BG109057A - N-[[5-метил-3-фенилизоксазол-4-ил]фенил]сулфонилпропиламид и негова натриева сол като прекурсори на инхибитори на сох-2 - Google Patents

N-[[5-метил-3-фенилизоксазол-4-ил]фенил]сулфонилпропиламид и негова натриева сол като прекурсори на инхибитори на сох-2 Download PDF

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Publication number
BG109057A
BG109057A BG109057A BG10905798A BG109057A BG 109057 A BG109057 A BG 109057A BG 109057 A BG109057 A BG 109057A BG 10905798 A BG10905798 A BG 10905798A BG 109057 A BG109057 A BG 109057A
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BG
Bulgaria
Prior art keywords
methyl
compounds
phenyl
phenylisoxazol
anhydride
Prior art date
Application number
BG109057A
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English (en)
Inventor
John Talley
James Malecha
Stephen Bertenshaw
Matthew Graneto
Jeffrey Carter
Jinglin Li
Srinivasan Nagarajan
David Brown
Jr. Donald Rogier
Thomas Penning
Ish Khanna
Xiangdong Xu
Richard Weier
Original Assignee
G.D.Searle & Co
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Publication date
Application filed by G.D.Searle & Co filed Critical G.D.Searle & Co
Publication of BG109057A publication Critical patent/BG109057A/bg

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract

Изобретението се отнася до метод за получаване на прекурсори на инхибитори на СОХ-2, N-[[4- (5-метил-3- фенилизоксазол- 4-ил) фенил] сулфонил] пропанамид или N-[[4- (5-метил-3-фенилизоксазол-4- ил)]сулфонил] пропанамид, тяхна натриева сол и техни фармацевтично приемливи соли.

Description

СОЛ КАТО ПРЕКУРСОРИ НА ИНХИБИТОРИ НА СОХ-2
Област на техниката [0001] Настоящото изобретение се отнася до противовъзпалителни фармацевтични средства и, по-специално, до прекурсори на съединения, които селективно инхибират циклооксигеназа-2.
Предшестващо състояние на техниката [0002] Прилагането на нестероидални противовъзпалителни лекарства (NSAIDs) за успокояване на болка и за спадане на оток.
свързани с възпаление, могат да предизвика! тежки странични реакции, включващи появата на язви, застрашаващи живота. Неотдавнашното откритие на индуцируем ензим, свързан с възпаление (“простагландин
Ί ·· 4 · 4 ·· ·· 44 44
4 4 4 44 · 444
4 · · · · ·4···
44····· « · · * ** · 4·· · ··
44·· · ·· ···· ·····
G/Ή синтаза П” или “циклооксигеназа-2 (СОХ-2)”), обезпечава жизнеспособна мишена за инхибиране. която по-ефективно редуцира възпалението и води до появяване па по-слаби и по-малко драстични странични ефекти.
[0003] Описани са съединения, които селективно инхибират циклооксигеназа-2. В US-A~5.380.738 са описани оксазоли, които селективно инхибират циклооксигеназа-2. В US-A-5,344,991 са описани циклопентени, които селективно инхибират циклооксигеназа-2. В US-A5,393,790 (съответстващ на WO-A-9521817) са описани спиросъединения, които селективно инхибират циклооксигеназа-2 и, следователно, са приложими за лечение на възпаление. В WO-A-9415932 са описани производни на тиофен и фуран, които селективно инхибират циклооксигеназа-2. В WO-A-9427980 са описани оксазоли, които селективно инхибират циклооксигеназа-2. В WO-A-9413635 са описани съединения, които селективно инхибират циклооксигеназа-2. В WO-A9420480 са описани съединения, които селективно инхибират циклооксигеназа-2. В WO-A-9515316 са описани производни па пиразолилеулфоамид, които селективно инхибират циклооксигеназа-2. В някои случаи, обаче, са изгодни прекурсори на противовъзпаличелни съединения, особено, когато прекурсорите притежават повишена водоразтворимоет или забавено начало на действие.
[0004] Описани са заместени сулфонамиди. 11иразолилсулфонилкарбамидите са описани като имащи възможна хиногликемична активност (Н. Paid Allah, Н. Mokhtar, Ind. J. Chem., 27, 245 (1988)). B JP 1,045,374 са описани водоразтворими гетразолиеви съединения, приложими при анализи за определяне на редуциращи вещества. D. Mukerjec el al. {Acta. Pharma. Jugcsl., 31, 151 (1981)] описват гетразолиеви сулфонамиди като антивирусни средства. В JP 4,277,724 са описани грифенилпиразолини като нелинеен оптичен материал. В JP 1,045,374 е • · · · · · · • · · · ·· • · · · ·· • ······ « · • · ·· · съдинения за черно-бял са описани заместени
В US-A-5,387,592 са като антагонисти на ···· · ·· · · · · описано приложението на хетероциклични фотографски материал. В US-A-5,389,635 имидазоли, като антагонисти на ангиотензин II. описани производни на заместен бензимидазол, ангиотензин II. G. Dorofeenko et al., [Khim. Farm. Zh., 16, 920 (1982)] описва пиридиниеви соли като антивирусни агенти. В US-A-5,338,749 са описани диарилзаместени противоартритни средства. В съединения, които селективно хетероциклични съединения като
WO-A-9426731 са описани гиофепови инхибират циклооксигеназа-2. В WO-A
9500501 са описани съединения, които селективно инхибират циклооксигеназа-2 и, по-специално, описан е 3-(4-(трифлуорацетиламиносулфонил) фенил)-2-(4-флуорфенил)тиофен. Т. Ivanov [Mh. Chem., 97, 1499 (1966)] описва получаването на производни на диарилиндон като възможни индикатори, като специално е описан 2-(4-(Ъ1-метиламиносулфонил) фенил)-3-фенилиндон.
[0005] J. Larsen и Н. Bundgaard [Int. J. Pharmaceutics, 37, 87 (1987)] описват отделянето на N-ацилсулфонамиди като потенциални производни на прекурсор. J. Larsen et al., [Int. J. Pharmaceutics, 47, 103 (1988)] описва оценяването на N-метилсулфонамиди като потенциални производни на прекурсор.
[0006] В WO-A-9603388 са описани 1,2-заместени имидазолилови съединения за лечение на възпаление.
[0007] В Bioorganic & Medicinal Chemistry Letters, Vol. %, No. 18, pp. 2123-2128, 1995 е описан синтезът и биологичната оценка на 2,3диарилтиофени като селективни инхибитори на СОХ-2 и СОХ-1.
[0008] В WO-A-9619462 са описани производни на оксазол и тяхното приложение като антипиретици, аналгетици и противовъзпалителни средства. В WO-A-9619463 също са описани производни на оксазол.
[0009] Напоследък се чувства нужда от съединения, подходящи за инжектируеми противовъзпалителни състави. Установено е, че съеди ненията, съгласно настоящото изобретение, не са ефикасни като прекурсори.
Техническа същност на изобретението [0010] N-[[4-( 5-метил-3-фенилизоксазол-4-ил]фенил]сулфонилпропанамид и Ь1-[[4-(5-метил-3-фенилизоксазол-4-ил]пропанамид, натриева сол, са заместени сулфонамидни съединения с приложение като прекурсори.
[0011] Споменатите съединения могат да се използват за, но без да е ограничение, лечение на възпаление на пациент или за лечение на други нарушения, свързани с циклооксигеназа-2, като аналгетик при облекчаване на болка или главоболие, или като антипиретик за лечение на треска. Например, съединенията, съгласно настоящото изобретение, могат да бъдат полезни при лечение на артрит, включващ, но без да е ограничение, ревматоиден артрит, спондилоартропатии, подагрен артрит, остеоартрит, лупус еригематозус и юношески артрит. Тези съединения, съгласно настоящото изобретение, могат да бъдат полезни при лечение па астма, бронхит, менструални спазми, преждевременно раждане, тендинит, бурсит, състояния, свързани с кожата, като псориазис, екзема, изгаряния и дерматит, и при следоперативно възпаление, включващо офталмологична операция като отстраняване на перде и рефрактивна операция. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни също и при лечение на стомашно-чревни състояния, като възпаление на червата, болест на Crohn, гастрит, синдром на чувствителните черва и язвен колит. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни за превенция или лечение на рак, като колоректален рак и рак на гърдата, на белия дроб, на простатата, на цервикса и кожата.
• · · · • · • · · · • · • · • · ·
Съединенията, съгласно настоящото изобретение, могат да бъдат полезни при лечение на възпаление при такива заболявания, като васкуларни болести, главоболие вследствие мигрена, периартритна нодоза, тироидит, апластична анемия, болест на Hodgkin, склеродома, ревматична треска, диабет от тип I, болест на невромускулните връзки, включваща миастения гравис, болест на мозъка, включваща множествена склероза, саркодоза, нефротичен синдром, синдром на Behcek полимиозит, гипгивит, нефрит.
свръхчувствителност, селинг, появяващ се след нараняване, миокардиална исхемия. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни също и при лечение на очни болести, като ретинит, регинонагии. увеит, очна фотофобия и силно нараняване на очната тъкан. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни също и при лечение на белодробно възпаление, като такова, свързано с вирусни инфекции и цистична фиброза. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни също и при лечение на някои нарушения на централната нервна система, като кортикални деменции, включващи болест на Alzheimer, и увреждане на централната нервна система, вследствие на удар, исхемия или травма. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни като противовъзпалителни средства, например, за лечение на артрит при значително по-малко вредни странични реакции. Съединенията, съгласно настоящото изобретение, moi ат да бъдат полезни също и при лечение на алергични риниги, синдром на респираторен дистрес, синдром на ендотоксичен шок и атеросклероза. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни също и при облекчаване на болка, без да се ограничава до следоперативна болка, зъбобол, мускулна болка и болка в резултат на раково заболяване. Съединенията, съгласно настоящото изобретение, могат да бъдат полезни за превенция на деменции, като болеет на Alzheimer.
··· 6·· ·· · ···· • · · · · · · · · · ··· · · · · ···· ······· · · ·· · · • · ··· ·· · ···· · ·· ···· ·· ··· [0012] Освен че са ефикасни при лечение па хора, съединенията, съгласно настоящото изобретение, са ефикасни също и във ветеринарната медицина за лечение на домашни животни, екзотични животни и селскостопански животни, включващи бозайници и гризачи. По-предночитаншс животни включват коне, кучета и котки.
[0013] Съединенията, съгласно настоящото изобретение, могат да се използват също и при комбинирана терапия, частично или напълно, вместо други конвенционални противовъзпалителни средства, например, заедно със стероиди, ттестероидални противовъзпалителни лекарства (NSAlDs), инхибитори на 5-липоксигеназа, антагонисти на LTB4 и инхибитори па 1ТА} хидролиза.
[0014] Подходящите инхибитори на LTB4 включват, освен други, и ебселен, Bayer Вау-х-1005, Ciba Geigy съединение CGS-25019C, Leo Denmark съединение 1-,111-615. Lilly съединение LY-293111, Ono съединение ONO-4057, Terumo съединение TMK-688, Lilly съединения Ι,Υ-213024, 264086 и 292728, ΟΝΟ съединение ONO-LB-457, Searle съединение SC-53228, калцитрол, Lilly съединения LY-210073, ! Y 223982, LY-233469 и LY-255283, ONO съединение ONO-LB-448, Searle съединения SC-41930, SC-50605 и SC-51146, и SK&F съдинение SKFO 104493. Предпочита се, инхибиторите на 1,ТВ4 да бъдат подбирани между ебселен, Bayer Вау-х-1005, Ciba Geigy съединение CGS-25019С, Leo Denmark съединение ЕТН-615, Lilly съединение LY-293111, Ono съединение ONO-4057 и Terumo съединение ТМК-688.
[00151 Подходящите инхибитори на 5-LO включват, освен други, и мазопрокол, тенидап, зилеутон, пранлукаст, тепоксалин, рилопирокс, флезетастин хидрохлорид, еназадрем фосфат и бунапроласт.
[0016] Съединенията, съгласно настоящото изобретение, могат да се използват също и при комбинирана терапия с опиати и други аналгетици, като морфин, меперидин или кодеин.
• · ·· · е · · ·· ··· ···· · · · • · · «· · · · ··· ••••••a · · · · · · • · ··· ··· «··· · ·· ···· ·· ··· [0017] Терминът “инхибитор на циклооксигеназа-2” включва съединения, които селективно инхибират циклооксигеназа-2, по-добре от циклооксигеназа-1. Предпочита се съединенията да притежават 1С50 на циклооксигеназа-2 по-малък от около 0.5 μΜ и, също така, да имат селективно съотношение на инхибиране на циклооксигеназа-2 по-голямо от това на циклооксигеназа-1 с поне 50, за предпочитане, поне 100. Даже повече се предпочита, съединенията да притежават 1С5о на циклооксигеназа-1, по-голям от около 1 μΜ, като още повече се предпочита, по-голям от 20 μΜ. Такава предпочитана селективност може да индикира способност за намаляване на появата па обичайни индуцирани от несгероидални противовъзпалителни лекарства странични реакции.
[0018] Фразата “терапевтично активен” служи за окачествяване на количеството на всяко лекарствено средство за използване в комбинираната терапия, с което ще се постигне подобряване в тежестта и честотата на появяване на странични ефекти в по-голяма степен, отколкото при лечение с всяко лекарствено средство поотделно, доколкото избягването на вредните странични ефекти обикновено се свързва с алтернативно лечение.
[0019] Фразата “комбинирана терапия”, с която се дефинира използването на инхибитор на циклооксигеназа-2 заедно с друго лекарствено средство, се отнася до последователно администриране на всяко лекарствено средство при даден режим, който осигурява благоприятни ефекти на лекарст вената комбинация и, също така сс отнася до съвместно едновременно администриране на тези лекарствени средства, например в единична капсула, съдържаща фиксирано съотношение на тези активни лекарствени средства, или в множество отделни капсули, съдържащи всяко лекарствено средство.
·« ·· ····· • · · · v · · ··· · · ······ ···*··· · · · · ·· • · ··· · ·· ···· · ·· ···· ·· ··· [0020] Терминът “прекурсор” се отнася до съединения, които са прекурсори на лекарства, които при администриране върху пациент и следващо абсорбиране, in vivo се превръщат в активни съставки при някой процес, като метаболизъм. Другите продукти на процеса на превръщане лесно се отделят от тялото. От по-предпочитапите прекурсори се получават продукти на процеса на превръщане, които обикновено се приемат за безопасни.
[0021] Настоящото изобретение се отнася до метод за получаване на N-[ [4-( 5-метил- 3 -фенилизокса зо л-4 нл]фенил] сулфонилпропанамвд или N-[ [4-( 5-метил-3-фенилизоксазол-4-ил |сулфонил]пропана мид, тяхна натриева сол или тяхна фармацевтично приемлива сол.
Основни синтетични мегоди [0022] Прекурсорите на инхибитора на циклооксигеназа-2, съгласно настоящото изобретение, могат да бъдат синтезирани по следните методи:
1. М-[[4-(5-метил-3-фенилизоксазол-4-ил]фепил]сулфонилпропанамид:
а) третиране на Я-[[4-(5Метил-3'фенилизокса.зол~4-ил]фенил] сулфонамид е подходящ ацилиращ агент, подбран от групата, състояща се от анхидрид, киселинен хлорид, ацилимидазол или активен естер, в присъст вие на база и подходящ разтворител и
б) изолиране на съединението посредством хроматография или кристализация.
2. Н-[[4-(5-мстил-3-фсншшзоксазо;ъ4-ил]сулфонил]11ропанамид, натриева сол:
третиране на Н-[[4-(5-метил--3-фенилизоксазол-4-ил)фенил] сулфонил]нропанамид със силна натриева база, като натриев хидроксид.
·· · • * ··♦·
9.·· • ·
[0023] Широка гама от разтворители може да бъде използвана достатъчно дълго, докато разтворителите не взаимодействат с добавената силна база, като предпочитани са етанол и тетрахидрофуран.
[0024] Следващите примери включват подробно описание на методите за получаване на Щ[4-(5-метил-3-фенилизоксазол-4ил]фенил]сулфоиилиронанамид или и-[[4-(5-мстил-3-фенилизоксазол-4ил]сулфонил]пропанамид, натриева сол. Всички използвани части са тегловни и температурата е дадена в градуси по Целзий, ако не е посочено друго. NMR-спектрите на всички съединения са в съответствие с тяхната
показана структура.
Примери за изпълнение на изобретението
Пример 1
№[[4-(5-метил-3-фенилизоксазол-4-ил)фенил]сулфонил]пропанамил [0025] Анхидрид на пропионовата киселина (9.39 mmol) и триетиламин (3.97 mmol) се прибавят към разтвор на 4-[5-мстил-3фенилизоксазол-4-ил]бензенсулфонамид (3.31 mmol) и Ν,Ν-диметилпиридин (0.202 g) в сух тетрахидрофуран. След разбъркване в продължение на 18 часа при стайна температура реакционната смес се концентрира. Остатъкът се разтваря в етилацетат, промива се добре с 1N ·· · 10 ·· .·*. .·.!··“ ··· · · · · · · · • · · · · * · · *·· ······· · · ·· · · . · .♦· .·· ««··· ·· ···· ·» ··· солна киселина и разсол, суши се над безводен магнезиев сулфат и се концентрира до получаване на 1.0 g (81%) от желания продукт като кристално вещество.
[0026] Т. т. 148.9-151,0°С. Ή NMR (CDCI3/3OO MHz) 8.60 (brs,lH), 8.04 (d,2H,./=8.7 Hz), 7.38-7.31 (m,7H), 2.50 (s,3H), 2.32 (q,2H/-7.2 Hz), 1.10 (t,311,/-7.2 Hz). FABLRMS m/z 371 (M+H). FABHRMS m/z 371.1049 (М-ьН), изчислено 371.1066. Елементен анализ: изчислено за C19Hl8N2O4S: С, 61.61; Н, 4.90; N, 7.56. Намерено: С, 61.52; Н, 4.92; N, 7.53.
Пример 2
№-[[4-(5-метил-3-фенилизоксазол-4-ил)фенил]сулфонил]пропанамид, натриева сол [0027J Смес на Н-[[4-(5-метил-3-фенилизоксазол-4-ил)фенил] сулфонил]пропанамид (Пример 1) (0.83 mmol) и натриев хидроксид (0.33 ml, 2.5N) в етанол се концентрират до сухо. Остатъкът се разтваря в етанол и отново се концентрира. Остатъкът се суши под вакуум до получаване на 0.32 g (97%) кристален продукт.
[0028] Т.т. 271.9-272.7°С. Ή NMR (D20/300 MHz) 7.57 (d,211,/-8.4 Hz), 7.30-6.90 (m,7H), 2.12 (s,3H), 2.00 (q,2H/-7.8 Hz), 0.83 (t,3H,/-7.8 Hz). FABLRMS m/z 393 (M+H). Елементен анализ: изчислено за C19H17N2O4SNa: С, 58.61; Η, 4.37; Ν, 7.14. Намерено: С, 57.92; Η, 4.53; Ν, 6.95.

Claims (9)

11.··
ПАТЕНТНИ ПРЕТЕНЦИИ
1. Метод за получаване на парекоксиб, Ь1-[[4-(5-метил-3фенилизоксазол-4-ил)фенил]сулфонил]пропанамид, съединение с Формула:
характеризиращ се с това, че включва взаимодействие на [4-(5-метил-3фенилизоксазол-4-ил]бензенсулфонамид с ацилиращ агент в присъствие на база и разтворител.
2. Метод, съгласно претенция 1, характеризиращ се е това, че ацилиращият агент с подбран между анхидриди, киселинни хлориди, ацилимидазоли и активни естери на пропионова киселина.
3. Метод, съгласно претенция I, характеризиращ се с това, че ацилиращият агент е пропионов анхидрид.
4. Метод, съгласно претенция 1, характеризиращ се с това, че разтворителят е теграхидрофуран.
5. Метод за получаване на парекоксиб, Ь1-[[4-(5-метил-3фенилизоксазол-4-ил)фенил]сулфонил]пропанамид, или негова фармацевтично приемлива сол, характеризиращ се с това, че включва получаване на Ь18(М-ацилиран)сулфонамид посредством взаимодействие на [4-(5метил-3-фенилизоксазол-4-ил]бензенсулфонамид с излишък от анхидрид, киселинен хлорид или карбамилхлорид, в присъствие на трегична аминна база и третиране на споменатия Ьщ(№-ацилиран)сулфонамид с около два еквивалента силна база до получаване на солта.
12..
6. Метод, съгласно претенция 5, характеризиращ се с това, че анхидридът или киселинния! хлорид е нропионов анхидрид или пропионилхлорид.
7. Метод, съгласно претенция 5, характеризиращ се с това, че третичната аминна база е триетиламин или Ν,Ν-диметилпиридин.
8. Метод, съгласно претенция 5, характеризиращ се с това, че разтворителят е тетрахидрофуран.
9. Метод, съгласно претенция 5, характеризиращ се с това, че силната база е натриев хидроксид.
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