RS38404A - Analozi lipoksina a4 - Google Patents

Analozi lipoksina a4

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Publication number
RS38404A
RS38404A YU38404A YUP38404A RS38404A RS 38404 A RS38404 A RS 38404A YU 38404 A YU38404 A YU 38404A YU P38404 A YUP38404 A YU P38404A RS 38404 A RS38404 A RS 38404A
Authority
RS
Serbia
Prior art keywords
alkyl
aryl
aralkyl
haloalkyl
group
Prior art date
Application number
YU38404A
Other languages
English (en)
Inventor
John Bauman
William Guilford
John Parkinson
Werner Skuballa
Babu Subramanyam
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23325714&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=RS38404(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Publication of RS38404A publication Critical patent/RS38404A/sr
Publication of RS51005B publication Critical patent/RS51005B/sr

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    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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Abstract

Ovaj pronalazak je usmeren na analoge lipoksina A4 sledeće formule (I) i (II): pri čemu su R1, R2 i R3, R4 i R5 kako je to ovde opisano. Ovi analozi su korisni u lečenju inflamatornih i autoimunih poremećaja kod ljudi. Ovi analozi su takođe korisni u lečenju inflamacije pulmonalnog i respiratornog trakta kod ljudi.

Description

ANALOZI LIPOKBINAA4
STANJE TEHNIKE
Oblast pronalaska
Pronalazak se odnosi na analoge lipoksina A4, njihovu upotrebu u lecenju inflamatornih i autoimunih poremecaja i inflamacije pulmonalnog i respiratornog trakta, i farmaceutske sastave koji sadrze analoge i postupke njihovog pripremanja.
Opis uporedne naucne literature
Lipoksini, zajedno sa leukotrienima, prostaglandinima, i tromboksanima,
cine grupu bioloski aktivnih oksigenovanih masnih kiselina koje se sve zajedno nazivaju ejkozanoidi. Ejkozanoidi su potpuno sintetizovane de novo iz membrare fosfolipida putem kaskade arasidonske kiseline enzima. Od njihovog inicijalnog otkrica godine 1984, postalo je ocigledno da lipoksini, kji su strukturalno jedinstvena klasa ejkozanoida, poseduju mocne antiinflamatorne osobine koje sugerisu da mogu imati terapeutski potencijal (Serhan, C.N.,Prostaglandins(1997), Vol. 53, pp. 107-137; O'Meara, Y.M.
et al.,Kidney Int.(Suppl.) (1997), Vol. 58, pp. S56-S61; Brady, H.R. et al.,
Curr. Opin. Nephrol. Hypertens.(1996), Vol. 5, pp. 20-27; \ Serhan, C.N.,
Biochem. Biophys. Acta.(1994), Vol. 1212, pp. 1-25). Od posebnog interesa je sposobnost lipoksina da antagonizuju pro-inflamatorne funkcije leukotriena dodatno drugim inflamatornim sredstvima kao sto je platelet aktivacioni faktor, FMLP, imuni kompleksi i TNFa. Lipoksini su tako mocna anti-neutrofilna (PMN) sredstva koja inhibiraju PMN hemopremestanje, homotipnu agregaciju, adheziju, migraciju kroz endotelijalne i epitelijalne celije, marginaciju/dijapedezu i infiltracije tkiva (Lee, T.H., et al.,Clin. Sci.
(1989), Vol. 77, pp. 195-203; Fiore, S., et al.,Biochemistry(1995), Vol. 34,
pp. 16678-16686; Papyianni, A., et al.,J. Immunol.(1996), Vol. 56, pp.
2264-2272; Hedquist, P., et al.,Acta. Physiol. Scand.(1989), Vol. 137, pp.
157-572; Papyianni, A., et al.,Kidney Intl.(1995), Vol. 47, pp. 1295-1302).
Dodatno, lipoksini su sposobni da regulisu nanize ekspresiju endotelijalnog P-selektina i adhezivnost za PMN-ove (Papyianni, A., et al.,J. Immunol.
(1996), Vol. 56, pp. 2264-2272), kontrakciju bronhijalnog i vaskularnog glatkog misica, kontrakciju i adhezivnost celija koje nose poruku (Dahlen,
S.E., et al.,Adv. Exp. Med. Biol.(1988), Vol. 229, pp. 107-130; Christie,
P.E., et al.,Am. Rev. Respir. Dis.(1992), Vol. 145, pp. 1281-1284; Badr,
K.F., et al.,Proc. Natl. Acad. Sci.(1989), Vol. 86, pp. 3438-3442; i Brady,
H.R., et al.,Am. J. Physiol.(1990), Vol. 259, pp. F809-F815) i hemopremestanje eozinofila i degranulaciju (Soyombo, O., et al.,Allergy
(1994), Vol. 49, pp. 230-234).
Ovaj jedinstveni anti-inflamatorni profil lipoksina, posebno lipoksirfa A4\
ubrzava interes za iskoristavanje njihovog potencijala kao terapeutika za lecenje inflamatornih ili autoiminih poremecaja i inflamacije pulmonalnog i respiratornog trakta. Takvi poremecaji i inflamacija koji prikazuju izrazeni inflamatorni infiltrat su od posebnog interesa i ukljucuju dermatoloske
poremecaje, kao sto su psorijaza, i reumatoidni artritis, i respiratorni poremecaji, kao sto je astma.
Kao sa drugim endogenim ejkozanoidima, lipoksini koji se prirodno pojavljuju su nestabilni proizvodi koji se brzo metabolisu i dezaktiviraju (Serhan, C.N.,Prostaglandins(1997), Vol. 53, pp. 107-137). Ovo ogranicava razvoj polje istrazivanja lipoksina, posebno u pogledu na in vivo farmakolosko procenjivanje anti-inflamatornog profila lipoksina. Nekoliko U.S. Patenata su izdani usmeravanjem na jedinjenja koja imaju aktivan polizaj lipoksina A4, ali sa duzim polu-zivotom tkiva. Videti, n.pr. U.S. Patent brojeve 5,441,951 i 5,648,512, otkrica koja su ovde u potpunosti inkorporisana putem reference. Ova jedinjenja zadrzavaju aktivnost vezivanja receptora lipoksina A4i mocne in vitro i in vivo anti-inflamatorne osobine prirodnih lipoksina (Takano, T., et al.,J. Clin. Invest.(1998), Vol.
101, pp. 819-826; Scalia, R., et al.,Proc. Natl. Acad. Sci.(1997), Vol. 94, pp.
9967-9972; Takano, T., et al.,J. Exp. Med.(1997), Vol. 185, pp. 1693-1704;
Maddox, J.F., et al.,J. Biol. Chem.(1997), Vol. 272, pp. 6972-6978; Serhan,
C.N., etal.,Biochemistry (1995), Vol.34, pp. 14609-14615).
Sve ovde navedene reference, ukljucujuci objavljene patentne prijave i clanci u casopisima, su ovde u potpunosti inkorporisane putem reference.
KRATKA SUSTINA PRONALASKA
Ovaj pronalazak je usmeren na mocne, selektivne i metabolicki/hemijski stabilne analoge lipoksina A4i na njihovu upotrebu u lecenju inflamatornih i autoimunih poremecaja i inflamacije pulmonalnog ili respiratornog trakta kod sisara, posebno ljudi.
U jednom aspektu, pronalazak je usmeren na jedinjenje formule (I) ili formule (II):
pri cemu:
su svaki R<1>, R<2>i R<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(gde je t 1 ili 2) ili-N(R7)R8; ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu:
(gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ill aril);
svaki R<4>je -R<9->R<12>, -R<9->R<13->R<11>, -R<9->O-R1<0>-R<11>, -R<9->0-R<12>, -R<9->
C(O)-R<10->R<1>1,-R9-N(R<7>)-<R10->R<11>, -R<9->S(O),-R<10>-R<11>(gde je t 0 do 2), ili -R<9>-
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, -
C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, ili -C(S)N(R<7>)R<8>;
svaki R7 je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>,
ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, -
S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>
ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i
R<14>je alkil, aril ili aralkil;
kao jedan stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so.
U sledecem aspektu, ovaj pronalazak je usmeren na farmaceutske sastave korisne u lecenju inflamatornog ili autoimunog poremecaja kod sisara,
posebno coveka, pri cemu se sastav sastoji od jednog ili vise farmaceutski prihvatljivih inertnih punilaca i terapeutski efikasne kolicine jedinjenja formule (I) ili formule (II) kako su gore opisana.
U sledecem aspektu, ovaj pronalazak je usmeren na farmaceutske sastave korisne u lecenju inflamacije pulmonalnog ili respiratornog trakta kod sisara,
posebno coveka, pri cemu se sastav sastoji od jednog ili vise farmaceutski prihvatljivih inertnih punilaca i terapeutski efikasne kolicine jedinjenja formule (I) ili formule (II) kako su gore opisana.
U sledecem aspektu, ovaj pronalazak je usmeren na postupke za lecenje inflamatornog ili autoimunog poremecaja kod sisara, posebno coveka, pri cemu se postupak sastoji od davanja sisaru kome je potrebna terapeutski efikasne kolicine jedinjenja formule (I) ili (II) kao su gore opisana.
U sledecem aspektu, pronalazak je usmeren na postupke lecenja inflamacije pulmonalnog ili respiratornog trakta kod sisara, pri cemu se postupak sastoji od davanja sisaru, posebno coveku, kome je potrebna, terapeutski efikasne kolicine jedinjenja formule (I) ili (II) kao su gore opisana.
DETALJAN OPIS PRONALASKA
A. Definicije
Kako se to ovde koristi clanovi za oblike jednine u engleskom jeziku "a",
"and", i "the" ukljucuju treferente u mnozini osim ukoliko kontekst ne diktira drugacije. Na primer, rec jedinjenje sa neodredenim clanom u jednini ("a compound") se odnosi na jedno ili vise takvih jedinjenja, dok rec enzim sa odredenim clanom u jednini ("the enzyme") ukljucuje odredeni enzim kao i druge clanove familije i njegove ekvivalente kako je to poznato strucnjacima u ovoj oblasti nauke. Sta vise, kako se to koristi u opisu i zahtevima, osim ukoliko nije specificno naglaseno da je drugacije, sledeci pojmovi imaju naznaceno znacenje: "Alkil" se odnosi na s lancem u normalnom nizu ili racvasti lanac ugljovodonik radikal koji se sastoji samo od atoma ugljenika i vodonika, koji ne sadrzi nezasicenost, i koji ima od jednog do osam atoma ugljenika, i koji je zakacen na ostatak molekula putem jednogube veze, n.pr., metil, etil, n-propil, 1-metiletil (izo-propil), n-butil, n-pentil, 1,1-dimetiletil (t-butil), i slicno.
Osim ukoliko se ne tvrdi drugacije specificno u opisu, alkil radikal moze biti opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od cijano, nitro, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>,
-R<9->C(0)OR<s>, -R<9>-C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R9-N(R6)C(0)RG„ -R<9->
S(0)tOR<6>(gde je t 0 do 2), -R<9->S(0),R<6>(gde je t 0 do 2), -R<9->S(0)tN(R<6>)2
(gde je t 0 do 2) gde je svaki R<5>i R<9>kako je to definisano u Sustini pronalaska a svaki R<16>je vodonik, alkil ili aralkil. Osim ukoliko se ne tvrdi drugacije specificno u opisu, razume se da takva supstitucija moze nastupiti na bilo kom ugljeniku alkil grupe.
"Alkilen lanac" se odnosi na s lancem u normalnom nizu ili racvasti divalentni lanac ugljovodonika koji se sastoji samo od ugljenika i vodonika,
koji ne sadrzi nezasicenost i koji ima od jednog do osam atoma ugljenika,
n.pr., metilen, etilen, propilen, n-butilen, i slicno.
"Alkenil" se odnosi na s lancem u normalnom nizu ili racavasti monovalentni lanac ugljovodonik radikal koji se sastoji samo od atoma ugljenika i vodonika, koji sadrzi bar jednu dvogubu vezu, koji ima od dva do osam atoma ugljenika, i koji je zakacen na ostatak molekula jednogubom vezom,
n.pr., etenil, prop-1-enil, but-1-enil, pent-1-enil, penta-1,4-dienil, i slicno.
Osim ukoliko se ne tvrdi drugacije specificno u opisu, alkenil radikal moze biti opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od cijano, nitro, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9>-N(R<6>)2, -R<9->
C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R<9->
N(R<6>)C(0)R<6>, -R<9->S(0)tOR<6>(gde je t 0 do 2), -R<9->S(0)tR<6>(<g>de je t 0 do 2), -
R<9->S(0)tN(R<6>)2(gde je t 0 do 2) gde je svakiR<6>iR<9>kako je to definisano u Sustini pronalaska a svaki R16 je vodonik, alkil ili aralkil. Osim ukoliko se ne tvrdi drugacije specificno u opisu, razume se da takva supstitucija moze nastupiti na bilo kom ugljeniku alkenil grupe.
"Alkenilen lanac" se odnosi na s lancem u normalnom nizu ili racvasti divalentni lanac ugljovodonika koji se sastoji samo od atoma ugljenika ,i vodonika, sadrzi bar jednu dvogubu vezu i ima od dva do osam atoma ugljenika, n.pr., etenilen, prop-1-enilen, but-1-enilen, pent-1-enilen, heksa-1,4-dienilen, i slicno.
"Alkinil" se odnosi na s lancem u normalnom nizu ili racvasti monovalentni lanac ugljovodonik radikal koji se sastoji samo od atoma ugljenika i vodonika, sadrzi bar jednu trogubu vezu, ima od dva do osam atoma ugljenika, i koji je zakacen na ostatak molekula putem jednogube veze,
n.pr., etinil, prop-1-inil, but-1-inil, bent-1-inil, pent-3-inil, i slicno. Osim ukoliko se ne tvrdi drugacije specificno u opisu, alkinil radikal moze biti opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od cijano, nitro, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>,
-R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->
S(0)tOR<6>(gde je t 0 do 2), -R<9->S(0)tR<6>(gde je t 0 do 2), -R<9->S(0)tN(R<5>)2
(gde je t 0 do 2) gde je svaki R<6>i R<9>kako je to definisano u Sustini pronalaska a svaki R<16>je vodonik, alkil ili aralkil. Osim ukoliko se ne tvrdi drugacije specificno u opisu, razume se da takva supstitucija moze nastupiti na bilo kom ugljeniku alkinil grupe.
"Alkinilen lanac" se odnosi na s lancem u normalnom nizu ili racavsti divalentni lanac ugljovodonika koji se sastoji samo od ugljenika i vodonika,
sadrzi bar jednu trogubu vezu i koji ima od dva do osam atoma ugljenika,
n.pr., etinilen, prop-1-inilen, but-1-inilen, pent-3-inilen, heksa-1,4-diinilen, i slicno.
"Alkoksi" se odnosi na radikal formule -ORagde je Raalkil radikal kako je to gore definisano, n.pr., metoksi, etoksi, n-propoksi, 1-metiletoksl (izo-propoksi), n-butoksi, n-pentoksi, 1,1-dimetiletoksi (t-butoksi), i slicno.
"Amino" se odnosi na -NH2radikal.
"Aril" se odnosi na fenil ili naftil radikal. Osim ukoliko nije specificno navedeno drugacije u opisu, pojam "aril" ili prefiks "ar-" (kao sto je to "aralkil") ukljucuju aril radikale koji mogu biti opciono supstituisani sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkenila,
halo, haloalkila, cijano, nitro, arila, aralkila, cikloalkila, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)0R<6>, -R<9->C(0)N(R<6>)2;-R<9->
N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0)t0R<6>(gde je t 0 do 2), -R<9->
S(0)tR<s>(gde je t 0 do 2), -R<9->S(0)tN(R<6>)2(gde je t 0 do 2) gde je svaki R<5>i R<9>kako je to definisano u Sustini pronalaska a svaki R<16>je vodonik, alkil ili aralkil. Osim ukoliko se ne tvrdi drugacije specificno u opisu, razume se da takva supstitucija moze nastupiti na bilo kom ugljeniku aril grupe.
"Aralkil" se odnosi na radikal formule -RaRbgde je Raalkil radikal kako je to gore definisano a Rbje aril radikal kako je to gore definisano, n.pr., benzil, i slicno. Aril radikal moze biti opciono supstituisan kako je to gore opisano.
"Karboksi" se odnosi na -C(0)OH radikal.
Kako se to ovde koristi, jedinjenja koja su "komercijalno dostupna" mogu biti dobijenaiza standardnih komercijalnih izvora ukljucujuci Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee Wi, ukljucujuci Sigma Chemical Ifluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lanchasire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, ,U.K.)„ Chemservice Inc. (West Chester PA), Crestcent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Codac Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals Inc. (Costa Mesa CA),
Key Organics (Cornwall U.K.), Lancaster Synthesis (Wintham NH),
Maybridge Chemical Co. Ltd. (Cornwall UK), Parish Chemical Co. (Orem UT), Tfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rochford IL), Riedel de Haen AG (Hannover, Nemacka),
Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland,
OR), Trans World Chemicals, Inc. (Rockville MD) i Wako Chemicals USA,
Inc. (Richmond VA).
Kako se to ovde koristi, "postupci poznati strucnjaku iz ove oblasti nauke"
moze biti identifikovano kroz razlicite knjige referenci i baze podataka.
Odgovarajuce knjige referenci i studija koje daju u detalje sintezu reaktanata korisnih u pripremanju jedinjenja sadasnjeg pronalaska, ili obezbeduju reference clanaka koji opisiju pripremanje, ukljucuju na primer, "Synthetic Organic Chemistry", Jonh Wiley & Sons, Inc., New York; S. R. Sandler et al.,
"Organic Functional Group Preparations, " 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A.
Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March,
"Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-lnterscience, New York, 1992. Specificni i analogni reaktanti mogu takode biti identifikovani kroz indekse hemakalija pripremljenih od strane Chemical Abstract Service od the American Chemical Society, koji su dostupni u najvecem broju javnih i univerzitetskih biblioteka, kao i kroz on-lajn baze podataka (the American Chemical Society, Washington,- D.C,
vw^cs.or<q>mogu se kontaktirati za vise detalja). Hemikalije koje su poznate ali ne i komercijalno dostupne u katalozima mogu biti pripremljene od strane kuca za uobicajenu hemijsku sintezu, dok mnoge od standardnih kuca za nabavku hemikalija (n.pr., one koje su gore navedene po redu)
obezbeduju uobicajene usluge sinteze.
Kako se to ovde koristi "odgovarajuci uslovi" za obavljanje sintetickog koraka su eksplicitno dati ovde ili mogu biti primecene putem reference prema publikacijama usmerenim na postupke koji se upotrebljavaju u sintetickoj organskoj hemiji. Knjige referenci i studija koje su prethodno odredene koje daju podrobno sintezu reaktanata korisnih za pripremanje jedinjenja sadasnjeg pronalaska, ce takode dati odgovarajuce uslove za obavljanje sintetickog koraka prema sadasnjem pronalasku.
"Klatrati" kako se to ovde koristi se odnose na supstance koje ucvrsti gasove, tecnosti ili jedinjenja kao ukljuceni kompleksi tako da se kompleksom moze rukovati u cvrstom obliku a ukljuceni konstituent (ili "gost" molekul) se potom oslobada dejstvom rastvaraca ili putem topljenja.
Pojam "klatrat" se ovde koristi interchangeably sa fazom "ukljuceni molekul"
ili sa frazom "ukljuceni kompleks". Klatrati koji se korist u trenutnom pronalasku se pripremaju iz ciklodekstrina. Za ciklodekstrine je svuda poznato da imaju sposobnost da formiraju klatrate (odnosn, ukljucena jedinjenja) za razlicitim molekulima. Videti, na primer,Inclusion Compounds,izdato od strane J.L. Atwood, J.E.D. Davies, i D.D. MacNicol,
London, Orlando, Academic Press, 1984; Goldberg, I., "The Significance of Molecular Type, Shape and Complementarity in Clathrate Inclusion",Topics in Current Chemistry (1988),Vol. 149, pp. 2-44; Weber, E. et al., "Functional Group Assisted Clathrate Formation - Scissor-Like and Roof-Shaped Host Molecules",Topics in Current Chemistry(1988), Vol, 149, pp. 45-135; i MacNicol, D.D. et al., "Clathrates and Molecular Inclusion Phenomena",Chemical Society Reviews(1978), Vol. 7, No. 1, pp. 65-87. Za konverziju u ciklodekstrin klatrate je poznato da povecava stabilnost i rastvorljivost odredenih jedinjenja, pri cemu olaksava njihovu upotrebu kao farmaceutskih agenasa. Videti, na primer, Saenger, W., "Cyclodextrin Inclusion Compounds in Research and Industry",Angew. Chem. Int. Ed. Engl.(1980), Vol. 19, pp. 344-362; U.S. Patent br. 4,886,788 (Schering AG); U.S. Patent br. 6,355,627 (Takasago); U.S. Patent br. 6,288,119 (Ono Pharmaceuticals);
U.S. Patent br. 6,110,969 (Ono Pharmaceuticals); U.S. Patent br. 6,235,780
(Ono Pharmaceuticals); U.S. Patent br. 6,262,293 (Ono Pharmaceuticals);
U.S. Patent br. 6,225,347 (Ono Pharmaceuticals); i U.S. Patent br.
4,935,446 (Ono Pharmaceuticals).
"Ciklodekstrin" se odnosi na ciklicne oligosaharide koji se sastoje od bar sest glukopiranoza jedinica koje su pridruzene zajedno putem a(1-4)veza.
Oligosaharidi prsten formira ispupcenje sa primarnim hidroksilnim grupama ostataka glukoze koja lezi na uskom kraju ispupcenja. Sekundarne glukopiranoza hidroksilne grupe su locirane na sirem kraju. Za ciklodekstrine je pokazano da formiraju ukljucene komplekse sa hidrofobicnim milekulima u tacnim rastvorima vezivanjem molekula u njihove supljine. Formiranje takvih kompleksa stiti "gost" molekul od gubitka isparavanjem, od napada od strane kiseonika, vidljivog i ultraljubicastog svetla i od intra- i intermolekularnih reakcija. Takvi kompleksi takode sluze da "ucvrste" isparljiv materijal dok se kompleks ne sretne sa vrucim vlaznim okruzenjem, u kom ce trenutku kompleks da se rastvori i disocira u gost molekul i ciklodekstrin. U svrhe ovog pronalaska, sest-glukoza jedinica koja sadrzi ciklodekstrin je specifikovana kao a-ciklodekstrin, do1< su ciklodekstrini sa sedam i osam glukoza ostataka oznaceni kao (3-ciklodekstrin i y-ciklodekstrin, svaki posebno. Najuobicajenija alternativa ciklodekstrin nomenklaturi je imenovanje ovih jedinjenja kao cikloamiloza.
"Cikloalkil" se odnosi na stabilni monovalentni monociklicni ili biciklicni radikal ugljovodonika koji se sastoji samo od atoma ugljenika i vodonika, ima tri do deset atoma ugljenika, i koji je zasicen i zakacen na ostatak molekula putem jednogube veze, n.pr., ciklopropil, ciklobutil, ciklopentil, cikloheksil,
dekalinil, i slicno. Osim ukoliko nije specificno navedeno drugacije u opisu,
pojam "cikloalkil" ima nameru da ukljuci cikloalkil radikale koji su opciono supstituisani sa jednim ili vise suptituenata nezavisno odabranih od grupe koja se sastoji od alkila, alkenila, halo, haloalkila, haloalkenila, cijano, nitro,
arila, aralkila, cikloalkila, heterociklila, heterociklilalkila, -R<9->OR<s>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->
N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0)tOR<6>(gde je t 0 do 2), -R<9->
S(0)tR<6>(gde je t 0 do 2), -R<9->S(0)tN(R<6>)2(gde je t 0 do 2) gde je svaki R<6>i R<9>kako je to definisano u Sustini pronalaska a svaki R<16>je vodonik, alkil ili aralkil. Osim ukoliko nije specificno navedeno drugacije u opisu, razume se da takva supstitucija moze nastupiti na bilo kom ugljeniku cikloalkil grupe.
"Cikloalkilen" se odnosi na stabilni divalentni monociklicni ili biciklicni ugljovodonik koji se sastoji samo od atoma ugljenika i vodonika, ima od tri do deset atoma ugljenika, i koji je zasicen i zakacen za ostatak molekula putem dve jednogube veze, n.pr., ciklopropilen, ciklobutilen, ciklopentilen,
cikloheksilen, dekalinilen i slicno. Osim ukoliko nije specificno navedeno drugacije u opisu, pojam "cikloalkilen" se smatra da ukljucuje cikloalkilen ostatke koji su opciono suptituisani sa jednim ili vise supstituenata nezavisno odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija, hidroksija, amino, i karboksija.
"Halo" se odnosi na bromo, hloro, jodo ili fluoro.
"Haloalkil" se odnosi na alkil radikal, kako je gore definisan, koji je supstituisan sa jednim ili vise halo radikala, kako je to gore definisano, n.pr.,
trifluorometil, difluorometil, tihlorometil, 2,2,2-tirfluoroetil, 1-fluorometil-2-fluoroetil, 3-bromo-2-fluorpropil, 1-bromometil-2-bromoetil, i slicno.
"Haloalkoksi" se odnosi na radikal formule -Ore gde je Rc haloalkil radikal kako je to gore definisano, n.pr., trifluorometoksi, difluorometoksi,
trihlorometoksi, 2,2,2-trifluoroetoksi, 1-fluorometil-2-fluoroetoksi, 3-bromo-2-fluoropropoksi, 1-bromometil-2-bromoetoksi, i slicno.
"Sisar" ukljucuje ljude i dimace zivotinje, kao sto su macke, psi, svinje,
goveda, ovde, koze, konji, zecevi, i slicno.
"Opcioni" ili "opciono" znaci da potonji opisani dogadaji posledica mogu ili mogu da se ne dese, i da opis ukljucuje instance gde navedeni dogadaj ili posledica nastupaju ili instance gde se to ne desava. Na primer, "opciono supstituisani aril" znaci da aril radikal mize ili ne mora biti supstituisan i da opis ukljucuje i supstituisane aril radikale i aril radikale koji nemaju supstituciju.
"Farmaceutski prihvatljiva so" ukljucuje i kisele i bazne adicione soli.
"Farmaceutski prihvatljiva kisela adiciona so" se odnosi na one scA\ koje zadrzavaju biolosku efikasnost i osobine slobodnih baza, koje nisu bioloski ili na drugi nacin nepozeljne, i koje su formirane sa neorganskim kiselinama kao sto su hlorovodonicna kiselina, bromvodonicna kiselina, sumporna kiselina, azotna kiselina, fosforna kiselina, i slicno, i organskim kiselinama kao sto su sircetna kiselina, trifluorosircetna kiselina, propijonska kiselina,
glikolna kiselina, pirogrozdana kiselina, oksalna kiselina, maleinska kiselina,
malonska kiselina, cilibarna kiselina, fumarna kiselina, vinska kiselina,
limunova kiselina, benzojeva kiselina, cimetna kiselina, bademova kiselina,
metansulfo kiselina, etansulfokiselina, p-toluensulfo kiselina, salicilna kiselina, i slicno.
"Farmaceutski prihvatljiva bazna adiciona so" se odnosi na one soli koje zadrzavaju biolosku efikasnost i osobine slobodnih kiselina, koje nisu bioloski ili na drugi nacin nepozeljne. Ove soli se pripremaju iz dodavanja neorganske baze ili organske baze slobodnoj kiselini. Soli izvedene iz neorganskih baza ukljucuju, ali nisu ogranicene na, natrijum, kalijum, litijum,
amonijum, kalcijum, magnezijum, gvozde, cink, bakar, mangan, aliuminijum soli i slicno. Pretpostavljene neorganske soli su amonijum, natrijum, kalijum,
kalcijum, i magnezijum soli. Soli izvedene iz organskih baza ukljucuju, ali nisu ogranicene na, soli primarnih, sekundarnih i tercijarnih amina,
supstituisane amine ukljcujuci supstituisane amine koji se pojavljuju u prirodi, ciklicne amine i bazne jon izmenjivacke smole, kao sto su izopropilamin, 2-dimetilaminoetanol, 2-dietilaminoetanol, dicikloheksilamin,
lizin, arginin, histidin, kafein, prokain, hidrabamin, holin, betain,
etilenediamin, glukozamin, metilglukamin, teobromin, purine, piperazin,
piperidin, N-etilpiperidin, poliamin smole i slicno. Posebno pretpostavljene organske baze su izopropilamin, dietilamin, etanolamin, trimetilamin,
dicikloheksilamin, holin i kafein.
"Prolekovi" ima nameru da oznaci jedinjenje koje moze biti konvertovano pod fizioloskim uslovima ili putem razlaganja rastvaracem u bioloski aktivno jedinjenje pronalaska. Tako se, pojam "prolek" odnosi na metabolicki prekursor jedinjenja pronalaska koji je farmaceutski prihvatljiv. Prolek moze
biti neaktivan kada se daje subjekto kome je neophodan, ali se konvertujein vivou aktivno jedinjenje pronalaska. Prolekovi se tipicno brzo transformisuin vivoda daju prinos maticnog jedinjenja pronalaska, na primer, hidrolizom u krvi. Prolek jedinjenje cesto nudi prednosti rastvorljivosti, kompatibilnosti sa tkivom ili odlozeno oslobadanje u organizmu sisara (videti, Bundgard, H.,
Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
Razmatranje prolekova je dato kod Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems,"A. C. S. Symposium Series,Vol. 14, i kodBioreversible Carriers in Drug Design,ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, i oba su ovde inkorporisana u celosti putem reference.
Pojam "prolek" takode ima nameru da ukljuci kovalentno vezane nosace koji oslobadaju aktivno jedinjenje pronalaskain vivokada se takav prolek da sisaru. Prolekovi jedinjenja pronalaska mogu biti pripremljeni modifikovanjem funksionalnih grupa prisutnih u jedinjenju pronalaska na takav nacin da se modifikacije rascepaju, bilo tokom rutinske manipulacije iliin vivo,u maticno jedinjenje pronalaska. Prolekovi ukljucuju jedinjenja pronalaska gde je hidroksi, amino ili merkapto grupa vezana na bilo koju grupu koja se, kada se prolek jedinjenje pronalaska da sisaru, cepa da formira slobodnu hidroksi, slobodnu amino ili slobodnu merkapto grupu,
svaku posebno. Primeri prolekova ukljucuju, ali nisu ograniceni na, acetat,
format i benzoat derivate alkohola i funkcionalne grupe amina u jedinjenjima pronalaska i slicno.
"Stabilno jedinjenje" i "stabilna struktura" imaju nameru da naznace jedinjenje koje je dovoljno robustno da prezivi izolaciju iz reakcione smese do korisnog stepena cistoce, i formulaciju u efikasni terapeutski agens.
"Terapeutski efektivna kolicina" se odnosi na kolicinu jedinjenja pronalaska koja je, kada se da sisaru, posebno coveku, kome je neophodna, dovoljna da se izvede lecenje, kako je to dole definisano, inflamatornih ili autoimunih poremecaja ili inflamacije pulmonalnog ili respiratornog trakta. Kolicina jedinjenja pronalaska koja konstituise "terapeutski efektivnu kolicinu" ce se rezlikovati u zavisnosti od jedinjenja, inflamatornog ili autoimunog poremecaja, ili inflamacije pulmonalnog ili respiratornog trakta, i od njihove ozbiljnosti, i starosti sisara koji se leci, ali moze rutinski biti odredena od strane strucnjaka u ovoj oblasti nauke imajuci u vidu njegovo sopstveno znanje i ovo otkrice.
"Leciti" ili "lecenje" kako se to ovde koristi pokriva lecenje inflamatornog ili autoimunog poremecaja kod sisara, pretpostavljeno coveka, ili lecenje inflamacije pulmonalnog ili respiratornog trakta kod sisara, pretpostavljeno coveka, i ukljucuje:
(i) prevenciju od pojavljivanja poremecaja ili inflamacije kod sisara, posebno, kada je takav sisar predisponiran na poremcaj ali jos nije dijagnostikovano da ga ima; (ii) inhibiciju poremecaja ili inflamacije, odnosno, zaustavljanje njihovog razvoja; ili (iii) ublazavanje poremecaja ili inflamacije, odnosno, izazivanje regresije poremecaja ili inflamacije.
Jedinjenja pronalaska, kao jedan stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so, mogu sadrzati jedan ili vise asimetricnih centara i mogu se tako podici do enantiomera, diasteromera, i drugih steroizomernih oblika koji mogu biti definisani, u pogledu apsolutne stereohemije, kao (R)- ili (S)- ili, kao (D)- ili (L)- za amino kiseline. Sadasnji pronalazak ima nameru da ukljuci sve takve moguce izomere, kao i, njihove racemske i opticki ciste oblike. Opticki aktivni (R)- ili (S)- ili, kao (D)- ili (L)-izomeri mogu biti pripremljeni upotrebom hiralnih sintona ili hiralnih reagensa, ili resena upotrebom konvencionalnih tehnika. Kada jedinjenja koja su ovde opisana sadrze olifinske dvogube veze ili druge centre geometrijske asimetrije, i ukoliko nije specifikovano drugacije, ima se namera da jedinjenja ukljuce oba i E i Z geometrijske izomere. Na isti nacin,
tautomerni oblici se takode imaju ukljuciti.
Nomenklatura koja se ovde koristi je modifikovani oblik sistema I.U.P.A.C.
nomenklature gde su jedinjenja pronalaska ovde imenovana kao derivati heksadekanski ostatci. Na primer, sledeca jedinjenja formule (I) gde su R1,
R2 i R3 svaki -OR<6>((gde jeR<6>vodonik); R<4>je -R9-O-R10-R11 (gde je R<9>
direktna veza, R<10>je metilen a R<11>je -C)0=OH); a R<5>je fenil supstituisan na 4-poziciji sa fluoro, odnosno,
je ovde nazvano kao (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina. Osim ako nije drugacije navedeno putem nomenklature, imena jedinjenja imaju nameru da uljuce bilo koji pojedinacni stereoizomer, enantiomer, racemat ili njihovu smesu.
U svrhe ovog otkrica, u onim jedinjenjima pronalaska gde R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu heterociklicnu strukturu: razume se da te strukture ukljucuju sledece reversne strukture:
B. Korisnost jedinjenja pronalaska
Jedinjenja pronalaska su analozi lipoksina A4koji imaju slicnu biolosku aktivnost prirodnog lipoksina A4, ali sa pojacanom otpornoscu na metaboliticku degradaciju. U skladu sa tim, jedinjenja pronalaska su korisna u lecenju inflamatornih i autoimunih poremecaja kod sisara, posebno kod ljudi. Posebno, jedinjenja pronalaska su korisna u inhibiranju akutne ili hronicne inflamacije ili inflamatornog ili autoimunog odgovora koji je posredovan putem neutrofila, eozinofila, T limfocita, NK celija i drugih imunih celija koje doprinose patogenezi inflamatornih, imunih ili autoimunih bolesti.
Jedinjenja su takode korisna u lecenju proliferativnih poremecaja ukljucujuci,
ali ne ogranicavajuci na, one povezane sa rastrojstvima kod inflamatornog ili imunog odgovora, kao sto je kancer. Jedinjenja su takode korisna kao inhibitor! angiogenskih odgovora u patogenezi kancera.
U skladu sa tim, jedinjenja se mogu koristiti da se lece sledeci inflamatorni i autoimuni poremecaji kod sisara, posebno ljudi: anafilakticke reakcije,
alergijske reakcije, alergijski kontaktni dermatitis, alergijski rinitis, hemijski i ne-specificno iritantni kontaktni dermatitis, urtikarija, atopicni dermatitis,
psorijaza, septicki ili endotoksicni sok, hemoragicni sok, sindromi slicni soku,
sindromi curenja kapilara izazvani imunoterapijom kancera, akutni respiratorni sindrom bola, traumatski sok, imuno- i patogeno-izazvane pneumonije, imuna kompleksom-posredovana pulmonalna povreda i hronicna obstruktivna polmonalna bolest, inflamatorne bolesti utrobe ukljucujuci ulcerativni kolitis, Crohn-ova bolest i post-hirurska trauma,
gastrointestinalni cirevi, bolesti povezane sa ishemija-reperfuzija povredom ukljucujuci akutnu miokardijalnu ishemiju i infarkt, aktuni renalni pad,
ishemicne bolesti utrobe i akutni hemoragicni ili ishemicni udar, imuno-kompleks-posredovani glomerulonefritis, autoimune bolesti ukljucujuci diabetis mellitus zavisan od insulina, skleroza multipleks, reumatoidni artritis,
osteoartritis i sistemski lupus erythematosus, akutno i hronicno odbacivanje transplantiranog organa, transplant arterioskleroze i fibroze, kardiovaskularni poremecaji ukljucujuci hipertenziju, aterosklerozu, aneurizmu, kriticna ishemija noge, periferna arterijska okulzivna bolest i Reynaud-ov sindrom,
komplikacije kod dijabetisa ukljucujuci nefropatiju, neuropatiju i retinopatiju,
okularni poremecaji ukljucujuci makularnu degeneraciju i glaukom,
neurodegenerativni poremecaji ukljucujuci odlozenu neurodegeneraciju kod mozdanog udara, Alzheimer-ova bolest, Parkinskon-ova bolest, encefalitis i HIV demencija, inflamatorni i neuropatski bol, ukljucujuci artriticni bol,
penodontalna bolest ukljucujuci gingivitis, infekcije uha, migrenu, benignu hiperplaziju prostate, kanceri ukljucujuci, ali ne ogranicavajuci na, leukemije i limfomi, kancer prostate, kancer dojke, kancer pluca, malingi melanom,
renalni karcinom, tumori glave i vrata i kolorektalni kancer.
Jedinjenja su takode korisna u lecenju folikulitisa izazvanog inhibitorima epidermalnog faktora rasta (EGF) ili kinaze receptora epidermalnog faktora rasta (EGFR) koja se koristi u lecenju cvrstih tumora. Klinicke probe su otkrile folikulitis (inflamacija follicle kose koja se manifestuje putem ozbiljnog akni slicnog osipa koze na lieu, grudima i gornjem delu leda) kao glavnu dozu - ogranicavajuci sporedni efekat takvih lecenja. Takav folikulitis je povezan sa infiltracijom neutrofila sto sugerise da su proizvodi koji se izluce putem aktiviranih neutrofila uzrok inflamacije. Analozi lipoksina A4 trenutnog pronalaska inhibiraju od strane neutrofila ili eozinofila posredovanu inflamaciju, i stoga su korisni u lecenju takvog folikulitisa, pri cemu poboljsavaju kvalitet zivota pacijenata sa lecenim kancerom ali takode dopustaju povecanje doze EGF inhibitora ili EGFR kinaza inhibitora ili produzenje trajanja lecenja, sto rezultira u poboljsanoj efikasnosti zeljenog inhibitora.
Jedinjenja su takode korisna u lecenju pulmonalne ili respiratorne inflamacije, uklucujuci, ali ne ogranicavajuci na, astmu, hronicni bronhitis,
bronhiolitis, bronhiolitis obliterans (ukljucujuci takav sa organizovanjem pneumonije), alergijsku inflamaciju respiratornog trakta (ukljucujuci rinitis i
sinusitis), eozinofilicni granulom, pneumonije, pulmonalne fibroze,
pulmonalne manifestacije bolesti vezivnog tkiva, akutna i hronicna povreda pluca, hronicne obstruktivne pulmonalne bolesti, respiratorni sindrom bola kod odraslih osoba, i drugi ne-infektivni inflamatorni poremecaji pluca koji se karakterisu infiltracijom eazinofila.
Na primer, jedinjenja pronalaska su korisna u inhibiciji: eazinofilom posredovane inflamacije pluca ili tkiva; neutrofilom posredovana inflamacija pluca; limfocitom posredovana inflamacija pluca; proizvodnja citokina i hemokina, ukljucujuci interleukin-5, interleukin-13 i eotaksin; generacija lipidnog medijatora, ukljucujuci prostaglandin E2 i cisteinil leukotriene; hiper-odgovaranje vazdusnog puta; i vaskularna inflamacija i inflamacija vazdusnog puta.
C. Testiranje jedinjenja pronalaska
Obelezje inflamacije je adhezija i transmigracija neutrofila, oezinofila i drugih inflamatornih celija kroz endotelijum. Slican proces je primecen za migraciju celija kroz polarizovane epitelijalne celije kje se pojavljuju u plucima, gastrointestinalnom traktu i drugim organima. Modeli celijske kulture ovih procesa su dostupni i koriste se da pokazu da lipoksin A4i stabilni analozi lipoksina A4inhibiraju transmigraciju humanih neutrofila kroz humane endotelijalne celije i epitelijalne celije, ukljucujuci humanu intesfinalnu celijsku liniju T84. U skladu sa tim, strucnjak iz ove oblasti nauke moze da testira jedinjenja pronalaska na nijihovu sposobnost da inhibiraju transmigraciju humanih neutrofila i eozinofila kroz humane endotelijalne celije i epitelijalne celije obavljanjem ogleda slicnog onom opisanom kod Colgan, S.P., et al.,J. Clin. Invest.(1993), Vol. 92, No. 1, pp. 75-82 i Serhan, C.N., et al.,Biochemistry (1995),Vol. 34, No. 44, pp. 14609-14615.
Model punjenja vazduha i/ili model misjim zimosanom izazvan peritonitis mogu se upotrebljavati da se proceniin vivoefikasnost jedinjenja pronalaska u lecenju odgovora na inflamaciju. Ovo su akutni eksperimentalni modeli inflamacije koji se karakterisu infiltriranjem inflamatomih celija u lokalizovanu oblast. Videti, n.pr.,in vivooglede opisane kod Ajuebor, M.N:, et al.,
Immunology(1998), Vol. 95, pp. 625-630; Gronert, K., et al.,Am. J. Pathol.
(2001), Vol. 158, pp. 3-9; Pouliot, M., etal.,Biochemistry (2000),Vol. 39, pp.
4761-4768; Clish, C.B., et al.,Proc. Natl. Acad. Sci. U. S. A.(1999), Vol. 96,
pp. 8247-8252; i Hachicha, M., et al.,J. Exp. Med.(1999), Vol. 189, pp.
1923-30.
Zivotinjski modeli (odnosno,in vivoogledi) mogu biti iskoristeni da se utvrdi efikasnost jedinjenja pronalaska u lecenju astme i povezanih poremecaja pulmonalnog i respiratornog trakta, ukljucujuci, ali ne ogranicavajuci na, astmu. Videti, n.pr., oglede opisane kod De Sanctis, G.T., et al.,Journal of Clinical Investigation(1999), Vol. 103, pp. 507-515 i Campbell, et al.,J.
Immunol.(1998), Vol. 161, No. 12, pp. 7047-7053.
D. Davanje jedinjenja pronalaska
Davanje jedinjenja pronalaska, kao jedinicnih stereoizomera, smese stereoizomera, ili kao racemske smese stereoizomera; ili kao njihovog ciklodekstrin klatrata, ili kao njihove farmaceutski prihvatljive soli, u cistom obliku ili u odgovarajucem farmaceutskom sastavu, moze se obaviti putem bilo kog prihvacenog nacina davanja ili agenasa koji sluze za slicna iskoristavanja. Tako davanje moze biti, na.primer, oralno, nazalno, parenteralno, pulmonalno, mesno, transdermalno, ili rektalno, u obliku cvrstog, polu-cvrstog, liofilisanog pudera, ili tecnih oblika doze, kao sto su na primer, tablete, supozitorije, pilule, meke elasticne i od tvrdog zelatina kapsule, puderi, rastvori, suspenzije, aerosoli, flasteri, i slicno, pretpostavljeno u jedinicnim oblicima doze odgovarajucim za prosto davanje preciznih doza. Sastavi ce ukljuciti konvencionalan famraceutski nosac ili inertni punilac i jedinjenje pronalaska kao aktivno sredstvo, i, dodatno, moze ukljuciti druge medicinske agense, farmaceutske agense, nosace,
adjuvante, itd.
Uopsteno govoreci, u zavisnosti od nameravanog nacina davanja,
farmaceutski prihvatljivi sastavi ce sadrzati oko 0,1% do oko 99,9% po masi jeidnjenje(a) pronalaska, kao jedinicni stereoizomer, smesa stereoizomera,
ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so, i 99,9 do 1,% po masi odgovarajuci farmaceutski inertni punilac. Pretpostavljeno, sastav ce biti oko 5% do 75%
po masi jedinjenje (a) pronalaska, ili kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so, sa ostatkom koji je odgovarajuci farmaceutski inertni punilac.
Pretpostavljeni put davanje je oralni, upotrebom pogodnog rezima dfievne doze koji se moze podesiti prema stepenu ozbiljnosti bolesti-stanja koje se ima leciti. Za takvo oralno davanje, farmaceutski prihvatljiv sastav koji sadrzi jedinjenje(a) pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so, se formira pugdm inkorporacije jednog ili vise normalno uposlenih farmaceutski prihvatljivih inertnih punilaca, kao sto su, na primer, farmaceutski stepeni manitola, laktoza, skrob, prethodno zelatinizirani skrob, magnezijum stearat,
natrijum saharin, talk, derivati celuloza etra, glukoza, zelatin, saharoza,
citrat, propil galat, i slicno. Takvi sastavi ce uzeti oblik rastvora, suspenzija,
tableta, pilula, kapsula, pudera, formulacija za odlozeno oslobadanje i slicno.
Pretpostavljeno takvi sastavi ce biti u obliku kapsule, kapleta ili tablete i prema tome takode ce sadrzati razredivac kakav je laktoza, saharoza,
dikalcijum fosfat, i slicno; dezintegrant kao sto je kroskarmeloza natrijum ili od toga nastali derivati; mazivo kao sto je magnezijum stearat i slicno; i vezivno sredstvo kao sto je skrob, guma arabika, polivinilpirolidon, zelatin,
derivati celuloza etra, i slicno.
Jedinjenja pronalaska, ili njihove farmaceutski prihvatljive soli, mogu takode biti formulisani u supozitorij upotrebom, na primer, oko 0,5% do oko 50%
aktivnog sastojka smestenog u nosacu koji se polako rastvara u telu, n.pr.,
polioksietilen glikoli i polietilen glikoli (PEG), n.pr., PEG 1000 (96%) i PEG
4000 (4%).
Tecni sastavi koji se farmaceutski mogu davati mogu, na primer, biti pripremljeni rastvaranjem, dispergovanjem, itd., jedinjenja pronalaska (oko 0,5% do oko 20%), kao jedinicni stereoizomer, smesa stereoizomera,'ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so, i opcioni farmaceutski prihvatljivi adjuvanti u nosacu, kao sto su, na primer, voda, slani rastvor, vodena dekstroza, glicerin, etanol i slicno, da time formiraju rastvor ili suspenziju. Ukoliko se to zeli, farmaceutski sastav pronalaska moze takode da sadrzi manje kolicine pomocnih supstanci kao sto su agensi za vlazenje ili emulgovanje, pH puferski agensi, antioksidanti, i slicno, kao sto su, na primer, limunova kiselina, sorbitan monolaurat, trietanolamin oleat, butilovani hidroksitoluen, itd.
Aktuelni postupci pripremanja takvih oblika doze su poznati, i bice ocigledni,
strucnjacima iz ove oblasti nauke; na primer, videti Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,
Pennsylvania, 1990). Sastav koji se daje ce, u svakom slucaju, sadrzati terapeutski efektivnu kolicinu jedinjenja pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera;
ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so,
za lecenje bolesti-stanja koje se karakterise inflamacijom u skladu sa ucenjima ovog pronalaska.
Jedinjenja pronalaska, ili njihove farmaceutski prihvatljive soli, se daju u terapeutski efektivnoj kilicini koji ce varirati u zavisnosti od razlicitih faktora ukljucujuci aktivnost specificnog jedinjenja koje je uposleno; metabolicku stabilnost i duzinu dejstva jedinjenja; starost, telesnu tezinu, opste zdravlje, pol, i dijetu pacijenta; nacin i vreme davanja; brzinu excretion; kombinaciju leka; ozbiljnost odredene bolesti-stanja; i terapiju kojoj je podvrgnut domacin. Uopsteno govoreci, terapeutski efektivna dnevna doza je dd oko 0,14mg do oko 14,3mg/kg telesne tezine na dan po jedinjenju pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so; pretpostavljeno, od oko 0,7mg do oko 10mg/kg telesne tezine na dan; a najpozeljnije, od oko 1,4mg do oko 7,2mg/kg telesne tezine na dan. Na primer, za davanje osobi teskoj 70 kg, doza jedinjenja pronalaska ce biti u rasponu od oko 10 mg do oko 1,0 gram na dan, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera;
ili kao njihov ciklodekstrin klatrat, ili kao njihova farmaceutski prihvatljiva so,
pretpostavljeno od oko 50 mg do oko 700 mg na dan, a najpozeljnije od oko 100 mg do oko 500 mg na dan.
E. Pretpostavljene realizacije
Od jedinjenja pronalaska kako su postavljena gore u Sustini pronalaska,
posebno je pretpostavljeno nekoliko grupa jedinjenja.
U skladu sa tim, pretpostavljena grupa jedinjenja pronalaska su ona jedinjenja formule (I):
pri cemu:
su svakiR<1>,R<2>iR<3>nezavisno halo, -OR<6>, -SR<6>, ili -N(R<7>)R<8>;
svaki R<4>je -R<9->R<12>, -R9-Rl3-R11, -R9-O-R10-R11, -R<9->0-R<12>, -R<9->
C(O)-R<10->R<11>, -R<9->N(R<7>)-R<10->R<11>, -R9-S(O)rR10-R11 (gde je t 0 do 2), ili -R<9->
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aralkil, -C(0)R<7>, -C(0)OR<7>;
svaki R7 je nezavisno vodonik, alkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>ili -C(0)N(R<7>)2;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>ili -
C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen.
Od ove grupe jedinjenja, pretpostavljena podgrupa jedinjenja je ona podgrupa jedinjenja gde: su svaki R<1>, R2 iR<3>nezavisno halo, -OR<6>, ili -SR<6>;
svaki R4je-R9-O-R10-R11;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R6 je nazavisno vodonik, alkil, aril ili aralkil;
svaki R<7>je nezavisno vodonik, alkil, aril, ili aralkil;
R<9>je direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac,
s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen; i
Od ove podgrupe jedinjenja, pretpostavljena klasa jedinjenja je ona klasa jedinjenja<g>de:
R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila,
haloalkoksija);
R6 je vodonik, alkil, aril ili aralkil;
svaki R7 je nezavisno vodonik, alkil, aril, ili aralkil;
R9 je direktna veza;
R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac; i
Od ove klase jedinjenja, pretpostavljena jedinjenja su odabrana od grupe koja se sastoji od sledecih jedinjenja: (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina, metil estar; i
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-tnhidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina.
Sledeca pretpostavljena grupa jedinjenja pronalaska je ona grupa jedinjenja sa formulom (II):
gde:
su svakiR1,R<2>iR<3>nezavisno halo, -OR<6>, -SR<6>, ili -N(R<7>)R<8>;
svaki R<4>je -R<9->R<12>, -R<9->R<13->R<11>, -R9-O-R10-R11, -R<9->0-R<12>, -R<9->
C(O)-R10-R<11>, -R<9->N(R<7>)-R<10->R<11>, -R<9->S(O)t-R<10->R<11>(gde je t 0 do 2), ili -R<9>-
C(F)2-R9-R11;
svaki R<J>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aralkil, -C(O) R<7>ili -
C(0)OR<7>;
svaki R<7>je nezavisno vodonik, alkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>ili -C(0)N(R<7>)2;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>ili -
C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen.
Od ove grupe jedinjenja, pretpostavljena podgrupa jedinjenja je ona podgrupa jedinjenja gde:
su svaki R<1>, R<2>iR<3>nezavisno halo, -OR<6>ili -SR<6>;
R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril ili aralkil;
svaki R<7>je nezavisno vodonik, alkil, aril, ili aralkil;
R<9>je direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen; i
Od ove podgrupe jedinjenja, pretpostavljena klasa jedinjenja je ona klasa jedinjenja gde:
R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija; R6je vodonik, alkil, aril, ili aralkil; svaki R<7>je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil; R9 je direktna veza; R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac; i
Od ove klase jedinjenja, pretpostavljena jedinjenja su odabrana od grupe koja se sastoji od sledecih jedinjenja: (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina;
(5S,6S,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar; i
(5S,6S,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina.
Od postupaka koji koriste jedinjenja pronalaska kako su gore postavljena u Sustini pronalaska, pretpostavljena upotreba jedinjenja je lecenje psorijaze,
atopicni dermatitis, skleroza multipleks ili akutni hemoragicni ili ishemicni mozdani udar kod ljudi. Sledeca pretpostavljena upotreba ovih jedinjenja je lecenje astme kod ljudi.
F. Pripremanje jedinjenja pronalaska
Razume se da su sledeci opis, kombinacije supstituenata i/ili promenjljivih opisanih formula dozvoljeni samo ako takvi doprinosi rezultiraju u stabilnim jedinjenjima.
Takode ce se ceniti od strane strucnjaka iz ove oblasti nauke da u dole opisanim postupcima funkcionalne grupe intermedijarnih jedinjenja mogu imati potrebu da budu zasticena odgovarajucim zastitnim grupama. Takve funkcionalne grupe ukljucuju hidroksi, amino, merkapto i karbonsku kiselinu. Odgovarajuce zastitne grupe za hidroksi ukljucuju trialkilsilil ili diarilalkilsilil (n.pr., t-butildimetilsilil, t-butildifenilsilil ili trimetilsilil), tatrahidropiranil, benzil, i slicno. Odgovarajuce zastitne grupe za amino, amidino i gvanidino ukljucuju t-butoksikarbonil, benziloksikarbonil, i slicno. Odgovarajuce zastitne grupe za merkapto ukljucuju -C(0)-R (gde je R alkil, aril ili aralkil), p-metoksibenzil, tritil i slicno. Odgovarajuce zastitne grupe za karbonsku kiselinu ukljucuju alkil, aril ili aralkil estre.
Zastitne grupe mogu biti dodate ili uklonjene prema standardnim tehnikama,
koje su dobro poznate strucnjacima iz ove oblasti nauke i i kako su ovde opisane.
Upotreba zastitnih grupa je opisana detaljno kod Green, T.W. and P.G.M: Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience. Zastitna grupa moze takode biti polimer smola kao sto je Wang smola ili 2-hlorotritil hlorid smola.
Takode ce se ceniti od strane strucnjaka u ovoj oblasti nauke, iako takvi zasticeni derivati jedinjenja formule (I) i formule (II), kako je to opisano gore u Sustini pronalaska, ne moraju da poseduju famrakolosku aktivnost kao takvu, mogu biti davani sisarima koji imaju inflamatorni ili autoimuni poremecaj, ili inflamaciju pulmonalnog i respiratornog trakta, i potom se metabolisu u telu da formiraju jedinjenja pronalaska koja su farmakoloski aktivna. Takvi derivati mogu prema tome biti opisani kao "prolekovi". Svi prolekovi jedinjenja formule (I) i (II) su ukjluceni u obim pronalaska.
U pogodne svrhe, samo su jedinjenja pronalaska gde je R<9>veza a R<1>,R<2>i R<3>su hidroksi opisani u sledecim Reakcionim semama. Takode se ima razumeti, da ce ipak, strucnjak iz ove oblasti nauke biti sposoban da napravi druga jedinjenja pronalaska u svetlu sledeceg otkrica, ukljucujuci Preparate i Primere, i informaciju poznatu strucnjacima iz oblasti hemijske sinteze.
1. Pripremanje jedinjenja formule ( D)
Jedinjenja formule (D) su intermedijarni proizvodi u pripremanju pronalaska.
Pripremaju se kako je to opisano u donjoj Reakcionoj semi 1:
Jedinjenja formule (A) i formule (Aa) su komercijalno dostupna ili mogu biti pripremljena prema postupcima poznatim strucnjacima iz ove oblasti nauke.
Uopsteno govoreci, jedinjenja formule (D) se pripremaju prvo tretiranjem jedinjenja formule (A) sa ketonom formule (Aa) u prisustvu kiseline,
pretpostavljeno sumporne kiseline, na ambijentalnoj temperaturi oko 30
minuta do oko 2 sata, pretpostavljeno oko 1,5 sat. Vrednost pH rezultirajuce reakcione smese se onda podesava na oko pH 7,0 sa odgovarajucom bazom. Jedinjenje formule (B) se onda izoluje iz reakcione smese putem standardnih tehnika izolacije, kao sto je filtriranje ili koncentracija.
Jedinjenje formule (B) u protonskom rastvaracu, pretpostavljeno vodi, se onda tretira sa odgovarajucim redukcionim sredstvom, pretpostavljeno natrijumborhidridom, na temperatuream izmedu oko 0°C i 5°C. Reakciona smesa se mesa oko 1 sat do oko 2 sata, pretpostavljeno oko 2 sata, pre nego sto se doda blaga kiselina da se potrosi visak prisutnog redukcionog sredstva i da se podesi pH naoko pH 6,0. Rezultirajuca reakciona smesa se ohladi do izmedu oko 0°C i 5°C. Agens za cepanje glikola, kao sto je natrijumperjodat, se potom dodaje smesi. Rezultirajuca reakciona smesa se mesa na ambijentalnoj temperaturi oko 1 sat do oko 2 sata, pretpostavljeno oko 2 sata. Jedinjenje formule (D) se onda izoluje iz reakcione smese standardnim tehnikama izolacije, kao sto je organska ekstrakcija i koncentracija.
Alternativno, drugi alkil, aril i aralkil ketoni mogu se upotrebiti umesto ketona formule (Aa) da se formira ketal formule (B). Dodatno, moze se upotrebiti odgovarajuci aldehid umesto ketona formule (Aa) da se formira korespondirajuci acetal, koji moze dalje biti tretiran kako je to ovde opisano da se formira jedinjenje formule (D). Za opis razlicitih zastitnih grupa za 1,2-diole, videti Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-lnterscience.
2. Pripremanje jedinjenja formule ( M)
Jedinjenja formule (M) su intermedijarni proizvodi u pripremanju jedinjenja pronalaska. Ona su pripremljena kao je to dole opisano u Reakcionoj semi 2 pri cemu je R<7a>alkil, aril ili aralkil, R<10>je kako je to opisano u Sustini pronalaska, svaki R<14>je nezavisno vodonik ili alkil, R<14a>je vodonik ili alkil, a Xii X2su svaki nezavisno halo: Jedinjenja formule (E), formule (Ee), formule (H) i formule (K) su komercijalno dostupna, ili mogu biti pripremljena prema postupcima poznatim strucnjacima iz ove oblasti nauke.
Uopsteno, jedinjena formule (M) se pripremaju prvo uklanjanjem vode,
ukoliko je to potrebno, iz jedinjenja formule (E) putem standardnih tehnika.
Jedinjenje formule (E), u aprotonskom anhidrovanom rastvaracu, kao sto je aceton kada je svak R<14>metil a R<14a>vodonik, se onda tretira sa jedinjenjem formule (Ea) u prisustvu kiselinskog katalizatora, kao sto je d1-10-kamforsulfo kiselina, na ambijentalnoj temperaturi. Reakciona smesa se mesa oko 2 sata do oko 4 sata, pretpostavljeno oko 3 sata, i onda cini baznom dodavanjem baze kao sto je gas amonijak. Onda se izoluje jedinjenje formule (F) putem standardnih tehnika izolovanja, kao sto je filtriranje, koncentracija, organska ekstrakcija i koncentracija.
Vodeni rastvor jedinjenja formule (F) se onda tretira sa redukcionim sredstvom, pretpostavljeno hladnim natrijumborhidridom u vodi. Rezultujuca reakciona smesa se mesa oko 3 sata do oko 6 sati, pretpostavljeno oko 5
sati, i onda tretira sa kiselinom, pretpostavljeno sircetnom kiselinom, da ukloni visak borhidrida i da se podesi pH do oko 6,0. Jedinjenje formule (G)
se izoluje iz reakcione smese standardnim tehnikama, kao sto je ekstrakcija vodeenog sloja i njegova koncentracija.
Jedinjenje formule (G) se onda tretira sa jedinjenjem formule (H) u prisustvu baze, pretpostavljeno natrijumhidroksida. Reakciona smesa se mesa oko 6
sati do oko 24 sata, pretpostavljeno oko 12 sati. Jedinjenje formule (J) se izoluje iz reakcione smese putem standardnih tehnika izolovanja i rastvara u aprotonskom rastvaracu, pretpostavljeno dimetilformamidu (DMF). Onda se
dodaje rastvoru jedinjenje formule (K), i rezultirajuca smesa se mesa oko 6
sati do oko 24 sata, pretpostavljeno oko 12 sati. Onda se izoluje iz reakcione smese jedinjenje formule (L) standardnim tehnikama izolovanja,
kao sto je pranje soli, ekstrakcija i koncentracija.
Jedinjenje formule (L) u vodi i polarnom aprotonskom ko-rastvaracu, kao sto je aceton, se tretira sa agensom za cepanje glikola, kao sto je natrijumperjodat. Izoluje se jedinjenje formule (M) iz reakcione smese putem standardnih tehnika izolovanja, kao sto je ekstrakcija, pranje soli i koncentracija.
3 Pripremanje jedinjenja formule ( Q)
Jedinjenja formule (Q) su intermedijarni proizvodi u pripremanju jedinjenja pronalaska. Pripremaju se kako je to dole opisano u Reakcionoj semi 3 pri cemu je Ph fenil a PG-i je zastitna grupa za trogubu vezu, n.pr.,
fenildimetilsilil, difenilmetilsilil, ili trimetilsilil:
Jedinjenje formule (N) je komercijalno dostupno ili moze biti pripremljeno postupcima poznatim strucnjacima iz ove oblasti nauke.
Uopsteno, Wittig reagens formule (Q) se priprema prvo dehidrogenovanjem jedinjenja formule (N) tretmanom sa organometalnim jedinjenjem,
pretpostavljeno n-butillitijumom, na temperaturama izmedu -30°C i -15°C,
pretpostavljeno oko -20°C. Zastitna grupa, pretpostavljeno trimetilsilil, se potom dodaje jedinjenju pod standardnim uslovima generacije zastitne grupe. Zasticeno jedinjenje formule (O) se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto su ekstrakcija organskih slojeva i koncentracija.
Jedinjenje formule (O) u aprotonskom rastvaracu, pretpostavljeno dihlormetanu, se onda tretira sa reagensom za bromovanje, kao sto je N-bromosukcinimid, u prisustvu trifenilfosfina na temperaturama izmedu oko -
10°C i oko 0°C. Reakcionoj smesi se dopusta da se zagreje do ambijentalne temperature i mesa se oko 1 sat do oko 3 sata, pretpostavljeno 2 sata. Izoluje se jedinjenje formule (P) iz reakcione smese putem standardnih tehnika izolovanja, kao sto su koncentracija i pretvaranje u prasak sa inertnim organskim rastvaracem, kao sto je heksan.
Jedinjenje formule (P) se onda tretira sa malim viskom molarne kolicine triarilfosfina, pretpostavljeno trifenilfosfinom, pod standardnim uslovima za formiranje Wittig reagensa da se formira ylide fosfora formule (Q) (Wittig reagens reakcija).
4. Pripremanje jedinjenja formule ( W)
Jedinjenja formule (W) su intermedijarni proizvodi u pripremanju jedinjenja pronalaska. Ona se pripremaju kako je to dole opisano u Reakcionoj semi 4
gde je PG-, zastitna grupa, X^je halo, R<10>je kako je to gore opisano u Sustini pronalaska, a R7aiR<7b>su svaki nezavisno alkil, aril ili aralkil:
Jedinjenja formule (D) i formule (Q) se pripremaju pstupcima koji su ovde otkriveni. Jedinjenja formule (S) su komercijalno dostupna, ili mogu biti pripremljena prema postupcima poznatim strucnjacima iz ove oblasti nauke.
Uopsteno, jedinjenja formule (W) se pripremaju prvo tretiranjem jedinjenja formule (D) sa malim viskom molarne kolicine jedinjenja formule (Q) pod standardnim uslovima Wittig reakcije da se formira jedinjenje formule (R),
koje je izolovano iz reakcione smese standardnim tehnikama izolovanja.
Jedinjenje formule (R) se onda tretira sa jedinjenjem formule (S) u aprotonskom rastvaracu, kao sto je tetrahidrofuran (THF) u prisustvu jake baze, kao sto je natrijumhidroksid, i na temperaturi od oko 50°C do oko 70°C, pretpostavljeno oko 63°C. Reakcionoj smesi se dopusta da se ohladi do ambijentalne temperature. Izoluje se jedinjenje formule (T) iz reakcione smese putem standardnih tehnika izolovanja, kao sto je organska ekstrakcija i koncentracija.
Jedinjenje formule (T) u aprotonskom rastvaracu, kao sto je metilenhlorid, se tretira sa elementarnim jodom na ambijentalnoj temperaturi pod standardnim uslovima. Geometrijski izomer formule (U) se izoluje iz reakcione smese putem standardnih tehnika izolovanja.
Jedinjenje formule (U) u aprotonskom rastvaracu, kao sto je THF, se-onda deprotektuje i hidrolise u jedinjenje formule (V) pod standardnim uslovima deprotekcije i hidrolize. Izoluje se jedinjenje formule (V) iz reakcione smese putem standardnih tehnika izolovanja, kao stoje ekstrakcija i koncentracija. Jedinjenje formule (V) u aprotonskom rastvaracu se onda tretira sa agensom za esterifikovanje, kao sto je trimetilsilildiazometan, pod standardnim uslovima esterifikacije da se formira jedinjenje formule (W),
koje se izoluje iz reakcione smese putem standardnih tehnika izolovanja,
kao sto je ekstrakcija, koncentracija i preciscavanje putem hromatografije.
5. Pripremanje jedinjenja formule ( Ta) i formule ( Ua)
Jedinjenja formule (Ta) i formule (Ua) su intermedijarni proizvodi u pripremanju jedinjenja pronalaska i mogu biti pripremljena kako je to dole opisano u Reakcionoj semi 5 pri cemu je R<7a>alkil, aril ili aralkil, R10je kako j<e>to gore opisano u Sustini pronalaska, R<14>je alkil a R<14a>je vodonik ili alkil: Jedinjenja formule (Q) i formule (M) se pripremaju prema postupcima koji su ovde otkriveni.
Uopsteno, jedinjenja formule (Ua) se pripremaju prvo tretiranjem jedinjenja formule (M) sa malom kolicinom molarnog viska jedinjenja formule (Q) pod standardnim uslovima Wittig reakcije da se formira jedinjenje formule (Ta),
koje se onda tretira sa elementarnim jodom pod slicnim uslovima koji su gore opisani da se formiraju jedinjenja formule (Ua). Jedinjenje formule (Ua)
se onda tretira na slican nacin kako je to gore opisano za jedinjenja formule (U) da se formira odgovarajuce jedinjenje formule (W) kako je to gore opisano.
6. Pripremanje jedinjenja formule ( DP)
Jedinjenja formule (DD) su intermedijarni proizvodi u pripremanju jedinjenja pronalaska. Pripremaju sa na nacin kako je to opisano dole u Reakcionoj semi 6 gde je R<5>kako je to gore opisano u Sustini pronalaska, a X2je halo: Jedinjenja formule (X), N.O-dimetilhidrokilamin, etinilmagnezijum bromid i 3,5-dinitrobenzoil hlorid su komercijalno dostupna, ili mogu biti pripremljena postupcima poznatim strucnjacima iz ove oblasti nauke.
Uopsteno, jedinjenja formule (DD) se pripremaju prvo tretiranjem jedinjenja formule (X) u aprotonskom rastvaracu, pretpostavljeno metilenhloridu, sa kolicinom molarnog viska acil halid reagensa, pretpostavljeno oksalil hloridom, na ambijentalnoj temperaturi. Reakcionoj smesi se dopusta da se mesa oko 6 sati do oko 24 sata, pretpostavljeno oko 12 sati. Jedinjenje formule (Y) se izoluje iz reakcione smese standardnim tehnikama izolovanja,
kao sto je koncentracijain vacuo.
Jedinjenje formule (Y) se onda tretira sa hidroksilaminom, pretpostavljeno,
N,0-dimetilhidrokilaminom ili sa 1,2-oksazolidinom, u prisustvu alkalne baze,
kalijum karbonata, pod standardnim uslovima acilovanja amina. Izoluje se iz reakcione smese jedinjenje formule (Z) putem standardnihz tehnika izolovanja, kao sto su organska ekstrakcija i koncentracija.
Jedinjenje formule (Z) u aprotonskom rastvaracu, pretpostavljeno THF, se onda tretira sa odgovarajucim Grignard reagenskom, kao sto je HC=CMgBr pod standardnim uslovima da se formira jedinjenje formule (AA), koje se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto je ekstrakcija organskog rastvaraca, filtriranje i koncentracija. Jedinjenje formule (AA) se onda tretira sa hiralnim redukcionim sredstvom pod standardnim uslovima redukcije da se formira jedinjenje formule (BB), koje se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto je filtriranje, koncentracija i preciscavanje putem hromatografije bleska, kao smesa enantiomera. Enantiomerni visak semoce utvrditi hiralnom analitickom HPLC.
Enantiomerni visak se poboljsava putem rekrisalizacije aril estra koji se formira tretiranjem jedinjenja formule (BB) u aprotonskom rastvaracu, pretpostavljeno metilen hloridu, sa kolicinom molarnog viska aroil halida,
pretpostavljeno 3,5-dinitrobenzoil hloridom, na temperaturi izmedu oko -5°C
i 0°C, u prisustvu baze, pretpostavljeno trietilamina, i aktivacione kilicine dimetilaminopiridina (DMAP). Reakciona smese se mesa na ambijentalnoj temperaturi oko 30 minuta do 1 sat, pretpostavljeno 40 minuta. Jedinjenje formule (Bba) se izoluje iz reakcione smese putem standarnih tehnika izolovanja, kao sto je ekstrakcija, filtriranje i rekristalizacija i utvrduje se putem analiticke HPLC da ima vise od 98% enantiomernog viska.
Jedinjenje formule (Bba) u protonskom rastvaracu, pretpostavljeno metanolu, se tretira sa alkalnom bazom, pretpostavljeno kalijumkarbonatom.
Reakciona smesa se mesa oko 3 sata do oko 5 sati, pretpostavljeno 3,5
sata i reakcije se onda prigusi dodavanjem kiseline, pretpostavljeno sircetne kiseline. Jedinjenje formule (BB) koje ima 98% enantiomerni visak se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto je filtriranje i koncentracija filtrata.
Jedinjenje formule (BB) se onda tretira sa sredstvom za halogenovanje,
pretpostavljeno N-bromosukcinimidom, u prisustvu katalizatora, kao sto je srebro nitrat, na ambijentalnoj temperaturi. Onda se izoluje iz reakcione smese jedinjenje formule (CC) putem standardnih tehnika izolovanja, kao sto je koncentracijain vacuo,filtriranje i elucija sa organskim rastvaracima.
Jedinjenje formule (CC) se onda hidrogenuje pod standardnim uslovima hidrogenovanja za trogube veze, kao sto je tretman sa redukcionim sredstvom, pretpostavljeno smesom litijum aluminijum hidrida i aluminijum hlorida, da se formira jedinjenje formule (DD), koje se izoluje iz reakcione smese standardnim tehnikama izolovanja.
7. Prirpemanje jedin jenje formule ( la), formule ( lb) i formule ( Ha)
Jedinjenja formule (la), formule (lb) i formule (1 la) su jedinjenja pronalaska.
Pripremaju se kako je to opisano dole u Reakcionoj semi 7 pri cemu su R<5>i R<10>kako je to gore opisano u Sustini pronalaska a R7b je alkil, aril ili aralkil:
Jedinjenja formule (DD) i formule (W) se pripremaju postupcima koji su ovde otkriveni. Alternativno, jedinjenja koja korespondiraju sa jedinjenjima (W)
koja su sacinjena iz jedinjenja formule (Ua) mogu se upotrebiti u gornjoj reakcionoj semi da proizvedu odgovarajuca jedinjenja pronalaska.
Uopsteno, jedinjenja formule (la), formule (lb) i formule (lla) se pripremaju prvo tretiranjem jedonjenja formule (DD) u aprotonskom rastvaracu,
pretpostavljenoTHF, sa jedinjenjem formule (W) u aprotonskom rastvaracu,
pretpostavljeno THF, pod standardnim uslovima Sonogashira sparivanja,
kao sto je u prisustvu barakjodida, amin baze i paladijum katalizatora.
Reakciona smesa se mesa na ambijentalnoj temperaturi oko 30 minuta do oko 1 sat, pretpostavljeno oko 45 minuta. Izoluje se jedinjenje formule (EE)
iz reakcione smese putem standardnih tehnika izolovanja, kao sto je filtriranje, elucija sa organskim rastvaracem i preciscavanje putem hromatografije.
Jedinjenje formule (EE) u protonskom rastvaracu, pretpostavljeno metanolu,
se onda tretira sa kiselinom, pretpostavljeno hlorovodonicnom kiselinom.
Reakciona smesa se mesa na ambijentalnoj temperaturi oko 12 sati do oko 48 sati, pretpostavljeno oko 48 sati. Iz reakcione smese se izoluje jedinjenje formule (lla) putem standardnih tehnika izolovanja, kao sto je podesavanje pH reakcione smese na pH 7,0 i preciscavanje putem hromatografije reversne faze.
Jedinjenja formule (lla) u protonskom rastvaracu, pretpostavljeno metanolu,
se onda redukuje do jedinjenja formule (la) putem postupka opisanog kodHelv. Chim. Acta.(1987). Jedinjenje formule (la) se onda hidrolizuje do jedinjenja formule (lb) pod standardnim uslovima hidrolize u baznoj sredini.
Dodatno, jedinjenja formule (lla) u protonskom rastvaracu, pretpostavljeno metanolu, mogu onda biti hidrolizovana pod standardnim uslovima hidrolize u baznoj sredini da se formiraju jedinjenja formule (lla) u kome je R<7b>vodonik.
8. Pripremanje jedinjenja formule ( lib)
Jedinjenja formule (lib) su jedinjenja pronalaska. Ona su pripremljena kako je to dole opisano u Reakcionoj semi 8 pri cemu su q, p, R<5>, R<10>, i R<15>kako je to opisano u Sustini pronalaska a R7b je alkil, aril ili aralkil: Jedinjenja formule (E), (FF), (Q), i (Sa) su komercijalno dostupna ili mogu biti pripremljena prema postupcima koji su ovde otkriveni ili putem postupaka poznatih strucnjacima iz ove oblasti nauke.
Uopsteno, jedinjenja formule (lib) se pripremaju prvo mesanjem smese jedinjenja formule (E) i bakarsulfata u jedinjenju formule (FF) pod azotom,
dok se jaka kiselina, kao sto je sumporna kiselina, dodaje reakcionij smesi.
Rezultujuca reakciona smesa se zagreje do ambijentalne temperature,
pretpostavljeno oko 29°C, i dopusta joj se da se mesa izmedu oko 8 sati i 16
sati, pretpostavljeno oko 12 sati. Reakciona smesa se filtrira i rezultujuci filtrat se opere sa organskim rastvaracem, pretpostavljeno etilacetatom.
Filtrat se onda tretira sa bazom, pretpostavljeno amonijum hidroksidom, i rezultujuca cvrsta supstanca se uklanja filtriranjem. Izoluje se jedinjenje formule (GG) iz filtrata putem standardnih tehnika izolovanja, kao sto je ekstrakcija organskim rastvaracima i dalje filtriranje.
Kolicina molarnog viska redukcionog sredstva, kao pto je natrijumborhidrid,
u protonskom rastvaracu, kao sto je metanol, se onda ohladi do oko 0°C i potom tretira sa jedinjenjem formule (GG) u protonskom rastvaracu, kao sto je metanol. Rezultujucoj reakcionoj smesi se dopusta da se mesa izmedu oko 4 sata do oko 8 sati, pretpostavljeno oko 4 sata. Po zavrsetku zeljene reakcije, kiselina, pretpostavljeno sircetna kiselina, se onda dodaje reakcionoj smesi da potrosi visak redukcionog sredstva i da se podesi pH
reakcione smese do oko pH 6. Onda se izoluju jedinjenje formule (HH) iz reakcione smese putem standardnih tehnika izolovanja, kao sto je filtriranje,
koncentracija cvrstih supstanci, ekstrakcija organskim rastvaracem, i talozenje.
Smesa jedinjenja formule (HH) i jedinjenja formule (Sa) u aprotonskom rastvaracu, kao sto je toluen se onda mesaju a dodaje se alkalna baza, kao sto je natrijum hidroksid u vodi. Katalizator transfera faze, kao sto je tetrabutilamonijum sulfat, se dodaje reakcionoj smesi i reakciona smesa se mesa izmedu oko 8 sata i 16 sati, pretpostavljeno oko 12 sati. Izoluje se jedinjenje formule (JJ) iz reakcone smese putem standardnih tehnika izolovanja, kao sto je ekstrakcija sa baznim organski rastvaracima,
koncentracija, i hromatografija.
Jedinjenje formule (JJ) u polarnom organskom rastvaracu, kao sto je aceton,
se onda tretira sa kolicinom molarnog viska perjodata u vodi. Rezultujuca
reakciona smesa se onda mesa energicno pod azotom od oko 4 sata do oko 8 sati, pretpostavljeno oko 4 sata. Rastvarac se uklanjain vacuona ambijentalnoj temperaturi. Izoluje se jedinjenje formule (KK) iz reakcione smese putem standardnih tehnika izolovanja, kao sto je ekstrakcija organskim rastvaracem i koncentracija organskih slojeva.
Jedinjenje formule (Q) u aprotonskom rastvaracu, pretpostavljeno THF se ohladi do oko -30°C pod andihrovanim uslovima i onda tretira postepeno sa jakom bazom, pretpostavljeno n-butillitijumom. Reakcionoj smesi se dopusta da se zagreje do oko 0°C i mesa se izmedu oko 15 minuta i 1 sat,
pretpostavljeno oko 15 minuta. Reakciona smesa se onda ohladi do ok -
30°C i potom tretirasa ekvimolarnom kolicinom jedinjenja formule (KK) u aprotonskom rastvaracu, pretpostavljeno THF. Rezultujuca reakciona smesa se mesa izmedu oko 30 minuta do 2 sata, pretpostavljeno oko 1 sat na temperaturi od oko -30°C. Reakcija se prigusi dodavanjem odgovarajuce kiseline, kao sto je kalijum fosfat. Jedinjenje formule (LL) se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto je pranje soli, koncentracija, i talozenje.
Jedinjenje formul e(LL) se tretira na nacin slican tretmanu jedinjenja formule (T) u gornjoj Reakcionoj semi 4 da se dobije jedinjenje formule (MM) koje se onda tretira na nacin slican tretmanu jedinjenja formule (U) u gornjoj Reakcionoj semi 4 da se dobije jedinjenje formule (NN). `
Jedinjenje formule (NN) se onda tretira sa jedinjenjem formule (DD) na nacin slican onom opisanom za tretman jedinjenja formule (W) u gornjoj Reakcionoj semi 7 da se dobije jedinjenje formule (lib).
9. Pripremanje jedinjenja formula ( He) i ( lid)
Jedinjenja formula (lie) i (lid) su ista jedinjenja kao jedinjenja formule (lla)
koja su gore opisana, osim sto je pocetni materijal iz kojeg se pripremaju,
odnosno, jedinjenje formule (lib), pripremljeno razlicitom sintezom nego pocetni materijal za jedinjenja formule (lla). U skladu sa tim, jedinjenja formula (lie) i (lid) se pripremaju kako je to dole opisano u Reakcionoj semi 9 pri cemu su q, p, R<5>, R<10>, i R<15>kako je to gore opisano u Sustini pronalaska a R<7b>je alkil, aril ili aralkil:
Jedinjenja formule (lib) se pripremaju kako je to gore opisano u Reakcionoj semi 8.
Uopsteno, jedinjenja formule (II) i (lid) se pripremaju prvo tretiranjem jedinjenja formule (lib) sa kiselinom, kao sto je sircetna kiselina,
pretpostavljeno sircetna kiselina, pretpostavljeno razredena sa organskim rastvaracem, kao sto je etilacetat, na temperaturama izmedu oko 50°C i oko 60°C, pretpostavljeno na oko 50°C, tokom vremena izmedu oko 10 sati i oko 20 sati, pretpostavljeno 20 sati. Organski reagensi i rastvaraci se uklanjaju destilacijomin vacuo.Jedinjenje formule (II) se izoluje iz reakcione smese putem standardnih tehnika izolovanja, kao sto je ekstrakcija organskim rastvaracima i koncentracija. Jedinjenje formule (lie) se onda tretira uslovima hidrilize i onda se izoluje jedinjenje formule (lid) iz reakcione smese putem standardnih tehnika izolovanja, kao sto je hromatografija.
Dodatno gore opisanim Reakcionim semama i sledecim Preparatima i Primerima, druga jedinjenje pronalaska mogu biti pripremljena prema postupku poznatom onim koji su poznati strucnjacima iz ove oblasti nauke.
Na primer, jedinjenja pronalaska gde R<1>-SR<6>, -S(0)tR<7>, ili -N(R<7>)R<8>(gde su R<b>, R<7>i R<8>vodonik) mogu biti pripremljeni tretiranjem jedinjenja formule (EE)
ili jedinjenja formule (U) (kakoje to gore opisano) sa odgovarajucim hidroksi-zastitnim agensom da se zastiti slobodna hidroksi grupa, i onda tretiranjem zasticenog jedinjenja formule (EE) ili jedinjenja formule (U) sa odgovarajucom kiselinom da bi se cepao katal. Rezultirajuce di-hidroksi jedinjenje moze onda biti tretirano pod standardnim uslovima hidrolize u kiseloj sredini da se formira odgovarajuci lakton. Slobodan hidroksi moze onda biti derivatizovan da formira odgovarajucu odlazecu grupu, i potonja supstitucija sa odgovarajucim supstituisanim tiolom ili aminom, praceno hidrolizom u kiseloj sredini koja ce formirati jedinjenje pronalaska gde je R<1>-
SR<6>, -S(0)tR<7>, ili -N(R<7>)R<8>.
Jedinjenje pronalaska gde je R<3>-SR<6>, -S(0)tR<7>, ili -N(R<7>)R<8>mogu biti pripremljena derivatizovanjem slobodnog hidroksija jedinjenja formule (EE)
da se formira odgovarajuca odlazeca grupa, i potom reagovanjem derivatizovanog jedinjenja sa odgovarajucim supstituisanim nukleofilom.
Jedinjenja pronalaska gde je R<2>R<1>-SR<6>, -S(0)tR<7>, ili -N(R7)R<8>mogu biti pripremljena pripremanjem laktona kako je to gore opisano, i potom zastitom slobodnog hidroksija kako je to gore opisano. Rezultirajuce jedinjenje moze onda biti tretirano standardnim uslovima hidrolize u kiseloj sredini da se formira odgovarajuca kiselina. Slobodna hidroksi grupa moze onda biti derivatizovana da se formira odgovarajuca odlazeca grupa, i potom supstitucija sa odgovarajucim supstituisanim nukleofilom, preceno de-protekcijom ce formirati jedinjenja pronalaska gde je R<2->SR<6>, -S(0)tR<7>, ili -
N(R<7>)R<8.>
Jedinjenja pronalaska gde je R<4>-Rb-N(R7)-R10-R11 mogu biti pripremljena tretiranjem jedinjenja formule (F) kako je to gore opisano sa odgovarajucim supstituisanim aminom pod standardnim uslovima redukcione aminacije i potom tretiranjem rezultirajuceg jedinjenja na nacin kako je to gore opisano da se formira odgovarajuce jedinjenje pronalaska. Jedinjenja pronalaska gde je R<4>-R9-N(R7)-R10-R11 mogu biti pripremljena derivatizovanjem primarnog hidroksija jedinjenja formule (G) kako je to gore opisano da se formira odgovarajuca odlazeca grupa, i potom reagovanjem rezultirajuceg jedinjenja sa odgovarajucim tiol alkoksidom da se formira zeljeni proizvod, koji moze dalje biti oksidiran pod standardnim uslovima oksidacije da se formira zeljeno sulfinil ili sulfonil jedinjenje.
Jedinjenja pronalaska gde R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabaranu iz sledeceg:
mogu biti pripremljena tretiranjem jedinjenja formule (la) ili (lla) kako je to gore opisano pri cemu su R<1>i R<2>nezavisno odabrani od hidroksija, tiola ili amina sa odgovarajucim sredstvom za acilovanje, kao sto je fosgen, pod kiselim uslovima.
Jedinjenja pronalaska gde je R<4>-R9-R13-R11 mogu biti pripremljena prema postupcima slicnim onim objavljenim kod Rodriguez, A.R., et al.,
Tetrahedron Letters(2001), Vol. 42, pp. 6057-6060.
Jedinjenja pronalaska gde je R<4>-R<12>mogu biti pripremljena derivatizovanjem jedinjenja formule (G) kako je to gore opisano da se formira odgovarajuca odlazeca grupa na primarnom hidroksiju, i potom tretiranjem rezultirajuceg jedinjenja sa odgovarajucim hidroksi zastitnim agensom da bi se zastitili preostali hidroksiji. Odlazeca grupa moze onda biti premestena sa odgovarajucim aril kupratom ili Grignard-ovim reagensom.
Jedinjenja pronalaska gde je R4-R9-O-R10-R11 mogu biti pripremljena prema postupcima koji su ovde opisani upotrebom odgovarajuce supstituisane soli haloalkanske kiseline, soli haloalkenske kiseline, soli haloalkinske kiseline ili soli halocikloalkanske kiseline. Alternativno, jedinjenje gde je R10 cikloalkilen moze biti pripremljeno alkilovanjem odgovarajuceg jedinjenja koje sadrzi alkenilen sa odgovarajucim alkil dihalidom.
Jedinjenja pronalaska gde je R<4->R<9->0-R<12>mogu biti pripremljena tretiranjem jedinjenja formule (G) sa odgovarajucim haloaralkilom (gde je halo na alkil lancu) pod uslovima supstitucije.
Jedinjenja pronalaska gde je R<4>-R9-C(O)-Rl0-R11 mogu biti pripremljena hidratacijom odgovarajuceg jedinjenja pronalaska gde je R<4->R<9>-R<13->R<11>pri cemu je R<13>alkenilen lanac pod standardnim uslovima hidratacije da se formira odgovarajuci alkohol, i potom oksidacijom alkohola u odgovarajuci keton.
Jedinjenja pronalaska gde je R<4>-R<9->N(R<7>)-R<10->R<11>ili -R<9->S(O)rR1<0>-R1<1>
mogu biti pripremljena na slican nacin kako je to gore opisano za jedinjenja gde su Rb iR<b>-SR<6>, -S(0)rR<7>i -N(R<7>)R<8>.
Jedinjenja pronalaska gde je R4 -R9-C(F)2-R9-R11 mogu biti pripremljena iz odgovarajuceg ketona upotrebom odgovarajuceg reagensa za fluorovanje,
kao sto je (dietilamino)sumpor trifluorid (DAST).
Jedinjenja pronalaska gde je R<6>alkil, aril, aralkil, -C(0)R<7>, -C(S)R<7>,
C(0)OR<14>, ili -C(S)OR<14>mogu biti pripremljena reagovanjem jedinjenja formule (la) ili (lla) sa odgovarajucim halidom pod standardnim uslovima supstitucije. Jedinjenja pronalaska gde je R<6>-C(S)R<7>, -C(0)N(R<7>)R<8>, ili - C(S)N(R<7>)R<8>mogu biti pripremljena reagovanjem jedinjenja formule (la) ili (lla) sa odgovarajucim supstituisanim izocijanatom ili izotiocijanatom.
Sva jedinjenja pronalaska kako se gore pripremaju koja postoje u obliku slobodne baze ili kiseline mogu biti konvrertovana u njihove farmaceutski prihvatljive soli putem tretmana sa odgovarajucom neorganskom ili organskom bazom ili kiselinom. Soli jedinjenja koja su gore pripremljena mogu biti konventovane u njihov oblik slobodne baze ili kiseline standardnim tehnikama. Razume se da polimorfni, amorfni oblici, anhidrati, hidrati, solvati i soli jedinjenja pronalaska imaju nameru da budu u rasponu pronalaska.
Da bi se pripremili ciklodekstrin klatrati ovog pronalaska, analozi lipoksina A4
formule (I) i (II), ili analozi lipoksina A4koji su opisani i za koje je zatrazena zastita u U.S. Patentu br. 5,441,951; U.S. Patentu br. 5,079,261; U.S.
Patentu br. 5,648,512; i U.S. Patentu br. 6,048,897, kako su opisani u Sustini pronalaska, mogu biti rastvoreni u farmakoliski prihvatljivom rastvaracu, n.pr., u alkoholu, pretpostavljeno etanolu, u ketonu, n.pr., acetonu ili u etru, n.pr., dietil etru, i mesaju se sa vodenim rastvorima a-ciklodekstrina, p-ciklodekstrina ili y-ciklodekstrina, pretpostavljeno (3-ciklodekstrina, na 20°C do 80°C; ili kiseline analoga lipoksina A4kako je gore definisano u Sustini pronalaska u obliku vodenih rastvora njihovih soli (n.pr., Na" ili K" soli) mogu biti domesane sa ciklodekstrinom i potonji rastvor sa ekvivalentnom kilicinom kiseline (n.pr., HCI ili H2S04) da se dobije odgovarajuci ciklodekstrin klatrat.
Na ovom mestu ili posle hladenja, odgovarajuci ciklodekstrin klatrati se odvajaju u obliku kristala. Pa ipak, takode je moguce konvertovati uljana i takode kristalna jedinjenja formule (I) i/ili formule (II), kako je to definisano gore u Sustini pronalaska, prilicno dugim mesanjem (n.pr., 1 sat do 14 dana) na ambijentalnoj temperaturi, tretmanom sa vodenim rastvorom ciklodekstrina, u odgovarajuci oblik ciklodekstrin klatrata. Klatrati onda mogu biti izolovani kao cvrsti, sa slobodnim protokom kristali usisavanjem rastvaraca i susenjem.
Ciklodekstrini koji se upotrebljavaju u ovom pronalasku su komercijalno dostupni, na primer, od Aldrich Chemical Co., ili mogu biti pripremljeni postupcima poznatim strucnjacima u ovoj oblasti nauke. Videti, na primer,
Croft, A.P. et al., "Synthesis of Chemically Modified Cyclodextrins",
Tetrahedron(1983), Vol. 39, No. 9, pp. 1417-1474. Odgovarajuci ciklodekstrini ce ukljuciti razlicite grupe onih koji proizvode klatrate jedinjenja formule (I) i formule (II) kako je to gore postavljeno. Videti, na primer, J.E.F. Reynolds (ed.) Martindale, Teh Extra Pharmacopoeia 28th ed. The Pharmaceutical Press, London 1982, p. 333 i 389-390 i O.-A. Neumueller (ed.), Roempps Chemie-Lexikon, 8. Aufl. Frankh'sche Verlagshandlung,
Stuttgart 1981, p. 763-764, 841, 1053-1054.
Putem odabira odgovarajucih kilicina ciklodekstrina i vode moguce je dobiti nove klatrate u stehiometrijskom sastavu sa sadrzajem efektivne supstance koja se moze reprodukovati. Klatrati mogu biti upotrebljeni u suvom higroskopnom obliku ili manje higroskopnom obliku koji sadrzi vodu. Tipicni molarni odnosi ciklodekstrina prema jedinjenju formule (I) ili jedinjenju formule (II) je 2:1 (ciklodektrimjedinjenje).
Sledeca specificna pripremanja i primeri su obezbedeni kao vodic koji asistira u izvodenju pronalaska, i namaju nameru da ogranicavaju obim pronalaska.
PRIPREMANJE 1
Jedinjenja formule (B) i (D)
A. Talog D-riboze (50 g, 0,33 mol) u acetonu (500 ml_) se mesa na ambijentalnoj temperaturi posto se doda koncentrovana sumporna kiselina (1,25 mL). Reakciona smesa se mesa 30 minuta da se dobije bistri rastvor i onda mesa dodatno jedan sat. Vrednost pH reakcione smese se podesi na oko pH 7 sa kalcijum hidroksidom (-7,0 g). Rezultirajuci talog se filtrira kroz jastucic celita. Filtrat se koncentrise da se dobije 64,8 g D-ribofuranoza-3,4-acetonid, jedinjenje formule (B) kao blago obojeno ulje, NMR: (CDCI3) 6
1,30 (s, 3H), 1,47 (s, 3H) 2,05 (s, 1), 3,7 (m, 3H), 4,38 (m, 1H), 4,56 (d, 1H),
4,96 (d, 1H), 5,38 (d, 1H) ppm.
B. Na slican nacin mogu biti pripremljena jedinjenja koja korespondiraju sa jedinjenjem formule (B). C. Talog natrijumborhidrida (10,7 g, 0,34 mol) u vodi (0,75 L) se ohladi u ledenom kupatilu i tretira sa D-ribofuranoza-3,4-acetonidom (64,6 g,
0,34 mol) u vodi (1,25 L). Reakciona smesa se mesa oko 2 sata pre dodavanje sircetne kiseline (-23 mL) da potrosi visak borhidrida i da podesi pH do oko pH 6. Reakciona smesa se ohladi u ledenom kupatilu pre dodavanja natrijumperjodata (72,7 g, 0,34 mol) u porcijama. Reakciona smesa semesa oko 2 sata na ambijentalnoj temperaturi, koncentrise pod smanjenim pritiskom i ekstrakuje sa etilacetatom (3x). Kombinovani rastvori etilacetata se operu sa slanim rastvorom, osuse preko natrijumsulfata, i koncentrisu da daju 47,4 g (3,4-izopropiliden)eritroza, jedinjenje formule (D),
kao bezbojno viskozno ulje: NMR (DMSO) 6 1,22 (s, 3H), 1,32 (s, 3H), 3,28
(d, 1H), 3,78 (m, 2H), 4,38 (d, 1H), 4,76 (m, 1H), 5,12 (m, 1H) ppm.
D. Na slican nacin mogu se pripremiti druga jedinjenja formule (D)
PRIPREMANJE 2
Jedinjenja formule (F), formule (G), formule (L) i formule (M)
A. Talog L-ramnoza hidrata (100 g, 0,55 mol) se suspenduje u 1:1
smesi acetona i toluena (1 L) i koncentise. Postupak se ponavlja tri puta upotrebom povecavanja visokih koncentracija toluena. Boca se postavi pod visoki vakuum da se uklone tragovi toluena. Anhidrovani ostatak se rastvara u acetonu (600 mL) i tretira sa metoksipropenom (68 mL, 0,71 mol),
piridinium tozilatom (3 g) i d1-10-kamforsulfo kiselinom (3 g). Reakcija se mesa na ambijentalnoj temperaturi oko 3 sata. Reakciona smesa se bazifikuje kljucanjem u amonijak gasu i sirupasta tecnost se rastvara u vodi i ekstrakuje etilacetatom (3x). Kombinovani organski slojevi se operu sa vodom (2x) i slanim rastvorom, osuse, i koncentrisu da daju 102 g (3,4-izopropiliden)ramnozu, jedinjenje formule (F), kao viskozno ulje;<1>H NMR
(CDCI3)61,32 (m, 6H), 1,45 (s, 3H) 3,92 (m, 1H), 4.05 (m, 1H), 4,59 (d,
1H), 4,87 (m, 1H), 5,2 (s, 1H) ppm.
B. Talog natrijumborhidrida (52 g, 1,4 mmol) u vodi (600 mL) se ohladi u ledenom kupatilu i tretira sa (3,4-izopropiliden)ramnozom (78 g,
0,38 mmol) u vodi (900 mL). Reakciona smesa se mesa oko 5 sati pre dodavanja sircetne kiseline da potrosi visak borhidrida i da podesi pH na oko pH 6 (oko 130 mL). Vodeni sloj se koncentrise pod redukovanim pritiskom.
Ostatak ( u minimalnoj kolicini vode) se ekstrakuje sa etilacetatom (3x).
Kombinovani organski slojevi se osuse, i koncentrisu da daju 70 g 5-(hidroksimetil)-4-(1,2-dihidroksipropil)-2,2-dimetil-1,3-dioksolan, jedinjenje formule (G), kao bezbojno viskozno ulje;<1>H NMR (CD3OD) 8 1,23 (d, 3H),
1,34 (s, 3H), 1,47 (s, 3H), 3,37 (m, 1H), 3,7 (m, 3H), 4,21 (m, 1H), 4,42 (m,
1H)ppm.
C. Rastvor 4-(hidroksimetil)-5-(1,2-dihidroksipropil)-2,2-dimetil-1,3-dioksolan (63 g, 0,33 mol) i natrijumjodoacetat (75 g, 0,36 mol) u vodi se tretira sa cvrstim natrijum hidroksidom (16 g, 0,35 mol). Reakciona smesa semesa preko noci i onda opere sa etilacetatom i etrom. Vodeni sloj se koncentrise. Rezultirajuci ostatak se rastvara u DMF (20 mL) i tretira sa jodometanom (37 mL, 0,6 mol). Rezultujuca reakciona smesa se mesa preko noci. Reakciona smesa se razreduje sa dve zapremine slane vode i ekstrakuje sa etilacetatom (6x). Kombinovani organski slojevi se osuse, i koncentrisu da daju 20 g 2-[[(4S,5R)-5-(1,2-dihidroksipropil)-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estar, jedinjenje formule (L),
kao bezbojno viskozno ulje;<1>H NMR (CDCI3) 8 1,27 (d, 3H), 1,38 (s, 3H),
1,48 (s, 3H), 3,57 (m, 1H), 3,77 (s, 3H), 3,8 (m, 2H), 4,13 (m, 2H), 4,4 (m,
2H)ppm.
D. Rastvor 2-[|(4S,5R)-5-(1,2-dihidroksipropil)-2,2-dimetil-1,3-dioksolan-4-il|metoksi]etanska kiselina, metil estar (20 g, 72 mmol) u acetonu (20 mL) se razblazuje sa vodom (400 mL) i tretira sa cvrstim natrijum perjodatom (26,13 g, 122 mmol). Reakcija se analizira putem TLC i potpuno se zavrsava posle mesanja 1 sat. Reakciona smesa se ekstrakuje sa etilacetatom (3x). Kombinovani organski slojevi se operu sa slanim rastvorom, osuse, i koncentrisu da daju 12,6 g 2-[[(4S,5S)-5-formil-2,2-dimetil-1,3-dioksolan-4-i!]metoksi]etanska kiselina, metil estar, jedinjenje formule (M), kao slabo zuto viskozno ulje;<1>H NMR (CDCI3) 8 1,38 (s, 3H), 1,57 (s, 3H), 3,75 (m, 2H), 3,7 (s, 3H), 4,08 (m, 2H), 4,42 (m, 1H), 4,54 (m,
1H), 9,64 (d, 1H) ppm.
E. Na slican nacin se pripremaju sledeca jedinjenja formule (M): 2-[[(4S,5S)-5-formil-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, etil estar;
2-|2-|(4S,5S)-5-formil-2,2-dimetil-1,3-dioksolan-4-il]etoksi]etanska kiselina, etil estar;
2-[2-[(4S,5S)-5-formil-2,2-dimetil-1,3-dioksolan-4-il]etoksi]etanska kiselina, metil estar;
2-[[(4S,5S)-5-formil-2,2-dietil-1,3-dioksolan-4-il]metoksi]etanska kiselina, etil estar;
2-[2-[(4S,5S)-5-formil-2,2-dietil-1,3-dioksolan-4-il]etoksi]etanska kiselina, etil estar;
2-[2-[(4S,5S)-5-formil-2,2-dietil-1,3-dioksolan-4-il]etoksi]etanska kiselina, metil estar;
2-[f(4S,5S)-5-formil-2-metil-2-etil-1,3-dioksolan-4-il]metoksi]etanska kiselina, etil estar;
2-[2-[(4S,5S)-5-formil-2-metil-2-etil-1,3-dioksolan-4-il]etoksi]etanska kiselina, etil estar;
2-[2-[(4S,5S)-5-formil-2-metil-2-etil-1,3-dioksolan-4-il]etoksi]etanska kiselina, metil estar;
2-[[(4S,5S)-5-formil-2-metil-2-etil-1,3-dioksolan-4-il]metoksi]etanska kiselina, t-butil estar; i
2-[2-|(4S,5S)-5-formil-2-metil-2-etil-1,3-dioksolan-4-il]etoksi]etanska kiselina, t-butil estar;
PRIPREMANJE 3
Jedinjenja formule (O), formule (P) i formule (Q)
A. Rastvor pent-2-en-4-in-1-ol (58 g, 0,7 mol) u anhidrovanom tetrahidrofuranu (THF) (1,0 L) pod atmosferom azota u 3,0 L 4-sa kruznim grlom-na dnu boca se mehanicki mesa i hladi u suvi led/2-propanol kupatilu dok se rastvor n-butillitijuma u heksanu (0,35 L, 2M, 0,77 mol) dodaje pri brzini da se odrzi temperatura ispod -20°C. Posle 10 minuta, dodaje se fini hlorotrimetilsilan (93 g, 0,77 mol). Reakciji se dopusta da se zagreje do ambijentalne temperature tokom oko 1 sat. Reakcija se tretira sa zasicenim amonijum hloridom i razblazuje se heksanom. Vodeni sloj se opere sa heksanom. Kombinovani organski ekstrakti se operu sa vodom i slanim rastvorom, osuse i koncentrisu. Ostatak se rastvara u THF (-690 mL),
tretiraju sa 1N hlorovodonicnom kiselinom (75 mL), i mesa preko noci.
Vodeni sloj se odvaja i opere sa etrom. Kombinovani organski slojevi se operu sa vodom (3x) i slanim rastvorom, osuse i koncentrisu da se dobije 106 g ulja. Ostatak se destilira pod vakuumom kroz 15 cm kolonu sa dvostrukim zidovima da se dobije 72,6 g 5-trimetilsililpent-2-en-4-in-1-ol,
jedinjenje formule (O), kao skoro bezbojno ulje; b.p. 71-77°C / 0,4 mm Hg;
<1>H NMR (300 mHz, CDCI3) J 0,18 (s, 9H), 1,7 (bs, 1H), 4,18 (d, 2H), 5,75 (d,
1H), 6,29 (dm, 1H) ppm.
B. N-Bromosukcinimid (85,3 g, 0,48 mol) se dodaje u porcijama skoro homogenom rastvoru trifenilfosfina (128,2 g, 0,49 mol) i 5-trimetilsililpent-2-en-1-ola (72,5 g, 0,47 mol) u dihlormetanu (600 mL) pod azotom i hladi se u suvi led/2-propanol kupatilu do inicijalne temperature ispod -20°C. Interna temperatura reakcione smese se odrzava na -10°C do 0°C tokom dodavanja podesavanjem brzine dodavanja. Kupatilu se dopusta da se zagreje do ambijentalne temperature. Posle 2 sata, reakcija je zavrsena. Reakciona smesa se koncentrise pod vakuumom do tanke smese i ostatak se pretvara u prasak sa heksanom (250 mL). Suspenzija se filtrira i cvrsti delovi i silika gel se isperu sa heksanom (10 x 150 mL) da se dobije 44 g (89% prinos) 1-bromo-5-trimetiisililpent-2-en-4-in, jedinjenje formule (P), kao bledo zuto ulje;<1>H NMR (300 mHz, CDCI3) 8 0,19 (s, 9H),
3,95 (d, 2H), 5,75 (d, 1H), 6,31 (dt, 1H) ppm. C. Trifenilfosfin (64,1 g, 0,244 mol) se dodaje rastvoru 1-bromo-5-trimetilsililpent-2-en-4-ina (44,26 g, 0,204 mol) u toluenu (204 mL). Smesa se mesa na ambijentalnoj temperaturi pod atmosferom azota. Posle 3 dana suspenzija se razreduje sa metil terc-butil etrom (408 mL), mesa 1 sat na ambijentalnoj temperaturi, i talog se sakuplja filtriranjem. Kolac filtera se opere sa metil terc-butil etrom i osusi pod vakuumom na 30°C da se dobije 79 g 5-trimetilsililpent-2-en-4-iniltrifenil-fosfonijum bromid, jedinjenje formule (Q), kao nepravilno beli puder:<1>H NMR (300 mHz, CDCI3) 8 0,14 (s, 9H),
5,08 (dd, 2H), 5,91 (dt, 1H), 6,22 (dd, 1H), 7,6-8,0 (m, 15H); Anal.
Izracunata za C26H28BrPSi zahteva C 65,13, H 5,89, Br 16,66, P 6,46;
pronadeno C 64,95, H 5,78, Br 16,96, P 6,31.
D. Na slican nacin mogu biti pripremljena ostala jedinjenja formule
(Q).
PRIPREMANJE 4
Jedinjenja formule (R), formule (T), formule (U), formule (V), formule (L),
formule (MM), i formule (NN)
A. Talog 5-trimetilsililpent-2-en-4-iniltrifenil-fosfonijum bromida (115 g, 0,24 mol) u THF (1 L) se mesa pod azotom, ohladi u suvi led/2-propanol kupatiliu, i tretira sa rastvorom n-butillitijuma u heksanu (2M, 120 mL, 0,24 mol) putem kapljicastog dodavanja. Posle oko 5 minuta, kupatilo za hladenje se uklanja i temperaturi reakcione smese se dopusta da se povisi do <0°C (interno). Reakciona smesa se postavlja ponovo u suvi led/2-propanol kupatilo. Reakciona smesa se mesa kao rastvor (2,3-izopropiliden)eritroza (36,6 g, 0,23 mol) u 200 mL THF koji se dodaje kapljicasto. Reakcionoj smese se dopusta da se zagreje do ambijentalne temperature preko noci. Reakciona smesa se onda ohlasi sa suvi led/2-propanol i tretira se sa zasicenom NH4CI. Rezultirajuci vodeni sloj se opere sa etilacetatom, organski slojevi se kombinuju i operu sa vodom i slanim rastvorom, osuse, tretiraju sa silika gelom i koncentrisu. Heksan/etilacetat (3:1) se dodaje smese da natalozi necistoce, i rastvor se filtirira i koncentrise. Rezultirajuci ostatak se tretira sa etrom i heksanom (1:1), silika gelom, filtrira i koncentrise da da 50 g proizvoda. Preciscavanje putem hromatografije na silika gelu upotrebom etra u heksanu kao gradijenta daje 13,9 g smese (4S,5R)-5-|(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-4-(hidroksimetil)-1,3-dioksolan i (4S,5R)-5-[(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-4-(hidroksimetil)-1,3-dioksolan, jedinjenje formule (R); NMR samo za (1Z,3E) izomer:<1>H NMR (CDCI3) 6 0,1 (s, 9H),
1,22 (s, 3H), 1,38 (s, 3H), 1,6 (m, 1H), 3,36 (m, 2H), 4,12 (m, 1H), 4,93 (m,
1H), 5,4 (t, 1H), 5,51 (d, 1H), 6,03 (t, 1H), 6,67 (dd, 1H) ppm.
B. Rastvor smese (4S,5R)-5-[(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-4-(hidroksimetil)-1,3-dioksolan i (4S,5R)-5-|(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-4-(hidroksimetil)-1,3-dioksolan (14 g, 50 mmol) i t-butil bromoacetata (9,6 mL, 65 mmol) u 150 mL THF se ohladi u ledenom kupatilu i tretira sa cvrstim natrijuhidridom (60%, 2,5 g, 65 mmol). Talogu se dopusta da se zagreje do ambijentalne temperature preko noci, Reakcija se analizira sa TLC i oko 40% je zavrsena. Reakcija se onda zagreva u uljanom kupatilu sa temperaturom 63°C oko 7 sati. Reakcionoj smesi se dopusta da se ohladi i sipa se u smesu leda, etilacetata, zasicenog amonijumhlorida. Vodeni sloj se opere sa etilacetatom (2x). Kombinovani organski slojevi se opreu sa vodom i slanim rastvorom, osuse tretiraju sa silika gelom i koncentrisu. Preciscavanje putem hromatografije na siliga gelu upotrebom etra u heksanu kao gradijenta daje 5,2 g smese 2-[[(4S,5R)-5-[(1 E,3E)-6-(trimetilsilil)-l ,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, 1,1-dimetiletil estar i 2-[[(4S,5R)-5-[(1Z,3E)-6-(trimetilsilil)-l ,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-iljmetoksijetanska kiselina, 1,1-dimetiletil estar, jedinjenje formule (T); NMR
samo za (1Z.3E) izomer:<1>H NMR (CDCI3) 6 0,01 (s, 9H), 1,22 (s, 3H), 1,28
(s, 9H), 1,38 (s, 3H), 3,33 (m, 2H), 3,80 (m, 2H), 4,25 (m, 1H), 4,9 (m, 1H),
5,35 (m, 1H), 5,48 (dd, 1H), 6,0 (t, 1H), 6,72 (dd, 1H) ppm. C. Rastvor smese 2-[[(4S,5R)-5-[(1E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, 1,1-dimetiletil estar i 2-[[(4S,5R)-5-[(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, 1,1-dimetiletil estar u metilen hloridu se tretira sa jodom dok se ne dobije trajna crvena boja.
Smesi se dopusta da odstoji preko noci. NMR analizapokazuje da je konverzija zavrsena. Reakcija se tretira sa vodenim rastvorom Na2S204i opere sa vodom i slanim rastvorom, osusi, tretira sa silika gelom i koncentrise da da 4,3 g 2-[[(4S,5R)-5-[(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, 1,1-dimetiletil estar, jedinjenje formule (U), kao viskozno ulje;<1>H NMR (CDCI3) 6 0,01 (s,
9H), 1,22 (s, 3H), 1,28 (s, 9H), 1,38 (s, 3H), 3,33 (m, 2H), 3,80 (m, 2H), 4,25
(m, 1H), 4,5 (m, 1H), 5,43 (m, 1H), 5,58 (dd, 1H), 6,23 (dd, 1H), 6,44 (dd,
1H)ppm.
D. Na slican nacin i upotrebom jedinjenja formule (LL) sacinjeno je sledece jedinjenje formule (MM): 1,1-dimetil J J (2S,3R)-3-[(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-1,4-dioksaspiro[4,5]dec-2-il]metoksi]etanoat, [a]D= -14,351 (10,566 mg/c3 u MeOH);<1>H NMR (CDCI3) 6 0,15 (s, 9H), 1,3 (m, 2H), 1,4 (s, 9H), 1,6 (m,
8H), 3,45 (m, 2H), 3,92 (m, 2H), 4,34 (m, 1H), 4,62 (m, 1H), 5,54 (d, 1H),
5,72 (dd, 1H), 6,26 (dd, 1H), 6,56 (dd, 1H) ppm.
E. Rastvor 2-[[(4S,5R)-5-[(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, 1,1-dimetiletil estar u THF se tretira sa rastvorom tetrabutilamonijumfluorida u THF u porcijama. Reakciona smesa se onda mesa preko noci. Reakciona smesa se razblazi sa voda i 1N NaOH rastvorom (1:1) i mesa preko ? noci.
Reakciona smesa se sipa u smesu etilacetata i zasicenog amonijumhlorida.
Vodeni sloj se opere sa etilacetatom (2x). Kombinovani organski slojevi se operu sa vodom i slanim rastvorom, osuse, tretiraju sa silika gelom i koncentrisu da daju 2,8 g 2-[[(4S,5R)-5-[(1E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, jedinjenje formule (V), kao ulje:<1>H NMR (CDCI3)81,37 (s, 3H), 1,46 (s, 3H), 3,06 (s, 1H), 3,49 (m,
2H), 4,37 (m, 1H), 4,65 (t, 1H), 5,54 (d, 1H), 5,66 (dd, 1H), 6,28 (dd, 1H),
6,58 (dd, 1H) ppm.
F. Na slican nacin i upotrebom jedinjenja formule (MM) priprema se sledece jedinjenje formule (NN): 1,1-dimetil | {(2S,3R)-3-[(1 E,3E)-1,3-heksadien-5-ini1|-1,4-dioksaspiro|4,5]dec-2-il]metoksi]etanoat,<1>H NMR (CDCI3)80,13 (m, 2H),
1,4 (s, 9H), 1,6 (m, 8H), 3,02 (m, 2H), 3,05 (m, 2H), 3,96 (m, 2H), 4,38 (q,
1H), 4,66 (t, 1H), 5,54 (dd, 1H), 5,78 (dd, 1H), 6,33 (dd, 1H), 6,65 (dd, 1H)
ppm.
G. Rastvor 2-[[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina u THF se ohladi u ledenom kupatilu i tretira sa rastvorom trimetilsilildiazometana u THF u porcijama. Visak diazometana se razlozi sa sircetnom kiselinom i smesa se razredi sa etrom i opere vodom, zasicenim natrijum bikarbonatom, vodom (2x), i slanim rastvorom, osusi, tretira sa silika gelom i koncentrise. Preciscavanje hromatografijom na silika gelu upotrebom etra u heksanu kao gradijenta dalje 0,9 g 2-[[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksiJetanska kiselina, metil estar, jedinjenje formule (W),
kao ulje:<1>H NMR (CDCI3)81,37 (s, 3H), 1,51 (s, 3H), 3,06 (s, 1H), 3,49 (m,
2H), 3,74 (s, 3H), 4,16 (m, 2H), 4,42 (m, 1H), 4,65 (t, 1H), 5,60 (dd' 1H),'
5,79 (dd, 1H), 6,33 (dd, 1H), 6,65 (dd, 1H) ppm.
H. Na slican nacin kako je to gore opisano pripremljena su sledeca jedinjenja koja korespondiraju sa jedinjenjima formule (W).
2-| | (4S,5R)-5-((1 E,3E)-1,3-heksadien-5-inil|-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, etil estar;
2-||(4S,5R)-5-L(1 E,3E)-1,3-heksadien-5-inilj-2,2-dimetil-1,3-dioksolan-4-il]metoksi)etanska kiselina, t-butil estar;
2-|2-| (4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]etoksi]etanska kiselina, etil estar;
2-[2-| (4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-illetoksi]etanska kiselina, t-butil estar;
2-|2-| (4S,5R)-5-| (1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il|etoksiJetanska kiselina, metil estar;
2-[3-[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]propoksi]etanska kiselina, etil estar;
2-[3-|(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]propoksi]etanska kiselina, t-butil estar;
2-[3-[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]propoksi]etanska kiselina, metil estar;
4-| [(4S,5R)-5-| (1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]buterna kiselina, etil estar;
4-[ [(4S,5R)-5-| (1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]buterna kiselina, t-butil estar;
4-[[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksilbuterna kiselina, etil estar;
4-[[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]buterna kiselina, t-butil estar;
PRIPREMANJE 5
Jedinjenja formule (Ta) i formule (Ua)
A. Talog 5-trimetilsililpent-2-en-4-iniltrifenil-fosfonijum bromida,
jedinjenje formule (Q), (8,5 g, 17,7 mmol) u THF (120 mL) se mesa pod azotom, ohladi u suvi led/acetonitril kupatilu, i tretira sa rastvorom n-butillitijuma u heksanu (2M, 8 mL, 16 mmol) putem kapljicastog dodavanja.
Suvo ledeno kupatilo se zameni sa ledenim kupatilom i reakciona smesa se mesa oko 15 minuta sve dok se ne dobije homogena smesa. Suvo ledeno kupatilo se zameni i reakciona smesa se tretira sa rastvorom 2-[[(4S,5S)-5-formil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estrom, jedinjenjem formule (M), (3,7 g, 16 mmol) u 60 mL THF. Reakciona smesa se mesa u suvom ledenom kupatilu 1 sat, koje se onda menja sa ledenim kupatilom. Posle 1. sata, reakciona smesa se razredi sa etrom i monobaznim kalijum fosfatom. Vodeni sloj se opere sa etrom. Kombinovani organski slojevi se operu sa vodom i slanim rastvorom, osuse, filtriraju kroz jastuce silika gela, i koncentrisu. Heksan/etilacetat (-3:1 smesa) se dodaje ostatku da se nataloze necistoce. Ostatak se filtrira i koncentrise. Rezultirajuci ostatak se tretira sa etrom i heksanom (1:1), preceno silika gelom, filtriranjem i koncentracijom da se dobije 9,2 g 1:3 smese trifenilfosfin oksida i 2-[|(4S,5R)-5-[(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil|-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estar, jedinjenje formule (Ta);<1>H NMR (CDCI3)60,01 (s, 9H), 1,2 (s, 3H), 1,33 (s, 3H£ 3,33
(m, 2H), 3,56 (s, 3H), 3,90 (m, 2H), 4,25 (m, 1H), 4,88 (m, 1H), 5,32 (t, 1H),
5,48 (d, 1H), 5,98 (t, 1H), 6,68 (dd, 1H) ppm (NMR je samo za estar).
B. Rastvor gornjeg ostatka u metilen hloridu se tretira sa dovoljnom kolicinom joda da se odrzi crvena boja i dopusta se da odstoji 3 sata na svetlosti. Reakciona smesa se onda tretira sa zasicenim vodenim natrijum hiposulfitom, osusi sa natrijum sulfatom, filtrira kroz jastuce silika gela, i koncentrise da se dobije 4,53 g proizvoda. Hromatografija na silika gelu upotrebom 5 do 100% etra u heksanu kao gradijenta daje 2,74 g 2-| [(4S,5R)-5-[(1 E,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estar, jedinjenje formule (Ua);
<1>H NMR (CDCI3) 6 0,01 (s, 9H), 1,18 (s, 3H), 1,33 (s, 3H), 3,3 (m, 2H), 3,56
(s, 3H), 3,90 (m, 2H), 4,25 (m, 1H), 4,48 (m, 1H), 5,46 (m, 1H), 5,58 (dd,
1H), 6,14 (t, 1H), 6,44 (dd, 1H) ppm.
C. Na slican nacin mogu se pripremiti druga jedinjenja formule (Ua).
PRIPREMANJE 6
Jedinjenja formule (Z), formule (Z), formule (AA), formule (BB), formule (CC)
i formule (DD)
A. Oksalil hlorid (60 mL, 686 mmol) i dimetilformamid (DMF) (8
kapi, kat.) se dodaju izmesanoj suspenziji 2-(4-fluorofenoksi)etanske kiseline (97,3 g, 572 mmol) u dihlormetanu (500 mL) Posle 22 sata, smesa se koncentrise pod vakuumom da se dobije 108 g 2-(4-fluorofenoksi)etanska kiselina hlorid, jedinjenje formule (Z), kao zuto ulje u kvantitativnom prinosu;
1H NMR (CDCI3) 5 4,90 (s, 2H), 6,84 (m, 2H), 6,99 (m, 2H) ppm.
B. 2-(4-Fluorofenoksi)etanska kiselina hlorid se polako dodaje izmesanoj suspenziji N,0-dimetilhidroksiamin hidrohlorida (55,80 g, 572
mmol) u zasicenom K2C03i etilacetatu (375 mL). Nastupa skromna eksotermicka reakcija (reakcije vecih razmera se ohlade u ledenom
kupatilu) i posle 20 minuta, reakciona smesa se podeli izmedu vode i etra.
Sloj etra se opere sa 1M HCI i zasicenim NaCI, osusi preko Mg S04.
Osuseni rastvor se filtrira i koncentrise pod vakuumom da se dobije N-metoksi-N-metil-2-(4-fluorofenoksi)etanamid, jedinjenje formule (Z), kao zuto ulje koje se ucvrsti u nepravilno bele cvrste kristale, 113,05 g (73% prions iz pocetne kiseline);<1>H NMR (CDCI3, 400 mHz) 8 3,21 (s, 3H), 3,73 (s, 3H),
4,75 (s, 2H), 6,87 (m, 2H), 6,95 (m, 2H) ppm.
C. Rastvor etinilmagnezijum bromida (0,5 M, u THF, 508 mL, 254
mmol), se dodaje polako, da struji na dole po zidu boce, u ledenoj vodi ohladenom rastvoru N-metoksi-N-metil-2-(4-fluorofenoksi)etanamida (20,00
g, 74 mmol) u THF (100 mL). Posle dodatnih 30 minuta na 0°C, reakciona smesa se sipa u energicno izmesanu smesu 1M NaH2S04(1700 mL) i etra (1 L). Slojevi se odvajaju i vodeni sloj se ekstrakuje sa etrom (700 mL).
Kombinovane organske faze se operu sa slanim rastvorom i osuse preko MgS04, filtrira, i koncentrise pod vakuumom. Ostatak se precisti elutovanje kroz zapusac od silika gela (10 cm x 3 cm) sa 1:4 etanpet. Etar da se dobije 27,65 g (91% prinos) 4-(4-fluorofenoksi)-1-butin-3-ona, jedinjenje formule (AA), kao cvrsta supstanca koja se topi na niskoj temperaturi;<1>H NMR
(CDCI3) 8 3,40 (s, 1H), 4,70 (s, 2H), 6,85 (m, 2H), 7,0 (t, 2H) ppm.
D. Rastvor R-Alpine-Borane<®>(0,5 M u THF, 930 mL, 465 mmol) se isparava do suvog stanja pod vakuumom da se dobije oko 150 g razredenog-sirupa. 4-(4-Fluorofenoksi)-1-butin-3-on (27,6 g, 155 mmol) se dodaje i kada se primeti eksotermicka reakcija, reakciona smesa se ohladi sa led/voda kupatilom, a onda se dopusta da se zagreje do ambijentalne temperature. Posle dva dana, reakciona smesa se ohladi do 0°C i dodaje se acetaldehid (26 mL, 465 mmol) da se prigusi visak reagensa. Posle mesanja na ambijentalnoj temperaturi 2 sata, reakciona smesa se postavi pod vakuum i mesa prvo na 0°C jedan sat, onda na 65°C 2 sata. Reakciona smesa se ohladi do ambijentalne temperature i dodaje se etar (300 mL) pod azotom. Etanolamin (30 mL, 465 mmol) se dodaje kapljicasto na 0°C i rezultirajuca reakciona smesa se uskladisti u zamrzivac preko noci.
Rezultirajuci talog se uklanja filtriranjem i opere sa hladnim etrom.
Kombinovani filtrati se koncentrisu pod vakuumom. Sirovi proizvod se precisti putem hromatografije bleska na 2,5 L koloni silika gela sa 10-25%
etil acetata u heksanu kao eluent da se dobije 27 g (3S)-4-(4-fluorofenoksi)-3-hidroksi-1-butin, jedinjenje formule (BB), u kvantitativnom prinosu;<1>H
NMR (CDCI3) 8 2,56 (s, 1H), 4,10 (m, 2H), 4,78 (m, 1H), 6,85 (m, 2H), 7,0
(m, 2H). Za ovaj materijal je utvrdeno da je oko 64% ee baziran na hiralnoj HPLC njegovog 3,5-dinitrobenzoil estra (videti dole).
E. Rastvoru (3S)-4-(4-fluorofenoksi)-3-hidroksi-1-butina (proc. 490
mmol) u metilen hloridu (1 L) se dodaje 3,5-dinitrobenzoil hlorid (125 g, 539
mmol) na izmedu -5°C i 0°C, praceno sporim dodavanjem trietilamina (10,8
mL, 77 mmol) i kataliticke kolicine dimetilaminopiridina (DMAP) (20 mg).
Posto se smesa mesa na ambijentalnoj temperaturi 40 minuta, reakcija se oprezno podeli izmedu metilen hlorida i vodene NaHC03. Vodeni sloj se ekstrakuje sa dihlormetanom, i kombinovani organski slojevi se operu sa vodom i slanim rastvorom, i osuse preko Na2S04. Rastvor se filtrira kroz jastuce silika gela sa metilen hloridom sto daje sirovi proizvod kao stavna cvrsta supstanca. Brza rekristalizacija iz 99:1 smese metanoksircetna kiselina (5 L) daje 101 g enantiomerno obogacenog proizvoda, (3S)-4-(4-fluorofenoksi)-3-(3'.5'-dinitrobenzoil)oksi-1-butin, jedinjenje formule (Bba)
kao sitnozrnaste bele iglice kristala. Za ovaj materijal je utvrdeno da ima vise od 98% ee putem analiticke HPLC upotrebom Diacel Chiralpak AD<®>
(4,6 X 250 mm, 60% 2-propanol/heksan, 1 mL/min), koji odvaja (R) (11,5
min) i (S) (19,3 min) enantiomere;<1>H NMR (CDCI3) 6 2,65 (s, 1H), 4,40 (m,
2H), 6,05 (m, 1H), 6,90 (m, 2H), 7,0 (t, 2H), 9,15 (s, 2H), 9,25 (s, 1H) ppm.
F. Rastvoru (3S)-4-(4-fluorofenoksi)-3-(3'.5'-dinitrobenzoil)oksi-1 -
butina (10,35 g, 98% ee, 27,6 mmol) u THF (115 mL), se dodaje metanol (115 mL) i K2C03(0,58 g). Posle 3,5 sata mesanja, reakciona smesa se prigusi sa sircetnom kiselinom (2 mL). Rastvaraci isparavaju i rezultirajuci talog se filtrira i cvrsta supstance se opere sa etrom. Filtrat se koncentrise i ponavlja se sekvenca pranja filtriranje/etar. Koncentracija daje 4,02 g (3S)-4-(4-fluorofenoksi)-3-hidroksi-butin (98% ee), jedinjenje formule (BB);<1>H
NMR (CDCI3) 6 2,56 (s, 1H), 4,10 (m, 2H), 4,78 (m, 1H), 6,85 (m, 2H), 7,0
(m,2H).
G. Smesa (3S)-4-(4-fluorofenoksi)-3-hidroksi-butina (2,5 g, 14
mmol), N-bromosukcinimida (NBS) (2,74 g, 15,4 mmol) i AgN03(0,12 g, 0,7
mmol) u acetonu (70 mL) se mesa na ambijentalnoj temperaturi. Bledi rastvor postaje zamucen tokom 30 minuta. Smesa se koncentrise pod vakuumom i rezultirajuci ostatak se filtrira kroz zapusac silika gela (1X5
cma9 elutovan sa 1-4 etilacetaLheksan da se dobije (3S)-1-bromo-4-(4-fluorofenoksi)-3-hidroksi-1-butin, jedinjenje formule (CC), kao bledo zuto ulje koje sadrzi nesto etilacetata, 4,75 g (kvant.);<1>H NMR (CDCI3) 6 3,95-4,15
(m, 2H), 4,75 (m, 1H), 6,86 (m, 2H), 6,97 (m, 2H) ppm.
H. AICI3(2,79 g, 21 mmol) se dodaje u porcijama smesi litijum aluminijum hidrida (LAH) (1,06 g, 28 mmol) i etra (70 mL). Rastvor (3S)-1-bromo-4-(4-fluorofenoksi)-3-hidroksi-1-butin (14 mmol) u etru (10 mL) se dodaje oprezno. Primecuje se energicna reakcija sa evolucijom gasa.
Smesa se zagreva do refluka u vodenom kupatilu tokom 30 minuta.
Reakciona smesa se onda ohladi do 0°C i tretira sa 2,8 mL vode (spora,
energicna reakcija), 2,8 mL 15% NaOH, i konacno 8,4 mL vode.
Rezultirajuca suspenzija se onda mesa 10 minuta, filtrira i cvrsti delovi se operu sa THF i etrom. Rastvor se koncentrise pod vakuumom da se dobije 2,94 g (81% prinos za dva koraka) (1Z,3S)-1-bromo-4-(4-fluorofenoksi)-3-hidroksi-1-buten, jedinjenje formule (DD);<1>H NMR (CDCI3) 6 2,41 (t, 1H),
3,85 (dd, 1H), 3,99 (dd, 1H), 4,50 (m, 1H), 6,31 (dd, 1H), 6,52 (dd, 1H), 6,83
(m, 2H), 6,97 (t, 2H) ppm.
PRIPREMANJE 7
Jedinjenja formule (EE)
A. U pod plamenom osusenu bocu, rastvor (1Z,3S)-1-bromo-4-(4-fluorofenoksi)-3-hidroksi-1-butena (0,84 g, 3 mmol),
tetrakis(trifenilfosfin)paladijum(0) (0,13 g, 0,2 mmol) i bakar(l) jodida (60 mg,
0,3 mmol) u THF (50 mL) i dietilaminu (5 mL, 48 mmol) se pazljivo deoksigenizuje kljucanjem u argonu gasu 45 minuta. Reakcija se mesa kako se dodaje 2-[[(4S,5R)-5-[(1 E,3E)-1,3-heksadien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estar, (0,9 g, 3,2 mmol) u THF
(50 mL), koji je deoksigenizovan kljucanjem u argonu 45 minuta. Posle oko 4 sata, reakcija je obavljena. Reakciona smesa se razrecTuje sa heksanom i filtrira kroz jastucic silika gela i silika gel se elutuje sa etrom. Kombinovarri filtrati se koncentrisu da daju ulje. Preciscavanje putem hromatografije upotrebom 20-75% gradijente etra u heksanu daje 1,1 g 2-[[(4S,5R)-5-[(1E,3E,6Z,8S)-8-hidroksi-9-(4-fluorofeniksi)-1,3,6-nonatrien-5-inil]-2,2-dimetil-1,3-dioksolan-4-il]metoksi]etanska kiselina, metil estar, jedinjenje formule (EE), kao ulje; 1H NMR (CDCI3) 6 1,37 (s, 3H), 1,5 (s, 3H), 3,52 (m,
2H), 3,75 (s, 3H), 3,83 (m, 2H), 4,13 (m, 2H), 4,44 (m, 1H), 5,74 (m, 1H),
5,76 (m, 2H), 6,05 (m, 1H), 6,17 (m, 1H), 6,29 (m, 1H), 6,58 (dd, 1H), 6,88
(m, 4H) ppm.
B. Na slican nacin mogu se pripremiti druga jedinjenja formule
(EE).
PRIPREMANJE 8
Jedinjenja formule (GG)
A. Talog bakar sulfata (175 g, 1,09 mol, 2 ekv.) i ramnoza hidrata (100 g, 0,55 mol) u sveze destilisanom cikloheksanonu (330 g) se mesa pod azotom dok se koncentrovana sumporna kiselina (1,5 mL) dodaje odjednom.
Reakciona smesa se zagreje do oko 29°C interno. Reakcionoj smesi se dopusta da se mesa preko noci. Reakcija se analizira putem TLC
(etilacetat) i obavljena je. Reakciona smesa se filtrira kroz jastuce celita i cvrste supstance se opreu sa etilacetatom. Filtrat se tretira sa oko 1,5 mL
koncentrovanog amonijum hidroksida do pH 7, a rezultirajuci cvrsti delovi se uklanjaju filtriranjem. Filtrat se koncentrise pod redukovanim pritiskom da se dobije bezbojno ulje. Ostatak se rastvara u etru i tretira sa heksanom i dopusta da odstoji preko noci. Rezultirajuca cvrsta supstanca se izoluje filtriranjem i osusi da se dobije 92,3 g (0,31 mol, 57%) (2R,3R)-3-(1,2-dihidroksipropil)-1,4-dioksaspiro[4,5]dekan-2-karboksaldehid, kao nepravilno belo cvrsto telo; [cc]D = +0,457 (10,485 mg/c<3>MeOH);<1>H NMR (CDCI3) 6
1,34 (d, 3H), 1,40 (m, 2H), 1,6 (m, 8H), 2,78 (d, 1H), 3,0 (s, 1H), 3,9 (m, 1H),
4,07 (m, 1H), 4,6 (d, 1H), 4,9 (m, 1H), 5,4 (s, 1H) ppm.
B. Na slican nacin se pripremaju druga jedinjenja formule (GG).
PRIPREMANJE 9
Jedinjenja formule (HH)
A. Talog natrijumborhidrida (34,2 g, 0,9 mol) u metanolu (400 mL)
se ohladi u ledenom kupatilu i tretira sa (2R,3R)-3-(1,2-dihidroksipropil)-1,4-dioksaspiro(4,5jdekan-2-karboksaldehidom (92 g, 0,27 mol) rastvorenom u 200 mL metanola. Reakciona smesa se mesa oko 4 sata. Reakcija je obavljena i sircetna kiselina se dodaje da potrosi visak borhidrida i da podesi pH na oko 6 (oko 120 mL). Reakciona smesa se koncentrise i rastvara u etilacetatu. Relzultirajuce cvrsto telo se uklanja filtriranjem. Kombinovani filtrati se osuse, i koncentrisu da daju blago zuto viskozno ulje. Ostatak se rastvara u etru i tretira sa heksanom da natalozi proizvod. Cvrsti oblici se izoluju filtriranjem i osuse da daju 81,2 g (2R,3S) a<2->(1-hidroksietil)-1,4-dioksaspiro[4,5]dekan-2,3-dimetanol kao nepravilno belo cvrsto telo: [«]D =
+5,494 (10,119 mg/c<3>MeOH); 1H NMR (CDCI3) 6 1,28 (d, 3H), 1,43 (m, 2H),
1,7 (m, 8H), 3,42 (dd, 1H), 3,7 (m, 3H), 4,25 (m, 1H), 4,42 (dd, 1H) ppm.
B. Na slican nacin pripremaju se druga jedinjenja formule (HH).
PRIPREMANJE 10
Jedinjenja formule (JJ)
A. Smesa (2R,3S) a<2->(1-hidroksietil)-1,4-dioksaspiro[4,5]dekan-2,3-dimetanola (81 g, 0,32 mol) i t-butil bromoacetata (77 g, 0,39 mol, 1,2
ekv.) u 1 L toluena se mesa sa mehanickom mesalicom dok se dodaje 80
mL natrijum hidroksida u vodi (25% po masi). Katalizator transfera faze,
tetrabutilamonijum sulfat (7,8 g, 23 mmol, 0,07 ekv.), se dodaje i reakciona
smesa se mesa preko noci i prati putem TLC. Reakciona smesa se razredi sa etilacetatom i zasicenim bodenim monobaznim kalijum fosfatom.
Kombinovani organski slojevi se osuse i koncentrisu da se dobije bistro ulje.
Hromatografija na 1 Kg silika gela upotrebom kao gradijenta u koraku 20%
etra u heksanu daje cistu frakciju koja se kombinuje sa ranijom frakcijom da se dobije 50,8 g (44%) 1,1-dimetiletil 2-[[(2S,3R) 3-(1,3-dihidroksipropil)-1,4-dioksaspiro|4,5]dek-2-il]metoksi]acetat kao ulje: [a]D = +8,587 (10,301
mg/c<3>MeOH);<1>H NMR (CDCI3) 6 1,24 (d, 3H), 1,35 (m, 2H), 1,47 (s, 9H),
1,6 (m, 8H), 3,6 (m, 2H), 3,8 (m, 2H), 3,95 (m, 2H), 4,32 (m, 1H), 4,4 (m, 1H)
ppm.
B. Na slican nacin pripremaju se druga jedinjenja formule (JJ).
PRIPREMANJE 11
Jedinjenja formule (KK)
A. Rastvor 1,1-dimetiletil 2-[[(2S,3R) 3-(1,3-dihidroksipropil)-1,4-dioksaspiro|4,5]dek-2-il]metoksi]acetata (50 g, 138 mmol) u acetonu (350
mL) se tretira sa rastvorom perjodata (50 g, 235 mmol, 1,7 ekv.) u vodi (1,2
L). Reakciona smesa se mesa energicno pod azotom i prati putem TLC.
Posle otprilike 4 sata, reakcija je obavljena ptuem TLC analize. Aceton se uklanja pod redukovanim pritiskom bez zagrevanja. Reakciona smesa se ekstrakuje sa etilacetatom (3 x 500 mL). Kombinovani organski slojevi se osuse i koncentrisu pod redukovanim pritiskom bez zagrevanja da se dobije 40 g 1,1-dimetiletil 2-[[(2S,3S) 3-formil-1,4-dioksaspiro[4,5]dek-2-iljmetoksijacetat kao bistro ulje: [ct]D = -1,142 (10,147 mg/c<3>MeOH);<1>H
NMR (CDCI3)61,38 (m, 2H), 1,42 (s, 9H), 1,61 (m, 8H), 1,73 (m, 2H), 3,52
(dd, 1H), 3,72 (dd, 1H), 3,88 (s, 2H), 4,38 (dd, 1H), 4,52 (m, 1H), 9,62 (s,
1H) ppm.
B. Na slican nacin pripremaju se druga jedinjenja formule (KK).
PRIPREMANJE 12
Jedinjenja formule (LL)
A. Talog 5-trimetilsililpent-2-en-4-iniltrifenil-fosfonijum bromida,
jedinjenja formule (Q), (67,1 g, 0,14 mol) u THF (875 mLI se mesa pod azotom, hladi u suvom ledenom acetonitril kupatilu (-30X interno), i tretira sa rastvorom n-butillitijuma (66,5 mL, 0,133 mol, 2M u heksanu) putem kapljicastog dodavanja. Suvo ledeno kupatilo se zameni sa ledenim kupatilom i reakcija se mesa oko 15 minuta do homogenosti, dobija se smesa crvene boje. Suvo ledeno kupatilo se zameni i reakciona smesa se hladi do oko -30°C. Reakciona smesa se tretira sa rastvorom 1,1-dimetiletil 2-[[(2S,3S) 3-formil-1,4-dioksaspiro[4,5]dek-2-il]metoksi]acetatom (40 g,
0,127 mol) u 125 mL THF. Reakciona smesa se mesa 1 sat u suvom ledenom kupatilu. Sa internom temperaturom od oko -30°C, reakciona smesa se razreduje sa zasicenim kalijum fosfatom (pH=5). Vodeni sloj se opere sa etrom (3x). Kombinovani organski slojevi se operu sa vodom i slanim rastvorom, osuse, tretiraju sa silika gelom, i koncentrisu. Ostatak se razreduje sa oko 3:1 smesom heksana prema etilacetatu da se nataloze necistoce. Rezultirajuci talog se filtrira i cvrsto telo se opere sa smesom heksan/etilacetat. Filtrat se koncentrise. Postupak se ponavlja upotrebom smese etra i heksana (1:1) i tretmanom sa silika gelom da se dobije 50,29 g 1,1-dimetiletil [[(2S,3R)-3-[(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inil]-1,4-dioksaspiro[4,5]dek-2-il]metoksi]etanoat kao ulje. Proton NMR analiza
proizvoda koji naznacava smesu 2:1 E,Z- prema E,E-izomerima. Podasi za Z,E izomer mogu biti ekstrakovani iz smese:<1>H NMR (CDCI3)60,15 (s, 9H),
1,3 (m, 2H), 1,4 (s, 9H), 1,6 (m, 8H), 3,45 (m, 2H), 3,92 (m, 2H), 4,34 (m,
1H), 5,02 (m, 1H), 5,48 (dd, 1H), 5,6 (d, 1H), 6,16 (dd, 1H), 6,82 (dd, 1H)
ppm.
B. Na slican nacin pripremaju se druga jedinjenja formule (KK).
Primer 1
Jedinjenja formule (lla)
A. Rastvor 2-[[(4S,5R)-5-[(1 E,3E,6Z,8S)-8-hidroksi-9-(4-fluorofenoksi)-1,3,6-nonatrien-5-inil]-2,2-dimetil-1,3-dioksolan-4-iljmetoksijetanska kiselina, metil estar, (1,1 g, 1,8 mmol) u metanolu (25 mL)
se tretira sa 1 mL 1 N hlorovodonicne kiseline i reakcija se mesa 2 dana.
Vrednost pH reakcije se podesava do neutralnosti. Preciscavanje na preparativnoj refersnoj fazi polu-prip kolone upotrebom gradijenta acetonitrila u vodi daje prinos 1,1 g (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska
kiselina, metil estar, kao ulje;<1>H NMR (CDCI3)63,67 (m, 2H), 3,75 (s, 3H),
3.83 (m, 1H), 3,95 (m, 1H), 4,13 (m, 2H), 4,37 (m, 1H), 4,58 (m, 1H), 5,73
(dd, 1H), 5,86 (dd, 1H), 6,04 (dt, 1H), 6,17 (m, 1H), 6,40 (m, 1H), 6,58 (m,
1H), 6,9 (m, 4H) ppm.
B. Na slican nacin priprema se sledece jedinjenje formule (lla): (5S,6S,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar. C. Rastvor (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar, (0,4 g, 0,95 mmol) u metanolu (20 mL) se tretrira sa 1 N NaOH (tec) (4 mL, 4 mmol) rastvorom i mucka se i dopusta da odstoji tri sata. Reakciona smesa se onda tretira sa zasicenim kalijum monofosfatom i sipa na HP20 kolonu. Elucija sa gradijentom metanola u vodi daje 0,35 g (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselinu, koja se ucvrsti posle stajanja;<1>H NMR (CDCI3) 6 3,63 (m, 2H), 3,667 (m, 1H), 3,91 (m, 2H), 4,113 (s, 2H), 4,150 (t, 1H), 4,498 (m, 1H), 5,762 (dd, 1H), 5,953 (dd, 1H), 6,003 (dt, 1H), 6,202 (dd, 1H), 6,380 (dd, 1H), 6,928 (m, 2H), 6,988 (m, 2H) ppm. D. Na slican nacin priprema se sledece jedinjenje formule (lla);
(5S,6S,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina.
E. Na slican nacin kako je gore opisano pripremaju se sledeca jedinjenja formule (II): (2E,5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-2,7,9,13-tetraen-11-inska kiselina;
(2E,5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-2,7,9,13-tetraen-11-inska kiselina, metil estar;
(5R,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3--oksaheksadeka-7,9,13-trien-11-inska kiselina;
(5R,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar;
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inamid;
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-N,N-dimetil-3-oksaheksadeka-7,9,13-trien-11-inamid;
(7S,8R,9E,11E,15E,17S)-18-(4-fluorofenoksi)-7,8,17-trihidroksi-5-oksaoktadeka-9,11,15-trien-13-inska kiselina;
(7S,8R19E,11E,15El17S)-18-(4-fluorofenoksi)-7,8,17-trihidroksi-5-oksaoktadeka-9,11,15-trien-13-inska kiselina, metil estar;
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-tiaheksadeka-7,9,13-trien-11-inska kiselina;
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-azaheksadeka-7,9,13-trien-11-inska kiselina;
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,15-dihidroksi-6-(metilamino)-3-oksaheksadeka-7,9,13-trien-11-inska kiselina; i
(5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,15-dihidroksi-6-amino-3-oksaheksadeka-7,9,13-trien-11-inska kiselina.
F. Jedinjenje formule (lla) kako su gore pripremljena se tretiraju sa odgovarajucim agensom za acilovanje, kao sto je fosgen, pod kiselim uslovima da se dobije prinos sledecih jedinjenja: [[5-[(1E,3E,7E,9R)-10-(4-fluorofenoksi)-9-hidroksi-1,3,7-dekatrien-5-inil]-2-okso-1,3-dioksolan-4-il]metoksi]sircetna kiselina;
f[5-[(1E,3E,7E,9R)-10-(4-fluorofenoksi)-9-hidroksi-1,3,7-dekatrien-5-inil]-2-okso-1,3-oksatiolan-5-il]metoksi]sircetna kiselina; i
[[5-[(1 E,3E,7E,9R)-10-(4-fluorofenoksi)-9-hidroksi-1,3,7-dekatrien-5-inil]-2-okso-5-oksazolidinil]metoksi]sircetna kiselina.
Primer 2
Jedinjenja formule (lib)
A. Rastvor (1Z,3S)-1-bromo-4-(4-fluorofenoksi)-3-hidroksi-1-butena (16,6 g, 63 mmol), cvrstog tetrakistrifenilfosfinPd(=) (3,67 g, 3 mmol),
i Cu(l) jodida (1,2 g, 6,3 mmol) u dietilaminu (50 mL) i THF (800 mL) se mesa i deoksigenizuje kljucanjem argona kroz smesu 90 minuta. Dodavanje argona se nastavlja dok se slicno deoksigenizovani rastvor (kljucanje argona) 1,1-dimetiletil [[(2S,3R)-3-[(1Z,3E)-6-(trimetilsilil)-1,3-heksadien-5-inilj-1,4-dioksaspiro[4,5]dek-2-il]metoksi]etanoata (23 g, 63 mmol) u 200 mL
THF kapljicasto dodaje tokom oko 3 sata. Reakcija se prati putem TLC
analize. Posle oko 2 dodatna sata, reakcija je obavljena putem TLC analize.
Reakciona smesa se razreduje sa heksanom (oko 400 mL), tretira sa silika gelom (oko 40 g) i filtrira. Cvrsto telo se opere sa 1.1 rastvorom etra i heksana. Filtrat se koncentrise da se dobije 36,8 g ulja. Ostatak se rastvori u etru, tretira sa heksanom, i dopusta se da odstoji preko vikenda. Krajnje obojeni materijal se ukloni filtriranjem kroz jastuce silika gela i proizvod se elutuje sa etrom. Zeljene frakcije se koncentrisu da daju ulje. Preciscavanje putem hromatografije na 1 Kg silika gela upotrebom 15-50% gradijenta etra u heksanu daje 16,9 g 1,1-dimetiletil |[(2S,3R)-3-[(1 E,3E,7E,9S)-10-(4-fluorofenoksi)-9-hidroksi-1,3,7-dekatrien-5-inil]-1,4-dioksaspiro[4,5]dek-2-iljmetoksijetanoata kao ulje: [a]D = -21,174 (10,165 mg/c<3>u MeOH);<1>H
NMR (CDCI3) 6 1,3 (m, 2H), 1,4 (s, 9H), 1,6 (m, 8H), 2,42 (s, 1H), 3',5 (d<*>
2H), 3,96 (m, 4H), 4,38 (q, 1H), 4,58 (m, 1H), 4,66 (t, 1H), 5,72 (m, 1H), 5,78
(dd, 1H), 6,03 (m, 1H), 6,16 (dd, 1H), 6,33 (dd, 1H), 6,58 (dd, 1H), 6,88 (m,
4H)ppm.
B. Na slican nacin pripremaju se druga jedinjenja formule (lib).
Primer 3
Jedinjenja formule (lie) i formule (lid)
A. Rastvor 1,1-dimetiletil [|(2S,3R)-3-[(1 E,3E,7E,9S)-10-(4-fluorofenoksi)-9-hidroksi-1,3,7-dekatrien-5-inil]-1,4-dioksaspiro[4,5]dek-2-il)metoksi)etanoata (1 g, 2,8 mmol) u sircetnoj kiselini (50 mL) i postavlja na 55°C uljanom kupatilu 20 sati. Reakcija se obavlja putem TLC analize. Sircetna kiselina i etilacetat se uklanjaju destilacijom pod visokim vakuumom. Ostatak se razredi sa vodom i ekstrakuje sa etilacetatom (3x). Kombinovani organski slojevi se operu sa vodom, zasicenim vodeim natrijum karbonatom, vodom, i slanim rastvorom, osuse i koncentrisu da se dobije 0,9 g ulja. Hromatografija na HP-20 koloni koja elutuje sa gradijentom metanola u vodi daje (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11 -inska kiselina, t-butil estar (jedinjenje formule (He)). Kombinovane frakcije se tretiraju sa rastvorom 1 N natrijum hidroksida (2 mL) i koncentrise. Reakcija je obavljena putem TLC posle oko 1 sat i postavlja na HP20 koloni. Hromatografija upotrebom gradijenta metanola u vodi daje 0,3 g (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina; koja prelazi u cvrsto stanje odstojeci;<1>H NMR (CDCI3) 6 3,63 (m, 2H), 3,667 (m, 1H), 3,91 (m, 2H),
4,113 (s, 2H), 4,150 (t, 1H), 4,498 (m, 1H), 5,762 (dd, 1H), 5,953 (dd, 1H),
6,003 (dt, 1H), 6,202 (dd, 1H), 6,380 (dd, 1H), 6,596 (dd, 1H), 6,928 (m* 2H),'
6,988 (m, 2H) ppm.
B. Na slican nacin se pripremaju jedinjenja formule (lie) i formule (lid).
Primer 4
Jedinjenja formule (I)
A. Aktivirani cink se priprema iz 10 g zinka i redukcijom obavljenom upotrebom postupka opisanog kod Helv. Chim. Acta (1987), Vol.
70, p. 1025). Rastvor (5S,6R,7E,9E,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar, (0,8
g, 1,2 mmol) u metanolu (4 mL) se dodaje talogu aktiviranog cinka u razmeri 1:1 metanokvoda (45 mL). Balon se mesa energicno pod azotom tokom 24-60 sati. Smesa se filtrira kroz jastuce Celite 545 i ispere sa metanolom (3x25 mL). Preciscavanje putem hromatografije na reversnoj polu-prip koloni upotrebom gradijenta acetonitrila i vode daje 55 mg (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina, metil estar, kao ulje;<1>H-NMR (400
mHz, metanol-d4)63,62 (m, 2H), 3,75 (s, 3H), 3,93 (m, 2H), 4,13 (m, 3H),
4,58 (m, 1H), 5,85 (m, 2H), 6,14 (m, 2H), 6,36 (m, 2H), 6,77 (m, 1H), 6,96
(m, 5H) ppm.
B. Na slican nacin mogu biti pripremljena druga jedinjenja formule
(I).
C. Rastvor (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina, 'metil estar, (25 mg, 59 nMol) u metanolu (5 mL) se tretira sa 1 N NaOH (vod) (25
(.iL, 25(imol) rastvorom i mucka a potom mu se dopusta da odstoji. Posle zavrsetka, reakcija se tretira sa zasicenim kalijum monofosfatom.
Preciscavanje putem hromatografije na HP20 kolini elutovanoj sa vodenim metanol gradijentom daje 10 mg (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraensku kiselinu;<1>H-NMR (CD3OD) 6 3,6 (m, 3H), 3,88 (m, 4H), 4,18 (m, 1H), 4,52
(m, 1H), 5,84 (m, 2H), 6,03 (m, 2H), 6,34 (m, 2H), 6,74 (m, 1H), 6,95 (m, 5H)
ppm.
D. Na slican nacin kako je to gore opisano, pripremaju se sledeca jedinjenja formule (I): (2E,5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksiheksa-2,7,9,11,13-dekapentanska kiselina;
(2E,5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksiheksa-2,7,9,11,13-dekapentanska kiselina, metil estar;
(5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetranska kiselina;
(5R,6R,7E,9E,11Z.13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetranska kiselina, metil estar;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenamid;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-N,N-dimetil-3-oksa-7,9,11,13-heksadekatetraenamid;
(7S,8R,9E,11E,13Z,15E,17S)-18-(4-fluorofenoksi)-7,8,17-trihidroksi-5-oksa-9,11,13,15-oksadekatetranska kiselina;
(TS^R^EJIE.iaZ.ISE.IZSJ-IS^-fluorofenoksip.S.IZ-trihidroksi-S-oksa-9,11,13,15-oksadekatetranska kiselina, metil estar;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-tia-7,9,11,13-heksadekatetranska kiselina;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-aza-7,9,11,13-heksadekatetranska kiselina;
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,15-dihidroksi-6-(metilamino)-3-oksa-7,9,11,13-heksadekatetranska kiselina; i
(5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,15-dihidroksi-6-amino-3-oksa-7,9,11,13-heksadekatetranska kiselina.
Primer 5
Ovaj primer ilustruje pripremanje reprezentativnih farmaceutskih sastava za oralno davanje koji sadrze jedinjenje pronalaska, kao jedinicni stereoizomer,
ili kao recemsku smesu stereoizomera, ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Gornji sastojci su pomesani i dispergovani u kapsule od zelatina sa tvrdom-Ijuskom koje sadrze 100 mg svaka, a jedna kapsula bi bila otprilike ukupna dnevna doza.
Gornji sastojci sa izuzetkom magnezijum stearata su kombinovani i granulirani upotrebom vode kao tecnosti za granulaciju. Formulacija se onda osusi, mesa sa magnezijum stearatom i formira u tablete sa odgovarajucom masinom za pravljenje tableta.
Jedinjenje pronalaska se rastvara u propilen glikolu, polietilen glikolu 400 i polisorbatu 80. Dovoljna kolicina vode se onda dodaje sa mesanjem da se dobije 100 mL rastvora koji se filtrira i stavlja u boce.
Gornji sastojci se tope, mesaju i pune u meke eiasticne kapsule.
Jedinjenje pronalaska se rastvara u celuloza/solana rastvoru, filtrira i stavlja u boce za upotrebu.
Primer 6
Ovaj primer ilustruje pripremanje reprezentativne farmaceutske formulacije za parenteralno davanje koja sadrzi jedinjenje pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera;
ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Jedinjenje pronalaska se rastvara u propilen glikolu, polietilen glikolu 400 i polisorbatu 80. Dovoljna kolicina 0,9% slanog rastvora se onda dodaje sa mesanjem da se dobije 100 mL I.V. rastvora koji se filtrira kroz filter membranu od 0,2 m i pakuje pod sterilnim uslovima.
Primer 7
Ovaj primer ilustruje pripremanje reprezentativne farmaceutske formulacije u oblik supozitorija koji sadrzi jedinjenje pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera;
ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Sastojci se tope zajedno u mesaju u parnom kupatilu, i sipaju u modle koje sadrze 2,5 g ukupne tezine.
Primer 8
Ovaj primer ilustruje pripremanje reprezentativne farmaceutske formulacije za insuflaciju koja sadrzi jedinjenje pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Sastojci se melju, mesaju, i pakuju u insuflator opremljen sa pumpom za doziranje.
Primer 9
Primer ilustruje pripremanje reprezentativne farmaceutske formulacije u nebularnom obliku koja sadrzi jedinjenje pronalaska, kao jedinicni stereoizomer, smesa stereoizomera, ili kao racemska smesa stereoizomera;
ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Jedinjenje pronalaska se rastvara u etanolu i mesa sa vodom. Formulacija se onda pakuje u nebulajzer opremljen sa pumpom za doziranje.
Primer 10
Ovaj primer ilustruje pripremanje reprezentativne farmaceutske formulacije u oblik aerosola koja sadrzi jedinjenje pronalaska, kao jedinicni stereoizomer,
smesa stereoizomera, ili kao racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so:
Jedinjenje pronalaska se disperguje u oleinsku kiselinu i reaktivnim sredstvima. Rezultujuca smesa se onda sipa u aerosol kontejner koji se podesava putem ventila za merenje.
Primer 11
(In Vitro ogled)
Ogledi trans-epitelne i trans-endotelijalne migracije
Kultura humanih endotelijalnih celija pupcane vene ( HUVEC) :
Humane endotelijalne celije pupcane vene (HUVEC) se kultivisu prema postupcima otkrivenim kod Serhan, C.N:, et al.,Biochemistry(1995), Vol.
34, No. 44, pp. 14509-14615. Tacnije, HUVEC se upotrebljavaju na'
prolazima 1 i 2 i izoluju se varenjem kolegenaze (0,1% koolageneaze,
CLS3; Worthington Biochem. Corp., Freehold, New Jersey) i razmnozavaju se na zelatinom oblozenim plocama kulture celija (Costar Corp., Cambridge,
Massachusetts) u RPMI 1640 medijumu celijske kulture (Bio Whittaker Inc.,
Walkersville, Maryland) dopunjenim sa 15% serumom govedeg mladunceta
(BCS) (Hyclone Laboratories, Logan, Utah), 15% NU-serumom (Collaborative Research Inc., Lexington, Massachusetts), 50 u.g/mL
endotelijalnim mitogenom (Biomedical Technologies Inc., Stoughton,
Massachusetts), 8 jedinica/mL heparina, 50 jedinica/mL penicilina, i 50
ug/mL streptomicinom. Za oglede transmigracije HUVEC se zaseju i gaje da se sliva na zelatinom oblozene (1%) polikarbonantne propustljive nosace (umetke) sa povrsinom od 0,33 cm<2>(Costar Inc., Cambridge, MA).
Kultura epitelijalne celije:
T84celije se uzgajaju u 1:1 smesi dulbecco-ovog modifikovanog Eagle medijuma i Hams F-12 medijuma dodatno snabdevenim sa 15 mM HEPES
puferom (pH 7,5), 14 mM NaHC03, 40 ug/mL penicilinom, 8 (ig/mL
ampicilinom, 90 ug/mL streptomicinom, i sa 5% seruma novorodenog mladunceta (Dharmasathaphorn et al., 1990). Za apikalne do bazolateralne eksperimente transmigracije, T84monoslojevi se uzgajaju na kolagenom oblozenim, polikarbonatnim propustljivim nosacima (umetcima) sa povrsinom od 0,33 cm<2>(Costar Inc., Cambridge, MA) kako je to opisano kod Parkos, C.A., et al.,J. clin. Invest.(1991), Vol. 88, pp. 1605-1612. Za fizioloski usmerene, bazolateralne do apikalne eksperimente transmigracije neutrofila, T84celije se postavljaju na plocu sa donje strane 0,33 cm<2>
polikarbonatnih filetera koji su blago oblozeni sa kolagenom repa-pacova kako je to opisano kod Parkos, C.A., et al.. Dopusteni rast invertnih monoslojeva, koji tako dopustaju neutrofilima da se smeste putem gravitacije u neposredni subepitelijalni deo.
Ogled:
Humani polimorfonuklearni leukociti (PMN) se izoluju iz normalnih humanih dobrovoljaca i suspenduju pri koncentraciji od 5x10<7>celija/mL u modifikovanom Hanks izbalansiranom slanom rastvoru (HBSS), bez Ca<2+>i Mg2\ sa 10 mM Hepes, pH 7,4, (Sigma). Pre dodavanja PMN, monoslojevi T84epitelijalnih ili HUVEC endotelijalnih celija se ekstenzivno ispiraju u HBSS da se otklone preostale serum komponente. PMN je prethodno izlozen jedinjenjime pronalaska pri koncentraciji u rasponu od 10~11 do 10~<7>
M 15 minuta na 25°C. Ogled transmigracije se obavlja dodavanjem PMN
(40uL) HBSS-u (koji sadrzi Ca<2+>i Mg<2+>, 160 )_iL) u gornje komore posto se doda hemoatraktant (10 nM fMLP) suprotnim (donjim) komorama. PMN se ne pere osloboden od jedinjenja pronalaska pre dodavanja na monoslojeve.
PMN (1x106) se doaju u nultom vremenu. Transmigraciji se dopusta da se nastavi 60 minuta. Svi eksperimenti se obavljaju u okruzenju na 37 °C da se osigura da se endotelijalni/epitelijalni monoslojevi, rastvori, plasticna oprema, itd., odrzavaju na uniformnoj temperaturi od 37 °C. Transmigracija se kvantifikuje ogledanjem na PMN azurofilicne granule markeru mijeloperoksidaze (MPO). Posle svakog ogleda transmigracije, ne-spojeni PMN se ekstenzivno operu sa povrsine monosloja i PMN ekvivalenti (PMN CE), procenjeni u odnosu na standardnu krivu, se procenjuju kako se broj PMN koji su kompletno presle na monosloj (na primer, preko monosloja u rezervoar kupatila).
Jedinjenja pronalaska, kada se testiraju u ovom ogledu, demonstriraju sposonbost da inhibiraju transmigraciju PMN preko polarizovanih monoslojeva epitelijalnih celija i vaskularnih endotelijalnih celija, koji su polozaji dva vazna imuna dogadaja u odbrani domacina i inflamaciji.
Primer 12
(In vivo ogled)
Ogled hemopremestanja
Eksperimenti hemopremestanja se obavljaju na sveze pripremljenim neutrofilima (PMN) dobijenih iz cele krvi date od strane zdravih dobrovoljaca. Krv se antikoagulise (heparin), centrifugira pri maloj brzini i sa plateletom bogatom plazma se uklanja usisavanjem. Preostala krv se mesa sa jednakom zapreminom fosfatom puferovanim slanim rastvorom minusCa<2+>/Mg<2+>, pH 7,4 (PBS"'") i dodaje se jednaka zapremina 3% dekstrana u PBS"'", uzorak se izmesa i dopusta mu se da se stisa. Gornji sloj obogacen belim krvnim zrncima (- 25 mL) se nanese na 15 mL jastuk Ficoll-Hypaqque i centrifugira na 400 g 30 minuta na 18-22 °C. Gornji slojevi su usisani PMN
celijska peleta se podvrgava hipotonicnom lizisu crvenog krvnog zrnca.
PMN se opere dva puta i resuspenduje u Hank's Balanced Salt Solutin minus Ca<2+>/Mg<2+>, pH 7,4 (HBSS"'") na 1x10"<7>celija/mL u cevi centrifuge. 2,5
liM Calcein-AM (Molecular Probes cat #C3100) se dodaje i celije se inkubiraju 25 minuta na ambijentalnoj temperaturi, onda postavljaju u inkubator sa temperaturom 37 °C 5 minuta. Celije se onda centrifugiraju i operu dva puta u HBSS"'" da se ukloni preostali Calcein-AM. Neutrofili se konacno resuspenduju na 2x10<7>/mL sa HBSS' + 10 mM HEPES, pH 7,4.
Ogledi hemopremestanja se obavljaju na specijalnim plocama sa 96
bazencica. Filter of 3 |_im se vezuje za metalni ram i selektivno se oblaze sa hidrofobicnom maskom oko svakog bazencica. Hidrofobicna maska dopusta direktno dodavanje celija gornju stranu filtera. Neutrofili (15 uL,
1,5x10<5>celija/bazencic) se dodaju na vrh ChemoTx® ploce (Cat #101-3).
Za proucavanja inhibicije, PMN se prethodno inkubira 15 minuta sa jedinjenjem pronalaska. Pre dodavanja PMN na gornju komoru, 30uL
hemoatraktanta (10 nM fMLP ili 10 nM LTB4ili F-12 medijum kulture (bez crvenog fenola) se dodaje donjoj komori, filter podmetac se onda postavi na mesto i dodaje se PMN na filter sa 8-kanalnom uredajem za pipete. Ogled ploca se inkubira 90 minuta na 5% C02+95% vazduha na 37°C. Posle inkubacije, filter podmetac se uklanja i ploca se cita u Victor II citacu place (485nrn-pobudivanje/535nm emisija). Fluorescentno oznacene celije koje su migrirale kroz filter u donju komoru se mere.
Kada se testira u ovom ogledu, jedinjenje pronalaska demonstriraju sposobnost da inhibiraju hemopremestanje humanog neutrofila.
Primer 13
(In vivo ogled)
Misji cimosanom izazvani model peritonitisa
Sledeci ogled se uptrebljava da se proceni sposobnost jedinjenja pronalaska da inhibiraju inflamaciju koju karakterise celijska infiltracija u lokalizovanu oblast.
Jedinjenje pronalaska u 0,1% etanol/PBS nosacu se daje intravenoznim putem, intra-peritonelno, potkozno ili intra-gastricnim davanje sest do osam nedelja starim FVB misevima (prosecno 21 g) kupljenim od Charles "River Laboratories. Za intra-gastricna proucavanja, 200^iL koncentracije svakog jedinjenja se isporucuje upotrebom zivotinjskih igala za hranjenje. Otprilike cetrdeset pet minuta kasnije, 1 mL (1 mg/mL) cimosana A se ubrizgava u peritoneum. Dva i po sata posle intra-peritonelnog ubrizgavanja, misevi se eutanizuju sa prekomernom dozom izoflurana i sakupljaju se peritonelne lavaze sa 5 mL PBS koji sadrzi kalcijum i magnezijum. Ukupni leukociti se prebroje putem svetlosne mikroskopije i izracunava se procenat inhibicije u odnosu na kontrolu sa nosacem. Za diferencijalne inhibitorne efekte na neutrofilima, eosinofilima, monocitima i limfocitima, -250.000 celija se transferee na staklene slajdove i oboji sa 0,4% Wright Giemsa Stain, izdiferencirane putem brojanja pod mikroskopom (x40) i izracunava se procenat inhibicije u odnosu na kontrolu sa nosacem.
Kada se testira u ovom ogledu, jedinjenja pronalaska demonstriraju sposobnost da inhibiraju migraciju inflamatornih celija (odnosno, neutrofila,
monocita, i limfocita) u peritoneum. Prema tome, jedinjenja pronalaska pokazuju da su korisna u lecenju inflamatornog poremecaja uin vivomodelu.
Primer 14
(In vivo ogled)
Sledeci ogled moze biti izveden na slican nacin kao ogled opisan kod Campbell,E.M., etal., J. Immunol.(1998), Vol. 161, No. 12, p. 7047-7053.
Ogled iskoristava CBA/J miseva nacinjenih osetljivima sa rastvorljivim antigenima buba svabe u nekompletnom Freund-ovom adjuvantu intraperitonelno. Ogled koristi 6-8 zivotinja u svakoj grupi/vremenskoj'tacki,' ukljucujuci grupu za kontrole. Posle 14 dana, misevi se nacine osetljivim sa rastvorljivim antigenom buba svabe putem intranazalnog davanja, praceno 3-5 dana kasnije sa intratrahealnim ubrizgavanjem antigena buba svabe.
Misevima moze biti dat drugi intratrahealni izazov 48 sati posle primarnog.
Pre konacnog izazova, alergicni misevi primaju jednu od 3 doza jedinjenja pronalaska. Posle 8 i 24 sata posle izazova, misevi se ispituju na hiperreaktivnost vazdusnog puta i akumulacija podsetova leukocita se prate u bronhoalveolarnoj lavazi (BAL) i histoliskim sekcijama. Drugi izazov se daje u vreme kada pronadena znacajna kolicina inflamacije u i oko vazdusnog puta, uklucujuci eozinofile. Ovaj scenario je reprezentativan za ono sto se desava kod hronicnih astmaticara. Ovaj odgovor hronicne faze je mnogo ozbiljniji i ima znacajno vise nivoe infiltriranja leukocita i sinergisticko povecanje u broju i aktivaciji eozinofila. Inflamacija zavisi od Th1 tipa imunog odgovora. Ova analiza dopusta identifikaciju da li jedinjenje pronalaska moze da umanje odgovor, odnosno, migraciju leukocita i klinicki relevantnu fiziologiju vazdusnog puta.
Dodatno gornjoj analizi, razliciti uzorci se sakupljaju iz proucavanja,
ukljucujuci BAL fluid i tkivo pluca, dalje analize se mogu sprovesti da utvrde nacin u kome jedinjenja pronalaska umanjuju odgovore. Specificno, citokin (IL-4, IL-5, IL10, IL-13, IL-18, TNF, IFN, itd.) nivoi u homogenatima BAL
fluida i tkiva pluca mogu biti analizirani, kao i nivoi peroksidaze histamina i eozinofila (videti Wu, W., et al.,Journal of Clinical Investigation(2000), Vol.
105, pp. 1455-1463).
Zivotinje:
Zenski C57/BL6 misevi su kupljeni od bilo The Jackson Laboratory^ (Bar Harbor, ME) ili Charles River Breeding Laboratories (Wilmington, MA) i odrzavaju se u standarnim od patogena oslobodenim uslovima. Svi materijali se dobijaju od Sigma Chemical Company (St. Louis, MO) osim ukoliko nije drugacije naznaceno.
Cinjenjeosetljivim i indukcija odgovora vazdusnog puta:
Normalni C57/BL6 misevi se imuniziraju sa 10j^ig alergena buba svabe (Bayer) u IFA na nulti dan. Da bi se lokalizovao odgovor na pluca, misevima se daju intranazalno 10 |ag alergena buba svabe u 10 u.L razredivaca na dan 14. Ovaj inicijalni intranazalni alergenom izaziva mali celularni infiltrat u pluca miseva posle histoloskog ispitivanja. Misevi se onda izazivaju 6 dana kasnije (ovde i nadalje primarni odgovor na izazov) putem intratrahealnog davanja 10 ug alergena buba svabe u 50 llL sterilnog PBS ili samo sa PBS
(tecni nosac). Magnituda regrutovanja leukocita u oba kontrolnom nosacu i misevima izazvanim sa alergenom buba svabe se ispituje histoloski. Samo misevi izazavani sa alergenom buba svabe pokazuju zanacajan inflamatorni odgovor koji ukljucuje infiltriranje mononuklearne celije i eozinofila. Nekim misevima je dato drugo intratrahealno ubrizgavanje bilo alergena buba svabe (10^g u 50 |aL) ili razredivac kao kontrola i potom su analizirani (sekundarni odgovor na ponovni izazov). U odvojenim proucavanjima,
dejstvo anti-murin MIP-1a i anti-murin eotaksin poliklonalnih antitela na odgovore izazvane sa alergenom buba svabe se procenjuju davanjem misevima koji su ucinjeni osetljivima i.p. doze antitela (0,5 mL, titri od 10<6>/mL) 1 sat pre svakog izazova alergenom. Normalni zecji serum (NRS)
se upotrebljava kao kontrola. Poliklonalna antitela su ranije demonstrirala da blokiraju hemoprenosenje murine eozinofilain vitro.
Merenje hiperaktivnosti vazdusnog puta:
Hiperaktivnost vazdusnog puta se meri upotrebom Buxco misjeg pletismografa, koji je specificno dizajniran za nisko plimske zapremine (Buxco) kako je to ranije opisano kod Lukacs, N.W., et al., J. Immunol.
(1992, Vol. 13, pp. 501. Ukratko, mis koji se testira se anestezira sa natrijum pentobarbitalom i inkubira putem traheje sa 18-metalnom cevi. Mise se potom ventilira sa Harvard pumpnim ventilatorom (plimska zapremina = 0,4 mL, fekvencija = 120 udisaja/min., pozitivni krajnji-izdisajni pritisak 2,5 do 3,0 cm H20 i repna vena se cannulated sa 27-gauge iglom za ubrizgavanje metaholin izazova. Pletismograf se zapecati i citanja se prate putem kompjutera. Posto je kutija zatvoreni sistem, promena u zapremini pluca je predstavljena promenom u pritisku u kutiji (Pkutjja), koji se meri diferencijalnim transduktorom. Sistem se kalibrira sa brizgalica koja isporucuje poznatu zapreminu od 2 mL. Drugi transduktor se upotrebljava da meri pritisak slobodnih tokova pri otvaranju traheja cevi (Paw), koja se odnosi na telo kutije (odnosno, pleuralni pritisak, i da obezbedi merenje transpulmonalnog pritiska (Ptp = Paw-Pkutija)- Transduktor traheje se kalibrira pri konstantnom pritisku od 20 cm H20. Otpor se izracunava Buxco-ovom softverom deljenjem promen u pritisku (Ptp) sa promenom u protoku (F)
(JPtp/JF; jedinice = cm H20/mL/s) u dve vremenske tacke od krive zapremine, bazirane na procentu udisajne zapremine. Kada se mis navuce na kutiju ona se ventilira 5 minuta pre dobijanja citanja. Kada se jednom osnovni nivoi stabilizuju i uzmu se inicijalna citanja, daje metaholin izazov preko repne vene sa kanila. Posle utvrdivanja krive doza-odgovor (0,001 do 0,5 mg), bira se optimalna doza (0,1 mg metaholina) koja se upotrebjava kroz ostatak eksperimenata u ovom proucavanju. Posle izazova metaholinom, odgovor se prati i vrh otpornosti vazdusnog puta se belezi kao mera hiperaktivnosti vazdusnog puta.
Jedinjenja pronalaska, kada se testiraju u gornjem ogledu, demonstriraju sposobnost da smenje otpornost vazdusnog puta na zivotinjskom modelu kod astme.
Kako je sadasnji pronalazak opisan u pogledu njegovih specificnih realizacija, treba da se razume od strane strucnjaka u ovoj oblasti nauke da razlicite promene moug biti ucinjenje i da ekvivalenti mogu biti zamenjeni bez napustanja istinskog duha i obima pronalaska. Dodatno, mnoge modifikacije mogu biti ucinjene da se prilagodi odredenoj situaciji, materijalu, sastavu koji je u pitanju, postupku, koraku ili koracima u postupku, u odnosu na predmet, duh i obim sadasnjeg pronalaska. Sve takve modifikacije su ukljucene u obim ovde navedenih zahteva.
1. Jedinjenje formule (I) ili formule (II):
jiaznaceno time, sto:
su svaki R<1>, R<2>iR<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(gde je t 1 ili 2) ili -N(R<7>)R8;ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu: (gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ili aril); svaki R<4>je -R<9->R<12>, -R9-R13-R11, -R<9->O-R<10->R<11>, -R<9->0-R<12>, -R<9->C(O)-R<10->R<11>, -R9-N(R7)-R10-R11, -R<9->S(O),-R<10->R<11>(gde je t 0 do 2), ili -R<9->C(F)2-R9-R11; svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija); svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, - C(S)R<7>, -C(0)OR<14>, -C(S)OR14, -C(0)N(R<7>)R<8>, ili -C(S)N(R<7>)R<8>; svaki R7 je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil; R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>, ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>); svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac; svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen; svaki R<11>je nazavisno -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol; R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>ili -C(0)N(R')2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija); R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i R14 je alkil, aril ili aralkil; kao jedinicni stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so. 2. Jedinjenje prema zahtevu 1 odabrano od formule (I):
, naznaceno time, sto:
su svaki R<1>, R2 i R<3>nezavisno halo, -OR<6>, -SR<6>, ili -N(R<7>)R<8>;
svaki R<4>je -R<9->R<12>, -R9-R13-R11, -R<9->O-R<l0->R<11>, -R<9->0-R<12>, -R<9->
C(O)-R<10->R<11>, -R<9>-N(R7)-R10-R1<1>, -R9-S(O),-R10-R11 (gde je t 0 do 2), ili -R<9>-
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo i haloalkoksija);
svaki R6 je nazavisno vodonik, alkil, aralkil, -0(O)R<7>, -C(0)OR<7>;.,
svaki R7 je nezavisno vodonik, alkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR7 ili -C(0)N(R<7>)2;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>ili -
C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen.
3. Jedinjenje prema zahtevu 2,naznaceno time,sto: '
su svaki R<1>, R2 i R<3>nezavisno halo, -OR<6>, ili -SR<6>;
svaki R4je-R9-O-R10-R11;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril ili aralkil;
svaki R<7>je nezavisno vodonik, alkil, aril, ili aralkil;
R<9>je direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac,
s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen; i
svaki R11 je -C(0)OR<7>ill -C(0)N(R<7>)2.
4. Jedinjenje prema zahtevu 3,naznaceno time,sto:
svaki R<1>, R2 i R3je -OR6; R<4>je-R<9->O-R<l0->R<11>; R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila, haloalkoksija); R6 je vodonik, alkil, aril ili aralkil; svaki R<7>je nezavisno vodonik, alkil, aril, ili aralkil; R9 je direktna veza; R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac; i 5. Jedinjenje prema zahtevu 4, naznaceno time, sto je odabrano od grupe koja se sastoji od sledeceg: (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina, metil estar; i (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksa-7,9,11,13-heksadekatetraenska kiselina. 6. Jedinjenje prema zahtevu 1 odabrano od formule (II):
. naznaceno time, sto:
su svakiR1, R2 i R<3>nezavisno halo, -OR<6>, -SR<6>, ili -N(R<7>)R<8>;
svaki R<4>je -R<9->R<12>, -R9-R13-R11, -R9-O-R10-R11, -R<9->0-R<12>, -R<9->
C(O)-R10-R11, -R9-N(R7)-R10-R11, -R<9->S(O)t-R<10->R<11>(gde je t 0 do 2), ili -R<9->
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R6 je nazavisno vodonik, alkil, aralkil, -C(O) R<7>ili -
C(0)OR<7>;
svaki R7 je nezavisno vodonik, alkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>ili -C(0)N(R<7>)2;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>ili -
C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen.
7. Jedinjenje prema zahtevu 6,naznaceno time,sto:
su svakiR1, R2 iR<3>nezavisno halo, -OR<6>ili -SR<6>;
R4je _R9_O-R10-R11;
R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril ili aralkil;
svaki R7 je nezavisno vodonik, alkil, aril, ili aralkil;
R<9>je direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen; i
8. Jedinjenje prema zahtevu 7, naznaceno time, sto:
svaki R<1>, R2 i R<3>je-OR<6>;
R4je -R9-O-R10-R11;
R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, i haloalkoksija;
R<6>je vodonik, alkil, aril, ili aralkil;
svaki R7 je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R9 je direktna veza;
R<10>je s lancem u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac; i
9. Jedinjenje prema zahtevu 8,naznaceno time,sto je odabrano od grupe koja se sastoji od sledeceg: (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15'trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar; (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien 11-inska kiselina; (5S,6S,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina, metil estar; i (5S,6S,7E,9E,11Z,13E,15S)-16-(4-fluorofenoksi)-5,6,15-trihidroksi-3-oksaheksadeka-7,9,13-trien-11-inska kiselina. 10. Farmaceutski sastav koristan u lecenju inflamatornog i autoimunog poremecaja kod sisara,naznacen time,sto se sastoji od jednog ili vise farmaceutski prihvatljivih inertnih punilaca i terapeutski efikasne kolicine jedinjenja formule (I) ili formule (II):
pri cemu:
su svakiR<1>,R<2>iR<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(gde je t 1 ili 2) ili -N(R7)R8; ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu:
(gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ili aril);
svaki R<4>je -R<9->R<12>, -R<9->R<13->R<11>, -R9-O-R10-R11, -R<9->0-R<12>, -R<9->'
C(O)-R<10->R<11>, -R<9>-N(R7)-R10-R1<1>, -R<9->S(O)t-R<10->R" (gde je t 0 do 2), ili -R<9->
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, -
C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, ili -C(S)N(R<7>)R<8>;
svaki R<7>je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>,
ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, ,
S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>
ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i
R14 je alkil, aril ili aralkil;
kao jedan stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so.
11. Farmaceutski sastav prema zahtevu 10, naznacen time, sto je sisar covek. 12. Farmaceutski sastav koristan u lecenju inflamacije pulmonalnog ili respiratornog trakta kod sisara,naznacen time,sto se sastoji od jednog ili vise farmaceutski prihvatljivih inertnih punilaca i terapeutski efikasne kolicine jedinjenja formule (I) ili formule (II):
pri cemu:
su svakiR1,R<2>iR<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(gde je t 1 ili 2) ili -N(R<7>)R8;ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu:
(gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ili aril);
svaki R<4>je -R<9->R<12>, -R9-R13-R11, -R<9->O-R<10->R<11>, -R<9->0-R<12>, -R<9->
C(O)-R<10->R<11>, -R9-N(R7)-R10-R11, -R<9->S(O)t-R<10->R<11>(gde je t 0 do 2), ili -R<9->
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, -
C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, ili -C(S)N(R<7>)R<8>;
svaki R<7>je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>,
ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(O)OR');
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, -
S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>
ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i
R<14>je alkil, aril ili aralkil;
kao jedan stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so.
13. Farmaceutski sastava prema zahtevu 12, naznacen time, sto je sisar covek. 14. Postupak lecenja inflamatornog ili autoimunog poremecaja kod sisara,naznacen time,sto se sastoji od davanja sisaru kome je neophodno terapeutski efikasne kolicine jedinjenja formule (I) ili formule (II):
pri cemu:
su svakiR<1>,R<2>i R<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(gde je t 1 ili 2) ili -N(R7)R8; ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu:
(gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ili aril);
svaki R<4>je -R<9->R<12>, -R9-R13-R11, -R9-O-R10-R11, -R<9->0-R<12>, -R<9->
C(O)-R<10->R<11>, -R<9->N(R<7>)-R<10->R<11>, -R9-S(O)rR10-R11 (gde je t 0 do 2), ili -R<9->
C(F)2-R9-R11;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, -
C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, ili -C(S)N(R7)R8;
svaki R7 je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>,
ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R11 je nazavisno -C(0)OR<7>, -C(0)N(R7)2, -P(0)(OR7)2> t S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>
ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i
R<14>je alkil, aril ili aralkil;
kao jedan stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so.
15. Postupak prema zahtevu 14,naznacen time,sto je sisar covek.
16. Postupak prema zahtevu 15,naznacen time,sto je inflamatorni ili autoimuni poremecaj odabran od grupe koja se sastoji od sledeceg: alergijski kontaktni dermatitis, alergijski rinitis, hemijski i ne-specificno iritantni kontaktni dermatitis, urtikarija, atopicni dermatitis, psorijaza, akutna miokardijalna ishemija i infarkt, akutni hemoragicni ili ishemicni mozdani udar, skleroza multipleks, reumatoidni artritis, osteoartritis i sistemski lupus erythematosus, akutno i hronicno odbacivanje transplantiranog organa,
transplant arterioskleroze i fibroze, kardiovaskularni poremecaji ukljucujuci hipertenziju, aterosklerozu, aneurizmu, kriticna ishemija noge, periferna arterijska okulzivna bolest i Reynaud-ov sindrom, dijabetska nefropatija,
dijabetska neuropatija i dijabetska retinopatija, odlozena neurodegeneracija kod mozdanog udara, Alzheimer-ova bolest, Parkinskon-ova bolest, benigna hiperplazija prostate, leukemija, limfoma, kancer prostate, kancer dojke,
kancer pluca, maligni melanom, renalni karcinom, tumori glave i vrata i kolorektalni kancer.
17. Postupak lecenja inflamacije pulmonalnog ili respiratornog trakta kod sisara,naznacen time,sto se postupak sastoji od davanja sisaru kome je neophodno terapeutski efiksane kolicine jedinjenja formule (I) ili (II):
pri cemu:
su svakiR<1>, R2 i R<3>nezavisno halo, -OR<6>, -SR<6>, -S(0)tR<7>(<g>de je 11 ili 2) ili -N(R7)R8; ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju monociklicnu heterociklicnu strukturu odabranu od sledeceg: ili R<1>i R<2>zajedno sa ugljenicima na koje su zakaceni formiraju sledecu biciklicnu heterociklicnu strukturu:
(gde je q 0 do 3, p je 1 do 4 a svaki R<15>je vodonik, alkil, aralkil ili aril);
svaki R<4>je -R<9->R<12>,-R<9->R<13->R<11>, -R<9->O-R<10->R<11>, -R<9->0-R<12>, -R<9->
C(O)-R10-R11, -R<9->N(R<7>)-R<10->R<11>, -R<9->S(O)t-R<10->R<11>(gde je t 0 do 2), ili -R<9->
C(F)2-R<9->R<11>;
svaki R<5>je aril (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila, haloalkoksija) ili aralkil (opciono supstituisan sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo,
haloalkila i haloalkoksija);
svaki R<6>je nazavisno vodonik, alkil, aril, aralkil, -C(0)OR<7>, -
C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, ili -C(S)N(R<7>)R<8>;
svaki R<7>je nezavisno vodonik, alkil, cikloalkil, aril, ili aralkil;
R<8>je nazavisno vodonik, alkil, aril, aralkil, -C(0)R<7>, -C(0)OR<14>,
ili cikloalkil (opciono supstituisan sa jednim ili vise supstituenata odabaranih iz grupe koja se sastoji od alkila, -N(R<7>)2, i -C(0)OR<7>);
svaki R<9>je nazavisno direktna veza ili sa lancem u normalnom nizu ili racavasti alkilen lanac;
svaki R<10>je nazavisno s lance u normalnom nizu ili racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac, s lancem u normalnom nizu ili racvasti alkinilen lanac ili cikloalkilen;
svaki R<11>je nazavisno -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, -
S(0)2OR<7>, -S(0)2N(H)R<7>ili tetrazol;
R<12>je aril (supstituisan sa -C(0)OR<7>ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila,
alkoksija, halo, haloalkila i haloalkoksija) ili aralkil (supstituisan sa -C(0)OR<7>
ili -C(0)N(R<7>)2i opciono sa jednim ili vise supstituenata odabranih iz grupe koja se sastoji od alkila, alkoksija, halo, haloalkila i haloalkoksija);
R<13>je racvasti alkilen lanac, s lancem u normalnom nizu ili racvasti alkenilen lanac ili cikloalkilen; i
R14 je alkil, aril ili aralkil;
kao jedan stereoizomer, smesa stereoizomera, racemska smesa stereoizomera; ili kao njegov ciklodekstrin klatrat, ili kao njegova farmaceutski prihvatljiva so.
18. Postupak prema zahtevu 17,naznacen time,sto je sisar covek.
19. Postupak prema zahtevu 15,naznacen time,sto je inflamatorni i autoimuni poremecaj odabran iz grupe koja se sastoji od sledeceg: septicki ili endotoksicni sok, hemoragicni sok, sindromi slicni soku, sindromi curenja kapilara izazvani imunoterapijom kancera, akutni respiratorni sindrom bola, traumatski sok, imuno- i patogeno-izazvane pneumonije, imuna kompleksom-posredovana pulmonalna povreda, imuna kompleksom-posredovana hronicna obstruktivna polmonalna bolest, inflamatorne bolesti utrobe, akutni renalni pad, ishemicna bolest utrobe, imuno-kompleksom-posredovani glomerulonefritis , diabetis mellitus zavisan od insulina, okularni poremecaji, HIV demencija, encefalitis, inflamatorni i neuropatski bol.periodontalna bolest, i infekcije uha. 20. Postupak prema zahtevu 19,naznacen time,sto je inflamatorni ili autoimuni poremecaj inflamatorna bolest utrobe odabrana od grupe koja se sastoji od Crohn-ove bolesti, ulcerativnog kolitisa i gastrointestinalnih cireva. 21. Postupak prema zahtevu 20, naznacen time, sto je inflamatorni ili autoimuni poremecaj Crohn-ova bolest.
BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to lipoxin A4analogs, their use in treating inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation, and pharmaceutical compositions containing the analogs and processes for their preparation.
Description of the Related Art
Lipoxins, together with leukotrienes, prostaglandins, and thromboxanes, constitute a group of biologically active oxygenated fatty acids collectively referred to as the eicosanoids. Eicosanoids are all synthesised de novo from membrane phospholipid via the arachidonic acid cascade of enzymes. Since their initial discovery in 1984, it has become apparent that lipoxins, which are a structurally unique class of eicosanoids, possess potent anti-inflammatory properties that suggest they may have therapeutic potential (Serhan, C.N.,Prostaglandins(1997), Vol. 53, pp. 107-137; O'Meara, Y.M.et al, Kidney Int. ( Suppl.)(1997), Vol. 58, pp. S56-S61; Brady, H.R.et al, Curr. Opin. Nephrol. Hypertens.(1996), Vol. 5, pp. 20-27; and Serhan, C.N.,Biochem. Biophys. Acta.(1994), Vol. 1212, pp. 1-25). Of particular interest is the ability of lipoxins to antagonise the pro-inflammatory functions of leukotrienes in addition to other inflammatory agents such as platelet activating factor, FMLP, immune complexes and TNFa. Lipoxins are thus potent anti-neutrophil (PMN) agents which inhibit PMN chemotaxis, homotypic aggregation, adhesion, migration across endothelial and epithelial cells, margination/diapedesis and tissue infiltration (Lee, T. H.,et al, Clin. Sci.(1989), Vol. 77, pp. 195-203; Fiore, S.,et al, Biochemistry(1995), Vol. 34, pp. 16678-16686; Papyianni, A.,et al, J. Immunol.(1996), Vol. 56, pp. 2264-2272; Hedqvist, P.,et al, Acta. Physiol. Scand.(1989), Vol. 137, pp. 157-572; Papyianni, A.,et al, Kidney Intl.(1995), Vol. 47, pp. 1295-1302). In addition, lipoxins are able to down-regulate endothelial P-selectin expression and adhesiveness for PMNs (Papyianni, A.,et al, J. Immunol(1996), Vol. 56, pp. 2264-2272), bronchial and vascular smooth muscle contraction, mesangial cell contraction and adhesiveness (Dahlen, S.E.,et al, Adv. Exp. Med. Biol.(1988), Vo.. 229, pp. 107-130; Christie, P.E.,et al, Am. Rev. Respir. Dis.(1992), Vol. 145, pp. 1281-1284; Badr,.K.F.,et al, Proc.
Natl. Acad. Sci.(1989), Vol. 86, pp. 3438-3442; and Brady, H.R.,et al., Am. J. Physiol.
(1990), Vol. 259, pp. F809-F815) and eosinophil chemotaxis and degranulation (Soyombo, 0.,et al, Allergy(1994), Vol. 49, pp. 230-234).
This unique anti-inlfammatory profile of lipoxins, particularly lipoxin A4, has prompted interest in exploiting their potential as therapeutics for the treatment of inflammatory or autoimmune disorders and pulmonary and respiratory tract inflammation. Such disorders and inflammation which exhibit a pronounced inflammatory infiltrate are of particular interest and include dermatologic diseases, such as psoriasis, and rheumatoid arthritis, and respiratory disorders, such as asthma.
As with other endogenous eicosanoids, naturally occurring lipoxins are unstable products which are rapidly metabolized and inactivated (Serhan, C.N.,Prostaglandins(1997), Vol. 53, pp. 107-137). This has limited the development of the lipoxin field of research, particularly with respect to in vivo pharmacological assessment of the anti-inflammatory profile of lipoxins. Several U.S. Patents have issued directed to compounds having the active site of lipoxin A4, but with a longer tissue half-life. See,e. g.,U.S. Patent Nos. 5,441,951 and 5,648,512, the disclosures of which are incorporated in full by reference herein. These compounds retain lipoxin A4receptor binding activity and the potent in vitro and in vivo anti-inflammatory properties of natural lipoxins (Takano, T.,et al,J. Clin. Invest.(1998), Vol. 101, pp. 819-826; Scalia, R.,et al,Proc. Natl. Acad. Sci. (1997), Vol. 94, pp. 9967-9972; Takano, T.,et al., J. Exp. Med.(1997), Vol. 185, pp. 1693-1704; Maddox, J.F.,et al,J. Biol. Chem. (1997), Vol. 272, pp. 6972-6978; Serhan, C.N.,etal, Biochemistry (1995),Vol. 34, pp. 14609-14615).
All of the references cited herein, including published patent applications and journal articles, are incorporated in full by reference herein.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to potent, selective and metabolically/chemically stable lipoxin A4analogs and their use in treating inflammatory or autoimmune disorders and pulmonary or respiratory tract inflammation in mammals, particularly humans.
In one aspect, the invention is directed to compound of formula (I) or formula (II):
wherein:
each R<1>, R<2>and R<3>are independently halo, -OR<6>, -SR<6>, -S(0)tR<7>(where t is 1 or 2) or -N(R<7>)R<8>; or R<1>and R<2>together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following: or R<1>and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R9-R12, -R9-R,3-Rn, -R9-O-R,0-R", -R<9->0-R<12>, -R9-C(O)-R10-R", -R<9->N(R<7>)-R<10->R", -R^S^t-R^-R<11>(where t is 0 to 2), or -R9-C(F)2-R9-R";
each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or
aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>,
-C(S)R<7>,-C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, or -C(S)N(R<7>)R<8>; each R<7>is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R" is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, -S(0)2OR<7>, -S(0)2N(H)R7 or tetrazole;
R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and
R<14>is alkyl, aryl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
In another aspect, this invention is directed to pharmaceutical compositions useful in treating an inflammatory or autoimmune disorder in a mammal, particularly a human, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II) as described above.
In another aspect, this invention is directed to pharmaceutical compositions useful in treating pulmonary or respiratory tract inflammation in a mammal, particularly a human, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II) as described above.
In another aspect, this invention is directed to methods of treating an inflammatory or autoimmune disorder in a mammal, particularly a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) or (II) as described above.
In another aspect, this invention is directed to methods of treating pulmonary or respiratory tract inflammation in a mammal, wherein the method comprises adminstering to a mammal, particularly a human, in need thereof, a therapeutically effective amount of a compound of formula (I) or formula (II):
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
As used herein the singular forms "a", "and", and "the" include plural treferents unless the context clearly dictates otherwise. For example, "a compound" refers to one or more of such compounds, while "the enzyme" includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art. Furthermore, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond,e. g.,methyl, ethyl, H-propyl, 1-methylethyl (/so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (/-butyl), and the like. Unless stated otherwise specifically in the specification, the alkyl radical may be optionally substituted by one or more substituents selected from the group consisting of cyano, nitro, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)0R<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0)t0R<6>(where t is 0 to 2), -R<9->S(0)tR<6>(where t is 0 to 2), -R<9->S(0),N(R<6>)2(where t is 0 to 2) where each R<6>and R<9>is as defined above in the Summary of the Invention and each R<16>is hydrogen, alkyl or aralkyl. Unless stated otherwise specifically in the specification, it is understood that such substitution can occur on any carbon of the alkyl group. "Alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. "Alkenyl" refers to a straight or branched monovalent hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, the alkenyl radical may be optionally substituted by one or more substituents selected from the group consisting of cyano, nitro, -R<9->OR<6>, -R9-N=N-0-R16, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0)tOR<6>(where t is 0 to 2), -R<9->S(0)tR<6>(where t is 0 to 2), -R<9->S(0)tN(R<6>)2(where t is 0 to 2) where each R<6>and R<9>is as defined above in the Summary of the Invention and each R<16>is hydrogen, alkyl or aralkyl. Unless stated otherwise specifically in the specification, it is understood that such substitution can occur on any carbon of the alkenyl group. "Alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one double bond and having from two to eight carbon atoms, e.g., ethenylene, prop-l-enylene, but-l-enylene, pent-l-enylene, hexa-l,4-dienylene, and the like. "Alkynyl" refers to a straight or branched monovalent hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, prop-l-ynyl, but-l-ynyl, pent-l-ynyl, pent-3-ynyl, and the like. Unless stated otherwise specifically in the specification, the alkynyl radical may be optionally substituted by one or more substituents selected from the group consisting of cyano, nitro, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0),OR<6>(where t is 0 to 2), -R<9->S(0),R<6>(where t is 0 to 2), -R<9->S(0)tN(R<6>)2(where t is 0 to 2) where each R<6>and R<9>is as defined above in the Summary of the Invention and each R<16>is hydrogen, alkyl or aralkyl. Unless stated otherwise specifically in the specification, it is understood that for radicals, as defined below, that contain a substituted alkynyl group that the substitution can occur on any carbon of the alkynyl group.
"Alkynylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to eight carbon atoms, e.g., ethynylene, prop-l-ynylene, but-1-ynylene, pent-3-ynyIene, hexa-1,4-diynylene, and the like.
"Alkoxy" refers to a radical of the formula -ORawhere Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
"Amino" refers to the -NH2radical.
"Aryl" refers to a phenyl or naphthyl radical. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals which may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, cycloalkyl, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R<9->N(R<6>)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R9-N(R6)C(0)OR16, -R<9->N(R<6>)C(0)R<6>, -R<9->S(0)tOR<6>(where t is 0 to 2), -R9-S(0)tR6 (where t is 0 to 2), -R<9->S(0)tN(R<6>)2(where t is 0 to 2) where each R<6>and R<9>is as defined above in the Summary of the Invention and each R<16>is hydrogen, alkyl or aralkyl. Unless stated otherwise specifically in the specification, it is understood that such substitution can occur on any carbon of the aryl group.
"Aralkyl" refers to a radical of the formula -RaRbwhere Ra is an alkyl radical as defined above and Rb is an aryl radical as defined above, e.g., benzyl, and the like. The aryl radical may be optionally substituted as described above.
"Carboxy" refers to the -C(0)OH radical.
As used herein, compounds which are "commercially available" may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc.
(Toronto, Canada), Bionet (Cornwall, U.K.),Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co.
(Rockford IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc.
(Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA).
As used herein, "methods known to one of ordinary skill in the art" may be identified though various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present invention, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandleret al,"Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Specific and analogus reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., www.acs.org may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses( e. g.,those listed above) provide custom synthesis services.
As used herein, "suitable conditions" for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry. The reference books and treatise set forth above that detail the synthesis of reactants useful in the preparation of compounds of the present invention, will also provide suitable conditions for carrying out a synthetic step according to the present invention.
"Clathrates" as used herein refers to substances which fix gases, liquids or compounds as inclusion complexes so that the complex may be handled in solid form and the included constituent (or "guest" molecule) subsequently releases by the action of a solvent or by melting. The term "clathrate" is used interchangeably herein with the phrase "inclusion molecule" or with the phrase "inclusion complex". Clathrates used in the instant invention are prepared from cyclodextrins. Cyclodextrins are widely known as having the ability to form clathrates( i. e.,inclusion compounds) with a variety of molecules. See, for example,Inclusion Compounds,edited by J.L. Atwood, J.E.D. Davies, and D.D. MacNicol, London, Orlando, Academic Press, 1984; Goldberg, I., "The Significance of Molecular Type, Shape and Complementarity in Clathrate Inclusion",Topics in Current Chemistry(1988), Vol. 149, pp. 2-44; Weber, E.et al,"Functional Group Assisted Clathrate Formation - Scissor-Like and Roof-Shaped Host Molecules",Topics in Current Chemistry(1988), Vol. 149, pp. 45-135; and MacNicol, D.D.et al.,"Clathrates and Molecular Inclusion Phenomena",Chemical Society Reviews(1978), Vol. 7, No. 1, pp. 65-87. Conversion into cyclodextrin clathrates is known to increase the stability and solubility of certain compounds, thereby facilitating
their use as pharmaceutical agents. See, for example, Saenger, W., "Cyclodextrin Inclusion Compounds in Research and Industry",Angew. Chem. Int. Ed. Engl. (1980),Vol. 19, pp. 344-362; U.S. Patent No. 4,886,788 (Schering AG); U.S. Patent No. 6,355,627 (Takasago); U.S. Patent No. 6,288,119 (Ono Pharmaceuticals); U.S. Patent No. 6,110,969 (Ono Pharmaceuticals); U.S. Patent No. 6,235,780 (Ono Pharmaceuticals); U.S. Patent No. 6,262,293 (Ono Pharmaceuticals); U.S. Patent No. 6,225,347 (Ono Pharmaceuticals); and U.S. Patent No. 4,935,446 (Ono Pharmaceuticals).
"Cyclodextrin" refers to cyclic oligosaccharides consisting of at least six glucopyranose units which are joined together by a(l-4) linkages. The oligosaccharide ring forms a torus with the primary hydroxyl groups of the glucose residues lying on the narrow end of the torus. The secondary glucopyranose hydroxyl groups are located on the wider end. Cyclodextrins have been shown to form inclusion complexes with hydrophobic molecules in aqueous solutions by binding the molecules into their cavities. The formation of such complexes protects the "guest" molecule from loss of evaporation, from attack by oxygen, visible and ultraviolet light and from intra- and intermolecular reactions. Such complexes also serve to "fix" a volatile material until the complex encounters a warm moist environment, at which point the complex will dissolve and dissociate into the guest molecule and the cyclodextrin. For purposes of this inveniton, the six-glucose unit containing cyclodextrin is specified as a-cyclodextrin, while the cyclodextrins with seven and eight glucose residues are designated as p-cyclodextrin and y-cyclodextrin, respectively. The most common alternative to the cyclodextrin nomenclature is the naming of these compounds as cycloamyloses.
"Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, -R<9->OR<6>, -R<9->N=N-0-R<16>, -R9-N(R6)2, -R<9->C(0)R<6>, -R<9->C(0)OR<6>, -R<9->C(0)N(R<6>)2, -R<9->N(R<6>)C(0)OR<16>, -R<9->N(R<6>)C(0)R<6>, -R9-S(0),OR6 (where t is 0 to 2), -R<9->S(0)tR<6>(where t is 0 to 2), -R<9->S(0)tN(R<6>)2(where t is 0 to 2) where each R<6>and R<9>is as defined above in the Summary of the Invention and each R<16>is hydrogen,
alkyl or aralkyl. Unless stated otherwise specifically in the specification, it is understood that such substitution can occur on any carbon of the cycloalkyl group.
"Cycloalkylene" refers to a stable divalent monocyclic or bicyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by two single bonds, e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, decalinylene and the like. Unless otherwise stated specifically in the specification, the term "cycloalkylene" is meant to include cycloalkylene moieties which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, amino, and carboxy.
"Halo" refers to bromo, chloro, iodo or fluoro.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
"Haloalkoxy" refers to a radical of the formula -ORcwhere Rc is an haloalkyl radical as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1 -fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, l-bromomethyl-2-bromoethoxy, and the like.
"Mammal" includes humans and domesticated animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
"Pharmaceutically acceptable salt" includes both acid and base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred"-inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
"Prodrugs" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is convertedin vivoto an active compound of the invention. Prodrugs are typically rapidly transformedin vivoto yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H.,Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T.,et al,"Pro-drugs as Novel Delivery Systems,"A. C. S. Symposium Series,Vol. 14, and inBioreversible Carriers in Drug Design,ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound of the inventionin vivowhen such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation orin vivo,to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention and the like.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
"Therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, particularly a human, in need thereof, is sufficient to effect treatment, as defined below, for inflammatory or autoimmune disorders or pulmonary or respiratory tract inflammation. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the inflammatory or autoimmune disorder, or pulmonary or respiratory tract inflammation, and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein covers the treatment of a inflammatory or autoimmune disorder in a mammal, preferably a human, or the treatment of a pulmonary or respiratory tract inflammation in a mammal, preferably a human, and includes:
(i) preventing the disorder or inflammation from occurring in a mammal, in particular, when such mammal is predisposed to the disorder but has not yet been diagnosed as having it; (ii) inhibiting the disorder or inflammation, i.e., arresting its development; or (iii) relieving the disorder or inflammation, i.e., causing regression of the disorder or inflammation.
The compounds of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as(/?)-or ( S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active( R)-and ( S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include bothEand Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
The nomenclature used herein is a modified form of the I.U.P.A.C. nomenclature system wherein the compounds of the invention are named herein as derivatives of the hexadecanoic moiety. For example, the following compound of formula (I) where R<1>, R2 and R<3>are each -OR6 (where R<6>is hydrogen); R<4>is -R9-0-R10-R11 (where R9 is a direct bond, R<10>is methylene and R11 is -C(O)OH); and R<5>is phenyl substituted at the 4-position by fluoro,i. e.,
is named herein as( 5S, 6R, 7E, 9E,\lZ,13£,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,l 1,13-hexadecatetraenoic acid. Unless otherwise indicated by the nomenclature, compound names are intended to include any single stereoisomer, enantiomer, racemate or mixtures thereof.
For purposes of this disclosure, in those compounds of the invention wherein R<1>and R<2>together with the carbons to which they are attached form the the following heterocyclic structures: it is understood that the structures include the following reverse structures:
B. Utility of the Compounds of the Invention
The compounds of the invention are lipoxin A4analogs that have similar biological activity of natural lipoxin A4, but with an enhanced resistance to metabolic degradation. Accordingly, the compounds of the invention are useful in treating inflammatory or autoimmune disorders in mammals, particularly in humans. In particular, the compounds of the invention are useful in inhibiting acute or chronic inflammation or an inflammatory or autoimmune response that is mediated by neutrophils, eosinophils, T lymphocytes, NK cells or other immune cells which contribute to the pathogenesis of inflammatory, immune or autoimmune diseases. The compounds are also useful in the treatment of proliferative disorders including, but not limited to, those associated with derangements in the inflammatory or immune response, such as cancer. The compounds are also useful as inhibitors of angiogenic responses in the pathogenesis of cancer.
Accordingly, the compounds can be used to treat the following inflammatory or autoimmune disorders in mammals, particularly humans: anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases including ulcerative colitis, Crohn's disease and post-surgical trauma, gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury including acute myocardial ischemia and infarction, acute renal failure, ischemic bowel disease and acute hemorrhagic or ischemic stroke, immune-complex-mediated glomerulonephritis, autoimmune diseases including insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus, acute and chronic organ transplant rejection, transplant arteriosclerosis and fibrosis, cardiovascular disorders including hypertension, atherosclerosis, aneurysm, critical leg ischemia, peripheral arterial occlusive disease and Reynaud's syndrome, complications of diabetes including diabetic nephropathy, neuropathy and retinopathy, ocular disorders including macular degeneration and glaucoma, neurodegenerative disorders including delayed neurodegeneration in stroke, Alzheimer's disease, Parkinson's disease, encephalitis and HIV dementia, inflammatory and neuropathic pain, including arthritic pain, periodontal disease including gingivitis, ear infections, migraine, benign prostatic hyperplasia, cancers including, but not limited to, leukemias and lymphomas, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer.
The compounds are also useful in treating folliculitis induced by inhibitors of epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) kinase used in the treatment of solid tumors. Clinical trials have revealed folliculitis (inflammation of the hair follicle manifested by severe acne-like skin rash on the face, chest and upper back) as a major dose-limiting side effect of such treatments. Such folliculitis is associated with an infiltraiton of neutrophils suggesting products secreted by activated neutrophils to be the cause of the inflammation. The lipoxin A4analogs of the instant invention inhibit neutrophil or eosinophil-mediated inflammation, and are therefore useful in treating such folliculitis, thereby improving the quality of life of the treated cancer patients but also allowing for the increase of the dosage of the EGF inhibitor or EGFR kinase inhibitor or the extension of the duration of the treatment, resulting in improved efficacy of the desired inhibitor.
The compounds are also useful in the treatment of pulmonary and respiratory inflammation, including, but not limited to, asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans (including such with organizing pneumonia), allergic inflammation of the respiratory tract (including rhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lungcharacterized byeosinophil infiltration.
For example, the compounds of the invention are useful in the inhibition of: eosinophil-mediated inflammation of the lung or tissues; neutrophil-mediated inflammation of the lung; lymphocyte-mediated inflammation of the lung; cytokine and chemokine production, including interleukin-5, interleukin-13 and eotaxin; lipid mediator generation, including prostaglandin E2and cysteinyl leukotrienes; airway hyper-responsiveness; and airway and vascular inflammation.
C. Testing of the Compounds of the Invention
A hallmark of inflammation is the adhesion and transmigration across endothelium of neutrophils, eosinophils and other inflammatory cells. A similar process is observed for the migration of cells across polarized epithelial cells that occur in the lung, gastrointestinal tract and other organs. Cell culture models of these processes are available and have been used to show that lipoxin A4and stable lipoxin A4analogs inhibit the transmigration of human neutrophils across human endothelial cells and epithelial cells, including the human intestinal epithelial cell line T84. Accordingly, one of ordinary skill in the art can test the compounds of the invention for their ability to inhibit the transmigration of human neutrophils and eosinophils across human endothelial cells and epithelial cells by performing assays similar to those described in Colgan, S.P.,et al, J. Clin. Invest.(1993), Vol. 92, No. 1, pp. 75-82 and Serhan, C.N.,et al, Biochemistry (1995),Vol. 34, No. 44, pp. 14609-14615.
The air pouch model and/or the mouse zymosan-induced peritonitis model may be used to evaluate thein vivoefficacy of the compounds of the invention in treating an inflammatory response. These are acute experimental models of inflammationcharacterized byinfiltration of inflammatory cells into a localized area. See,e. g.,thein vivoassays described in Ajuebor, M.N.,et al, Immunology(1998), Vol. 95, pp. 625-630; Gronert, K.,et al, Am. J. Pathol.(2001), Vol. 158, pp. 3-9; Pouliot, M.,et al, Biochemistry(2000), Vol. 39. pp. 4761-4768; Clish, C.B.,et al, Proc. Natl. Acad Sci. U. S. A.(1999), Vol. 96, pp. 8247-8252; and Hachicha, M.,et al, J. Exp. Med.
(1999), Vol. 189, pp. 1923-30.
Animal models( i. e., in vivoassays) may also be utilized to determine the efficacy of the compounds of the invention in treating asthma and related disorders of the pulmonary and respiratory tract, including, but not limited to, asthma. See,e. g.,the assays described in De Sanctis, G.T.et al, Journal of Clinical Investigation (1999),Vol. 103, pp. 507-515 and Campbell, E.M.,et al., J. Immunol.(1998), Vol.161, No. 12, pp. 7047-7053.
D. Administration of the Compounds of the Invention
Administration of a compound of the invention, as a single stereoisomers, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, pulmonary, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, patches, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 0.1% to about 99.9% by weight of a compound(s) of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, and 99.9% to 1.0% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75%o by weight of a compound(s) of the invention, or as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, is formed by the incorporation of one or more of the normally employed pharmaceutically acceptable excipient(s), such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or
tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50%o active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, and optional pharmaceutical acceptable adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, for treatment of a disease-statecharacterized byinflammation in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
E. Preferred Embodiments
Of the compounds of the invention as set forth above in the Summary of the Invention, several groups of compounds are particularly preferred.
Accordingly, a preferred group of compounds of the invention are those compounds of formula (I):
wherein:
R1, R2 and R<3>are each independently halo, -OR<6>, -SR6 or -N(R<7>)R<8>; each R<4>is -R9-R12, -R9-R13-Rn, -R<9>-O-R<10>-Rn, -R<9->0-R<12>, -R<9->C(O)-R<10->R", -R<9->N(R<7>)-R<10->R", -R<9->S(O)rR<10>-R<M>(where t is 0 to 2), or - R<9->C(F)2-R<9->R";
R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
each R<6>is independently hydrogen, alkyl, aralkyl, -C(0)R<7>or -C(0)OR7;
each R<7>is independently hydrogen, alkyl, aryl, or aralkyl;
R<8>is independently hydrogen, alkyl, aryl, aralkyl, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>);
each R<9>is independently a direct bond or a straight or branched alkylene chain;
each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
each R<11>is independently -C(0)OR<7>or -C(0)N(R<7>)2;
R1<2>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy);
R is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene.
Of this group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: R<1>, R2 and R3 are each independently halo, -OR<6>, or -SR<6>; R4 is-R9-O-Rl0-R";
R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
each R6 is independently hydrogen, alkyl, aryl, or aralkyl;
each R7 is independently hydrogen, alkyl, aryl, or aralkyl;
R<9>is a direct bond or a straight or branched alkylene chain;
R<10>is an straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; and R'1 is -C(0)OR7 or -C(0)N(R<7>)2.
Of this subgroup of compounds, a preferred class of compounds is that class of compounds wherein: R<1>, R<2>and R<3>are each -OR6;
R4 is -R9-O-R10-Ru;
R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
R<6>is hydrogen, alkyl, aryl, or aralkyl;
each R7 is independently hydrogen, alkyl, aryl, or aralkyl;
R<9>is a direct bond;
R<10>is a straight or branched alkylene chain, a straight or branched alkenylene chain, or a straight or branched alkynylene chain; and
R<11>is -C(0)OR<7>or -C(0)N(R<7>)2.
Of this class of compounds, preferred compounds are selected from the group consisting of the following compounds:( 5S, 6RJE, 9E, 11Z, 1 3E, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester; and
(55,6/?,7£,9£,llZ,13E,155')-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid.
Another preferred group of compounds of the invention is that group of compounds of formula (II):
wherein:
R<1>, R2 and R<3>are each independently halo, -OR<6>, -SR<6>or -N(R<7>)R<8>; each R<4>is -R9-R12, -R<9->R<l3>-Rn, -R<9>-O-R<10->R'-R9-0-R1<2>, -R9-C(O)-R,0-Rn, -R9-N(R7)-R10-Rn, -R<9->S(O)rR<10>-R<u>(where t is 0 to 2), or - R9-C(F)2-R9-R";
R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
each R<6>is independently hydrogen, alkyl, aralkyl, -C(0)R<7>or -C(0)OR<7>;
each R<7>is independently hydrogen, alkyl, aryl, or aralkyl;
R<8>is independently hydrogen, alkyl, aryl, aralkyl, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>);
each R<9>is independently a direct bond or a straight or branched alkylene chain;
each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
each R<11>is independently -C(0)OR<7>or -C(0)N(R<7>)2;
R<12>is aryl (substituted by -C(0)OR7 or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy);
R is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene.
Of this group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: R<1>, R2 and R3 are each independently halo, -OR<6>, or -SR<6>;
R4is-R9-O-Rl0-Rn;
R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
each R<6>is independently hydrogen, alkyl, aryl, or aralkyl;
each R7 is independently hydrogen, alkyl, aryl, or aralkyl;
R9 is a direct bond or a straight or branched alkylene chain;
R<10>is an straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; and
R<11>is -C(0)OR7 or -C(0)N(R<7>)2.
Of this subgroup of compounds, a preferred class of compounds is that class of compounds wherein: R<1>, R2 and R3 are each -OR6;
R4 is-R9-O-R,0-R";
R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
R6 is hydrogen, alkyl, aryl, or aralkyl;
each R7 is independently hydrogen, alkyl, aryl, or aralkyl;
R<9>is a direct bond;
R<10>is a straight or branched alkylene chain, a straight or branched alkenylene chain, or a straight or branched alkynylene chain; and
R11 is -C(0)OR<7>or -C(0)N(R<7>)2.
Of this class of compounds, preferred compounds are selected from the group consisting of the following compounds:( 5S, 6R, 7E, 9E, 1 3E, 1 5S)-\6-(4-fluorophenoxy)-5,6,15-trihydroxy-3-
oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester;
( 5S, 6R, 1E, 9E, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3 -
oxahexadeca-7,9,13-trien-11-ynoic acid;
(5S,65,7£,9£, 1 3E, 155)-l 6-(4-fluorophenoxy)-5,6,15-trihydroxy-3-
oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester; and
(55,65,7£,9£, 1 3E, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-
oxahexadeca-7,9,13-trien-11-ynoic acid.
Of the methods of using the compounds of the invention as set forth above in the Summary of the Invention, a preferred use of the compounds is the treatment of psoriasis, atopic dermatitis, multiple sclerosis or acute hemorrhagic or ischemic stroke in humans. Another preferred use of the compounds is the treatment of asthma in humans.
F. Preparation of the Compounds of the Invention
It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
It will also be appreciated by those skilled in the art that in the processes described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl( e. g.,t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for 1,2-dihydroxys include ketal- and acetal-forming groups. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(0)-R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.
Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein.
The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience. The protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotrityl chloride resin.
It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of formula (I) and formula (II), as described above in the Summary of the Invention, may not possess pharmacological activity as such, they may be administered to a mammal having an inflammatory or autoimmune disorder, or a pulmonary and respiratory tract inflammation, and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of formula (I) and (II) are included within the scope of the invention.
For convenience purposes, only compounds of the invention wherein R<9>is a bond and R', R<z>, and RJ are hydroxy are depicted in the following Reaction Schemes. It is also understood, however, that one of ordinary skill in the art would be able to make the other compounds of the invention in light of the following disclosure, including the Preparations and Examples, and information known to those of ordinary skill in the chemical synthesis field.
1. Preparation of Compounds of Formula ( D)
Compounds of formula (D) are intermediates in the preparation of the invention. They are prepared as described below in Reaction Scheme 1:
Compounds of formula (A) and formula (Aa) are commercially available or may be prepared according to methods known to those of ordinary skill in the art.
In general, compounds of formula (D) are prepared by first treating a compound of formula (A) with a ketone of formula (Aa) in the presence of an acid, preferably sulfuric acid, at ambient temperature for about 30 minutes to about 2 hours, preferably for about 1.5 hours. The pH of the resulting reaction mixture is then adjusted to about pH 7.0 with an appropriate base. The compound of formula (B) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and concentration.
The compound of formula (B) in a protic solvent, preferably water, is then treated with an appropriate reducing agent, preferably sodium borohydride, at temperatures between about 0°C and 5°C. The reaction mixture is stirred for about 1 hour to about 2 hours, preferably for about 2 hours, before a mild acid is added to consume the excess reducing agent present and to adjust the pH to about pH 6.0. The resulting reaction mixture is cooled to between about 0°C and 5°C. A glycol cleaving agent, such as sodium periodate, is then added to the mixture. The resulting reaction mixture is stirred at ambient temperature for about 1 hour to about 2 hours, preferably for about 2 hours. The compound of formula (D) is then isolated from the reaction mixture by standard isolation techniques, such as organic extraction and concentration.
Alternatively, other alkyl, aryl and aralkyl ketones may be used instead of the ketone of formula (Aa) to form the ketal of formula (B). In addition, an appropriate aldehyde may be used intead of the ketone of formula (Aa) to form the corresponding acetal, which may be further treated as described herein to form the compound of formula (D). For a description of various protecting groups for 1,2-diols, see Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience.
2. Preparation of Compounds of Formula ( M)
Compounds of formula (M) are intermediates in the preparation of compounds of the invention. They are prepared as described below in Reaction Scheme 2 wherein R<7a>is alkyl, aryl or aralkyl, R<10>is as described above in the Summary of the Invention, each R<14>is independently hydrogen or alkyl, R<14a>is hydrogen or alkyl, and X| and X2are each independently halo:
Compounds of formula (E), formula (Ee), formula (H) and formula (K) are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (M) are prepared by first removing water, if needed, from the compound of formula (E) by standard techniques. The compound of formula (E), in an aprotic anhydrous solvent, such as acetone when each R<14>is methyl and R<l4a>is hydrogen, is then treated with a compound of formula (Ea) in the presence of an acid catalyst, such as dl-10-camphorsulfonic acid, at ambient temperature. The reaction mixture is stirred for about 2 hours to about 4 hours, preferably for about 3 hours, and then made basic by the addition of a base, such as ammonia gas. The compound of formula (F) is then isolated from the reaction mixture by standard isolation techniques, such as filtration, concentration, organic extraction and concentration.
An aqueous solution of the compound of formula (F) is then treated with a reducing agent, preferably cold sodium borohydride in water. The resulting reaction mixture is stirred for about 3 hours to about 6 hours, preferaby for about 5 hours, and then treated with an acid, preferably acetic acid, to remove excess borohydride and to adjust the pH to about 6.0. The compound of formula (G) is isolated from the reaction mixture by standard techniques, such as extraction of the aqueous layer and concentration thereof.
The compound of formula (G) is then treated with a compound of formula (H) in the presence of a base, preferably sodium hydroxide. The reaction mixture is stirred for about 6 hours to about 24 hours, preferably for about 12 hours. The compound of formula (J) is isolated from the reaction mixture by standard isolation techniques and dissolved in an aprotic solvent, preferably dimethylformamide (DMF). A compound of formula (K) is then added to the solution, and the resulting mixture is stirred for about 6 hours to about 24 hours, preferably for about 12 hours. The compound of formula (L) is then isolated from the reaction mixture by standard isolation techniques, such as salt wash, extraction and concentration.
The compound of formula (L) in water and a polar aprotic co-solvent, such as acetone, is treated with a glycol cleaving agent, such as sodium periodate. The compound of formula (M) was isolated from the reaction mixture by standard isolation techniques, such as extraction, salt wash and concentration.
3. Preparation of Compounds of Formula ( CO
Compounds of formula (Q) are intermediates in the preparation of the compounds of the invention. They are prepared as described below in Reaction Scheme 3 wherein Ph is phenyl and PGiis a protecting group for the triple bond, e.g., phenyldimethylsilyl, diphenylmethylsilyl, or trimethylsilyl:
The compound of formula (N) is commercially available are may be prepared according to methods known to those skilled in the art.
In general, the Wittig reagent of formula (Q) is prepared by first dehydrogenating the compound of formula (N) by treatment with an organometallic compound, preferably «-butyllithium, at temperatures of between -30°C and -15°C, preferably at about -20°C. A protecting group, preferably trimethylsilyl, is then added to the compound under standard protecting group generation conditions. The protected compound of formula (O) is isolated from the reaction mixture by standard isolation techniques, such as extraction of the organic layers and concentration.
The compound of formula (O) in an aprotic solvent, preferably dicloromethane, is then treated with a brominating agent, such as iV-bromosuccinimide, in the presence of triphenylphosphine at temperatures of between about -10°C and about 0°C. The reaction mixture is allowed to warm to ambient temperature and stirred for about 1 hour to about 3 hours, preferably for about 2 hours. The compound of formula (P) is isolated from the rection mixture by standard isolation techniques, such as concentration and trituration with an inert organic solvent, such as hexane.
The compound of formula (P) is then treated with a slight excess of molar amount of a triarylphosphine or trialkylphosphine, preferably triphenylphosphine, under standard Wittig reagent forming conditions to form the phosphorus ylide of formula (Q) (theWittig reaction reagent).
4. Preparation of Compounds of Formula ( W)
Compounds of formula (W) are intermediates in the preparation of the compounds of the invention. They are prepared as described below in Reaction Scheme 4 wherein PG) is a protecting group, Xi is a halo, R<10>is as described above in the Summary of the Invention, and R<7a>and R<7b>are each independently alkyl, aryl or aralkyl:
Compounds of formula (D) and formula (Q) are prepared by methods disclosed herein. Compounds of formula (S) are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (W) are prepared by first treating a compound of formula (D) with a slightly excess molar amount of a compound of formula (Q) under standard Wittig reaction conditions to form a compound of formula (R), which is isolated from the reaction mixture by standard isolation techniques.
The compound of formula (R) is then treated with a compound of formula (S) in an aprotic solvent, such as tetrahydrofuran (THF) in the presence of a strong base, such as sodium hydroxide, and at a temperature of about 50°C to about 70°C, preferably at about 63°C. The reaction mixture is allowed to cool to ambient temperature. The compound of formula (T) was isolated from the reaction mixture by standard isolation techniques such as organic extraction and concentration.
The compound of formula (T) in an aprotic solvent, such as methylene chloride, is treated with elemental iodine at ambient temperature under standard conditions. The geometric isomer of formula (U) is isolated from the reaction mixture by standard isolation techniques.
The compound of formula (U) in an aprotic solvent, such as THF, is then deprotected and hydrolyzed to the compound of formula (V) under standard de-protection and hydrolysis conditions. The compound of formula (V) is isolated from the reaction mixture by standard isolation techniques, such as extraction and concentration.
The compound of formula (V) in an aprotic solvent is then treated with an esterifying agent, such as trimethylsilyldiazomethane, under standard esterification conditions to form the compound of formula (W), which is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by chromatography.
5. Preparation of Compounds of Formula ( Ta) and Formula ( Ua)
Compounds of formula (Ta) and formula (Ua) are intermediates in the preparation of the compounds of the invention and may be prepared as described below in Reaction Scheme 5 wherein R<7a>is alkyl, aryl or aralkyl, R<10>is as described above in the Summary of the Invention, R<14>is alkyl and R<14a>is hydrogen or alkyl:
Compounds of formula (Q) and formula (M) are prepared according to methods disclosed herein.
In general, compounds of formula (Ua) are prepared by first treating a compound of formula (M) with a slightly excess molar amount of a compound of formula (Q) under standard Wittig reaction conditions to form a compound of formula (Ta), which is then treated with elemental iodine under similar conditions as described above to form compounds of formula (Ua). The compound of formula (Ua) is then treated in a similar manner as described above for the compounds of formula (U) to form the corresponding compound of formula (W) as described above.
6. Preparation of Compounds of Formula ( DP)
Compounds of formula (DD) are intermediates in the preparation of the compounds of the invention. They are prepared as described below in Reaction Scheme 6 wherein R5 is as described above in the Summary of the Invention, and X2is halo:
Compounds of formula (X), N, O-dimethylhydroxylamine, ethynylmagnesium bromide and 3,5-dinitrobenzoyl chloride are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (DD) are prepared by first treating a compound of formula (X) in an aprotic solvent, preferably methylene chloride, with an excess molar amount of an acyl halide reagent, preferably oxalyl chloride, at ambient temperature. The reaction mixture is allowed to stir for about 6 hours to about 24 hours, preferably for about 12 hours. The compound of formula (Y) is isolated from the reaction mixture by standard isolation techniques, such as concentrationin vacuo.
The compound of formula (Y) is then treated with an hydroxylamine, preferably, A^,0-dimethylhydroxylamine or a 1,2-oxazolidine, in the presence of an alkaline base, potassium carbonate, under standard amine acylation conditions. The compound of formula (Z) is isolated from the reaction mixture by standard isolation techniques, such as organic extraction and concentraiton.
The compound of formula (Z) in an aprotic solvent, preferably THF, is then treated with the appropriate Grignard reagent, such as HC=CMgBr under standard conditions to form a compound of formula (AA), which is isolated from the reaction mixture by standard isolation techniques, such as organic solvent extraction, filtration and concentration. The compound of formula (AA) is then treated with a chiral reducing agent under standard reducing conditions to form a compound of formula (BB), which is isolated from the reaction mixture by standard isolation techniques, such as filtration, concentration and purification by flash chromatography, as a mixture of enantiomers. The enantiomeric excess can be determined by chiral analytical HPLC.
The enantiomeric excess is improved by recrystallization of an aryl ester formed by treating the compound of formula (BB) in an aprotic solvent, preferably methylene chloride, with an excess molar amount of an aroyl halide, preferably 3,5-dinitrobenzoyl chloride, at a temperature of between about -5°C and 0°C, in the presence of a base, preferably triethylamine, and an activating amount of dimethylaminopyridine (DMAP). The reaction mixture is stirred at ambient temperature for about 30 minutes to 1 hour, preferably for 40 minutes. The compound of formula (BBa) is isolated from the reaction mixture by standard isolation techniques, such as extraction, filtration and recrystallization and is determined to have greater than 98% enantiomeric excess by analytical HPLC.
The compound of formula (BBa) in a protic solvent, preferably methanol, is treated with an alkaline base, preferably potassium carbonate. The reaction mixture is stirred for about 3 hours to about 5 hours, preferably for about 3.5 hours and the reaction is then quenched by the addition of acid, preferably acetic acid. The compound of formula (BB) having a 98% enantiomeric excess is isolated from the reaction mixture by standard isolation techniques, such as filtration and concentration of the filtrate.
The compound of formula (BB) is then treated with a halogenating agent, preferably TV-bromosuccinimide, in the presence of a catalyst, such as silver nitrate, at ambient temperature. The compound of formula (CC) is then isolated from the reaction mixture by standard isolation techniques, such as concentrationin vacuo,filtration and elution with organic solvents.
The compound of formula (CC) is then hydrogenated under standard hydrogenation conditions for triple bonds, such as treatment with a reducing agent, preferably a mixture of lithium aluminum hydride and aluminum chloride, to form a compound of formula (DD), which is isolated from the reaction mixture by standard isolation techniques.
7. Preparation of Compounds of Formula ( la). Formula ( lb) and Formula ffla)
Compounds of formula (la), formula (lb) and formula (lla) are compounds of the invention. They are prepared as described below in Reaction Scheme 7 wherein R<5>and R<10>are as described above in the Summary of the Invention and R7bis alkyl, aryl or aralkyl:
Compounds of formula (DD) and formula (W) are prepared by methods disclosed herein. Alternatively, compounds corresponding to compounds of formula
(W) which are made from compounds of formula (Ua) may be used in the above reaction scheme to produce corresponding compounds of the invention.
In general, compounds of formula (la), formula (lb) and formula (lla) are prepared by first treating a compound of formula (DD) in an aprotic solvent, preferably THF, with a compound of formula (W) in an aprotic solvent, preferably THF, under standard Sonogashira coupling conditions, such as in the presence of copper iodide, an amine base and a palladium catalyst. The reaction mixture is stirred at ambient temperature for about 30 minutes to about 1 hour, preferably for about 45 minutes. The compound of formula (EE) is isolated from the reaction mixture by standard isolation techniques, such as filtration, elution with organic solvent and purification by chromatography.
The compound of formula (EE) in a protic solvent, preferably methanol, is then treated with an acid, preferably hydrochloric acid. The reaction mixture is stirred at ambient temperature for about 12 hours to about 48 hours, preferably for about 48 hours. The compound of formula (lla) is isolated from the reaction mixture by standard isolation techniques, such as adjusting the pH of the reaction mixture to pH 7.0 and purification by reverse phase chromatography.
Compounds of formula (lla) in a protic solvent, preferably methanol, is then reduced to a compound of formula (la) by the method described inHelv. Chim. Acta.(1987). The compound of formula (la) is then hydrolyzed to a compound of formula (lb) under standard basic hydrolysis conditions.
In addition, compounds of formula (lla) in a protic solvent, preferably methanol, may then be hydrolyzed under standard basic hydrolysis conditions to form compounds of formula (lla) herein R<7b>is hydrogen.
8. Preparation of Compounds of Formula ( lib)
Compounds of formula (lib) are compounds of the invention. They are prepared as described below in Reaction Scheme 8 wherein q, p, R<5>, R<10>, and R15 are as described above in the Summary of the Invention and R<7b>is alkyl, aryl or aralkyl:
Compounds of formulae (E), (FF), (Q), and (Sa) are commercially available or may be prepared according to methods disclosed herein or by methods known to one of ordinary skill in the art.
In general, the compounds of formula (lib) are prepared by first stirring a mixture of a compound of formula (E) and copper sulfate in a compound of formula (FF) under nitrogen while a strong acid, such as sulfuric acid, is added to the reaction mixture. The resulting reaction mixture is warmed to ambient temperature, preferably to about 29°C, and allowed to stir for a period of between about 8 hours and 16 hours, preferably for about 12 hours. The reaction mixture is filtered and the resulting filtrate is washed with an organic solvent, preferably ethyl acetate. The filtrate is then treated with a base, preferably ammonium hydroxide, and the resulting solid is removed by filtration. The compound of formula (GG) is isolated from the filtrate by standard isolation techniques, such as extraction by organic solvents and further filtration.
An excess molar amount of a reducing agent, such as sodium borohydride, in a protic solvent, such as methanol, is then cooled to about 0°C and then treated with a compound of formula (GG) in a protic solvent, such as methanol. The resulting reaction mixture is allowed to stir for between about 4 hours to about 8 hours, preferably for about 4 hours. Upon completion of the desired reaction, an acid, preferably acetic acid, is then added to the reaction mixture to consume the excess reducing agent and to adjust the pH of the reaction mixture to about pH 6. The compound of formula (HH) is then isolated from the reaction mixture by standard isolation techniques, such as filtration, concentration of the solids, extraction by organic solvent, and precipitation.
A mixture of a compound of formula (HH) and a compound of formula (Sa) in an aprotic solvent, such as toluene is then stirred as a alkaline base, such as sodium hydroxide in water, is added. A phase transfer catalyst, such as tetrabutylammonium sulfate, is added to the reaction mixture and the reaction mixture is stirred for a period of about between 8 hours and 16 hours, preferably for about 12 hours. The compound of formula (JJ) is isolated from the reaction mixture by standard isolation techniques, such as extraction by basic organic solvents, concentration, and chromatography.
The compound of formula (JJ) in a polar organic solvent, such as acetone, is then treated with an excess molar amount of periodate in water. The resulting reaction mixture is then stirred vigorously under nitrogen for a period of from about 4 hours to about 8 hours, preferably for about 4 hours. The solvent is removedin vacuoat ambient temperature. The compound of formula (KK) is isolated from the reaction mixture by standard isolation techniques, such as extraction by organic solvent and concentration of organic layers.
A compound of formula (Q) in an aprotic solvent, preferably THF is cooled to about -30°C under anhydrous conditions and then treated gradually with a strong base, preferably rc-butyllithium. The reaction mixture is allowed to warm to about 0°C and stirred for a period of between about 15 minutes and 1 hour, preferably for about 15 minutes. The reaction mixture is then cooled to about -30°C and then treated with an equimolar amount of a compound of formula (KK) in an aprotic solvent, preferably THF. The resulting reaction mixture is stirred for a period of between about 30 minutes to 2 hours, preferably for about 1 hour at a temperature of about -30°C. The reaction was quenched by the addition of an appropriate acid, such as potassium phosphate. The compound of formula (LL) is isolated from the reaction mixture by standard isolation techniques, such as salt wash, concentration, and precipitation.
The compound of formula (LL) is treated in a manner similar to the treatment of the compound of formula (T) in Reaction Scheme 4 above to afford a compound of formula (MM), which is then treated in a manner similar to the treatment of the compound of formula (U) in Reaction Scheme 4 above to afford a compound of formula (NN).
Compounds of formula (NN) are then treated with a compound of formula (DD) in a manner similar to that described for the treatment of compounds of formula (W) in Reaction Scheme 7 above to afford a compound of formula (lib).
9. Preparation of Compounds of Formulae ( He") and did)
Compounds of formulae (lie) and (lid) are the same as compounds of formula (lla) described above, except that the starting material from which they are prepared,i. e.,compound of formula (lib), is prepared by a different synthesis than the starting material for compounds of formula (lla). Accordingly, the compounds of formulae (lie) and (lid) are prepared as described below in Reaction Scheme 9 wherein q, p, R<5>, R<10>, and R<15>are as described above in the Summary of the Invention and R is alkyl, aryl or aralkyl:
Compounds of formula (lib) are prepared as described above in Reaction Scheme 8.
In general, compounds of formula (lie) and (lid) are prepared by first treating a compound of formula (lib) with an acid, such as acetic acid, preferably acetic acid, preferably diluted with an organic solvent, such as ethyl acetate, at temperatures of between about 50°C and about 60°C, preferably at about 50°C, for a period of between about 10 hours and about 20 hours, preferably for a period of 20 hours. The organic reagents and solvents are removed by distillationin vacuo.The compound of formula (lie) is isolated from the reaction mixture by standard isolation techniques, such as extraction by organic solvents and concentration. The compound of formula (lie) is then treated to hydrolysis conditions and the compound of formula (lid) is then isolated from the reaction mixture by standard isolation techniques, such as chromatography.
In addition to the above described Reaction Schemes and the following Preparations and Examples, other compounds of the invention may be prepared according to method known to those of ordinary skill in the art.
For example, compounds of the invention wherein R<1>is -SR<6>, -S(0)tR<7>, or -N(R<7>)R<8>(where R<6>, R<7>andR<8>are hydrogen) may be prepared by treating the compound of formula (EE) or a compound of formula (U) (as described above) with a suitable hydroxy-protecting agent to protect the free hydroxy group, and then treating the protected compound of formula (EE) or compound of formula (U) with a suitable acid in order to cleave the ketal. The resulting di-hydroxy compound may then be treated under standard acid hydrolysis conditions to form the corresponding lactone. The free hydroxy may then be derivatized to form a suitable leaving group, and subsequent substitution with the appropriately substituted thiol or amine, followed by acid hydrolysis will form compound of the invention wherein R<1>is -SR<6>, -S(0)(R<7>, or
-N(R<7>)R<8>.
Compounds of the invention wherein R<3>is -SR<6>, -S(0)tR<7>, or -N(R<7>)R8 may be prepared by derivatizing the free hydoxy of a compound of formula (EE) to form a suitable leaving group, and then reacting the derivatized compound with the appropriately substituted nucleophile.
Compounds of the invention where R<2>is -SR<6>, -S(0)tR<7>, or -N(R<7>)R<8>may be prepared by preparing the lactone as described above, and then protecting the free hydroxy as described above. The resulting compound may then be treated to standard acid hydrolysis conditions to form the corresponding acid. The free hydroxy group may then be derivatized to form a suitable leaving group, and subsequent substitution with the appropriately substituted nucleophile, followed by de-protection will form compounds of the invention wherein R<2>is -SR<6>, -S(0)tR<7>, or -N(R<7>)R8.
Compounds of the invention where R<4>is -R<9->N(R<7>)-R<10>-R<n>may be prepared by treating a compound of formula (F) as described above with an appropriately substituted amine under standard reductive amination conditions and then treating the resulting compound in the manner described above to form the corresponding compound of the invention. Compounds of the invention where R<4>is - R^OVR^-R<11>may be prepared by derivatizing the primary hydroxy of the compound of formula (G) as described above to form a suitable leaving group, and then reacting the resulting compound with the appropriate thiol alkoxide to form the desired product, which can be further oxidized under standard oxidation conditions to form the desired sulfinyl and sulfonyl compound.
Compounds of the invention wherein R<1>and R<2>together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
may be prepared by treating a compound of formula (la) or (lla) as described above wherein R and R are independently selected from hydroxy, thiol or amine with an appropriate acylating agent, such as phosgene, under acid conditions.
Compounds of the invention wherein R<4>is -R<9->R<l3>-R<u>may be prepared according to the methods similar to those disclosed in Rodriguez, A.R.,et al., Tetr ahedron Letters(2001), Vol. 42, pp. 6057-6060.
Compounds of the invention wherein R<4>is -R<9->R<12>may be prepared by derivatizing a compound of formula (G) as described above to form a suitable leaving group on the primary hydroxy, and then treating the resulting compound with an appropriate hydroxy protecting agent in order to protect the remaining hydroxys. The leaving group can then be displaced with the appropriate aryl cuprate or Grignard reagent.
Compounds of the invention wherein R<4>is -R<9>-O-R<10->R" may be prepared according to methods described herein using the appropriately substituted haloalkanoic acid salt, haloalkenoic acid salt, haloalkynoic acid salt or halocycloalkanoic acid salt. Alternatively, compound wherein R<10>is cycloalkylene may be prepared by alkylating the corresponding alkenylene-containing compound with the appropriate alkyl dihalide.
Compounds of the invention wherein R<4>is -R<9->0-R<12>may be prepared by treating the compound of formula (G) with the appropriate haloaralkyl (where the halo is on the alkyl chain) under substitution conditions.
Compounds of the invention wherein R<4>is -R<9->C(O)-R<l0>-R<u>may be prepared by hydrating the corresponding compound of the invention wherein R4 is -R<9->R<l3->R" wherein R<13>is an alkenylene chain under standard hydration conditions to form the corresponding alcohol, and then oxidizing the alcohol to the corresponding ketone. Compounds of the invention wherein R<4>is -R<9->N(R<7>)-R<I0->R" or -R<9->S(O),-R<10->R" may be prepared in a similar manner as described above for compounds of the invention wherein R<1>and R2 are -SR<6>, -S(0)t-R7 and -N(R<7>)R<8>.
Compounds of the invention wherein R<4>is -R<9->C(F)2-R<9>-R<H>may be prepared from the corresponding ketone using the appropriate fluorinating agent, such as (diethylamino)sulfur trifluoride (DAST).
Compounds of the invention wherein R<6>is alkyl, aryl, aralkyl, -C(0)R<7>, -C(S)R<7>, -C(0)OR<14>, or -C(S)OR<14>may be prepared by reacting a compound of formula (la) or (lla) with the appropriate halide under standing substitution conditions. Compounds of the invention wherein R<6>is -C(0)N(R<7>)R<8>or -C(S)N(R<7>)R<8>may be prepared by reacting a compound of formula (la) or (lla) with the appropriately substituted isocyanate or isothiocyanate.
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques. It is understood that all polymorphs, amorphous forms, anhydrates, hydrates, solvates and salts of the compounds of the invention are intended to be within the scope of the invention.
To prepare the cyclodextrin clathrates of this invention, the lipoxin A4analogs of formula (I) and formula (II), or the lipoxin A4analogs described and claimed in U.S. Patent No. 5,441,951; U.S. Patent No. 5,079,261; U.S. Patent No. 5,648,512; and U.S. Patent No. 6,048,897, as defined above in the Summary of the Invention, can be dissolved in a pharmacologically acceptable solvent,e. g.,in an alcohol, preferably ethanol, in a ketone,e. g.,acetone or in an ether,e. g.,diethyl ether, and mixed with aqueous solutions of a-cyclodextrin, (i-cyclodextrin or y-cyclodextrin, preferably p-cyclodextrin, at 20°C to 80°C; or the acids of the lipoxin A4analogs as defined above in the Summary of the Invention in the form of the aqueous solutions of their salts( e. g.,Na' or K salts) can be admixed with a cyclodextrin and after solution with the equivalent amount of an acid( e. g.,HC1 or H2SO4) to afford the corresponding cyclodextrin clathrate.
At this point or after cooling, the corresponding cyclodextrin clathrates separate in the form of crystals. However, it is also possible to convert oily and also crystalline compounds of formula (I) and/or formula (II), as defined above in the Summary of the Invention, by rather long stirring( e. g.,for 1 hour to 14 days) at ambient temperature, by treatment with an aqueous solution of cyclodextrins, into the corresponding cyclodextrin clathrate form. The clathrates can then be isolated as solid, free-flowing crystals by suctioning off the solvents and drying.
Cyclodextrins used in this invention are commercially available, for example, from Aldrich Chemical Co., or can be prepared by methods known to those skilled in the art. See, for example, Croft, A.P.et al.,"Synthesis of Chemically Modified Cyclodextrins",Tetrahedron(1983), Vol. 39, No. 9, pp. 1417-1474. Suitable cyclodextrins will include a wide variety of those which produce clathrates of the compounds of formula (I) and formula (II) as set forth above. See, for example, J. E. F. Reynolds (ed.) Martindale, The Extra Pharmacopoeia 28th ed. The Pharmaceutical Press, London 1982, p. 333 and 389-390 and O.-A. Neumueller (ed.), Roempps Chemie-Lexikon, 8. Aufl. Franckh'sche Verlagshandlung, Stuttgart 1981, p. 763-764, 841, 1053-1054.
By selection of the suitable amounts of cyclodextrins and water it is possible to obtain the new clathrates in a stoichiometric composition with a reproducible content of effective substance. The clathrates can be used in a dry hygroscopic form or in a water-containing, but less hygroscopic form. Typical molar ratios of cyclodextrin to a compound of formula (I) or a compound of formula (II) is 2:1 (cyclodextrimcompound).
The following specific preparations and examples are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention.
PREPARATION 1
Compounds of formula(B)and (D)
A. A slurry of D-ribose (50 g, 0.33 mol) in acetone (500 mL) was stirred at ambient temperature as concentrated sulfuric acid (1.25 mL) was added. The reaction mixture was stirred for 30 minutes to give a clear solution and then stirred for an additional hour. The pH of the reaction mixture was adjusted to about pH 7 with calcium hydroxide (~7.0 g). The resulting slurry was filtered through a pad of celite. The filtrate was concentrated to give 64.8 g of D-ribofuranose-3,4-acetonide, the compound of formula (B) as a slightly colored oil, NMR: (CDC13) 5 1.30 (s, 3H), 1.47 (s, 3H) 2.05 (s, 1), 3.7 (m, 3H), 4.38 (m, 1H), 4.56 (d, 1H), 4.80 (d, 1H), 4.96 (d, 1H), 5.38 (d, 1H) ppm.
B. In a similar manner, compounds corresponding to the compound of formula (B) may be prepared. C. A slurry of sodium borohydride (10.7 g, 0.34 mol) in water (0.75 L) was cooled in an ice bath and treated with the D-ribofuranose-3,4-acetonide (64.6 g, 0.34 mol) in water (1.25 L). The reaction mixture was stirred for about 2 hours before the addition of acetic acid (~23 mL) to consume excess borohydride and to adjust the pH to about pH 6. The reaction mixture was cooled in an ice bath before the addition of sodium periodate (72.7 g, 0.34 mol) in portions. The reaction mixture was stirred for about 2 hours at ambient temperature, concentrated under reduced pressure and extracted with ethyl acetate (3x). The combined ethyl acetate solutions were washed with brine, dried over sodium sulfate, and concentrated to give 47.4 g of (3,4-isopropylidene)erythrose, a compound of formula (D), as a colorless viscous oil: NMR (DMSO) 8 1.22 (s, 3H), 1.32 (s, 3H), 3.28 (d, 1H), 3.78 (m, 2H), 4.38 (d, 1H), 4.76 (m, 1H), 5.12 (m, 1H) ppm. D. In a similar manner, other compounds of formula (D) may be prepared.
PREPARATION 2
Compounds of formula (F), formula (G), formula (L) and formula (M)
A. Solid L-rhamnose hydrate (100 g, 0.55 mol) was suspended in a 1:1 mixture of acetone and toluene (1 L) and concentrated. The process was repeated three times using increasing higher concentration of toluene. The flask was placed under high vacuum to remove traces of toluene. The anhydrous residue was dissolved in acetone (600 mL) and treated with methoxypropene (68 mL, 0.71 mol), pyridinium tosylate (3 g) and dl-10-camphorsulfonic acid (3 g). The reaction was stirred at ambient temperature for about 3 hours. The reaction mixture was basified by bubbling in ammonia gas and resulting solids were removed by filtration. The filtrate was concentrated and the syrupy liquid was dissolved in water and extracted with ethyl acetate (3x). The combined organic layers were washed with water (2x) and brine, dried, and concentrated to give 102 g of (3,4-isopropylidene)rhamnose, a compound of formula (F), as a viscous oil; 'H NMR (CDC13) 5 1.32 (m, 6H), 1.45 (s, 3H), 3.92 (m, 1H), 4.05 (m, 1H), 4.59 (d, 1H), 4.87 (m, 1H), 5.2 (s, 1H) ppm.
B. A slurry of sodium borohydride (52 g, 1.4 mmol) in water (600 mL) was cooled in an ice bath and treated with the (3,4-isopropylidene)rhamnose (78 g, 0.38 mmol) in water (900 mL). The reaction mixture was stirred for about 5 hours before the addition of acetic acid to consume excess borohydride and to adjust the pH to about pH 6 (about 130 mL). The aqueous layer was concentrated under reduced pressure. The residue (in a minimum amount of water) was extracted with ethyl acetate (3x). The combined organic layers were dried, and concentrated to give 70 g of 5-(hydroxymethyl)-4-(l,2-dihydroxypropyl)-2,2-dimethyl-l,3-dioxolane, a compound of formula (G), as a colorless viscous oil; 'H NMR (CD3OD) 5 1.23 (d, 3H), 1.34 (s, 3H), 1.47 (s, 3H), 3.37 (m, 1H), 3.7 (m, 3H), 4.21 (m, 1H), 4.42 (m, lH)ppm. C. A solution of 4-(hydroxymethyl)-5-(l,2-dihydroxypropyl)-2,2-dimethyl-l,3-dioxolane (63 g, 0.33 mol) and sodium iodoacetate (75 g, 0.36 mol) in water was treated with solid sodium hydroxide (16 g, 0.35 mol). The reaction mixture was stirred overnight and then washed with ethyl acetate and ether. The aqueous layer was concentrated. The resulting residue was dissolved in DMF (20 mL) and treated with iodomethane (37 mL, 0.6 mol). The resulting reaction mixture was stirred overnight. The reaction mixture was diluted with two volumes of salt water and extracted with ethyl acetate (6x). The combined organic layers were dried, and concentrated.to give 20 g of 2-[[(45,5/?)-5-(l,2-dihydroxypropyl)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (L), as a colorless viscous oil;<]>H NMR (CDCI3) 5 1.27 (d, 3H), 1.38 (s, 3H), 1.48 (s, 3H), 3.57 (m, 1H), 3.77 (s, 3H), 3.8 (m, 2H), 4.13 (m, 2H), 4.4 (m, 2H) ppm. D. A solution of 2-[[(4S,5/?)-5-(l>2-dihydroxypropyl)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester (20 g, 72 mmol) in acetone (20 mL) was diluted with water (400 mL) and treated with solid sodium periodate (26.13 g, 122 mmol). The reaction was analyzed by TLC and was complete after stirring for 1 hour. The reaction mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried, and concentrated.to give 12.6 g of 2-[[(4S,55)-5-formyl-2,2-dimethyl-l ,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (M), as a slightly yellow viscous oil; 'H NMR (CDCI3) 8 1.38 (s, 3H), 1.57 (s, 3H), 3.75 (m, 2H), 3.7 (s, 3H), 4.08 (m, 2H), 4.42 (m, 1H), 4.54 (m, 1H),9.64 (d, 1H) ppm.
E. In a similar manner, the following compounds of formula (M) are prepared: 2-[[(4S,5S>5-formyl-2,2-dimethyl-l,3-dioxoIan-4-yl]m acid, ethyl ester;
2-[2-[(45,55)-5-formyl-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, ethyl ester;
242-[(45',55)-5-formyl-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, methyl ester;
2-[[(4iS',5S)-5-formyl-2,2-diethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, ethyl ester;
2-[2-[(45,,55')-5-formyl-2,2-diethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, ethyl ester;
2-[2-[(45,55)-5-formyl-2,2-diethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, methyl ester;
2-[[(45,55)-5-formyl-2-methyl-2-ethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, ethyl ester;
2-[2-[(45,5S)-5-formyl-2-methyl-2-ethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, ethyl ester;
2-[2-[(45,55)-5-formyl-2-methyl-2-ethyl-1,3-dioxolan-4-yl]ethoxy]ethanoic acid, methyl ester;
2-[[(45,55)-5-formyl-2-methyl-2-ethyl -1,3-dioxolan-4-yl]methoxy]ethanoic acid,/-butyl ester; and
2-[2-[(4S,5S> 5-formyl-2-methyl-2-ethyl-1,3-dioxolan-4-yl]ethoxy]ethanoic acid,/-butyl ester.
PREPARATION 3
Compounds of formula (O), formula (P) and formula (Q)
A. A solution of pent-2-en-4-yn-l-ol (58 g, 0.7 mol) in anhydrous tetrahydrofuran (THF) (1.0 L) under a nitrogen atmosphere in a 3.0 L 4-neck round-bottom flask was mechanically stirred and cooled in a dry ice/2-propanol bath as a solution of n-butyllithium in hexane (0.35 L, 2M, 0.77 mol) was added at a rate to maintain a temperature below -20°C After 20 minutes, neat chlorotrimethylsilane (93 g, 0.77 mol) was added. After 20 minutes, a solution of n-butyllithium in hexane (0.35 L, 2M, 0.77 mol) was added at a rate to maintain a temperature below -20°C After 10 minutes, neat chlorotrimethylsilane (93 g, 0.77 mol) was added. The reaction was allowed to warm to ambient temperature over about 1 hour. The reaction was treated with saturated ammonium chloride and diluted with hexane. The aqueous layer was washed with hexane. The combined organic extracts were washed with water and brine, dried and concentrated. The residue was dissolved in THF (-690 mL), treated with IN hydrochloric acid (75 mL), and stirred overnight. The aqueous layer was separated and washed with ether. Combined organic layers were washed with water (3x) and brine, dried and concentrated to give 106 g of an oil. The residue was distilled under vacuum through a 15 cm jacketed column to obtain 72.6 g of 5-trimethylsilylpent-2-en-4-yn-l-ol, a compound of formula (O), as a nearly colorless oil: b.p. 71-77°C / 0.4 mm Hg; 'H-NMR (300 mHz, CDC13) 5 0.18 (s, 9H), 1.7 (bs, 1H), 4.18 (d, 2H), 5.75 (d, 1H), 6.29 (dm, 1H) ppm.
B. Af-Bromosuccinimide (85.3 g, 0.48 mol) was added in portions to a nearly homogeneous solution of triphenylphosphine (128.2 g, 0.49 mol) and 5-trimethylsilylpent-2-en-4-yn-l-ol (72.5 g, 0.47 mol) in dichloromethane (600 mL) under nitrogen and cooled in a dry ice/2-propanol bath to an initial temperature of below -20°C. The internal temperature of the reaction mixture was maintained at -10"C to 0°C throughout the addition by adjusting the rate of addition. The bath was allowed to warm to ambient temperature. After 2 hours, the reaction was complete. The reaction mixture was concentrated under vacuum to a thick paste and the residue was triturated with hexane (250 mL). The suspension was filtered and the solids and silica gel were rinsed with hexane (10 x 150 mL). The filtrate was concentrated under vacuum (30°C/60 mtorr) to obtain 44 g (89% yield) of l-bromo-5-trimethylsilylpent-2-en-4-yne, a compound of formula (P), as a pale yellow oil: 'H-NMR (300 mHz, CDC13) 5 0.19 (s, 9H), 3.95 (d, 211), 5.75 (d, HI), 6.31 (dt, 1H) ppm. C. Triphenylphosphine (64.1 g, 0.244 mol) was added to a solution of l-bromo-5-trimethylsilylpent-2-en-4-yne (44.26 g, 0.204 mol) in toluene (204 mL). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 3 days the suspension was diluted with methyl tert-butyl ether (408 mL), stirred for 1 hour at ambient temperature, and the precipitate was collected by filtration. The filter cake was washed with methyl tert-butyl ether and dried under vacuum at 30"C to get 79 g of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (Q), as an off-white powder: 'H-NMR (300 mHz, CDC13) 5 0.14 (s, 9H), 5.08 (dd, 2H), 5.91 (dt, 1H), 6.22 (dd, 1H), 7.6-8.0 (m, 15 H); Anal. Calculated for C26H28BrPSi requires C 65.13, H 5.89, Br 16.66, P 6.46; found C 64.95, H 5.78, Br 16.96, P 6.31. D. In a similiar manner, other compounds of formula (Q) may be prepared.
PREPARATION 4
Compounds of formula (R), formula (T), formula (U), formula (V), formula (L),
FORMULA (MM), AND FORMULA (NN)
A. A slurry of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide (115 g, 0.24 mol) in THF (1 L) was stirred under nitrogen, cooled in a dry ice/2-propanol bath, and treated with a solution of «-butyllithium in hexane (2M, 120 mL, 0.24 mol) via dropwise addition. After about 5 minutes, the cooling bath was removed and the temperature of the reaction mixture was allowed to rise to <0°C (internal). The reaction mixture was placed again in a dry ice/2-propanol bath. The reaction mixture was stirred as a solution of (2,3-isopropylidene)erythrose (36.6 g, 0.23 mol) in 200 mL of THF was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was then cooled with dry ice/2-propanol and treated with saturated NH4CI. The resulting aqueous layer was washed with ethyl acetate. The organic layers were combined and washed with water and brine solution, dried, treated with silica gel and concentrated. Hexane/ethyl acetate (3:1) was added to the mixture to precipitate impurities, and the solution was filtered and concentrated. The resulting residue was treated with ether and hexane (1:1), silica gel, filtered and concentrated to give 50 g of product. Purification by chromatography on silica gel using a gradient of ether in hexane gave 13.9 g of a mixture of (45,,5^)-5-[(l£,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-4-(hydroxymethyl)-l,3-dioxolane and (4S,,5i?)-5-[(lZ,3£T)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-4-(hydroxymethyl)-l,3-dioxolane, a compound of formula (R); NMR for (1Z,3£) isomer only:'H NMR (CDC13) 5 0.1 (s, 9H), 1.22 (s, 3H), 1.38 (s, 3H), 1.6 (m, 1H), 3.36 (m, 2H), 4.12 (m, 1H), 4.93 (m, 1H), 5.4 (t, 1H), 5.51 (d, 1H), 6.03 (t, 1H), 6.67 (dd, 1H) ppm.
B. A solution of a mixture of (45,5/?)-5-[(l£,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyI-4-(hydroxymethyl)-l,3-dioxolane and(45,,57?)-5-[(lZ,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-4-(hydroxymethyl)-l,3-dioxolane (14 g, 50 mmol) and/-butyl bromoacetate (9.6 mL, 65 mmol) in 150 mL of THF was cooled in an ice bath and treated with solid sodium hydride (60%, 2.5 g, 65 mmol). The slurry was allowed to warm to ambient temperature overnight. The reaction was analyzed by TLC and was about 40% complete. The reaction was then heated in a 63°C oil bath for about 7 hours. The reaction mixture was allowed to cool and was poured into a mixture of ice, ethyl acetate, and saturated ammonium chloride. The aqueous layer was washed with ethyl acetate (2x). The combined organic layers were washed with water and brine solution, dried, treated with silica gel and concentrated. Purification by chromatography on silica gel using a gradient of ether in hexane gave 5.2 g of a mixture of 2-[[(45,5/?)-5-[(l£,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l ,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester and 2-[[(45,5/?)-5-[(lZ,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester, a compound of formula (T); NMR for(IZ, 3£)isomer only:<!>H NMR (CDC13) 5 0.01 (s, 9H), 1.22 (s, 3H), 1.28 (s, 9H), 1.38 (s, 3H), 3.33 (m, 2H), 3.80 (m, 2H), 4.25 (m, 1H), 4.9 (m, 1H), 5.35 (m, 1H), 5.48 (dd, 1H), 6.0 (t, 1H), 6.72 (dd, 1H) ppm. C. A solution of a mixture of2-[[(4S,5tf)-5-[(l£,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester and 2-[[(4lS,5^)-5-[(lZ,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l ,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester in methylene chloride was treated with iodine until a red color persisted. The mixture was allowed to stand overnight. NMR analysis showed complete conversion. Reaction was treated with an aqueous solution of Na2S204and washed with water and brine, dried, treated with silica gel and concentrated to give 4.3 g of 2-[[(45,5/?)-5-[(l£,3£)-6-(trimeth<y>lsil<y>l)-l,3-hexadien-5-<y>n<y>l]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester, a compound of formula (U), as a viscous oil; 'H NMR (CDC13) 6 0.01 (s, 9H), 1.22 (s, 3H), 1.28 (s, 9H), 1.38 (s, 311), 3.33 (m, 2H), 3.80 (m, 2H), 4.25 (m, 1H), 4.5 (m, 1H), 5.43 (m, 1H), 5.58 (dd, 1H), 6.23 (dd, 1H), 6.44 (dd, 1H) ppm. D. In a similar manner and using the compound of formula (LL), the following compound of formula (MM) was made: 1,1 ,-dimethylethyl {{(25',3/?)-3-[(l£,3£)-6-(trimethylsilyl)-1,3-hexadien-5-ynyl]-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate, [a]D= -14.351 (10.566 mg/cc in MeOH); 'HNMR (CDC13) 5 0.15 (s, 9H), 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 3.45 (m, 2H), 3.92 (m, 2H), 4.34 (m, 1H), 4.62 (m, 1H), 5.54 (d, 1H), 5.72 (dd, 1H), 6.26 (dd, 1H), 6.56 (dd, 1H) ppm.
E. A solution of 2-[[(45,5/?)-5-[(l£,3F)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l ,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester in THF was treated with a solution of tetrabutylammonium fluoride in THF in portions. The reaction mixture was then stirred overnight. The reaction mixture was diluted with water and 1 N NaOH solution (1:1) and stirred overnight. The reaction mixture was poured into a mixture of ethyl acetate and saturated ammonium chloride. The aqueous layer was washed with ethyl acetate (2x). The combined organic layers were washed with water and brine solution, dried, treated with silica gel and concentrated to give 2.8 g of 2-[[(4S,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, a compound of formula (V), as an oil: 'H NMR (CDCb) 8 1.37 (s, 3H), 1.46 (s, 3H), 3.06 (s, 1H), 3.49 (m, 2H), 4.06 (m, 2H), 4.37 (m, 1H), 4.65 (t, 1H), 5.54 (d, 1H), 5.66 (dd, 1H), 6.28 (dd, 1H), 6.58 (dd, 1H) ppm.
F. In a similar manner and using a compound of formula (MM), the following compound of formula (NN) was prepared: 1,1 ,-dimethylethyl{{( 2S, 3R)- 3-[( lE, 3E)-\,3-hexadien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate, 'H NMR (CDC13) 5 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 3.02 (m, 2H), 3.05 (m, 2H), 3.96 (m, 2H), 4.38 (q, 1H), 4.66 (t, 1H), 5.54 (dd, 1H), 5.78 (dd, 1H), 6.33 (dd, 1H), 6.65 (dd, 1H) ppm.
G. A solution of 2-[[(45,57?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid in THF was cooled in an ice bath and treated with a solution of trimethylsilyldiazomethane in THF in portions. Excess diazomethane was decomposed with acetic acid and the mixture was diluted with ether and washed with water, saturated sodium bicarbonate, water (2x), and brine, dried, treated with silica gel and concentrated. Purification by chromatography on silica gel using a gradient of ether in hexane gave 0.9 g of 2-[[(4S,5/?)-5-[(l£,3£)-l ,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (W), as an oil:<!>H NMR (CDCI3) 5 1.37 (s, 3H), 1.51 (s, 3H), 3.06 (s, 1H), 3.49 (m, 2H), 3.74 (s, 3H), 4.16 (m, 2H), 4.42 (m, 1H), 4.65 (t, 1H), 5.60 (dd, 1H), 5.79 (dd, 1H), 6.33 (dd, 1H), 6.65 (dd, 1H) ppm.
H. In a similar manner as described above, the following compounds corresponding to the compounds of formula (W) are prepared.
2-[[(45,5i?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, ethyl ester;
2-[[(4S,5tf )-5-[( 1 E, 3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid,/-butyl ester;
2-[2-[(45,5^)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, ethyl ester;
2-[2-[(4.S,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid,/-butyl ester;
2-[2-[(45,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy]ethanoic acid, methyl ester;
2-[3-[(4S,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]propoxy]ethanoic acid, ethyl ester;
2-[3-[(45,5/?)-5-[(l£,3F)-l,3-hexadien-5-ynyl]-2,2-dimethyI-l,3-dioxolan-4-yl]propoxy]ethanoic acid, /-butyl ester;
2-[3-[(45,57?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]propoxy]ethanoic acid, methyl ester;
4-[[(45,5^)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]butanoic acid, ethyl ester;
4-[[(4lS,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]butanoic acid,/-butyl ester;
4-[[(45,5^)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]butanoic acid, ethyl ester; and
4-[[(45,5/?)-5-[(l£,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]butanoic acid, /-butyl ester.
PREPARATION 5
Compounds of formula (Ta) and formula (Ua)
A. A slurry of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (Q), (8.5 g, 17.7 mmol) in THF (120 mL) was stirred under nitrogen, cooled in a dry ice/acetonitrile bath, and treated with a solution of /7-butyllithium in hexane (2M, 8 mL, 16 mmol) via dropwise addition. The dry ice bath was replaced with an ice bath and the reaction mixture was stirred for about 15 minutes until a homogeneous mixture was obtained. The dry ice bath was replaced and the reaction mixture was treated with a solution of 2-[[(4S',5S)-5-formyl-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (M), (3.7 g, 16 mmol) in 60 mL of THF. The reaction mixture was stirred in a dry ice bath for 1 hour, which was then replaced with the ice bath. After 1 hour, the reaction mixture was diluted with ether and monobasic potassium phosphate. The aqueous layer was washed with ether. The combined organic layers were washed with water and brine, dried, filtered through a pad of silica gel, and concentrated. A hexane/ethyl acetate (-3:1 mixture) was added to the residue to precipitate impurities. The residue was filtered and concentrated. The resulting residue was treated with ether and hexane (1:1), followed by silica gel, filtration and concentration to give 9.2 g of a 1:3 mixture of triphenylphosphine oxide and 2-[[(45',5/?)-5-[(lZ,3£)-6-(trimethylsilyl)-1,3-fiexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (Ta); 'H NMR (CDC13) 5 0.01 (s, 9H), 1.2 (s, 3H), 1.33 (s, 3H), 3.33 (m, 2H), 3.56 (s, 3H), 3.90 (m, 2H), 4.25 (m, 1H), 4.88 (m, 1H), 5.32 (t, 1H), 5.48 (d, 1H), 5.98 (t, 1H), 6.68 (dd, 1H) ppm (NMR for ester only).
B. A solution of the above residue in methylene chloride was treated with sufficient quantity of iodine to maintain a red color and allowed to stand for 3 hours in the light. The reaction mixture was then treated with saturated aqueous sodium hyposulfite, dried with sodium sulfate, filtered through a pad of silica gel, and concentrated to give 4.53 g of product. Chromatography on silica gel using a gradient of 5 to 100% ether in hexane gave 2.74 g of 2-[[(45,5/?)-5-[(l£,3E)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (Ua); *H NMR (CDC13) 5 0.01 (s, 9H), 1.18 (s, 3H), 1.33 (s, 3H), 3.3 (m, 2H), 3.56 (s, 3H), 3.90 (m, 2H), 4.25 (m, 1H), 4.48 (m, 1H), 5.46 (m, 1H), 5.58 (dd, 1H), 6.14 (t, 1H), 6.44 (dd, 1H) ppm. C. In a similar manner, other compounds of formula (Ua) may be prepared.
PREPARATION 6
Compounds of formula (Y), formula (Z), formula (AA), formula (BB), formula
(CC) AND FORMULA (DD)
A. Oxalyl chloride (60 mL, 686 mmol) and dimethylformamide (DMF) (8 drops, cat.) were added to a stirred suspension of 2-(4-fluorophenoxy)ethanoic acid (97.3 g, 572 mmol) in dichloromethane (500 mL). After 22 hours, the mixture was concentrated under vacuum to obtain 108 g of 2-(4-fluorophenoxy)ethanoic acid chloride, a compound of formula (Y), as a yellow oil in quantitative yield; 'H NMR (CDC13) 6 4.90 (s, 2H), 6.84 (m, 2H), 6.99 (m, 2H) ppm.
B. 2-(4-Fluorophenoxy)ethanoic acid chloride was added slowly to a stirred suspensionof N,Odimethylhydroxylaminehydrochloride (55.80 g, 572 mmol) in saturated K2CO3and ethyl acetate (375 mL). A moderately exothermic reaction occurred (larger scale reactions are cooled with an ice bath), and after 20 minutes, the reaction mixture was partitioned between water and ether. The ether layer was washed with 1 M HC1 and saturated NaCl, and dried over MgS04. The dried solution was filtered and concentrated under vacuum to give A/-methoxy-iV-methyl-2-
(4-fluorophenoxy)ethanamide, a compound of formula (Z), as a yellow oil which solidified to an off-white crystalline solid, 113.05 g (73 % yield from starting acid); 'H NMR (CDC13,400 mHz) 5 3.21 (s, 3H), 3.73 (s, 3H), 4.75 (s, 2H), 6.87 (m, 2H), 6.95 (m, 2H) ppm. C. A solution of ethynylmagnesium bromide (0.5 M in THF, 508 mL, 254 mmol), was added slowly, as a stream down the side of the flask, to an ice water cooled solution of A^-methoxy-A^-methyl-2-(4-fluorophenoxy)ethanamide (20.00 g, 74 mmol) in THF (100 mL). After an additional 30 minutes at 0°C, the reaction mixture was poured into a vigorously stirred mixture of 1M NaH2S04(1700 mL) and ether (1 L). The layers were separated and the aqueous layer then extracted with ether (700 mL). The combined organic phases were washed with brine and dried over MgS04, filtered, and concentrated under vacuum. The residue was purified by eluting through a plug of silica gel (10 cm x 3 cm) with 1:4 ethenpet. ether to afford 27.65 g (91 % yield) of 4-(4-fluorophenoxy)-l-butyn-3-one, a compound of formula (AA), as a low melting solid;<!>H NMR (CDC13) 5 3.40 (s, 1H), 4.70 (s, 2H), 6.85 (m, 2H), 7.0 (t, 2H) ppm. D. A solution of R-Alpine-Borane<®>(0.5 M in THF, 930 mL, 465 mmol) was evaporated to dryness under vacuum to get about 150 g of a thick syrup. 4-(4-Fluorophenoxy)-l-butyn-3-one (27.6 g, 155 mmol) was added and when an exothermic reaction was observed, the reaction mixture was cooled with an ice/water bath, then allowed to warm to ambient temperature. After two days, the reaction mixture was cooled to 0°C and acetaldehyde (26 mL, 465 mmol) was added to quench the excess reagent. After stirring at ambient temperature for 2 hours the reaction mixture was placed under vacuum and stirred first at 0°C for one hours, then at 65°C for 2 hours. The reaction mixture was cooled to ambient temperature and ether (300 mL) was added under nitrogen. Ethanolamine (30 mL, 465 mmol) was added drop-wise at 0°C and the resulting reaction mixture was stored in the freezer overnight. The resulting precipitate was removed by filtration and washed with cold ether. The combined filtrates were concentrated under vacuum. The crude product was purified by flash chromatography on a 2.5 L column of silica gel with 10-25 % ethyl acetate in hexane as eluant to obtain 27 g of (3.S)-4-(4-fluorophenoxy)-3-hydroxy- 1-butyne, a compound of formula (BB), in quantitative yield;<*>H NMR (CDC13) 8 2.56 (s, 1H), 4.10 (m, 2H), 4.78 (m, 1H), 6.85 (m, 2H), 7.0 (m, 2H). This material was determined to be about 64% ee based on chiral HPLC of its 3,5-dinitrobenzoyl ester (see below).
E. To a solution of (3S)-4-(4-lfuorophenoxy)-3-hydroxy-1-butyne (est. 490 mmol) in methylene chloride (1 L) was added 3,5-dinitrobenzoyl chloride (125 g, 539 mmol) at between -5°C and 0°C , followed by slow addition of triethylamine (10.8 mL, 77 mmol) and a catalytic amount of dimethylaminopyridine (DMAP) (20 mg). After the mixture was stirred at ambient temperature for 40 minutes, the reaction mixture was cautiously partitioned between methylene chloride and aqueous NaHCC>3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and brine, and dried over Na2S04. The solution was filtered through a pad of silica gel with methylene chloride which gave crude product as a tan solid. Rapid recrystallization from 99:1 mixture of methanol:acetic acid (5 L) gave 101 g of the enantiomerically enriched product, (35)-4-(4-fluorophenoxy)-3-(3',5'-dinitrobenzoyl)oxy-1-butyne, a compound of formula (BBa) as fluffy white needles. This material was determined to have greater than 98% ee by analytical HPLC using a Diacel Chiralpak AD® (4.6 X 250 mm, 60% 2-propanol/hexane, 1 inL/min), which separates the (R) (11.5 min) and the (S) (19.3 min) enantiomers; 'H NMR (CDC13) 5 2.65 (s, 1H), 4.40 (m, 2H), 6.05 (m, 1H), 6.90 (m, 2H), 7.0 (t, 2H), 9.15 (s, 2H), 9.25 (s, 1H) ppm.
F. To a solution of (35)-4-(4-fluorophenoxy)-3-(3',5'-dinitrobenzoyl)oxy-1-butyne (10.35 g, 98% ee, 27.6 mmol) in THF (115 mL), was added methanol (115 mL) and K2CO3(0.58 g). After stirring for 3.5 hours, the reaction mixture was quenched with acetic acid (2 mL). The solvents were evaporated and the resulting slurry was filtered and the solid was washed with ether. The filtrate was concentrated and the filtration/ether wash sequence was repeated. Concentration gave 4.02 g of (35)-4-(4-fiuorophenoxy)-3-hydroxy-1-butyne (98%) ee), a compound of formula (BB); 'll NMR (CDC13) 5 2.56 (s, III), 4.10 (m, 2H), 4.78 (m, III), 6.85 (m, 2H), 7.0 (m, 2H).
G. A mixture of (35)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (2.5 g, 14 mmol), Af-bromosuccinimide (NBS) (2.74 g, 15.4 mmol) and AgN03(0.12 g, 0.7 mmol) in acetone (70 mL) was stirred at ambient temperature. The pale solution became cloudy over 30 minutes. The mixture was concentrated under vacuum and the resulting residue was filtered through a plug of silica gel (1X5 cm) eluted with 1:4 ethyl acetate:hexane to obtain (35)- l-bromo-4-(4-fluorophenoxy)-3-hydroxy- 1-butyne, a compound of formula (CC), as a pale yellow oil containing some ethyl acetate, 4.75 g (quant.); 'H NMR (CDC13) 5 3.95-4.15 (m, 2H),4.75 (m, 1H), 6.86 (m, 2H), 6.97 (m, 2H) ppm.
H. A1C13(2.79 g, 21 mmol) was added in portions to a mixture of lithium aluminum hydride (LAH) (1.06 g, 28 mmol) and ether (70 mL). A solution of (35)-l-bromo-4-(4-fluorophenoxy)-3-hydroxy-l-butyne (14 mmol) in ether (10 mL) was added cautiously. A vigorous reaction with evolution of gas was observed. The mixture was warmed to reflux on a water bath for 30 minutes. The reaction mixture was then cooled to 0°C and treated with 2.8 mL water (slowly, vigorous reaction), 2.8 mL 15% NaOH, and finally 8.4 mL water. The resulting suspension was then stirred 10 minutes, filtered and the solids were washed with THF and ether. The solution was concentrated under vacuum to afford 2.94 g (81 % yield for two steps) of (IZ, 3S)-1-bromo-4-(4-lfuorophenoxy)-3-hydroxy-l-butene, a compound of formula (DD);<l>H NMR (CDC13) 5 2.41 (t, 1H), 3.85 (dd, 1H), 3.99 (dd, 1H), 4.50 (m, 1H), 6.31 (dd, 1H), 6.52 (dd, 1H), 6.83 (m, 2H), 6.97 (t, 2H) ppm. I. In a similar manner, other compounds of formula (DD) may be prepared:
PREPARATION 7
Compounds of formula (EE)
A. In a flame dried flask, a solution of (IZ, 35)-l-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (0.84 g, 3 mmol), tetrakis(tirphenylphosphine)palladium(0) (0.13 g, 0.2 mmol) and copper(I) iodide (60 mg, 0.3 mmol) in THF (50 mL) and diethylamine (5 mL, 48 mmol) was carefully deoxygenated by bubbling in argon gas for 45 minutes. The reaction was stirred as a solutionof 2-[[(4S, 5R)- 5-[( lE,3£)-l,3-hexadien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (0.9 g, 3.2 mmol) in THF (50 mL), which had been deoxygenated by bubbling in argon for 45 minutes, was added. After about 4 hours, the reaction was complete. The reaction mixture was diluted with hexane and filtered through a pad of silica gel and the silica gel was eluted with ether. The combined filtrates were concentrated to give an oil. Purification by chromatography using a 20-75% gradient of ether in hexane gave 1.1 gof 2-[[(4S,5^?)-5-[(l£,3£,6Z,8S,)-8-hydroxy-9-(4-fluorophenoxy)-l,3,6-nonatrien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (EE), as an oil; 'H NMR (CDCI3) 5 1.37 (s, 3H), 1.5 (s, 3H), 3.52 (m, 2H), 3.75 (s, 3H), 3.83 (m, 2H), 4.13 (m, 2H), 4.44 (m, 1H), 5.74 (m, 1H), 5.76 (m, 2H), 6.05 (m, 1H), 6.17 (m, 1H), 6.29 (m, 1H), 6.58 (dd, 1H), 6.88 (m, 4 H) ppm.
B. In a similar manner, other compounds of formula (EE) may be prepared.
PREPARATION 8
Compounds of Formula (GG)
A. A slurry of copper sulfate (175 g, 1.09 mol, 2 eq) and rhamnose hydrate (100 g, 0.55 mol) in freshly distilled cyclohexanone (330 g) was stirred under nitrogen as concentrated sulfuric acid (1.5 mL) was added at once. The reaction mixture was warmed to about 29°C internal. The reaction mixture was allowed to stir overnight. The reaction was analyzed by TLC (ethyl acetate) and was complete. The reaction mixture was filtered through a pad of celite and the solid was washed with ethyl acetate. The filtrate was treated with about 1.5 mL of concentrated ammonium hydroxide to pll 7, and the resulting solid was removed by filtration. The filtrate was concentrated under reduced pressure to give a colorless oil. The residue was dissolved in ether and treated with hexane and allowed to stand overnight. Resulting solid was isolated by filtration and dried to give 92.3 g (0.31 mol, 57%) of (2/?,3/?)-3-(l,2-dihydroxypropyl)-l,4-dioxaspiro[4,5]decane-2-carboxaldehyde, as an off-white solid: [a]D = +0.457 (10.485 mg / cc MeOH); 'H NMR (CDC13) 5 1.34 (d, 3H), 1.40 (m, 2H), 1.6 (m, 8H), 2.78 (d, 1H), 3.0 (s, 1 H), 3.9 (m, 1H), 4.07 (m, 1H), 4.6 (d, 1H), 4.9 (m, 1H), 5.4 (s, lH)ppm.
B. In a similar manner, other compounds of formula (GG) are prepared.
PREPARATION 9
Compounds of Formula (HH)
A. A slurry of sodium borohydride (34.2 g, 0.9 mol) in methanol (400 mL) was cooled in an ice bath and treated with (2/?,3/?)-3-(l,2-dihydroxypropyl)-l,4-dioxaspiro[4,5]decane-2-carboxaldehyde (92 g, 0.27 mol) dissolved in 200 mL of methanol. The reaction mixture was stirred for about 4 hours. The reaction was complete and acetic acid was added to consume excess borohydride and to adjust the pH to about 6 (about 120 mL). The reaction mixture was concentrated and dissolved in ethyl acetate. The resulting solid was removed by filtration. The combined filtrates were dried, and concentrated to give a slightly yellow viscous oil. The residue was dissolved in ether and treated with hexane to precipitate the product. Solids were isolated by filtration and dried to give 81.2 g of( 2R, 3S)a<2->(l-hydroxyethyl)-l,4-dioxaspiro[4,5]decane-2,3-dimethanol as an off-white solid: [a]D = +5.494 (10.119 mg/cc MeOH); 'H NMR (CD3OD) 8 1.28 (d, 3H), 1.43 (m, 2H), 1.7 (m, 8H), 3.42 (dd, 1H), 3.7 (m, 3H), 4.25 (m, 1H), 4.42 (dd, 1H) ppm.
B. In a similar manner, other compounds of formula (HH) are prepared.
PREPARATION 10
Compounds of Formula (JJ)
A. A mixture of( 2R, ?>S)a<2->(l-hydroxyethyl)-l,4-dioxaspiro[4,5]decane-2,3-dimethanol (81 g, 0.32 mol) and/-butyl bromoacetate (77 g, 0.39 mol, 1.2 eq) in 1 L of toluene was stirred with a mechanical stirrer as 80 mL of sodium hydroxide in water (25% by weight) was added. Phase transfer catalyst, tetrabutylammonium sulfate (7.8 g, 23 mmol, 0.07 eq), was added and the reaction mixture was stirred overnight and monitored by TLC. The reaction mixture was diluted with ethyl acetate and saturated aqueous potassium phosphate monobasic. The combined organic layers were dried and concentrated to give a clear oil. Chromatography on 1 Kg of silica gel using a step gradient of 20%> ether in hexane, 50% ether in hexane, and ether gave 34 g of pure product and 38 g of an impure fraction. Chromatography on the mixed fraction using a gradient of ether in hexane gave a pure fraction which was combined with the earlier fraction to give 50.8 g (44%>) of 1,1-dimethylethyl[[( 2S, 3R)3-(l,3-dihydroxypropyl)-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate as an oil: fa]D = +8.587 (10.301 mg / cc MeOH). 'H NMR (CDCI3) 8 1.24 (d, 3H), 1.35 (m, 2H), 1.47 (s, 9H), 1.6 (m, 8H), 3.6 (m, 2H), 3.8 (m, 2H), 3.95 (m, 2H), 4.32 (m, 1H), 4.4 (m, 1H) ppm.
B. In a similar manner, other compounds of formula (JJ) are prepared.
PREPARATION 11
Compounds of Formula (KK)
A. A solution of 1,1-dimethylethyl[[(25,37?)3-(l,3-dihydroxypropyl)-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (50 g, 138 mmol) in acetone (350 mL) was treated with a solution of periodate (50 g, 235 mmol, 1.7 eq) in water (1.2 L). The reaction mixture was stirred vigorously under nitrogen and monitored by TLC. After about 4 hours, the reaction was complete by TLC analysis. Acetone was removed under reduced pressure without heating. The reaction mixture was extracted with ethyl acetate (3x 500 mL). The combined organic layers were dried and concentrated under reduced pressure without heating to give 40 g of 1,1-dimethylethyl [[(25,35) 3-formyl-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate as a clear oil: [a]D= -1.142 (10.147 mg/cc in MeOH); 'H NMR (CDC13) 5 1.38 (m, 2H), 1.42 (s, 9H), 1.61 (m, 8H), 1.73 (m, 2H), 3.52 (dd, 1 H), 3.72 (dd, 1 H), 3.88 (s, 2H), 4.38 (dd, 1 H), 4.52 (m, 1H), 9.62 (s, 1H) ppm.
B. In a similar manner, other compounds of formula (KK) are prepared.
PREPARATION 12
Compounds of Formula (LL)
A. A slurry of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (Q), (67.1 g, 0.14 mol) in THF (875 mL) was stirred under nitrogen, cooled in a dry ice acetonitrile bath (-30°C internal), and treated with a solution of «-butyllithium (66.5 mL, 0.133 mol, 2M in hexane) via dropwise addition. The dry ice bath was replaced with an ice bath and the reaction was stirred for about 15 minutes until a homogeneous, red-colored mixture was obtained. The dry ice bath was replaced and the reaction mixture was cooled to about -30°C. The reaction mixture was treated with a solution of 1,1-dimethylethyl [[(25,35) 3-formyl-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (40 g, 0.127 mol) in 125 mL of THF. The reaction mixture was stirred for 1 hour with the dry ice bath. With the internal temperature around -30°C, the reaction mixture was diluted with saturated potassium phosphate (pH = 5). The aqueous layer was washed with ether (3x). Combined organic layers were washed with water and brine, dried, treated with silica gel, and concentrated. The residue was diluted with about 3:1 mixture of hexane to ethyl acetate to precipitate the impurities. The resulting slurry was filtered and the solid was washed with the hexane/ethyl acetate mixture. The filtrate was concentrated. The procedure was repeated using a mixture of ether and hexane (1:1) and treatment with silica gel to give 50.29 g of 1,1-dimethylethyl [[(25,3/?)-3-[(lZ,3£)-6-(trimethylsilyI)-l,3-hexadien-5-ynyl]-l ,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate as an oil. Proton NMR analysis of the product indicated a 2:1 mixtureof E, Z-to is.iwsomers. The data for the for theZ, Eisomer can be extracted from the mixture: 'H NMR (CDC13) 8 0.15 (s, 9H), 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 3.45 (m, 2H), 3.92 (m, 2H), 4.34 (m, 1H), 5.02 (m, 1H), 5.48 (dd, 1H), 5.6 (d, 1H), 6.16 (dd, 1H), 6.82 (dd, 1H) ppm.
B. In a similar manner, other compounds of formula (KK) are prepared.
Example 1
Compounds of formula (lla)
A. A solution of 2-[[(45,5^)-5-[(l£,3£,6Z,85,)-8-hydroxy-9-(4-fluorophenoxy)-l,3,6-nonatrien-5-ynyl]-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (1.1 g, 1.8 mmol) in methanol (25 mL) was treated with 1 mL of 1 N hydrochloric acid and the reaction was stirred for 2 days. The pH of the reaction was adjusted to neutrality. Purification on preparative reverse phase semi-prep column using a gradient of acetonitrile in water yielded 1.1 g of (55,6tf ,7£,9£, 13£, 155)- 16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, as an oil; 'H NMR (CDC13) 5 3.67 (m, 2H), 3.75 (s, 3H), 3.83 (m, 1H), 3.95 (m, 1H), 4.13 (m, 2H), 4.37 (m, 1H), 4.58 (m, 1H), 5.73 (dd, 1H), 5.86 (dd, 1H), 6.04 (dt, 1H), 6.17 (m, 1H), 6.40 (m, 1H), 6.58 (m, 1H), 6.9 (m, 4H) ppm.
B. In a similar manner, the following compound of formula (lla) was prepared: (55,6.S,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester. C. A solution of (55,6/?,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-ll-ynoic acid, methyl ester, (0.4 g, 0.95 mmol) in methanol (20 mL) was treated with 1 N NaOH (aq) (4 mL, 4 mmol) solution and shaken and allowed to stand for three hours. The reaction mixture was then treated with saturated potassium monophosphate and poured onto an HP20 column. Elution with a gradient of methanol in water gave 0.35 g of( 5S, 6RJE, 9E,\ 3E,\ 5S)-\ 6-( 4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-l 1-ynoic acid, which solidified upon standing; 'H NMR (CD3OD) 6 3.63 (m, 2H), 3.667 (m, 1H), 3.91 (m, 2H), 4.113 (s, 2H), 4.150, (t, 1H), 4.498, (m, 1H), 5.762 (dd, 1H), 5.953 (dd, 1H), 6.003 (dt, 1H), 6.202(dd, 1H), 6.380 (dd, 1H), 6.596 (dd, 1H), 6.928 (m, 2H), 6.988 (m, 2H) ppm. D. In a similar manner, the following compound of formula (lla) was prepared: (5S,65,7£,9£, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid.
E. In a similar manner as described above, the following compounds of formula (II) are prepared:{ 2E, 5S, 6RJE, 9E, 13£, 155)- 16-(4-fluorophenoxy)-5,6,15 -
trihydroxyhexadeca-2,7,9,13-tetraen-l 1-ynoic acid;
(2£,55,6tf,7£,9£, 1 3E,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxyhexadeca-2,7,9,13-tetraen-l 1-ynoic acid, methyl ester;
( 5R, 6RJE, 9E, 1 3E,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid;
( 5R, 6RJE, 9E, 13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester;
(55,6i?,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-
oxahexadeca-7,9,13-trien-11 -ynamide;
(55,6tf ,7£,9£, 1 3E,155)-16-(4-lfuorophenoxy)-5,6,15-trihydroxy-A^-dimethyl-3-oxahexadeca-7,9,l 3-trien-11-ynamide;
(75,8^,9£,ll£,15£,175)-18-(4-fluorophenoxy)-7,8,17-trihydroxy-5-oxaoctadeca-9,11,15-trien-13-ynoic acid;
(75,8tf ,9£, 11£, 15£, 175)-18-(4-fluorophenoxy)-7,8,17-trihydroxy-5-oxaoctadeca-9,11,15-trien-13-ynoic acid, methyl ester;
(55,6i?,7£,9£,13£,155)-16-(4-fluoro<p>henoxy)-5,6,15-trih<y>droxy-3-
thiahexadeca-7,9,13-trien-l 1-ynoic acid;
( 5S, 6RJE, 9E, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-
azahexadeca-7,9,13-trien-11-ynoic acid;
(55,6^,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,15-dihydroxy-6-(methylamino)-3-oxahexadeca-7,9,13-trien-l 1-ynoic acid; and
( 5S, 6RJE, 9E, 13£,155)-16-(4-fluorophenoxy)-5,15-dihydroxy-6-amino-3-oxahexadeca-7,9,13-trien-l 1-ynoic acid.
F. The compounds of formula (lla) as prepared above are treated with the appropriate acylating agent, such as phosgene, under acidic conditions to yield the following compounds: [[5-[(l£,3£,7£,9J/?)-10-(4-fluorophenoxy)-9-hydroxy-l,3,7-decatrien-5-ynyl]-2-oxo-l ,3-dioxolan-4-yl]methoxy]acetic acid;
[[5-[(l£,3£,7£,9^)-10-(4-fluorophenoxy)-9-hydroxy-l,3,7-decatrien-5-
ynyl]-2-oxo-l,3-oxathiolan-5-yl]methoxy]acetic acid; and
[[5-[(l£,3£,7£,9i?)-10-(4-fluorophenoxy)-9-hydroxy-l,3,7-decatrien-5-ynyl]-2-oxo-5-oxazolidinyl]methoxy]acetic acid.
Example 2
Compounds of formula (lib)
A. A solution of( IZ,35)-l-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (16.6 g, 63 mmol), solid tetrakistriphenylphosphinePd(O) (3.67 g, 3 mmol), and Cu(I) iodide (1.2 g, 6.3 mmol) in diethylamine (50 mL) and THF (800 mL) was stirred and deoxygenated by bubbling argon through the mixture for 90 minutes. Argon addition continued as a similarly deoxygenated solution (argon bubbling) of 1,1-dimethylethyl [[(25,37?)-3-[(lZ,3£)-6-(trimethylsilyl)-l,3-hexadien-5-ynyl]-l,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate (23 g, 63 mmol) in 200 mL of THF was added dropwise over about 3 hours. The reaction was monitored by TLC analysis. After about an additional 2 hours, the reaction was complete by TLC analysis. The reaction mixture was diluted with hexane (about 400 mL), treated with silica gel (about 40 g) and filtered. The solid was washed with a 1:1 solution of ether and hexane. The filtrate was concentrated to give 36.8 g of an oil. The residue was dissolved in ether, treated with hexane, and allowed to stand over the weekend. Highly colored material was removed by filtration through a pad of silica gel and product eluted with ether. The desired fractions were concentrated to give an oil. Purification by chromatography on 1 Kg of silica gel using a 15-50% gradient of ether in hexane gave 16.9 g of 1,1-dimethylethyl[[( 2S,3/?)-3-[(l£,3£,7£,95)-10-(4-fluorophenoxy)-9-hydroxyl-l,3,7-decatrien-5-ynyl]-l,4-dioxaspiro[4,5]dec-2-yl]methoxy] ethanoate as an oil: [a]D = - 21.174 (10.165 mg/cc in MeOH); 'H NMR (CDC13) 5 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 2.42 (s, 111), 3.5 (d, 2H), 3.96 (m, 4H), 4.38 (q, III), 4.58 (m, 1H), 4.66 (t, 1H), 5.72 (m, 1H), 5.78 (dd, 1H), 6.03 (m, 1H), 6.16 (dd, 1H), 6.33 (dd, 1H), 6.58 (dd, 1H), 6.88 (m, 4H) ppm.
B. In a similar manner, other compounds of formula (lib) are prepared.
Example 3
Compounds of formula (lie) and formula (lid)
A. A solution of 1,1- dimethylethyl[[( 2S, 3^)-3-[(l£,3£,7£,95')-10-(4-fluorophenoxy)-9-hydroxyl-l,3,7-decatrien-5-ynyl]-l,4-dioxaspiro[4,5]dec-2-yljmethoxy] ethanoate (1 g, 2.8 mmol) in acetic acid (50 mL) was diluted with ethyl acetate (50 mL) and placed in a 55°C oil bath for 20 hours. The reaction was complete by TLC analysis. Acetic acid and ethyl acetate were removed by distillation under high vacuum. The residue was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water, saturated aqueous sodium carbonate, water, and brine solution, dried and concentrated to give 0.9 g of an oil. Chromatography on an HP-20 column eluting with a gradient of methanol in water gave
( 5S, 6RJE, 9E, 13£, 1 5S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-
trien-11-ynoic acid,/-butyl ester (a compound of formula (He)). The combined fractions were treated with 1 N sodium hydroxide solution (2 mL) and concentrated. The reaction was complete by TLC after about 1 h and placed on an HP20 column. Chromatography using a gradient of methanol in water gave 0.3 g of (55,6/?,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid; which solidified upon standing; 'H NMR (CD3OD) 5 3.63 (m, 2H), 3.667 (m, 1H), 3.91 (m, 2H), 4.113 (s, 2H), 4.150, (t, 1H), 4.498, (m, 1H), 5.762 (dd, 1H), 5.953 (dd, 1H), 6.003 (dt, 1H), 6.202 (dd, 1H), 6.380 (dd, 1H), 6.596 (dd, 1H), 6.928 (m, 2H), 6.988 (m, 2H) ppm.
B. In a similar manner, other compounds of formula (lie) and formula (lid) are prepared.
Example 4
Compounds of formula (I)
A. Activated zinc was prepared from 10 g of zinc and the reduction carried out using the procedure described inHelv. Chim. Acta(1987), Vol. 70, p. 1025). A solution of (55,6i?,7£,9£,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, (0.8 g, 1.2 mmol) in methanol (4 mL) was added to a slurry of activated zinc in 1:1 methanoLwater (45 mL). The flask was stirred vigorously under nitrogen for 24-60 hours. The mixture was filtered through a pad of Celitc 545 and rinsed with methanol (3x25 mL). Purification by chromatography on a reverse phase semi-prep column using a gradient of acetonitrile and water afforded 55 mg of (5S,6#,7£,9£,1 lZ,13£,15S>16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,l 1,13-hexadecatetraenoic acid, methyl ester, as an oil; 'H-NMR (400 mHz, methanol-d4) 5 3.62 (m, 2H), 3.75 (s, 3H), 3.93 (m, 2H), 4.13 (m, 3H), 4.58 (m, 1H), 5.85 (m, 2H), 6.14 (m, 2H), 6.36 (m, 2H), 6.77 (m, 1H), 6.96 (m, 5H) ppm.
B. In a similar manner, other compounds of formula (I) may be prepared.
C. A solution of( 5S, 6RJE, 9E, 11Z, 1 3E, 1 5S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,l 1,13-hexadecatetraenoic acid, methyl ester, (25 mg, 59
nMol) in methanol (6 mL) was treated with 1 N NaOH (aq) (25 uL, 25 umol) solution and shaken and allowed to stand. Upon completion, the reaction was treated with saturated potassium monophosphate. Purification by chromatography on an HP20 column eluted with an aqueous methanol gradient gave 10 mg of(55,6tf ,7£,9£, 11Z,13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid;<*>H NMR (CD3OD) 8 3.6 (m, 3H), 3.88 (m, 4H), 4.18 (m, 1H), 4.52 (m, 1H), 5.84 (m, 2H), 6.03 (m, 2H), 6.34 (m, 2H), 6.74 (m, 1H), 6.95 (m, 5H) ppm. D. In a similar manner as described above, the following compounds of formula (I) are prepared:(2£,55,6/?,7£,9£, 11Z,13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxyhexa-2,7,9,11,13-decapentaenoic acid;
(2£,55,6/?,7£,9£, 11Z,13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxyhexa-2,7,9,11,13-decapentaenoic acid, methyl ester;
(5#,6fl,7£,9£, 11Z,13 £, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3 - oxa-7,9,11,13-hexadecatetraenoic acid;
(5/?,6/?,7£,9£,llZ,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester;
(55,6i?,7£,9£,llZ,13£,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenamide;
( 5S, 6RJE, 9E, 11Z, 1 3E, 155)-l 6-(4-fluorophenoxy)-5,6,15-trihydroxy-N, yV-dimethyl-3-oxa-7,9,11,13-hexadecatetraenamide;
(75,8 R, 9E, 11 E, 13Z, 15£, 175)-18-(4-lfuorophenoxy)-7,8,17-trihydroxy-5 -
oxa-9,11,13,15-octadecatetraenoic acid;
(75,8fl,9£, 11 £, 13Z,15£, 175)-18-(4-fluorophenoxy)-7,8,17-trihydroxy-5 - oxa-9,11,13,15-octadecatetraenoic acid, methyl ester;
(55,6fl,7£,9£, 11Z, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3 - thia-7,9,11,13-hexadecatetraenoic acid;
( 5S, 6RJE, 9E, 1 IZ, 13£, 155)-l 6-(4-fiuorophenoxy)-5,6,15-trihydroxy-3-aza-7,9,11,13-hexadecatetraenoic acid;
(55,6/?,7£,9£, 11Z,13£, 155)-16-(4-fluorophenoxy)-5,15-dihydroxy-6-(methylamino)-3-oxa-7,9,11,13-hexadecatetraenoic acid; and
(55,6/?,7£,9£, 11Z, 13£,155)-16-(4-fluorophenoxy)-5,15-dihydroxy-6-amino-3-oxa-7,9,l 1,13-hexadecatetraenoic acid.
Example 5
This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The above ingredients are mixed and dispensed into hard-shell gelatin capsules containing 100 mg each, one capsule would approximate a total daily dosage.
The above ingredients with the exception of the magnesium stearate are combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with an appropriate
tableting machine.
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL of the solution which is filtered and bottled.
The above ingredients are melted, mixed and filled into soft elastic capsules.
The compound of the invention is dissolved in the cellulose/saline solution, filtered and bottled for use.
Example 6
This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 mL of the I.V. solution which is filtered through a 0.2 m membrane filter and packaged under sterile conditions.
Example 7
This example illustrates the preparation of a representative pharmaceutical composition in suppository form containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
Example 8
This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing pump.
Example9
This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The compound of the invention is dissolved in ethanol and blended with water. The formulation is then packaged in a nebulizer equipped with a dosing pump.
Example 10
This example illustrates the preparation of a representative pharmaceutical formulation in aerosol form containing a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof:
The compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container fitted with a metering valve.
Example 11
(In Vitro Assay)
Trans-epithelial and trans-endothelial migration assays
Culture of Human Umbilical Vein Endothelial Cells ( HUVEC) :
Human umbilical vein endothelial cells (HUVEC) were cultured according to the methods disclosed in Serhan, C.N.,et al, Biochemistry(1995). Vol. 34, No. 44, pp. 14509-14615. In particular, HUVEC were used at passages 1 and 2 and were isolated by collegenase digestion (0.1% collagenase, CLS3; Worthington Biochem. Corp., Freehold, New Jersey) and propagated on gelatin-coated (1%>) tissue culture plates (Costar Corp., Cambridge, Massachusetts) in RPMI 1640 cell culture medium (BioWhittaker Inc., Walkersville, Maryland) supplemented with 15%> bovine calf serum (BCS) (Hyclone Laboratories, Logan, Utah), 15% NU-serum (Collaborative Research Inc., Lexington, Massachusetts), 50<p>g/mL endothelial mitogen (Biomedical Technologies Inc., Stoughton, Massachusetts), 8 units/mL heparin, 50 units/mL penicillin, and 50 ug/mL streptomycin. For transmigration assays HUVEC were seeded and grown to confluence on gelatin-coated (1%) polycarbonate permeable supports (inserts) with a surface area of 0.33 cm<2>(Costar Inc., Cambridge, MA).
Epithelial Cell Culture:
T84cells were grown in a 1:1 mixture of Dulbecco's modified Eagle medium and Hams F-12 medium supplemented with 15 mM HEPES buffer (pH 7.5), 14 mM NaHCCb, 40 ug/mL penicillin, 8 ug/mL ampicillin, 90 ug/mL streptomycin, and 5% newborn calf serum (Dharmasathaphornet al,1990). For apical-to-basolateral transmigration experiments, Tg4monolayers were grown on collagen-coated, polycarbonate permeable supports (inserts) with a surface area of 0.33 cm2 (Costar Inc., Cambridge, MA) as described in Parkos,C.A.,e/ al, J. Clin. Invest.(1991), Vol. 88, pp. 1605-1612. For physiologically directed, basolateral-to-apical neutrophil transmigration experiments, Tg4cells were plated on the underside of 0.33 cm<2>polycarbonate filters that had been lightly coated with rat-tail collagen as described in Parkos, C. A.,et al..This permitted growth of inverted monolayers, which thus allowed neutrophils to settle by gravity into the immediate subepithelial compartment.
Assay:
Human polymorphonuclear leukocytes (PMN) were isolated from normal human volunteers and suspended at a concentration of 5xl0<7>cells/mL in modified Hanks balanced salt solution (HBSS), without Ca<2+>and Mg2+, with lOmM Hepes, pH 7.4, (Sigma). Prior to the addition of PMN, T«4epithelial or HUVEC endothelial cell monolayers were extensively rinsed in HBSS to remove residual serum components. PMN were pre-exposed to compounds of the invention at concentrations ranging from 10"" to 10"<7>M for 15 minutes at 25°C. The transmigration assay was performed by the addition of PMN (40 ul) to HBSS (containing Ca<2+>and Mg<2+>, 160 pi) in the upper chambers after chemoattractant (10 nM fMLP) was added to the opposing (lower) chambers. PMN were not washed free of the compounds of the invention prior to addition to monolayers. PMN (1x106) were added at time 0. Transmigration was allowed to proceed for 60 minutes. All experiments were performed in a 37°C environment to ensure that endothelial/epithelial monolayers, solutions, plasticware, etc., were maintained at uniform 37°C temperature. Transmigration was quantitated by assaying for the PMN azurophilic granule marker myeloperoxidase (MPO). Following each transmigration assay, non-adherent PMN were extensively washed from the surface of the monolayer and PMN cell equivalents (PMN CE), estimated from a standard curve, were assessed as the number of PMN which had completely traversed the monolayer( i. e.,across the monolayer into the reservoir bath).
The compounds of the invention, when tested in this assay, demonstrated the ability to inhibit the transmigration of PMN across polarized monolayers of epithelial cells and vascular endothelial cells, which are sites of two important immune events in host defense and inflammation.
Example 12
(In VivoAssay)
ChemotaxisAssay
Chemotaxis experiments were performed on freshly prepared human neutrophils (PMN) obtained from whole blood donated by healthy volunteers. Blood was anticoagulated (heparin), centrifuged at low speed and platelet-rich plasma removed by aspiration. The remaining blood was mixed with an equal volume of phosphate buffered saline minus Ca<+2>/Mg<+2>, pH 7.4 (PBS"<7>") and an equal volume of 3% dextran in PBS"'" was added, sample mixed and allowed to settle. The upper layer enriched for white blood cells (-25 mL) was applied to a 15 mL cushion of Ficoll-Hypaque and centrifuged at 400g for 30 minutes at 18-22 "C. The upper layers were aspirated and the PMN cell pellet subjected to hypotonic red blood cell lysis. PMN were washed twice and resuspended in Hank's Balanced Salt Solution minus Ca<+2>/Me<+2>pH 7.4 (HBSS7") at lxlO<7>cells/mL in a centrifuge tube. 2.5 uM Calcein-AM (Molecular Probes cat #C3100) was added and the cells incubated for 25 minutes at ambient temperature, then placed in a 37°C incubator for 5 minutes. The cells were then centrifuged and washed twice in HBSS"'" to remove residual Calcein-AM. Neutrophils were finally resuspended at 2 xl0<7>/mL with HBSS"'" + 10 mM HEPES, pH 7.4.
Chemotaxis assays were performed with specialized 96-well plates. The 3 urn filter was bonded to a metallic frame and was selectively coated with a hydrophobic mask around each well. This hydrophobic mask allowed for the direct addition of cells to the topside of the filter. Neutrophils (15 uL, 1.5xl0<5>cells/well) were added to the top of the ChemoTx® plate (Cat #101-3). For inhibition studies, PMN were pre-incubated for 15 minutes with a compound of the invention. Prior to adding PMN to the top chamber, 30 uL of chemoattractant (10 nM fMLP or 10 nM LTB4or F-12 culture medium (without phenol red) was added to the lower chamber, the filter mat was then snapped in place and PMN added to the filter with an 8-channel pipettor. The assay plates were incubated for 90 minutes at 5% CO2+ 95% air at 37°C. After incubation, the filter mat was removed and the plate was read in the Victor II plate reader (485nm-excitation/535nm emission). The fluorescently tagged cells that have migrated through the filter into the lower chamber were measured.
When tested in this assay, the compounds of the invention demonstrated the ability to inhibit human neutrophil chemotaxis.
Example 13
(In VivoAssay)
Mouse zymosan-induced peritonitis model
The following assay was used to evaluate the ability of the compounds of the invention to inhibit inflammationcharacterized bycellular infiltration into a localized area.
A compound of the invention in 0.1% ethanol/PBS vehicle was administered via intravenous, intra-peritoneal, subcutaneous or intra-gastric delivery to six to eight week-old FVB mice (average 21 g) purchased from Charles River Laboratories. For intra-gastric studies, 200 uL of each compound concentration were delivered using animal feeding needles. Approximately forty-five minutes later, 1 mL (1 mg/mL) zymosan A was injected into the peritoneum. Two and a half hours after the intra-peritoneal injection, mice were euthanized with an overdose of isoflurane and peritoneal lavages with 5 mL of PBS containing calcium and magnesium were collected. Total leukocytes were enumerated by light microscopy and percentage inhibition relative to vehicle control is calculated. For differential inhibitory effects on neutrophils, eosinophils, monocytes and lymphocytes, -250,000 cells were transferred to glass slides and stained with 0.4%> of Wright Giemsa Stain, differentiated by counting under a microscope (x40) and percentage inhibition relative to vehicle control calculated.
When tested in this assay, the compounds of the invention demonstrated the ability to inhibit the migration of inflammatory cells( i. e.,neutrophiles, monocytes and lymphocytes) into the peritoneum. Accordingly, the compounds of the invention were shown to be useful in treating an inflammatory disorder in anin vivomodel.
Example 14
(In VivoAssay)
The following assay may be performed in a similar manner as the assay described in Campbell, E.M.,et al., J. Immunol.(1998), Vol. 161, No. 12, p. 7047-7053.
The assay utilizes CBA/J mice sensitized with soluble cockroach antigents in incomplete Freund's adjuvant intraperitoneally. The assay uses 6-8 animals in each group/time point, including a group for controls. After 14 days, the mice are sensitized again sensitized with soluble cockroach antigen by an intranasal administration, followed 3-5 days later with anintratrachealinjection of cockroach antigen. The mice can be given a secondintratrachealchallenge at 48 hrs post-primary. Prior to the final challenge, the allergic mice receive one of 3 doses of a compound of the invention. After 8 and 24 hours post-challenge, the mice are examined for airway hyperreactivity and the accumulation of leukocyte subsets are monitored in the bronchoalveolar lavage (BAL) and in histologic sections. The second challenge is given at a time when there is a considerable amount of inflammation found within and around the airway, including eosinophils. This scenario is representative of what occurs in chronic asthmatics. This chronic stage response is much more severe and has significantly higher levels of leukocyte infiltration and a synergistic increase in the numbers and activation of eosinophils. This inflammation is dependent upon Th2 type immune responses. This analysis allows for the identification of whether a compound of the invention can attenuate the responses,i. e.,leukocyte migration and the clinically relevant airway physiology.
In addition to the above analysis, various samples collected from the study, including the BAL fluid and lung tissue, further analysis may be performed to determine the manner in which the compounds of the invention are attenuating the responses. Specifically, cytokine (IL-4JL-5, IL10, IL-13, IL-18, TNF, IFN,etc.)levels in the BAL fluid and the lung tissue homogenates can be analyzed, as well as histamine and eosinophil peroxidase levels (see Wu, W.,et al., Journal of Clinical Investigation
(2000), Vol. 105, pp. 1455-1463).
Animals:
Female C57/BL6 mice were purchased from either The Jackson Laboratory, (Bar Harbor, ME) or Charles River Breeding Laboratories (Wilmington, MA) and were maintained under standard pathogen-free conditions. All materials were obtained from Sigma Chemical Company (St. Louis, MO) unless otherwise indicated.
Sensitization and induction of the airway response:
Normal C57/BL6 mice were immunized with 10 ug of cockroach allergen (Bayer) in IFA on day 0. In order to localize the response to the lung, the mice were given an intranasal administration of 10 pg of cockroach allergen in 10 uL of diluent on day 14. This initial intranasal allergen induced little cellular infiltrate into the lungs of the mice upon histological examination. Mice were then challenged 6 days later (referred to hereafter as primary challenge response) by intratracheal administration of 10 ug of cockroach allergen in 50 uL of sterile PBS or with PBS alone (vehicle). The magnitude of leukocyte recruitment in both the vehicle control and cockroach allergen-challenged mice was examined histologically. Only the cockroach allergen-challenged mice displayed a significant inflammatory response that included mononuclear cell and eosinophil infiltration. Some mice were given a second intratracheal injection of either cockroach allergen (10 ug in 50 uL) or diluent control and subsequently analyzed (secondary rechallenge response). In separate studies, the effect of the anti-murine MlP-la and anti-murine eotaxin polyclonal antibodies on cockroach allergen-induced responses were assessed by giving sensitized mice an i.p. dose of the antibody (0.5 mL, titers of 10<6>/mL) at 1 hour prior to each allergen challenge. Normal rabbit serum (NRS) was used as a control. Polyclonal antibodies had previously been demonstrated to block the chemotaxis of murine eosinophilsin
vitro.
Measurement of airway hyperactivity:
Airway hyperactivity was measured using Buxco mouse plethysmography which is specifically designed for the low tidal volumes (Buxco) as previously described in Lukacs, N.W.,et al, J. Immunol.(1992), Vol. 13, pp. 501. Briefly, the mouse to be tested was anesthetized with sodium pentobarbital and incubated via cannulation of the trachea with an 18-gauge metal tube. The mouse was subsequently ventilated with a Harvard pump ventilator (tidal volume = 0.4 mL, frequency = 120 breaths/min., positive end-expiatory pressure 2.5 to 3.0 cm H20 and the tail vein was cannulated with a 27-gauge needle for injection of the methacholine challenge. The plethysmograph was sealed and readings were monitored by computer. Since the box was a closed system, a change in lung volume was represented by a change in box pressure (Pbox), which was measured by a differential transducer. The system was calibrated with a syringe that delivered a known volume of 2 mL. A second transducer was used to measure the pressure swings at the opening of the trachea tube (Paw), referenced to the body box (i.e., pleural pressure, and to provide a measure of transpulmonary pressure (Ptp = Paw-Pbox)- The trachea transducer was calibrated at a constant pressure of 20 cm H20. Resistance was calculated by the Buxco software by dividing the change in pressure (Ptp) by the change in flow (F) (5Ptp/5F; units = cm H20/mL/s) at two time points from the volume curve, based upon a percentage of the inspiratory volume. Once the mouse was hooked up to the box it was ventilated for 5 minutes prior to acquiring readings. Once baseline levels were stabilized and initial readings were taken, a methacholine challenge was given via the cannulated tail vein. After determining a dose-response curve (0.001 to 0.5 mg), an optimal dose was chosen
(0.1 mg of methacholine) which was used throughout the rest of the experiments in this study. After the methacholine challenge, the response was monitored and the peak airway resistance was recorded as a measure of airway hyperactivity.
Compounds of the invention, when tested in the above assay, demonstrated the ability to decrease airway resistance in an animal model for asthma.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (21)

  1. What is claimed is: 1. A compound of formula (I) or formula (II): wherein: each R<1>, R<2>and R<3>are independently halo, -OR<6>, -SR<6>, -S(0)tR<7>(where t is 1 or 2) or -N(R7)R8;or R1 and R<2>together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
    or R<1>and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R9-R12, -R9-R,3-Rn, -R9-O-Rl0-R", -R<9->0-R<12>, -R<9->C(0)-R'°-R", -R9-N(R7)-RI0-R", -R9-S(O)rRl0-R" (where t is 0 to 2), or - R<9->C(F)2-R<9->R"; each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, - C(S)R<7>, -C(0)OR14, -C(S)OR14, -C(0)N(R<7>)R<8>, or -C(S)N(R<7>)R<8>; each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each Ru is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R<7>or tetrazole; R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and R<14>is alkyl, aryl or aralkyl; as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
  2. 2. The compound of Claim 1 selected from formula (I): wherein: R<1>, R<2>and R3 are each independently halo, -OR<6>, -SR<6>or -N(R<7>)R<8>; each R<4>is -R9-R12, -R<9->R<l3>-Ru, -R9-O-R10-Ru, -R<9->0-R<12>, -R<9->C(O)-R<10->R", -R<9->N(R<7>)-R,<0->R", -R<9->S(O)t-R,<0->R" (where t is 0 to 2), or R<9->C(F)2-R<9->R"; R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy); each R<6>is independently hydrogen, alkyl, aralkyl, -C(0)R<7>or -C(0)OR<7>; each R<7>is independently hydrogen, alkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R<11>is independently -C(0)OR7 or-C(0)N(R7)2; R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene.
  3. 3. The compound of Claim 2 wherein: R<1>, R<2>and R<3>are each independently halo, -OR<6>, or -SR<6>; R4is-R9-O-R10-R"; R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, or aralkyl; each R7 is independently hydrogen, alkyl, aryl, or aralkyl; R<9>is a direct bond or a straight or branched alkylene chain; R<10>is an straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; and R<11>is -C(0)OR7 or -C(0)N(R<7>)2.
  4. 4. The compound of Claim 3 wherein: R<1>, R<2>and R<3>are each -OR<6>; R4is-R9-O-R,0-R"; R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy); R<6>is hydrogen, alkyl, aryl, or aralkyl; each R7 is independently hydrogen, alkyl, aryl, or aralkyl; R<9>is a direct bond; R<10>is a straight or branched alkylene chain, a straight or branched alkenylene chain, or a straight or branched alkynylene chain; and R<11>is -C(0)OR7 or -C(0)N(R<7>)2.
  5. 5. The compound of Claim 4 selected from the group consisting of the following:( 5S, 6RJE, 9E, 11Z, 1 3E,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester; and( 5S, 6RJE, 9E, 11Z, 1 3E, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3 -oxa-7,9,11,13-hexadecatetraenoic acid.
  6. 6. The compound of Claim 1 selected from formula (II): wherein: R<1>, R2 and R<3>are each independently halo, -OR<6>, -SR6 or -N(R<7>)R<8>; each R<4>is -R9-R12, -R<9->R<13>-Rn, -R9-O-R,0-RM, -R9-0-R12, -R<9->C(O)-R<10->R", -R<9->N(R<7>)-R<I>0-<R>", -R<9->S(O)t-R<10>-R<n>(where t is 0 to 2), or - R9-C(F)2-R9-R11; R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy); each R<6>is independently hydrogen, alkyl, aralkyl, -C(0)R<7>or -C(0)OR7; each R<7>is independently hydrogen, alkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R<11>is independently -C(0)OR7 or -C(0)N(R7)2; R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene.
  7. 7. The compound of Claim 6 wherein: R<1>, R<2>and R3 are each independently halo, -OR<6>, or -SR<6>; R<4>is-R<9->O-R<l0->R";
    R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
    each R<6>is independently hydrogen, alkyl, aryl, or aralkyl; each R<7>is independently hydrogen, alkyl, aryl, or aralkyl;
    R<9>is a direct bond or a straight or branched alkylene chain;
    R<10>is an straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; and
    R<11>is -C(0)OR<7>or -C(0)N(R<7>)2.
  8. 8. The compound of Claim 7 wherein:
    R<1>, R<2>and R3 are each -OR6;
    R4is-R9-O-R10-R";
    R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, and haloalkoxy);
    R6 is hydrogen, alkyl, aryl, or aralkyl;
    each R7 is independently hydrogen, alkyl, aryl, or aralkyl; R<9>is a direct bond;
    R<10>is a straight or branched alkylene chain, a straight or branched alkenylene chain, or a straight or branched alkynylene chain; and
    R" is -C(0)OR7 or -C(0)N(R<7>)2.
  9. 9. The compound of Claim 8 selected from the group consisting of the following: (5S,67?,7£,9£,13£,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester;(55,6#,7£,9£, 1 3E,155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-l 1-ynoic acid; (55,65,7£,9£, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester; and (5S,65,7£,9£, 13£, 155)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid.
  10. 10. A pharmaceutical composition useful in treating an inflammatory or autoimmune disorder in a mammal, which composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II): wherein: each R<1>, R2 and R<3>are independently halo, -OR<6>, -SR<6>, -S(0)tR7 (where t is 1 or 2) or -N(R<7>)R<8>; or R and R together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
    or R<1>and R<2>together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R9-R12, -R<9->R<13>-Rn, -R^O-R<10>^<1>', -R9-0-R12, -R<9->C(O)-R<l>0-<R>", -R<9->N(R<7>)-R<10->R", -R<9->S(O)t-R<l0->R" (where t is 0 to 2), or - R<9->C(F)2-R<9->R"; each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, - C(S)R<7>, -C(0)OR14, -C(S)OR14, -C(0)N(R<7>)R8, or -C(S)N(R<7>)R<8>; each R<7>is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R" is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R7 or tetrazole; R<12>is aryl (substituted by -C(0)OR7 or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and R<14>is alkyl, aryl or aralkyl; as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
  11. 11. The pharmaceutical composition of Claim 10 wherein the mammal is a human.
  12. 12. A pharmaceutical composition useful in treating pulmonary or respiratory tract inflammation in a mammal, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II): wherein: each R<1>, R<2>and R<3>are independently halo, -OR<6>, -SR<6>, -S(0)tR<7>(where t is 1 or 2) or -N(R<7>)R<8>; or R<1>and R2 together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
    or R<1>and R<2>together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R9-R12, -R<9->R<13>-Ru,-R<9>-O-R<10>-Rn, -R9-0-R12, -R<9->C(O)-R<l0->R", -R<9->N(R<7>)-R<10->R", -R<9->S(O)t-R,0-<R>" (where t is 0 to 2), or - R<9->C(F)2-R<9->R"; each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, - C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, or -C(S)N(R<7>)R<8>; each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R<11>is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R7 or tetrazole; R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and R<14>is alkyl, aryl or aralkyl; as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
  13. 13. The pharmaceutical composition of Claim 12 wherein the mammal is a human.
  14. 14. A method of treating an inflammatory or autoimmune disorder in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) or (II): wherein: each R<1>, R<2>and R3 are independently halo, -OR<6>, -SR<6>, -S(0)tR7 (where t is 1 or 2) or -N(R<7>)R<8>; or R<1>and R<2>together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
    or R I and R 2together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R9-R12, -R9-Rl3-Rn, -R<9>-O-R<l0>-Rn, -R9-0-R12, -R9-C(0)-Rio-R", -R<9->N(R<7>)-R<10->R", -R<9->S(O)rR<l0>-R<n>(where t is 0 to 2), or R<9->C(F)2-R<9->R"; each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, - C(S)R<7>, -C(0)OR14, -C(S)OR<14>, -C(0)N(R<7>)R<8>, or -C(S)N(R<7>)R<8>; each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R" is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R7 or tetrazole; R<12>is aryl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); R<13>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and R<14>is alkyl, aryl or aralkyl; as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
  15. 15. The method of Claim 14 wherein the mammal is a human.
  16. 16. The method of Claim 15 wherein the inflammatory or autoimmune disorder is selected from the group consisting of the following: allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, acute myocardial ischemia and infarction, acute hemorrhagic or ischemic stroke, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus, acute and chronic organ transplant rejection, transplant arteriosclerosis and fibrosis, hypertension, atherosclerosis, aneurysm, critical leg ischemia, peripheral arterial occlusive disease,Reynaud's syndrome, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, delayed neurodegeneration in stroke, Alzheimer's disease, Parkinson's disease, benign prostatic hyperplasia, leukemia, lmphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer.
  17. 17. A method of treating pulmonary or respiratory tract inflammation in a mammal, wherein the method comprises adminstering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) or formula (II): wherein: each R<1>, R<2>and R3 are independently halo, -OR<6>, -SR<6>, -S(0)tR<7>(where t is 1 or 2) or -N(R<7>)R<8>; or R<1>and R<2>together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
    or R<1>and R<2>together with the carbons to which they are attached form the following bicyclic heterocyclic structure: (where q is 0 to 3, p is 1 to 4 and each R<15>is hydrogen, alkyl, aralkyl or aryl); each R<4>is -R<9->R<12>, -R<9->R,<3>-Rn, -R<9>-O-R,<0>-Rn, -R9-0-R12, -R<9->C(O)-R<l0->R", -R<9->N(R<7>)-R<I0->R", -R<9->S(O)rR<10->R" (where t is 0 to 2), or - R<9->C(F)2-R<9->R"; each R<5>is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy); each R<6>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, - C(S)R<7>, -C(0)OR<14>, -C(S)OR<14>, -C(0)N(R<7>)R<8>, or -C(S)N(R<7>)R<8>; each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R<8>is independently hydrogen, alkyl, aryl, aralkyl, -C(0)R<7>, -C(0)OR<14>, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, -N(R<7>)2, and -C(0)OR<7>); each R<9>is independently a direct bond or a straight or branched alkylene chain; each R<10>is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene; each R" is independently -C(0)OR<7>, -C(0)N(R<7>)2, -P(0)(OR<7>)2, - S(0)2OR<7>, -S(0)2N(H)R7 or tetrazole;R1<2>is aryl (substituted by -C(0)OR7 or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by -C(0)OR<7>or -C(0)N(R<7>)2and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);R1<3>is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and R<14>is alkyl, aryl or aralkyl; as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
  18. 18. The method of Claim 17 wherein the mammal is a human. .
  19. 19. The method of claim 15 wherein the inflammatory or autoimmune disorder is selected from the group consisting of the following: septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndrome induced by cancer immunotherapy, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonias, immune-compelx-mediated pulmonary injury, immune-complex-mediated chronic obstructive pulmonary disease, inflammatory bowel disease, acute renal failure, ischemic bowel disease, immune-complex-mediated glomerulonephritis, insulin-dependent diabetes mellitus, ocular disorders, HIV dementia, encephalitis, inflammatory and neuropathic pain, periodontal disease, and ear infections.
  20. 20. The method of claim 19 wherein the inflammatory or autoimmune disorder is an inflammatory bowel disease selected from the group consisting of Crohn's disease, ulcerative colitis and gastrointestinal ulcers.
  21. 21. The method of claim 20 wherein the inflammatory or autoimmune disorder is Crohn's disease.
    ABSTRACT OF THE DISCLOSURE This invention is directed to lipoxin A4analogs of the following formula (I) and (II):
    wherein R<l>, R<2>, R<3>, R<4>and R<5>are described herein. These analogs are useful in treating inflammatory and autoimmune disorders in humans. These analogs are also useful in treating pulmonary or respiratory tract inflammation in humans.
YUP-384/04A 2001-11-06 2002-11-05 Analozi lipoksina a4 RS51005B (sr)

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