PT100304A - Compostos inibidores de proteases retrovirais, sua preparacao e uso e composicoes farmaceuticas que os contem - Google Patents

Compostos inibidores de proteases retrovirais, sua preparacao e uso e composicoes farmaceuticas que os contem Download PDF

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Publication number
PT100304A
PT100304A PT100304A PT10030492A PT100304A PT 100304 A PT100304 A PT 100304A PT 100304 A PT100304 A PT 100304A PT 10030492 A PT10030492 A PT 10030492A PT 100304 A PT100304 A PT 100304A
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Portugal
Prior art keywords
aminocarbonyl
pyridylmethyl
difluoro
amino
diphenyl
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PT100304A
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English (en)
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Hing L Sham
Daniel W Norbeck
Dale J Kempf
Chen Zhao
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Abbott Lab
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Publication of PT100304A publication Critical patent/PT100304A/pt

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07F9/32—Esters thereof
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Description

-3- //' 73 739 4681.PG.03 ... »Λ·φ
MEMÓRIA DESCRITIVA
Este é uma continuação em parte do pedido de patente dos E.U.A. nB de série 518730, depositado em 9 de Maio, 1990, o qual é uma continuação em parte do pedido de patente dos E.U.A. na de série 456124, depositado em 22 de Dezembro, 1989, o qual é uma continuação em parte do pedido de patente dos E.U.A. na de série 405604, depositado em 8 de Setembro , 1989, o qual é uma continuação em parte do pedido de patente dos E.U.A. na de série 355945, depositado em 23 de Maio, 1989.
Campo Técnico
Este invento foi realizado com apoio do governo sob o contrato η® AI27220-01 concedido pelo National Institute of Allergy and Infectious Diseases. O governo possui certos direitos neste invento. 0 presente invento refere-se a novos compostos e a uma composição e processo para a inibição de proteases retrovirais e em particular para a inibição da protease do vírus da imunodeficiência humana (HIV), a uma composição e processo para o tratamento de uma infecção retroviral e em particular uma infecção pelo HIV, processos para preparar estes compostos e intermediários sintéticos empregues nestes processos.
Antecedentes na arte
Os retrovírus são aqueles vírus que utilizam um intermediário de ácido ribonucleico (ARN) e um ácido desoxi-ribonucleico (ADN)-polimerase dependente de ARN, transcriptase inversa, durante o seu ciclo de vida. Os retrovírus incluem, mas não estão limitados a vírus do ARN da família Retroviridae. e também aos vírus de ADN das famílias Hepadnavirus e Caulimovirus. Os retrovírus provocam uma variedade de estados de doença no Homem, em animais e em plantas. Alguns dos retrovírus mais importantes do ponto de vista patológico incluem os vírus da imunodeficiência humana (HIV-1 e HIV-2), os quais provocam a síndroma da imunodeficiência adquirida (SIDA) no Homem, o vírus da hepatite B, o qual provoca hepatite e carcinomas hepáticos no -4- 73 739 4681.PG.03
Homem, os vírus I, II, IV e V linfotróficos da célula T humana, os quais provocam leucemia celular aguda humana, e os vírus de leucemia bovina e felina os quais provocam leucemia em animais domésticos.
As proteases são enzimas que clivam proteínas em ligações peptídicas específicas. Muitas funções biológicas são controladas ou mediadas por proteases e pelos seus inibidores de proteases complementares. Por exemplo, a protease renina cliva o péptido angiotensinogénio para produzir o péptido angiotensina I. A angiotensina I é ainda clivada pela protease enzima de conversão da angiotensina (ACE) para formar o péptido hipotensivo angiotensina II. Sabe-se que os inibidores de renina e da ACE reduzem a pressão sanguínea elevada in vivo. Um inibidor de uma protease retroviral deve proporcionar um agente terapêutico para doenças provocadas pelos retrovírus.
Os genomas dos retrovírus codificam uma protease que é responsável pelo processamento proteolítico de um ou mais precursores de poliproteínas tais como os produtos dos genes pol e aaq. Ver Wellink, Arch. Virol. 98. 1 (1988). As proteases retrovirais processam, mais comummente, o precursor aaq em proteínas do núcleo, e processam também o precursor pol em transcriptase inversa e protease retroviral. Em adição, as proteases retrovirais são específicas de sequência. Ver Pearl, Nature 328 482 (1987). 0 processamento correcto do precursor de poliproteínas pela protease retroviral é necessário para a montagem de viriões infecciosos. Mostrou-se que a mutagénese in vitro que produz vírus deficientes em protease leva à produção de formas imaturas de núcleos que carecem de infectividade. Ver Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Portanto, a inibição de proteases retrovirais proporciona um objecto atractivo para a terapia antiviral. Ver Mitsuya, Nature 325 775 (1987).
Os tratamentos correntes para as doenças virais envolvem 73 739 4681.PG.03
-5-
usualmente a administração de compostos que inibem a sintese de ADN virai. Os tratamentos correntes para a SIDA (Dagani, Chem. Eng. News, 23 de Novembro, 1987 pp. 41-49) envolvem a administração de compostos tais como a 2',3'-didesoxicitidina, o fosfonoformato tri-sódico, o 21-tungsto-9-antimoniato de amónio, a l-beta-D-ribofuranosil-l,2,4-triazolo-3-carboxamida, a 3'-azido-3'-desoxitimidina, e a adriamicina, que inibem a síntese de ADN virai; compostos tais como a AL-721 e o poliami-noacetato os quais podem evitar a penetração do HIV na célula hospedeira; e compostos que tratam as infecções oportunistas provocadas pela imunossupressão resultante da infecção pelo HIV. Nenhum dos correntes tratamentos da SIDA provou ser totalmente eficaz no tratamento e/ou inversão da doença. Em adição, muitos dos compostos correntemente utilizados para tratar a SIDA provocam efeitos laterais adversos incluindo baixa contagem de plaquetas, toxicidade renal e citopenia da medula óssea.
Descricão do invento
De acordo com o presente invento, há compostos inibidores de proteases retrovirais de fórmula:
na qual é alquilo inferior, cicloalquilo, fenilo ou seus derivados substituídos nos quais o grupo alquilo inferior, cicloalquilo ou fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; R2 é fenilo, um grupo heterocíclico aromático ou fenilo substituído em que o anel fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; 73 739 4681.PG.03 -6-
r
0 c II
m na qual i é 0 a 3 e é seleccionado, independentemente em cada ocorrência, de entre hidrogénio, alquilo inferior, ciclo-alquilalquilo, haloalquilo, hidroxialquilo, alcoxialquilo, tioalcoxialquilo, aminoalquilo, alquilaminoalquilo, dialquil-aminoalquilo, carboxialquilo, alcoxicarbonilalquilo e aminocarbonilalquilo e T é
V II R6-W-Y—c— na qual R6 é arilo, um grupo heterocíclico ou arilo substituído em que o anel arilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo, V é O ou S, W é CH2, -CH2CH2-, -CH=CH- ou -D-CH=CH- em que D é O, S ou NH e Y está ausente, 0, S ou N(R7) em que R7 é hidrogénio ou alquilo inferior; ou T é R15C(0)-, R15C(S)- ou R15S(0)2- em que R15 é alquilo inferior, arilo ou um grupo heterocíclico; e Z é -C(0)- ou -CH(OH)-; ou um seu sal farmaceuticamente aceitável; com a condição de que o composto seja diferente de 5-(N-benziloxicarbonilisoleucil)amino-3,3-difluoro-l,6-difenil-4--oxo-hexano .
Os compostos deste invento que possuem um átomo de carbono assimétrico podem existir na forma de enantiómeros puros ou na forma de misturas racémicas. Os compostos deste invento que possuem dois ou mais átomos de carbono assimétricos podem existir na forma de diastereómeros puros, misturas de diastereómeros, racematos diastereoméricos ou misturas de racematos diastereoméricos. 0 presente invento inclui dentro do seu âmbito todas as formas isoméricas. Os termos configuração "S" e HR", quando aqui utilizados, são como definidos pela IUPAC 73 739 4681.PG.03 -7-
jiãss®«csíp» 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
Os termos "Gly" e "Vai", quando aqui utilizados, referem-se a glicina e valina, respectivamente. Em geral, as abreviaturas de aminoácidos aqui utilizadas seguem a IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem. 1984, 158 9-31). 0 termo "alquilo inferior", quando aqui utilizado, refere-se a radicais alquilo de cadeia linear ou ramificada contendo de 1 a 6 átomos de carbono incluindo, mas não limitados a, metilo, etilo, n-propilo, iso-propilo, n-butilo, iso-butilo, sec-butilo, n-pentilo, 1-metilbutilo, 2,2-dimetilbutilo, 2-metilpentilo, 2,2-dimetilpropilo, n-hexilo e similares. 0 termo "cicloalquilo", quando aqui utilizado, refere-se a um anel alifático possuindo 3 a 7 átomos de carbono incluindo, mas não limitado a, ciclopropilo, ciclopentilo, ciclo-hexilo e similares. O termo "arilo", quando aqui utilizado, refere-se a um sistema de anel carbocíclico, monocíclico ou bicíclico possuindo um ou mais aneis aromáticos incluindo, mas não limitado a, fenilo, naftilo, tetra-hidronaftilo, indanilo e similares. O termo "arilalquilo", quando aqui utilizado, refere-se a um grupo arilo ligado a um radical alquilo inferior incluindo, mas não limitado a, benzilo, 1-naftilmetilo e similares. O termo "alquilamino", quando aqui utilizado, refere-se a um radical alquilo inferior ligado a vim radical NH. 0 termo "dialquilamino", quando aqui utilizado, refere-se a -NR3QR31 em que R30 e R31 são seleccionados, independentemente um do outro, de entre grupos alquilo inferior. 4/ 73 739 4681.PG.03
V" -8- O termo "anel heterocíclico" ou "heterocíclico", quando aqui utilizados, referem-se a qualquer anel de 3 ou 4 membros contendo um heteroátomo seleccionado de entre oxigénio, azoto e enxofre; ou a um anel de 5 ou 6 membros contendo um, dois ou três átomos de azoto; um átomo de azoto e um átomo de enxofre; ou um átomo de azoto e um átomo de oxigénio. O anel de 5 membros possui 0-2 ligações duplas e o anel de 6 membros possui 0-3 ligações duplas. Os heteroátomos azoto podem estar opcionalmente quaternizados. O termo "heterocíclico" inclui também grupos bicíclicos nos quais qualquer um dos aneis heterocíclicos anteriores está fundido com um anel benzeno ou um anel ciclo-hexano ou outro anel heterocíclico. Os heterocíclicos incluem; pirrolilo, pirrolinilo, pirrolidinilo, pirazolilo, pirazolinilo, pirazolidinilo, imidazolilo, imidalinilo, imidazolidinilo, piridilo, piperidinilo, pirazinilo, piperazinilo, pirimidinilo, piridazinilo, oxazolilo, oxazolidinilo, isoxazolilo, isoxazolidinilo, morfolinilo, tiazo-lilo, tiazolidinilo, isotiazolilo, isotiazolidinilo, indolilo, quinolinilo, isoquinolinilo, benzimidazolilo, benzotiazolilo, benzoxazolilo, furilo, tienilo e benzotienilo.
Os heterocíclicos podem ser não substituídos ou monos-substituídos ou dissubstituídos com substituintes seleccionados, independentemente uns dos outros, de entre hidroxi, halo, oxo (=0), alquilimino (R*N= em que R* é um grupo alquilo inferior), amino, alquilamino, dialquilamino, alcoxi, polialcoxi, haloal-quilo, cicloalquilo, arilo, arilalquilo, -COOH, -SO3H e alquilo inferior. Para além disso, os heterociclos contendo azoto podem estar N-protegidos. O termo "halo" ou "halogéneo", quando aqui utilizado, refere-se a -Cl, -Br, -I ou -F.
Os termos "alcoxi" e "tioalcoxi", quando aqui utilizados, referem-se a R320- e R32S-, respectivamente, em que R32 é um grupo alquilo inferior ou benzilo. 0 termo "polialcoxi", quando aqui utilizado, refere-se a .¾3EK3®f*
73 739 4681.PG.03 -9--OR33 em que R33 é uma cadeia linear ou ramificada contendo 1-5 ligações cn,-0-Cn// em que n' e n" são seleccionados, independentemente um do outro, de entre 1 a 3, incluindo, mas não limitado a, metoxietoximetoxi, metoximetoxi e similares. 0 termo "haloalquilo", quando aqui utilizado, refere-se a um radical alquilo inferior no qual um ou mais dos átomos de hidrogénio estão substituídos por halogéneo incluindo, mas não limitado a, clorometilo, trifluorometilo, l-cloro-2-fluoroetilo e similares. 0 termo "cicloalquilalquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo cicloalquilo incluindo, mas não limitado a, ciclo-hexilmetilo e similares. O termo "hidroxialquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo hidroxi (-0H). 0 termo "alcoxialquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo alcoxi. 0 termo "tioalcoxialquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo alcoxi. O termo "aminoalquilo11, quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo amino (-NH2). O termo "alquilaminoalquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo alquilamino (i.e., R40NH- em que R40 é alquilo inferior). 0 termo ,,dialquilaminoalquilon, quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo dialquilamino (i.e., R4iR42N_ em ÇIU© R4i e R42 s^° 73 739 4681.PG.03
10- <r seleccionados, independentemente um do outro, de entre alquilo inferior). O termo "carboxialquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo carboxilo (-COOH). 0 termo "alcoxicarbonilalquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo alcoxicarbonilo (i.e., R430C(0)- em que R43 é alquilo inferior). O termo "aminocarbonilalquilo", quando aqui utilizado, refere-se a um radical alquilo inferior ao qual está ligado um grupo aminocarbonilo (i.e., -0(0)1¾¾).
O termo "N-protegido" ou "grupo N-protector", quando aqui utilizado, refere-se àqueles grupos com que se pretende proteger a extremidade N de um aminoácido ou péptido ou para proteger um grupo amino contra reacções indesejáveis durante os procedimentos sintéticos. Os grupos N-protectores compreendem carbamatos, amidas, derivados de N-alquilo, derivados de aminoacetal, derivados de N-benzilo, derivados de imina, derivados de enamina e derivados do heteroátomo N, todos eles estão descritos em Greene, "Protective Groups In Organic Synthesis, "John Wiley & Sons, New York (1981), o qual se incorpora aqui para referência. Em particular, os grupos N-protectores incluem formilo, benzoílo, pivaloílo, benzilo, fenilsulfonilo, t-butiloxicarbonilo (Boc), benziloxicarbonilo (Cbz) e similares.
Os compostos representativos do invento incluem: 5(S)-(N-benziloxicarbonil-(L)-isoleucil)-amino-3,3-difluoro-1,6--difenil-4-oxo-hexano; 5(S)-(N-benziloxicarbonil-(L)-terc-leucil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano; 5(S)-(N-benziloxicarbonil-(L)-asparaginil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano; 4 73 739 4681.PG.03 e .·
-11- sv <*s v' ^3 5(S)-(N-benziloxicarbonil-glicil-(L)-valinil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano; 5(S)-(N-(2-piridil)metoxicarbonil-glicil-(L)-valinil)-amino-3,3--difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(3-piridil)metoxicarbonil-glicil-(L)-valinil)-amino-3,3--difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(4-piridil)metoxicarbonil-glicil-(L)-valinil)-amino-3,3--difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(2-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; ) 5(S)-(N-(3-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(4-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1f 6-difenil-4-oxo-hexano; 5(S) — (N—(2-piridilmetil)-N-(metil)aminocarbonil-glicil-(L) --valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(3-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(4-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(2-(2-piridil)etanossulfonil)-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-acetilglicil-(L)-valinil)-amino-3,3-difluoro-1,6-difenil--4-oxo-hexano; e > 5(S)-(N-(metanossulfonil)-glicil-(L)-valinil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano.
Os compostos do invento podem ser preparados como esboçado nos processos mostrados nos esquemas I e II. De acordo com o esquema I, faz-se reagir oxazolidinona χ (em que R·^ é definido como anteriormente e R10 ® um grupo activador, tal como -N(0CH3) (CH3) e similares) com um reagente organometálico R2CH2M (2.) (em que R2 é definido como anteriormente e M é um ião metálico, por exemplo, R2CH2Li, R2CH2MgCl e similares). Pode-se preparar a oxazolidinona X de acordo com o procedimento descrito no Pedido de Patente Europeia N2 EP402646, publicado em 19 de Dezembro, 1990 (pedido de patente dos E.U.A. Na de série 518730, depositado em 9 de Maio, 1990, o qual se incorpora aqui para 73 739 4681.PG.03
'iieaeaBSSFJ -12-
referência). Converte-se então a difluorocetona 3. no composto 4 (por exemplo, por redução ao álcool, formação do mesilato, eliminação na olefina e hidrogenação). A desprotecção do composto 4. (por exemplo, por tratamento com hidróxido de bário e similares), seguida por acoplamento com o ácido carboxílico £>, ou um seu derivado activado, proporciona o difluoroalcool 6a. A oxidação de 6a (por exemplo, com Na2Cr207/ácido acético e similares) proporciona 6b. 0 esquema II ilustra um processo alternativo para a preparação da forma desprotegida de 4. (i.e., 12). Oxida-se o aminoalcool N-protegido 7. (R-j^ é definido como anteriormente e R20 é um grupo N-protector, por exemplo, t-butiloxicarbonilo) (por exemplo, por oxidação de Swern) para proporcionar o aldeído 8.. A reacção do aldeído 8, com acetileno substituído 9. (R2 é definido como anteriormente) e zinco num solvente inerte proporciona o difluoroalcool 10. A hidrogenação de 10 dá 11, o qual pode ser desprotegido para proporcionar 12.
I
73 739 4681.PG.03 -13 <S0* i\
ESQUEMA I //
1) desprotecção -►
2) T-CH(R4)C02H5. ia oxidação
/~· -14- 73 739 4681.PG.03 (1ά
ESQUEMA II
12 73 739 4681.PG.03 c
/. · -15-
Os intermediários úteis para a preparação dos compostos I incluem compostos de fórmula:
R R21NH
na qual R-^ é alquilo inferior, cicloalquilo, fenilo ou seus derivados substituídos nos quais o grupo alquilo inferior, cicloalquilo ou fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; R2 é fenilo, um grupo heterociclico aromático ou fenilo substituído em que o anel fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; R2i é hidrogénio ou um grupo N-protector; e R22 é hidrogénio, ou R21 e R22, tomados conjuntamente, são -c(0)-
Outros intermediários úteis para a preparação dos compostos I incluem os compostos de fórmula:
T-(NHCH(R4)C(0))m-OH na qual mé0a3eR4é seleccionado, independentemente em cada ocorrência, de entre hidrogénio, alquilo inferior, cicloalquil-alquilo, haloalquilo, hidroxialquilo, alcoxialquilo, tioalcoxi-alquilo, aminoalquilo, alquilaminoalquilo, dialquilaminoalquilo, carboxialquilo, alcoxicarbonilalquilo e aminocarbonilalquilo e
V T é
II
R6 - W - Y—C na qual R6 é arilo, um grupo heterociclico ou arilo substituído em que o anel arilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de 73 739 4681.PG.03 .-,y «ií5ae%jgí -16- 3S^ entre hidroxi, alcoxi, tioalcoxi e halo, V é O ou S, W é CH2/ -CH2CH2-f -CH=CH- ou -D-CH=CH- em que D é O, S ou NH e Y está ausente, O, S ou N(R7) em que R7 é hidrogénio ou alquilo inferior; ou T é R15C(0)-, R15C(S)- ou R15S(0)2- em que R15 é alquilo inferior, arilo ou um grupo heterocíclico; ou um halogeneto de ácido ou vun seu derivado éster activado.
Os derivados halogenetos de ácido dos intermediários anteriores incluem o cloreto de ácido. Os derivados éster activados dos intermediários anteriores incluem ésteres activados comummente utilizados pelos peritos na arte para a activação de grupos ácido carboxílico para o acoplamento com uma amina para formar uma ligação peptídica incluindo, mas não limitados a, anidridos derivados de ácido fórmico e acético, anidridos derivados de halogenetos de alcoxicarbonilo tais como o cloreto de isobutiloxicarbonilo e similares, ésteres derivados de N-hidroxissuccinimida, ésteres derivados de N-hidroxiftalimida, ésteres derivados de N-hidroxibenzotriazolo, ésteres derivados de N-hidroxi-5-norborneno-2,3-dicarboxamida, ésteres derivados de 4-nitrofenol, ésteres derivados de 2,4,5-triclorofenol e similares.
Os exemplos seguintes servirão ainda para ilustrar a preparação dos novos compostos do invento.
Exemplo 1 5(S)-(N-Benziloxicarbonil-(L)-valinil)-amino-1-(2-piridil)--6-fenil-3.3-difluoro-4-oxo-hexano IA. 4fS^-Benzil-5(R)-(2'-(27.2/-difluoro-N/-metoxi-N/-metil-ace-tamido)-2-oxazolidinona A uma solução de 1,36 g do derivado 2-oxazolidinona do ácido 4(S)-amino-5-fenil-2,2-difluoro-3(R)-hidroxipentanóico (Pedido de Patente Europeia η8 EP402646, publicado em 19 de Dezembro, 1990) em 20 ml de dimetilformamida (DMF) adicionou-se sucessivamente, 615 mg de hidrocloreto de N,0-dimetil-hidroxilamina, 2,11 ml de trietilamina e 1,47 g de hidrocloreto 73 739 4681.PG.03 <r íí.v .<uxug&< yr -17- de l-(3-dimetil-aminopropil)-3-etilcarbodiimida. Agitou-se a mistura reaccional à temperatura ambiente durante a noite. Removeu-se o solvente em vácuo e extractou-se o resíduo com acetato de etilo e lavou-se sucessivamente com carbonato de sódio aquoso saturado e cloreto de sódio aquoso saturado, depois secou-se e concentrou-se. A cromatografia em sílica gel (20% de acetato de etilo/cloreto de metileno) proporcionou 1,3 g do produto desejado. % RMN (CDC13): δ 2,85 (m, 2H), 3,10 (m, 2H), 3,20 (S, 3H), 3,73 (S, 3H), 4,10 (m, 1H), 4,90 (m, 1H), 5,10 (S largo, 1H), 7.25 (m, 5H). l.B 4(S Ϊ-Benzil-5 fR^-f3/-T3/.3'-difluoro-2'oxo-1' — (2-piridilΐ-propil))-2-oxazolidinona A 500 mg do produto do exemplo IA em 10 ml de tetra--hidrofurano (THF) a -78°C, adicionou-se uma solução do derivado de lítio de 2-picolina (preparado por adição de 2,5 ml de uma solução 1,6 M de n-BuLi em hexano a 0,39 ml de 2-picolina em 5 ml de THF a -78°C). Após agitação durante 30 minutos a -78°C, e depois durante 30 minutos a -10°C, interrompeu-se a reacção por adição de solução de cloreto de amónio aquosa saturada. Extractou-se então esta mistura com acetato de etilo. Secaram-se as fases orgânicas combinadas e concentraram-se. A cromatografia em sílica gel (2-5% de metanol/cloreto de metileno) proporcionou 405 mg do produto desejado. ^-H RMN (CDC13): S 2,80 (m, 1H), 3,05 (m, 1H), 4,30 (m, 1H), 4,85 (m, 1H), 5,0 (s largo, 1H), 5,90 (s, 1H), 7,05-7,30 (m, 7H), 7,70 (m, 1H), 8,05 (d, 1H). 1C. 5fS)-amino-l-(2-piridil^-6-fenil-3. 3-difluoro-4fRWhidroxi--hexano A 15 0 mg do produto do exemplo 1B em metanol a 0°C, adicionou-se uma solução de 30 mg de boro-hidreto de sódio em 10 ml de metanol. Após agitação durante 30 minutos, isolou-se o produto. Tratou-se o produto bruto com 1,1 equivalentes de trietilamina e 1,0 equivalentes de cloreto de metanossulfonilo em cloreto de metileno para proporcionar o derivado mesilato. Tratou-se o mesilato bruto com 5 equivalentes de DBU em 5 ml de tolueno a 80°C para proporcionar a olefina. Hidrogenou-se a olefina utilizando 10% de Pd/C como catalisador e metanol como -18- 73 739 4681.PG.03 solvente. Hidrolisou-se o produto resultante utilizando hidróxido de bário em dioxano/água l:l para proporcionar o produto desejado. Espectro de massa: (M+l)=307. l.D 5(S WN-Benziloxicarbonil-( L)-valinil)-amino-l-( 2-piridil)-6-fenil-3.3-difluoro-4-oxo-hexano A 100 mg do produto resultante do exemplo 1C em 5 ml de DMF adicionou-se, sucessivamente, 100 mg de N-benziloxicarbonil-(L)--valina, 160 mg de HOBt, 0,117 ml de trietilamina e 160 mg de hidrocloreto de l-(3-dimetilaminopropil)-3-etilcarbodiimida. Agitou-se a mistura reaccional à temperatura ambiente durante a noite. Isolou-se o produto e purificou-se por cromatografia em sílica gel (2% de metanol/cloreto de metileno) para proporcionar 145 mg do álcool bruto, o qual se oxidou por dissolução em 5 ml de ácido acético e adição de 1,1 equivalentes de dicromato de sódio (Synthesis, 466(1989)), resultando o produto desejado. % KMN (CDC13): δ 0,81 (d, 3H), 0,90 (d, 3H), 2,05 (m, 1H), 2,50-3,30 (m, 6H), 3,95 (m, 1H), 5,05 (s, 2H), 5,20 (d largo, 1H), 5,30 (m, 1H), 6,30 (d largo, 1H), 7,10-7,35 (m, 7H), 7,60 (m, 1H), 8,50 (m, 1H). Espectro de massa: (M+l)=538.
Exemplo 2 5 f s1-(N-(2-piridil)-metoxicarbonil-(L)-valinil)-amino-3.3--difluoro-l.6-difenil-4-oxo-hexano Desprotegeu-se a 4(S)-benzil-5(R)-(3'-(3',3'-difluoro-l'--fenilpropil)-2-oxazolidinona (Pedido de Patente Europeia na EP402646, publicado em 19 de Dezembro, 1990) por tratamento com hidróxido de bário. Acoplou-se o difluoroaminoalcool resultante a 5-(N-(2-piridil)metoxicarbonilJvalina utilizando N-etil-N'--(dimetilaminopropil)carbodiimida, 1-hidroxibenzotriazolo e trimetilamina em dimetilformamida (DMF). A oxidação do composto resultante de acordo com o exemplo 1D utilizando dicromato de sódio em ácido acético proporcionou o composto desejado (65%). l-H RMN (CDCI3): δ 0,82 (d, 3H), 0,90 (d, 3H), 2,05 (m, 1H), 2,35 (m, 2H), 2,80-2,95 (m, 2H), 3,30 (m, 1H), 3,95 (q, 1H), 5,20 (s, 2H), 5,30 (m, 1H), 6,20 (d largo, 1H), 7,10-7,30 (m, 12H), 7,70 (t, 1H), 8,60 (d, 1H).
73 739 4681.PG.03 -19 Exemplo 3 5(S)-(N-f2-PiridilΊ-metilaminocarbonil-fL)-valinil)-amino-3,3--difluoro-1,6-difenil-4-oxo-hexano Utilizando o procedimento do exemplo 2, mas substituindo a 5-(N-(2-piridil)-metoxicarbonil)-valina por 5-(N-(2-piridil)--metilaminocarbonil)-valina preparou-se o composto desejado. ^-H RMN (CDCI3): S 0,82 (d, 3H), 0,90 (d, 3H), 2,07 (m, 1H), 2,30 (m, 1H), 2,80-3,30 (m, 4H), 4,10 (q, 1H), 4,45 (d, 1H), 5,30 (m, 1H), 5,55 (t, 1H), 6,50 (d, 1H), 7,12-7,30 (m, 12H), 7,65 (m, 1H), 8,50 (m, 1H).
Exemplo 4 5(S)-fN-Benziloxicarbonil-alicil-(L)-valinil)-amino-3.3-difluoro· 1.6-difenil-4-oxo-hexano
Utilizando o procedimento do exemplo 2, mas substituindo a 5-(N-(2-piridil)-metoxicarbonil)-valina por 5-(N-Cbz-glicil-va-lina preparou-se o produto desejado. RMN (CDCI3): δ 0,80 (d, 3H), 0,88 (d, 3H), 2,05 (m, 1H), 2,40 (m, 2H), 2,70-3,30 (m, 4H), 3,70 (m, 2H), 4,20 (q, 1H), 5,10 (s, 2H), 5,30 (m, 1H) , 6,30 (m, 2H), 7,12-7,38 (m, 15H).
Exemplo 5 N-t-Butiloxicarbonil-f1.6-difenil-3.3-difluoro--4(R,S)-hidroxi-5(S)-amino-hexino A uma solução de l g de Boc-fenilalaninal em 12 ml de THF adicionou-se 1,05 g de pó de zinco e 0,16 g de cloreto mercuríco. A esta solução sonicada adicionou-se uma solução de 0,25 g de bromodifluorometilfenilacetileno em 4 ml de THF durante um período de uma hora. Filtrou-se o excesso de zinco e concentrou-se o filtrado e lavou-se com solução de KHS04 aq. a 10% A extracção com EtOAc (3 x 100 ml), a secagem com Na2S04 anidro e a evaporação do solvente em vácuo, proporcionaram um óleo amarelo que foi purificado por cromatografia em coluna de sílica gel para dar 1,09 g do produto desejado (68%). Espectro de massa: (M+l) = 402. % RMN (CDCI3): δ 1,34 (s, 9H), 2,95-3,20 (m, 2H), 3,90-4,10 (m, 2H), 5,05 (d largo, 1H), 7,25-7,50 (m, 10H). ,φ' 73 739 4681.PG.03 -20- éí *<3ι
Exemplo 6
N-t-Butiloxicarbonil-f1.6-difenil-3.3-difluoro--4CR.S)-hidroxi-5(S)-amino-hexano A uma suspensão de 21 mg de paládio a 10% sobre carbono adicionou-se uma solução de metanol do produto resultante do exemplo 5. Agitou-se a suspensão vigorosamente sob uma atmosfera de hidrogénio. Após uma hora, retirou-se o catalisador por filtração e concentrou-se o filtrado para dar 81 mg (95%) do produto desejado. Espectro de massa: (M+l)= 406. -^H RMN (CDCI3): δ 1,40 (s, 9H), 2,25 (m, 2H), 2,70-3,10 (m, 4H), 3,50 (m, 1H), 3,70(m, 1H), 4,0 (m, 1H), 4,90 (d largo, 1H), 7,25 (m, 10H).
Exemplo 7 1.6-Difenil-3.3-difluoro-4(R.S)-hidroxi-5(S)-amino-hexano A 1 g do produto resultante do exemplo 6 adicionou-se 5 ml de ácido trifluoroacético e 5 ml de diclorometano. Após uma hora à temperatura ambiente, concentrou-se a solução num óleo. Dissolveu-se o óleo em 100 ml de EtOAc e lavou-se com solução de NaHC03 saturada. Secou-se a camada orgânica com Na2S04 anidro e a evaporação do solvente em vácuo proporcionou um sólido branco, 740 mg (98%). Espectro de massa: (M+l) = 306.
Exemplo 8 5(S)-fN-f 2-(2-Piridil)etanossulfonil)-qlicil-(L)-valinil)-amino--3.3-difluoro-1.6-difenil-4-oxo-hexano O acoplamento de N-(2-(2-piridil)etanossulfonil)-glicil--valina ao produto resultante do exemplo 7 utilizando o procedimento do exemplo 2, seguido por oxidação com dicromato de sódio em ácido acético proporcionaram o produto desejado. Espectro de massa: (M+l) = 629. ΧΗ RMN (CDCI3): δ 0,75 (d, 3H), 0,85 (d, 3H), 2,10 (m, 1H), 2,40 (m, 2H), 2,80 (m, 3H), 3,30 (m, 3H), 3,60 (m, 2H), 3,68 (d largo, 2H), 4,20 (m, 1H), 5,30 (m, 1H), 5,95 (m, 1H), 6,60 (d, 1H), 6,80 (d, 1H), 7,20 (m, 12H), 7,60 (m, 1H), 8,50 (d, 1H).
73 739 4681.PG.03 -21-
Exemplo 9 5(S WN-Acetilqlicil-(L)-valinil)-amino-3,3--difluoro-1,6-difenil-4-oxo-hexano
Utilizando o procedimento descrito no exemplo 8, mas substituindo o N-(2-(2-piridil)etanossulfonil)-glicil-valina por N-acetil-glicil-valina, preparou-se o produto desejado. Espectro de massa: (M+l) = 502. % RMN (CDC13): δ 0,80 (d, 3H), 0,88 (d, 3H) , 2,03 (S, 3H), 2,02 (m, 1H), 2,45 (m, 2H), 2,80 (t, 2H), 2,92 (m, 1H), 3,30 (m, 1H), 3,89 (m, 2H), 4,20 (m, 1H), 5,30 (m, 1H), 6,20 (m, 1H), 6,40 (t, 2H), 7,25 (m, 10H).
Exemplo 10 5(S)-(N-fMetanossulfonill-qlicil-(:L^-valinil^-amino-3.3-difluoro -1.6-difenil-4-oxo-hexano
Utilizando o procedimento descrito no exemplo 8, mas substituindo o N-(2-(2-piridil)etanossulfonil)-glicil-valina por N-(metanossulfonil)-glicil-valina, preparou-se o produto dese-jado. Espectro de massa: (M+l) = 538. 1H RMN (CDC13): δ 0,81 (d, 3H), 0,88 (d, 3H), 2,05 (m, 1H), 2,35 (m, 2H), 2,85 (m, 3H), 2,95 (s, 3H), 3,30 (dd, 1H), 3,80 (d, 2H), 4,20 (m, 1H), 5,20 (m, 1H), 5,30 (m, 1H), 6,30 (d, 1H), 6,55 (d, 1H), 7,25 (m, 10H).
Exemplo 11
Utilizando os processos esboçados anteriormente, prepararam-se os compostos seguintes: (a) 5-(N-benziloxicarboni1-(L)-isoleucil)-amino-3,3-difluoro-1,6--difenil-4-oxo-hexano; (b) 5-(N-benziloxicarbonil-(L)-terc-leucil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano; (c) 5-(N-benziloxicarbonil-(L)-asparaginil)-amino-3,3-difluoro--1,6-difenil-4-oxo-hexano; (d) 5(S)-(N-(2-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-l,6-difenil-4-oxo-hexano; (e) 5(S)-(N-(3-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano ? (f) 5(S)-(N-(4-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 73 739
4681.PG.03 -22- é.
(g) 5(S)-(N-(2-piridilmetil)aminocarbonil-glicil-(L)-valinil)--amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; (h) 5(S)-(N-(3-piridilmetil)aminocarbonil-glicil-(L)-valinil)--amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; (i) 5(S)-(N-(4-piridilmetil)aminocarbonil-glicil-(L)-valinil)--amino-3,3-difluoro-1,6-difenil-4-oxo-hexano? (j) 5(S)-(N-(2-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; (k) 5(S) — (N-(3-piridilmetil)-N-(metil)aminocarbonil-glicil-(L) --valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; e (l) 5(S)-(N-(4-piridilmetil)-N-(metil)aminocarbonil-glicil-(L) --valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano;
Ensaio fluoroqénico para análise de inibidores da protease
do HIV
Pode-se determinar a potência inibidora dos compostos do invento pelo processo seguinte.
Dissolve-se um composto do invento em DMSO e dilui-se ainda uma pequena alíquota com DMSO a 100 vezes a concentração final desejada para o teste. Realiza-se a reacção num tubo de 6 x 50 mm num volume total de 300 microlitros. As concentrações finais dos componentes no tampão reaccional são: acetato de sódio 125 mM, cloreto de sódio 1 M, ditiotreitol 5 mM, albumina de soro bovino 0,5 mg/ml, substrato fluorogénico 1,3 /iM, dimetilsulfóxido 2% (v/v), pH 4,5. Após a adição do inibidor, coloca-se a mistura reaccional no porta-células do fluorómetro e incuba-se a 30“C durante vários minutos. Inicia-se a reacção por adição de uma pequena alíquota de protease de HIV fria. Regista-se a intensidade de fluorescência (excitação a 340 nm, emissão a 490 nm) como função do tempo. Determina-se a velocidade da reacção para os primeiros seis a oito minutos. A velocidade observada é directamente proporcional ao número de moles de substrato clivadas por unidade de tempo. 0 IC50 é a concentração de composto de teste necessária para inibir a protease em 50%.
Substrato fluorogénico: Dabcyl-Ser-Gln-Asn-Tyr-Pro-Ile-Val-
73 739 4681.PG.03 -23
Gln-EDANS em que DABCYL = ácido 4-(4-dimetilaminofenil)-azobenzóico e EDANS = ácido 5-((2-aminoetil)amino)naftaleno-l--sulfónico. A tabela 1 mostra as potências inibidoras de compostos do invento contra a protease do HIV-1. TABELA 1
Composto do exemplo_IC5Q (nM) 1 14 2 2,2 3 2,9 4 1,0 8 2,5 9 3,2 10 2,2 11c 21
Os resultados indicam que os compostos são eficazes como inibidores da protease do HIV-1.
Actividade antiviral
Pode-se determinar a actividade anti-HIV dos compostos do invento em células MT4 de acordo com o procedimento de Pauwels et al., (J. Virol. Methods 1988, 20, 309). 0 IC50 é a concentração de composto que dá 50% de inibição do efeito citopático do HIV. 0 LC50 é a concentração de composto para a qual 50% das células permanecem viáveis. A tabela 2 mostra as potências inibidoras de compostos do invento contra o HIV-13B em células MT4. (segue Tabela)
gaeecSP* lç5Q. um >100 21 >100 >100 >100 >100 >100 >100 73 739 4681.PG.03 -24-
Tabela 2
Composto do exemplo_IC5Q (uM) 1 5,7 2 6,3 3 7,6 4 1,9 8 4,9 9 8,6 10 4,3 llc 10,4
Os resultados indicam que os compostos são eficazes como inibidores do efeito citopático do HIV em culturas celulares.
Podem-se utilizar os compostos do presente invento na forma de sais derivados de ácidos inorgânicos ou orgânicos. Estes sais incluem, mas não estão limitados aos seguintes: acetato, adipa-to, alginato, citrato, aspartato, benzoato, benzenossulfonato, bissulfato, butirato, canforato, canforsulfonato, digluconato, ciclopentanopropionato, dodecilsulfato, etanossulfonato, gluco--heptanoato, glicerofosfato, hemissulfato, heptanoato, hexanoa-to, fumarato, hidrocloreto, hidrobrometo, hidro-ideto, 2-hidroxi-etanossulfonato, lactato, maleato, metanossulfonato, nicotinato, 2-naftalenossulfonato, oxalato, pamoato, pectinato, persulfato, 3-fenilpropionato, picrato, pivalato, propionato, succinato, tartarato, tiocianato, p-toluenossulfonato e undeca-noato. Os grupos contendo azoto básico podem também ser quater-nizados com agentes tais como halogenetos de alquilo inferior, tais como cloretos, brometos e iodetos de metilo, etilo, propilo e butilo; sulfatos de dialquilo tais como sulfatos de dimetilo, dietilo, dibutilo e diamilo, halogenetos de cadeia longa tais como cloretos, brometos e iodetos de decilo, laurilo, miristilo e estearilo, halogenetos de aralquilo como brometos de benzilo e fenetilo, e outros. Obtêm-se assim produtos solúveis ou dispersáveis em água ou óleo. 73 739 4681.PG.03 25
Os exemplos de ácidos que se podem empregar para formar sais de adição de ácido farmaceuticamente aceitáveis incluem ácidos inorgânicos tais como ácido clorídrico, ácido sulfúrico e ácido fosfórico e ácidos orgânicos tais como ácido oxálico, ácido maleico, ácido succínico e ácido cítrico. Outros sais incluem sais com metais alcalinos ou metais alcalino-terrosos, tais como sódio, potássio, cálcio ou magnésio ou com bases orgânicas.
Os compostos do invento são úteis para a inibição de uma protease retroviral, em particular a protease do HIV, in vitro ou in vivo. Os compostos do presente invento são também úteis para o tratamento ou profilaxia de doenças causadas por retrovírus, especialmente a síndroma da imunodeficiência adquirida ou uma infecção pelo HIV no Homem ou noutro mamífero. A dose total diária administrada a um hospedeiro numa única dose ou em doses divididas pode ser em quantidades de, por exemplo, entre 0,001 e 100 mg/kg de peso corporal diariamente e mais usualmente de 0,1 a 10 mg. As composições de dosagem unitária podem conter estas quantidades ou seus submúltiplos para perfazer a dose diária. A quantidade de ingrediente activo que pode ser combinada com os materiais transportadores para produzir uma forma de dosagem única variará dependendo do hospedeiro tratado e do modo particular de administração.
No entanto, será entendido que o nível da dose específico para qualquer paciente particular dependerá de uma variedade de factores incluindo a actividade do composto específico empregue, idade, peso corporal, saúde geral, sexo, dieta, tempo de administração, via de administração, velocidade de excreção, combinação de drogas e gravidade da doença particular sujeita a terapia.
Podem-se administrar os compostos do presente invento oralmente, parentericamente, sublingualmente, por inalação de 73 739 4681.PG.03 -26-
vaporizado, rectalmente ou topicamente em formulações de dosagem unitária contendo transportadores, adjuvantes, e veículos convencionais, não tóxicos, farmaceuticamente aceitáveis, como desejado. A administração tópica pode também envolver o uso de administração transdérmica tal como emplastros transdérmicos ou dispositivos de iontoforese. 0 termo parentérico, guando aqui utilizado, inclui injecções subcutâneas, injecção intravenosa, intramuscular, intraesterna, ou técnicas de infusão.
As preparações injectáveis, por exemplo, suspensões aquosas ou oleaginosas estéreis injectáveis, podem ser formuladas de acordo com a arte conhecida utilizando agentes de dispersão ou molhantes e agentes de suspensão adequados. A preparação injectável estéril pode também ser uma solução ou suspensão injectável estéril num diluente ou solvente não tóxico, parentericamente aceitável, como por exemplo, uma solução em 1,3-propanodiol. Entre os veículos e solventes aceitáveis que podem ser empregues estão a água, a solução de Ringer e a solução de cloreto de sódio isotónica. Além disso, empregam-se convencionalmente óleos fixos, estéreis, como solventes ou meios de suspensão. Para este fim, pode-se empregar qualquer óleo brando estável incluindo mono- ou di-glicéridos sintéticos. Em adição, ácidos gordos tais como o ácido oleíco, encontram uso na preparação de injectáveis.
Podem-se preparar supositórios para administração rectal da droga misturando a droga com um excipiente não irritante adequado tal como a manteiga de cacau e polietilenoglicois, que são sólidos a temperaturas normais mas líquidos à temperatura rectal e irão portanto derreter no recto e libertar a droga.
As formas de dosagem sólidas para administração oral podem incluir cápsulas, comprimidos, pílulas, pós e grânulos. Nestas formas de dosagem sólidas, pode-se misturar o composto activo com pelo menos um diluente inerte tal como sacarose, lactose ou amido. Estas formas de dosagem podem também compreender, como é prática normal, substâncias adicionais para além dos diluentes
73 739 4681.PG.03 -27-inertes, p. ex., agentes lubrificantes tais como o estearato de magnésio. No caso de cápsulas, comprimidos e pílulas, as formas de dosagem podem também compreender agentes tampão. Adicionalmente, podem-se preparar comprimidos e pílulas com revestimentos entéricos.
As formas de dosagem líquidas para administração oral podem incluir emulsões, soluções, suspensões, xaropes e elixires farmaceuticamente aceitáveis contendo diluentes inertes comummente utilizados na arte, tais como a água. Estas composições podem também compreender adjuvantes, tais como agentes molhantes, emulsionantes e agentes de suspensão, e agentes edulcorantes, aromatizantes e perfumantes.
Podem-se também administrar os compostos do presente invento na forma de lipossomas. Como é conhecido na arte, os lipossomas são geralmente derivados de fosfolípidos ou de outras substâncias lipídicas. Os lipossomas são formados por cristais líquidos hidratados mono- ou multi-lamelares que estão dispersos num meio aquoso. Pode-se utilizar qualquer lípido não tóxico, fisiologicamente aceitável e metabolizável, capaz de formar lipossomas. As presentes composições na forma de lipossomas podem conter, para além de um composto do presente invento, estabilizadores, conservantes, excipientes e similares. Os lípidos preferidos são os fosfolípidos e as fosfatidilcolinas (lecitinas), tanto naturais como sintéticos.
Os processos de formação de lipossomas são conhecidos na arte. Ver, por exemplo, Prescott, Ed., Methods in Cell Biolocryf Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Embora um composto do invento possa ser administrado como o único agente farmacêutico activo, eles podem também ser utilizados em combinação com um ou mais imunomoduladores, agentes antivirais, outros agentes anti-infecciosos ou vacinas. Os outros agentes antivirais a administrar em combinação com um composto do presente invento incluem AL-721, interferão beta, polimanoacetato, ganciclovir, didesoxicitidina, fosfonoformato
73 739 4681.PG.03 -28-trissódico, HPA-23, eflonitina, Péptido T, Reticulose (nucleofosfoproteína), zidovudina (AZT), ansamicina LM 427, trimetrexato, UA001, ribavirina, interferão alfa, oxetanocina, DDC, DDI, cilobut G e aciclovir. Os imunomoduladores que se podem administrar em combinação com um composto do presente invento incluem bropirimina, Ampligénio, anticorpo anti-interferão alfa humano, factor estimulador de colónias, CL246738, Imreg-1, Imreg-2, ditiocarbamato de dietilo, interleucina-2, interferão alfa, inosina pranobex, metionina encefalina, tripéptido de muramilo, TP-5, eritropoietina, naltrexona e factor de necrose tumoral. Outros agentes anti-infecciosos que podem ser administrados em combinação com um composto do presente invento incluem o isetionato de pentamidina. Pode-se utilizar qualquer uma das várias vacinas do HIV ou da SIDA em combinação com um composto do presente invento.
Será entendido que os agentes que podem ser combinados com os compostos do presente invento para o tratamento ou profilaxia da SIDA ou de uma infecção pelo HIV não estão limitados aos listados acima, mas incluem, em princípio, qualquer agente útil para o tratamento ou profilaxia da SIDA ou de uma infecção pelo HIV.
Quando administrados na forma de combinações, os agentes terapêuticos podem ser formulados na forma de composições separadas que são dadas ao mesmo tempo ou em tempos diferentes, ou os agentes terapêuticos podem ser dados na forma de uma única composição. O que se descreveu é meramente ilustrativo do invento e não se pretende que limite o invento aos compostos descritos. Pretendem-se incluir as variações e mudanças óbvias aos peritos na arte dentro do âmbito e natureza do invento, que estão definidos nas reivindicações anexas.

Claims (10)

  1. 73 739 4681.PG.03 -29-
    REIVINDICACÕES 1 - Composto, caracterizado por ter a fórmula:
    na qual é alquilo inferior, cicloalquilo, fenilo ou seus derivados substituídos nos quais o grupo alquilo inferior, cicloalquilo ou fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; R2 é fenilo, um grupo heterocíclico aromático ou fenilo substituído em que o anel fenilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo; T
    na qual mé0a3eR4é seleccionado, indepentemente em cada ocorrência, de entre hidrogénio, alquilo inferior, cicloalquil-alquilo, haloalquilo, hidroxialquilo, alcoxialquilo, tioalcoxi-alquilo, aminoalquilo, alquilaminoalquilo, dialquilaminoalquilo, carboxialquilo, alcoxicarbonilalquilo e aminocarbonilalquilo e V T é r6-w-y-C na qual R6 é arilo, um grupo heterocíclico ou arilo substituído em que o anel arilo está substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo, V é 0 ou S, W é CH2, -CH2CH2-, -CH=CH- ou -D-CH=CH- em que D é 0, S ou NH e Y está ausente, 0, S ou N(R7) em que R7 é hidrogénio ou alquilo inferior; ou T é R15C(0)-, R15C(S)- ou R15S(0)2- em que R15 é 73 739 4681.PG.03 -30-
    alquilo inferior, arilo ou um grupo heterocíclico; e Z é —C(O)- ou -CH(OH)-; ou um seu sal farmaceuticamente aceitável; com a condição de que o composto seja diferente de 5--(N-benziloxicarbonilisoleucil)amino-3,3-difluoro-1,6-difenil-4--oxo-hexano.
  2. 2 - Composto de acordo com a reivindicação 1, caracteriza-do por ser fenilo; R2 ser fenilo, 2-piridilo, 3-piridilo ou 4-piridilo; m ser 2; R4 ser seleccionado independentemente em cada ocorrência, de entre hidrogénio e isopropilo; Z ser -C(0)-e T ser benziloxicarbonilo, N-(2-piridilmetil)aminocarbonilo, N--(3-piridilmetil)aminocarbonilo, N-(4-piridilmetil)aminocarboni-lo, 2-piridilmetoxicarbonilo, 3-piridilmetoxicarbonilo, 4-piri-dilmetoxicarbonilo, N-(2-piridilmetil)-N-(metil)aminocarbonilo, N-(3-piridilmetil)-N-(metil)aminocarbonilo, ou N-(4-piridilme-til)-N-(metil)aminocarbonilo.
  3. 3 - Composto, caracterizado por ter a fórmula: Ri
    (CH2)2 ^2 na qual é fenilo; R2 é fenilo;
    na qual m é 2, R4 é seleccionado, independentemente em cada ocorrência, de entre hidrogénio e alquilo inferior e v II T é R6—W—Y—C— em que Rg é arilo, um grupo heterocíclico ou seus derivados substituídos em que o anel arilo ou heterocíclico está 73 739 4681.PG.03 /; Jjt / "SKMHIÉJ5& -31- , · <Kt> j substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo, V é O ou S, W é CH2, -CH2CH2-, -CH=CH- ou -D-CH=CH- em que Déo, SouNHeY está ausente, o, s ou n(R7) em que R7 é hidrogénio ou alquilo inferior; ou T é r15C(0)-, R-^jjC(S)- ou Rj_5S(0)2- em que R-^ é alquilo inferior, arilo ou um grupo heterocíclico; ou um seu sal farmaceuticamente aceitável.
  4. 4 - Composto de acordo com a reivindicação 3, caracteriza-do por R4 ser seleccionado, independentemente em cada ocorrência, de entre hidrogénio e isopropilo e T ser benziloxicarbonilo, N-(2-piridilmetil)aminocarbonilo, N-(3-piri-dilmetil)aminocarbonilo, N-(4-piridilmetil)aminocarbonilo, 2-pi-ridilmetoxicarbonilo, 3-piridilmetoxicarbonilo, 4-piridilmetoxi-carbonilo, N-(2-piridilmetil)-N-(metil)aminocarbonilo, N-(3--piridilmetil)-N-(metil)aminocarbonilo, ou N-(4-piridilmetil)--N-(metil)aminocarbonilo.
  5. 5 - Composto, caracterizado por ter a fórmula:
    na qual R-^ é fenilo; R2 é fenilo; r3 é O
    IIrc_ na qual R4 é isopropilo e v II T é R6-W-Y-C- na qual Rg é arilo, um grupo heterocíclico ou seus derivados substituídos em que o anel arilo ou heterocíclico está -32- -32- e'-:' : 73 739 4681.PG.03 substituído com um ou dois substituintes seleccionados, independentemente um do outro, de entre hidroxi, alcoxi, tioalcoxi e halo, V é 0 ou S, W é CH2/ -CH2CH2-/ -CH=CH- ou -D-CH=CH- em que DéO, SouNHeY está ausente, 0, S ou N(R7) em que R7 é hidrogénio ou alquilo inferior; ou T é R15C(0)-, R^gC(S)- ou R-^SÍO^- em que R^g é alquilo inferior, arilo ou um grupo heterocíclico; ou um seu sal farmaceuticamente aceitável.
  6. 6 - Composto de acordo com a reivindicação 7, caracteriza-do por T ser benziloxicarbonilo, N-(2-piridilmetil)aminocarbo-nilo, N-(3-piridilmetil)aminocarbonilo, N-(4-piridilmetil)amino-carbonilo, 2-piridilmetoxicarbonilo, 3-piridilmetoxicarbonilo, 4-piridilmetoxicarbonilo, N-(2-piridilmetil)-N-(metil)aminocar-bonilo, N-(3-piridilmetil)-N-(metil)aminocarbonilo, ou N-(4--piridilmetil)-N-(metil)aminocarbonilo.
  7. 7 - Composto, caracterizado por ser seleccionado de entre o grupo que consiste em: 5(S)-(N-benziloxicarbonil-glicil-(L)-valinil)-amino-3,3-difluo-ro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(2-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(3-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano ? 5(S)-(N-(4-piridil)metoxicarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(2-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(3-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(4-piridilmetil)aminocarbonil-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difeni1-4-oxo-hexano; 5(S)-(N-(2-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(3-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(S)-(N-(4-piridilmetil)-N-(metil)aminocarbonil-glicil-(L)--valinil)-amino-3,3-difluoro-1,6-difenil-4-oxo-hexano; 33- 73 739 4681.PG.03 5(S)-(N-(2-(2-piridil)etanossulfonil)-glicil-(L)-valinil)-amino--3,3-difluoro-1,6-difenil-4-oxo-hexano; 5(s)-(N-acetilglicil-(L)-valinil)-amino-3,3-difluoro-l,6-dife-nil-4-oxo-hexano; e 5(S)-(N-(metanossulfonil)-glicil-(L)-valinil)-amino-3,3-difluoro-l, 6-difenil-4-oxo-hexano; ou um seu sal farmaceuticamente aceitável.
  8. 8 - Processo de preparação de um composto de acordo com a reivindicação 1, caracterizado por compreender a reacção de um composto de fórmula:
    h2n oh com um composto de fórmula T-(NHCH(R4)C(0))m-0H
  9. 9 - Composição farmacêutica, caracterizada por compreender uma quantidade eficaz de um composto de acordo com a reivindicação 1 com veículos ou diluentes farmaceuticamente aceitáveis.
  10. 10 - Composto de acordo com a reivindicação 1 para uso como medicamento. Lisboa. 26. M 1992 Por ABBOTT LABORATORIES =0 AGENTE 0FICIAL=
PT100304A 1991-03-27 1992-03-26 Compostos inibidores de proteases retrovirais, sua preparacao e uso e composicoes farmaceuticas que os contem PT100304A (pt)

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