibit or block the biologocal activity of the hiv protease enzyme, causing the replication of the hiv virus to terminate. These compounds as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingrediants, are suitable for treating patients or hosts infected with the hiv virus, which is known to cause aids.

Substituted pipecolinic and acid derivatives as HIV protease inhibitors.

Disclosed herein are compounds of formula 1 wherein x is a terminal group, for example, an aryloxycarbonyl, an alkanoyl or an optionally mono or disubstituted carbamoyl, b is absent or an amino acid residue, for example, val or asn, r1 is hydrogen or a ring substituent, for example, fluoro or methyl, r2 is alkyl and y is a ring substituent for example, phenoxy, 2-pyridinylmethoxy, phenylthio or 2-pyridinylthio. The compounds inhibit the activity of human immunodeficiency virus (hiv)protease and interfere with hiv induced cytopathogenic effects in human cells. These properties render the compounds useful for combating hiv infections.

Piperazine and piperidine derivatives.

The present invention relates to piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage asssociated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage or for stimulating nerve growth.

Treatment of insulin resistance with growth hormone secretagogues.

This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula i, where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula i are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula i. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound ...

New carbonylated (AZA) cyclohexanes as dopamine D3receptor ligands

Heterocyclic compounds as inhibitors of rotamase enzymes.

Compounds of the formula: wherein r1, y, w, a and r2 are as defined above are inhibitors of rotamase enzymes in particular fkbp-12 and fkbp-52. The compounds therefore moderate neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases and nerve damage.

FKBP inhibitors.

Compounds of formula (i), their salts and solvates, wherein the substituents are as described herein, are fkbp inhibitors.

Carbamoyloxy derivatives of mutiline and their use as antibacterials.

Derivatives of mutiline of formula (1a)and pharmaceutically acceptable salts and derivatives thereof, in which r1 is ethyl or vinyl, y is a carbamoyloxy group, which the n-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections.

SUBSTITUTED PIPECOLINIC ACID DERIVATIVES AS HIV PROTEASE INHIBITORS

Novel process

Hydroxy pipecolate hydroxamic acid derivatives as MMP Inhibitors.

A compound of formula (I) wherein R1, R2 R3, R4 R, R6, R7, R8, R9 and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, and other diseases characterized by matrix metalloproteinase or mammalian reprolysin activity. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S), COX-2 inhibitors and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Caspase inhibitors and uses thereof.

This invention provides caspase inhibitors having the formula: (i)wherein ring a is an optionally substituted piperidine, tetrahydorquinoline or tettrahydroisoquinolone ring; r1 is hydrogen, chn2, r, or -ch2y; r is an optionally substituted group selected from an aliphatic group, an aryl group, an aralkyl group, a heterocyclic group, or an heterocyclylalkyl group; y is an electronegative leaving group; r2 is co2h, ch2co2h, or esters, amides or isosteres thereof; an optionally substituted aryl group; and r3 is hydrogen, an optionally substituted c1-6alkyl, f2, cn, aryl or r3 is attched to ar to form an unsaturated or partially saturated five or six membered fused ring having 0-2 heteroatoms. The compounds ae useful for treating caspase-mediated disease in mammals.

NOVEL PROCESS

Treatment of insulin resistance

2-Adrenergic receptor agonists

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.

New carbonylated (AZA) cyclohexanes as dopamine D3 receptor ligands

Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

HIV protease inhibitors

N,N' -substituted-1,3-diamino -2-hydroxypropane derivatives.

Disclosed are compounds of the formula (0, wherein the variables RN, RC, R1, R25, R2, and R3 are as defined herein. These compounds have activity as inhibitors of betasec-retase and are therefore useful in treating a variety of discorders such as Alzheimer's Disease.

P-SUBSTITUTED ASYMMETRIC UREAS AND MEDICAL USES THEREOF

Phenoxyethyl piperidine compounds

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

b2- Adrenergic receptor agonists.

Disclosed are multibinding compounds which are b2-adrenergic receptor agonists and are useful in the treatment and prevention of respiratory diseases such as asthma, bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

Hiv protease inhibitors

Carbamoyloxy derivatives of mutiline and their useas antibacterials.

pharmaceutical composition comprising a proteinaseinhibitor and a monoglyceride

Inhibitors of métalloendopeptidase neutral in the treatment of the hypertention.

Arylthio compounds as antibacterial and antiviral agents

Heterocyclially substituted benzoylureas, method for their production and their use as medicaments.

N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives.

Treatment of insulin resistance with growth hormone secretagogues

Substituted pipecolinic acid derivatives as hiv protease inhibitors

Hydroxy pipecolate hydroxamic acid derivatives as MMP inhibitors.

Derived from the quinolyl propyl piperidin and their use as antimicrobic agents.

FKBP inhibotors.

Process of obtaining new amilides.

Caspase inhibitors and uses thereof

2-Adrenergic receptor agonists

P-SUBSTITUTED ASYMMETRIC UREAS AND MEDICAL USES THEREOF

Treatment of insulin resistance

Heterocyclic compounds as inhibitors of rotamase enyzmes

Caspase inhibitors and uses thereof

Materials and Methods for the Treatment of Hypertension

The present invention is directed to materials and methods for the treatment of hypertension and ischemia comprising administering at least one therapeutic agent selected from the group consisting of vascular endothelial growth factor-C product and vascular endothelial growth factor-D product, and optionally, when treating hypertension, a standard of care anti-hypertensive agent.

Development of Novel Detergents for Use in PCR Systems

This disclosure relates to novel detergents for use in various procedures including, for example, nucleic acid amplification reactions such as polymerase chain reaction (PCR). Methods for preparing the modified detergents are also described.

SOLUBLE FMS-LIKE TYROSINE KINASE-1 (sFLT-1) ANTIBODY AND RELATED COMPOSITION, KIT, METHODS OF USING, AND MATERIALS AND METHOD FOR MAKING

An isolated antibody that specifically binds to sFlt-1 or a fragment thereof having (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 2, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 4, or (iii) both (i) and (ii), a pharmaceutical composition and a kit comprising such an antibody, a method of making such an antibody, a method of determining the presence, amount or concentration of sFlt-1 or a fragment thereof in a test sample, a method of treating a patient in therapeutic or prophylactic need of an antagonist of sFlt-1, an isolated nucleic acid comprising a nucleotide sequence encoding the amino acid sequence of (i) SEQ ID NO: 2, (ii) SEQ ID NO: 4, or (iii) both (i) and (ii), optionally as part of a vector, and a host cell comprising and expressing such a nucleic acid.

PYRENYLOXYSULFONIC ACID FLUORESCENT AGENTS

The invention provides a novel class of reactive fluorescent agents that are based on a pyrene sulfonic acid nucleus. The agents are readily incorporated into conjugates with other species by reacting the reactive group with a group of complementary reactivity on the other species of the conjugate. Also provided are methods of using the compounds of the invention to detect and/or quantify an analyte in a sample. In an exemplary embodiment, the invention provides multi-color assays incorporating the compounds of the invention. 125.-. (canceled)27. The compound of wherein s is 1 and t is 2.28. The compound of wherein the linker arm comprises a straight-chain claim 26 , saturated chain of atoms and includes unsubstituted polyalkylene.30. The compound of wherein s is 1 and t is 2.32. The conjugate of wherein s is 1 and t is 2.33. The conjugate of wherein the linker arm comprises a straight-chain claim 31 , saturated chain of atoms and includes unsubstituted polyalkylene.35. The conjugate of claim 34 , wherein the linker arm comprises a cleavable group.36. The conjugate of claim 34 , wherein the linker arm comprises —C(O)NH— claim 34 , —C(O)O— claim 34 , —NH— claim 34 , —S— claim 34 , or —O—.37. The conjugate of claim 34 , wherein s is 1 claim 34 , and t is 2.38. A kit for the detection of an analyte in a sample claim 26 , wherein said kit comprises a compound of .39. A kit for the detection of an analyte in a sample claim 29 , wherein said kit comprises a compound of .40. A kit for the detection of an analyte in a sample claim 31 , wherein said kit comprises a conjugate of .41. A kit for the detection of an analyte in a sample claim 34 , wherein said kit comprises a conjugate of . NOT APPLICABLENOT APPLICABLENOT APPLICABLEThe present invention relates to novel fluorescent compounds that have utility in detecting one or more selected analytes in a sample. The invention is of use in a variety of fields including immunology, diagnostics, molecular biology and fluorescence ...

METHOD FOR PRODUCING OPTICALLY ACTIVE 3-AMINOPIPERIDINE OR SALT THEREOF

The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof. In the method, a racemic nipecotamide is stereoselectively hydrolyzed to obtain an optically active nipecotamide and an optically active nipecotic acid in the presence of an enzyme source derived from an organism, and then the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by aroylation, Hofmann rearrangement, deprotection of the amino group and further deprotection; or the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by selective protection with BOC, Hofmann rearrangement and further deprotection. It is possible by the present invention to produce an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate from an inexpensive and easily available starting material by easy method applicable to industrial manufacturing. 118.-. (canceled) The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate, and to intermediates useful for producing the 3-aminopiperidine.As methods for producing an optically active 3-aminopiperidine or salt thereof, or a derivative of optically active 3-aminopiperidine, for example, the following methods are known:1) a method, wherein L-ornithine monohydrochloride is methyl-esterified, and then (S)-3-amino piperidone is obtained by chromatography with an ion exchange resin, the (S)-3-amino piperidone is reacted with lithium aluminum hydride to be (S)-3-aminopiperidine, an inorganic salt is removed by filtration, and the target compound is purified (Non-patent Document 1);2) a method, wherein ethyl nipecotate is optically resolved using L-tartaric acid, the nitrogen atom is protected with benzyloxycarbonyl group, the ethyl ester is hydrolyzed in alkaline condition, Curtius rearrangement is carried out using ...

PRODRUGS OF A PIPERIDINYL DERIVATIVE AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

The present application describes prodrugs of the compound of formula (I): 3. A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of .4. A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of .5. A method for modulation of chemokine or chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of .6. The method of claim 5 , wherein the chemokine or chemokine receptor activity is CCR-1 or CCR-1 receptor activity.7. A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of ; wherein said disorder is selected from osteoarthritis claim 1 , aneurysm claim 1 , fever claim 1 , cardiovascular effects claim 1 , Crohn's disease claim 1 , congestive heart failure claim 1 , autoimmune diseases claim 1 , HIV-infection claim 1 , HIV-associated dementia claim 1 , psoriasis claim 1 , idiopathic pulmonary fibrosis claim 1 , transplant arteriosclerosis claim 1 , physically- or chemically-induced brain trauma claim 1 , neuropathic pain claim 1 , inflammatory bowel disease claim 1 , alveolitis claim 1 , ulcerative colitis claim 1 , systemic lupus erythematosus claim 1 , nephrotoxic serum nephritis claim 1 , glomerulonephritis claim 1 , asthma claim 1 , multiple sclerosis claim 1 , atherosclerosis claim 1 , rheumatoid arthritis claim 1 , restenosis claim 1 , organ transplantation claim 1 , multiple myeloma claim 1 , colorectal cancer claim 1 , hepatocellular cancer and other cancers.8. A method for treating inflammatory diseases comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of .9. A method for preparing a medicament for the treatment ...

Process for the preparation of enantiomerically enriched cyclic beta-aryl or heteroaryl carbocyclic acids

The present invention relates to a process for the preparation of cis substituted cyclic β-aryl or heteroaryl carboxylic acid derivatives in high diastereo- and enantioselectivity by enantioselective hydrogenation in accordance with the following scheme wherein X, Ar, n, and m are defined herein and corresponding salts thereof.

QUATERNARY HETEROATOM CONTAINING COMPOUNDS

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): 3. The method of claim 2 , wherein:{'sup': '1', 'Ris selected from halogen and an optionally substituted group selected from alkyl, carbocyclyl, carbocyclylalkyl, cyanoalkyl, aralkyl, heteroaralkyl, hydroxyalkyl, haloalkyl, acylalkyl, alkoxycarbonylalkyl, and aryloxycarbonylalkyl;'}{'sup': 2', '12', '7', '8', '11, 'R, R, R, R, and Rare independently selected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl;'}{'sup': 3', '4', '5', '13', '14', '15, 'R, R, R, R, R, and Rare independently selected at each occurrence from hydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and aralkyloxy;'}{'sup': 6', '9', '10, 'R, R, and Rare independently selected at each occurrence from hydrogen, hydroxyl, and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide.'}4. The method of claim 3 , wherein:{'sup': '1', 'Ris selected from halogen, alkyl, optionally substituted aralkyl, optionally substituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionally substituted hydroxyalkyl; and'}{'sup': 6', '9', '10, 'R, R, and Rare independently selected at each occurrence from optionally substituted aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, and aryloxycarbonyl.'}5. The method of claim 4 , wherein:{'sup': '6', 'X is —NR—;'}{'sup': 7', '7, 'Z is selected from —C(O)— and —CRR—;'}{'sup': 8', '8, 'A at each occurrence is —CRR—;'}{'sup': 10', '11', '11, 'W is selected from —NR ...

PROLINAMIADE DERIVATIVES AS THROMBIN INHIBITOR, PREPRARATION METHOD AND APPLICATION THEREOF

Provided are a compound of formula (I), pharmaceutically acceptable salts thereof, preparation methods and applications thereof for inhibiting thrombin, and applications in the treatment and prevention of thrombin-mediated and thrombin-related diseases. 6. The compound of formula (I) claim 1 , pharmaceutically acceptable salt and pharmaceutically acceptable prodrug thereof according to claim 1 , characterized in that the pharmaceutically acceptable salt is selected from the salts derived from pharmaceutically acceptable inorganic acid and organic acid.7. The compound of formula (I) claim 6 , pharmaceutically acceptable salt and pharmaceutically acceptable prodrug thereof according to claim 6 , characterized in that the inorganic acid and organic acid are selected from sulfuric acid claim 6 , sulfurous acid claim 6 , hydrochloric acid claim 6 , acetic acid claim 6 , hydrobromic acid claim 6 , nitric acid claim 6 , phosphoric acid claim 6 , metaphosphoric acid claim 6 , pyrophosphoric acid claim 6 , maleic acid claim 6 , fumaric acid claim 6 , succinic acid claim 6 , citric acid claim 6 , perchloric acid claim 6 , p-toluenesulfonic acid claim 6 , tartaric acid claim 6 , formic acid claim 6 , acetic acid claim 6 , propanoic acid claim 6 , heptylic acid claim 6 , oxalic acid claim 6 , benzoic acid claim 6 , propandioic acid claim 6 , succinic acid claim 6 , succinic acid claim 6 , cis-butenedioic acid claim 6 , hydroxybutanoic acid claim 6 , citric acid claim 6 , methanesulfonic acid claim 6 , benzenesulfonic acid claim 6 , lactic acid or mandelic acid.8. The compound of formula (I) claim 6 , pharmaceutically acceptable salt and pharmaceutically acceptable prodrug thereof according to claim 6 , characterized in that the inorganic acid and organic acid are selected from hydrochloric acid or acetic acid.9. The compound of formula (I) claim 1 , pharmaceutically acceptable salt and pharmaceutically acceptable prodrug thereof according to claim 1 , characterized in that the ...

PROCESS FOR PREPARING CYCLIC AMINE COMPOUNDS

A cyclic amine compound having a prescribed configuration can be efficiently prepared by reducing an imine derivative in the presence of a sulfonic acid. Specifically, a cyclic amine compound which is substituted with an amino group and a carboxyl group in which both groups are arranged in the trans configuration can be prepared efficiently. 2. The process according to claim 1 , wherein Ris Calkyloxy group claim 1 , Calkenyloxy group claim 1 , Caralkyloxy group claim 1 , Caryloxy group claim 1 , Ctrialkylsilyloxy group claim 1 , amino group claim 1 , Calkylamino group claim 1 , Calkenylamino group claim 1 , Caralkylamino group claim 1 , Carylamino group claim 1 , Cdialkylamino group claim 1 , Cdialkenylamino group claim 1 , Cdiaralkylamino group claim 1 , Cdiarylamino group claim 1 , thiol group claim 1 , Calkylthio group claim 1 , Calkenylthio group claim 1 , Caralkylthio group claim 1 , or Carylthio group.3. The process according to claim 1 , wherein the sulfonic acid is sulfuric acid or camphorsulfonic acid; and the reducing agent is borane.4. The process according to claim 1 , wherein Ris benzyloxy group or dibenzylamino group; Ris hydrogen atom; Ris benzyloxy group; and n is 2.5. The process according to claim 4 , further comprising the steps of forming a salt of said cyclic amine compound and oxalic acid claim 4 , and precipitating the salt as a solid in methanol claim 4 , in ethanol claim 4 , in isopropanol claim 4 , in a mixed solvent containing methanol claim 4 , in a mixed solvent containing ethanol claim 4 , or in a mixed solvent containing isopropanol.7. The process according to claim 6 , wherein P is benzyloxycarbonyl group. The present invention relates to a process for producing a cyclic amine compound, specifically, a cyclic amine compound which has an amino group and a carboxyl group as substituents and their configuration is trans, and especially a trans-5-aminopiperidine-2-carboxylic acid derivative, which is useful for an intermediate for ...

PHENOXYETHYL PIPERIDINE COMPOUNDS

The present invention provides a compound of the Formula II: 2. A compound according to wherein Ris H.3. A compound according to wherein Ris H and Ris methyl.8. A method of treating osteoarthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , as in .9. A method of treating rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof claim 1 , as in .10. A method of treating pain associated with osteoarthritis or rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof claim 1 , as in .11. A pharmaceutical composition claim 1 , comprising a compound or a pharmaceutically acceptable salt thereof as in in combination with one or more pharmaceutically acceptable carriers claim 1 , diluents claim 1 , or excipients.12. The pharmaceutical composition according to claim 11 , further comprising one or more other therapeutic agents. The present invention relates to novel phenoxyethyl piperidine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.The present invention is in the field of treatment of inflammatory conditions, such as arthritis, including osteoarthritis and rheumatoid arthritis, and further including pain associated with these conditions. Arthritis affects millions of patients in the United States alone and is a leading cause of disability. Treatments often include NSAIDs (nonsteroidal anti-inflammatory drugs) or COX-2 inhibitors, which may produce untoward cardiovascular and/or gastrointestinal side effects. As such, ...

PROCESS INTERMEDIATES AND METHODS FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE

Methods are provided for the synthesis of key intermediates for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl. Such intermediates are also provided. 135-. (canceled)36. An ethyl (2R ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate comprising in an amount HCl between about 1 mol/mol and about 2 mol/mol.37. A solvate of the compound of having an organic solvent or water content of at least 0.5 mol/mol.38. A dihydrochloride form of the compound of having a weight/weight chloride content between about 12 and about 16%.39. A dihydrochloride form of the compound of claim 36 , wherein said compound is solvated by ethanol and has a weight/weight chloride content between about 11 and about 15%.40. A Method for obtaining ethyl (2R claim 36 ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl claim 36 , solvated or unsolvated claim 36 , comprising exposing a mixture of ethyl (2R claim 36 ,4R)-1-[(2S)-2-amino-5[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S claim 36 ,4S)-1-[(2S)-2-amino-5[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl claim 36 , solvated or unsolvated claim 36 , to an organic or aqueous solvent or to a mixture thereof claim 36 , followed by the selective precipitation and isolation of ethyl (2R claim 36 ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl claim 36 , solvated or unsolvated.41. The method of comprising:a) exposing a mixture of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, and ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl] ...

COMPOSITIONS COMPRISING 4'-O-GLUCURONIDE EPICATECHIN AND METHODS OF MAKING AND USING SUCH COMPOSITIONS

Compositions can comprise the flavanol metabolite 4′-O-glucuronide epicatechin (4GEC). In some embodiments, the composition can be used in a method for blood vessel dilation and/or increased delivery of blood flow to tissues in the body, for example by administering the composition to an individual having or at risk of high blood pressure or a cardiovascular disease. In some embodiments, the compositions are used for weight maintenance or weight loss. The compositions are preferably administered orally as a food product in which the 4′-Oglucuronide is present in a concentration of at least 0.01 mg/g of the food product. 1. A method for blood vessel dilation and/or increased delivery of blood flow to tissues in the body , the method comprising administering a composition comprising 4′-O-glucuronide epicatechin to an individual.2. The method of wherein the composition is orally administered to the individual as a food product in which the 4′-O-glucuronide epicatechin is present in a concentration of at least 0.01 mg/g of the food product.3. The method of wherein the composition is administered to the individual at least once a day for at least one week.4. The method of wherein the 4′-O-glucuronide epicatechin is chemically synthesized.5. (canceled)6. The method of wherein the individual has or is at risk of a cardiovascular disease.7. The method of wherein the composition is administered to the individual in an amount that achieves a therapeutic effect selected from the group consisting of reduced blood pressure claim 1 , stimulation of protein synthesis claim 1 , improvement of blood circulation claim 1 , improvement of blood brain circulation claim 1 , increased release of growth factors claim 1 , enhanced immune function claim 1 , and combinations thereof claim 1 , the method comprising administering to the individual a composition comprising 4′-O-glucuronide epicatechin.8. The method of wherein the composition is administered to the individual in an amount that ...

METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC ACID

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below: The present application is a Divisional application of U.S. application Ser. No. 15/108,141, filed Jun. 24, 2016, which is a National Stage of international Patent Application No. PCT/JP2014/084518 filed Dec. 26, 2014, which claims priority to Japanese Application No. 2013-272766 filed Dec. 27, 2013. The disclosures of U.S. application Ser. No. 15/108,141 and International Patent Application No. PCT/JP2014/084518 are incorporated by reference herein in their entireties.The present invention relates to a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and synthetic intermediates thereof (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid, which is produced by the method of the present invention, is useful as a synthetic intermediate for a β-lactamase inhibitor and the like.(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is a useful intermediate for the synthesis of an agent and the like that inhibits β-lactamases in bacteria exhibiting the resistance against the β-lactam class of antibiotics, which β-lactamases are the major cause of the resistance in the bacteria.A production method using glutamic acid or pyroglutamic acid as a starting raw material has been known as a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. Specifically, Patent Document 1 describes that a protected 5-hydroxypiperidine-2-carboxylic acid compound as an intermediate of N-protected oxo-azacycloalkylcarboxylic acids is produced from pyroglutamic acid as a starting raw material through the homologation process to increase carbon atoms and the cyclization process.Moreover, Non-Patent Document 1 describes that a protected 5-hydroxypiperidine-2-carboxylic acid compound is produced from glutamine as a starting raw material through the homologation process to increase carbon atoms and the cyclization process.Non-Patent ...

CARBOXAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Inhibitors of HBV replication of formula (I) 113.-. (canceled)14. A compound selected from the group consisting of:(S)—N-(3-bromo-4,5-difluorophenyl)-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;(S)—N-(3-bromo-4,5-difluorophenyl)-1-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;(S)—N-(3-bromo-4,5-difluorophenyl)-1-(2-(tert-butylamino)-2-oxoacetyl)pyrrolidine-3-carboxamide;(3S)—N-(4-fluoro-3-methylphenyl)-1-{[(1-methylethyl)amino] (oxo)acetyl}pyrrolidine-3-carboxamide;(S)-1-(2-(cyclopentylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)pyrrolidine-3-carboxamide;(S)—N-(4-fluoro-3-methylphenyl)-1-(2-(((R)-1-hydroxypropan-2-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;(3S)—N-(4-fluoro-3-methylphenyl)-1-{[(3-methyloxetan-3-yl)amino]-(oxo)acetyl}pyrrolidine-3-carboxamide;(3S)—N-(4-fluoro-3-methylphenyl)-1-[{[(1R)-1-methylpropyl]amino}(oxo)acetyl]pyrrolidine-3-carboxamide;(3S)—N-(4-fluoro-3-methylphenyl)-1-{oxo[(3S)-tetrahydrofuran-3-ylamino]-acetyl}pyrrolidine-3-carboxamide;(2S,3S)—N-(4-fluoro-3-methylphenyl)-2-methyl-1-{[(3-methyloxetan-3-yl)-amino](oxo)acetyl}pyrrolidine-3-carboxamide;(S)—N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;(3S)—N-(4-fluoro-3-methylphenyl)-1-{[(1-methylethyl)amino] (oxo)acetyl}piperidine-3-carboxamide;(S)—N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-((1-(trifluoromethyl) cyclopropyl)amino)acetyl)pyrrolidine-3-carboxamide;(S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;(S)—N-(3-chloro-4-fluorophenyl)-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;(S)—N-(3-chloro-4,5-difluorophenyl)-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)pyrrolidine-3-carboxamide;N-(4-fluoro-3-methylphenyl)-5-methyl-1-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)pyrrolidine-3-carboxamide;N-(3-chloro-4,5-difluoro- ...

PIPECOLIC ESTERS FOR INHIBITION OF THE PROTEASOME

The present disclosure relates to chemical compounds that modulate proteasome activity, pharmaceutical compositions containing such compounds, and use of these compounds and compositions for the treatment of disorders of uncontrolled cellular proliferation such as, for example, a cancer. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention. 2. The compound of claim 1 , wherein n is 1.34-. (canceled)5. The compound of claim 1 , wherein Ris selected from (CH)Cyand Cy.6. The compound of claim 1 , wherein Ris CHCy.710-. (canceled)1315-. (canceled)16. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of and a pharmaceutically acceptable carrier.1720-. (canceled) This application claims the benefit of U.S. Provisional Application No. 62/623,861, filed on Jan. 30, 2018, the contents of which is incorporated herein by reference in its entirety.The Sequence Listing submitted Jan. 30, 2019 as a text file named “21105_0050P1_ST25.txt,” created on Jan. 30, 2019, and having a size of 496 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).The proteasome is an essential protease that regulates intracellular processes and maintains biological homeostasis through the proteolytic degradation of misfolded and redundant proteins (Glickman et al. (2002) 82: 373-428). Inhibition of the proteasome induces apoptosis, which has translated in the clinic as a means to treat various cancers, most notably multiple myeloma and mantle cell lymphoma (Jankowska et al. (2013) 19: 1010-1028; Adams, J. (2004) 4: 349-360; Kuhn et al. (2011) 11: 285-295). The activities of the proteasome, the essential, multifunctional human proteolytic assembly, are not infrequently found to be affected by compounds with non-proteasomal primary targets. For example, this is the case with chloroquine (Sprangers et al. (2008) 47: 6727-6734), ...

ANTIVIRAL COMPOUNDS

The present invention provides compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection. 2. The compound of claim 2 , wherein Ris H and X is CH.3. The compound of claim 2 , wherein n is 2.4. The compound of claim 2 , wherein n is 1.5. The compound of claim 4 , wherein Ris —C(═O)N(R) claim 4 ,6. The compound of claim 4 , wherein Ris monocyclic or bicyclic heteroaryl claim 4 , optionally substituted with one or more R.7. The compound of claim 4 , wherein Ris —C(═O)OR.8. The compound of claim 7 , wherein R is lower alkyl.9. The compound of claim 8 , wherein Ris lower alkyl or cycloalkyl.10. The compound of claim 9 , wherein Ris cyclohexyl.11. A compound selected from the group consisting of:(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid tert-butyl ester;(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester;1-Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid methyl ester;1-Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic ...

Automated Synthesis of Small Molecules Using Chiral, Non-Racemic Boronates

Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification. 1144-. (canceled)145. A method of deprotecting a pinene-derived iminodiacetic acid (PIDA) boronate , comprising:contacting a solution comprising the chiral, non-racemic PIDA boronate and a solvent with a solid-supported ammonium hydroxide reagent, thereby deprotecting the chiral, non-racemic PIDA boronate and forming a boronic acid and a PIDA.146. The method of claim 145 , wherein the solvent comprises THF.147. The method of claim 145 , wherein the solid-supported ammonium hydroxide reagent binds the PIDA.148. The method of claim 145 , further comprising the steps of removing the solvent by filtration claim 145 , leaving the boronic acid and PIDA ligand trapped inside the solid-supported ammonium hydroxide reagent; and adding additional solvent.149. The method of claim 148 , wherein the additional solvent is THF.150. The method of claim 145 , further comprising washing the solid-supported ammonium hydroxide reagent with an organic solution comprising an organic solvent and an acid in a quantity greater than that needed to neutralize the solid- ...

PIPECOLATE-DIKETOAMIDES FOR TREATMENT OF PSYCHIATRIC DISORDERS

The present invention relates to compounds having a pipecolate diketoamide scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said pipecolate diketoamide compounds can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions. 5. Compound according to selected from the group consisting of:2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1S,2R)-1-hydroxy-2-methylcyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid,(S)—((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl) 1-(2-((1S,2R)-1-hydroxy-2-methylcyclohexyl)-2-oxoacetyl)piperidine-2-carboxylate,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1S,2R)-2-ethyl-1-hydroxy-cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid,(S)—((R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl)1-(2-((1S,2R)-2-ethyl-1-hydroxycyclohexyl)-2-oxoacetyl)piperidine-2-carboxylate,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1S,2S)-1-hydroxy-2-(hydroxyl methyl)cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1R,2R)-1-hydroxy-2-methyl cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1R,2R)-2-ethyl-1-hydroxy cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(2-cyclohexyl-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy) acetic acid,2-{3-[(1R)-3-(3,4-dimethoxyphenyl)-1-({1-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidin-2-yl}carbonyloxy)propyl]phenoxy}acetic acid,2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-oxo-2-(4-phenoxyphenyl)acetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid, and2-(3-((R)-3-(3,4-dimethoxyphenyl)-1 ...

PROCESSES FOR PREPARING HETEROCYCLIC COMPOUNDS INCLUDING TRANS-7-OXO-6-(SULPHOOXY)-1,6-DIAZABICYCLO[3,2,1]OCTANE-2-CARBOXAMIDE AND SALTS THEREOF

The present invention relates to compounds and processes for preparing compounds of Formula (I), 114-. (canceled)16. The compound of claim 15 , wherein R5 is benzyloxy and R6 and R7 are hydrogen.17. The compound of claim 15 , wherein R5 is allyl or trialkylsilyl and R6 and R7 are hydrogen.18. The compound of claim 15 , wherein R5 is benzyloxy and R1 claim 15 , R2 claim 15 , R6 and R7 are hydrogen.19. The compound of claim 15 , wherein R1 is a heterocycle.20. The compound of claim 15 , wherein R7 is amide.21. The compound of claim 15 , herein R1 is piperidinyl claim 15 , R5 is benzyloxy and R2 claim 15 , R6 and R7 are hydrogen.22. The compound of claim 15 , wherein R1 claim 15 , R2 and R6 are hydrogen.23. The compound of claim 15 , wherein R5 is OSOH.24. The compound of claim 15 , wherein R1 claim 15 , R2 and R6 are hydrogen claim 15 , R5 is OSOH and R7 is carbamoyl.25. The compound of claim 15 , wherein R1 is piperidinyl claim 15 , R2 and R6 are hydrogen claim 15 , R5 is OSOh and R7 is carbamoyl.2644-. (canceled)45. A pharmaceutical composition comprising the compound of or a salt thereof claim 15 , and a pharmaceutical acceptable carrier.48. A pharmaceutical composition comprising the compound of or a salt thereof claim 45 , and a pharmaceutical acceptable carrier. This application claims priority under 35 U.S.C. §119, based on U.S. Provisional Application Ser. No. 61/498,522 filed on Jun. 17, 2011, which is hereby incorporated by reference in its entirety.The present invention relates to novel compounds and processes for preparing compounds of Formula (I), including compounds such as trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof (e.g., NXL-104).U.S. Pat. No. 7,112,592 discloses novel heterocyclic compounds and their salts, processes for making the compounds and methods of using the compounds as antibacterial agents. One such compound is sodium salt of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide. ...

CYCLIC AMIDES AS METAP-2 INHIBITORS

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

THROMBIN INHIBITORS

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: (I) or a pharmaceutically acceptable salt thereof, wherein Q is CH, NR, O, S, S(O) or S(O), wherein Ris H, Calkyl, aryl, or Ccycloalkyl; Ris a heterocycle or —(CRR)1-2NH2, wherein Rand R, each time in which they occur, are independently H, Calkyl, —CHF, —CHF, CFor —CHOH; Ris OH, NHor NHSOCH; and Ris Calkyl. 3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris tetrazole or —CHNH.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein Ris —CHNH.5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris OH.6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —C(CH).7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H or CH.8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H.9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H.11. A compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , which is(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]piperidine-2-carboxamide,(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]piperazine-2-carboxamide,(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4-methylpiperazine-2-carboxamide,(3 S)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]morpholine-3-carboxamide,(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide,(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1-oxide, or(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3- ...

CYTOTOXIC AND ANTI-MITOTIC COMPOUNDS, AND METHODS OF USING THE SAME

Compounds having cytotoxic and/or anti-mitotic activity are disclosed. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. Also disclosed are compositions having the structure: (T)-(L)-D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having cytotoxic and/or anti-mitotic activity. 4. The compound according to or , wherein each optionally substituted alkyl , optionally substituted alkylamino , optionally substituted cycloalkyl , optionally substituted aryl , optionally substituted heterocyclyl and optionally substituted heteroaryl is , independently , optionally substituted with ═O , ═S , —OH , —OR , —OCR , —SH , —SR , —SOCR , —NH , —N , —NHR , —N(R) , —NHCOR , —NRCOR , —I , —Br , —Cl , —F , —CN , —COH , —COR , —CHO , —COR , —CONH , —CONHR , —CON(R) , —COSH , —COSR , —NO , —SOH , —SORor —SORwherein each Ris , independently , alkyl optionally substituted with halogen , —OH or —SH.5. The compound according to or , wherein each optionally substituted aryl and optionally substituted heteroaryl is , independently , selected from the group consisting of optionally substituted phenyl , optionally substituted naphthyl , optionally substituted anthracyl , optionally substituted phenanthryl , optionally substituted furyl , optionally substituted pyrrolyl , optionally substituted thiophenyl , optionally substituted benzofuryl , optionally substituted benzothiophenyl , optionally substituted quinolinyl , optionally substituted isoquinolinyl , optionally substituted imidazolyl , optionally substituted thiazolyl , optionally substituted oxazolyl , and optionally substituted pyridinyl.128. The composition according to any one of - wherein R claims 2 , R claims 2 , and R claims 2 , are each methyl.138. The composition according to any one of - claims 2 , wherein Ris H claims 2 , Ris methyl claims 2 , and Ris methyl.1413. A pharmaceutical composition ...

TRANS-ISOMERIC HETEROCYCLIC COMPOUNDS AND PREPARATION THEREOF

A trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof: 2. The compound of claim 1 , wherein Ris C-Calkyl.3. The compound of claim 2 , wherein Ris methyl.8. The method of claim b claim 2 , wherein Ris C-Calkyl.9. The method of claim 8 , wherein Ris methyl.10. The method of claim 6 , wherein the palladium catalyst is Pd(OH)/C claim 6 , Pd/C claim 6 , Pd(OAc) claim 6 , Pd/AlO claim 6 , or a combination thereof claim 6 , optionally containing Pt/C or Rh/C; and the content of palladium in the palladium catalyst is 0.01 wt % to 30 wt %.11. The method of claim 6 , wherein the inert solvent is HO claim 6 , a C-Cester claim 6 , a C-Ccycloalkane claim 6 , tetrahydrofuran (THF) claim 6 , dimethylformamide (DMF) claim 6 , acetonitrile claim 6 , a C-Calcohol claim 6 , an alkylene glycol monoalkyl ether claim 6 , an alkylene glycol monoalkyl ether carboxylate claim 6 , an amide-based solvent claim 6 , an organic acid claim 6 , or a combination thereof claim 6 , optionally combined with one or more inorganic acids.12. The method of claim 11 , wherein the inert solvent is HO claim 11 , a C-Cester claim 11 , a C-Ccycloalkane claim 11 , THF claim 11 , DMF claim 11 , a C-Calcohol claim 11 , propylene glycol monomethyl ether claim 11 , propylene glycol monomethyl ether acetate claim 11 , N claim 11 ,N-dimethylacetamide claim 11 , a C-Ccarboxylic acid claim 11 , a C-Csulfonic acid claim 11 , or a combination thereof claim 11 , optionally combined with hydrochloric acid.13. The method of claim 12 , wherein the inert solvent is HO claim 12 , methanol claim 12 , ethanol claim 12 , isopropanol claim 12 , formic acid claim 12 , acetic acid claim 12 , ethyl acetate claim 12 , methanesulfonic acid claim 12 , or a combination thereof claim 12 , optionally combined with hydrochloric acid.14. The method of claim 11 , wherein the inert solvent is an organic acid or a combination of the organic acid with one or more solvents selected from the group consisting ...

TREPROSTINIL PRODRUGS

Provided are novel prodrugs of treprostinil, as well as methods of making and methods of using these prodrugs. 146-. (canceled)48. A pharmaceutical composition claim 47 , comprising (A) an effective amount of the compound of and (B) a pharmaceutically acceptable carrier.49. A method of treating pulmonary hypertension comprising administering to a subject in need thereof the composition of .50. The method of claim 49 , wherein the composition is administered orally.51. The method of claim 49 , wherein the subject has detectable treprostinil plasma levels for at least 24 hours following said administration.52. The method of claim 49 , wherein the composition is administered by an injection.53. The method of claim 52 , wherein the administration is performed subcutaneously.54. The method of claim 53 , wherein said administration is continuous subcutaneous administration.55. The method of claim 52 , wherein said administration results in no or less pain at a site of the injection compared to administering treprostinil.56. The method of claim 49 , wherein the subject is a human being.57. The method of claim 49 , wherein upon said administration said compound converts to a metabolic product claim 49 , which consists essentially of treprostinil.58. The method of claim 57 , wherein said metabolic product consists of treprostinil.61. The method of claim 60 , wherein Ris C-Calkylene and each of Rand Rare H.62. The method of claim 49 , wherein Ris —C(O)—CHR—N(R) claim 49 , wherein Ris the side group of an amino acid.63. The method of claim 62 , wherein the amino acid is alanine claim 62 , valine or glycine.64. The method of claim 49 , wherein Ris a third drug moiety linked to the compound via an ester.65. The method of claim 49 , wherein the second drug moiety is a pain relief drug moiety.66. The method of claim 49 , wherein the second drug moiety is a nonsteroidal anti-inflammatory drug moiety.67. The method of claim 66 , wherein the second drug moiety is selected from the ...

NIPECOTIC ACID DERIVATIVE AND USE THEREOF FOR MEDICAL PURPOSES

A compound has an sEH-inhibiting activity and provides a pharmaceutical having a therapeutic effect and a prophylactic effect on chronic renal disease and pulmonary hypertension based on the sEH-inhibiting action. The nipecotic acid derivatives are represented by the chemical formula below and pharmaceutically acceptable salts thereof. 16.-. (canceled)8. The nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to claim 7 , wherein{'sup': 2', '3', '2', '3, 'sub': 1', '6', '2', 'l, 'Rand Reach independently represents a hydrogen atom or C-Calkyl, or together represent —(CH)—, with the proviso that Rand Rdo not simultaneously represent a hydrogen atom;'}{'sup': '4', 'Rrepresents a substituent in the 2-position of the benzene ring; and'}{'sup': '5', 'Rrepresents a substituent in the 4-position of the benzene ring.'}9. The nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to claim 7 , wherein{'sup': 1', '6', '7', '6', '7, 'sub': '2', 'Rrepresents —N(R)C(═O)Ror —N(R)S(═O)R;'}{'sup': '4', 'sub': 1', '6, 'Rrepresents a halogen atom, or C-Calkyl or alkyloxy;'}{'sup': '5', 'sub': 1', '6, 'Rrepresents a halogen atom, cyano, or C-Calkyl or alkyloxy; and'}{'sup': '6', 'Rrepresents a hydrogen atom.'}10. A pharmaceutical comprising as an effective component the nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to .11. A soluble epoxide hydrolase inhibitor comprising as an effective component the nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to .12. A therapeutic or prophylactic agent for chronic renal disease or pulmonary hypertension claim 7 , said agent comprising as an effective component the nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to .13. The nipecotic acid derivative or a pharmaceutically acceptable salt thereof according to claim 8 , wherein{'sup': 1', '6', '7', '6', '7, 'sub': '2', 'Rrepresents —N(R)C(═O) ...

IMMUNE CHECKPOINT INHIBITORS, COMPOSITIONS AND METHODS THEREOF

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Xis aryl.3. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Xis aryl optionally substituted by halogen claim 1 , (C-C)alkyl or (C-C)haloalkyl.4. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Yis NH(R) or N(R)(R).5. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris (C-C)alkyl or halogen.6. The compound of claim 5 , or a stereoisomer claim 5 , a tautomer or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris CH.7. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Rand Rare independently H claim 1 , (C-C)alkyl or Rand Rcombine together with the nitrogen atom to form a heterocyclyl.8. The compound of claim 7 , or a stereoisomer claim 7 , a tautomer or a pharmaceutically acceptable salt thereof claim 7 , wherein Rand Rare independently H or (C-C)alkyl claim 7 , wherein (C-C)alkyl is optionally substituted by OH or C(O)OH.9. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein Rand Rcombine together with the nitrogen atom to form a heterocyclyl claim 1 , optionally substituted by C(O)OH.10. The compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable salt thereof claim 1 , wherein “n” is 1.11. A compound of claim 1 , or a stereoisomer claim 1 , a tautomer or a pharmaceutically acceptable ...

CARBOXAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Inhibitors of HBV replication of formula (I) 112-. (canceled)16. The compound of claim 13 , wherein each of Ra claim 13 , Rb claim 13 , Rc claim 13 , Rd claim 13 , Re claim 13 , Rf claim 13 , Rg claim 13 , Rh and Ri is hydrogen.17. The compound of claim 13 , wherein at least one of Ra claim 13 , Rb claim 13 , Rc claim 13 , Rd claim 13 , Re claim 13 , Rf and Rg is methyl.18. The compound of claim 13 , wherein Ris fluoro.19. The compound of claim 13 , wherein Ris selected from the group consisting of fluoro claim 13 , chloro claim 13 , —CHF claim 13 , —CHF claim 13 , —CF claim 13 , —CN and methyl.20. The compound of claim 13 , wherein Ris selected from the group consisting of fluoro claim 13 , chloro and bromo.21. The compound of claim 13 , wherein Ris fluoro; Ris selected from the group consisting of fluoro claim 13 , chloro claim 13 , —CHF claim 13 , —CHF claim 13 , —CF claim 13 , —CN and methyl; and Ris selected from the group consisting of fluoro claim 13 , chloro and bromo.22. The compound of claim 13 , wherein Ris fluoro and Ris methyl.23. The compound of claim 13 , wherein Ris fluoro; Ris selected from the group consisting of fluoro and chloro; and Ris selected from the group consisting of hydrogen claim 13 , fluoro and chloro.24. The compound of claim 13 , wherein Ris a branched C-Calkyl optionally substituted with one or more fluoro.25. The compound of claim 13 , wherein Ris selected from the group consisting of —CH(CH) claim 13 , —CH(CH) claim 13 , —CH(CH) claim 13 , —(CH)(CH)CH claim 13 , —(CH)(CH)CH—OH claim 13 , —CH(CH)CF claim 13 , CH(CH)CF.26. The compound of claim 13 , wherein Ris —CH(CH).27. The compound of claim 13 , wherein Ris —CH(CH)CF.28. The compound of claim 13 , wherein Ris fluoro; and Ris —CH(CH)CF.29. The compound of claim 13 , wherein Ris a 4-5 membered saturated ring containing one oxygen claim 13 , said 4-5 membered saturated ring optionally substituted with methyl.30. A pharmaceutical composition comprising the compound of and a ...

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Chemical entities that are curcumin derivatives, pharmaceutical compositions and methods of treatment of cancer are described. 2. At least one chemical entity of wherein Ris chosen from hydrogen claim 1 , optionally substituted alkyl claim 1 , optionally substituted cycloalkyl claim 1 , and optionally substituted heterocycloalkyl.3. At least one chemical entity of wherein Ris chosen from optionally substituted alkyl claim 1 , optionally substituted cycloalkyl claim 1 , and optionally substituted heterocycloalkyl.4. At least one chemical entity of wherein Rand Rare independently chosen from optionally substituted alkyl.5. At least one chemical entity of wherein Rand Rare joined together to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.6. At least one chemical entity of wherein Rand Rare joined together to form an optionally substituted pyrrolidin-1-yl claim 5 , morpholin-1-yl claim 5 , piperidin-1-yl claim 5 , piperazin-1-yl claim 5 , 1 claim 5 ,4-diazepan-1-yl claim 5 , and 1 claim 5 ,4-diazocan-1-yl.7. At least one chemical entity of any one of to wherein Ris chosen from hydrogen claim 5 , optionally substituted alkyl claim 5 , optionally substituted cycloalkyl claim 5 , optionally substituted heterocycloalkyl claim 5 , optionally substituted aryl claim 5 , optionally substituted heteroaryl claim 5 , optionally substituted aminocarbonyl claim 5 , and optionally substituted phosphato.8. At least one chemical entity of wherein Ris chosen from hydrogen claim 7 , optionally substituted lower alkyl claim 7 , and optionally substituted aminocarbonyl.9. At least one chemical entity of wherein Ris hydrogen.10. At least one chemical entity of wherein Ris optionally substituted lower alkyl.11. At least one chemical entity of wherein Ris methyl.12. At least one chemical entity of wherein Ris lower alkyl substituted with hydroxyl or amino.13. At least one chemical entity of wherein Ris optionally substituted aminocarbonyl.14. At least one chemical ...

PROCESSES AND INTERMEDIATES IN THE PREPARATION OF C5aR ANTAGONISTS

Intermediates and methods are provided for the preparation of selected C5aR antagonist compounds. 18.-. (canceled).10. A compound of claim 9 , in salt form as a L-DTTA salt.11. A compound of claim 9 , wherein Ris CF.12. A compound of claim 9 , wherein Ris Cl.13. A compound of claim 9 , in salt form as a bis L-DTTA salt.15. A method in accordance with claim 14 , wherein Ris CF claim 14 , Ris F claim 14 , and Ris CH.16. A method in accordance with claim 14 , wherein Ris CF claim 14 , Ris Cl claim 14 , and Ris H.17. A method in accordance with claim 14 , wherein Ris Cl claim 14 , Ris F claim 14 , and Ris CH.18. A method in accordance with claim 14 , wherein LG is halogen.1920.-. (canceled). This application is a continuation of U.S. patent application Ser. No. 14/867,669 filed Sep. 28, 2015, which application claims the benefit of priority to U.S. Provisional Application Ser. No. 62/057,107, filed Sep. 29, 2014, each of which is incorporated herein by reference.NOT APPLICABLEThe complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus infected cells and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful, and even potentially life-threatening consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in various disorders including septic shock; myocardial, as well as, intestinal ischemia/reperfusion injury; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.The activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and C5b-9 membrane attack complexes (MAC), all which mediate inflammatory responses by affecting leukocyte chemotaxis; activating macrophages, neutrophils, platelets, mast cells and endothelial cells; and increasing vascular permeability, ...

FREE BASE CRYSTALLINE FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR

Provided herein is a free base crystalline form of a complement component 5a receptor having the formula of Compound 1 12.-. (canceled)3. The method of claim 11 , wherein the free base crystalline form of Compound 1 is further characterized by XRPD peaks at 12.4 claim 11 , 15.2 claim 11 , 16.1 claim 11 , 24.4 claim 11 , and 24.7 degrees 2θ (±0.2 degrees 2θ)4. The method of claim 11 , wherein the free base crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with .5. The method of claim 11 , wherein the free base crystalline form of Compound 1 is further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at around 216° C.6. The method of claim 11 , wherein the free base crystalline form of Compound 1 is further characterized by a melting point onset of about 213° C. as determined by differential scanning calorimetry thermogram (DSC).7. The method of claim 11 , wherein the free base crystalline form of Compound 1 is further characterized by a DSC substantially in accordance with .810.-. (canceled)12. The method of claim 11 , wherein the disease or disorder is an inflammatory disease or disorder.13. The method of claim 12 , wherein the disease or disorder is selected from the group consisting of neutropenia claim 12 , sepsis claim 12 , septic shock claim 12 , Alzheimer's disease claim 12 , multiple sclerosis claim 12 , stroke claim 12 , inflammatory bowel disease claim 12 , age-related macular degeneration claim 12 , chronic obstructive pulmonary disorder claim 12 , inflammation associated with burns claim 12 , lung injury claim 12 , osteoarthritis claim 12 , atopic dermatitis claim 12 , chronic urticaria claim 12 , ischemia-reperfusion injury claim 12 , acute respiratory distress syndrome claim 12 , systemic inflammatory response syndrome claim 12 , multiple organ dysfunction syndrome claim 12 , tissue graft rejection claim 12 , cancer and hyperacute ...

METHOD FOR TREATING SARCOIDOSIS-ASSOCIATED PULMONARY HYPERTENSION

There is a method of treating or preventing sarcoidosis-associated pulmonary hypertension in a patient. The method has the step of administering to the patient a therapeutically effective amount of one or more compounds: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, or (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing. 1. A method of treating or preventing sarcoidosis-associated pulmonary hypertension in a human patient comprising administering to the patient a therapeutically effective amount of about 1 mg/kg/day to about 50 mg/kg/day of a compound selected from the group consisting of (i) (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof , (ii) (S)-8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroeth-oxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof , and (iii) a combination of the foregoing.2. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally.3. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally by a dosage form selected from the group consisting of capsules claim 1 , tablets claim 1 , powders claim 1 , and granules.4. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally in the form of a liquid.5. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered one to four times per day.6. The method of claim 1 , wherein ...

PROCESSES AND INTERMEDIATES IN THE PREPARATION OF C5aR ANTAGONISTS

Intermediates and methods are provided for the preparation of selected C5aR antagonist compounds. 2. A compound of claim 1 , in salt form as a bis L-DTTA salt.6. A method of any of claim 1 , or claim 1 , wherein Ris CF claim 1 , Ris F claim 1 , and Ris CH.7. A method of any of claim 1 , or claim 1 , wherein Ris CF claim 1 , Ris Cl claim 1 , and Ris H.8. A method of any of claim 1 , or claim 1 , wherein Ris Cl claim 1 , Ris F claim 1 , and Ris CH.10. A compound of claim 9 , in salt form as a L-DTTA salt.11. A compound of claim 9 , wherein Ris CF.12. A compound of claim 9 , wherein Ris Cl.13. A compound of claim 9 , in salt form as a bis L-DTTA salt.15. A method in accordance with claim 14 , wherein Ris CF claim 14 , Ris F claim 14 , and Ris CH.16. A method in accordance with claim 14 , wherein Ris CF claim 14 , Ris Cl claim 14 , and Ris H.17. A method in accordance with claim 14 , wherein Ris Cl claim 14 , Ris F claim 14 , and Ris CH.18. A method in accordance with claim 14 , wherein LG is halogen. This application claims the benefit of priority to U.S. Provisional Application Ser. No. 62/057,107, filed Sep. 29, 2014, the entire content of which is incorporated herein by reference.NOT APPLICABLENOT APPLICABLEThe complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus infected cells and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful, and even potentially life-threatening consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in various disorders including septic shock; myocardial, as well as, intestinal ischemia/reperfusion injury; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.The activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and ...

Quaternary ammonium salt compound, preparation method therefor and use thereof

A quaternary ammonium salt compound of formula I is fast-acting and has a long-term local anaesthetic effect after a single administration, the sensory nerve block time being longer than the motor nerve block time, has both a long-acting local anaesthetic effect and a selective local anaesthetic effect, and also significantly reduces the side effects of quaternary ammonium salt compounds with the structural features of surfactants and is highly safe; thus, the compound of formula I and the pharmaceutically acceptable salt thereof can be used for the preparation of saft drugs having a long-term local anaesthetic effect and a selective local anaesthetic effect

PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED 3-AMINOPIPERIDINE

The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, as in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrateand crystalline (S)-3-aminopiperidine-dihydrochloride-monohydrate. 2. The process according to claim 1 , wherein the carboxylic acid A is selected from (S)-2-phenyl sulfonylamino-propionic acid claim 1 , (S)-2-(4-methylphenyl)sulfonylamino-propionic acid claim 1 , (S)-2-(4-chlorophenyl)sulfonylamino-propionic acid claim 1 , (R)-2-(3-phenylureido)-propionic acid and (R)-2-(3-(4-chlorophenyl)ureido)-propionic acid.3. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its S-enantiomer claim 1 , the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution claim 1 , suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine claim 1 , in particular a racemic mixture of the enantiomers of 3-aminopiperidine claim 1 ,{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'where the chiral carboxylic acid A is the compound of the formula A, as defined in , where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.'}4. The process according to claim 3 , wherein the carboxylic acid A is selected from (R)-2-phenyl sulfonylamino-propionic acid claim 3 , (R)-2-(4-methylphenyl)sulfonylamino-propionic acid claim 3 , (R)-2-(4-chlorophenyl)sulfonylamino-propionic acid claim 3 , (S)-2-(3-phenylureido)-propionic acid and (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid.5. The acid-addition salt of 3-aminopiperidine with the chiral carboxylic acid A ...

PROCESSES FOR PREPARING HETEROCYCLIC COMPOUNDS INCLUDING TRANS-7-OXO-6-(SULPHOOXY)-1,6-DIAZABICYCLO[3,2,1]OCTANE-2-CARBOXAMIDE AND SALTS THEREOF

The present invention relates to compounds and processes for preparing compounds of Formula (I), 2. The process of claim 1 , wherein R1 claim 1 , R2 and R7 are hydrogen and R3 is OSOH.3. The process of claim 1 , wherein R1 is piperidinyl claim 1 , R2 and R7 are hydrogen and R3 is OSOH.4. The process of claim 1 , wherein R4 is benzyloxy.5. The process of claim 1 , wherein R5 is benzyloxy and R6 and R7 are hydrogen.6. The process of claim 1 , wherein R5 is allyl or trialkylsilyl and R6 is hydrogen.7. The process of claim 1 , comprising treating the compound of Formula (III) with 9-fluorenylmethoxycarbonyl.8. The process of claim 1 , comprising treating the compound of Formula (III) with N claim 1 ,N-carbonyl diimidazole.9. The process of claim 1 , further comprising treating the compound formed after treatment of compound of Formula (III) with a SOcomplex.10. The process of claim 1 , wherein the compound of Formula (I) is trans-7-oxo-6-(sulphooxy)-1 claim 1 ,6-diazabicyclo[3 claim 1 ,2 claim 1 ,1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof.11. The process of claim 1 , wherein the compound of Formula (I) is sodium ({[(2S claim 1 ,5R)-2-carbamoyl-7-oxo-1 claim 1 ,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulphonyl)oxidanide.12. The process of claim 1 , wherein the compound of Formula (II) is benzyl (2S claim 1 ,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate.13. The process of claim 1 , wherein the compound of Formula (III) is (2S claim 1 ,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide.14. The process of claim 13 , comprising treating (2S claim 13 ,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide to prepare (2S claim 13 ,5R)-6-(benzyloxy)-7-oxo-1 claim 13 ,6-diazabicyclo[3.2.1]octane-2-carboxamide.16. The compound of claim 15 , wherein R5 is benzyloxy and R6 and R7 are hydrogen.17. The compound of claim 15 , wherein R5 is allyl or trialkylsilyl and R6 and R7 are hydrogen.18. The compound of claim 15 , wherein R5 is benzyloxy and R1 claim ...

GLYCOSIDASE INHIBITORS AND USES THEREOF

The invention provides compounds for inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc. 2. (canceled)3. The compound of wherein the compound is selected from the following group:(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-(hydroxymethyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N,1-dimethylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(5-methylhexyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(4-phenylbutyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-1-((E)-3-([1,1′-biphenyl]-4-yl)allyl)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)-1-(3-([1,1′-biphenyl]-4-yl)propyl)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methylpiperidine-2-carboxamide (2S,3R,4S)-1-hexyl-3,4-dihydroxy-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-N,1-dimethylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-1-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxypiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxy-1-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-methyl-1-phenethylpiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxy-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3S,4R,5S,6R)—N-ethyl-4-fluoro-3,5-dihydroxy-6-methyl-1-phenethylpiperidine-2-carboxamide;(2R, ...

Pyrenyloxysulfonic acid fluorescent agents

The invention provides a novel class of reactive fluorescent agents that are based on a pyrene sulfonic acid nucleus. The agents are readily incorporated into conjugates with other species by reacting the reactive group with a group of complementary reactivity on the other species of the conjugate. Also provided are methods of using the compounds of the invention to detect and/or quantify an analyte in a sample. In an exemplary embodiment, the invention provides multi-color assays incorporating the compounds of the invention.

SYNTHETIC PEPTIDES, PRODRUGS, PHARMACEUTICAL COMPOSITIONS AND USES

The present invention relates to smooth muscle tone modulating synthetic peptides. It also refers to pharmaceutical compositions containing such peptides and to the uses thereof in the treatment of disturbances in which the modulation of the smooth muscle tone is beneficial. 3. The peptide of claim 2 , wherein the pharmacologically active peptide sequence of formula (2) is SEQ ID NO: 17 claim 2 , SEQ ID NO: 18 claim 2 , SEQ ID NO: 19 claim 2 , SEQ ID NO: 20 claim 2 , SEQ ID NO: 22 claim 2 , SEQ ID NO: 23 claim 2 , SEQ ID NO: 24 or SEQ NO ID: 5.4. The peptide of claim 1 , wherein the pharmacologically active peptide sequence of formula (2) has from 15 to 18 contiguous amino acid residues claim 1 , with the proviso that it does not consist in SEQ ID NO: 27.5. The peptide of claim 1 , wherein the pharmacologically active peptide sequence of formula (2) has 18 contiguous amino acid residues claim 1 , with the proviso that it does not consist in SEQ ID NO: 27.6. The peptide of claim 1 , further comprising at least a second peptide or protein claim 1 , with the proviso that it does not consist in SEQ ID NO: 27.8. The peptide of claim 7 , wherein H claim 7 , acetyl claim 7 , chloride claim 7 , or trifluoroacetyl is covalently bonded to the N-terminus of —Z—X—Z′—.9. A peptide of claim 7 , wherein OH or NHis covalently bonded to the C-terminus of —Z—X—Z′—.10. (canceled)11. A peptide of claim 1 , wherein the peptide is linked to a half-life enhancing moiety selected from the group consisting of albumin-binding moieties.12. The peptide of claim 11 , wherein the N-terminus is covalently bonded to an acetyl claim 11 , and wherein the C-terminus is covalently bonded to an NH.13. A peptide of claim 1 , in the form of a multimer claim 1 , comprising two or more peptides having a sequence of formula (2) interspaced by amino acid-based cleavable linkers.14. A pharmaceutical composition claim 1 , comprising one or more peptides defined in any of and a pharmaceutically acceptable ...

AMORPHOUS FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR

Provided herein is an amorphous form of a complement component 5a receptor having the formula of Compound 1 2. The amorphous form of Compound 1 according to claim 1 , characterized by an X-ray powder diffraction pattern substantially in accordance with .3. The amorphous form of Compound 1 according to claim 1 , further characterized by a glass transition temperature of about 108° C. claim 1 , as determined by differential scanning calorimetry.4. The amorphous form of Compound 1 according to claim 1 , further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with .5. The amorphous form of Compound 1 according to claim 1 , further characterized by a weight loss of about 0.015% up heating to around 235° C. claim 1 , as measured by thermal gravimetric analysis (TGA).6. The amorphous form of Compound 1 according to claim 1 , further characterized a thermal gravimetric analysis (TGA) thermogram substantially in accordance with .7. The amorphous form of Compound 1 according to claim 1 , further characterized by a weight gain of about 0.44% after undergoing a dynamic vapor sorption (DVS) cycle from about 0% relative humidity (RH) to about 95% RH at 25° C.8. The amorphous form of Compound 1 according to claim 1 , further characterized by a weight gain of about 0.31% after undergoing a dynamic vapor sorption (DVS) cycle from about 0% relative humidity (RH) to about 65% RH at 25° C.9. The amorphous form of Compound 1 according to claim 1 , further characterized by a dynamic vapor sorption (DVS) plot that does not exhibit any hysteresis between adsorption and desorption.10. The amorphous form of Compound 1 according to claim 1 , further characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with .11. The amorphous form of Compound 1 according to claim 1 , further characterized by a scanning electron microscopy (SEM) image having predominantly spherical particles.12. The amorphous form of Compound 1 ...

SALT FORMS OF A COMPLEMENT COMPONENT C5A RECEPTOR

Provided herein are salt forms of a complement component 5a receptor having the formula of Compound 1 1. The salt form of claim 139 , wherein the salt form is a besylate salt.2. The besylate salt of claim 1 , in a single crystalline form which is substantially free of other crystalline or amorphous forms.3. The besylate salt of claim 2 , wherein the single crystalline form is besylate salt Form I.4. The besylate salt Form I claim 3 , according to claim 3 , characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9 claim 3 , 13.3 claim 3 , 16.2 claim 3 , 17.6 and 21.8 degrees 2θ (±0.2 degrees 2θ).5. The besylate salt Form I claim 4 , according to claim 4 , further characterized by XRPD peaks at 6.6 claim 4 , 7.6 claim 4 , 14.5 claim 4 , 16.2 claim 4 , and 28.2 degrees 2θ (±0.2 degrees 2θ).6. The besylate salt Form I claim 4 , according to claim 4 , characterized by an X-ray powder diffraction pattern substantially in accordance with .7. The besylate salt Form I claim 4 , according to claim 4 , further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at around 207.2° C.8. The besylate salt Form I claim 4 , according to claim 4 , further characterized by a melting point onset of about 200.6° C. as determined by differential scanning calorimetry thermogram (DSC).9. The besylate salt Form I claim 4 , according to claim 4 , wherein said DSC thermogram is substantially in accordance with .10. The besylate salt Form I claim 4 , according to claim 4 , further characterized by a weight loss of about 0.14% upon heating to around 202.9° C. claim 4 , as measured by thermal gravimetric analysis (TGA).11. The besylate salt Form I claim 4 , according to claim 4 , further characterized a thermal gravimetric analysis (TGA) thermogram substantially in accordance with .12. The besylate salt Form I claim 4 , according to claim 4 , further characterized by a weight gain of about 0.5% after undergoing a dynamic ...

PROCESSES FOR CONVERTING CARBOXAMIDES TO THIOCARBOXAMIDES

Process for converting a carboxamide to a thiocarboxamide includes reacting (a) a substrate that comprises a heteroatom-containing moiety and a carboxamide moiety with (b) a dialkyl dithiophosphate and/or a salt thereof. The heteroatom-containing moiety includes a heteroatom selected from the group consisting of N, O, and S. Processes for preparing piperidine-4-thiocarboxamide are described. 1. A process for converting a carboxamide to a thiocarboxamide , the process comprising:reacting (a) a substrate that comprises a heteroatom-containing moiety and a carboxamide moiety with (b) a dialkyl dithiophosphate and/or a salt thereof;wherein the heteroatom-containing moiety comprises a heteroatom selected from the group consisting of N, O, and S.5. The process of claim 1 , wherein the heteroatom-containing moiety comprises a nitrogen atom.6. The process of claim 1 , wherein the heteroatom-containing moiety comprises a heterocyclic moiety selected from the group consisting of aziridine claim 1 , azirine claim 1 , diazirine claim 1 , oxaziridine claim 1 , azetidine claim 1 , azete claim 1 , diazetidine claim 1 , pyrrolidine claim 1 , pyrrole claim 1 , imidazolidine claim 1 , imidazole claim 1 , pyrazolidine claim 1 , pyrazole claim 1 , oxazolidine claim 1 , oxazole claim 1 , isoxazolidine claim 1 , isoxazole claim 1 , thiazolidine claim 1 , thiazole claim 1 , isothiazolidine claim 1 , isothiazole claim 1 , triazoles claim 1 , furazan claim 1 , oxadiazole claim 1 , thiadiazole claim 1 , dithiazole claim 1 , tetrazole claim 1 , piperidine claim 1 , pyridine claim 1 , piperazine claim 1 , diazines claim 1 , morpholine claim 1 , oxazine claim 1 , thiomorpholine claim 1 , thiazine claim 1 , triazine claim 1 , tetrazine claim 1 , azepane claim 1 , azepine claim 1 , homopiperazine claim 1 , diazepine claim 1 , thiazepine claim 1 , azocane claim 1 , azocine claim 1 , tetrahydropyran claim 1 , and combinations thereof.9. The process of claim 8 , wherein Rand Rare hydrogen.10. The ...

BIGUANIDE COMPOUNDS AND USE THEREOF

The present invention relates to biguanide compounds and use thereof, more particularly, to biguanide derivatives exhibiting excellent effects for inhibition of cancer cell proliferation and inhibition of cancer metastasis and recurrence, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and a method of prevention or treatment of cancer comprising the step of administering an effective amount of the composition to a subject in need thereof. 2. The compound according to claim 1 , wherein the compound is selected from the group consisting of:N1-pyrrolidine-N5-(benzo[1,3]dioxol-5-ylmethyl)biguanide,N1-pyrrolidine-N5-(4-methoxy)phenyl biguanide,N1-pyrrolidine-N5-(3-chloro-4-methoxy)phenyl biguanide,N1-pyrrolidine-N5-(2,6-difluoro-N5-methyl)phenyl biguanide,N1-pyrrolidine-N5-(4-dimethylamino)phenyl biguanide,N1-pyrrolidine-N5-(4-isopropyl)phenyl biguanide,N1-pyrrolidine-N5-(3-phenoxy)phenyl biguanide,N1-pyrrolidine-N5-(N-biphenyl-3-yl)biguanide,N1-pyrrolidine-N5-(N-biphenyl-4-yl)biguanide,N1-pyrrolidine-N5-(4′-fluorobiphenyl-3-yl)biguanide,N1-pyrrolidine-N5-(3′-fluorobiphenyl-4-yl)biguanide,N1-pyrrolidine-N5-(4-fluoro)phenethyl biguanide,N1-pyrrolidine-N5-(2-phenylpropane-2-yl)biguanide,N1-pyrrolidine-N5-(5,6,7,8-tetrahydronaphthalene-2-yl)biguanide,N1-pyrrolidine-N5-((1,2,3,4-tetrahydronaphthalene-1-yl)biguanide,N1-(S)-2-methyl pyrrolidine-N5-(4-(trifluoromethoxy)phenyl biguanide,N1-(S)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,N1-(R)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,N-ethyl-4-((3-(imino(pyrrolidin-1-yl)methyl)guanidino)methyl)benzamide,N-ethyl-3-((3-(imino(pyrrolidin-1-yl)methyl)guanidino)methyl)benzamide,N1-pyrrolidine-N5-(4-(2-aminoethyl)phenyl biguanide,N—(N-(4-(2-oxo-2-(piperidin-1-yl)ethylthio)phenyl)carbamimidoyl)pyrrolidine-1-carboximidamide, andS)-3-hydroxy-N—(N-(4-(2-oxo-2-(piperidin-1-yl)ethylthio)phenyl)carbamimidoyl)pyrrolidine-1-carboximidamide.3. The ...

Method for producing heterocyclic compound

Provided is a production method of a synthetic intermediate for a heterocyclic compound having a renin inhibitory activity and useful as a prophylactic or therapeutic drug for diabetic nephropathy, hypertension and the like. A production method of a compound represented by the formula (III-1a), the formula (III-1b), the formula (III-1c) and/or the formula (III-1d); wherein each symbol is as described in DESCRIPTION, or a salt thereof, including reacting a compound represented by the formula (Ia) or (Ib): wherein each symbol is as described in DESCRIPTION, or a salt thereof with a compound represented by the formula (II): wherein each symbol is as described in DESCRIPTION, or a salt thereof, in the presence of an aluminum compound and a chiral amine compound.

DEVELOPMENT OF NOVEL DETERGENTS FOR USE IN PCR SYSTEMS

This disclosure relates to novel detergents for use in various procedures including, for example, nucleic acid amplification reactions such as polymerase chain reaction (PCR). Methods for preparing the modified detergents are also described. 2. The compound of claim 1 , wherein:{'sup': '1', 'sub': 8', '16', '8', '16, 'Ris a (C-C) alkyl or (C-C) substituted alkyl;'}{'sup': 2', '3, 'sub': '3', 'Rand Rare each independently H or CH;'}{'sup': 4', '5', '3', '5, 'sub': 2', 'n', '2', 'n', '1', '30', '1', '30', '1', '30', '1', '30, 'Rand Rare each independently H, (CH)NH, (CH)N, or, alternatively, Ris taken together with Rto form a 5- or 6-membered ring which is optionally substituted with at least one (C-C) alkyl, (C-C) substituted alkyl, (C-C) heteroalkyl, (C-C) substituted heteroalkyl; and'}each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.5. The composition of claim 4 , wherein:{'sup': '1', 'sub': 8', '16', '8', '16, 'Ris a (C-C) alkyl or (C-C) substituted alkyl;'}{'sup': 2', '3, 'sub': '3', 'Rand Rare each independently H or CH;'}{'sup': 4', '5', '3', '5, 'sub': 2', 'n', '2', 'n', '1', '30', '1', '30', '1', '30', '1', '30, 'Rand Rare each independently H, (CH)NH, (CH)N, or, alternatively, Ris taken together with Rto form a 5- or 6-membered ring which is optionally substituted with at least one (C-C) alkyl, (C-C) substituted alkyl, (C-C) heteroalkyl, (C-C) substituted heteroalkyl; and'}each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.7. The composition of claim 4 , wherein said polymerase is thermostable.9. The kit of claim 8 , wherein:{'sup': '1', 'sub': 8', '16', '8', '16, 'Ris a (C-C) alkyl or (C-C) substituted alkyl;'}{'sup': 2', '3, 'sub': '3', 'Rand Rare each independently H or CH;'}{'sup': 4', '5', '3', '5, 'sub': 2', 'n', '2', 'n', '1', '30', '1', '30', '1', '30', '1', '30, 'Rand Rare each ...

COMPOUNDS FOR BINDING TO THE PLATELET SPECIFIC GLYCOPROTEIN IIb/IIIa AND THEIR USE FOR IMAGING OF THROMBI

The present invention relates to novel fluorine containing compounds, methods for their preparation, the intermediates of the synthesis, their use as diagnostic agents, especially for imaging of thrombi. The invention relates to positron emission tomography (PET) agents and associated precursor reagents, and methods for producing such radiolaveled agents for imaging of thrombi in a mammalian body. More particularly, the invention relates to small nonpeptide, high-affinity, specific-binding glycoprotein 11b/IIIa antagonists for imaging of thrombi. 16.-. (canceled)11. Compounds of Formula I according to claim 7 , selected from:tert-butyl 4-{3-[(3R)-3-({(1S)-3-methoxy-1-[3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)-phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,tert-butyl 4-{3-[(3R)-3-({3-methoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,tert-butyl 4-{3-[(3R)-3-({(1S)-3-methoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat,tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)-phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}-ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate;tert-butyl 4-{3-[(3R)-3-({1-[5-(4-chloro-3-cyanophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl} ...

Process for the Separation of Optical Isomers of Racemic 3-Alkylpiperidine-Carboxylic Acid Ethyl Esters

The subject-matter of the invention is process for the separation of optical isomers of racemic 3-alk-3-carboxylic acid ethyl esters of formula rac-I with the resolving agent (II) (−)-2,3:4,5-di-O-izopropylidene-2-keto-L-gulonic acid (hereinafter: diacetone-L-ketogulonic acid). 1. A process for the preparation of the high enantiomerically pure optical isomers ((R)-Ia-c and (S)-Ia-c) of the 3-alkylpiperidine-3-carboxylic acid ethyl esters of formula rac-I (wherein in the formula I the meaning of R can be methyl group (Ia) , ethyl group (Ib) or isopropyl group (Ic)) characterized in that the rac-Ia-c amines are dissolved separately in a suitable organic solvent , preferably in acetone at a temperature between 0° C. and 56° C. , reacted with an amount of 0.8-1.2 molequivalent of (−)-2 ,3:4 ,6-di-O-isopropylidene-2-keto-L-gulonic acid (diacetone-L-ketogulonic acid) resolving agent of formula II , preferably with the monohydrate thereof and after dissolving the resolving agent optionally , the solution is seeded with pure diastereomeric salt prepared from Ia-c enantiomers having appropriate configuration and resolving agent II , then after cooling of the mixture , the diastereomeric salt is separated by filtration and the appropriate high enantiomeric purity (R)-Ia or (R)-Ib or (S)-Ic enantiomers are liberated either from the crystalline (R)-Ia.II or (R)-Ib.II or (S)-Ic.II salts directly or after their recrystallization from an organic solvent , preferably from isopropanol , and optionally obtain therefrom the crystalline (R)-Ia.HCl , (R)-Ib.HCl and (S)-Ic.HCl salts in an organic solvent with hydrochloric acid which are separated by filtration and isolate the high enantiomeric purity crystalline products of (S)-Ia.HCl , (S)-Ib.HCl and (R)-Ic.HCl by the separation from the (S>>R)-Ia.II , (S>>R)-Ia.II and (R>>S)-Ia.II salts remaining in the residues obtained from the filtrate of the diastereomeric salt formation and recrystallization in the same manner as the crystalline ...

DEUTERATED COMPOUNDS AS IMMUNOMODULATORS

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I):

BIGUANIDE COMPOUNDS AND USE THEREOF

The present invention relates to biguanide compounds and use thereof, more particularly, to biguanide derivatives exhibiting excellent effects for inhibition of cancer cell proliferation and inhibition of cancer metastasis and recurrence, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and a method of prevention or treatment of cancer comprising the step of administering an effective amount of the composition to a subject in need thereof. 2. The compound according to claim 1 , wherein the compound is selected from the group consisting of:N1-pyrrolidine-N5-(benzo[1,3]dioxol-5-ylmethyl) biguanide,N1-pyrrolidine-N5-(4-methoxy)phenyl biguanide,N1-pyrrolidine-N5-(3-chloro-4-methoxy)phenyl biguanide,N1-pyrrolidine-N5-(2,6-difluorophenyl)-N-methyl)phenyl biguanide,N1-pyrrolidine-N5-(4-dimethylamino)phenyl biguanide,N1-pyrrolidine-N5-(4-isopropyl)phenyl biguanide,N1-pyrrolidine-N5-(3-phenoxy)phenyl biguanide,N1-pyrrolidine-N5-(N-biphenyl-3-yl) biguanide,N1-pyrrolidine-N5-(N-biphenyl-4-yl) biguanide,N1-pyrrolidine-N5-(4′-fluorobiphenyl-3-yl) biguanide,N1-pyrrolidine-N5-(3′-fluorobiphenyl-4-yl) biguanide,N1-pyrrolidine-N5-(4-fluoro)phenethyl biguanide,N1-pyrrolidine-N5-(2-phenylpropane-2-yl) biguanide,N1-pyrrolidine-N5-(5,6,7,8-tetrahydronaphthalene-2-yl) biguanide,N1-pyrrolidine-N5-((1,2,3,4-tetrahydronaphthalene-1-yl) biguanide,N1-(S)-2-methyl pyrrolidine-N5-(4-(trifluoromethoxy)phenyl biguanide,N1-(S)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,N1-(R)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,N1-3-hydroxy methyl pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,N1-pyrrolidine-N5-4-benzamide biguanide,N1-pyrrolidine-N5-4-methyl-N-ethyl benzamide biguanide,N1-pyrrolidine-N5-4-(2-oxo-2-(piperidine-1-yl)ethyl thio)phenyl, andN1-(S)-2-hydroxy pyrrolidine-N5-4-(2-oxo-2-(piperidine-1-yl)ethyl thio)phenyl biguanide.3. The compound according to claim 1 , wherein the compound of ...

SMALL MOLECULE BASED ANTIBODY-RECRUITING COMPOUNDS FOR CANCER TREATMENT

The present invention relates to chimeric (including bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds bind to the urokinase-type plasminogen activator receptor (uPAR) on the surface of a cancer cell, including a metastatic cancer cell, and consequently recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) against a large number and variety of cancers, thus providing cancer cell death and an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer. 1. A compound according to the general formula:{'img': {'@id': 'CUSTOM-CHARACTER-00021', '@he': '3.22mm', '@wi': '4.57mm', '@file': 'US20180155332A1-20180607-P00001.TIF', '@alt': 'custom-character', '@img-content': 'character', '@img-format': 'tif'}, 'Where is a moiety which binds to an active site of urokinase-type plasminogen activator receptor (uPAR) on the surface of cancer cells of a patient or subject;'}{'img': {'@id': 'CUSTOM-CHARACTER-00022', '@he': '3.22mm', '@wi': '3.89mm', '@file': 'US20180155332A1-20180607-P00002.TIF', '@alt': 'custom-character', '@img-content': 'character', '@img-format': 'tif'}, 'is an antibody binding moiety comprising a hapten which is capable of binding to an antibody in said patient or subject (preferably an endogenous antibody which pre-exists in the patient or subject without having to be raised prior to therapy);'}{'img': [{'@id': 'CUSTOM-CHARACTER-00023', '@he': '3.22mm', '@wi': '4.57mm ...

THERAPEUTIC AGENT AND THERAPEUTIC METHOD FOR PULMONARY HYPERTENSION

The present invention relates to a therapeutic agent for pulmonary hypertension comprising an interleukin-5 receptor (hereinafter, abbreviated to “IL-5R”)-inhibiting compound and therapeutic method therefor. More specifically, the present invention relates to a therapeutic agent for pulmonary hypertension comprising an antibody or an antibody fragment capable of specifically binding to the extracellular region of IL-5R and a therapeutic method therefor. 115-. (canceled)16. A method for treating pulmonary hypertension , comprising administering an antibody or an antibody fragment thereof which binds to the extracellular region of an interleukin-5 receptor (IL-5R) to inhibit an IL-5R-expressing cell.17. The method according to claim 16 , wherein the antibody removes an IL-5R-expressing cell.18. The method according to claim 16 , wherein the antibody has antibody-dependent cellular cytotoxic activity (ADCC activity).19. The method according to claim 16 , wherein the antibody has IL-5R-neutralizing activity.20. The method according to claim 16 , wherein the antibody inhibits group 2 innate lymphoid cell (ILC2)-dependent IL-5R-expressing cell growth.21. The method according to claim 16 , wherein the method is characterized by at least one of the following (i) to (iii):(i) the IL-5R-expressing cell is at least one cell of an eosinophil, a basophil, and a mast cell;(ii) the method inhibits the growth of a vascular smooth muscle cell; and(iii) the method inhibits pulmonary vascular remodeling.22. The method according to claim 16 , wherein the antibody is any one antibody selected from a monoclonal antibody and a recombinant antibody.23. The method according to claim 16 , wherein the antibody comprises a human Fc region or a human constant region.24. The method according to claim 16 , wherein the antibody comprises heavy chain (H chain) CDR1 to CDR3 respectively comprising the amino acid sequences represented by SEQ ID NOs: 1 to 3 and light chain (L chain) CDR1 to CDR3 ...

AUTOMATED SYNTHESIS OF SMALL MOLECULES USING CHIRAL, NON-RACEMIC BORONATES

Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification. 14-. (canceled)6. The compound of claim 5 , wherein R* is a chiral group of at least 90% enantiomeric excess.7. The compound of claim 5 , wherein R* is a chiral group of at least 95% enantiomeric excess.14. The compound of claim 5 , wherein Rand R claim 5 , taken together claim 5 , form a 5-10-membered cycloalkyl or aromatic ring claim 5 , or form a 5-10-membered heterocyclic or heteroaromatic ring comprising 1-3 heteroatoms independently selected from the group consisting of O claim 5 , N claim 5 , and S.21. (canceled)22. The compound of claim 5 , wherein m is 0.2329-. (canceled)31. The compound of claim 30 , wherein the carbon atom marked “*” in formula (IV) is a chiral carbon atom of at least 90% enantiomeric excess.32164-. (canceled) This application is a continuation of U.S. patent application Ser. No. 14/692,088, filed on Apr. 21, 2015, now U.S. Pat. No. 9,388,131, which is a divisional of U.S. patent application Ser. No. 14/112,985, filed on Dec. 12, 2013, now U.S. Pat. No. 9,012,658, which is a §371 national stage application based on ...

CARBOXAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Inhibitors of HBV replication of formula (I) 3. A compound according to or , wherein Ris selected from hydrogen , Fluoro , Chloro , —CHF , —CN , —CFor methyl.4. A compound according to anyone of to wherein at least two of R , Rand Rare Fluoro , Chloro or Bromo.5. A compound according to any one of the previous claims wherein Ris methyl.6. A compound according to any one of the previous claims wherein Rcontains a 3-7 membered saturated ring optionally containing one oxygen , such 3-7 membered saturated ring optionally substituted with methyl.7. A compound according to any one of the previous claims wherein Ris a 4 or 5 membered saturated ring containing one oxygen , such 4 or 5 membered saturated ring optionally substituted with methyl.8. A compound according to any one of to , wherein Ris a branched C-Calkyl optionally substituted with one or more Fluoro.11. A compound according to any one of the previous claims for use in the prevention or treatment of an HBV infection in a mammal.12. A pharmaceutical composition comprising a compound according to any of to , and a pharmaceutically acceptable carrier.13. A compound according to any one of to , or a pharmaceutical composition according to in combination with at least one other anti-HBV agent. The Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (). Its genome contains 4 overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 envelope proteins; and the X gene.Upon infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cccDNA) in the nucleus of the host cell and the viral mRNAs are transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also codes for core protein and Pol, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.HBV has ...

Neprilysin inhibitors

In one aspect, the invention relates to compounds having the formula: where R 1 -R 5 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.

METHOD FOR PRODUCING OPTICALLY ACTIVE 3-AMINOPIPERIDINE OR SALT THEREOF

The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof. In the method, a racemic nipecotamide is stereoselectively hydrolyzed to obtain an optically active nipecotamide and an optically active nipecotic acid in the presence of an enzyme source derived from an organism, and then the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by aroylation, Hofmann rearrangement, deprotection of the amino group and further deprotection; or the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by selective protection with BOC, Hofmann rearrangement and further deprotection. It is possible by the present invention to produce an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate from an inexpensive and easily available starting material by easy method applicable to industrial manufacturing. 121-. (canceled) The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate, and to intermediates useful for producing the 3-aminopiperidine.As methods for producing an optically active 3-aminopiperidine or salt thereof, or a derivative of optically active 3-aminopiperidine, for example, the following methods are known:1) a method, wherein L-ornithine monohydrochloride is methyl-esterified, and then (S)-3-amino piperidone is obtained by chromatography with an ion exchange resin, the (S)-3-amino piperidone is reacted with lithium aluminum hydride to be (S)-3-aminopiperidine, an inorganic salt is removed by filtration, and the target compound is purified (Non-patent Document 1);2) a method, wherein ethyl nipecotate is optically resolved using L-tartaric acid, the nitrogen atom is protected with benzyloxycarbonyl group, the ethyl ester is hydrolyzed in alkaline condition, Curtius rearrangement is carried out using ...

NITROGEN CONTAINING COMPOUNDS AND THEIR USE

Compounds of Formula (I), their preparation and use in preventing or treating bacterial infections are disclosed. 2. A process according to claim 1 , wherein compound of Formula (III) is obtained by reacting a compound of Formula (II) with 1-hydroxybenzotriazole ammonium salt in presence of dicyclohexylcarbodiimide.3. A process according to claim 1 , wherein compound of Formula (VI) is obtained by reacting a compound of Formula (V) with trimethylsulfoxonium iodide and sodium hydride in presence of triethylamine and dimethylsulfoxide.4. A process according to claim 1 , wherein compound of Formula (XIII) is obtained by cyclizing a compound of Formula (XII) with triphosgene in presence of triethylamine and N claim 1 ,N-dimethylaminopyridine claim 1 , followed by purification using column chromatography.5. A process according to claim 4 , wherein eluent used for column chromatography is mixture of ethyl acetate and hexane.7. A process according to claim 6 , wherein the racemic isomers of compound of Formula (XI) are isolated by treating with methanol.9. A process according to claim 8 , wherein sulfonation of a compound of Formula (XIIIa) is achieved by using sulfur trioxide dimethylformamide complex.10. A process according to claim 8 , wherein compound of Formula (XIIIb) is passed through a column packed with Amberlite sodium to provide a compound of Formula (I).11. A compound of Formula (I) in crystalline form.12. A process of preparing a compound of Formula (I) in crystalline form claim 8 , said process comprising crystallizing a compound of Formula (I) from one or more solvents selected from acetone claim 8 , ethanol claim 8 , water claim 8 , acetonitrile claim 8 , toluene or tetrahydrofuran.13. A compound of Formula (I) according to having X-ray powder diffraction peaks at: 5.18 (±0.2) claim 11 , 5.33 (±0.2) claim 11 , 10.21 (±0.2) claim 11 , 17.52 (±0.2) claim 11 , 18.57 (±0.2) claim 11 , 19.37 (±0.2) claim 11 , 20.29 (±0.2) claim 11 , 25.40 (±0.2) claim 11 , 26.39 ...

METHOD FOR TREATING PULMONARY ARTERIAL HYPERTENSION AND ASSOCIATED PULMONARY ARTERIAL HYPERTENSION

There is a method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient. The method has the step of systemically administering to the patient a therapeutically effective amount of one or more compounds: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, or (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing. There is also a method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient by systemically administering a therapeutically effective amount of a THP1 inhibitor from about 1 mg/kg/day to about 50 mg/kg/day 1. A method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient comprising systemically administering to the patient a therapeutically effective amount of a compound selected from the group consisting of (i) (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof , (ii) (S)-8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroeth-oxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof , and (iii) a combination of the foregoing , wherein the therapeutically effective amount is about 1 mg/kg/day to about 50 mg/kg/day.2. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally.3. The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally by a dosage form selected from ...

PROCESS FOR PREPARATION OF SODIUM (2S, 5R)-6-(BENZYLOXY)-7-OXO-1,6-DIAZABICYCLO[3.2.1]OCTANE-2-CARBOXYLATE

2. The process according to claim 1 , wherein the compound of Formula (IV) is obtained by treating the compound of Formula (II) with trimethylsilyl chloride in presence of methanol.4. The process according to claim 3 , wherein the compound of Formula (II) is converted to the compound of Formula (III) in presence of hydrochloric acid.6. The process according to claim 5 , wherein the compound of Formula (VII) is obtained by reacting the compound of Formula (VI) with 4-methoxybenzyl alcohol in presence of a carboxylic group activating agent.7. The process according to claim 6 , wherein the carboxylic group activating agent is selected from the group consisting of 1 -ethyl-3-(3-methylaminopropyl)carbodiimide hydrochloride claim 6 , 1-hydroxy benzotriazole claim 6 , dicyclohexylcarbodiimide claim 6 , carbonyldiimidazole; and a mixture thereof.8. The process according to claim 5 , wherein cyclization is carried out in presence of triphosgene claim 5 , triethylamine and 4-dimethylaminopyridine.10. (canceled)13. The process according to claim 1 , wherein cyclization is carried out in presence of triphosgene claim 1 , triethylamine and 4-dimethylaminopyridine. This application claims priority to Indian Patent Application No. 1192/MUM/2014 filed on Mar. 29, 2014, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.The invention relates to a process for preparation of sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate.A compound of Formula (I), chemically known as sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate, can be used as an intermediate in the synthesis of several antibacterial compounds and is disclosed in PCT International Patent Application No. PCT/IB2013/059264. The present invention discloses a process for preparation of a compound of Formula (I).In one general aspect, there is provided a process for preparation of a compound of Formula (I), said ...

NOVEL COMPOUNDS FOR USE IN PCR SYSTEMS AND APPLICATIONS THEREOF

This disclosure relates to novel compounds for use in various compositions, kits and methods, including, for example, use in polymerase storage buffers and in nucleic acid synthesis or amplification reactions such as a polymerase chain reaction (PCR). Methods for preparing the novel compounds are also described. 3. A composition comprising a polymerase and the compound of .4. The composition of claim 3 , wherein said polymerase is thermostable.5. The composition of claim 3 , comprising one or more of the following:a) at least one nucleotide triphosphateb) DTTc) KCl{'sup': '2', 'd) MgCl'}e) Kathonf) EDTAg) gelatinh) Trisi) glycerolj) BSA6. The composition of claim 3 , further comprising a polymerase inhibitor.7. The composition of claim 6 , wherein said polymerase inhibitor is at least one oligonucleotide inhibitor.8. The composition of claim 6 , wherein said polymerase inhibitor is at least one antibody inhibitor.9. The composition of claim 3 , wherein said polymerase is stable for at least about one month to about three years.10. A kit comprising a storage or reaction composition comprising a polymerase and the compound of .11. The kit of claim 10 , wherein said polymerase is thermostable.12Thermus aquaticus. The kit of claim 11 , wherein said polymerase is a polymerase isolated from (Taq) polymerase.13. The kit of claim 11 , further comprising a polymerase inhibitor.14. A method for increasing the efficiency of a polymerase claim 11 , said method comprising the steps of:{'claim-ref': {'@idref': 'CLM-00002', 'claim 2'}, 'a) mixing a target nucleic acid with at least one polymerase, at least one primer, dNTPs, and the compound according to ; and,'}b) amplifying said target nucleic acid.15. The method of claim 14 , wherein said increased efficiency is the same as the efficiency when the polymerase is in the presence of NP-40 and/or Tween® 20 instead of said compound.16. The method of claim 14 , wherein said increased efficiency is greater than the efficiency when the ...

4-(AZACYCLOALKYL)BENZENE-1,3-DIOL COMPOUNDS AS TYROSINASE INHIBITORS, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN HUMAN MEDICINE AND IN COSMETICS

4-(Azacycloalkyl)benzene-1,3-diol compounds are described corresponding to general formula (I) below: 223.-. (canceled) This application is a continuation of copending U.S. patent application Ser. No. 14/200,954, filed Mar. 7, 2014, which is a continuation of U.S. patent application Ser. No. 13/611,546, filed Sep. 12, 2012, now U.S. Pat. No. 8,697,726, which is a continuation of U.S. patent application Ser. No. 13/131,363, filed Sep. 12, 2011, now U.S. Pat. No. 8,299,259, which is a National Stage of PCT/EP2009/066268, filed Dec. 2, 2009, and designating the United States (published in the English language on Jun. 10, 2010 as WO 2010/063774 A1; the title and abstract were also published in English), which claims benefit of U.S. Provisional Patent Application No. 61/193,460, filed Dec. 2, 2008 and also claims priority under 35 U.S.C. §119 to French Patent Application No. 0858207, filed Dec. 2, 2008, each of the earlier applications being hereby expressly incorporated by reference in their entirety and each assigned to the assignee hereof.The invention relates to novel 4-(azacycloalkyl)benzene-1,3-diol compounds as industrial and useful products. It also relates to the process for the preparation thereof and to the use thereof, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for use in the treatment or prevention of pigmentary disorders.Skin pigmentation, in particular human skin pigmentation, is the result of melanin synthesis by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes which transfer melanin into the upper layers of keratinocytes which are then transported to the surface of the skin through differentiation of the epidermis (Gilchrest B A, Park H Y, Eller M S, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing V J, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909).Among the enzymes of melanogenesis, tyrosinase is a ...

Prodrugs of Compounds that Enhance Antifungal Activity and Compositions of Said Prodrugs

The invention relates to prodrugs for use in the inhibition of histone deacetylase. The prodrugs of the present invention have good aqueous solubility and good aqueous stability. The prodrugs of the invention advantageously are metabolized to the active ingredient in plasma or in the blood stream of a warm-blooded animal. The invention also provides compositions and, and methods for making the prodrugs, and methods for using the prodrugs to treat fungal infections. 1. A compound of the formula{'br': None, 'sup': 2', '2', 'x, 'Cy-L-Ar—Y—C(O)N(R)—Z'} Cy is —H, cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which is optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;', {'sup': '2', 'sub': 1', '6', '2', '6', '2, 'Lis C-Csaturated alkylene or C-Calkenylene, wherein the alkylene or alkenylene optionally is substituted, and wherein one or two of the carbon atoms of the alkylene is optionally replaced by O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O);'}, 'Ar is arylene, wherein said arylene optionally is additionally substituted and optionally is fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which is optionally substituted; and', {'sup': '2', 'Yis a chemical bond or a straight- or branched-chain saturated alkylene, which is optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an α-amino acyl moiety;'}], 'or a pharmaceutically acceptable salts thereof, wherein'}{'sup': x', '20, 'Ris —H, OH, or —R;'}{'sup': 20', '21, 'Z is —O—Ror —Rwherein'}{'sup': '20', 'claim-text': [{'sup': '10', '—C(O)—R,'}, {'sup': 40', '41, 'sub': 'n', '—C(O)-[C(R)(R)]OP(O)(OH)(OH),'}, {'sup': 31', '40', '41, 'sub': n', '2, '—C(O)N(R)[C(R)(R)]SOOH, or'}, {'sup': 40', '41', '40', '41', '42, 'sub': n', 'n, '—C(O)NH[C(R)(R)]C(O)O[C(R)(R)]R;'}], 'each —Ris'}{'sup': '10', 'claim-text': [{'sup': 40', '41', '42, ...

METHOD FOR TREATING SARCOIDOSIS-ASSOCIATED PULMONARY HYPERTENSION

There is a method of treating or preventing sarcoidosis-associated pulmonary hypertension in a patient. The method has the step of administering to the patient a therapeutically effective amount of one or more compounds: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, or (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing. 1. A method of treating or preventing sarcoidosis-associated pulmonary hypertension in a patient comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of (i) (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof , (ii) (S)-8-(2-amino-6-((R)-1-(5-chloro-[1 ,1′-biphenyl]-2-yl)-2 ,2 ,2-trifluoroeth-oxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof , and (iii) a combination of the foregoing.2. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally.3. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally by a dosage form selected from the group consisting of capsules claim 1 , tablets claim 1 , powders claim 1 , and granules.4. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally in the form of a liquid.5. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered one to four times per day.6. The method of claim 1 , wherein the compound is (S)-ethyl 8-(2-amino-6-((R)-1-(5- ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION AND PAIN

The invention relates to the compounds of formula V or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula V and methods for the treatment of inflammation and pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, oral mucosal inflammatory or oral infectious diseases. 2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , wherein said pharmaceutical composition is formulated to treat inflammation mediated pain in a patient in need thereof with an effective amount of said pharmaceutical composition claim 2 , and wherein said pharmaceutical composition is administered to the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal administration claim 2 , syrup claim 2 , lozenge claim 2 , spray claim 2 , mucoadhesive claim 2 , buccal formulation claim 2 , mucoadhesive tablet claim 2 , topical administration claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal administration claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. The pharmaceutical composition of claim 3 , wherein said inflammation mediated pain is caused by oral mucositis claim 3 , oral ulceration claim 3 , oral inflammation claim 3 , oral infection claim 3 , oral wounds claim 3 , dental surgery claim 3 , post-tosillectomy claim 3 , odontostomatology claim 3 , gingivitis claim 3 , stomatitis claim 3 , glossitis claim 3 , aphthous ulcers claim 3 , pharyngitis claim 3 , tonsillitis claim 3 , radiation or intubation mucositis.5. A method of ...

NITROGEN CONTAINING COMPOUNDS AND THEIR USE

Compounds of Formula (I), their preparation and use in preventing or treating bacterial infections are disclosed. 2. A process according to claim 1 , wherein compound of Formula (III) is obtained by reacting a compound of Formula (II) with 1-hydroxybenzotriazole ammonium salt in presence of dicyclohexylcarbodiimde.3. A process according to claim 1 , wherein compound of Formula (VI) is obtained by reacting a compound of Formula (V) with trimethylsulfoxonium iodide and sodium hydride in presence of triethylamine and dimethylsulfoxide.4. A process according to claim 1 , wherein compound of Formula (XIII) is obtained by cyclizing a compound of Formula (XII) with triphosgene in presence of triethylamine and N claim 1 ,N-dimethylaminopyridine claim 1 , followed by purification using column chromatography.5. A process according to claim 4 , wherein eluent used for column chromatography is mixture of ethyl acetate and hexane.7. A process according to claim 6 , wherein the racemic isomers of compound of Formula (XI) are isolated by treating with methanol.9. A process according to claim 8 , wherein sulfonation of a compound of Formula (XIIIa) is achieved by using sulfur trioxide dimethylformamide complex.10. A process according to claim 8 , wherein compound of Formula (XIIIb) is passed through a column packed with Amberlite sodium to provide a compound of Formula (I).11. A compound of Formula (I) in crystalline form.12. A process of preparing a compound of Formula (I) in crystalline form claim 8 , said process comprising crystallizing a compound of Formula (I) from one or more solvents selected from acetone claim 8 , ethanol claim 8 , water claim 8 , acetonitrile claim 8 , toluene or tetrahydrofuran.13. A compound of Formula (I) according to having X-ray powder diffraction peaks at: 5.18 (±0.2) claim 11 , 5.33 (±0.2) claim 11 , 10.21 (±0.2) claim 11 , 17.52 (±0.2) claim 11 , 18.57 (±0.2) claim 11 , 19.37 (±0.2) claim 11 , 20.29 (±0.2) claim 11 , 25.40 (±0.2) claim 11 , 26.39 ...

PROCESS FOR PREPARING A COMPOUND USEFUL FOR PRODUCING AN OPTICALLY ACTIVE DIAZABICYCLOOCTANE COMPOUND

A process for preparing the compound of the following formula (E): This application is a divisional application of application Ser. No. 13/173,002 filed on Jun. 30, 2011. This application claims the benefit under 35 USC 119(e)(i) of provisional application Ser. No. 61/459,954 filed on Dec. 22, 2010. The entire contents of each of application Ser. No. 13/173,002 and provisional application Ser. No. 61/459,954 are incorporated by reference herein.The present invention relates to an optically active diazabicyclooctane derivative defined by formula (F) below, which is useful as a pharmaceutical intermediate for β-lactamase inhibitor, and a process for preparing the same.Penicillins and cephalosporins are β-lactam antibiotics which are most widely and frequently used in the clinic. However, the development of resistance to β-lactam antibiotics by various pathogens severely has had a damaging effect on maintaining the effective treatment of bacterial infections. The most significant known mechanism related to the development of bacterial resistance is the production of class A, C, and D β-lactamases having a serine residue at the active center. These enzymes decompose the β-lactam antibiotic, resulting in the loss of the antimicrobial activities. Class A β-lactamases preferentially hydrolyze penicillins while class C β-lactamases have a substrate profile favoring cephalosporins. As commercially available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam are known, and these inhibitors are effective mainly against class A β-lactamase producing bacteria, and used as a mixture with a penicillin antibiotic. However, 250 types or more of β-lactamases have been reported to date, and among them, in addition to the expansion of class C β-lactamases as well as extended-spectrum β-lactamase (ESBL) belonging to class A and D β-lactamases, further resistant bacteria which produce class A KPC-2β-lactamase decomposing even carbapenem as a last resort for β-lactam ...

IONIZABLE CATIONIC LIPID FOR RNA DELIVERY

What is described is a compound 2. The compound of claim 1 , wherein Lis a bond.3. The compound of claim 2 , wherein X is S.4. The compound of claim 2 , wherein X is O.5. The compound of claim 2 , wherein each of Rand Ris a linear alkyl.6. The compound of claim 2 , wherein each of Rand Ris a linear alkyl or alkenyl.7. The compound of claim 2 , wherein one or both of Land Lis a linear alkylene.8. The compound of claim 2 , wherein each of Land Lis a bond.9. The compound of claim 8 , wherein Lis a bond.10. A method of making the compound of claim 9 , comprising a step of reacting pyrrolidine-3 claim 9 ,4-dicarboxylic acid with a protecting group.11. The compound of claim 8 , wherein Lis a methylene.12. A method of synthesis of the compound of claim 11 , wherein piperidine-3 claim 11 ,5-dicarboxylic acid group is a starting material.13. The compound of claim 1 , wherein Lis an alkylene.14. The compound of claim 12 , wherein X is S.15. The compound of claim 12 , wherein X is O.16. The compound of claim 12 , wherein each of Rand Ris a linear alkyl.17. The compound of claim 12 , wherein each of Rand Ris a linear alkyl or alkenyl.18. The compound of claim 12 , wherein each of Land Lis a linear alkylene.19. The compound of claim 17 , wherein Lis a bond.20. The compound of claim 17 , wherein Lis a methylene. This application claims benefit under 35 U.S.C. § 119(e) of Provisional U.S. Patent Application No. 62/457,060, filed Feb. 9, 2017, the contents of which is incorporated herein by reference in its entirety.A number of different types of nucleic acids are currently being developed as therapeutics for the treatment of a number of diseases. These nucleic acids include DNA in gene therapy, plasmids-based interfering nucleic acids, small interfering nucleic acids for use in RNA interference (RNAi), including siRNA, miRNA, antisense molecules, ribozymes and aptamers. As these molecules are being developed, there has been developed a need to produce them in a form that is stable ...

APOE4-TARGETED THERAPUTICS THAT INCREASE SIRT1

A link between ApoE4 allele and sirtuins expression level is identified that is believed to be associated with elevated risk for the promotion of processing of amyloid precursor protein (APP) by the non-amyloidogenic pathway in a mammal leading to elevated risk for Alzheimer's disease. Compounds are identified that upregulate sirtuins (e.g., SirT1) expression levels and appear to be useful in the treatment and/or prophylaxis of MCI and/or Alzheimer's disease. 2. The compound of claim 1 , wherein said compound is not any of compounds 1 claim 1 , 2 claim 1 , 4 claim 1 , 5 claim 1 , 6 claim 1 , 7 claim 1 , 8 claim 1 , 11 claim 1 , and 15 in Table 6.4. The compound according to any one of - claim 1 , wherein Rand Rare independently selected from the group consisting of hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , and butyl.7. The compound according to any one of - claim 1 , wherein Ris CH.8. The compound of claim 7 , wherein Ris H.9. The compound of claim 7 , wherein Ris CH.10. The compound according to any one of - claim 7 , wherein Ris O.11. The compound according to any one of - claim 7 , wherein Ris NHR.12. The compound according to any one of - claim 7 , wherein Ris NH.13. The compound according to any one of - claim 7 , wherein Rand Rare independently selected from the group consisting of hydrogen claim 7 , halogen claim 7 , and CH.14. The compound of claim 13 , wherein Rand Rare independently selected from the group consisting of H claim 13 , Cl claim 13 , and F.15. The compound of claim 13 , wherein Rand Rare both Cl.16. The compound of claim 13 , wherein Rand Rare both F.17. The compound of claim 13 , wherein Ris Cl and Ris F claim 13 , or Ris F and Ris Cl.18. The compound of claim 13 , wherein Ris H and Ris F.19. The compound of claim 13 , wherein Ris H and Ris Cl.20. The compound of claim 13 , wherein Ris H and Ris CH.21. The compound according to any one of - claim 13 , wherein Ris selected from the group consisting of H claim 13 , CH ...

NOVEL COMPOUNDS FOR USE IN PCR SYSTEMS AND APPLICATIONS THEREOF

This disclosure relates to novel compounds for use in various compositions, kits and methods, including, for example, use in polymerase storage buffers and in nucleic acid synthesis or amplification reactions such as a polymerase chain reaction (PCR). Methods for preparing the novel compounds are also described. 1. (canceled)319.-. (canceled)20. A method for inhibiting inactivation of a polymerase in a thermal cycling process claim 2 , said method comprising contacting said polymerase with the compound of during the thermal cycling process.21. The method of claim 20 , wherein said inhibition of polymerase inactivation is the same as the inhibition of polymerase inactivation when the polymerase is in the presence of NP-40 and/or Tween® 20 instead of said compound.22. The method of claim 20 , wherein said inhibition of polymerase inactivation is greater than the inhibition of polymerase inactivation when the polymerase is in the presence of NP-40 or Tween® 20 instead of said compound.2325.-. (canceled)26. The method of claim 20 , wherein said polymerase is thermostable.2738.-. (canceled)39E. coliE. coliE. coliE. coliE. coliT. aquaticusB. stearothermophilusEuryarchaeotaS. cerevisiae. The method of claim 20 , wherein said polymerase is selected from the group consisting of T7 DNA polymerase claim 20 , eukaryotic mitochondrial DNA Polymerase γ claim 20 , prokaryotic DNA polymerase I claim 20 , prokaryotic DNA polymerase II claim 20 , prokaryotic DNA polymerase III claim 20 , prokaryotic DNA polymerase IV claim 20 , prokaryotic DNA polymerase V claim 20 , eukaryotic polymerase α claim 20 , eukaryotic polymerase β claim 20 , eukaryotic polymerase γ claim 20 , eukaryotic polymerase δ claim 20 , eukaryotic polymerase ε claim 20 , eukaryotic polymerase η claim 20 , eukaryotic polymerase ζ claim 20 , eukaryotic polymerase ι claim 20 , eukaryotic polymerase κ claim 20 , DNA polymerase I claim 20 , DNA polymerase III alpha subunit claim 20 , DNA polymerase III epsilon subunits ...

COMPOUNDS USEFUL FOR PRODUCING AN OPTICALLY ACTIVE DIAZABICYCLOOCTANE COMPOUND

A compound of the following compound (B): This application is a divisional application of application Ser. No. 14/287,380 filed on May 27, 2014, which is a divisional application of application Ser. No. 13/173,002 filed on Jun. 30, 2011 (U.S. Pat. No. 8,772,490). This application claims the benefit under 35 USC 119(e)(i) of provisional application Ser. No. 61/459,954 filed on Dec. 22, 2010. The entire contents of each of application Ser. No. 14/287,380, application Ser. No. 13/173,002 and provisional application Ser. No. 61/459,954 are incorporated by reference herein.The present invention relates to an optically active diazabicyclooctane derivative defined by formula (F) below, which is useful as a pharmaceutical intermediate for β-lactamase inhibitor, and a process for preparing the same.Penicillins and cephalosporins are β-lactam antibiotics which are most widely and frequently used in the clinic. However, the development of resistance to β-lactam antibiotics by various pathogens severely has had a damaging effect on maintaining the effective treatment of bacterial infections. The most significant known mechanism related to the development of bacterial resistance is the production of class A, C, and D β-lactamases having a serine residue at the active center. These enzymes decompose the β-lactam antibiotic, resulting in the loss of the antimicrobial activities. Class A β-lactamases preferentially hydrolyze penicillins while class C β-lactamases have a substrate profile favoring cephalosporins. As commercially available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam are known, and these inhibitors are effective mainly against class A β-lactamase producing bacteria, and used as a mixture with a penicillin antibiotic. However, 250 types or more of β-lactamases have been reported to date, and among them, in addition to the expansion of class C β-lactamases as well as extended-spectrum β-lactamase (ESBL) belonging to class A and D β-lactamases, ...

Method for Producing cis-5-hydroxy-2-piperidinecarboxylic Acid Derivative, and Method for Purifying cis-5-hydroxy-2-piperidinecarboxylic Acid

The present invention aims to provide a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid with high purity, and a method for producing its derivative. The present invention provides a method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative, which method comprises a step of converting cis-5-hydroxy-2-piperidinecarboxylic acid into a compound(s) of Formula (1) and/or Formula (2) (wherein Rrepresents a protective group for an amino group, and R2 represents a C-Calkyl group), and a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid. 2. The method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative according to claim 1 , comprising a step of reactingcis-5-hydroxy-2-piperidinecarboxylic acid with an acid halide and/or acid anhydride to convert said cis-5-hydroxy-2-piperidinecarboxylic acid into a compound of Formula (1).3. The method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative according to claim 1 , comprising a step of reacting cis-5-hydroxy-2-piperidinecarboxylic acid with an acid halide and/or acid anhydride claim 1 , and then with an alcohol in the presence of an acid catalyst claim 1 , to convert said cis-5-hydroxy-2-piperidinecarboxylic acid into a compound of Formula (2).5. The method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative according to claim 1 , wherein said cis-5-hydroxy-2-piperidinecarboxylic acid is cis-5-hydroxy-2-piperidinecarboxylic acid synthesized by bacterial reaction and/or enzymatic reaction.6. The method for regenerating cis-5-hydroxy-2-piperidinecarboxylic acid according to claim 4 , wherein said cis-5-hydroxy-2-piperidinecarboxylic acid is cis-5-hydroxy-2-piperidinecarboxylic acid synthesized by bacterial reaction and/or enzymatic reaction.8. The method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid according to claim 7 , wherein said impurity is 2-piperidinecarboxylic acid or an analogue thereof.9. The method for purifying cis ...

BETA-LACTAMASE INHIBITOR AND PROCESS FOR PREPARING THE SAME

A process for preparing a diazabicyclooctane compound represented by the following formula (I): This application is a Divisional application of U.S. application Ser. No. 14/872,988, filed Oct. 1, 2015, which is a Divisional application of U.S. application Ser. No. 14/404,288, filed Nov. 26, 2014 (U.S. Pat. No. 9,181,250), which is a U.S. National Stage application of International Application No. PCT/JP2013/064971, filed May 30, 2013, which claims priority of Japanese Application No. 2012-122603, filed May 30, 2012, the entire contents of all of which are incorporated by reference herein.The present invention relates to a novel diazabicyclooctane derivative represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof. The present invention also relates to a process for preparing the same, and a use thereof as a β-lactamase inhibitor for the treatment of bacterial infection. The present invention further relates to a pharmaceutical composition and a method of treating bacterial infection using the compound of the present invention.Penicillins and cephalosporins are β-lactam antibiotics which are most widely and frequently used in the clinic. However, the acquisition of resistance to β-lactam antibiotics by various pathogens severely has had a damaging effect on maintaining the effective treatment of bacterial infections. The most significant known mechanism related to the acquisition of bacterial resistance is the production of class A, C, and D β-lactamases having a serine residue at the active center. These enzymes decompose the β-lactam antibiotic, resulting in the loss of the antimicrobial activities. Class A β-lactamases preferentially hydrolyze penicillins while class C β-lactamases have a substrate profile favoring cephalosporins. As commercially available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam are known, and these inhibitors are effective mainly against class Aβ-lactamase producing bacteria, and ...

METHODS FOR ADMINISTERING ANGIOTENSIN II

The present disclosure relates to the use of angiotensin II, angiotensin III, or angiotensin IV in therapeutic methods for the treatment of hypotension, especially catecholamine-resistant hypotension. 1. A method of treating hypotension in a human patient , comprising:measuring a ratio of blood concentration of angiotensin I to blood concentration of angiotensin II in a sample from the patient; andif the ratio of blood concentration of angiotensin I to blood concentration of angiotensin II is at or above a threshold level, administering to the patient a composition comprising angiotensin II.2. The method of claim 1 , wherein the threshold level is about 0.5 claim 1 , about 1.0 claim 1 , about 1.3 claim 1 , about 1.6 claim 1 , about 2.0 claim 1 , about 5.0 claim 1 , or about 10.0.38-. (canceled)9. The method of any one of claim 1 , wherein if the ratio of blood concentration of angiotensin I to blood concentration of angiotensin II is at or above the threshold level claim 1 , the composition comprising angiotensin II is administered to the patient at an initial rate of about 5 ng/kg/min claim 1 , about 10 ng/kg/min claim 1 , or about 20 ng/kg/min.1011-. (canceled)12. The method of any one of claim 1 , wherein the patient has acute respiratory distress syndrome.13. The method of any one of claim 1 , wherein the patient has received an angiotensin converting enzyme inhibitor (ACE inhibitor) within a preceding period of time or is receiving an ACE inhibitor.14. (canceled)15. The method of claim 13 , wherein the preceding period of time is about 1 hour to about 72 hours.16. (canceled)17. The method of claim 13 , wherein the patient is receiving an ACE inhibitor and method further comprises ceasing administration of ACE inhibitor if the if the ratio of angiotensin I to angiotensin II at or above the threshold level.18. The method of claim 1 , wherein the patient has an initial mean arterial pressure of 55 mm Hg or less prior to administering the composition.19. The method ...

NOVEL TRIPEPTIDE

Provided is a novel peptide having ACE inhibitory activity. Specifically, provided is a tripeptide consisting of Leu-Arg-Ala. 17-. (canceled)8. A tripeptide consisting of Leu-Arg-Ala.9. A composition comprising the tripeptide of .10. The composition according to claim 9 , which is a food composition or a pharmaceutical composition.11. The composition according to claim 9 , which is an oral composition.12. A method for inhibiting angiotensin-converting enzyme activity claim 8 , comprising administrating to a subject in need thereof an effective amount of the tripeptide of .13. The method according to claim 12 , wherein the tripeptide is administered in an amount of 10 to 300 μg by an adult per day.14. The method according to claim 12 , wherein the tripeptide is administered for 9 to 12 weeks or longer.15. A method for lowering blood pressure claim 8 , comprising administrating to a subject in need thereof an effective amount of the tripeptide of .16. The method according to claim 15 , wherein the tripeptide is administered in an amount of 10 to 300 μg by an adult per day.17. The method according to claim 15 , wherein the tripeptide is administered for 9 to 12 weeks or longer. The present invention relates to a novel tripeptide, and an ACE-inhibiting composition, a blood pressure-lowering composition, and the like that comprise the tripeptide.Angiotensin-converting enzyme (angiotensin I-converting enzyme; also referred to as “ACE” in the present specification) is an enzyme that converts angiotensin I into angiotensin II. Angiotensin II has the action of increasing blood pressure by, for example, contracting blood vessels. It is known that when the action of ACE is inhibited, the production of angiotensin II is suppressed, thereby showing an anti-hypertensive effect. Accordingly, ACE-inhibitory substances are used, for example, as active ingredients of blood pressure-lowering agents, and food-related components suitable for people with elevated blood pressure.As the ...

Processes for preparation of 4-aminoindane compounds and related aminoindane amides

A process for preparation of 4-aminoindane compounds of a first formula, salts and enantiomers thereof including: a) hydrogenating a 1,2-dihydroquinoline of a second formula to give a corresponding tetrahydroquinoline of a third formula; b) acylating the tetrahydroquinoline of the third formula with a carboxylic acid derivative of a fourth formula to obtain a corresponding acyl derivative compound of a fifth formula; c) rearranging the acyl derivative compound of the fifth formula under acidic conditions so as to give an acyl indane compound of a sixth formula or an addition salt thereof; and d) hydrolysing the acyl group of the acyl indane compound of the sixth formula so as to obtain the 4-aminoindane derivatives of the first formula.

Process for the preparation of enantiomerically enriched 3-aminopiperidine

The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, and in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrate and crystalline (S)-3-aminopiperidine-di-hydrochloride-monohydrate.

DEUTERATED COMPOUNDS AS IMMUNOMODULATORS

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I): 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Ris selected from the group consisting of CHand CD.3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Ris selected from the group consisting of CH claim 1 , CD claim 1 , CHOH and CDOH.4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Ris D.5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Rand Rare each H.6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript n is 0 claim 1 , 1 or 2.7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript o is 0 or 1.8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript q is 0 or 1.9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript p is 0 claim 1 , 1 claim 1 , 4 or 9.10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript m is 0.11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the subscript m is 0; the subscript n is 0 claim 1 , 1 or 2; the subscript o is 0 or 1; the subscript p is 0 claim 1 , 1 claim 1 , 4 or 9; and the subscript q is 0 or 1.12. The compound of claim 1 , which is in the form of a pharmaceutically acceptable salt.13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.14. The pharmaceutical composition of claim 13 , formulated for oral claim 13 , intravenous claim 13 , transdermal or subcutaneous administration.15. The pharmaceutical composition of or claim 13 , further comprising one or more additional therapeutic agents.16. The pharmaceutical composition of claim 15 , wherein the one or ...

METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC ACID

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below: 1. A compound represented by formula (6a) below:{'sup': '3', 'wherein X represents Cl, Br, or I, P′ represents a tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group, and Rrepresents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms,'}or a compound represented by formula (4a) below:{'sup': '2', 'wherein X represents Cl, Br, or I, P′ represents a tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group, and Rrepresents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms, or a compound represented by formula (3a) belowwherein X represents Cl, Br, or I, and P′ represents a tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group,or a compound represented by formula (2a) below:{'sup': '1', 'wherein X represents Cl, Br, or I, Rrepresents a hydrogen atom or an optionally substituted alkyl group containing 1 to 4 carbon atoms, P″ represents a tetrahydropyranyl group or ethoxyethyl group.'} The present application is a Divisional application of U.S. application Ser. No. 15/705,349, filed Sep. 15, 2017, which is Divisional application of U.S. application Ser. No. 15/108,141, filed Jun. 24, 2016, which is a National Stage of International Patent Application No. PCT/JP2014/084518 filed Dec. 26, 2014, which claims priority to Japanese Application No. 2013-272766 filed Dec. 27, 2013. The disclosures of U.S. application Ser. No. 15/705,349, Ser. No. 15/108,141 and International Patent ...

METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC ACID

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below: 2. The method for producing (2S claim 1 ,5S)/(2R claim 1 ,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 1 , further comprising (ii) the step 6 of:cleaving the amide bond in the compound (9) and hydrolyzing the lactone in the compound (9) to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. The present application is a Continuation Application of U.S. application Ser. No. 15/705,349, filed Sep. 15, 2017, which is Divisional Application of U.S. application Ser. No. 15/108,141, filed Jun. 24, 2016, which is a National Stage of International Patent Application No. PCT/JP2014/084518 filed Dec. 26, 2014, which claims priority to Japanese Application No. 2013-272766 filed Dec. 27, 2013. The disclosures of U.S. application Ser. No. 15/705,349, Ser. No. 15/108,141 and International Patent Application No. PCT/JP2014/084518 are incorporated by reference herein in their entireties.The present invention relates to a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and synthetic intermediates thereof. (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid, which is produced by the method of the present invention, is useful as a synthetic intermediate for a β-lactamase inhibitor and the like.(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is a useful intermediate for the synthesis of an agent and the like that inhibits β-lactamases in bacteria exhibiting the resistance against the β-lactam class of antibiotics, which β-lactamases are the major cause of the resistance in the bacteria.A production method using glutamic acid or pyroglutamic acid as a starting raw material has been known as a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. Specifically, Patent Document 1 describes that a protected 5-hydroxypiperidine-2-carboxylic acid compound as an intermediate of N-protected oxo- ...

Process for producing solid amino acid

The problem to be solved by the present invention is to ea lily and efficiently produce an amino acid having 2 to 7 carbon atoms as a high-purity solid without complicated operation, which is useful as a synthetic intermediate for medicines or agrochemicals. The present invention is characterized in comprising a step of precipitating solid amino acid with high purity. In the present invention, the by-produced salt composed of the sulfonic acid and the amine was removed to the mother liquor by reacting an amine with a sulfonic acid salt of amino acid in an aprotic polar solvent, or by reacting a sulfonic acid with an amine salt of amino acid in an aprotic polar solvent. The sulfonic acid salt of amino acid, for example, may be produced by reacting a N-(tert-butoxycarbonyl) amino acid with a sulfonic acid, or by reacting an amino acid tert-butyl ester with a sulfonic acid.

PROCESS INTERMEDIATES AND METHODS FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE

Methods are provided for the synthesis of key intermediates for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl. Such intermediates are also provided. 1. The compound Ethyl (2R ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate , being a dihydrochloride solvated by ethanol and having a weight/weight chloride content between 11 and 15% and an ethanol content of at least 0.5 mol/mol.2. The compound of claim 1 , having a weight/weight chloride content between 13.5 and 14.5%.3. The compound of claim 1 , having an ethanol content of between 0.7 and 1 mol/mol.4. The compound of claim 1 , having a weight/weight chloride content between 11 and 15% and an ethanol content of between 0.7 and 1 mol/mol.5. The compound of claim 1 , having a weight/weight chloride content between 13.5 and 14.5% and an ethanol content of at least 0.5 mol/mol.6. The compound of claim 1 , having a weight/weight chloride content between 13.5 and 14.5% and an ethanol content of between 0.7 and 1 mol/mol. This application is a continuation application of U.S. Ser. No. 15/235,488 filed Aug. 12, 2016 which is a divisional of U.S. application Ser. No. 14/009,529 filed Dec. 9, 2013 which is a National Phase application of PCT International Application No. PCT/EP2012/055331, International Filing Date, Mar. 26, 2012, claiming priority to Italian Patent Application No. MI2011A000545, filed Apr. 4, 2011, each of which is hereby incorporated by reference in its entirety. To the extent appropriate, a claim of priority is made to each of the above disclosed applications.An object of the present invention is a method for the synthesis of a key intermediate for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl.Argatroban ...

Antiviral Compounds

The present invention provides compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection. 2. The compound of claim 2 , wherein Ris H and X is CH.3. The compound of claim 2 , wherein n is 2.4. The compound of claim 2 , wherein n is 1.5. The compound of claim 4 , wherein Ris —C(═O)N(R) claim 4 ,6. The compound of claim 4 , wherein Ris monocyclic or bicyclic heteroaryl claim 4 , optionally substituted with one or more R.7. The compound of claim 4 , wherein Ris —C(═O)OR.8. The compound of claim 7 , wherein R is lower alkyl.9. The compound of claim 8 , wherein Ris lower alkyl or cycloalkyl.10. The compound of claim 9 , wherein Ris cyclohexyl.11. A compound selected from the group consisting of:(2S,4S)-1 -Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid tent-butyl ester;(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester;(2S,4R)-1-Cyclohexyhnethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid ethyl ester;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester;1-Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-5-benzooxazol-2-yl-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide;(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid methyl ester;1-Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-methyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(5-phenyl-oxazol-2-yl)-pyrrolidin-3-yl]-amide;1-Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide;(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic ...

Phenoxyethyl Cyclic Amine Derivatives and Their Activity as EP4 Receptor Modulators

The present invention provides a compound of the Formula (I): wherein X, R, R, R, R, R, R, R, R, R, and Rare as defined herein, or a pharmaceutically acceptable salt thereof. 2. The compound or salt according to wherein R is methyl.3. The compound or salt according to wherein Ris F and Ris F.4. The compound or salt according to wherein Ris methyl and Ris methyl.5. The compound or salt according to wherein Ris F and Ris F.8. A method of treating osteoarthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound claim 1 , or pharmaceutically acceptable salt thereof claim 1 , according to .9. A method of treating rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof claim 1 , according to .10. A method of treating pain associated with osteoarthritis or rheumatoid arthritis in a patient claim 1 , comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof claim 1 , according to .11. (canceled)12. (canceled)13. (canceled)14. (canceled)15. A pharmaceutical composition claim 1 , comprising a compound or a pharmaceutically acceptable salt thereof according to with one or more pharmaceutically acceptable carriers claim 1 , diluents claim 1 , or excipients. The present invention relates to certain novel phenoxyethyl compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.The present invention is in the field of treatment of inflammatory conditions, such as arthritis, including osteoarthritis and rheumatoid arthritis, and further including pain associated with these conditions. Arthritis affects millions of patients in the United States alone ...

METHOD FOR PREPARING (R)-PRAZIQUANTEL

The invention relates to a new method for preparing (R)-praziquantel. In the invention, by taking advantage of the high stereo selectivity, site selectivity and region selectivity of an enzyme, an intermediate of a pure optical and chiral (R)-praziquantel are obtained by means of the dynamic kinetic resolution of an enantiomer from the synthesized racemate or derivatives thereof, and the (R)-praziquantel is obtained by using various conventional and mature organic chemical reactions with higher yield. The method of the invention has the potential advantages of easily available raw materials, low cost, environmentally safer process and convenience for large-scale production. Also, the purity of the end product can be more than 98%. By adopting the invention, the quality of the product is improved and a basis for developing high quality of active pharmaceutical ingredients and formulations is established, and thus the pending industrial problem of purifying praziquantel over 30 years becomes solvable. 2. The method for preparing (R)-praziquantel as claimed in claim 1 , wherein R is selected from the group consisting of methyl claim 1 , ethyl claim 1 , isopropyl and tert-butyl.3Aspergillus niger, Candida rugosa, Candida cylindracea, Rhizomucor miehei, Candida Antarctica, Pseudomonas cepacia, Pseudomonas fluorescens, Thermomyces lanuginose, Bacillus subtilis, Fusarium solani pisi, AlcaligenesRhizopus niveus, Mucor javanicusRhizopus oryzaeThermomyces lanuginose, Fusarium solani pisi, Bacillus subtilis, Pseudomonas cepaciaPseudomonas fluorescens.. The method for preparing (R)-praziquantel as claimed in claim 1 , wherein the lipase is selected from one or more microbial lipases derived from the group consisting of sp claim 1 , and claim 1 , and the lipases derived from and4. The method for preparing (R)-praziquantel as claimed in claim 1 , wherein the step (2) comprises:adding the racemic compound 3e, an ionic liquid, a solvent and an optional organic base to a sealed ...

PHOTOCLEAVABLE LINKER

There are provided, inter alia, photolabile compounds and methods useful for the formation of dimers of biological molecules and subsequent dissociation of the dimers. 2. The method of claim 1 , wherein Lis substituted or unsubstituted alkylene claim 1 , substituted or unsubstituted heteroalkylene claim 1 , substituted or unsubstituted cycloalkylene claim 1 , substituted or unsubstituted heterocycloalkylene claim 1 , substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.3. The method of claim 1 , wherein Lcomprises a nitrophenylene.4. The method of claim 1 , wherein said peptide is selected from the group consisting of a dynein intermediate chain (IC) peptide claim 1 , a fragment of IC peptide claim 1 , an analog of IC peptide claim 1 , a dynein intermediate chain IC2C peptide claim 1 , a fragment of dynein intermediate chain IC2C peptide claim 1 , and an analog of dynein intermediate chain IC2C peptide.5. The method of claim 4 , wherein said peptide is an IC peptide claim 4 , or fragment or analog thereof.6. The method of claim 5 , wherein said peptide binds LC8.7. The method of claim 4 , wherein said peptide is an dynein intermediate chain IC2C peptide claim 4 , or fragment or analog thereof.8. The method of claim 7 , wherein said peptide binds TcTex1.9. The method of claim 1 , wherein said first FKBP fused to a peptide and said second FKBP fused to a peptide further comprise a reporter group.10. The method of claim 9 , wherein said reporter group is a dye claim 9 , a radioactive moiety claim 9 , or a protein.11. A method for antagonizing a dynein-associated process in a cell claim 9 , said method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(i) contacting a cell with a compound of under conditions suitable to antagonize a dynein-associated process.'}12. The method of claim 11 , further comprising:(ii) monitoring a dynein-associated process in said cell.13. The method of claim 12 , wherein said monitoring monitors ...

GLYCOSIDASE INHIBITORS AND USES THEREOF

The invention provides compounds for inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc. 2. (canceled)3. The compound of wherein the compound is selected from the following group:(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-(hydroxymethyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N,1-dimethylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(5-methylhexyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-(hydroxymethyl)-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methyl-1-(4-phenylbutyl)piperidine-2-carboxamide;(2S,3R,4S,5R,6R)-1-((E)-3-([1,1′-biphenyl]-4-yl)allyl)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)-1-(3-([1,1′-biphenyl]-4-yl)propyl)-3,4,5-trihydroxy-6-(hydroxymethyl)-N-methylpiperidine-2-carboxamide (2S,3R,4S)-1-hexyl-3,4-dihydroxy-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-N-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-N,1-dimethylpiperidine-2-carboxamide;(2S,3R,4S,5R)-3,4,5-trihydroxy-1-methylpiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxypiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxy-1-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-methylpiperidine-2-carboxamide;(2S,3R,4S,5R,6R)—N-ethyl-3,4,5-trihydroxy-6-methyl-1-phenethylpiperidine-2-carboxamide;(2S,3R,4S,5R)—N-ethyl-3,4,5-trihydroxy-1-(3-phenylpropyl)piperidine-2-carboxamide;(2S,3S,4R,5S,6R)—N-ethyl-4-fluoro-3,5-dihydroxy-6-methyl-1-phenethylpiperidine-2-carboxamide;(2R, ...

Composition Comprising Lactobacillus Plantarum 2830 (ECGC 13110402)

The present invention relates to compositions comprising 2830 (ECGC 13110402), or mutant strain or strains thereof, for use in the treatment or prevention of hypertension. 1Lactobacillus plantarum. A composition comprising 2830 (ECGC 13110402) , or mutant strain or strains thereof , for use in the treatment or prevention of hypertension.2. The composition as claimed in claim 1 , for use in the treatment or prevention of hypertension in an individual having at least mild hypercholesterolaemia.3Lactobacillus plantarum. A foodstuff or food supplement composition comprising 2830 (ECGC 13110402) claim 1 , or mutant strain or strains thereof claim 1 , for use in the reduction claim 1 , prevention and/or control or hypertension.4Lactobacillus plantarum. The composition as claimed in any preceding claim claim 1 , wherein is administered in a dose in the range of 10cfu/g to 10cfu/g.5. The composition as claimed in any preceding claim wherein the composition is administered once or twice daily.6. The composition as claimed in any preceding claim wherein the composition is adminstered or taken after or during meals.7. The composition as claimed in any preceding claim claim 1 , wherein the composition is encapsulated.8Lactobacillus plantarum. The composition as claimed in any preceding claim wherein is concentrated and/or freeze dried.9. The composition as claimed in any preceding claim wherein the composition further comprises one or more active ingredients selected from: vitamins claim 1 , minerals claim 1 , phytochemicals claim 1 , antioxidants and combinations thereof.10. The composition as claimed in any preceding claim wherein the composition further comprises one or more additional hypertension reducing agents.11. The composition as claimed in any preceding claim wherein the composition is administered or taken in combination with one or more of the following: statins claim 1 , sterols and/or stanols.12. The composition as claimed in any preceding claim wherein the ...

METHOD FOR TREATING PULMONARY ARTERIAL HYPERTENSION AND ASSOCIATED PULMONARY ARTERIAL HYPERTENSION AND DAILY DOSING

There is a method of treating or preventing pulmonary arterial hypertension (PAH) or associated pulmonary arterial hypertension (APAH) in a patient. The method has the step of systemically administering to the patient a therapeutically effective amount of one or more compounds: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, or (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing. There is also a method of treating or preventing PAH or APAH in a patient by systemically administering a therapeutically effective amount of a THP1 inhibitor from about 1 mg/kg/day to about 50 mg/kg/day. There is a method for treating PAH or APAH in a patient with a single daily dose.

USE OF SUBSTITUTED 1-(ARYL ETHYNYL)-, 1-(HETEROARYL ETHYNYL)-, 1-(HETEROCYCLYL ETHYNYL)- AND 1-(CYCLOALKENYLETHYNYL)-BICYCLOALKANOLS AS ACTIVE AGENTS AGAINST ABIOTIC PLANT STRESS

The invention relates to the use of substituted 1-(arylethynyl)-, 1-(heteroarylethynyl)-, 1-(heterocyclylethynyl)- and 1-(cycloalkenylethynyl)bicycloalkanols or salts thereof 4. A treatment for plants claim 1 , comprising applying a nontoxic amount claim 1 , effective for increasing the resistance of plants to abiotic stress factors claim 1 , one or more of the compounds of the formula (I) and/or a respective salt thereof as claimed in .5. The treatment as claimed in claim 4 , wherein the abiotic stress conditions are one or more conditions selected from the group consisting of aridity claim 4 , cold stress claim 4 , heat stress claim 4 , drought stress claim 4 , osmotic stress claim 4 , waterlogging claim 4 , elevated soil salinity claim 4 , elevated exposure to minerals claim 4 , ozone conditions claim 4 , strong light conditions claim 4 , limited availability of nitrogen nutrients and limited availability of phosphorus nutrients.6. A compound of formula (I) and/or a respective salt thereof as claimed in in spray application to one or more plants and/or parts of plants in combinations with one or more active compounds selected from the group of the insecticides claim 1 , attractants claim 1 , acaricides claim 1 , fungicides claim 1 , nematicides claim 1 , herbicides claim 1 , growth regulators claim 1 , safeners claim 1 , substances which affect plant maturity and bactericides.7. A compound of formula (I) and/or a respective salt as claimed in in spray application to one or more plants and/or parts of plants in combination with one or more fertilizers.8. A compound of formula (I) and/or a respective salt as claimed in for application to one or more genetically modified cultivars claim 1 , seed thereof claim 1 , and/or to one or more cultivated areas on which cultivars grow.9. A spray solution comprising one or more of the compounds of formula (I) and/or respective salt thereof as claimed in capable of being used for enhancing resistance of one or more plants to ...

An Anticonvulsant Compound

The invention relates to pharmaceutical uses of compounds of formula (II). Particular aspects of the invention relate to the use of those compounds in treating, preventing or ameliorating a seizure-related disorder, bipolar disorder, mania, migraine, Alzheimer's disease, Parkinson's disease or stroke. 1. (canceled)3. The method of claim 2 , wherein Ris selected from a carboxylic acid claim 2 , amide or amine group with 1 to 5 C atoms claim 2 , preferably with 1 to 3 C atoms claim 2 , more preferably with 1 to 2 C atoms.4. The method of claim 2 , wherein Rcomprises methanoic acid or ethanoic acid.5. (canceled)7. (canceled)11. The method of claim 2 , wherein Ris an optionally substituted alkyl or alkenyl group with a backbone comprising 2 to 15 C atoms claim 2 , 3 to 10 C atoms claim 2 , 4 to 7 C atoms or 4 to 5 C atoms.12. The method of claim 2 , wherein Rcomprises a Calkyl group.13. The method of claim 2 , wherein Ris substituted with a Calkyl group claim 2 , preferably a Calkyl group claim 2 , more preferably a Calkyl group.14. The method of claim 2 , wherein Rcomprises one or more unsaturated bonds.15. The method of claim 2 , wherein the backbone of the alkyl or alkenyl group is interrupted by one or more heteroatoms claim 2 , preferably oxygen or nitrogen.16. The method of claim 2 , wherein the compound is cis-2-(4-butylcyclohexyl)ethanoic acid claim 2 , trans-2-(4-butylcyclohexyl)ethanoic acid claim 2 , cis-2-(4-pentylcyclohexyl)ethanoic acid claim 2 , trans-2-(4-pentylcyclohexyl)ethanoic acid claim 2 , 2-(4-butylphenyl)ethanoic acid claim 2 , 2-(4-pentylphenyl)ethanoic acid claim 2 , cis-4-butylcyclohexanecarboxylic acid claim 2 , trans-4-butylcyclohexanecarboxylic acid claim 2 , cis-4-pentylcyclohexanecarboxylic acid claim 2 , trans-4-pentylcyclohexanecarboxylic acid claim 2 , 4-butylbenzoic acid claim 2 , 4-pentylbenzoic acid claim 2 , cis-[4-(4-methylpentyl)cyclohexyl]acetic acid claim 2 , trans-[4-(4-methylpentyl)cyclohexyl]acetic acid claim 2 , cis-[4-(3- ...

PHARMACEUTICAL COMPOSITION COMPRISING EPIDITHIODIOXOPIPERAZINE COMPOUND OR DERIVATIVE THEREOF, OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, FOR PREVENTING OR TREATING PULMONARY HYPERTENSION

The present invention relates to a pharmaceutical composition for preventing or treating pulmonary arterial hypertension, which comprises an epidithiodioxopiperazine (ETP) compound or a derivative thereof, or a pharmaceutically acceptable salt thereof.

METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC ACID

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by formula (10) below: 3. The method for producing (2S claim 1 ,5S)/(2R claim 1 ,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 1 , further comprising (iii) the step 6 of:cleaving the amide bond in the compound (9) and hydrolyzing the lactone in the compound (9) to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid.4. The method for producing (2S claim 2 ,5S)/(2R claim 2 ,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 2 , wherein the step of decarboxylating the carboxyl group in the step 5(a) or the step 5(b) is performed in the presence of an organic base.7. The method for producing the compound (7) according to claim 6 , wherein the reaction of the compound (4) with the compound (5) in the step 2 is performed in the presence of an iodide salt.8. The method for producing the compound (7) according to claim 6 , wherein the cyclizing reaction of the compound (6) in the step 3 is performed in the presence of a quaternary ammonium salt.15. (canceled)1719-. (canceled) The present invention relates to a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and synthetic intermediates thereof. (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid, which is produced by the method of the present invention, is useful as a synthetic intermediate for a β-lactamase inhibitor and the like.(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is a useful intermediate for the synthesis of an agent and the like that inhibits β-lactamases in bacteria exhibiting the resistance against the β-lactam class of antibiotics, which β-lactamases are the major cause of the resistance in the bacteria.A production method using glutamic acid or pyroglutamic acid as a starting raw material has been known as a method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. Specifically, Patent Document 1 describes that a protected 5- ...

Nitrogen containing compounds and their use

Compounds of Formula (I), their preparation and use in preventing or treating bacterial infections are disclosed.

Multimeric piperidine derivatives

The technology relates in part to compounds that bind to multimeric ligand binding regions, referred to herein as “multimeric compounds.” In certain examples, the multimeric compounds provided herein bind to and multimerize polypeptides that bind to rimiducid, such as for example, chimeric polypeptides that comprise FKBP12 polypeptide variant regions. Multimeric compounds provided include those having a structure of Formula I. Where A, Z, Y, Z′ and A′ moieties are described herein.

ORAL SOLID PREPARATION AND USE THEREOF

The invention discloses an oral solid preparation containing any one, or a mixture of two or more of crystalline form I, II, III, and IV of the compound represented by formula (A). The oral solid preparation of the present invention disintegrates rapidly, increasing dissolution rate thereof, thereby improving bioavailability. In particular, it is possible to solve the problem that an active material (active ingredient), which is high hygroscopic and becomes sticky after moisture absorption, can not be effectively disintegrated by conventional disintegrants. The present invention further relates to a use of the oral solid preparation in preparing an angiotensin II receptor antagonist or a use thereof in preparing medicine for preventing and/or treating hypertension, chronic heart failure and diabetic nephropathy. 2. The oral solid preparation according to claim 1 , wherein the crystalline form of the compound of formula (A) is selected from at least one from the group consisting of crystalline form I claim 1 , crystalline form II claim 1 , crystalline form III and crystalline form IV;preferably, the crystalline form of the compound of formula (A) is selected from the crystalline form I, the crystalline form II or a mixture thereof;for example, a weight ratio of the crystalline form I to the crystalline form II may be from 1:99 to 99:1, such as from 5:95 to 95:5; as an example, the weight ratio of the crystalline form I to the crystalline form II may be from 1:9 to 9:1, from 2:8 to 8:2, from 3:7 to 7:3, from 4:6 to 6:4 or 5:5.3. The oral solid preparation according to claim 2 , wherein claim 2 ,{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'an X-ray powder diffraction pattern of the crystalline form I comprises characteristic peaks at diffraction angles (2-Theta) of 5.3±0.2°, 8.6±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form I further comprises characteristic peaks at diffraction angles (2-Theta) of 13.3±0.2°, 20.1±0.2°; further ...

AUTOMATED SYNTHESIS OF SMALL MOLECULES USING CHIRAL, NON-RACEMIC BORONATES

Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification. 1157-. (canceled)158. A method of deprotecting a chiral , non-racemic pinene-derived iminodiacetic acid (PIDA) boronate , comprising:contacting a solution comprising the chiral, non-racemic PIDA boronate and a solvent with an aqueous solution of NaOH, thereby deprotecting the chiral, non-racemic PIDA boronate and forming a boronic acid and free PIDA ligand.159. The method of claim 158 , wherein the solvent comprises tetrahydrofuran (THF).160. The method of claim 158 , further comprising the steps of adding diethyl ether claim 158 , thereby generating a biphasic mixture comprising an organic phase comprising the deprotected chiral claim 158 , non-racemic PIDA boronate and an aqueous phase; and isolating the organic phase comprising the boronic acid and free PIDA ligand from the aqueous phase.161. The method of claim 160 , further comprising the step of contacting the organic phase with one or more drying agents selected from the group consisting of magnesium sulfate claim 160 , diatomaceous earth claim 160 , and molecular sieves claim 160 , thereby ...

PHARMACEUTICAL COMPOSITION CONTAINING 2-{4-[N-(5,6-DIPHENYLPYRAZIN-2-YL)-N-ISOPROPYLAMINO]BUTYLOXY}-N-(METHYLSULFONYL)ACETAMIDE

A stabilized solid preparation containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is provided, namely, a solid preparation containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and D-mannitol having a specific surface area of 1.0 m/g or less. 1: A solid preparation comprising:2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide; and{'sup': 2', '2, 'D-mannitol having a specific surface area of larger than 0.2 m/g and smaller than 0.7 m/g.'}2: The solid preparation according to claim 1 , wherein the amount of D-mannitol is from 10 to 9500 parts by weight with respect to 1 part by weight of 2-{4-[N-(5 claim 1 ,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.3: The solid preparation according to claim 1 , wherein the amount of 2-{4-[N-(5 claim 1 ,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is from 0.1 to 2 wt % of the total weight of the solid preparation.422-. (canceled)23: The solid preparation according to claim 1 , wherein the amount of D-mannitol is from 15 to 95 wt % of the total weight of the solid preparation.24: The solid preparation according to claim 3 , wherein the amount of D-mannitol is from 15 to 95 wt % of the total weight of the solid preparation.25: The solid preparation according to claim 1 , further comprising one substance selected from the group consisting of cornstarch claim 1 , sucrose claim 1 , and crystalline cellulose.26: The solid preparation according to claim 3 , further comprising one substance selected from the group consisting of cornstarch claim 3 , sucrose claim 3 , and crystalline cellulose.27: The solid preparation according to claim 24 , further comprising one substance selected from the group consisting of cornstarch claim 24 , sucrose claim 24 , and crystalline cellulose.28: The solid preparation according to claim 1 , further ...

PROCESS INTERMEDIATES AND METHODS FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE

Methods are provided for the synthesis of key intermediates for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl. Such intermediates are also provided. 1. A Method for obtaining ethyl (2R ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl , solvated or unsolvated , comprising exposing a mixture of ethyl (2R ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S ,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl , solvated or unsolvated , to an organic or aqueous solvent or to a mixture thereof , followed by the selective precipitation and isolation of ethyl (2R ,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl , solvated or unsolvated.2. The method of comprising:a) exposing a mixture of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, and ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, to an organic solvent, preferably selected from among an alcohol, an ester or a mixture thereof at a temperature between about 0° C. and the reflux temperature;b) selective precipitation of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated;c) optionally, diluting the suspension obtained in step b) with an ester or alcohol or with an ester/alcohol mixture and, optionally, heating before or after said dilution at a temperature between about 40° C. and the reflux temperature between ...

Novel compounds for use in pcr systems and applications thereof

This disclosure relates to novel compounds for use in various compositions, kits and methods, including, for example, use in polymerase storage buffers and in nucleic acid synthesis or amplification reactions such as a polymerase chain reaction (PCR). Methods for preparing the novel compounds are also described.

BENZIMIDAZOLE INHIBITORS OF THE SODIUM CHANNEL

The invention relates to compounds useful in treating conditions associated with voltage-gated ion channel function, particularly conditions associated with sodium channel activity. More specifically, the invention concerns compounds (e.g., compounds according to any of Formulas (I)-(XIII) or Compounds (1)-(236) of Table 1) that are useful in treatment of a variety of diseases and conditions. 2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein each of R claim 1 , R claim 1 , and Ris claim 1 , independently claim 1 , H claim 1 , C1-C3 haloalkyl claim 1 , or halogen.3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein one of R claim 1 , R claim 1 , and Ris H.4. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein two of R claim 1 , R claim 1 , and Rare claim 1 , independently claim 1 , CF claim 1 , Cl claim 1 , or F.5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Rand Rare both H; or Rand Rare both CH; or Rand Rcombine to form an optionally substituted C3-C6 cycloalkyl; or Rand Rcombine to form an oxo (C═O) group.6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Rcombines with Rto form a three-to-six membered heterocyclyl ring claim 1 , or wherein Rand Rcombine to form an optionally substituted three-to-six membered heterocyclyl.7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris H.8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris H and Ris optionally substituted C1-C6 alkyl.12. The compound of claim 9 , or a pharmaceutically acceptable salt or solvate thereof claim 9 , wherein n is 1 claim 9 , and Rand Rare both H claim 9 , or Ris H and Ris optionally substituted C1-C6 alkyl.13. The compound of ...

Transdermal Therapeutic System Containing Asenapine

The present invention relates to transdermal therapeutic systems (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, such asenapine TTS for use in a method of treatment, processes of manufacture of such TTS as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment and to a method of treating a human patient by transdermal administration of asenapine. 2. The transdermal therapeutic system according to claim 1 , wherein the transdermal therapeutic system contains at least 0.70 mg/cm claim 1 , at least 0.80 mg/cm claim 1 , at least 0.82 mg/cm claim 1 , or at least 0.83 mg/cmasenapine.3. The transdermal therapeutic system according to claim 1 , wherein the transdermal therapeutic system contains from 0.70 mg/cmto 4.0 mg/cm claim 1 , from 0.80 mg/cmto 3.0 mg/cm claim 1 , from 0.82 mg/cmto 2.0 mg/cm claim 1 , or from 0.83 mg/cmto 1.7 mg/cmasenapine.4. The transdermal therapeutic system according to claim 1 , wherein the asenapine-containing matrix layer has an area weight that ranges from 90 to 230 g/m claim 1 , from 110 to 210 g/m claim 1 , or from 120 to 170 g/m.5. The transdermal therapeutic system according to claim 1 , wherein the asenapine-containing matrix layer composition does not comprise any of polysiloxanes and polyisobutylenes in an amount of more than 50% by weight of the asenapine-containing matrix layer composition.6. The transdermal therapeutic system according to claim 1 , wherein the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 5% by weight of the asenapine-containing matrix layer composition.7. The transdermal therapeutic system according to claim 1 , wherein the asenapine-containing matrix layer does not comprise isopropyl myristate in an amount of 1-10% by weight of the asenapine-containing matrix layer composition.8. The transdermal therapeutic system ...