PT837052E - Derivados amino bicíclicos e antagonistas de pgd 2 contendo esses derivados - Google Patents

Derivados amino bicíclicos e antagonistas de pgd 2 contendo esses derivados Download PDF

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PT837052E
PT837052E PT96918841T PT96918841T PT837052E PT 837052 E PT837052 E PT 837052E PT 96918841 T PT96918841 T PT 96918841T PT 96918841 T PT96918841 T PT 96918841T PT 837052 E PT837052 E PT 837052E
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meoh
alkyl
chcl
compound
hydrogen
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PT96918841T
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Tsunetoshi Honma
Akinori Arimura
Mitsuaki Ohtani
Tatsuo Tsuri
Junji Kishino
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Shionogi & Co
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Description

DESCRIÇÃO "DERIVADOS AMINO BICÍCLICOS E ANTAGONISTAS DE PGD 2 CONTENDO ESSES DERIVADOS"
AREA DA INVENÇÃO A presente invenção refere-se a derivados amino biciclicos e a antagonistas da prostaglandina D2 (doravante, mencionada como PGD2) que contêm esses derivados.
ANTECEDENTES DA INVENÇÃO
Conhece-se alguns derivados amino biciclicos úteis como antagonistas de tromboxano A2 (TXA2) (Publicação de Patente Japonesa N° JP63-139161). No entanto, a Publicação de Patente Japonesa N° JP63-139161 descreve apenas os compostos como sendo úteis como antagonistas de TXA2 e não sugere a sua utilidade como antagonistas de PGD2.
Nomeadamente, sabe-se que o TXA2 possui actividades tais como acção contra a aglutinação de plaquetas, trombogénese, etc. Por conseguinte, os antagonistas de TXA2 têm sido considerados como sendo úteis como antitrombóticos e, também, no tratamento do enfarte do miocárdio ou asma através do antagonismo da TXA2. 0 documento EP-A-608847 descreve sulfonamidas carbo- ciclicas como agonistas ou antagonistas de PGEZ. 0 documento EP-A-312906 descreve derivados de sulfo- namida, os quais podem ser utilizados como antagonistas de txa2. O documento EP-A-0226346 descreve derivados de sulfo- namida biciclica, os quais podem ser utilizados como fármacos antitrombóticos, antivasoconstrictores e antibroncoconstricto-res. 0 documento EP-A-0150709 descreve análogos de pros-taglandinas de tipo 7-oxabiciclo-heptano como agentes cardiovasculares, os quais são úteis no tratamento de doença 1 trombolítica. 0 documento EP-A-0290285 descreve derivados de sulfo-namida bicíclica e a sua utilização no tratamento de doenças tais como angina do peito, enfarte do miocárdio e enfarte cerebral.
Um antagonista do receptor de TXA2, "S-1452", é descrito em Int. Arc. Allergy Immunol. (1992) 98, 239-246, Arimura et al., "Antiasthmatic Activity of a Novel Thromboxane A2 Antagonist, S-1452, in Guinea Pigs" (XP 00 291 6327).
Por outro lado, o antagonista de PGD2 da presente invenção é útil no melhoramento de estados provocados por uma produção excessiva de PGD2. Especificamente, ele é útil como um fármaco para tratar doenças nas guais está envolvida a disfunção de mastócitos, por exemplo, mastocitose sistémica e distúrbio da activação sistémica de mastócitos, e também a contracção da tragueia, asma, rinite alérgica, conjuntivite alérgica, urticária, lesão devido a reperfusão isguémica e inflamação.
Como é evidente do precedente, o antagonista de TXA2 e o antagonista de PGD2 são completamente diferentes um do outro em termos do sitio activo, mecanismo de acção e aplicação, e têm caracteristicas muito diferentes. Consequentemente, nunca se esperou que qualquer composto pudesse possuir estas actividades em simultâneo. A PGD2 é produzida pelas PGG e PGH2 a partir de ácido araquidónico através da acção de ciclooxigenase activada por estimulação imunológica e não imunológica e é o prostanoide principal que é produzido e libertado a partir de mastócitos. A PGD2 possui várias actividades fisiológicas e patológicas potentes. Por exemplo, a PGD2 pode produzir contracção forte da traqueia, a qual provoca a asma brônquica, e, num estado alérgico sistémico, ela pode dilatar os vasos periféricos, o que leva a um choque anafiláctico. Em especial, tem sido prestada muita atenção à ideia que a PGD2 é uma das substâncias responsáveis pelos primeiros sintomas de obstrução nasal na 2 rinite alérgica. Por conseguinte, propôs-se o desenvolvimento de um inibidor da biossintese de PGD2 ou um antagonista do receptor de PGD2 como um fármaco para redução da obstrução nasal. No entanto é provável que o inibidor da biossintese da PGD2 afecte muito a síntese de prostaglandinas noutros organismos sendo, por conseguinte, desejável o desenvolvimento de um antagonista (bloqueador) específico para o receptor de PGD2.
DESCRIÇÃO DA INVENÇÃO
Os actuais requerentes estudaram intensamente para desenvolver antagonistas (bloqueadores) do receptor de PGD2 específicos para o receptor de PGD2, e constataram que os compostos da fórmula (Ib) abaixo ou os seus sais possuem uma actividade potente como antagonistas do receptor de PGD2 e são química e bioquimicamente estáveis.
Em conformidade, a presente invenção proporciona um antagonista de PGD2 o qual compreende um composto da fórmula (Ib) :
m em que é
3
ou em que A é alquileno o qual está opcionalmente interrompido por um heteroátomo ou fenileno, contém um grupo oxo, e/ou tem uma ligação insaturada; B é hidrogénio, alquilo, aralquilo ou acilo; R é COORi, CH2OR2 ou CON(R3)R4;
Ri é hidrogénio ou alquilo; R2 é hidrogénio ou alquilo; R3 e R4 são, cada um, independentemente hidrogénio, alquilo, hidroxilo ou alquilsulfonilo;
Xi é uma ligação simples, fenileno, naftileno, tiofenodiilo, indolediilo ou oxazolediilo; X2 é uma ligação simples, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-0-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C (Cl) =C (Cl)-, - (CH2) n~ r etinileno, -N(R5)-, -N(R5i)CO-, -N(R52)S02-, -n (R53) CON (R54)-CON(R55)- -S02N(R56)-, -o-, -S-, -S0-, -S02-, -C0-, oxadiazolediilo, tiadiazolediilo ou tetrazolediilo; X3 é alquilo, alcenilo, alcinilo, arilo, aralquilo, grupo heterociclico, cicloalquilo, cicloalcenilo, tiazolinilide_ nometilo, tiazolidinilidenometilo, -CH=NR6 ou -N=C(R7)Rs; R5, R5i, R52, R53, R54, R55 e R56 são, cada um, hidrogénio ou alquilo; R6 é hidrogénio, alquilo, hidroxilo, alcoxilo, carbamoiloxilo, tiocarbamoiloxilo, ureido ou tioureido; R7 e R8 são, cada um, independentemente alquilo, alcoxilo ou arilo; e n é 1 ou 2; em que um substituinte cíclico pode ter um até três substituin 4 tes seleccionados do grupo constituído por nitro, alcoxilo, sulfamoilo, amino substituído ou não substituído, acilo, aciloxilo, hidroxilo, halogéneo, alquilo, alcinilo, carboxilo, alcoxicarbonilo, aralcoxi-carbonilo, ariloxicarbonilo, mesiloxilo, ciano, alceniloxilo, hidroxialquilo, trifluorometilo, alquiltio, -N=PPh3, oxo, tioxo, hidroxiimino, alcoxiimino, fenilo e alquilenodioxilo, ou o seu sal ou hidrato deste; com a condição de que estejam excluídos os compostos (a) em que Xi e X2 são uma ligação simples, e X3 é fenilo; (b) em que Xi é uma ligação simples, X2 é -0- e X3 é benzilo; (c) (d) :f)
*NHC0“0-C{CH3}3NHC0~0~CíCH3)3 (e)
Os compostos das fórmulas:
5 (d)
NHC0~0~C(CH3)3 estão excluídos do âmbito da reivindicação 1 deste pedido/patente a título de limitações, as quais foram introduzidas na especificação após apresentação do pedido. Um ou mais destes compostos surgem em cada um dos documentos EP-A-22 634 6, EP-A-290285 e Chem. Pharm. Buli. 37(6), 1524-1533, K. Seno, S. Hagishita, "Thromboxane A2 Receptor Antagonists III, Synthesis and Pharmacologycal Activity of 6,6-Dimethylbicyclo[3.1.1]heptane Derivatives with a Substituted Sulfonylamino Group C-2," XP2058537. Estes compostos foram renunciados como antecipações acidentais, de acordo com as Decisões Gl/03 e G2/03.
Exemplos de compostos mais preferidos incluem os da fórmula (Ib) em que R é COORi (Ri é como definido acima) ou um seu sal ou hidrato.
De modo semelhante, exemplos dos compostos da presente invenção incluem os da fórmula (Ib) em que Xi é um fenileno ou tiofenodiilo, X2 é uma ligação simples, -N-N-, -CH=CH-, etinileno, -0-, -S-, -C0-, -C0N(R55)- (R55 é como definido acima), -N(R5i)C0- (R5i é como definido acima) e X3 é fenilo, ou um seu sal ou hidrato.
Exemplos de formas de realização mais preferidas incluem aquelas em que B é hidrogénio, Xi e X2 são ambos uma ligação simples, X3 é tienilo, tiazolilo, tiadiazolilo, isotiazolilo, pirrolilo, piridilo, benzofurilo, benzimidazolilo, benzotieni- 6 lo, dibenzofurilo, dibenzotienilo, quinolilo ou um seu sal ou hidrato. De modo semelhante, os exemplos incluem aqueles em que Xi é fenileno, tiofenodiilo, indolediilo ou oxazolediilo, X2 é uma ligação simples, -N=N-, etinileno, -S- ou -0-, e X3 é arilo ou um grupo heterocíclico, ou um seu sal ou hidrato.
Os compostos da fórmula geral (Ib) são compostos novos sintetizados pelos actuais requerentes.
Os termos utilizados ao longo da presente especificação são como definidos abaixo. 0 termo "alquileno" significa uma cadeia alquileno C1-C9 linear ou ramificada, por exemplo, metileno, metilmetileno, dimetilmetileno, metiletilmetileno, etileno, trimetileno, tetrametileno, pentametileno, hexametileno, heptametileno, octametileno, nonametileno ou semelhantes. 0 alquileno acima pode estar interrompido por heteroátomo(s) (átomo de oxigénio, enxofre, azoto, ou semelhantes) ou fenileno (e. g., 1.4- fenileno, 1,3-fenileno, 1,2-fenileno ou semelhantes), contêm um grupo oxo, e/ou tem uma ou mais ligações duplas ou triplas em qualquer uma das posições da cadeia. Os exemplos incluem - (CH2) 2-0-CH2-, - (CH2) 2-0-(CH2) 2-, - (CH2) 2-0- (CH2) 3-, -(CH2)2-0-(CH2)4-, -(CH2)2-0-(CH2)5-, -(CH2)2-0-(CH2)6-, -(ch2)2-s-(CH2)2-, - (CH2)3-S- (CH2)2-, -ch2-s-ch2-, -ch2-s- (CH2) 4-, -ch2- N(CH3)-CH2-, -ch2-nh- (CH2)2-, -(CH2)2-N(CH2CH3)-(CH2)3-, - (CH2) 2— 1.4- fenileno-CH2-, - (CH2) 2-0-l, 3-fenileno-CH2-, - (CH2) 2-0-l, 2- fenileno-CH2-, - (CH2) 2-0-l,4-fenileno-CH2-, -CH=CH-S-CH2-1,4-fenileno-CH2-, -CH=CH-S-1,3-fenileno-(CH2) 2-, 2-oxopropileno, 3- oxopentileno, 5-oxo-hexileno, vinileno, 1-propenileno, 2-propenileno, 1-butenileno, 2-butenileno, 3-butenileno, 1.2- butadienileno, 1,3-butadienileno, 1-pentenileno, 2-pente-nileno, 3-pentenileno, 4-pentenileno, 1,2-pentadienileno, 1.3- pentadienileno, 1,4-pentadienileno, 2,3-pentadienileno, 2.4- pentadienileno, 1-hexenileno, 2-hexenileno, 3-hexenileno, 4- hexenileno, 5-hexenileno, 1,2-hexadienileno, 1,3-hexadie-nileno 1,4-hexadienileno, 1,5-hexadienileno, 2,3-hexadienileno 7 2.4- hexadienileno 2,5-hexadienileno, 3,4-hexadienileno, 3.5- hexadienileno, 4,5-hexadienileno, 1,l-dimetil-4-hexeni-leno, 1-heptenileno, 2-heptenileno, 3-heptenileno, 4-hepteni-leno, 5-heptenileno, 2,2-dimetil-5-heptenileno, 6-hepteni-leno, 1,2-heptadienileno, 1,3-heptadienileno, 1,4-heptadieni-leno, 1,5-heptadienileno, 1,6-heptadienileno, 2,3-heptadienileno, 2,4-heptadienileno, 2,5-heptadienileno, 2,6-heptadienileno, 3,4-heptadienileno, 3,5-heptadienileno, 3,6-heptadienileno, 4,5-heptadienileno, 4,6-heptadienileno ou 5,6-hepta-dienileno, 1-propinileno, 3-butinileno, 2-pentinileno, 5-he-xinileno, 6-heptinileno, - (CH2) -CH=CH-0- (CH2) 2-, -CH2-S-(CH2) 3-, —CH2—cis—CH=CH—1,2-fenileno-CH2-, -CH=CH-1,4-fenileno-(CH2) 2-, -4-OXO-4,5-hexenileno- e semelhantes. 0 termo "alquilo" significa cadeia alquilo C1-C20 linear ou ramificado, por exemplo, metilo, etilo, n-propilo, i-propilo, n-butilo, i-butilo, s-butilo, t-butilo, n-pentilo, 1- pentilo, neopentilo, t-pentilo, hexilo, heptilo, octilo, nonilo, decilo, undecilo, dodecilo, tridecilo, tetradecilo, pentadecilo, hexadecilo, heptadecilo, octadecilo, nonadecilo, icosilo e semelhantes. 0 termo "arilo" significa anel monocíclico ou condensado C6-Ci4, por exemplo, fenilo, naftilo (e. g., 1-naftilo, 2- naftilo), antrilo (e. g. , 1-antrilo, 2-antrilo, 9-antrilo), fenantrilo (e. g., 2-fenantrilo, 3-fenantrilo, 9-fenantrilo), fluorenilo (e. g., 2-fluorenilo) e semelhantes. É especialmente preferido o fenilo. 0 termo "aralquilo" significa um grupo obtido substituindo um alquilo como definido acima com um arilo acima em quaisquer posições substituíveis do alquilo. Os exemplos incluem benzilo, fenetilo, fenilpropilo (e. g. , 3-fenil-propilo), naftilmetilo (e. g., α-naftilmetilo), antrilmetilo (e. g., 9-antrilmetilo), fenantrilmetilo (e. g., 3-fenan-trilmetilo) e semelhantes. 0 termo "acilo" significa acilo Cq-Cg resultante de um ácido carboxilico alifático, por exemplo, formilo, acetilo, propionilo, butirilo, valerilo e semelhantes. 0 termo "alquilsulfonilo" significa um grupo obtido substituindo um sulfonilo com um alquilo acima, por exemplo, metilsulfonilo, etilsulfonilo, propilsulfonilo e semelhantes. 0 termo "alcenilo" é uma cadeia alcenilo C2-C2o linear ou ramificada, a qual corresponde a um alquilo acima contendo uma ou mais ligações duplas. Os exemplos incluem vinilo, 1-propenilo, 2-propenilo, 1-butenilo, 2-butenilo, 3-butenilo, 1.2- butadienilo, 1-pentenilo, 1,2-pentadienilo, 2-hexenilo, 1.2- hexadienilo, 3-heptenilo, 1,5-heptadienilo, e semelhantes. 0 termo "alcinilo" é um alcinilo C2-C2o de cadeia linear ou ramificada, o qual corresponde a um alquilo acima contendo uma ou mais ligações triplas. Os exemplos incluem etinilo, 1-propinilo, 2-propinilo, 1-butinilo, 2-butinilo, 3-butinilo e semelhantes. 0 termo "grupo heterocíclico" significa um grupo cíclico de 5-7 membros contendo um ou mais heteroátomos independentemente seleccionados do grupo constituído por um átomo de oxigénio, enxofre e/ou azoto no anel, que está opcionalmente condensado com um anel de carbono ou com outro grupo heterocíclico em quaisquer posições substituíveis. Os exemplos incluem pirrolilo (e. g., 1-pirrolilo, 3-pirrolilo indolilo (e. g. , 2-indolilo, 3-indolilo, 6-indolilo carbazolilo (e. g., 2-carbazolilo, 3-carbazolilo), imidazo-lilo (e. g., 1-imidazolilo, 4-imidazolilo) , pirazolilo (e. g., 1-pirazolilo, 3-pirazolilo), benzimidazolilo (e. g., 2-ben-zimidazolilo, 5-benzimidazolilo), indazolilo (e. g., 3-inda-zolilo) , indolizinilo (e. g., 6-indolizinilo), piridilo (e. g., 2-piridilo, 3-piridilo, 4-piridilo) , quinolilo (e. g., 8-quinolilo), isoquinolilo (e. g., 3-isoquinolilo), acridilo (e. g., 1-acridilo), fenantridinilo (e. g., 2-fenantridinilo, 3-fenantridinilo), piridazinilo (e. g., 3-piridazinilo), piri- 9 midinilo (e. g. , 4-pirimidinilo) , pirazinilo (e. g., 2-pira-zinilo), cinolinilo (e. g., 3-cinolinilo), ftaladinilo (e. g., 5-ftaladinilo), quinazolinilo (e. g., 2-quinazolinilo), isoxazolilo (e. g., 3-isoxazolilo, 4-isoxazolilo), benzisoxa-zolilo (e. g., 1,2-benzisoxazol-4-ilo, 2, l-benzisoxazol-3--ilo), oxazolilo (e. g., 2-oxazolilo, 4-oxazolilo, 5-oxazo-lilo), benzoxazolilo (e. g., 2-benzoxazolilo), benzoxadiazo-lilo (e. g., 4-benzoxadiazolilo), isotiazolilo (e. g. , 3-iso-tiazolilo, 4-isotiazolilo) benzisotiazolilo (e. g., 1,2--benzisotiazol-3-ilo, 2,l-benzisothizol-5-ilo), tiazolilo (e. g., 2-tiazolilo), benzotiazolilo (e. g., 2-benzotia-zolilo), tiadiazolilo (e. g., 1,2,3-tiadiazol-4-ilo), oxadiazolilo (e. g., 1,3,4-oxadiazol-2-ilo), di-hidroxa-diazolilo (e. g., 4,5-di-hidro-l,2,4-oxadiazol-3-ilo) , furilo (e. g., 2-furilo, 3-furilo), benzofurilo (e. g., 3-benzo-furilo), isobenzofurilo (e. g., 1-isobenzofurilo) , tienilo (e. g., 2-tienilo, 3-tienilo), benzotienilo (1-benzotienilo, 2-benzotienilo), tetrazolilo (e. g., 5-tetrazolilo), benzo-dioxolilo (e. g., 1,3-benzodioxol-5-ilo), dibenzofurilo (e. g., 2-dibenzofurilo, 3-dibenzofurilo), dibenzoxepinilo (e. g., dibenz[b,f]oxepin-2-ilo), di-hidrodibenzoxepinilo (e. g., di-hidrobenz[b,f]oxepin-2-ilo), cromenilo (e. g., 2H-cromen-3-ilo, 4H-cromen-2-ilo), dibenzotiepinilo (e. g., dibenzo[b,f]tiepin-3-ilo, di-hidrobenzo[b,f]tiepin-3-ilo), morfolinilo (e. g., 1,4-morfolin-4-ilo), fenotiadinilo (2-fenotiadinilo), ciclopentatienilo (e. g., ciclopenta-[b]tiofen-3-ilo), ciclo-hexatienilo (e. g., ciclo-hexa[b]tio-fen-3-ilo), ciclo-heptatienilo (e. g., ciclo-hepta[b]tiofen-3--ilo), dibenzotienilo (e. g., 2-dibentienilo) , dibenzopiranilo (e. g., 2-dibenzopiranilo), dibenzo-p-dioxilo (e. g., 2-di-benzo-p-dioxilo) e semelhantes. 0 termo "cicloalquilo" significa alquilo ciclico C3-C8, por exemplo, ciclopropilo, ciclobutilo, ciclopentilo, ciclo-hexilo e semelhantes. 10 0 termo "cicloalcenilo" significa alcenilo cíclico C3-C8, por exemplo, ciclopropenilo (e. g., 1-ciclopropenilo), ciclobutenilo (e. g., 2-ciclobuten-l-ilo), ciclopentenilo (1-ciclopenten-l-ilo), ciclo-hexenilo (1-ciclo-hexen-l-ilo) e semelhantes. 0 termo "alcoxilo" significa alcoxilo Ci-C6, por exemplo, metoxilo, etoxilo, n-propoxilo, i-propoxilo, n-butoxilo e semelhantes.
Exemplos de amino substituído na definição de "amino substituído ou não substituído" incluem aminos mono- ou dissubstituídos, tais como metilamino, etilamino, dimetilamino, ciclo-hexilamino, fenilamino, difenilamino ou amino cíclico tal como piperidino, piperadino ou morfolino. 0 termo "aciloxilo" significa um aciloxilo derivado do "acilo" acima, por exemplo, acetiloxilo, propioniloxilo, butiriloxilo, valeriloxilo e semelhantes. 0 termo "halogéneo" significa flúor, cloro, bromo e iodo. 0 termo "alcoxicarbonilo" significa um grupo alcoxi-carbonilo derivado do "alcoxilo" acima, por exemplo, metoxicarbonilo, etoxicarbonilo, feniloxicarbonilo e semelhantes . 0 termo "aralquiloxicarbonilo" significa um grupo aralquiloxicarbonilo derivado do "aralquilo" acima, por exemplo, benziloxicarbonilo, fenetiloxicarbonilo e semelhantes . 0 termo "ariloxicarbonilo" significa um grupo ariloxicarbonilo derivado do "arilo" acima, por exemplo, feniloxicarbonilo, naftiloxicarbonilo e semelhantes. 0 termo "alceniloxilo" significa um grupo alceniloxilo derivado do "alcenilo" acima, por exemplo, viniloxilo, 1-propeniloxilo, 2-buteniloxilo e semelhantes. 0 termo "hidroxialquilo" significa um grupo hidroxialquilo derivado do "alquilo" acima, por exemplo, hidroximetilo, hidroxietilo, hidroxipropilo e semelhantes. 11 0 termo "alquiltio" significa um grupo alquiltio derivado do "alquilo" acima, por exemplo, metiltio, etiltio, propiltio e semelhantes. 0 termo "alquilenodioxilo" significa alquilenodioxilo C1-C3, por exemplo, metilenodioxilo, etilenodioxilo, propile-nodioxilo e semelhantes.
No caso de "fenileno, "naftileno", "tiofenodiilo", "indolediilo", "oxazolediilo", "oxadiazolediilo" e tetra-zolediilo", o grupo referido pode ligar-se aos grupos vizinhos em quaisquer duas posições substituíveis.
Nas definições acima, quando um substituinte (s) é cíclico, ele pode estar substituído com um até três substituintes seleccionados de nitro, alcoxilo, sulfamoilo, amino substituído ou não substituído, acilo, aciloxilo, hidroxilo, halogéneo, alquilo, alcinilo, carboxilo, alcoxi-carbonilo, aralcoxicarbonilo, ariloxicarbonilo, mesiloxilo, ciano, alceniloxilo, hidroxialquilo, trifluorometilo, alquiltio, -N=PPh3, oxo, tioxo, hidroxiimino, alcoxiimino, fenilo e alquilenodioxilo. 0(s) substituinte(s) podem estar ligados em quaisquer posições substituíveis no anel.
Os exemplos de sais do composto (Ib) incluem os preparados com um metal alcalino (e. g., lítio, sódio ou potássio), um metal alcalino-terroso (e. g. , cálcio), uma base orgânica (e. g., trometamina, trimetilamina, trietilamina, 2-aminobutano, t-butilamina, diisopropiletilamina, n-butil-metilamina, ciclo-hexilamina, diciclo-hexilamina, N-isopro-pilciclo-hexilamina, furfurilamina, benzilamina, metil-benzilamina, dibenzilamina, N,N-dimetilbenzilamina, 2-cloro-benzilamina, 4-metoxibenzilamina, 1-naftilenometilamina, dife-nilbenzilamina, trifenilamina, 1-naftilamina, 1-aminoantrace-no, 2-aminoantraceno, desidroabietilamina, N-metilmorfolina ou piridina), um aminoácido (e. g., lisina ou arginina) e semelhantes. 12 0 termo "hidrato" significa um hidrato do composto da fórmula (Ib) ou um seu sal. Os exemplos incluem mono- e di-hidratos.
Os compostos da presente invenção são representados pela fórmula (Ib) e são inclusive da forma de quaisquer tipos de compostos estereoisoméricos (e. g., diastereómeros, epimeros, enantiómeros) e racémicos.
Os compostos da fórmula geral (Ib) podem ser preparados fazendo reagir um composto amino da fórmula geral (II) com um derivado reactivo de ácido sulfónico ou ácido carboxilico que corresponda à estrutura parcial: Z-X1-X2-X3 como se mostra a seguir.
em que A, B, R, Xi, X2, X3, Y são como definidos acima e Z é -C0-. Um ácido carboxilico que corresponde à referida estrutura parcial é um composto da fórmula geral X3-X2-Xi-COOH . Derivado reactivo destes ácidos carboxilicos significa um halogeneto correspondente (e. g., cloreto, brometo, iodeto), anidrido ácido (e. g., anidrido ácido misto com ácido fórmico ou ácido acético), éster activo (e. g., éster de succinimida), e os exemplos destes incluem geralmente agentes de acilação para a acilação do grupo amino. 0 ácido carboxilico X3-X2-Xi--COOH pode ser utilizado na reacção tal qual sem se converter num derivado reactivo, na presença de um agente de condensação (e. g., diciclo-hexilcarbodiimida (DCC), l-etil-3-(3-dimetila-minopropil)carbodiimida, N,Ν'-carbonildiimidazole) os quais 13 são utilizados na reacção de condensação entre aminas e ácidos carboxilicos. A reacção pode ser realizada nas condições geralmente utilizadas para a acilação do grupo amino. Por exemplo, no caso da condensação utilizando um halogeneto ácido, a reacção é realizada utilizando um solvente, tal como um solvente de tipo éter (e. g., éter dietílico, tetra-hidrofurano, dioxano) , solvente do tipo benzeno (e. g., benzeno, tolueno, xileno), solvente de tipo hidrocarboneto halogenado (e. g., diclorometano, dicloroetano, clorofórmio), acetato de etilo, dimetilformamida, sulfóxido de dimetilo, acetonitrilo ou semelhantes, se necessário, na presença de uma base (e. g., base orgânica, tal como trietilamina, piridina, N,N-dimetilaminopiridina, N-metilmorfolina; base inorgânica, tal como hidróxido de sódio, hidróxido de potássio, carbonato de potássio ou semelhantes) sob arrefecimento, à temperatura ambiente ou sob aquecimento, de um modo preferido a uma temperatura que varia desde -20 °C até uma temperatura sob arrefecimento, ou desde a temperatura ambiente até à temperatura de refluxo do sistema reaccional, durante vários minutos até várias h, de um modo preferido durante 0,5 h até 24 h, de um modo mais preferido, durante 1 h até 12 h.
As condições reaccionais para a reacção entre outro derivado reactivo ou um ácido livre e uma amina (II) podem ser determinadas de um modo convencional dependendo das caracteristicas do respectivo derivado reactivo ou ácido livre. O produto reaccional pode ser purificado por métodos de purificação convencionais, por exemplo, a extracção com um solvente, cromatografia, recristalização ou semelhantes.
Os exemplos específicos do composto (II) como um material de partida para o presente método são como se segue. Os exemplos do composto 3-amino[2.2.1]bicíclico incluem o ácido 7-(3-aminobiciclo[2.2.1]hept-2-il)-5-heptenóico, ácido 14 7-(3-aminobiciclo[2.2.1]hept-2-il)-2, 2-dimetil-5-heptenóico, ácido 7-(N-metil-3-aminobiciclo[2.2.1]hept-2-il)-5-heptenóico, ácido 6-(3-aminobiciclo[2.2.1]hept-2-il)-5-hexenóico. Os exemplos específicos do composto 2-amino-6, 6-dimetil [3.1.1] bicícli_ co incluem o ácido 7-(2-amino-6,6-dimetilbiciclo[3.1.1]hept-3--il)-5-heptenóico. Nestes compostos de partida, a cadeia de ácido heptenóico pode estar saturada para formar uma cadeia de ácido heptanóico interrompida por um heteroátomo (s) ou um heterogrupo (s) tal como -0-, -S-, -NH-, ou um fenileno(s), ou substituída com um grupo oxo. Os exemplos de tais compostos incluem o ácido 7-(3-aminobiciclo[2.2.1]hept-2-il)heptanóico, ácido 4 —[2 —(2-aminobiciclo[3.1.1]hept-3-il)etoxifenilacético, ácido 7-(3-aminobiciclo[2.2.1]hept-2-il)-6-oxo-heptanóico.
Estes compostos de partida são descritos na Publicação de Patente Japonesa N° JP 63-139161 ou JP 01-52751, ou podem ser preparados segundo o método ali descrito. 0 ácido carboxílico X3-X2-X1-COOH que corresponde à estrutura parcial Z-X1-X2-X3 significa um ácido carboxílico com substituintes que correspondem aos X acima. Isto é, os exemplos incluem o ácido alcano-carboxílico, ácido alceno-carboxílico, ácido alcino-carboxílico, ácido cicloalcano- carboxílico, ácido cicloalceno-carboxílico, ácido aril-carboxílico, ácido aralquiloxi-carboxílico, ácido carboxílico substituído com heterociclo, ácido heteroarilalquil-carboxílico e ácido amino-carboxílico substituído. Cada um dos ácidos carboxílicos pode ter um substituinte(s) anterior. Estes ácidos carboxílicos estão comercialmente disponíveis ou podem ser facilmente sintetizados a partir de composto(s) conhecido(s) segundo um método conhecido. Na reacção, o ácido carboxílico pode ser convertido no derivado reactivo correspondente acima, se necessário. Por exemplo, quando é necessário um halogeneto ácido, o composto é feito reagir com halogeneto de tionilo (e. g., cloreto de tionilo), halogeneto de fósforo (e. g., tricloreto de fósforo, pentacloreto de 15 fósforo) ou halogeneto de oxalilo (e. g., cloreto de oxalilo) segundo um método conhecido como os descritos na literatura (e. g.r Shin-Jikken-Kagaku-Koza, vol. 14, pág. 1787 (1978);
Synthesis, 852-854 (1986); Shin-Jikken-Kagaku-Koza, vol. 22, pág. 115 (1992)). Os outros derivados reactivos também podem ser preparados segundo métodos conhecidos.
Entre os compostos (Ib) alvo, agueles em gue a cadeia lateral A contém uma ligação insaturada, em especial uma ligação dupla, também podem ser preparados fazendo reagir um derivado aldeído da fórmula geral (III) abaixo com um composto ileto que corresponde ao remanescente da cadeia lateral A-R nas condições da reacção de Wittig:
em que A, B, R, Xi, X2, X3, Y são como definido acima e Z é -C0-. 0 composto de partida (III) pode ser preparado segundo um método descrito, por exemplo, na Publicação de Patente Japonesa N° JP 02-256650. Além disso, um composto ileto que corresponde ao remanescente da cadeia A-R pode ser sintetizado fazendo reagir trifenilfosfina com um ácido alcanóico halogenado correspondente, ou um derivado éster, derivado éter ou derivado amida na presença de uma base segundo um método conhecido.
Entre os compostos (Ib) alvo, aqueles em que R é COOH podem ser convertidos num derivado éster, derivado álcool, derivado éter, derivado amida correspondente, se desejado. Por 16 exemplo, os derivados éster podem ser preparados esterifiçando um ácido carboxílico de um modo convencional. Um derivado éster, quando reduzido, dá um derivado álcool e um amidado dá um derivado de amida. Um derivado éter pode ser obtido por O-alquilação de um derivado álcool. 0 composto (Ib) da presente invenção exibe um efeito antaqonista contra a PGD2 in vitro através da ligação ao receptor PGD2, e é útil como um fármaco para tratar doenças nas quais está envolvida a disfunção de mastócitos devido à produção excessiva de PGD2. Por exemplo, o composto (Ib) é útil como um fármaco para tratar doenças, tais como a mastocitose sistémica e um distúrbio da activação sistémica de mastócitos, e também a contracção da traqueia, asma, rinite alérgica, conjuntivite alérgica, urticária, lesão devido a reperfusão isquémica e inflamação. 0 composto (Ib) apresenta um efeito preventivo na obstrução nasal in vivo e, por conseguinte, é especialmente útil como um fármaco para a tratar.
Quando se utiliza um composto (Ib) da presente invenção em tratamento, ele pode ser formulado em formulações correntes para administração oral e parentérica. Uma composição farmacêutica contendo um composto (Ib) da presente invenção pode estar numa forma para administração oral e parentérica. Especificamente, ele pode ser formulado em formulações para administração oral tais como comprimidos, cápsulas, granulados, pós, xarope e semelhantes; nas para administração parentérica, tal como solução ou suspensão injectável para injecção intravenosa, intramuscular ou subcutânea, inalador, gotas oftálmicas, gotas nasais, supositórios ou formulações percutâneas, tal como pomadas.
Ao preparar as formulações pode utilizar-se veículos, excipientes, solventes e bases conhecidas do técnico médio na matéria. No caso de comprimidos, eles são preparados prensando ou formulando um ingrediente activo em conjunto com 17 componentes auxiliares. Exemplos de componentes auxiliares utilizáveis incluem excipientes farmaceuticamente aceitáveis, tais como aglutinantes (e. g., amido de milho), enchimentos (e. g., lactose, celulose microcristalina) , desintegrantes (e. g., amido glicolato de sódio) ou lubrificantes (e. g., estearato de magnésio). Os comprimidos podem ser apropriadamente revestidos. No caso de formulações liquidas, tais como xaropes, soluções ou suspensões, elas podem conter agentes de suspensão (e. g., metilcelulose), emulsionantes (e. g., lecitina), conservantes e semelhantes. No caso de formulações injectáveis, elas podem estar na forma de soluções ou suspensões, ou emulsões oleosas ou aquosas, as quais podem conter agentes de estabilização de suspensão ou dispersantes, e semelhantes. No caso de um inalador, ele é formulado numa formulação liquida aplicável num inalador. No caso de gotas oftálmicas, ela é formulada numa solução ou numa suspensão. Especialmente, no caso de um fármaco nasal para tratar a obstrução nasal, ele pode ser utilizado como uma solução ou suspensão preparada por um método de formulação convencional, ou formulado como um pó utilizando um agente em pó (e. g., hidroxipropilcelulose, carbopole) , os quais são administrados na cavidade. Alternativamente, ele pode ser utilizado como um aerossol depois de embalar num recipiente especial com um solvente de baixo ponto de ebulição.
Embora a dosagem apropriada do composto (Ib) varie em função da via de administração, idade, peso corporal, género ou estado do doente, e do tipo de fármaco (s) utilizados em conjunto, se algum, e deva ser determinada, em última análise, pelo médico, no caso da administração oral, a dosagem diária pode estar geralmente entre cerca de 0,01-100 mg, de um modo preferido cerca de 0,01-10 mg, de um modo mais preferido cerca de 0,1-10 mg, por kg de peso corporal. No caso de administração parentérica, a dosagem diária pode estar geralmente entre cerca de 0,001-100 mg, de um modo preferido cerca de 0,001-1 mg, de um modo mais preferido cerca de 0,01-1 18 mg, por kg de peso corporal. A dosagem diária pode ser administrada em 1-4 divisões.
Os Exemplos seguintes são proporcionados para ilustrar adicionalmente a presente invenção e não são para ser interpretados como limitando o âmbito desta.
Exemplo 1
(Π-2)
(lk-11) (lk-12)
Dissolveu-se trifluoroacetato de (Z)-7-[(IS,2R,3R,4R)-3-aminobiciclo[2.2.1]hept-2-il]-5-heptenoato de metilo (II-2) (232 mg, 0,636 mmol), o qual foi preparado pelo método descrito no Exemplo de Referência 4 da Publicação de Patente Japonesa N° JP 63-139161, em cloreto de metileno (5 ml). À solução adicionou-se trietilamina (0,279 mL, 2,00 mmol) e cloreto de 4-bifenilcarbonilo sob arrefecimento em gelo e agitou-se durante 7 h à mesma temperatura. Purificou-se a mistura reaccional por cromatografia em coluna sobre sílica gel (acetato de etilo/n-hexano (1:4)) para produzir (Z)-7--[(IS,2R,3R,4R)-3-(4-bifenil)carbonilaminobiciclo[2.2.1]hept--2-il]-5-heptenoato de metilo (lk-11) (221 mg, 0,512 mmol).
Dissolveu-se o composto (lk-11) (190 mg, 0,440 mmol) em metanol (6 mL). À solução adicionou-se KOH 1 N (1,10 mL, 1,10 mmol) sob arrefecimento em gelo e agitou-se durante 15 h à temperatura ambiente. Concentrou-se a mistura reaccional in vacuo. Extraiu-se o resíduo, após a adição de água (20 mL) e HC1 1 N (2 mL) , com acetato de etilo. Lavou-se a camada orgânjL 19 ca com solução aquosa saturada de cloreto de sódio, secou-se sobre sulfato de sódio anidro e concentrou-se. Purificou-se o resíduo por cromatografia em coluna sobre sílica gel (acetato de etilo/hexano (1:1) contendo 0,3% de ácido acético) para produzir ácido (Z)-7-[(IS,2R,3R,4R)-3-(4-bifenil)carbonilami-nobiciclo[2.2.1]hept-2-il]-5-heptenóico (lk-12) (172 mg, 0,412 mmol). Rendimento 94%.
Os compostos seguintes também podem ser preparados do mesmo modo.
Os compostos preparados de acordo com o método descrito no Exemplo anterior são mostrados nos Quadros abaixo.
Quadro lk
N° Ri X!-X2-X3 lk-1 H lk-2 ch3 lk-3 H lk-4 H -*=—o~o lk-5 H —O 20 (continuação)
N° Ri X1-X2-X3 lk-6 H -O lk-7 H '™0“ohQ lk-8 H —Oo-O-OH lk-9 H lk-10 H -hQ-ohQ^och, lk-11 ch3 lk-12 H ^0“0 lk-13 H —Ok"^n”jO~oc^ lk-14 H 0 li lk-15 H lk-16 H lk-17 H “^Ol lk-18 H -OnrO lk-19 H OCHj lk-20 H -Q-s-Q 21
Quadro lm H N° Ri X1-X2-X3 lm-1 C"3 lm-2 \..t / w/ lm-3 CH3 /2=\ /^\ — lm-4 Vww/ VvrtV' lm-5 0 H 3 /yt y222\ *“\ )~*&**~ί } lm-6 ^ W \.....J lm-7 CH3 -O-.-O lm-8 lm-9 CH3 -0-0-0«. lm-10 lm-11 CH3 rzz\ /=\ lm-12 H w w lm-13 -O"°“0"oc^ lm-14 Vl.l. ..«»* \p..rf lm-15 ch3 /^K /^x --4. rt~QAc lm-16 T_T * - - t** ri lm-17 CH3 /i=\ —Λ—OH lm-18 \...>y v..,y lm-19 lm-2 0 ^ vv v-^y lm-21 H - 22 (continuação) N° Ri X1-X2-X3 lm-22 H —-OO lm-23 Bí ”7 *...... -Ο lm-24 H v~y lm-25 CH3 —V —O Ac lm-2 6 j~ j lm-27 ch3 ““W Λ~οη lm-2 8 H ^ lm-2 9 ch3 —d /V-OCHa lm-30 V..»/ lm-31 -0“='η"0 lm-32 H /=\ ?t ΓΛ “^JKC-N_O lm-33 H -Q£> lm-34 H CH3O. - /“Λ lm-35 H ÇHaOv — lm-3 6 H /=\ /=®\ —^ /)—N~N—4 /r-OCHj lm-37 H CHjO lm-38 H 0 ,OCHa /“=\ li /=< ~Λ_^°1Γ\_^ΟΟΗϊ OCHj 23 (continuação) N° Ri Xi-X2-X3 lm-3 9 H o -14 X» }~°CH3 OCHg lm-40 H O OCHa V-OCHa \wkhW ^ OCHa Quadro 2a 's*^vNHCOX1-Xj-X3 N° Ri X1-X2-X3 2a-l 2a-2 ch3 H -0-0 2a-3 ch3 2a-4 H -hQ^n^Q 2a-5 Na 2a-6 ch3 Γ\ 2a-7 H 2a-8 2a-9 ch3 H /»*% —V Λ'-'ΟΗΟ 2a-l 0 2a-l 1 ch3 H "0~V*nh w 24 (continuação) N° Ri X1-X2-X3 2a-12 2a-13 ch3 H -Ογ. s*~£ $ 2a-14 ch3 2a-15 H 2a-l 6 ch3 ~\J~\ 2a-17 H 0 2a-l 8 ch3 0 2a-l 9 H XrhO 2a-2 0 ch3 2a-21 H "Ό 2a-22 Na 2a-23 ch3 0 2a-24 H rsssv j| jrassv 2a-25 2a-2 6 ch3 H -«*-0-0 2a-27 2a-2 8 ch3 H -0°-£> 2a-2 9 ch3 2a-30 H 2a-31 ch3 ”0-Vn-^Q> 2a-32 2a-33 ch3 H ~~Ç)~^-uOí 2a-34 2a-35 ch3 H -Q.....^.....0 25 N° Ri 2a-36 ch3 2a-37 H 2a-38 ch3 NO 1 00 H 2a-4 0 ch3 2a-41 H 2a-42 ch3 2a-43 H 2a-44 ch3 2a-45 H 2a-4 6 ch3 2a-47 H 2a-4 8 ch3 2a-49 H 2a-50 ch3 2a-51 H 2a-52 ch3 2a-53 H 2a-54 ch3 2a-55 H 2a-56 ch3 2a-57 H 2a-58 ch3 2a-59 H 2a-60 ch3 (continuação) X1-X2-X3
(continuação)
N° Ri X1-X2-X3 2a-64 2a-65 ch3 H /-V O O-' 2a-66 2a-67 ch3 H 2a-68 ch3 «sv 2a-69 H O 2a-7 0 2a-71 ch3 H —C ^—OAc 2a-72 2a-73 ch3 H -OO-on 2a-74 2a-7 5 ch3 H -O-ohQ-cch, 2a-7 6 2a-77 ch3 H -^ --OAC 2a-7 8 2a-7 9 ch3 H -00» 2a-80 ch3 2a-81 H 2a-82 2a-83 ch3 H ~0“oac 2a-84 2a-85 ch3 H 2a-86 2a-87 ch3 H ~^O~0CH5 2a-88 2a-89 ch3 H "ÇO 0 2a-90 ch3 -Q 2a-91 H 27 (continuação) N° Ri X1-X2-X3 2a-92 ch3 -O 2a-93 H s 2a-94 ch3 1 cn H ~ir\ 2a-96 Na 2a-97 Ca1/2 2a-98 2a-99 ch3 H -0-0 2a-l0 0 ch3 2a-l01 H 2a-l02 ch3 Q-ch, 2a-103 H 0 J 2a-104 ch3 ~~^Ç^~-och3 2a-105 H 0CH3 2a-l0 6 ch3 H .p 2a-107 H r=\ N _/ \_) T 2a-l0 8 ch3 2a-l0 9 H -0-0 2a-l10 Na 2a-l11 2a-l12 ch3 H 2a-113 2a-114 ch3 H -0-3 2a-115 2a-l16 ch3 H —Och> 2a-117 2a-l18 ch3 H 2a-l19 H -Ç> OAc 28 (continuação) N° Ri X1-X2-X3 2a-12 0 H OH 2a-121 H -p 2a-122 H O 2a-123 H 1 0 Ò 2a-124 H -ch=-Ç) OH 2a-125 H 2a-126 H —^ ^—8# 2a-127 H — W Η r 2a-12 8 H irO 2a-12 9 H ΌΟ 2a-130 H ~J~\ O 2a-131 H ~Ç} b 2a-132 H 2a-133 H HÕ 29 (continuação)
N° Ri X1-X2-X3 2a-134 H "chjohQ 2a-135 H xo 2a-136 H 2a-137 H ^*—OCgHg : 2a-138 H —°CH(CHj)2 2a-139 H H 2a-140 H XO H 2a-141 H 2a-142 H O HjCO 2a-143 H HO^O 2a-144 H hyo 2a-145 H o-to 2a-14 6 H /=\ 9 /=\ 2a-147 H 30 (continuação)
N° Ri X1-X2-X3 2a-148 H 2a-14 9 H -=-0 2a-150 H 2a-151 H v 2a-152 H 2a-153 H 2a-154 H -Q-e* ............s.................. 2a-155 H -ço 2a-156 H ~0$ H 2a-157 H Τ'- «Λ" 2a-158 H V· 2a-159 H o-< 2a-l60 H -9 HOOC 2a-l61 H *V>-<n s 2a-l62 H /«SN ΛΓ— NOj 2a-l63 H “O 31 (continuação)
N° Ri X1-X2-X3 2a-l64 H 2a-l65 H 2a-l6 6 H Ό·°Όλ 2a-l67 H 2a-l68 H 2a-l6 9 H ^Q-s-Q-ocn, 2a-170 H -Γ0 S 2a-171 H H Rs^CHi 2a-172 H 2a-173 H V~* 2a-174 H V/8r Q 2a-175 H 2a-17 6 H w* 2a-177 H Q \,OCH, Q 32 (continuação) N° Ri
2a-178 H
2a-17 9 H
2a-l8 0 H
2a-l81 H
2 a—18 2 H
2a-183 H
2a-184 H
2a-185 H
2a-186 H
2a-187 H
2 a—18 8 H
2a-189 H
2a-l90 H X1-X2-X3
33 (continuação) N° Ri
2a-l91 H
2a-l92 H
2a-l93 H
2a-l94 H
2a-195 H
2a-196 H
2a-l97 H
2a-l98 H
2a-l99 H
2a-2 0 0 H
2 a-201 H
2a-2 02 H X1-X2-X3
34 (continuação) N° Ri X1-X2- 2a-203 H V 2a-204 2a-205 2a-2 0 6 Ya 2a-207 2a-2 0 8 2a-2 0 9 2a-210 2a-211 Vkx”1· S CHs 2a-212 S^VcHj 2a-213 W 2a-214 Vv 2a-215 2a-216 ^0 35 (continuação) N° Ri 2a-217 2a-218 2a-219 2a-22 0 2a-221 2a-222 2a-223 2a-224 2a-225 2a-22 6 2a-227 2a-22 8 X1-X2-X3
36 N°
Ri 2a-22 9 2a-230 2a-231 2a-232 2a-233 2a-234 2a-235 2a-236 2a-237 2a-238 2a-239 (continuação) X1-X2-X3 PHs
ξ CHa CHo
H,Cq
. //
HgCO
% /“S“^ // H$c
H3CO
OCHj
37 (continuação) N° Ri X1-X2-X3 2a-240 h3c ~-0"s"0 HjCO 2a-241 CH, ~~ÇjhOCHi 2a-242 .CH3 OCWj 2a-243 CHj HjCO 2a-244 OCR, h^c 2a-245 ochj ~C^sHQ 0½ 2a-24 6 OCHj ”C^s™0~cH5 2a-247 OCHj HjCO 2a-248 PCHs 0CH3 2a-24 9 OCHj —çy*o** 2a-250
HOHjC 38 N°
Ri (continuação) X1-X2-X3 2a-251 2a-252 2a-253 2a-254 2a-255 2a-256 2a-257 2a-258 2a-259 2a-2 60
39 (continuação) N°
Ri X1-X2-X3 2a-2 61 2a-2 62 2a-2 63 2a-2 64 2a-2 65 2a-2 6 6 2a-2 67 2a-2 68 2a-2 6 9 2a-270 2a-271 2a-272 2a-273
40 (continuação) N° Ri X1-X2-X3 2a-274 2a-275 2a-27 6 2a-277 Χ<£β 2a-278 xço CM» 2a-27 9 XXJO CjHs 2a-2 8 0 Ό0ΟΙ coch, j 2a-2 81 XOO H 2a-2 82 £CQ CH» 2a-283 XCO CaM5 2a-284 £¢0 COCH3 (continuação) N° Ri X1-X2-X3 2a-2 8 6 ttp M 2a-287 tro N CH3 2a-2 8 8 Xjcfl 2a-2 8 9 XjcD COCHj 2a-2 90 Xkf) H 2a-2 91 -CçP CHj 2a-2 92 -Qp 2a-2 93 XjcQ N COCH^ 2a-2 94 2a-2 95 i-m\ Ο λ»ϊ\ CHj 2a-2 96 .OCH3 OCHj 2a-2 97 -0^0-* 2a-2 98 —O~£'h"O"0chí 42 (continuação)
N° Ri X1-X2-X3 2a-2 99 HaCO OCHj CJCB, 2a-300 /=\ 9 /=\ PH» 2a-301 -OVp HjC 2a-302 2a-303 -0^0 X^wnl Vm*/ 2a-304 0 —ΐ—OCHj OCHj 2a-305 Ο 2a-306 *^C^H ^”~C^”0CH3 2a-307 H5CO OCHj h=\ 9 /=^ —\> >T~ocH3 OCHj 2a-308 /=\ 9 /=\ .CR, 2a-309 /=\ 9 /==\ -Oii·0·)./ HgC 2a-310 O ~^O^h"0 w“0“OC^ OCHj 2a-311 ~0~:fê'!r£D h3c 43 (continuação) N° Ri X1-X2-X3 2a-312 -Q-Jj-C-JHQ-OH 2a-313 -O-r-tQ-»1* 2a-314 /=\ 9 /=\ PH. 2a-315 HgCO OCHj ™V^h"^"h \_^~0CM3 0CN9 Quadro 2b ts^A*N-COXl-Xz-X3 CHj N° Ri X1-X2-X3 2b-l H 0 2b-2 H ~ΤΛ $ 44
Quadro 2c
N° Ri X1-X2-X3 2c-l H -O 2c-2 H -O 2c-3 H
Quadro 2d N° 2d-l 2d-2
Ri X1-X2-X3
H
H
Quadro 2e
N° Ri X1-X2-X3 2e-l H -o°-o 2e-2 H “O 2e-3 H T) s Quadro 2f 0^°'O-/COOR' ^Α'ΝΗΟΟ·Χ,·Χ3.Χ3 N° Ri X1-X2-X3 2f-l H -o-^-o 2 f-2 H r\ "\J 2f-3 H ~Q 46
Quadro 2g N° 2g-l
R3 X1-X2-X3
H SO2CH3
Quadro 2h
N° X!-X2-X3
2h-l 'O 2h-2 2h-3 2h-4 -OsO 2h-5 2h-6 “O3 O 47
Quadro 2i
N° X1-X2-X3 2i-l 2 i-2 S V=H, 2i-3 s 2i-4 2i-5 /==\ /=\ 2i-6 “O^ 48
Quadro 2j
N° X1-X2-X3 2 j-1 'h 2 j-2 S 2 j — 3 2 j -4 -0-0 2 j — 5 -OoO 2 j-6 0 49 N° 2k-l 2k-2 2k-3
Quadro 2k
X1-X2-X3
50 (continuação) N° X1-X2-X3 2k-4 ~0"s_0 2k-5 2k-6
As propriedades físico-químicas dos compostos anteriores são indicados abaixo. 0 número do composto abaixo corresponde ao descrito no Quadros acima. N° lk-1 [a] D= -25,4° (CHC13, c=l, 0 8, 23 °C) . N° lk-2 CDCI3 200 MHz 1,07-2,28 (14H, m) , 2,32(2H, t, J=7,4 Hz), 2,63(1H, m) , 3,63(3H, s), 3, 93(1H, m) , 5, 30-5, 52 (2H, m) , 6,35(1H, d, J=7,0
Hz), 7,48-7, 60 (3H, m) , 7, 88-8,02 (6H, m) . IV (CHCI3) : 3438, 3002, 2946, 2868, 1727, 1652, 1514, 1485, 1363, 1310, 1245, 1154/cm.
[a] D= -80,4° (CHCI3, c=l, 01, 24,0 °C) . N° lk-3 CDCI3 200 MHz 1, 10-2,26 (14H, m) , 2,37(2H, t, J=7,2 Hz), 2,60(1H, m) , 3, 93(1H, m) , 5, 30-5,50(2H, m) , 6,33(1H, d, J=7,5 Hz), 7,48- 7,58(3H, m), 7,88-7,99(6H, m). 51 IV (CHCla) : 3446, 3004, 2952, 2874, 1709, 1652, 1515, 1485, 1305, 1153/cm.
[α] D= -96,4° (CHC13, c=l, 05, 23, 0 °C) . N° lk-4 CDCI3 300 MHz; 1,05-2, 17 (14H, m) , 2,38(2H, t, J=7,2 Hz), 2,52 (1H, m) , 3,81(1H, m) , 5,33-5,50 (2H, m) , 6,08(1H, d, J=7, 6
Hz), 7,39-7,53 (3H, m), 7,57-7, 62 ( 6H, m) . IV (CHCI3) : 3420, 3250, 3008, 2948, 2870, 2660, 2208, 1735(sh), 1705, 1640, 1500/cm.
[a] D= -21,9±0,6° (CHCI3, c=l, 02, 22 °C) . N° lk-5 CDCI3 300 MHz; 1,05-2,14(14H, m), 2,38(2H, t, J=7,2 Hz), 2,51(1H, m) , 3, 81(1H, m) , 5, 34-5, 46 (2H, m) , 6,07(1H, d, J=7,6
Hz), 7,33-7,56(5H, m) . IV (CHCI3) : 3422, 3250, 3010, 2950, 2876, 2664, 2558, 2210, 1735 (sh), 1705, 1645, 1502, 1441, 1410, 1307, 1276/cm.
[a] D= -63,6+1,9° (CHC13, c=0,56, 22 °C) . N° lk-6 CDCI3 300 MHz 1, 04-2,24 (14H, m), 2,36(2H, t, J=7,5 Hz) , 2,58 (1H, m) 3,8 8(1H, m) , 5,30-5,43 (2H, m) , 6,21 (1H, d, J=7,2 Hz) 7,41-7,49 (3H, m) , 7,73-7,77 (2H, m) . IV (CHCI3): 3447, 3011, 2955, 1708, 1653, 1603, 1578 1515, 1486, 1457, 1312, 1211, 1164/cm.
[a] D= -60,3° (CHCI3, c=l, 0 0, 23 °C) . 52 N° lk-7 CDCI3 300 ΜΗζ 1, 04-2,22(14Η, m) , 2,36(2Η, t, J=7,2 Hz), 2,57(1H, m) , 3,87(1H, m) , 5,30-5,44(2H, m) , 6,17(1H, d, J=8,7 Hz), 6,99-7,40(7H, m), 7,73(2H, d, J=7,5 Hz). IV (CHCI3): 3449, 3013, 2955, 1739, 1708, 1651, 1609, 1588, 1522, 1487, 1243, 1227, 1169/cm.
[a] D= -60,2° (CHCI3, c=0, 92, 23 °C) . N° lk-8 CDCI3 300 MHz 1, 04-2,25(14H, m) , 2,34(2H, t, J=7,5 Hz), 2,56(1H, m) , 3,87(1H, m) , 5, 30-5,44(2H, m) , 6,19 (1H, d, J=7,5 Hz), 6, 83-6, 94 ( 6H, m) , 7,69 (2H, d, 11 00 > Hz) . IV (CHCI3) : 3599, 3455, 3012 , 2955, 1711, 1644, 1604, 1577, 1524, 1507, 1492, 1290, 1236, 1197, 1170/cm. [a] D= -47,7° (CHCI3, c=l, 01, 22 °C) . N° lk-9 CDCI3 300 MHz 1, 04-2,20(14H, m) , 2,31(3H, s) , 2,36(2H, t, J=7,2 Hz), 2,56 (1H, m) , 3,86(1H, m) , 5, 30-5, 43 (2H, m) , 6,16(1H, d, J=7,2
Hz), 7,00-7,11(6H, m), 7,74(2H, d, J=8,7 Hz). IV (CHCI3) : 3450, 3010, 2955, 1750, 1709, 1651, 1609, 1596, 1523, 1489, 1370, 1247, 1227, 1183/cm.
[a] D= -54,7° (CHCI3, C=1, 01, 22 °C) . N° lk-10 CDCI3 300 MHz 53 1,04-2,22 (14Η, m) , 2,35(2H, t, J=7,2 Hz), 2,56(1H, m) , 3,82(3H, s), 3,8 6(1H, m) , 5,30-5,43(2H, m) , 6,17(1H, d, J=6, 9
Hz), 6,89-7,01(6H, m), 7,70(2H, d, J=8,7 Hz). IV (CHC13): 3023, 2955, 1742, 1708, 1649, 1613, 1602, 1577, 1522, 1507, 1490, 1227, 1210, 1170/cm.
[a] D= -58,1° (CHCI3, c=l, 01, 22 °C) . N° lm-1 CDCI3 300 MHz 1, 06-2,25(14H, m) , 2,32(2H, t, J=7,4 Hz), 2,61(1H, m) , 3, 63(3H, s), 3, 91(1H, m) , 5, 33-5, 47 (2H, m) , 6,24(1H, d, J=6,9
Hz), 7,35-7,38 (3H, m) , 7,53-7, 60(4H, m) , 7,78(2H, m) . IV (CHCI3): 3438, 3008, 2946, 2875, 2212, 1732, 1650, 1605, 1519, 1496/cm.
[a] D= +76° (CHCI3, c=l, 39, 24 °C) . N° lm-2 CDCI3 300 MHz 1, 05-2,20(14H, m) , 2,36(2H, t, J=6,2 Hz), 2,59(1H, m) , 3,8 9(1H, m) , 5,29-5,48 (2H, m), 6,26(lH, d, J=7,0 Hz), 7,26-7,38 (3H, m) , 7,52-7, 60 (4H, m) , 7,73-7,77 (2H, m) . IV (CHCI3) : 3444, 3012, 2952, 2874, 2664, 2214, 1718(sh), 1708, 1649, 1605, 1520, 1498/cm.
[a]D= +81,4° (CHCI3, c=l,01, 23 °C) . N° lm-3 CDCI3 300 MHz 1, 06-2,23 (14H, m) , 2,32(2H, t, J=7,0 Hz), 2,62(1H, m) , 3,63(3H, s), 3, 93(1H, m) , 5, 30-5, 50 (2H, m) , 6,28(1H, d, J=7,0
Hz), 7,38-7,51(3H, m) , 7,58-7, 67(4H, m) , 7, 83-7, 88(2H, m) . 54 IV (CHC13) : 3438, 3008, 2948, 2875, 1783(w), 1727, 1650, 1608, 1580(w), 1523, 1501, 1482/cm.
[a] D= +59° (CHC13, C=1,4 9, 25 °C) . N° lm-4 CDCI3 300 MHz 1, 08-2,25(14H, m) , 2,36(2H, t, J=7,4 Hz), 2,59(1H, m) , 3,91(1H, m) , 5,28-5, 48(3H, m) , 6,29(1H, d, J=7,4 Hz), 7,38-7,50(3H, m), 7,61-7,67(4H, m), 7,81-7,86(2H, m). IV (CHCI3) : 3436, 3010, 2948, 2868, 1727, 1715(sh), 1649, 1615(w), 1524, 1502, 1482, 1372/cm.
[a] D= +72° (CHCI3, c=0, 98, 25 °C) . N° lm-5 CDCI3 300 MHz 1, 09-2,20 (14H, m) , 2,32(2H, t, J=7,2 Hz), 2,63(1H, m) , 3,63(3H, s), 3,92(1H, m) , 5,31-5,51(2H, m) , 6,35(1H, d, J=7, 0 Hz), 7,51-7,60 (3H, m) , 7, 92-7, 97(6H, m) . IV (CHCI3) : 3436, 3008, 2946, 2875, 1727, 1652, 1608(w), 1515, 1484/cm.
[a] D= +82° (CHCI3, c=0, 99, 25 °C) . N° lm-6 CDCI3 300 MHz 1, 09-2,23(14H, m) , 2,37(2H, t, J=7,2 Hz), 2,60(1H, m) , 3, 92 (1H, m) , 5, 30-5, 49 (2H, m) , 6,32(1H, d, J=7,4 Hz), 7,51-7,55 (3H, m), 7,85-7, 98 (6H, m) . IV (CHCI3) : 3436, 3010, 2950, 2875, 2670, 1727, 1715(sh) , 1650, 1605(w), 1515, 1484/cm.
[a]D= +84° (CHCI3, c=l, 54, 25 °C) . 55 N° lm-7 CDCI3 300 ΜΗζ 1, 03-2,18(14Η, m) , 2,32(2Η, t, J=7,4 Hz), 2,59(1H, m) , 3, 64 (3H, s), 3, 8 9 (1H, m) , 5,29-5, 49 (2H, m) , 6,16(1H, d, J=7,8
Hz), 6, 98-7,06 (4H, m), 7,14-7,20(1H, m), 7,34-7,41(2H, m), 7,73-7,78(2H, m). IV (CHCI3) : 3438, 3008, 2946, 2868, 1727, 1648, 1610, 1586, 1519, 1485/cm.
[a] D= +54° (CHCI3, c=l, 2 9, 25 °C) . N° lm-8 CDCI3 300 MHz 1, 06-2,21(14H, m) , 2,36(2H, t, J=7,5 Hz), 2,58(1H, m) , 3,8 8 (1H, m) , 5,31-5, 46 (2H, m) , 6,17(1H, d, J=6,9 Hz), 6, 99-7, 05(4H, m) , 7,15-7,21(H, m) , 7,36-7,41(2H, m) , 7,72-7,75(2H, m). IV (CHCI3) : 3436, 3010, 2948, 2868, 2675, 1730 (sh), 1709, 1647, 1608, 1586, 1520, 1485/cm.
[a] D= +56° (CHCI3, c=0, 97, 25 °C) . N° lm-9 CDCI3 300 MHz 1, 05-2,18(14H, m), 2,29-2,34(5H, m), 2,59(1H, m), 3,64(3H, s), 3,89(1H, m) , 5, 32-5, 46(2H, m) , 6,16(1H, d, J=7,5 Hz), 7,00-7,11(6H, m), 7,74-7,77 (2H, m) . IV (CHCI3) : 3440, 3010, 2946, 2868, 1729, 1649, 1595, 1519, 1488/cm.
[a] D= +47° (CHCI3, c=0, 82, 25°C.). N° lm-10 56 CDC13 300 MHz 1, 04-2,20(14H, m), 2,31-2,39 (5H, m), 2,57(1H, m) 3,87(1H, m) , 5,28-5, 47(2H, m) , 6,17(1H, d, J=7,0 Hz) 6,99-7,12(6H, m), 7,72-7,76(2H, m). IV (CHC13) : 3674, 3572, 3438, 3010, 2948, 2868, 2626 1748, 1710, 1648, 1615, 1520, 1489/cm.
[a] D= +51° (CHCI3, c=0, 91, 25 °C) . N° lm-11 CDCI3 300 MHz 1,04-2,16(14H, m) , 2,31(2H, t, J=7,2 Hz), 2,59(1H, m) 3, 63 (1H, m) , 5, 29-5, 49 (2H, m) , 6,24(H, d, J=7,4 Hz) 6,54(H, s), 6, 83-6, 93(6H, m), 7, 69-7,73(2H, m) . IV (CHCI3) : 3674, 3588, 3438, 3296, 3010, 2946, 2868 1725, 1646, 1603, 1520, 1504, 1489/cm.
[a] D= +51° (CHCI3, c=0, 91, 25 °C) . N° lm-12 CDC13 300 MHz 1,04 -2,21 (14H, m) , 2,33 (2H, t, J=8,0 Hz) , 2,56 (1H, m) 3,87 (1H, m) , 5,28-5,48(2H, m) , 6,2 3(1H, d, NI ix! 0 00 II >X> 6,75 (1H, m) , 6, 87-6, 94 ( 6H, m) , 7, 66-7,71(2H, m), 9,63 (1H s 1) . IV (CHCI3) : 3674, 3582, 3436, 3275, 3010, 2950, 2868 2675, 1727, 1710(sh), 1643, 1603, 1522, 1504, 1490/cm.
[a] D= +30° (CHC13, c=0, 97, 25 °C) . N° lm-13 CDCI3 300 MHz 1,01-2,18(14H, m) , 2,31(2H, t, J=7,4 Hz), 2,58(1H, m) , 3,63(3H, s), 3,82(3Η, s) , 3,89(1Η, m) , 5,29-5,48(2Η, m) , 6,14 (1Η, d, J=7,Ο Ηζ), 6, 88-7, 02 ( 6Η, m), 7,70-7,74 (2Η, m) . IV (CHC13) : 3442, 3402, 3004, 2946, 2868, 1727, 1648, 1600, 1518, 1499/cm.
[α] D= +42° (CHCI3, c=l, 82, 26 °C) . Ν° lm-14 CDCI3 300 ΜΗζ 1, 06-2,21(14Η, m) , 2,35(2Η, t, J=7,2 Hz), 2,55(1Η, m) , 3,82(3Η, s) , 3, 8 8(1Η, m) , 5,27-5,46 (2Η, m) , 6,16(1Η, d, J=7,2 Hz), 6, 88-7, 02(6Η, m) , 7, 68-7,73(2Η, m) . IV (CHCI3) : 3438, 3012, 2948, 2870, 2650, 1730(sh), 1709, 1647, 1615(sh), 1601, 1519, 1492/cm.
[α]D= +64° (CHCI3, c=0,7 0, 25 °C) . N° lm-15 CDCI3 300 MHz 1,05-2,20(14H, m), 2,29-2,36(5H, m), 2,62(1H, m), 3, 63(3H, s), 3, 92(1H, m) , 5, 30-5, 50 (2H, m) , 6,25(1H, d, J=7,2 Hz), 7,16-7,21 (2H, m) , 7,59-7, 64(4H, m) , 7, 83-7, 87(2H, m) . IV (CHCI3) : 3446, 3010, 2946, 2868, 1745(sh), 1728, 1650, 1615, 1525, 1507, 1486/cm.
[a] D= +65,0° (CHCI3, c=l, 02, 23 °C) . N° lm-16 CDCI3 300 MHz 1, 08-2,21(14H, m), 2,34-2,40(5H, m), 2,59(1H, m), 3,90(1H, m) , 5, 29-5, 48 (2)H, m) , 6,29(1H, d, J=7,0 Hz), 7,18 (2H, d, J=8, 6 Hz), 7,58-7, 64 (4H, m) , 7,83(2H, d, J=8,2 Hz) . 58 IV (CHCls) : 3438, 3012, 2948, 2870, 2622, 1749, 1710, 1649, 1610, 1526, 1508, 1487/cm.
[α] D= +66° (CHC13, c=l,21, 24 °C) . N° lm-17 CDCI3 300 MHz 1, 06-2,19 (14H, m) , 2,32(2H, t, J=7,2 Hz), 2,62(1H, m) , 3,63 (3H, s), 3, 93(1H, m) , 5,30-5,50 (2H, m) , 6,32(1H, d, J=7,6
Hz), 6,41 (1H, s), 6, 94 (2H, d, J=9, 0 Hz), 7,47(2H, d, J=9, 0
Hz), 7,58 (2H, d, J=8, 6 Hz), 7,81(2H, d, J=8,6 Hz). IV (CHCI3) : 3580, 3434, 3284, 3010, 2946, 2868, 1726, 1646, 1606, 1528, 1490/cm.
[a] D= +62,4° (CHCI3, c=l,01, 23 °C) . N° lm-18 CDCI3+CD3OD 300 MHz 1, 11-2,18 (14H, m), 2,32(2H, t, J=7,4 Hz), 2,59(1H, m) , 3,88 (1H, m) , 5, 30-5, 49 (2H, m) , 6,55(1H, d, J=7,0 Hz), 6, 92 (2H, d, J=8,6 Hz), 7,47 (2H, d, J=8,6 Hz), 7,59(2H, d, J=8,6 Hz), 7,79 (2H, d, J=8,2 Hz) . IV (Nujol) : 3398, 3175, 2725, 1696, 1635, 1601, 1531, 1510/cm.
[a] D= +99,5° (CH3OH, c=l,011, 25 °C) . N° lm-19 CDCI3 300 MHz 1, 05-2,20(14H, m) , 2,32(2H, t, J=7,4 Hz), 2,61(1H, m) , 3,63(3H, s), 3,83(3H, s), 3,94(1H, m) , 5, 30-5, 50 (2H, m) , 6,24 (1H, d, J=7,0 Hz), 6,99(2H, d, J=8,6 Hz), 7,63-7,63 (4H, m), 7,82(2H, d, J=8,6 Hz). 59 IV (CHC13) : 3440, 3006, 2946, 2875, 1726, 1649, 1606 1527, 1510, 1489/cm.
[α] D= +68° (CHC13, c=0, 8 8, 26 °C) . N° lm-20 CDCI3 300 MHz 1, 09-2,20(14H, m) , 2,35(2H, t, J=7,3 Hz), 2,58(1H, m) , 3,85 (3H, s), 3,8 9 (1H, m) 5,28-5,48(2H, m) , 6,35(1H, d, J=7,2
Hz), 6,98(2H, d, J=8,8 Hz), 7,51-7,61(4H, m), 7,81(2H, d, J=8,4 Hz), 8,34(1H, s 1) . IV (CHCI3) : 3446, 3012, 2952, 2881, 2640, 1730(sh), 1707, 1647, 1606, 1527, 1510, 1489/cm.
[a]D= +83° (CHCI3, c=l, 00, 25 °C) . N° lm-21 CDCI3 300 MHz 1,05-2,14(14H, m) , 2,37(2H, t, J=7,2 Hz) , 2,51 (1H, m) 3,81(1H, m) , 5, 34-5, 46 (2H, m) , 6,11(1H, d, J=7,5 Hz) 7,33-7,48(3H, m), 7,53-7,55(2H, m) . IV (CHCI3): 3420, 3250, 3008, 2948, 2870, 2660, 2210 1735(sh), 1705, 1645, 1503, 1441, 1409/cm.
[a] D= +59,2+1,0° (CHCI3, c=l, 023, 22 °C) . N° lm-22 CDCI3 300 MHz 1, 05-2,17(14H, m) , 2,37(2H, t, J=7,2 Hz), 2,52(1H, m) , 3,82(1H, m) , 5,32-5,47 (2H, m) , 6,20(1H, d, J=7,6 Hz), 7,38-7,53(3H, m) , 7,58-7, 61(6H, m) , 9,11(1H, s 1). IV (CHCI3) : 3420, 3250, 3010, 2984, 2870, 2675, 2208, 60 1730(sh), 1705, 1640, 1500, 1406/cm.
[α] D= +57,4° (CHC13, c=l, 83, 23 °C) . N° lm-23 CDCI3 300 MHz 1, 05-2,18 (14H, m) , 2,31(2H, t, J=7,5 Hz), 2,60(1H, m) , 3,63(3H, s) , 3,90(1H, m) , 5,32-5,47 (2H, m) , 6,22(1H, d, J=6, 9
Hz), 7,40-7,49(3H, m), 7,76-7,79 (2H, m) . IV (CHCI3) : 3438, 3008, 2946, 2868, 1727, 1651, 1603, 1585, 1521, 1484/cm.
[a] D= +52° (CHCI3, c=l, 4 9, 25 °C) . N° lm-24 CDCI3 300 MHz 1,05-2,21(14H, m) , 2,36(2H, t, J=7,2 Hz), 2,57(1H, m) , 3,8 9 (1H, m) , 5,28-5,47(2H, m) , 6,22(1H, d, J=7,0 Hz), 7,39-7,55(3H, m), 7,73-7,79(2H, m). IV (CHCI3) : 3676, 3572, 3436, 3010, 2948, 2875, 1730(sh), 1709, 1650, 1600, 1580, 1514, 1484/cm.
[a] D= +57° (CHCI3, c=0, 97, 26 °C) . N° lm-25 CDCI3 300 MHz 1, 04-2,18(14H, m), 2,28-2,35(5H, m), 2,59(1H, m), 3,62(3H, s), 3,8 8(1H, m) , 5,29-5,49 (2H, m) , 6,20(1H, d, J=7,2
Hz), 7,15 (2H, d, J=9, 0 Hz), 7,80(2H, d, J=8,8 Hz). IV (CHCI3) : 3436, 3010, 2946, 2868, 1752, 1727, 1653, 1602, 1519, 1491/cm.
[a]D= +53° (CHCI3, c=l, 63, 25 °C) . 61 N° lm-26 CDC13 300 ΜΗζ 1, 05-2,19(14Η, m), 2,32-2,38(5Η, m), 2,56(1Η, m), 3, 8 8 (1Η, m) , 5,29-5,47 (2Η, m) , 6,25(1Η, d, J=7,4 Hz), 7,15(2Η, d, J=9,0 Hz), 7,7 8 (2H, d, J=8,6 Hz). IV (CHCI3) : 3434, 3016, 3006, 2948, 2880, 2622, 1752, 1730 (sh), 1710, 1651, 1605, 1520, 1492/cm.
[a] D= +58° (CHCI3, c=3, 68, 24 °C) . N° lm-27 CDCI3 300 MHz 1, 05-2,16(14H, m) , 2,30 (2H, t, J=7,5 Hz), 2,57(1H, 3,62 (3H, s), 3,87(1H, m), 5,27-5, 47(2H, m) , 6, 32(1H, J=7,4 Hz), 6,85(2H, d, J=8,6 Hz), 7, 62(2H, d, V£> 00 II •d 8,35(1H, s) . IV (CHCI3) : 3580, 3450, 3216, 3010, 2946, 2868, 1726, 1640, 1608, 1584, 1528, 1496/cm.
[a] D= +56,2° (CHCI3, c=0,713, 23 °C) . N° lm-28 CDCI3 200 MHz 1,10-2,25 (14H, m) , 2,32(2H, t, J=7,2 Hz), 2,55(1H, s 1) , 3, 82-3, 93(1H, m), 5, 27-5, 47 (2H, m), 6,25(1H, d, J=7,4 Hz), 6,86 (2H, d, J=8, 6 Hz), 7,62(2H, d, J=8,6 Hz). IV (CHCI3) : 3438, 3242, 2675, 1730 (sh), 1708, 1639, 1607, 1585/cm. 62 N° lm-29 CDC13 300 ΜΗζ 1,05 -2,18(14H, m) , 2,31(2H, t, J=7,4 Hz), 2,58 (1H, m) 3, 64(3H, s), 3,85(3H, s), 3,89(1H, m) , 5, 29-5, 48 (2H, m) 6,14(1H, d, J=6,6 Hz), 6, 92(2H, d, O II •d Hz), 7,74(2H, d N O II • IV (CHCI3) : 3445, 3008, 2946, 2868, 1727, 1646, 1606 1578, 1523, 1493/cm.
[α] D= +53° (CHCI3, c=2, 03, 24 °C) . N° lm-30 CDCI3 300 MHz 1,04-2,21(14H, m) , 2,36(2H, t, J=7,3 Hz), 2,56(1H, m) , 3,85(3H, s), 3, 88(1H, m) , 5, 27-5, 46 (2H, m) , 6,15(1H, d, J=7,2 Hz), 6, 92(2H, d, J=8,6 Hz), 7,73(2H, d, J=8,6 Hz). IV (CHCI3): 3440, 3010, 2950, 2870, 2645, 1727, 1710(sh), 1646, 1606, 1575, 1524, 1494/cm.
[a]D= +62° (CHCI3, c=l,10, 24 °C) . N° lm-31 CDCI3+CD3OD 300 MHz 1, 16-2,20(14H, m) , 2,31(2H, t, J=7,2 Hz), 2,59(1H, m) , 3,85(1H, m), 5, 31-5,51(2H, m) , 7, 13-7,21(1H, m) , 7,31-7,42(2H, m) , 7, 68-7, 93(6H, m) . IV (Nujol): 3344, 3175, 2715, 2675, 1699, 1631, 1566/cm.
[a] D= +67° (CH3OH, c=l,01, 24 °C) . N° lm-32 CDCI3 200 MHz 63 1,09-2,23(14Η, m), 2,33(2H, t, J=7,l Hz), 2,57(1H, s 1), 3,40-3,93(9H, m), 4,41(1H, s 1), 5,29-5,48(2H, m), 6,44(1H, d, J=7,4 Hz), 7,43 (2H, d, J=8,2 Hz), 7,80(2H, d, J=7,8 Hz). IV (CHC13) : 3434, 3354, 1726, 1720 (sh), 1660(sh), 1626/cm. N° lm-33 CDCI3 200 MHz 1, 14-2,25(14H, m) , 2,37(2H, t, J=7,3 Hz), 2,64(1H, s 1), 3, 93-4,01(1H, m), 5,30-5,51 (2H, m), 6,47(1H, d, J=7,4 Hz), 7, 63-7,74(2H, m) , 7,79(2H, s) , 7, 89-7, 93(1H, m) , 8,00(1H, dd, J=2,3, 1,0 Hz), 8,30(1H, d, J=1,0 Hz), 8 , 65-8,73(2H, m) . IV (CHCI3) : 3450, 2675, 1728, 1707, 1649, 1528, 1509/cm.
[a]D= +82,8+1,2° (CHC13, c=l,01, 23 °C) . N° 2a-l [a] D= +69,0° (MeOH, c=l,01, 25 °C) N° 2a-2 CDCI3 300 MHz 0,99(1H, d, J=10,2 Hz), 1,15 e 1,24 (cada 3H, cada s) , 1,50-2,50 (14H, m) , 4,30(1H, m) , 5,35-5,52 (2H, m) , 6,32(1H, d, J=8,7 Hz), 7,36-7,49 (3H, m) , 7,58-7, 62 (2H, m) , 7,66 e 7,80(cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3116, 3014, 2925, 2870, 2663, 1708, 1651, 1610, 1524, 1504, 1484, 1472/cm.
[a] D= +64,1° (MeOH, c=l, 02, 25 °C) . N° 2a-3 [a] D= +76,6° (MeOH, c=l,18, 26 °C) . 64 N° 2a-4 CDC13 300 ΜΗζ 0, 99 (1Η, d, J=10,2 Hz), 1,15 e 1,25 (cada 3H, cada s) , 1, 64-2,51(14H, m) , 4,31(1H, m) , 5,36-5,53 (2H, m) , 6,33(1H, d, J=8,4z), 7,50-7,56 (3H, m) , 7, 85-7, 98 ( 6H, m) . IV (CHCI3) : 3515, 3452, 3014, 2925, 2870, 1740, 1708, 1654, 1517, 1486, 1470/cm.
[a] D= +79,5° (MeOH, c=l,18, 22 °C) . N° 2a-5 CD3OD 300 MHz 0,98(1H, d, J=9, 9 Hz), 1,18 e 1,25 (cada 3H, cada s) , 1,56-1,71(3H, m), 1, 98-2,40 (11H, m), 4,17(1H, m) , 5, 41-5,52(2H, m) , 7,52-7,61(3H, m), 7,91-8,01(6H, m) . IV (KBr): 3416, 3063, 2983, 2921, 2869, 1704, 1643, 1566, 1518, 1488, 1408/cm.
[a] D= +62,0° (MeOH, c=l, 00, 25 °C) . N° 2a-6 [a] D= +64,1° (MeOH, c=l,01, 25 °C) . N° 2a-7 [a] D= +65,3° (MeOH, c=0, 99, 25 °C) . N° 2a-8 [a] D= +74,0° (MeOH, c=l,01, 25 °C) . N° 2a-9 65 [α] D= +71,0° (MeOH, c=l,10, 25 °C) . N° 2a-l0 [a] D= +74,7° (MeOH, c=l, 0 0, 25 °C) . N° 2a-l1 [a] D= +72,1° (MeOH, c=l, 00, 25 °C) . N° 2a-12 [a] D= +53,1° (CHC13, c=l, 01, 26 °C) .
p.f. 155,0-156,0 °C N° 2a-13 CDCI3 300 MHz 3H, cada s) , , 6,4 4 (1H, d, J=8,7 Hz), 1713, 1652, 0,98(1H, d, J=10,2 Hz), 1,18 e 1,25(cada 1, 63-2,40(14H, m) , 4,30(1H, m) , 5,46-5,58(2H, m) J=8,4 Hz), 7,49 e 7,77 (cada 2H, cada d, 7,54 (1H, s) . IV (CHCI3) : 3689, 3378, 3028, 3014, 2924, 1602, 1522, 1496/cm.
[a] D= +78,3° (MeOH, c=0, 84, 25 °C) . p.f. 205,0-206,0 °C N° 2a-14 [a] D= +72,5° (MeOH, c=l, 07, 25 °C) . N° 2a-15 66 CDC13 300 MHz 0, 99 (1H, d, J=9, 9 Hz), 1,14 e 1,24 (cada 3H, cada s) , 1,55-2,44(14H, m) , 4,27(1H, m) , 5, 30-5, 50(2H, m) , 6,29(1H, d, J=9,0 Hz), 7,11 e 7,20 (cada 1H, cada d, J=16,2 Hz), 7,29-7,55(5H, m), 7,57 e 7,72(cada 2H, cada d, J=8,7 Hz). IV (CHC13) : 3453, 3083, 3022, 3013, 2925, 2870, 1708, 1650, 1607, 1560, 1522, 1496/cm.
[a]D= +72,3° (MeOH, c=l,00, 27 °C). p.f. 115,0-117,0 °C N° 2a-l6 CDCI3 300 MHz 0,92 (1H, d, J=10,2 Hz), 1,11 e l,23(cada 3H, cada s) , 1.50- 2,48(14H, m) , 3,62(3H, s) , 4,29(1H, m) , 5, 30-5, 50(2H, m) , 6,20(1H, d, J=8,7 Hz), 6,59 e 6, 68 (cada 1H, cada d, J=12,3 Hz), 7,23(5H, s), 7,29 e 7,59(cada 2H, cada d, J=8,l Hz). IV (CHCI3) : 3453, 3024, 3016, 2924, 2870, 1730, 1651, 1607, 1520, 1495/cm.
[a] D= +56,8° (MeOH, c=l, 04, 24 °C) . N° 2a-17 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,11 e l,23(cada 3H, cada s) , 1.50- 2,38(14H, m) , 4,26(1H, m) , 5,30-5,50(2H, m) , 6,23(1H, d, J=8,4 Hz), 6,59 e 6,70 (cada 1H, cada d, J=12,3 Hz), 7,23(5H, s), 7,30 e 7,57(cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3452, 3081, 3019, 3014, 2925, 2870, 2665, 1708, 1650, 1607, 1521, 1495/cm.
[a] D= +61,6° (MeOH, c=l, 00, 27 °C) . N° 2a-18 67 CDC13 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,11 e 1,23 (cada 3H, cada s) , 1.50- 2,50(14H, m) , 3,61(3H, s) , 4,31(1H, m) , 5, 35-5,51(2H, m) , 6,33(1H, d, J=8,4 Hz), 7,48-7, 64 (4H, m), 7,79-7,83 (2H, m), 7,91 (1H, dt, J=1,5 e 7,8 Hz), 8,01(1H, dt, J=l,5 e 7,8 Hz), 8,13(1H, t, J=l,5 Hz). IV (CHC13) : 3450, 3026, 3013, 2925, 2870, 1730, 1659, 1600, 1510/cm.
[ α ] D= +56,0° (MeOH, c=l,01, 25 °C) . N° 2a-l9 CDCI3 300 MHz 0, 95 (1H, d, J=9, 9 Hz), 1,14 e 1,21 (cada 3H, cada s) , 1,53-2, 60(14H, m) , 4,25(1H, m) , 5, 35-5, 64(2H, m) , 7,21(1H, d, J=7, 8 Hz), 7,49-7, 68 (4H, m) , 7,76-7,84(3H, m) , 8,25(1H, m) , 8,43(1H, m). IV (CHCI3) : 3382, 3196, 3025, 3015, 2925, 2870, 1725, 1652, 1599, 1577, 1521/cm.
[a] D= +55,9° (MeOH, c=l, 00, 25 °C) . N° 2a-20 CDCI3 300 MHz 0, 98 (1H, d, J=10,2 Hz), 1,13 e 1,24 (cada 3H, cada s) , 1.50- 2,50(14H, m) , 3,62(3H, s) , 4,31(1H, m) , 5, 35-5,51(2H, m) , 6,24 (1H, d, J=8,4 Hz), 7,40-7,52(3H, m) , 7,71-7,76(2H, m) . IV (CHCI3) : 3453, 3025, 3013, 2925, 2870, 1730, 1753, 1579, 1514, 1486/cm.
[a] D= +61,2° (MeOH, c=l, 04, 25 °C) . N° 2a-21 68 CDC13 300 MHz 0,98(1H, d, J=10,2 Hz), 1,13 e 1,23 (cada 3H, cada s) , 1.52- 2,50(14H, m) , 4,28(1H, m) , 5, 34-5,51(2H, m) , 6,27(1H, d, J=8,7 Hz), 7,41-7,53(3H, m), 7,71-7,74(2H, m) . IV (CHC13) : 3452, 3063, 3027, 3014, 2925, 2871, 1708, 1652, 1578, 1515, 1486/cm.
[a] D= +62,0° (MeOH, c=l,01, 27 °C) . N° 2a-22 ds-DMSO 300 MHz 0, 8 6 (1H, d, J=9, 9 Hz), 1,10 e 1,16 (cada 3H, cada s) , 1,42-1,52(3H, m) , 1, 85-2,46(11H, m) , 3,98(1H, m) , 5,32-5,43 (2H, m) , 7,41 (3H, m) , 7,88(2H, d, J=6, 6 Hz), 8,19(1H, d, J=6,6 Hz). IV (KBr): 3367, 3060, 2984, 2922, 2868, 1634, 1563, 1529, 1487/cm.
[a] D= +47,7(MeOH, c=l, 00, 25°C.)· N° 2a-23 [a] D= +62,7° (MeOH, c=l,01, 27 °C) . N° 2a-24 CDCI3 300 MHz 0, 99 (1H, d, J=10,2 Hz), 1,14 e l,25(cada 3H, cada s) , 1.52- 2,50(14H, m) , 4,31(1H, m) , 5,36-5,52(2H, m) , 6,34(1H, d, J=8,4 Hz), 7,47-7,52 (2H, m) , 7,59-7, 64 (1H, m) , 7,78-7,83 (6H, m) . IV (CHCI3): 3449, 3027, 3013, 2925, 2869, 1708, 1656, 1599, 1518, 1493/cm.
[a] D= +63,1° (MeOH, c=l, 00, 25 °C) . 69 N° 2a-25 [α] D= +35,1° (MeOH, c=l, 00, 25 °C) . N° 2a-26 [a] D= +35,5° (MeOH, c=l, 02, 25 °C) . N° 2a-27 CDC13 300 MHz 0,97(1H, d, J=10,2 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1.52- 2,50(14H, m), 3,63(3H, s), 4,29(1H, m) , 5,36-5,51 (2H, m), 6,18(1H, d, J=8,4 Hz), 7,01 e 7,71 (cada 2H, cada d, J=8,7 Hz), 6,98-7,05(2H, m), 7,16(1H, t, J=7,5 Hz), 7,34-7,41 (2H, m). IV (CHCI3): 3455, 3024, 3016, 2924, 2870, 1730, 1651, 1588, 1520, 1487/cm.
[a] D= +56,4° (MeOH, c=l,01, 25 °C) . N° 2a-28 CDCI3 300 MHz 0,98(1H, d, J=10,2 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1.52- 2,50(14H, m), 4,26(1H, m), 5,34-5,51 (2H, m), 6,20(1H, d, J=9,0 Hz), 7,01 e 7,70(cada 2H, cada d, J=9,0 Hz,), 6,98-7,15(2H, m) , 7,17(1H, t, J=7,5 Hz), 7,34-7,40 (2H, m) . IV (CHCI3) : 3454, 3031, 3018, 2925, 2870, 1708, 1650, 1588, 1523, 1487/cm.
[a] D= +56,2° (MeOH, c=l, 00, 25°C.). N° 2a-29 70 [a] D= +53,0 0 (MeOH, c=l, 03, 25 °C) . N° 2a-30 CDC13 300 MHz 0,97(1H, d, J=10,2 Hz), 1,10 e 1,23 (cada 3H, cada s) , 1,52-2,50(14H, m) , 4,25(1H, m) , 5,30-5,50(2H, m) , 6,23(1H, d, J=8,7 Hz), 6,36(1H, s) , 7,2 6-7,3 9 (1 OH, m) , 7,60 e 7,68 (cada 2H, cada d, J=8,4 Hz,). IV (CHC13) : 3451, 3088, 3064, 3029, 3014, 2925, 2869, 1707, 1652, 1522, 1495/cm. [a] D= +54,2° (MeOH, c=l,00, 25 °C). N° 2a-31 CDCI3 300 MHz 0,98(1H, d, J=10,2 Hz), 1,14 e 1,24 (cada 3H, cada s) , 1,50-2,50(14H, m), 3,63(3H, s), 4,31(1H, m) , 5,30-5,50 (2H, m), 6,2 6 (1H, d, J=8,4 Hz), 6,90(1H, t, J=7,4 Hz), 7,13(1H, d, J=8,7 Hz), 7,29(2H, t, J=8,0 Hz), 7,67-7,75(5H, m), 7,82 (1H, s) . IV (Nujol) : 1495/cm. 3380, 3244, 1723, 1638, 1601, 1578, 1535, [a] D= +73,6° (MeOH, c=0,50, 26 °C).
p.f. 133,0-134,0 °C N° 2a-32 [a] D= +56,1° (MeOH, c=l, 02, 26 °C) . N° 2a-33 CDCI3 300 MHz 71 0, 95 (1Η, d, J=10,2 Hz), 1,10 e l,21(cada 3H, cada s) , 1,50-2,50(14H, m), 4,25(1H, m) , 5,13(2H, s), 5,30-5,70(3H, m), 6,41(1H, d, J=8,2 Hz), 6,89(1H, s), 7,09(1H, s), 7,17 e 7,72(cada 2H, cada d, J=8,2 Hz), 7,62(1H, s). IV (CHC13) : 3450, 3125, 3031, 3013, 2925, 2870, 2467, 1917, 1708, 1654, 1615, 1575, 1523, 1497/cm.
[a] D= +55,2° (MeOH, c=l,01, 26 °C) . N° 2a-34 [a] D= +72,9° (MeOH, c=l, 03, 25 °C) . N° 2a-35 CDCI3 300 MHz 0, 98 (1H, d, J=10,2 Hz), 1,13 e l,24(cada 3H, cada s) , 1,52-2,48(14H, m) , 4,28(1H, m) , 5, 35-5,51(2H, m) , 6,28(1H, d, J=8,7 Hz), 7,34-7,37(3H, m) , 7,52-7,55(2H, m) , 7,58 e 7,71(cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3515, 3452, 3030, 3012, 2925, 2870, 1739 1708, 1652, 1607, 1555, 1521, 1497/cm.
[a] D= +74,3° (MeOH, c=l,01, 25 °C) . N° 2a-36 [a] D= +23,4° (MeOH, c=l, 07, 25 °C) . N° 2a-37 CDCI3 300 MHz 0, 83 (1H, d, J=10,5 Hz), 0,95 e 1,18 (cada 3H, cada s) 1,44-2,46(14H, m), 3,92(1H, m), 5, 34-5, 52(3H, m) 7,26-7,54 (9H, m) , 7,62(1H, s) . IV (CHCI3) : 3432, 3310, 3189, 3023, 3014, 2924, 2870 72 1704, 1610, 1594, [ α ] D= +25,3° Ν° 2a-38 [α] D= +70,9° Ν° 2a-39 [α] D= +70,6° Ν° 2a-40 [α] D= +74,7° Ν° 2a-41 [α] D= +72,10 Ν° 2a-42 [α] D= +69,2° Ν° 2a-43 [α] D= +70,8° Ν° 2a-44 [α] D= +60,4° Ν° 2a-45 1523, 1487/cm. (MeOH, c=l,00, 26 °C) (MeOH, c=l,02, 25 °C) (MeOH, c=l,01, 25 °C) (MeOH, c=l,00, 25 °C) (MeOH, c=l,01, 24 °C) (MeOH, c=l,00, 25 °C) (MeOH, c=l,00, 25 °C) (MeOH, c=l,00, 26 °C) 73 CDC13 300 MHz 0,97(1H, d, J=9, 9 Hz), 1,13 e 1,23 (cada 3H, cada s) , 1,55-2,52(14H, m) , 4,29(1H, m) , 5,34-5,54(2H, m) , 6,33(1H, d, J=9,0 Hz), 7, 10(1H, t, J=7,4 Hz), 7,34(2H, t, J=7,4 Hz), 7,52(2H, m) , 7,68 e 7,75(cada 2H, cada d, J=8,4 Hz), 7,80(1H, s), 8,10 (1H, s), 10,09 (1H, s) . IV (CHC13) : 3393, 3195, 3093, 3033, 3013, 2925, 2870, 1698, 1656, 1598, 1537, 1498/cm.
[a] D= +59,4° (MeOH, c=l,01, 24 °C) . N° 2a-46 [a] D= +63,5° (MeOH, c=l, 00, 25 °C) . N° 2a-47 CDCI3 300 MHz 0,97(1H, d, J=9, 9 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1,54-2,48(14H, m) , 4,29(1H, m) , 5,35-5,52(2H, m) , 6,32(1H, d, <d II co 7 Hz), 7,26 (1H, m) , 7,41 (2H, t, J=7,8 Hz), 7,64 (2H, d, II ^1 5 Hz), 7,73 e 7,77(cada 2H, cada d, J=8,4 Hz), 7,95 (1H, s), 9,20(1H, s) , 10,38(1H, s) . IV (CHCI3) : 3450, 3339, 3003, 2992, 2925, 2870, 1706, 1653, 1596, 1523, 1495/cm.
[a] D= +63,3° (MeOH, c=l, 00, 25 °C) . N° 2a-48 [a] D= +63,8° (MeOH, c=l, 00, 24 °C) . N° 2a-49 CDCI3 300 MHz 1,00(1H, d, J=10,5 Hz), 1,17 e l,26(cada 3H, cada s) , 1,55-2,52(14H, m) , 4,34(1H, m) , 5,36-5,54 (2H, m) , 6,35(1H, d, J=9, 0 Hz), 7,50-7, 62 (3H, m) , 7,90 e 3 (cada 2H, cada d, J=8,4 Hz), 8,21 (2H, m) . IV (CHC13) : 3451, 3029, 3022, 3016, 2925, 2870, 1708, 1655, 1542, 1508, 1498, 1471, 1459/cm.
[a] D= +63,5° (MeOH, c=l, 02, 250 °C) .
p.f. 135,0-137,0 °C N° 2a-50 [a] D= +68,9° (MeOH, c=l, 02, 24 °C) . N° 2a-51 de-DMSO 300 MHz 0,87(1H, d, J=9, 9 Hz), 1,10 e 1,17 (cada 3H, cada s) , 1,40-1,60(3H, m), 1,90-2,40(11H, m), 3,98(1H, m), 5,35-5,46 (2H, m) , 7,64(1H, s) , 7,65 e 7,91(cada 2H, cada d, J=8,7 Hz), 8, 0 6 (1H, d, J=6,0 Hz), 9,32(1H, s 1). IV (KBr): 3385, 2962, 1734, 1707, 1632, 1529, 1498/cm.
[a] D= +68,4° (MeOH, c=l,01, 24 °C) . N° 2a-52 [a] D= +76,2° (MeOH, c=l,01, 24 °C) . N° 2a-53 [a] D= +73,9° (MeOH, c=l, 02, 24 °C) . N° 2a-54 75 [α] D= +68,1° (MeOH, c=l, 00, 24 °C) . N° 2a-55 [a] D= +67,8° (MeOH, c=l, 00, 24 °C) . N° 2a-56 [a] D= +65,4° (MeOH, c=l, 03, 25 °C) . N° 2a-57 [a] D= +63,4° (MeOH, c=l,01, 24 °C) . N° 2a-58 [0793] [a] D= +66,6° (MeOH, c=l,01, 24 °C) . N° 2a-59 [a] D= +65,5° (MeOH, c=l, 00, 24 °C) . N° 2a-60 [a] D= +60,9° (MeOH, c=l, 02, 25 °C) . N° 2a-61 CDC13 300 MHz cada s) , ,28(1H, d, , 7,12 (2H, 8,47 (2H, 0, 97 (1H, d, J=10, 0 Hz), 1,10 e l,22(cada 3H, 1,50-2,50(14H, m) , 4,26(1H, m) , 5,30-5,54 (2H, m) , 6 J=8,6 Hz), 6,60 e 6,82 (cada 1H, cada d, J=12,4 Hz, ) d, J=6,0 Hz), 7,25 e 7,62(cada 2H, cada d, J=8,6 Hz), 76 d, J=6,0 Hz) . IV (CHC13): 3452, 3027, 3019, 3013, 2925, 2870, 2480, 1708, 1651, 1606, 1520, 1494/cm.
[a] D= +61,6° (MeOH, c=l,01, 25 °C) . N° 2a-62 [a] D= +72,0° (MeOH, c=0, 93, 25°C) . N° 2a-63 CDCI3 300 MHz 0, 99 (1H, d, J=10,2 Hz), 1,14 e l,24(cada 3H, cada s) , 1,50-2,50(14H, m) , 4,29(1H, m) , 5, 36-5, 55 (2H, m) , 6,35(1H, d, J=9,l Hz), 7,04 e 7,27(cada 1H, cada d, J=16,5 Hz), 7,37(2H, d, J=6, 6 Hz), 7,56 e 7,76(cada 2H, cada d, J=8,4 Hz), 8,57(2H, d, J=6,6 Hz). IV (CHCI3) : 3452, 3024, 3018, 3014, 2925, 2870, 2470, 1933, 1708, 1652, 1605, 1521, 1496/cm.
[a] D= +69,2° (MeOH, c=l,01, 25 °C) . N° 2a-64 [a] D= +56,9° (MeOH, c=l, 24, 25 °C) . N° 2a-65 CDCI3 300 MHz 0, 98 (1H, d, J=10,5 Hz), 1,12 e l,23(cada 3H, cada s) , 1,54-2,46(14H, m), 4,27(1H, m) , 5,23(2H, s), 5,34-5,52(2H, m), 6,26 (1H, d, J=8,4 Hz), 7,32-7,45(5H, m), 7,64 e 7,71(cada 2H, cada d, J=8,4 Hz), 8,15(1H, s) . IV (CHCI3): 3452, 3088, 3065, 3032, 3013, 2925, 2870, 1708, 1653, 1611, 1559, 1522, 1496/cm. 77 [α] D= +61,0° (MeOH, c=0,91, 25 °C) . N° 2a-66 [a] D= +76,0° (MeOH, c=l,01, 25 °C) . N° 2a-67 CDC13 300 MHz 0,98(1H, d, J=10,4 Hz), 1,14 e l,24(cada 1.54- 2,46(14H, m) , 4,28(1H, m) , 5,32-5,53 (2H, m) J=8,6 Hz), 6,92-7,31(cada 1H, cada d, J=16,4 Hz), J=5, 8 e 3,6 Hz), 7,12(1H, d, J=3, 6 Hz), 7,24(1H, 7,51 e 7,70 (cada 2H, cada d, J=8,4 Hz). IV (CHCI3) : 3453, 3029, 3013, 2925, 2870, 1604, 1524, 1515, 1494/cm.
[a] D= +76,2° (MeOH, c=l, 00, 24 °C) . p.f. 104,0-106,0 °C N° 2a-68 [a] D= +57,7° (MeOH, c=l,01, 25 °C) . N° 2a-69 CDCI3 300 MHz 0,99 (1H, d, J=10,2 Hz), 1,14 e l,24(cada 1.54- 2,48(14H, m) , 4,28(1H, m) , 5,34-5,53 (2H, m) J=9,0 Hz), 6,54-6,74(cada 1H, cada d, J=12,0 Hz), J=4, 8 e 3,3 Hz), 6,97(1H, dd, J=3,3 e 1,2 Hz), J=4,8 e 1,2 Hz), 7,44 e 7,70(cada 2H, cada d, J=8, IV (CHCI3) : 3453, 3025, 3010, 2925, 2870, 1607, 1559, 1523, 1493/cm.
[a] D= +58,4° (MeOH, c=l, 00, 25 °C) . 3H, cada s) , , 6,27 (1H, d, 7,02 (1H, dd, d, J=5,8 Hz), 1739, 1650, 3H, cada s) , , 6,2 9 (1H, d, 7,02(1H, dd, 7,13 (1H, dd, .7 Hz) . 1708, 1650, 78 N° 2a-7Ο [α] D= +48,6° (MeOH, c=l, 00, 25 °C) . N° 2a-71 CDC13 300 MHz 0,98(lHd, J=10,2 Hz), 1,12 e 1,23(cada 3H, cada s) , 1,52-2,46(14H, m) , 2,31(3H, s), 4,26(1H, m) , 5,33-5,52 (2H, m) , 6,20(1H, d, J=9,3 Hz), 7, 02-7,11(6H, m) , 7,70(2H, d, J=9,0 Hz) . IV (CHCI3) : 3460, 3031, 3022, 3011, 2925, 2870, 1750, 1708, 1650, 1608, 1597, 1523, 1490/cm.
[a] D= +48,9° (MeOH, c=l,01, 25 °C) . N° 2a-72 [a] D= +51,2° (MeOH, c=l, 02, 25 °C) . N° 2a-73 CDCI3 300 MHz 0,97(1H, d, J=9, 9 Hz), 1,11 e 1,23 (cada 3H, cada s) , 1,54-2,48(14H, m) , 4,27(1H, m) , 5,32-5,52 (2H, m) , 6,24(1H, d, J=9, 0 Hz), 6, 83-6, 94 (6H, m) , 7,65(2H, d, J=9,0 Hz). IV (CHCI3): 3598, 3451, 3199, 3033, 3012, 2925, 2870, 1708, 1642, 1604, 1524, 1507, 1491/cm.
[a] D= +52,2° (MeOH, c=l,01, 25°C.). N° 2a-74 [a] D= +51,5° (MeOH, c=0, 92, 250°C). 79 N° 2a-75 CDC13 300 ΜΗζ 0, 97 (1Η, d, J=10,2 Hz), 1,11 e 1,23 (cada 3H, cada s) , 1,55-2,46(14H, m) , 3,82(3H, s), 4,25(1H, m) , 5,32-5,52 (2H, m), 6,19(1H, d, J=8,7 Hz), 6,89-7,01 ( 6H, m), 7, 65-7, 68 (2H, m) . IV (CHCI3) : 3450, 3025, 3008, 2925, 2870, 2837, 1741, 1649, 1612, 1521, 1505, 1490/cm.
[a] D= +51,1° (MeOH, c=l, 00, 25 °C) . N° 2a-76 [a] D= +60,4° (MeOH, c=0, 98, 25 °C) . N° 2a-77 CDCI3 300 MHz 0,99(1H, d, J=10,5 Hz), 1,15 e 1,24 (cada 3H, cada s) , 1,54-2,48(14H, m) , 2,34(3H, s), 4,29(1H, m) , 5,32-5,54(2H, m), 6,32(1H, d, J=8,4 Hz), 7,19 e 7,60 (cada 2H, cada d, J=8,4 Hz), 7,63 e 7,79(cada 2H, cada d, J=8,4 Hz). IV (CHCI3) : 3452, 302-7, 3012, 2925, 2870, 1751, 1709, 1651, 1611, 1560, 1527, 1509, 1489/cm.
[a] D= +61,2° (MeOH, c=l, 00, 25 °C) . N° 2a-78 [a] D= +67,4° (MeOH, c=l,01, 25 °C). N° 2a-79 CDCI3 300 MHz 0,99(1H, d, J=10,2 Hz), 1,15 e 1,24(cada 3H, cada s) , 80 1,54-2,54(14Η, m) , 4,31(1H, m) , 5,32-5,54(2H, m) , 6,36(1H, d, J=8,2 Hz), 6,93 e 7,48(cada 2H, cada d, J=8,6 Hz), 7,59 e 7,75 (cada 2H, cada d, J=8,4 Hz). IV (CHC13) : 3593, 3448, 3192, 3030, 3010, 2925, 2870, 1708, 1644, 1608, 1591, 1559, 1530, 1516, 1491/cm.
[a] D= +65,8° (MeOH, c=l,01, 25 °C) . N° 2a-80 c=l,01, 25 °C).
[a] D= +66,9o (MeOH, N° 2a-81 CDCI3 300 MHz 0,99(1H, d, J=10,5 Hz), 1,15 e 1,24 (cada 3H, cada s) , 1,54-2,48(14H, m), 3,86(3H, s), 4,29(1H, m) , 5,34-5,52 (2H, m), 6,20(1H, d, J=8,7 Hz), 6,99 e 7,55 (cada 2H, cada d, J=9, 0 Hz), 7,61 e 7,77 (cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3450, 3009, 2925, 2870, 2838, 1740, 1708, 1650, 1608, 1557, 1528, 1512, 1491/cm.
[a] D= +66,2° (MeOH, c=l,01, 25 °C) . N° 2a-82 [a] D= +57,7° (MeOH, c=l, 02, 24 °C) . N° 2a-83 CDCI3 300 MHz 0,97(1H, d, J=10,2 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1,54-2,48(14H, m) , 2,33(3H, s), 4,26(1H, m) , 5,32-5,52 (2H, m), 6,25(1H, d, J=8,7 Hz), 7,16 e 7,75 (cada 2H, cada d, J=8,7 Hz). 81 IV (CHC13) : 3452, 3030, 3022, 3012, 2925, 2870, 1754, 1709, 1654, 1604, 1585, 1522, 1493/cm.
[α] D= +57,4° (MeOH, c=l,01, 24 °C) . N° 2a-84 [a] D= +57,8° (MeOH, c=l,01, 24 °C) . N° 2a-85 CDC13 300 MHz 0, 95 (1H, d, J=10,2 Hz), 1,12 e 1,22 (cada 3H, cada s) , 1,54-2,48(14H, m) , 4,25(1H, m) , 5, 32-5, 52 (2H, m) , 6,28(1H, d, J=8,7 Hz), 6,87 e 7,57(cada 2H, cada d, J=9,0 Hz). IV (CHCI3) : 3590, 3450, 3166, 3019, 3012, 2925, 2871, 1708, 1637, 1608, 1583, 1531, 1498/cm.
[a] D= +56,0° (MeOH, c=l,01, 24 °C) . N° 2a-86 [a] D= +59,3° (MeOH, c=l,01, 22 °C) . N° 2a-87 CDCI3 300 MHz 0, 98 (1H, d, J=10,0 Hz), 1,13 e l,23(cada 3H, cada s) , 1,54-2,48(14H, m) , 3,85(3H, s), 4,25(1H, m) , 5, 32-5, 53(2H, m) , 6,19 (1H, d, J=8,8 Hz), 6,93 e 7,69 (cada 2H, cada d, J=9,0 Hz). IV (CHCI3) : 3450, 3030, 3017, 3012, 2925, 2870, 2840, 1740, 1708, 1647, 1606, 1575, 1525, 1496/cm.
[a] D= +58,2° (MeOH, c=0, 99, 22°C). 82 N° 2a-88 [α] D= +50,9° (MeOH, c=l, 02, 25 °C) . N° 2a-89 CDC13 300 MHz 3H, cada s) , , 7,0 3 (1H, d, ddd, J=1,8, 2870, 1708, 0,99 (1H, d, J=10,2 Hz), 1,18 e l,26(cada 1,56-2,48(14H, m) , 4,29(1H, m) , 5,36-5,54 (2H, m) J=8,7 Hz), 7,21 (1H, s), 7,43(2H, m) , 7,74(1H, 6,9 e 8,7 Hz), 8,22(1H, dd, J=l,8 e 8,1 Hz). IV (CHCI3) : 3443, 3087, 3023, 3014, 2925, 1685, 1658, 1630, 1517, 1466/cm.
[a] D= +57,1° (MeOH, c=l,01, 22 °C) .
p.f. 117,0-118,0 °C N° 2a-90 [a] D= +54,1° (MeOH, c=l,01, 22 °C) . N° 2a-91 CDCI3 300 MHz 3H, cada s) , , 6,49-6,53 dd, J=0,9 e 2870, 1739, 0,97(1H, d, J=10,2 Hz), 1,13 e l,23(cada 1,52-2,46(14H,m) , 4,24(lH,m), 5,34-5,52(2H,m) (2H, m) , 7, 11 (1H, dd, J=0,9 e 3,6 Hz), 7,44(1H, 1,8 Hz) . IV (CHCI3) : 3437, 3033, 3022, 3014, 2925, 1708, 1655, 1595, 1520, 1472/cm.
[a] D= +55,0° (MeOH, c=l, 00, 22 °C) . N° 2a-92 [a] D= +50,3° (MeOH, c=l, 00, 22 °C) . 83 N° 2a-93 CDCI3 300 ΜΗζ 0,95( 1Η, d, J=10,5 Hz), 1,12 e 1,23 (cada 3H, cada s), 1,52-2,46 (14H, m) , 4,25(1H, m) , 5, 34-5, 52 (2H, m) , 6,12(1H, d, J=8,7 Hz) 7,07 (1H, dd, J=3,9 e 5,1 Hz), 7,45-7,48(2H, m) . IV (CHCI3) : 3450, 3023, 3011, 2925, 2870, 1739, 1708, 1645, 1531, 1501, 1471/cm.
[a] D= +49,1° (MeOH, c=l, 02, 24 °C) . N° 2a-94 [a] D= +51,5° (MeOH, c=l, 00, 24 °C) . N° 2a-95 CDCI3 300 MHz 0, 96 (1H, d, J=10,5 Hz), 1,11 e l,23(cada 3H, cada s) , 1,52-2,46(14H, m) , 4,25(1H, m) , 5, 34-5, 56 (2H, m) , 6,14(1H, d, J=8,7 Hz), 7,34 (2H, d, J=2,0 Hz), 7,85(1H, t, J=2,0 Hz). IV (CHCI3) : 3452, 3114, 3030, 3013 2925, 2870, 1708, 1649, 1535, 1498, 1471/cm.
[a] D= +55,5° (MeOH, c=l, 00, 25 °C) . p.f. 87,0-88,0 °C N° 2a-96 CD3OD 300 MHz 0, 94 (1H, d, J=10,2 Hz), 1,13 e l,22(cada 3H, cada s) , 1,50-1,76 (3H, m), 1, 94-2,39(11H, m), 4,11(1H, m), 5, 39-5,49(2H, m), 7,43-7,51 (2H, m) , 8,05(1H, m) . IV (KBr): 3369, 3084, 2985, 2921, 2868, 1630, 1566, 1538, 1503/cm.
[a] D= +38,8° (MeOH, c=l,01, 22 °C) . 84 N° 2a-97 CD3OD 300 ΜΗζ 3H, cada s) , , 10(1H, m), 1629, 1545, 0, 93 (1Η, d, J=9, 9 Hz), 1,13 e l,22(cada 1,48-1,58 (3H, m), 1, 96-2,36(11H, m) , 4 5, 35-5,50(2H, m) , 7,42-7,51(2H, m), 8,06(1H, m) . IV (KBr): 3447, 3087, 2987, 2922, 2868, 1501/cm.
[a] D= +52,9° (MeOH, c=l,01, 24 °C) . N° 2a-98 [a] D= +53,2° (MeOH, c=l, 02, 23 °C) . N° 2a-99 CDCI3 300 MHz 3H, cada s) , , 6,18 (1H, d, 1738, 1709, 0,97(1H, d, J=10,2 Hz), 1,12 e l,22(cada 1,26-2,45(24H, m) , 4,25(2H, m) , 5,34-5,52 (2H, m) J=8,7 Hz), 6,91 e 7,66(cada 2H, cada d, J=9,0 Hz) IV (CHCI3) : 3455, 3029, 3019, 2939, 2862, 1645, 1605, 1523, 1494/cm.
[a] D= +51,4° (MeOH, c=l, 0 0, 23 °C) . N° 2a-l00 [a] D= +49,3° (MeOH, c=l, 00, 24 °C) . N° 2a-l01 [a] D= +51,3° (MeOH, c=l, 00, 24 °C) . N° 2a-l02 85 [α] D= +48,8° (MeOH, c=l,01, 23 °C) . N° 2a-103 CDC13 300 MHz 0,94(1H, d, J=10,2 Hz), 1,12 e 1,22 (cada 3H, cada s) , 1,52-2,46(14H, m), 2,48(3H, d, J=0,3 Hz), 4,20(1H, m) , 5,32-5,54 (2H, m) , 6,46(1H, s 1), 7,12(1H, d, J=9, 0 Hz). IV (CHCI3) : 3415, 3144, 3029, 3011, 2926, 2871, 1708, 1671, 1598, 1538, 14564/cm.
[a] D= +49,6° (MeOH, c=l,01, 23 °C) . N° 2a-104 [a] D= +77,0° (MeOH, c=l, 02, 23 °C) . N° 2a-105 CDCI3 300 MHz 93(1H, d, J=9,9 Hz), 1,09 e 1,21(cada 3H, cada s) , 1,51-2,44(14H, m) , 3,90(6H, s), 4,20(1H, m), 5,38-5,50 (2H, m) , 5,87(1H, d, J=9,0 Hz), 6,25 e 7,54 (cada 1H, cada d, J=15, 6 Hz), 6,84 (1H, d, J=8,1 Hz), 7,03(1H, d, J=l,8 Hz), 7,09 (1H, dd, J=1,8 e 8,1 Hz). IV (CHCI3) : 3439, 3028, 3012, 2937, 2871, 2841, 1739, 1708, 1661, 1620, 1600, 1513/cm.
[a] D= +77,3° (MeOH, c=l,01, 23 °C) . N° 2a-l06 [a] D= +67,0° (MeOH, c=l, 00, 25 °C) . N° 2a-107 86 [α] D= +66,6° (MeOH, c=l,01, 24 °C) .
p.f. 168,0-170,0 °C N° 2a-l08 [a] D= +61,8(MeOH, c=l, 00, 22 °C) . N° 2a-l09 CDC13 300 MHz 0,96(1H, d, J=10,2 Hz), 1,10 e 1,22 (cada 3H, cada s) , 1,51-2,45 (14H, m), 4,25(1H, m), 5,33-5,49(2H, m), 6,21(1H, d, J=8,7 Hz), 7,25 e 7,60(cada 2H, cada d, J=8,7 Hz), 7,33-7,41 (5H, s) . IV (CHCI3) : 3453, 3062, 3028, 3014, 2925, 2870, 1739, 1708, 1651, 1594, 1557, 1515, 1481/cm.
[a] D= +61,0° (MeOH, c=l,01, 22 °C) . N° 2a-l10 CD3OD 300 MHz 0,94(1H, d, J=9, 9 Hz), 1,13 e 1,22 (cada 3H, cada s) , 1,54-2,37 (14H, m), 4,12(1H, m), 5,38-5,49 (2H, m), 7,25 e 7,68(cada 2H, cada d, J=8,7 Hz), 7,41(5H, s). IV (KBr): 3435, 3058, 2986, 2920, 2866, 1635, 1595, 1562, 1521, 1482, 1439, 1411/cm.
[a] D= +47,3° (MeOH, c=l,01, 23 °C) . N° 2a-l11 [a] D= +65,6° (MeOH, c=l,01, 24 °C) . 87 N° 2a-l12 CDC13 300 ΜΗζ 3H, cada s) , , 6,22 (1H, d, 2841, 1739, 0,97(1Η, d, J=10,2 Ηζ), 1,12 e l,23(cada 1,51-2,46(14Η, m) , 4,27(1Η, m) , 5,35-5,50(2Η, m) J=8,4 Hz), 7,40 e 7,66(cada 2H, cada d, J=9,0 Hz), IV (CHCI3) : 3439, 3028, 3012, 2937, 2871, 1708, 1661, 1620, 1600, 1513/cm.
[a] D= +65,6° (MeOH, c=l,01, 22 °C) . N° 2a-113 [a] D= +59,6° (MeOH, c=l, 00, 24 °C) . N° 2a-114 CDCI3 300 MHz 3H, cada s) , , 6,28 (1H, d, 2841, 1739, 0,98 (1H, d, J=10,2 Hz), 1,12 e l,24(cada 1,52-2,46 (14H, m) , 4,29(1H, m) , 5,35-5,51(2H, m) J=8,4 Hz), 7,70 e 7,83(cada 2H, cada d, J=8,4 Hz), IV (CHCI3) : 3439, 3028, 3012, 2937, 2871, 1708, 1661, 1620, 1600, 1513/cm.
[a] D= +60,6° (MeOH, c=l,01, 22 °C) . N° 2a-115 [a] D= +59,7° (MeOH, c=0, 99, 24 °C) . N° 2a-l16 CDCI3 300 MHz 3H, cada s) , 5,51 (2H, m) , 0,97 (1H, d, J=10,2 Hz), 1,12 e l,23(cada 1,52-2,46 (14H, m) , 2,39(3H, s), 4,27(1H, m), 5,33 88 6,24(1H, d, J=9,0 Hz), 7,23 e 7,62(cada 2H, cada d, J=8,4 Hz) . IV (CHCI3) : 3439, 3028, 3012, 2937, 2871, 2841, 1739, 1708, 1661, 1620, 1600, 1513/cm. [a] D= +59,7° (MeOH, c=0, 99, 24 °C) . N° 2a-117 [α] D= +56,7° (MeOH, c=l,00, 23 °C) . N° 2a-118 CDCI3 300 MHz 0, 96 (1H, d, J=10,2 Hz), 1,11 e 1,23 (cada 3H, cada s) , 1,53-2,44 (14H, m) , 4,23(1H, m) , 5, 34-5, 51 (2H, m) , 6,02(2H, s) , 6,13 (1H, d, J=8,7 Hz), 6,83(1H, dd, J=l,2 e 7,8 Hz), 7,22-7,25(2H, m). IV (CHCI3) : 3453, 3031, 3020, 3012, 2924, 2870, 1740, 1708, 1650, 1619, 1605, 1519, 1504, 1480/cm.
[a] D= +57,2° (MeOH, c=l, 02, 23 °C) . N° 2a-l19 CDCI3 300 MHz 0, 96 (1H, d, J=10,5 Hz), 1,07 e 1,23 (cada 3H, cada s) , 1,51-2,44(14H, m) , 2,32(3H, s), 4,26(1H, m) , 5, 37-5, 52(2H, m), 6,40 (1H, d, J=9, 0 Hz), 7,09(1H, m) , 7,30(1H, m) , 7,46(1H, m) , 7,66 (1H, m) . IV (CHCI3) : 3443, 3028, 3012, 2925, 2870, 1766, 1747, 1709, 1657, 1607, 1516, 1479/cm.
[a] D= +53,2° (MeOH, c=0,99, 21 °C) . N° 2a-120 89 CDC13 300 MHz 3H, cada s) , , 6,4 2(1H, d, ,4 Hz), 7,27 2924, 2870, 0,98 (1H, d, J=10,2 Hz), 1,14 e l,24(cada 1,53-2,44(14H, m) , 4,30(1H, m) , 5,35-5,52 (2H, m) , J=8,7 Hz), 6, 85 (1H, m) , 6,99(1H, dd, J=l,2 e 8 (1H, m) , 7,3 9 (1H, m) . IV (CHCI3) : 3463, 3033, 3021, 3014, 2992, 1708, 1643, 1597, 1523, 1488/cm. [a] D= +46,3° (MeOH, c=l,01, 21 °C). N° 2a-121 CDC13 300 MHz 3H, cada s) , -5,50 (2H, m) , 9, 7,7 e 8,4 8,32(1 H, d, 2924, 2870, 0,98(1H, d, J=10,2 Hz), 1,14 e l,23(cada 1,47-2,47 (14H, m) , 3,95(3H, s), 4,31(1H, m) , 5,32 6, 98 (1H, dd, J=0, 9 e 8,4 Hz), 7,09(1H, ddd, J=0,
Hz) , 7,45 (1H, m) , 8,19(1H, dd, J=2,1 e 8 ,1 Hz), O II >~D Hz) . IV (CHCI3) : 3400, 3078, 3028, 3020 , 3007, 2842, 1736, 1708, 1640, 1600, 1536, 1483, 1470/cm, [a] D= +38,1° (MeOH, O O OO C\1 C\1 0 \—1 11 0 N° 2a-122 [a] D= +42,3° (MeOH, c=0, 99, 23 °C) . N° 2a-123 [a] D= +38,7° (MeOH, c=l,00, 21 °C) . N° 2a-124
[a] D= +45,0° (MeOH, c=l,01, 21 °C) . p.f. 119,0-120,0 °C 90 N° 2a-125 [α] D= +49,8° (MeOH, c=l,01, 22 °C) . N° 2a-126 CDC13 300 MHz 0,97(1H, d, J=10,2 Hz), 1,11 e l,23(cada 3H, cada s) , 1,52-2,47(14H, m) , 4,26(1H, m) , 5,34-5,50(2H, m) , 6,22(1H, d, J=8,7 Hz), 7,55-7,61 (4H, m) . IV (CHCI3) : 3400, 3078, 3028, 3020, 3007, 2924, 2870, 2842, 1736, 1708, 1640, 1600, 1536, 1483, 1470/cm.
[a] D= +63,0(MeOH, c=l,01, 23°C.). 2a-127 CDCI3 300 MHz 0, 91 (1H, d, J=10,2 Hz), 1,10 e 1,20 (cada 3H, cada s) , 1,50-2,42(14H, m) , 4,23(1H, m) , 5, 31-5,51(2H, m) , 6,45(1H, d, J=8,4 Hz), 7,01(1H, t, J=7,4 Hz), 7,22(2H, m), 7,33-7,40 (4H, m) , 7,53(2H, d, J=9, 0 Hz), 8,30 e 8,48(cada 1H, cada s) IV (CHCI3) : 3452, 3028, 3022, 3015, 2925, 2870, 1708, 1654, 1590, 1514, 1478/cm.
[a] D= +59,5° (MeOH, c=l,01, 23 °C) . N° 2a-128 de-DMSO 300 MHz 0,84(1H, d, J=9, 9 Hz), 1,06 e 1,19 (cada 3H, cada s) , 1,37-2,37(14H, m) , 3,79(1H, m) , 5, 35-5,51(2H, m) , 6,08(1H, d, J=8,7 Hz), 6, 85-6, 90 (1H, m) , 7, 18-7,23 (2H, m) , 7,35-7,38 (2H, m) , 8,42 (1H, s), 12,00(1H, s) . IV (Nujol): 3395, 3345, 2925, 2866, 2623, 2506, 1697, 91 1658, 1638, 1597, 1557/cm.
[α] D= +26,0° (MeOH, c=l,01, 23 °C) . p.f. 164,0-166,0 °C N° 2a-129 CDC13 300 MHz 3H, cada s) , , 6,4 2 (1H, d, 8 e 8,6 Hz), 2870, 1708, 1,01 (1H, d, J=10,0 Hz), 1,17 e l,25(cada 1.54- 2,52(14H, m) , 4,34(1H, m) , 5,36-5,57(2H, m) J=8,6 Hz), 7,51-7,60 (2H, m) , 7,77(1H, dd, J=l, 7,85-7,96(3H, m), 8,24(1H, s 1). IV (CHCI3) : 3451, 3060, 3028, 3010, 2925, 1652, 1629, 1600, 1517, 1502/cm.
[a] D= +68,6° (MeOH, c=l, 00, 22 °C) . N° 2a-130 CDCI3 300 MHz 3H, cada s) , , 6,14(1H, d, 8,27 (1H, dd, 2664, 1708, 1,02(1H, d, J=10,2 Hz), 1,04 e 1,26(cada 1.54- 2,52(14H, m) , 4,41(1H, m) , 5,41-5,58(2H, m) J=9, 0 Hz), 7,43-7,59(4H, m) , 7, 85-7, 92 (2H, m) , J=l, 8 e 7,2 Hz) . IV (CHCI3) : 3436, 3032, 3010, 2924, 2870, 1652, 1512, 1498/cm.
[a]D= +93,9° (MeOH, c=l,00, 22 °C) p.f. 94,0-96,0 °C N° 2a-131 [a] D= +50,2° (MeOH, c=0,95, 21 °C) . N° 2a-132 92 [α] D= +10,9° (MeOH, c=0,92, 21 °C) . N° 2a-133 [a] D= +60,4° (MeOH, c=l,0 0, 21 °C) . N° 2a-134 [a] D= +38,5° (MeOH, c=l,01, 23 °C) . N° 2a-135
[a] D= +52,5° (MeOH, c=l,01, 23 °C) . p.f. 180,0-182,0 °C N° 2a-136
[a] D= +35,3° (MeOH, c=l, 02, 23 °C) . p.f. 79,0-80,0 °C
[0941] N° 2a-137 CDC13 300 MHz 9 0,97(1H, d, J=10,2 Hz), 1,11 e 1,22 (cada 3H, cada s) 1,4 3 (3H, t, J=6,9 Hz), 1,52-2,44 (14H, m) , 4,03(2H, q, J=6, Hz), 4,26(1H, m), 5,33-5,50 (2H, m), 6,19(1H, d, J=8,7 Hz) 6, 88 — 7, 00(6H, m) , 7, 65-7, 68 (2H, m) . IV (CHCI3): 3455, 3031, 3024, 3014, 2988, 2925, 2870 1741, 1708, 1649, 1602, 1521, 1504, 1490/cm.
[a]D= +52,0° (MeOH, c=l,01, 23 °C) . 93 N° 2a-138 CDCI3 300 ΜΗζ 0,97( 1Η, d, J=10,2 Hz), 1,11 e l,22(cada 3H, cada s) , 1,35 ( 6H, d, J=6,0 Hz), 1,53-2,46(14H, m), 4,25(1H, m) , 4,51 (1H, m) , 5,33-5,50 (2H, m) , 6,12(1H, d, J=9,0 Hz), 6, 87-6, 99 (6H, m), 7, 65-7, 68 (2H, m) . IV (CHCI3) : 3454, 3031, 3014, 2980, 2925, 2870, 1741, 1708, 1649, 1602, 1522, 1490/cm.
[a] D= +50,0° (MeOH, c=l, 05, 22 °C) . N° 2a-139 CDCI3 300 MHz 1,0 0 (1H, d, J=10,2 Hz), 1,16 e l,24(cada 3H, cada s), 1,59-2,52 (14H, m) , 4,31(1H, m) , 5, 40-5, 53 (2H, m) , 6,36(1H, d, J=8,7 Hz), 6,7 0 (1H, d, J=l,5 Hz), 7,12(1H, m) , 7,30(1H, m) , 7,47 (1H, dd, J=0,6 e 8,1 Hz), 7,61(1H, d, J=8,4 Hz). IV (CHCI3) : 3449, 8243, 3029, 3022, 3013, 2925, 2871, 1707, 1631, 1542, 1505/cm.
[a] D= +63,4° (MeOH, c=l, 00, 23 °C) .
p.f. 178,0-179,0 °C N° 2a-140 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,18 e l,23(cada 3H, cada s) , 1,57-2,50(14H, m) , 4,35(1H, m) , 5,32-5,56(2H, m) , 6,42(1H, d, J=8,7 Hz), 6,70 (1H, d, J=l,5 Hz), 7,21-7,24(2H m) , 7,46(1H, m) , 7,7 6 (1H, m) , 7,86(1H, d, J=3, 0 Hz), 10,20(1H, s) . IV (CHCI3) : 3465, 3010, 2924, 1739, 1604, 1546, 1504/cm.
[a] D= +39,4° (MeOH, c=l,01, 22 °C) .
p.f. 167,0-168,0 °C 94 N° 2a-141 CDC13 300 ΜΗζ 0,99(1Η, d, J=10,2 Hz), 1,14 e 1,24 (cada 3H, cada s) , 1,55-2,44(14H, m) , 3,84(3H, s), 4,27(1H, m) , 5,34-5,52(2H, m), 6,28(1H, d, J=9,0 Hz), 6,91 e 7,47(cada 2H, cada d, J=9, 0 Hz), 6,98 e 7,14(cada 1H, cada d, J=16,5 Hz), 7,54 e 7,70(cada 2H, cada d, J=8,7 Hz) .
IV (CHCI3) : 3453, 1708 , 1649, 1602, 1510, [a] D= +73,4° (MeOH p.f. 155,0-157,0 0 N° 2a-142 CDCI3 300 MHz 0,97(1H, d, J=10, 1,52 -2,45(14H, m) , 3, li 6,24 (1H, d, J=9,0 Hz) , Hz) , 6,77 e 7,16(cada 2H, cada d, J=8,1 Hz) . IV (CHCI3) : 3453, 1708 , 1649, 1606, 1510, [a] D= +60,7° (MeOH N° 2a-143 [a]D= +57,3° (MeOH N° 2a-144 [a] D= +12,2° (MeOH
p.f. 114,0-116,0 °C 95 N° 2a-145 CDC13 300 ΜΗζ 0, 95 (1Η, d, J=10,2 Ηζ), 1,10 e l,21(cada 3Η, cada s) , 1,52-2,44(14H, m) , 4,25(1H, m) , 5,33-5,49 (2H, m) , 6,37(1H, d, J=8,7 Hz), 7,45-7,47 (3H, m) , 7, 62-7, 66(2H m) , 7,69 e 7,80(cada 2H, cada d, J=7,5 Hz, ). IV (CHCI3) : 3449, 3058, 3027, 3012, 2925, 2870, 1708, 1655, 1513, 1481, 1043/cm.
[a] D= +61,0° (MeOH, c=l,01, 23 °C) . N° 2a-146 CDCI3 300 MHz 0, 95 (1H, d, J=10,5 Hz), 1,09 e l,21(cada 3H, cada s) , 1,50-2,41 (14H, m) , 4,25(1H, m) , 5,33-5,4 9 (2H, m) , 6,33(1H, d, J=8,4 Hz), 7,49-7, 61(3H, m) , 7,91-7,92(2H, m) , 7,82 e 7,97(cada 2H, cada d, J=8,7 Hz,). IV (CHCI3): 3447, 3029, 3023, 3015, 2925, 2870, 1708, 1660, 1514, 1484, 1321, 1161/cm.
[a] D= +62,0° (MeOH, c=l, 00, 22 °C) . N° 2a-147 CDCI3 300 MHz; 0,97(1H, d, J=10,2 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1,52-2,46 (14H, m), 2,51(3H, s), 4,26(1H, m), 5,34-5,51(2H, m), 6,23(1H, d, J=8,4 Hz), 7,26 e 7,64(cada 2H, cada d, J=8,4 Hz) . IV (CHCI3) : 3453, 3027, 3015, 2925, 2870, 2665, 1708, 1648, 1596, 1516, 1484/cm.
[a]D= +67,7° (MeOH, c=0,82, 226 °C) . 96 N° 2a-148 [α] D= +72,5° (MeOH, c=l,01, 25 °C) . N° 2a-149 [a] D= +67,8° (MeOH, c=0, 98, 25 °C) . N° 2a-150 CDC13 300 MHz 3H, cada s) , , 6,48 (1H, d, 2925, 2871, 0,94 (1H, d, J=10,2 Hz), 1,10 e l,23(cada 1,52-2,50(14H, m) , 4,22(1H, m) , 5,36-5,55 (2H, m) , J=8,4 Hz), 8,35 (1H, s), 8,90(1H, s). IV (CHCI3) : 3443, 3374, 3091, 3024, 3012, 1709, 1652, 1525, 1494/cm.
[a] D= +58,1° (MeOH, c=l,01, 23 °C) . p.f. 120,0-122,0 °C N° 2a-151 [a] D= +40,6° (MeOH, c=l,01, 23 °C) . N° 2a-152 CDCI3 300 MHz 3H, cada s) , -5,51 (2H, m) , 2925, 2870, 0,96(1H, d, J=10,5 Hz), 1,10 e 1,24(cada 1,50-2,50(14H, m) , 2,71(3H, s), 4,26(1H, m) , 5,37 6,02(1H, d, J=9,0 Hz), 8,73(1H, s). IV (CHCI3) : 3463, 3435, 3087, 3025, 3014, 1708, 1649, 1523, 1503/cm.
[a] D= +54,1° (MeOH, c=l, 02, 22 °C) . 97 N° 2a-153 CDC13 300 ΜΗζ 0,95(1Η, d, J=9, 9 Hz) , 1,11 e l,23(cada 3H, cada s) , 1,50-2,50(14H, m), 2,50(3H, s), 4,26(1H, m) , 5,36-5,51(2H, m), 6,01(1H, d, J=8,4 Hz), 6,88(1H, d, J=5,l Hz), 7,26(1H, d, J=5,1 Hz) . IV (CHCI3) : 3469, 3431, 3025, 3013, 2925, 2871, 2664, 1708, 1639, 1544, 1505/cm.
[a] D= +35,8° (MeOH, c=l, 03, 22 °C) . N° 2a-154 CDCI3 300 MHz 0, 95 (1H, d, J=9, 9 Hz), 1,10 e l,22(cada 3H, cada s) , 1.52- 2,46(14H, m), 2,51(3H, d, J=l,2 Hz), 4,26(1H, m) , 5,34-5,50(2H, m), 6,00(1H, d, J=8,4 Hz), 6,73(1H, dd, J=5,l e 3,6 Hz), 7,29 (1H, d, J=3, 6 Hz). IV (CHCI3): 3450, 3431, 3026, 3011, 2925, 2869, 1739, 1708, 1639, 1547, 1508/cm.
[a] D= +50,5° (MeOH, c=l,01, 22 °C) . N° 2a-155 CDCI3 300 MHz 0,99(1H, d, J=10,2 Hz), 1,19 e 1,25 (cada 3H, cada s) , 1.53- 2,48 (14H, m) , 4,31(1H, m) , 5, 36-5, 51 (2H, m) , 6,79(1H, d, J=9, 3 Hz), 7,29 (1H, m) , 7,41(1H, m) , 7,48(1H, s) , 7,51(1H, m) , 7,66(1H, d, J=8,1 Hz). IV (CHCI3) : 3436, 3029, 3024, 3015, 2925, 2871, 2670, 1708, 1659, 1598, 1510/cm.
[a] D= +69,1° (MeOH, c=l,01, 22 °C) . 98 N° 2a-156 CDC13:CD30D=10 :1 300 MHz 0,99(1H, d, J=9, 9 Hz), 1,11 e 1,21 (cada 3H, cada s) , 1,56-2,58(14H, m) , 4,22(1H, m) , 5,35-5,59 (2H, m) , 6,83(1H, d, J=8,4 Hz), 7,4 8 (1H, d, J=8,4 Hz), 7,61(1H, dd, J=l,5 e 8,4 Hz), 8,0 9 (1H, d, J=1,5 Hz), 8,12(1H, s). IV (KBr): 3422, 3115, 2985, 2922, 2869, 2609, 1708, 1636, 1578, 1529, 1470/cm.
[a] D= +62,8° (MeOH, c=l,01, 22 °C) . N° 2a-157 [a] D= +40,0° (MeOH, c=0, 95, 22 °C) . N° 2a-158 CDCI3 300 MHz 1,0 0 (1H, d, J=10,5 Hz), 1,17 e 1,24 (cada 3H, cada s), 1.54- 2,50(14H, m) , 4,34(1H, m) , 5, 36-5, 52(2H, m) , 7,80(1H, d, J=9, 0 Hz) , 9,30 (1H, s) . IV (CHCI3) : 3410, 3122, 3030, 3012, 2925, 2871, 2668, 1709, 1667, 1538, 1466/cm.
[a] D= +44,9° (MeOH, c=0, 99, 220 °C) . N° 2a-159 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,13 e 1,22 (cada 3H, cada s) , 1.55- 2,43(14H, m), 3,03(6H, s), 4,23(1H, m) , 5,32-5,51(2H, m), 6,16(1H, d, J=8,7 Hz), 6,87 e 7,63(cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3457, 3028, 3006, 2924, 2870, 2654, 1739, 1709, 1637, 1608, 1608, 1534, 1501/cm. 99 [ α] D= +64,8° (MeOH, c=l,01, 22 °C) . N° 2a-l60 dg-DMSO 300 MHz 0,83(1H, d, J=9, 9 Hz), 1,02 e 1,19 (cada 3H, cada s) , 1,38-1,61 (3H, m), 1, 90-2,32(11H, m), 3,90(1H, m), 5, 41-5,44 (2H, m) , 7,32(1H, dd, J=0,9 e 7,2 Hz), 7,45-7,60 (2H, m) , 7,77 (1H, dd, J=0,9 e 7,8 Hz), 8,03(1H, d, J=6, 9 Hz), 12,40 (1H, s) . IV (Nujol): 3315, 2924, 2856, 2656, 2535, 1737, 1703, 1637, 1598, 1581, 1541/cm.
[a] D= +78,5° (MeOH, c=l,01, 24 °C) . p.f. 161,0-162,0 °C N° 2a-l61 [a] D= +65,3° (MeOH, c=l, 00, 22 °C) . N° 2a-l62 CDC13 300 MHz 0,99(1H, d, J=10,2 Hz), 1,13 e 1,25 (cada 3H, cada s) , 1,53-2,45(14H, m) , 4,30(1H, m) , 5,36-5,51 (2H, m) , 6,32(1H, d, J=8,4 Hz), 7,88 e 8,28(cada 2H, cada d, J=9,0 Hz). IV (CHCI3) : 3448, 3029, 3016, 2925, 2870, 1708, 1664, 1602, 1527, 1484, 1347/cm.
[a] D= +72,7° (MeOH, c=l, 02, 22 °C) . N° 2a-l63 CDCI3 300 MHz 0,96 (1H, d, J=10,2 Hz), 1,11 e 1,23(cada 3H, cada s), 100 1,55-2,51(14Η, m) , 4,26(1H, m) , 5, 36-5, 57(2H, m) , 6,68(1H, d J=7,8 Hz), 7,41 (1H, dd, J=4,8 e 8,1Hz), 8,20(1H, d, J=8,l Hz) 8,6 6 (1H, d, J=4,8 Hz), 9,00(1H, s) . 2534, 1709, 3H, cada s) , 6, 63(1H, d, 2870, 2538, 3H, cada s) , -5,50 (2H, m) , d, J=8,4 Hz), 2806, 1739, IV (CHC13) : 3448, 3026, 3013, 2925, 2870, 1658, 1590, 1515, 1471/cm.
[a] D= +71,3° (MeOH, c=l,01, 22 °C) . N° 2a-l64 [a] D= +40,8° (MeOH, c=0, 98, 22 °C) . N° 2a-l65 CDCI3 300 MHz 0,96(1H, d, J=10,5 Hz), 1,11 e 1,24(cada 1,55-2,52(14H, m) , 4,24(1H, m) , 5, 37-5, 57(2H, m) , J=7,8 Hz), 7,59 e 8,63(cada 2H, cada d, J=6,0 Hz). IV (CHCI3) : 3447, 3346, 3028, 3016, 2925, 1941, 1708, 1662, 1556, 1516/cm.
[a] D= +75,4° (MeOH, c=l,01, 22 °C) . N° 2a-l66 CDCI3 300 MHz 0,97(1H, d, J=10,2 Hz), 1,11 e 1,22(cada 1,51-2,44 (14H, m) , 2,95(6H, s) , 4,25(1H, m) , 5,33 6,19(1H, d, J=8,7 Hz), 6,77 e 6,97(cada 2H, cada 6,94 e 7,65 (cada 2H, cada d, J=9,0 Hz). IV (CHCI3) : 3453, 3024, 3016, 2924, 2871, 1708, 1647, 1612, 1604, 1515, 1490/cm.
[a] D= +53,1° (MeOH, c=l, 02, 23 °C) . p.f. 104,0-105,5 °C 101 N° 2a-l67 CDCI3 300 ΜΗζ 1,01(1Η, d, J=9, 9 Hz), 1,19 e l,26(cada 3H, cada s) , 1.56- 2,53(14H, m) , 4,37(1H, m) , 5,35-5,55(2H, m) , 6,47(1H, d, J=8,4Hz), 7, 61-7,71(2H, m), 7,79(2H, s), 7,89-7, 97 (2H, m), 8,27(1H, d, J=2,1 Hz), 8,66-8,73(2H, m). IV (CHCI3) : 3450, 3024, 3014, 2925, 2870, 2667, 1707, 1650, 1531, 1509/cm.
[a] D= +70,5° (MeOH, c=l, 00, 22 °C) . N° 2a-l68 CDCI3 300 MHz 1,02 (1H, d, J=10,2 Hz), 1,20 e l,26(cada 3H, cada s), 1.56- 2,50(14H, m) , 4,38(1H, m) , 5,36-5,56(2H, m) , 6,51(1H, d, J=8,4 Hz), 7,61-7,93 (7H, m), 8,74(1H, d, J=8,4 Hz), 9,15 (1H, s) . IV (CHCI3) : 3517, 3451, 3060, 3028, 3011, 2925, 2870, 2664, 1709, 1651, 1519, 1498/cm.
[a] D= +54,4° (MeOH, c=l, 00, 23 °C) . N° 2a-169 CDCI3 300 MHz 0, 96 (1H, d, J=10,5 Hz), 1,09 e l,21(cada 3H, cada s) , 1,50-2,44(14H, m), 3,85(3H, s), 4,24(1H, m) , 5,32-5,48(2H, m), 6,19 (1H, d, J=8,4 Hz), 6,94 e 7,45(cada 2H, cada d, J=9,0 Hz), 7,11 e 7,45(cada 2H, cada d, J=8,7 Hz). IV (CHCI3) : 3516, 3453, 3029, 3009, 2925, 2870, 2840, 2665, 1708, 1650, 1593, 1515, 1493, 1482/cm.
[a] D= +57,8° (MeOH, c=l, 00, 23 °C) . 102 N° 2a-170 CDC13 300 ΜΗζ 0,98 (1Η, d, J=10,2 Hz), 1,15 e 1,24 (cada 3H, cada s), 1.52- 2,50(14H, m) , 4,28(1H, m) , 5, 33-5, 54 (2H, m) , 6,25(1H, d, J=8,2 Hz), 7,38-7,44(2H, m) , 7,74(1H, s), 7,81-7,86(2H, m) . IV (CHCI3) : 3517, 3448, 3427, 3024, 3013, 2925, 2870, 2669, 1708, 1650, 1562, 1535, 1500/cm.
[a] D= +61,6° (MeOH, c=l, 00, 23 °C) . N° 2a-171 CDCI3 300 MHz 0,96(1H, d, J=10,2 Hz, 1,11 e 1,22 (cada 3H, cada s) , 1.52- 2,42(14H, m) , 2,48(3H, s), 4,21(1H, m) , 6,31-5,52(2H, m), 6,06(1H, d, J=8,2 Hz), 6,97 e 7,59(cada 1H, cada d, J=l,2 Hz). IV (CHCI3) : 3452, 3113, 3028, 3007, 2925, 2870, 2669, 1708, 1645, 1554, 1509/cm.
[a] D= +52,4° (MeOH, c=l, 00, 23 °C) . N° 2a-172 CDCI3 300 MHz 0,96(1H, d, J=10,2 Hz), 1,09 e 1,28 (cada 3H, cada s) , 1,50-2,40(14H, m) , 2,69(3H, s), 4,24(1H, m) , 5,35-5,51(2H, m), 5,96 (1H, d, J=8,7 Hz), 7,03 e 7,07(cada 1H, cada d, J=5,4 Hz). IV (CHCI3) : 3451, 3031, 3013, 2925, 2870, 2666, 1708, 1647, 1542, 1497/cm.
[a] D= +51,2° (MeOH, c=l, 0 0, 23 °C) . N° 2a-173 CDCI3 300 MHz 103 0, 95 (1Η, d, J=10,2 Hz), 1,10 e 1,23 (cada 3H, cada s) , 1.50- 2,45 (14H, m) , 4,22(1H, m) , 5,35-5,49 (2H, m) , 6,05(1H, d, J=8,4 Hz), 7,26 e 7,75(cada 1H, cada d, J=l,5 Hz). IV (CHC13) : 3451, 3011, 3029, 3011, 2925, 2870, 1708, 1652, 1538, 1500/cm.
[a] D= +50,6° (MeOH, c=l,01, 23 °C) . N° 2a-174 CDCI3 300 MHz 0, 96 (1H, d, J=10,2 Hz), 1,13 e 1,23 (cada 3H, cada s) , 1,52-2,50 (14H, m) , 4,29(1H, m) , 5, 35-5, 51 (2H, m) , 7,02(1H, d, J=8,4 Hz), 7,32 e 8,16(cada 1H, cada d, J=3,9 Hz). IV (CHCI3) : 3417, 3115, 3023, 3014, 2925, 2870, 1708, 1645, 1530/cm.
[a] D= +48,8° (MeOH, c=l, 02, 23 °C) . N° 2a-175 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,14 e 1,23 (cada 3H, cada s) , 1.50- 2,52(14H, m), 2,52(3H, s), 4,29(1H, m) , 5,34-5,51(2H, m), 7,78(1H, d, J=9, 0 Hz), 7,24 e 7,52(cada 1H, cada d, J=5,4 Hz). IV (CHCls) : 3329, 3093, 3023, 3015, 2924, 2871, 1708, 1640, 1526/cm.
[a] D= +45,0° (MeOH, c=l,01, 23 °C) . N° 2a-176 CDCI3 300 MHz 0,95(1H, d, J=10,5 Hz) , 1,09 e 1,23 (cada 3H, cada s) 1,52-2,46 (14H, m) , 2,40(3H, d, J=0, 9 Hz), 4,24(1H, m) 5, 35-5, 51(2H, m) , 6,05 (1H, d, 00 II •d 7 Hz) , 6, 95(1H, m) , 7, 57 104 (1Η, d, J=3,3 Hz) . IV (CHCI3) : 3517, 3444, 3103, 3024, 3013, 1739, 1708, 1649, 1636, 1507/cm. [a] D= +54,8 0 (MeOH, O 0 00 c\] 1 -1 0 \—1 11 υ p.f. 97,0-99, O O O 2926, 2870, N° 2a-177 CDC13 300 MHz 3H, cada s) , -5,50 (2H, m) , 8,10 (1H, d, 2925, 2871, 3H, cada s) , - 6,09(1H, d, 3011, 2925, 3H, cada s) , 6,73(1H, d, 0,97(1H, d, J=10,2 Hz), 1,19 e 1,23(cada 1,52-2,45(14H, m) , 3,93(3H, s) , 4,27(1H, m) , 5,34 6,35(1H, d, J=3,3 Hz), 7,80(1H, d, J=8,7 Hz), J=3,3 Hz) . IV (CHCla): 3395, 3121, 3031, 3019, 3012, 1739, 1709, 1640, 1557, 1533/cm.
[a] D= +22,8° (MeOH, c=l,01, 23 °C) . p.f. 109,0-112,0 °C N° 2a-178 CDCI3 300 MHz 0,96(1H, d, J=10,5 Hz), 1,10 e 1,23(cada 1,51-2,45(14H, m) , 4,24(1H, m) , 5,35-5,50(2H, m) , J=8,4 Hz), 7,17-7,31 (6H, m), 7,95(1H, d, J=l,5 Hz) IV (CHC13) : 3510, 3451, 3062, 3031 , 3022, 2870, 2662, 1708, 1651, 1582, 1535, 1497, 1477/cm, [a] D= +47,9o (MeOH, c=l,01, 25 °C). N° 2a-179 CDCI3 300 MHz 0,96(1H, d, J=10,2 Hz), 1,14 e l,24(cada 1,52-2,48(14H, m) , 4,30(1H, m) , 5,36-5,52(2H, m) , 105 J=9,0 Hz), 6,26 e 7,37(cada 1H, cada d, J=6,0 Hz). IV (CHC13) : 3509, 3429, 3115, 3094, 3025, 3014, 2925, 2871, 2666, 1708, 1649, 1529, 1510/cm.
[a]D= +51,0° (MeOH, c=l, 02, 25 °C) . N° 2a-l80 CDCI3 300 MHz 0,95(1H, d, J=10,2 Hz), 1,14 e 1,24 (cada 3H, cada s) , 1.52- 2,46(14H, m), 3,89(3H, s), 4,21(1H, m) , 5, 35-5, 50(2H, m), 6,05(1H, d, J=8,4 Hz), 6,46 e 7,04(cada 1H, cada d, J=l,8 Hz). IV (CHCI3) : 3516, 3450, 3114, 3031, 3010, 2925, 2871, 1708, 1648, 1546, 1511, 1477/cm.
[a] D= +49,1° (MeOH, c=l,01, 25 °C) . N° 2a-181 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,14 e 1,23 (cada 3H, cada s), 1.52- 2,48(14H, m) , 2,42(3H, s), 4,31(1H, m) , 5, 34-5, 52(2H, m), 8,07(1H, d, J=9,3 Hz), 7,27 e 8,17(cada 1H, cada d, J=3,3 Hz). IV (CHCI3): 3510, 3301, 3112, 3023, 3007, 2924, 2871, 2663, 1708, 1636, 1534/cm.
[a] D= +41,0° (MeOH, c=0, 96, 25 °C) . N° 2a-182 CDCI3 300 MHz 0, 9 6 (1H, d, J=10,2 Hz), 1,11 e l,23(cada 3H, cada s) , 1.53- 2,46(14H, m), 2,51(3H, s), 4,21(1H, m) , 5,35-5,51(2H, m), 6,05(1H, d, J=8,l Hz), 7,26 e 7,78(cada 1H, cada d, J=l,8 Hz). IV (CHCI3) : 3509, 3450, 3109, 3024, 3012, 2925, 2870, 2666, 1708, 1650, 1535, 1498, 1471/cm. 106 [α] D= +52,9° (MeOH, c=0, 95, 25 °C) . N° 2a-183 CDC13 300 MHz 0,96(1H, d, J=10,5 Hz), 1,12 e 1,22 (cada 3H, cada s) , 1,52-2,46(14H, m) , 4,25(1H, m) , 5,33-5,51 (2H, m) , 6,17(1H, d, J=8,7 Hz), 7,01-7,05 (3H, m) , 7,14 e 7,62(cada 2H, cada d, J=8,7 Hz), 7,27-7,34 (2H, m) . IV (CHCI3) : 3428, 3026, 3015, 2925, 2870, 2666, 1739, 1708, 1643, 1613, 1594, 1526, 1499/cm.
[a] D= +64,8° (MeOH, c=l, 02, 23 °C) . N° 2a-l84 CDCI3 300 MHz 1,01(1H, d, J=10,2 Hz), 1,18 e 1,26 (cada 3H, cada s) , 1.55- 2,50 (14H, m) , 4,35(1H, m) , 5,35-5, 55 (2H, m) , 6,42(1H, d, J=8,7 Hz), 7,46-7,52 (2H, m) , 7,73(1H, dd, J=l,8 e 8,4 Hz), 7, 83-7, 89 (2H, m), 8,21(1H, m), 8,59(1H, d, J=l,5 Hz). IV (CHCI3) : 3451, 3031, 3014, 2925, 2870, 2660, 1739, 170821650, 1604, 1513, 1463/cm.
[a] D= +58,3° (MeOH, c=l, 00, 23 °C) . N° 2a-185 CDCI3 300 MHz 1,00(1H, d, J=10,2 Hz), 1,18 e 1,25 (cada 3H, cada s) , 1.55- 2,50(14H, m) , 4,34(1H, m) , 5, 35-5, 54(2H, m) , 6,36(1H, d, J=8,7 Hz), 7,37 (1H, t, J=7,4 Hz), 7,50(1H, m) , 7,57-7,59(2H, m) , 7,7 9 (1H, dd, J=l,8 e 8,1 Hz), 7,99(1H, d, J=7,8 Hz), 8,39(1H, d, J=1,8 Hz) . IV (CHCI3) : 3451, 3030, 3020, 2870, 2665, 1708, 1652, 107 1632, 1603, 1586, 1514, 1469, 1448/cm.
[α] D= +59,4° (MeOH, c=l,01, 24 °C) . N° 2a-186 CDC13 300 MHz 1, 0 0 (1H, d, J=10,5 Hz), 1,17 e 1,25 (cada 3H, cada s) , 1,54-2,50(14H, m) , 4,33(1H, m) , 5,35-5,54(2H, m) , 6,37(1H, d, J=8,7 Hz), 7,37(1H, t, J=7,4 Hz), 7,51(1H, t, J=7,8 Hz) , 7,5 6 (1H, m) , 7,70(1H, dd, J=l,2 e 8,4 Hz), 7,97(3H, m) . IV (CHCI3) : 3451 1708, 1652, 1577, 1517 , 3030, 3014, , 1488, 1471/cm. 2924, 2870, 2671, 1739, [a] D= +72,2° (MeOH, c=l, 00, 24 °C) . N° 2a-187 CDCI3 300 MHz 1, 0 0 (1H, d, J=9, 8 Hz), 1,18 e 1,25 (cada 3H, cada s) , 1,54-2,53 (14H, m) , 4,07(3H, s), 4,37(1H, m) , 5, 30-5, 54(2H, m), 7,34(1H, m) , 7,47(1H, s), 7,47-7, 60 (2H, m) , 7,93(1H, d, J=7,8
Hz), 8,43(1H, s), 8,4 9(1H, d, J=9,0 Hz). IV (CHCI3): 3397, 3074, 3027, 3020, 3009, 2924, 1738, 1708, 1647, 1633, 1534, 1465, 1453/cm.
[a] D= +43,7° (MeOH, c=l,01, 25 °C) . N° 2a-l88 CDCI3 300 MHz 0, 97 (1H, d, J=10,2 Hz), 1,11 e l,23(cada 3H, cada s) , 1,53-2,50(14H, m) , 4,23(1H, m) , 5,37-5,50(2H, m) , 6,10(1H, d, J=9, 0 Hz), 6,20 (1H, m) , 6,51(1H, m) , 6,97(1H, m) , 10,81 (1H, s 1) . IV (CHCI3) : 3450, 3236, 3112, 3029, 3015, 2925, 2871, 108 2645, 1701, 1616, 1558, 1516/cm.
[α] D= +50,6° (MeOH, c=l,01, 24 °C) . N° 2a-189 CDCI3 300 MHz 0,94(1H, d, J=9, 9 Hz), 1,11 e 1,23 (cada 3H, cada s) , 1,50-2,46(14H, m) , 3,93(3H, s) , 4,18(1H, m) , 5, 35-5, 52(2H, m) , 6, 03 (1H, d, J=9, 3 Hz), 6, 0 9 (1H, m) , 6,48(1H, m) , 6,73(1H, m) . IV (CHCI3) : 3452, 3102, 3028, 3007, 2925, 2871, 2666, 1739, 1708, 1650, 1536, 1499, 1471/cm.
[a] D= +49,8° (MeOH, c=l,01, 23 °C) . p.f. 101,5-103,5 °C N° 2a-l90 CDCI3 300 MHz 0, 94 (1H, d, J=10,2 Hz), 1,11 e 1,21 (cada 3H, cada s) , 1.54- 2,47(14H, m) , 4,23(1H, m) , 5, 33-5, 52 (2H, m) , 6,06(1H, d, J=9, 0 Hz), 6,34 (1H, m) , 6,75(1H, m) , 6,36(1H, m) , 9,71(1H, s 1) . IV (CHCI3) : 3470, 3215, 3030, 3020, 3010, 2925, 2871, 2664, 1709, 1613, 1564, 1510/cm.
[a] D= +43,3° (MeOH, c=l,01, 24 °C) . N° 2a-l91 CDCI3 300 MHz 0,96(1H, d, J=10,2 Hz), 1,11 e 1,22 (cada 3H, cada s) , 1.55- 2,44(14H, m) , 3,66 (3H, s), 4,20(1H, m), 5,35-5,51(2H, m), 5, 93 (1H, d, J=8,4 Hz), 6,27(1H, dd, J=l,8 e 2,7 Hz), 6,56 (1H, t, J=2,7 Hz), 7,19 (1H, t, J=l,8 Hz). IV (CHCI3) : 3452, 3031, 3018, 3006, 2925, 2871, 2662, 109 1736, 1710, 1634, 1609, 1556, 1498/cm.
[α] D= +43,1° (MeOH, c=l,01, 23 °C) . N° 2a-l92 CDC13 300 MHz 0, 96 (1H, d, J=10,5 Hz), 1,11 e 1,21 (cada 3H, cada s) , 1,43 (3H, t, J=7,5 Hz), 1,54-2,44 (14H, m) , 3,93 (2H, q, J=7,5
Hz), 4,21 (1H, m) , 5,33-5,51(2H, m), 5,94(1H, J=8,4 Hz), 6,27 (1H, dd, J=1, 8 e 2,7 Hz), 6,62(1H, t, J=2,7 Hz), 7,26 (1H, t, J=l,8 Hz) . IV (CHCI3) : 3630, 3452, 3032, 3018, 3006, 2925, 2871, 2661, 1735, 1710, 1633, 1610, 1555, 1497/cm.
[a]D= +40,1° (MeOH, c=l, 00, 23 °C) . N° 2a-l93 CDCI3 300 MHz 0,95(1H, d, J=10,2 Hz), 1,10 e l,22(cada 3H, cada s), 1,53-2,49(14H, m), 2,58(3H, s), 4,21(1H, m) , 5, 35-5, 54(2H, m), 6, 15 (1H, d, J=8,1 Hz), 6,52(1H, dd, J=l,8 e 3,6 Hz), 7,29 (1H, t, J=3,6 Hz), 7,94 (1H, t, J=l,8 Hz). IV (CHCI3) : 3516, 3450, 3410, 3152, 3027, 3015, 2925, 2871, 2670, 1732, 1648, 1574, 1509/cm.
[a] D= +45,0° (MeOH, c=l,01, 25 °C) . N° 2a-l94 CDCI3 300 MHz 0,99(1H, d, J=10,2 Hz), 1,11 e 1,24 (cada 3H, cada s) , 1,52-2,53(14H, m) , 4,34(1H, m) , 5,33-5,57(2H, m) , 6,21(1H, d, J=8, 6 Hz), 7,35-7,50 (2H, m) , 7,83(1H, s) 7,86(1H, m) , 8,31 (1H, m). 110 IV (CHC13) : 3443, 3067, 3013, 2925, 2870, 2665, 1708, 1651, 1515, 1493/cm.
[α] D= +55,7° (MeOH, c=l,01, 23 °C) . N° 2a-l95 CDC13 300 MHz 1,01 (1H, d, J=10,0 Hz), 1,06 e l,26(cada 3H, cada s), 1,50-2, 64(14H, m), 2,68(3H, s), 4,40(1H, m) , 5,36-5,61(2H, m), 6,02(1H, d, J=9,4 Hz), 7,30-7,42 (2H, m), 7,73-7, 86 (2H, m) . IV (CHCI3): 3510, 3434, 3062, 3029, 3014, 2924, 2871, 2669, 1708, 1650, 1563, 1539, 1500/cm.
[a] D= +72,4° (MeOH, c=l, 00, 23 °C) .
p.f. 111,0-112,0 °C N° 2a-l96 CDCI3 300 MHz 0,42 e 1,04 (cada 3H, cada s), 0,80(1H, d, J=10,0 Hz), 1,11-2,48(14H, m), 2,24(3H, s), 4,02(1H, m) , 5,23-5, 44(2H, m), 5,53(1H, d, J=8,8 Hz), 7,27-7,31 (2H, m), 7,42-7,48 (3H, m), 7, 93(1H, s) . IV (CHCI3): 3419, 3114, 3025, 3006, 2924, 2871, 2662, 1737, 1709, 1636, 1540, 1519/cm.
[a] D= +43,7° (MeOH, c=l,01, 23 °C) . N° 2a-l97 CDCI3 300 MHz 0,95(1H, d, J=10,0 Hz), 1,09 e 1,23 (cada 3H, cada s) , 1,54-2,46(18H, m), 2,77(4H, s 1), 4,21(1H, m) , 5,32-5,54 (2H, m) , 6, 02 (1H, d, J=8,6 Hz), 7,43(1H, s) . IV (CHCI3) : 3445, 3101, 3024, 3014, 2928, 2865, 2661, 111 1739, 1708 1646, 1550, 1507/cm.
[α] D= +51,9° (MeOH, c=l,01, 23 °C) . N° 2a-l98 CDCI3 300 MHz 0, 96 (1H, d, J=10,2 Hz), 1,11 e l,22(cada 3H, cada s) , 1,50-2,44 (14H, m) , 4,24(1H, m) , 4,42(2H, s) , 5, 35-5, 49 (2H, m) , 6,25 (1H, d, J=8,1 Hz), 7,33(1H, m) , 7,43(1H, dd, J=l,5 e 7,5
Hz) , 7,49(1H, d, J=8, 1 Hz), 7, 60-7, 63 (1H, m) , 7,68(1H, dd, 1—1 II 8 e 7,8 Hz), 8,02(1H, d, J=1,8 Hz), 8,19(1H, dd, J=1,5 e ι—1 00 Hz) . IV (CHCI3) : 3448, 3030, 3012, 2925, 2870, 1739, 1708, 1671 , 1588, 1559, 1514, 1472/cm. [a] D= +56,9° (MeOH, c=l,01, 24 °C) . N° 2a-l99 CDCI3 300 MHz 0, 96 (1H, d, J=10,2 Hz), 1,11 e 1,22 (cada 3H, cada s) , 1.51- 2,46 (14H, m) , 3,40(1H, m) , 3,76(1H, m) , 4,24(1H, m) , 5,33-5,51 (3H, m) , 6,25(1H, m) , 7,16(1H, m) , 7,24-7,33 (2H, m) , 7,4 6(1H, d, J=7,5 Hz), 7,52-7, 60(2H, m) , 7,85(1H, dd, J=l,8 e 5 Hz). IV (CHCI3): 3583, 3447, 3062, 3028, 3013, 2924, 2871, 2663, 1708, 1651, 1600, 1557, 1514, 1471/cm.
[a] D= +54,8° (MeOH, c=l, 00, 23 °C) . N° 2a-200 CDCI3 300 MHz 0,96(1H, d, J=10,2 Hz), 1,12 e 1,23 (cada 3H, cada s) , 1.51- 2,46(14H, m), 4,25(1H, m), 5,34-5,51(2H, m), 6,25(1H, d, 112 J=8,4 Hz), 7,02 e 7,10(cada 1H, cada d, J=12,3 Hz), 7,23-7,33 (4H, m) , 7,50(1H, m) , 7,64(1H, dd, J=l,8 e 7,8 Hz), 7,82 (1H, d, J=l,8 Hz) . IV (CHC13) : 3450, 3060, 3025, 3014, 2925, 2871, 2662, 1708, 1653, 1596, 1542, 1513, 1473/cm.
[a] D= +62,5° (MeOH, c=l, 00, 24 °C) . N° 2a-201 CDCI3 300 MHz 0,95(1H, d, J=9, 9 Hz), 1,15 e 1,22 (cada 3H, cada s) , 1,55-2, 60(14H, m) , 4,26(1H, m) , 5, 35-5, 63(2H, m) , 7,14(1H, d, J=9, 9 Hz), 7,34 e 7,40 (cada 1H, cada d, J=12,9 Hz), 7,62-7,73(4H, m), 8,25-8,30(2H, m), 8,72(1H, d, J=l,5 Hz). IV (CHCIs) : 3443, 3389, 3297, 3061, 3030, 3016, 2925 2870, 1708 1652, 1603, 1521, 1483, 1472, 13 0 9/cm. [a]D— +61, 1 0 (MeOH, c=l, PO CM 1—1 0 °C) . N° 2a-202 CDCI3 300 MHz 0, 96 (1H, d, J=10,2 Hz), 1,09 e l,22(cada 3H, cada s) , 1,52-2,43(14H, m), 2,63(3H, s), 4,25(1H, m) , 5,33-5,49(2H, m), 6,19(1H, d, J=8,4 Hz), 7,10 e 7,58(cada 2H, cada d, J=9,0 Hz), 7,21 (1H, m), 7,30-7,32 (2H, m), 7,46(1H, d, J=7,5 Hz) IV (CHCI3) : 3511, 3453, 3062, 3032, 3014, 2925 2870, 1739, 1708, 1650, 1595, 1556, 1516, 1482, 1471/cm.
[a] D= +60,2° (MeOH, c=l,01, 25 °C) . N° 2a-203 CDCI3 300 MHz 0,96(1H, d, J=10,5 Hz), 1,09 e 1,23(cada 3H, cada s), 113 1,52-2,43(14Η, m) , 4,23(1H, m) , 5,35-5,51(2H, m) , 5,93(1H, d J=8,7 Hz), 6,5 6 (1H, dd, J=0,9 e 1,8Hz), 7,43(1H, t, J=l,8 Hz) 7,92 (1H, dd, J=0,9 e 1,8 Hz). 2667 IV (CHC13) : 3517, 1708, 1656, 1588, [a]D= +46,7° (MeOH, N° 2b-l [a]D= +25,6° (MeOH, N° 2b-2 [a] D= +38,9o (MeOH, N° 2c-l [a]D= +60,5° (MeOH, N° 2c-2 [a] D= +55, 8 0 (MeOH, N° 2c-3 [a]D= +54,7° (MeOH, N° 2d-l [a] D= -6,2° (MeOH, N° 2d-2 3450, 3134, 3031, 1570, 1514/cm. c=0,92, 25 °C). c=l,01, 23 °C). c=l,01, 24 °C). c=l,01, 22 °C). c=0,92, 22 °C). c=l,01, 22 °C). c=l,00, 21 °C). 3008, 2925, 2870, 114 [ α] D= +15,8° (MeOH, c=0,34, 22° C) N° 2d-3 [a] D= +31,6° (MeOH, c=l,01, 22 °C) \—1 1 ω C\1 o 3 O 1 II Ω (MeOH, c=l,00, 22 °C). N° 2e-2 O 00 \—1 1 II Ω (MeOH, c=l,02, 23 °C). N° 2e-3 [a] D= -6,7° (MeOH, c=l,01, 23 °C). N° 2f-l O OO oo + II Ω (MeOH, c=l,01, 23 °C). N° 2f-2 O OO C\] 1 II Ω (MeOH, c=l,00, 22 °C). N° 2f-3 [a] D= -3,5° (MeOH, c=l,01, 22 °C) . N° 2g-l 115 [α] D= +54,6° (MeOH, c=l,01, 24 °C) .
Os compostos preparados nos Exemplos acima foram avaliados para actividade in vivo e in vitro segundo o método descrito nos exemplos Experimentais abaixo.
Experiência 1 Ligação ao Receptor da PGD2
Materiais e Método (1) Preparação da Fracção da Membrana de Plaquetas Humanas
Obteve-se uma amostra de sangue utilizando uma seringa de plástico contendo citrato de sódio a 3,8% a partir de veias de voluntários saudáveis (machos e fêmeas adultos), colocou-se num tubo de ensaio em plástico e misturou-se suavemente por inversão. Centrifugou-se em seguida a 1800 rpm, 10 min à temperatura ambiente e recolheu-se o sobrenadante contendo PRP (plasma rico em plaquetas). Recentrifugou-se o PRP a 2300 rpm, 22 min à temperatura ambiente para se obter plaquetas. Homogeneizou-se as plaquetas com um homogeneizador (Ultra-Turrax) após o que se centrifugou 3 vezes a 20.000 rpm, 10 min a 4 °C para se obter a fracção das membranas de plaquetas. Após a determinação da proteína, a fracção das membranas foi ajustada até 2 mg/mL e mantidas num frigorífico a -80 °C até serem utilizadas. (2) Ligação ao Receptor da PGD2 A uma solução da reacção de ligação (Tris 50 mM/HCl, pH 7,4, MgCl2 5 mM) (0,2 ml) adicionou-se a fracção das membranas de plaquetas (0,1 mg) e [3H]PGD2 5 nM (115 Ci/mmol), e fez-se 116 reagir a 4 °C durante 90 min. Uma vez concluída a reacção, filtrou-se a mistura reaccional através de um papel de filtro em fibra de vidro, lavou-se várias vezes com soro fisiológico arrefecido e mediu-se a radioactividade retida no papel de filtro. A ligação específica foi calculada subtraindo a ligação não específica (a ligação na presença de PGD2 10 μΜ) da ligação total. A actividade inibidora da ligação de cada composto foi exprimida como a concentração necessária para 50% de inibição (IC50) , a gual foi determinada representando uma curva de substituição através da representação da proporção de ligação (%) na presença de cada composto, em gue a proporção de ligação na ausência de um composto de ensaio é -100%. Os resultados são mostrados no Quadro abaixo. Número do composto Actividade (μΜ) 2a-4 0,54 2a-17 0, 12 2a-21 5,2 2a-2 8 0,046 2a-95 1, 6 2a-l0 9 0,003
Experiência 2 Avaliaçao da Actividade Antagonista do Receptor da PGD2 Utilizando Plaguetas Humanas
Obteve-se sangue periférico de um voluntário saudável utilizando uma seringa à gual se adicionou previamente 1/9 do volume de solução de ácido cítrico/dextrose. Submeteu-se a seringa a centrifugação a 180 g durante 10 min para se obter o sobrenadante (PRP: plasma rico em plaquetas). Lavou-se 3 vezes o RRP resultante com um tampão de lavagem e contou-se o número de plaquetas com um microcontador de células. Aqueceu-se uma 117 suspensão ajustada para conter plaquetas a uma concentração final de 5 x 108/mL a 37 °C, e submeteu-se em seguida a pré-tratamento com 3-isobutil-l-metilxantina (0,5 mM) durante 5 min. À suspensão adicionou-se um composto de ensaio a várias concentrações. Dez minutos depois, induziu-se a reacção através da adição de PGD2 0,1-2,0 μΜ, e parou-se 15 minutos mais tarde através da adição de HC1. Destruiu-se as plaquetas com um homogeneizador de ultra-sons. Após centrifugação, determinou-se o cAMP no sobrenadante através de um radioensaio. O antagonismo do receptor de PGD2 pelo fármaco foi avaliado como se segue. Determinou-se a cada concentração a proporção de inibição relativamente ao aumento de cAMP pela adição de PGD2 e calculou-se em seguida a concentração de fármaco necessária para 50% de inibição (IC50) . Os resultados são mostrados no Quadro abaixo. Número do composto Inibição do Aumento do cAMP de Plaquetas
Humanas (IC50) (μΜ) 2a-2 0,77 2a-4 0,49 2a-35 1,52 2a-7 5 0,71
Experiência 3 Experiência Utilizando o Modelo da Obstrução
Nasal O método utilizado para medir a resistência da cavidade nasal e avaliar a antiobstrução nasal utilizando um porquinho--da-índia é descrito a seguir.
Tratou-se uma solução de ovalbumina a 1% (OVA) com um nebulizador ultrassónico para se obter um aerossol. Sensibilizou-se um porquinho-da-índia Hartley macho inalando 2 118 vezes o aerossol durante 10 min em intervalos de uma semana. Sete dias após a sensibilização, expôs-se o porquinho-da-índia a um antigénio para iniciar a reacção. Em seguida fez-se uma incisão na traqueia sob anestesia com pentobarbital (30 mg/kg, i.p.) e inseriu-se cânulas na traqueia dos lados pulmonar e da cavidade nasal. O canal inserido do lado pulmonar foi ligado a um ventilador que proporciona 4 mL de ar 60 vezes/min. Depois de parar a respiração espontânea de um porquinho-da-índia com Garamina (2 mg/kg, i.v.), forneceu-se ar do lado do focinho com um ventilador à frequência de 70 vezes/min e mediu-se o caudal de 4 mL de ar/vez, e a pressão atmosférica necessária para arejamento utilizando um transdutor adaptado à bifurcação. A medição foi utilizada como um parâmetro da resistência da cavidade nasal. A exposição de um antigénio foi realizada produzindo um aerossol de solução de OVA a 3% OVA durante 3 min entre o ventilador e a cânula da cavidade nasal. Injectou-se o fármaco de ensaio por via intravenosa 10 min antes da exposição ao antigénio. Mediu-se continuamente a resistência nasal entre os 0 e os 30 min e exprimiu-se o efeito como a taxa de inibição relativamente à obtida para o veículo utilizando a AUC durante 30 min (no eixo vertical, resistência da cavidade nasal (cm H20), e no eixo horizontal, tempo (0-30 min)) como uma indicação. O resultado é mostrado abaixo. 119 Número do Composto Taxa de inibição (%) Notas 1 mg/kg (i.v.) 2a-4 60 2a-21 52 2a-2 8 54 2a-95 77 2a-96 77 10 mg/kg (p.o.) 2a-l0 9 73 2a-l10 66 10 mg/kg (p.o.) 2a-l94 79 Formulação 1 Preparação de Comprimidos Comprimidos contendo, cada um, 40 mg de principio activo foram preparados de um modo convencional.
Lisboa, 12 de Outubro de 2006 120

Claims (10)

  1. REIVINDICAÇÕES 1. Composto da fórmula (Ib):
    (Ib) em que e em que A interrompido grupo oxo, e/
    e alquileno o qual esta opc por um heteroátomo ou fenileno, ou tem uma ligação insaturada; ionalmente contém um B é hidrogénio, alquilo, aralquilo ou acilo; R é COORi, CH2OR2 ou CON(R3)R4; Ri é hidrogénio ou alquilo; R2 é hidrogénio ou alquilo; R3 e R4 são, cada um, independentemente hidrogénio, alquilo, hidroxilo ou alquilsulfonilo; 1 naftileno Xi é uma ligação simples, fenileno, tiofenodiilo, indolediilo ou oxazolediilo; X2 é uma ligação simples, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-0-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C (Cl) =C (Cl)-, -(CH2)n-, etinileno, -N(R5)-, -N(R5i)CO-, -N (R52) S02-, -N(R53)CON(R54)-, -con(r55)- -so2n(r56)-, -0-, -s-, -S0-, -S02-, -C0-, oxadiazolediilo, tiadiazolediilo ou tetrazolediilo; X3 é alquilo, alcenilo, alcinilo, arilo, aralquilo, grupo heterociclico, cicloalquilo, cicloalcenilo, tiazolinilidenometilo, tiazolidinilidenometilo, -CH=NR6 ou -N=C(R7)R8; R5, R51, R52, R53, R54, R55 e R56 São, cada um, hidrogénio ou alquilo; R6 é hidrogénio, alquilo, hidroxilo, alcoxilo, carba-moiloxilo, tiocarbamoiloxilo, ureido ou tioureido; R7 e R8 são, cada um, independentemente alquilo, alcoxilo ou arilo; e n é 1 ou 2; em que um substituinte cíclico pode ter um até três substituintes seleccionados do grupo constituído por nitro, alcoxilo, sulfamoílo, amino substituído ou não substituído, acilo, aciloxilo, hidroxilo, halogéneo, alquilo, alcinilo, carboxilo, alcoxicarbonilo, aralcoxi-carbonilo, ariloxi-carbonilo, mesiloxilo, ciano, alceni-loxilo, hidroxialquilo, trifluorometilo, alquiltio, -N=PPh3, oxo, tioxo, hidroxi-imino, alcoxiimino, fenilo e alquilenodioxilo, ou o seu sal ou hidrato deste; com a condição de que estejam excluídos os compostos (a) em que Xi e X2 são uma ligação simples, e X3 é fenilo; (b) em que Xi é uma ligação simples, X2 é -0- e X3 é benzilo; 2 e
    "NHC0~0~C(CH3)3 <j*| (f) ^^^002CH2 NHC0~0-C(CH3)3
  2. 2. Composto da reivindicação 1, um seu sal ou hidrato, em que:
  3. 3. Composto da reivindicação 2, um seu sal ou hidrato, em que R é COORi.
  4. 4. Composto da reivindicação 2, um seu sal ou hidrato, em que Xi é fenileno ou tiofenodiilo, X2 é uma ligação simples, -N=N-, -CH=CH-, etinileno, -0-, -S-, -C0-, -CON (R55) -, -N (R51) C0- e X3 é fenilo ou tienilo. 3
  5. 5. Composto da reivindicação 1, um seu sal ou hidrato que: em
    e
  6. 6. Composto da reivindicação 5, um seu sal ou hidrato, em que B é hidrogénio, Xi e X2 são ambos uma ligação simples, X3 é tienilo, tiazolilo, tiadiazolilo, isotiazolilo, pirrolilo, piridilo, benzofurilo, benzimidazolilo, benzotienilo, dibenzofurilo, dibenzotienilo, quinolilo ou indolilo.
  7. 7. Composto da reivindicação 5, um seu sal ou hidrato, em que Xi é fenileno tiofenodiilo, indolediilo ou oxazolediilo, X2 é uma ligação simples, -N=N-, -CH=CH-, etinileno, -S- ou -0-, e X3 é arilo ou um grupo heterociclico.
  8. 8. Composto da fórmula (Ib) abaixo, para utilização num método para tratar doenças em que está envolvida a disfunção de mastócitos, contracção da traqueia, asma, rinite alérgica, conjuntivite alérgica, urticária, lesão devido a reperfusão isquémica, obstrução nasal e inflamação: 4 A—R Ob) N—CQ-Xi-Xt—Xs i B em que e
    em que A é alquileno o qual está opcionalmente interrompido por um heteroátomo ou fenileno, contém um grupo oxo, e/ou tem uma ligação insaturada; B é hidrogénio, alquilo, aralquilo ou acilo; R é COORi, CH2OR2 ou CON(R3)R4; Ri é hidrogénio ou alquilo; R2 é hidrogénio ou alquilo; R3 e R4 são, cada um, independentemente hidrogénio, alquilo, hidroxilo ou alquilsulfonilo; Xi é uma ligação simples, fenileno, naftileno, tiofenodiilo, indolediilo ou oxazolediilo; X2 é uma ligação simples, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-0-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C (Cl) =C (Cl)-, -(CH2)n-, etinileno, -N(RS)-, -N(RSi)CO-, -N(R52)S02-, -N (R53) CON (R54) -, -CON(R55)- -S02N(R56)-, -0-, -S-, 5 -CO-, oxadiazolediilo, tiadiazolediilo -SO-, -so2-, ou tetrazolediilo; X3 é alquilo, alcenilo, alcinilo, arilo, aralquilo, grupo heterocíclico, cicloalquilo, cicloalcenilo, tiazolinilidenometilo, tiazolidinilidenometilo, -CH=NR6 ou -N=C(R7)R8; R5, R5i, R52, R53, R54, R55 e R5 6 são, cada um, hidrogénio ou alquilo; R6 é hidrogénio, alquilo, hidroxilo, alcoxilo, carbamoiloxilo, tiocarbamoiloxilo, ureido ou tioureido; R7 e R8 são, cada um, independentemente alquilo, alcoxilo ou arilo; e n é 1 ou 2; em que um substituinte cíclico pode ter um até três substituintes seleccionados do grupo constituído por nitro, alcoxilo, sulfamoilo, amino substituído ou não substituído, acilo, aciloxilo, hidroxilo, halogéneo, alquilo, alcinilo, carboxilo, alcoxicarbonilo, aral-coxicarbonilo, ariloxicarbonilo, mesiloxilo, ciano, alceniloxilo, hidroxialquilo, trifluorometilo, alquiltio, -N=PPh3, oxo, tioxo, hidroxiimino, alcoxiimino, fenilo e alquilenodioxilo, ou o seu sal ou hidrato deste; com a condição de que estejam excluídos os compostos (a) em que Xi e X2 são uma ligação simples e X3 é fenilo; (b) em que Xi é uma ligação simples, X2 é -0- e X3 é benzilo.
  9. 9. Utilização de um antagonista da PGD2 compreendendo um composto da fórmula (Ib) como definido na reivindicação 8, ou um seu sal ou hidrato, como um princípio activo no fabrico de uma composição farmacêutica para o tratamento de doenças nas quais está envolvida a disfunção de mastócitos, contracção da traqueia, asma, rinite alérgica, conjuntivite alérgica, urticária, lesão devido a reperfusão isquémica, obstrução nasal e inflamação. 6
  10. 10. Utilização de um antagonista da PGD2 compreendendo um composto da fórmula (Ib) como definido na reivindicação 9, ou um seu sal ou hidrato, como um principio activo no fabrico de uma composição farmacêutica para o tratamento de doenças nas quais está envolvida a disfunção de mastócitos, contracção da traqueia, asma, rinite alérgica, conjuntivite alérgica, urticária, lesão devido a reperfusão isquémica, obstrução nasal e inflamação. Lisboa, 12 de Outubro de 2006 7
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