HRP20010559A2 - Ketolide antibiotics - Google Patents
Ketolide antibiotics Download PDFInfo
- Publication number
- HRP20010559A2 HRP20010559A2 HR20010559A HRP20010559A HRP20010559A2 HR P20010559 A2 HRP20010559 A2 HR P20010559A2 HR 20010559 A HR20010559 A HR 20010559A HR P20010559 A HRP20010559 A HR P20010559A HR P20010559 A2 HRP20010559 A2 HR P20010559A2
- Authority
- HR
- Croatia
- Prior art keywords
- cr4r5
- alkyl
- aryl
- groups
- halo
- Prior art date
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- 239000003242 anti bacterial agent Substances 0.000 title description 3
- 229940088710 antibiotic agent Drugs 0.000 title description 3
- 239000003835 ketolide antibiotic agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 119
- -1 –NR4R5 Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 208000010362 Protozoan Infections Diseases 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 208000035143 Bacterial infection Diseases 0.000 claims description 17
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 241000251468 Actinopterygii Species 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
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- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
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- HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 claims description 4
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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Description
Pozadina izuma
Ovaj izum odnosi se na nove makrolidne spojeve, korisne kao antibakterijske i antiprotozojske tvari kod sisavaca, uključujući čovjeka, te kod riba i ptica. Ovaj izum se također odnosi na farmaceutske pripravke koji sadrže nove spojeve i na postupke tretiranja bakterijskih i protozojskih infekcija kod sisavaca, riba i ptica primjenom novih spojeva na sisavcima, ribama i pticama, kojima je potreban takav tretman.
Za makrolidne antibiotike se zna da su korisni u tretmanu širokog spektra bakterijskih i protozojskih infekcija kod sisavaca, riba i ptica. Takvi antibiotici uključuju razne derivate eritromicina A, poput azitromicina, koji je tržišno dostupan i navodi ga se u US patentima br. 4,474,768 i 4,517,359, koji su oba ovdje uključeni kao reference u svojoj cijelosti. Drugi makrolidni antibiotici opisani su i zahtjevani u PCT patentnoj prijavi objavljenoj kao WO 98/56800 (objavljena 17. prosinca 1998.), koja je naznačena za SAD; US patentu br. 5.527.780, objavljenom 18. lipnja 1996.; US privremenoj patentnoj prijavi br. 60/101263 (prijavljena 22. rujna 1998.) (zastupnički referentni broj PC 10406); US privremenoj patentnoj prijavi br. 60/111,728 (prijavljena 10. Prosinca 1998.) (zastupnički referentni broj PC 10494); PCT patentnoj prijavi objavljenoj kao WO 98/01546 (objavljena siječnja 15, 1998); PCT patentnoj prijavi objavljenoj kao WO 98/01571 (objavljena 15. siječnja 1998.); EP patentnoj prijavi objavljenoj pod br. 949268 (objavljena 13. listopada 1999.); i US patentu br. 5,747,467 (objavljen 5. svibnja 1998.). Svaki od prethodno navedenih US patenata i patentnih prijava i objavljenih EP i PCT međunarodnih patentnih prijava uključeni su ovdje kao reference u svojoj cijelosti. Poput azitromicina i drugih makrolidnih antibiotika, novi makrolidni spojevi iz ovog izuma posjeduju aktivnost protiv različitih bakterijskih i protozojskih infekcija, kao što je opisano niže.
Bit izuma
Ovaj izum odnosi se spojeve formule
[image]
i njihove farmaceutski prihvatljive soli i solvate, gdje:
X1 je O, –CR4R6– ili –NR4–;
X2 je =O ili =NOR1;
R1 je H ili C1-C10 alkil, gdje je 1-3 ugljika navedenog alkila izborno zamijenjeno heteroatomom odabranim između O, S i –N(R4)–, a navedeni alkil je izborno supstituiran s 1-3 supstituenta neovisno odabrana iz grupe koju čine –C(O)O(C1-C10 alkil), C1-C10 alkoksi, C1-C10 alkanoil, halo, nitro, cijano, 4-10-eročlani heterociklil, C1-C10 alkil, –NR4R5, C6-C10 aril, –S(O)n(C1-C10 alkil), gdje n je cijeli broj raspona od 0-2, i –SO2NR4R5;
R2 je –(CR4R5)n(4-10-eročlani heterocikl) ili –(CR4R5)n(C6-C10 aril), gdje n je cijeli broj od 0-6, a od 1-3 R4 ili R5 grupe –(CR4R5)n– ostatka prethodno navedenih R2 grupa izborno je zamijenjeno halo supstituentom, i heterociklički i arilni ostaci prethodno navedenih R2 grupa su izborno supstituirani s 1-4 R3 grupe;
svaki R3 neovisno je odabran između halo, cijano, nitro, trifluormetoksi, trifluormetila, azido, hidroksi, C1-C6 alkoksi, C1-C10 alkila, C2-C6 alkenila, C2-C6 alkinila, –C(O)R6, –C(O)OR6, –OC(O)R6, –NR6C(O)R7, –NR6C(O)NR1R7, –NR6C(O)OR7, –C(O)NR6R7, –NR6R7, –NR6OR7, –SO2NR6R7, –S(O)j(C1-C6 alkila), gdje j je cijeli broj od 0-2, –(CR1R2)t(C6-C10 arila), –(CR4R5)t(4-10-eročlanog heterocikla), –(CR4R5)qC(O)(CR4R5)t(C6-C10 arila), –(CR4R5)qC(O)(CR4R5)t(4-10-eročlanog heterocikla), –(CR4R5)tO(CR4R5)q(C6-C10 arila), –(CR4R5)tO(CR4R5)q(4-10-eročlanog heterocikla), –(CR4R5)qSO2(CR4R5)t(C6-C10 arila) i –(CR4R5)qSO2(CR4R5)t(4-10-eročlanog heterocikla), gdje q i t su svaki neovisno cijeli broj od 0-5, a 1 ili 2 ugljikova atoma iz prstena heterocikličkih ostataka prethodno navedenih R10 grupa su izborno supstituirani okso (=O) ostatkom, i alkilni, alkenilni, alkinilni, arilni i heterociklički ostaci prethodno navedenih R10 grupa su izborno supstituirani s 1-3 supstituenta neovisno odabrana između halo, cijano, nitro, trifluormetila, trifluormetoksi, azido, –OR6, –C(O)R6, –C(O)OR6, –OC(O)R6, –NR6C(O)R7, –C(O)NR6R7, –NR6R7, –NR6OR7, C1-C6 alkila, C2-C6 alkenila, C2-C6 alkinila, –(CR4R5)t(C6-C10 arila) i –(CR4R5)t(4-10-eročlanog heterocikla), gdje t je cijeli broj od 0-5;
svaki R4 i R5 neovisno je odabran između H i C1-C6 alkila;
svaki R6 i R7 neovisno je odabran između H, C1-C6 alkila, –(CR4R5)t(C6-C10 arila) i –(CR4R5)t(4-10-eročlanog heterocikla), gdje t je cijeli broj od 0-5, a 1 ili 2 ugljikova atoma iz prstena heterocikličke grupe izborno su supstituirani s okso (=O) ostatkom, i alkilni, arilni i heterociklički ostaci prethodno navedenih R6 i R7 grupa su izborno supstituirani s 1-3 supstituenta neovisno odabrana između halo, cijano, nitro, –NR4R5, trifluormetila, trifluormetoksi, C1-C6 alkila, C2-C6 alkenila, C2-C6 alkinila, hidroksi i C1-C6 alkoksi;
R8 je H, –C(O)(C1-C6 alkil), benzil, benziloksikarbonil ili (C1-C6 alkil)3silil;
R9 je C1-C6 alkil;
R10 je H ili C1-C10 alkil; a
R11 je odabran između klora, broma, joda, fluora i cijano;
uz uvjet da gdje X2 je =O, R11 je cijano, ili od 1-3 R4 ili R5 grupe –(CR4R5)n– ostatka R2 gore navedenih grupa su bilo C1-C6 alkil ili su zamijenjeni halo supstituentom.
Specifična ostvarenja iz ovog izuma uključuju spojeve formule 2 (što je specifično ostvarenje unutar roda formule 1)
[image] ,
gdje R12, R13, R14 i R15 se svakog neovisno bira između H, halo, metila i etila. Specifičnija ostvarenja uključuju spojeve formule 2, gdje R14 i R15su oba H, a R12 i R13 se svakog neovisno bira između H i metila. U poželjnom ostvarenju spojeva formule 2, R12, R13, R14 i R15 su svaki H.
Druga specifična ostvarenja iz ovog izuma uključuju spojeve formule 3 (što je specifično ostvarenje unutar roda formule 1)
[image] ,
gdje R12, R13, R14 i R15 se svakog neovisno bira između H, halo, metila i etila, uz uvjet da barem jedan od R12, R13, R14 i R15 nije H. Specifičnija ostvarenja uključuju spojeve formule 3, gdje R14 i R15 su oba H, R12 je metil, a R13 se bira između H i metila.
Ovaj izum također se odnosi na farmaceutske pripravke u tretmanu bakterijske ili protozojske infekcije, ili poremećaja povezanog s bakterijskom ili protozojskom infekcijom, kod sisavca, ribe ili ptice, koji sadrže terapeutski djelotvornu količinu spoja formule 1, ili njegove farmaceutski prihvatljive soli ili solvata, i farmaceutski prihvatljivu podlogu.
Ovaj izum također se odnosi na postupak tretiranja bakterijske ili protozojske infekcije, ili poremećaja povezanog s bakterijskom ili protozojskom infekcijom, kod sisavca, ribe ili ptice, koji se sastoji u primjeni na navedenom sisavcu, ribi ili ptici terapeutski djelotvorne količine spoja formule 1, ili njegove farmaceutski prihvatljive soli ili solvata.
Izraz "tretiranje", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, znači poništavanje, ublažavanje i inhibiranje napredovanja, ili sprječavanje poremećaja ili stanja na koje se takav izraz odnosi, te jednog ili više simptoma takvog poremećaja ili stanja. Izraz "tretman", kao što se ovdje upotrebljava, odnosi se na čin tretiranja, kao što je "tretiranje" definirano neposredno ranije.
Kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, izrazi ili fraze "bakterijska/e infekcija/e", "protozojska/e infekcija/e" i "poremećaji povezani s bakterijskim ili protozojskim infekcijama" uključuju slijedeće: upalu pluća, upalu srednjeg uha, upalu sinusa, upalu dušnica, upalu krajnika i mastoiditis, povezane s infekcijom bakterijama Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphilococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus ili Peptostreptococcus spp.; upalu ždrijela, reumatsku groznicu i glomerulonefritis, povezane s infekcijom bakterijama Streptococcus pyogenes, streptokokima grupe C i G, Corynebacterium diphtheriae ili Actinobacillus haemolyticum; infekcije dišnog sustava, povezane s infekcijom bakterijama Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae ili Chlamydia pneumoniae; infekcije krvi i tkiva, uključujući endokarditis i upalu koštane srži, uzrokovane bakterijama S. aureus, S. haemolyticus, E. faecalis, E faecium, E. durans, uključujući sojeve otporne na poznate antibakterijske tvari, poput, ali nije time ograničeno, beta-laktama, vankomicina, aminoglikozida, kinolona, kloramfenikola, tetracilina i makrolida; nekomplicirane infekcije i gnojne upale kože i mekih tkiva i babinju groznicu, povezane s infekcijom bakterijama Staphilococcus aureus, stafilokokima negativnim na koagulazu (tj. S. epidermidis, S. hemolyticus itd.), Streptococcus pyogenes, Streptococcus agalactiae, streptokoknim grupama C-F (streptokoki malih kolonija), streptokokima viridans, Corynebacterium minutissimum, Clostridium spp. ili Bartonella henselae; nekomplicirane infekcije mokraćnog sustava, povezane s infekcijom bakterijama Staphilococcus aureus, stafilokoknim vrstama negativnim na koagulazu ili Enterococcus spp.; upalu mokraćne cijevi i vrata maternice; spolno prenosive bolesti, povezane s infekcijom bakterijama Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum ili Neiserria gonorrhoeae; bolesti trovanja, povezane s infekcijom bakterijama S. aureus (trovanje hranom i sindrom toksičkog šoka), ili grupama streptokoka A, B i C; vrijedove, povezane s infekcijom bakterijom Helicobacter pylori; sistemske febrilne sindrome, povezane s infekcijom bakterijom Borrelia recurrentis; lajmboreliozu, povezanu s infekcijom bakterijom Borrelia burgdorferi; upalu očne spojnice, rožnice i suzne žlijezde, povezane s infekcijom bakterijama Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae ili Listeria spp.; bolest diseminiranog Mycobacterium avium kompleksa (Mycobacterium avium complex, MAC), povezanu s infekcijom bakterijama Mycobacterium avium ili Mycobacterium intracellulare; infekcije uzrokovane bakterijama Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansasii ili M. chelonei; upalu želuca i crijeva, povezan s infekcijom bakterijom Campylobacter jejuni; crijevne protozoe, povezane s infekcijom protozoom Cryptospoddium spp.; odontogenu infekciju, povezanu s infekcijom bakterijama streptokokima viridans; hripavac, povezan s infekcijom bakterijom Bordetella pertussis; plinsku gangrenu, povezanu s infekcijom bakterijama Clostridium perfringens ili Bacteroides spp.; i aterosklerozu ili kardiovaskularnu bolest, povezane s infekcijom bakterijama Helicobacter pylori ili Chlamydia pneumoniae. Bakterijske i protozojske infekcije i poremećaji povezani s takvim infekcijama, koje se može tretirati ili spriječiti kod životinja, uključuju slijedeće: dišnu bolest goveda, povezanu s infekcijom bakterijama P. haemolytica, P. multocida, Mycoplasma bovis ili Bordetella spp.; crijevnu bolest goveda, povezanu s infekcijom bakterijom E. coli ili protozoama (tj. kokcidijama, kriptosporidijama itd.); upalu vimena mliječnih krava, povezanu s infekcijom bakterijama S. aureus, Strep. uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, Klebsiella spp., Corynebacterium ili Enterococcus spp.; dirnu bolest svinja, povezanu s infekcijom bakterijama A. pleuro., P. multocida, ili Mycoplasma spp.; crijevnu bolest svinja, povezanu s infekcijom bakterijama E. coli, Lawsonia intracellularis, Salmonella ili Serpulina hyodysinteriae; upalu papaka goveda, povezanu s infekcijom bakterijom Fusobacterium spp.; upalu maternice goveda, povezanu s infekcijom bakterijom E. coli; dlakave bradavice goveda, povezane s infekcijom bakterijama Fusobacterium necrophorum ili Bacteroides nodosus; upalu očiju goveda, povezanu s infekcijom bakterijom Moraxella bovis; prerani pobačaj kod krava, povezan s infekcijom protozoama (tj. neosporium); upalu mokraćnog sustava pasa i mačaka, povezanu s infekcijom bakterijom E. coli; infekcije kože i mekih tkiva pasa i mačaka, povezane s infekcijom bakterijama S. epidermidis, S. intermedius, stafilokokima negativnim na koagulazu ili P. multocida; i infekcije zubiju ili usta pasa i mačaka, povezane s infekcijom bakterijama Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas ili Prevotella. Druge bakterijske i protozojske infekcije i poremećaji povezani s takvim infekcijama, koje se može tretirati ili spriječiti u skladu s postupkom iz ovog izuma navodi se u članku J. P. Sanford i drugi: "Sanford Guide To Antimicrobial Therapy", 26. izdanje, (Antimicrobial Therapy, Inc., (1996.)).
Izraz "halo", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje fluor, klor, brom ili jod. Poželjne halo grupe su fluor, klor i brom.
Izraz "alkil", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje zasićene jednovalentne ugljikovodične radikale, s prstenastim, ravnolančanim i/ili razgranatim ostacima. Treba shvatiti da, kako bi se uključilo prstenaste ostatke, alkilna grupa mora posjedovati barem 3 ugljikova atoma.
Izraz "alkenil", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje alkilne grupe, kao što je definirano gore, koje posjeduju barem 1 dvostruku vezu ugljik-ugljik u jednom dijelu alkilnog lanca. Izraz "alkinil", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje alkilne grupe, kao što je definirano gore, koje posjeduju barem 1 trostruku vezu ugljik-ugljik u jednom dijelu alkilnog lanca.
Izraz "aril", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje organski radikal deriviran iz aromatskog ugljikovodika uklanjanjem jednog vodika, poput fenila ili naftila. Izraz "4-10-eročlani heterocikl, kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje aromatske i nearomatske heterocikličke grupe, s jednim ili više heteroatoma, od kojih se svakog bira između O, S i N, gdje svaka heterociklička grupa ima od 4-10 atoma u svom sustavu prstena. Nearomatske heterocikličke grupe uključuju grupe sa samo 4 atoma u svom sustavu prstena, no aromatske heterocikličke grupe moraju imati barem 5 atoma u svom sustavu prstena. Heterocikličke grupe uključuju benzokondenzirane sustave prstena i sustave prstena supstituirane s jednim ili više okso ostataka. Primjer 4-eročlane heterocikličke grupe je azetidinil (deriviran iz azetidina). Primjer 5-eročlane heterocikličke grupe je tiazolil, a primjer 10-eročlane heterocikličke grupe je kinolinil. Primjeri nearomatskih heterocikličkih grupa su pirolidinil, tetrahidrofuranil, tetrahidrotienil, tetrahidropiranil, tetrahidrotiopiranil, piperidino, morfolino, tiomorfolino, tioksanil, piperazinil, azetidinil, oksetanil, tietanil, homopiperidinil, oksepanil, tiepanil, oksazepinil, diazepinil, tiazepinil, 1,2,3,6- tetrahidropiridinil, 2-pirolinil, 3-pirolinil, indolinil, 2H-piranil, 4H-piranil, dioksanil, 1,3-dioksolanil, pirazolinil, ditianil, ditiolanil, dihidropiranil, dihidrotienil, dihidrofuranil, pirazolidinil, imidazolinil, imidazolidinil, 3-azabiciklo[3.1.0]heksanil, 3-azabiciklo[4.1.0]heptanil, 3H-indolil i kinolizinil. Primjeri aromatskih heterocikličkih grupa su piridinil, imidazolil, pirimidinil, pirazolil, triazolil, pirazinil, tetrazolil, furil, tienil, izoksazolil, tiazolil, oksazolil, izotiazolil, pirolil, kinolinil, izokinolinil, indolil, benzimidazolil, benzofuranil, cinolinil, indazolil, indolizinil, ftalazinil, piridazinil, triazinil, izoindolil, pteridinil, purinil, oksadiazolil, tiadiazolil, furazanil, benzofurazanil, benzotiofenil, benzotiazolil, benzoksazolil, kinazolinil, kinoksalinil, naftiridinil i furopiridinil. Prethodno navedene grupe, kao što su derivirane iz gore navedenih spojeva, mogu biti C- ili N-vezane, gdje god je to moguće. Primjerice, grupa derivirana iz pirola može biti pirol-1-il (N-vezan) ili pirol-3-il (C-vezan).
Fraza "farmaceutski prihvatljiva/e sol/i", kao što se ovdje upotrebljava, ukoliko nije drugačije navedeno, uključuje soli kiselih ili alkalnih grupa koje mogu biti prisutne u spojevima formule 1. Spojevi formule 1 alkalne prirode mogu tvoriti široki raspon soli s različitim anorganskim i organskim kiselinama. Kiseline koje se može upotrijebiti u dobivanju farmaceutski prihvatljivih kiselih adicijskih soli takvih alkalnih spojeva formule 1 su one koje tvore neotrovne kisele adicijske soli, tj. soli koje sadrže farmaceutski prihvatljive anione, poput acetata, benzenesulfonata, benzoata, bikarbonata, bisulfata, bitartarata, borata, bromida, kalcij edetata, kamsilata, karbonata, klorida, klavulanata, citrata, dihidroklorida, edetata, edisliata, estolata, ezilata, etilsukcinata, fumarata, gluceptata, glukonata, glutamata, glikolilarsanilata, heksilrezorcinata, hidrabamina, hidrobromida, hidroklorida, jodida, izotionata, laktata, laktobionata, laurata, malata, maleata, mandelata, mezilata, metilsulfata, mukata, napsilata, nitrata, oleata, oksalata, pamoata (embonata), palmitata, pantotenata, fosfata/difosfata, poligalakturonata, salicilata, stearata, subacetata, sukcinata, tanata, tartarata, teoklata, tosilata, trietijodida i valerata.
Spojevi formule 1 kisele prirode mogu tvoriti alkalne soli s različitim farmakološki prihvatljivim kationima. Primjeri takvih soli uključuju soli alkalnih ili zemnoalkalnih metala, a osobito, soli natrija i kalija.
Ovaj izum također uključuje sve radioaktivno označene oblike spojeva formule 1, i njihovih farmaceutski prihvatljivih soli, gdje se radioaktivne markere bira između 3H, 11C i 14C. Takvi radioaktivno označeni spojevi korisni su kao istraživačko ili dijagnostičko oruđe.
Izvjesni spojevi formule 1 mogu imati asimetrične centre i stoga postojati u različitim enantiomernim oblicima. Ovaj izum odnosi se na upotrebu svih optičkih izomera i stereoizomera spojeva formule 1 i njihove smjese. Specifično, ovaj izum uključuje i E i Z izomere –OR1 grupe (gdje X2 je =NOR1) vezane na dušik oksimskog ostatka na C-9 makrolidnog prstena formule 1.
Ovaj izum također uključuje izotopski označene spojeve, i njihove farmaceutski prihvatljivih soli, identične onim navedenim za formulu 1, no uz činjenicu da je jedan ili više atoma zamijenjeno atomom atomske mase ili atomskog broja različitog od onog koji obično dolazi u prirodi. Primjeri izotopa koje se može uključiti u spojeve ovog izuma uključuju izotope vodika, ugljika, dušika, kisika, fosfora, fluora i klora, poput 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, odnosno 36Cl. Spojevi iz ovog izuma, njihovi predlijekovi i farmaceutski prihvatljive soli navedenih spojeva ili navedenih predlijekova, koji sadrže gore navedene izotope, i/ili razni izotopi drugih atoma ulaze u opseg ovog izuma. Izvjesne izotopski označene spojeve iz ovog izuma, primjerice one u koje se uključuje radioaktivne izotope, poput 3H i 14C, korisni su u testovima distribucije lijeka i/ili suspstratnih tkiva. Tricij, tj. 3H, i ugljik-14, tj. 14C, izotopi su osobito poželjni zbog lakoće njihova dobivanja i detektibilnosti. Osim toga, supstitucija težim izotopima, poput deuterija, tj. 2H, može imati izvjesne terapijske prednosti proizašle iz veće metaboličke aktivnosti, primjerice produljuje poluživot in vivo ili smanjuje prohtjeve doziranja, te stoga može biti poželjna u izvjesnim okolnostima. Izotopski označene spojeve formule 1 iz ovog izuma i njihove predlijekove može se, općenito, dobiti provođenjem postupaka opisanih u Shemama i/ili Primjerima i Dobivanjima niže, supstituiranjem izotopski neoznačenog reagensa s lako dostupnim radioaktivno označenim reagensom.
Ovaj izum također obuhvaća farmaceutske pripravke koji sadrže spojeve formule 1 i postupke tretiranja bakterijskih infekcija primjenom predlijekova spojeva formule 1. Spojeve formule 1 sa slobodnim amino, amido, hidroksi ili karboksilnim grupama može se prevesti u predlijekove. Predlijekovi uključuju spojeve gdje je aminokiselinski ostatak, ili polipeptidni lanac od 2 ili više (npr. 2, 3 ili 4) aminokiselinskih ostataka kovalentno vezan preko amidne ili esterske veze na slobodnu amino, hidroksi ili karboksilnu kiselinsku grupu spojeva formule 1. Aminokiselinski ostaci uključuju, sli se time ne ograničuju, 20 prirodnih aminokiselina konvencionalno označenih troslovnim simbolima, a također uključuje 4-hidroksiprolin, hidroksilizin, demozin, izodemozin, 3-metilhistidin, norvalin, beta-alanin, gama-aminomaslačnu kiselinu, citrulin, homocistein, homoserin, ornitin i metionin sulfon. Također su obuhvaćeni dodatni tipovi predlijekova. Primjerice, slobodne karboksilne grupe može se derivirati kao amid ili alkilne estere. Slobodne hidroksi grupe može se derivirati grupama koje uključuju, ali se time ne ograničuju, hemisukcinate, fosfatne estere, dimetilaminoacetate i fosforiloksimtiloksikarbonile, kao što je opisano u članku "Advanced Drug Delivery Reviews", 19, 115, (1996.). Karbamatni predlijekovi hidroksi i amino grupa također su uključeni, kao i karbonatni predlijekovi, sulfonatni esteri i sulfatni esteri hidroksi groupa. Također je obuhvaćeno deriviranje hidroksi groupa kao (aciloksi)metil i (aciloksi)etil etera, gdje acilna grupa može biti alkilni ester, izborno supstituiran s grupama koje uključuju, ali se time ne ograničuju, eterske, aminske i karboksilno kiselinske funkcionalnosti, ili gdje kiselinska grupa je aminokiselinski ester, kao što je opisano gore. Predlijekovi ovog tipa opisani su u članku "J. Med. Chem.", 39, 10, (1996.). Slobodne amine može se također derivirati kao amid, sulfonamid ili fosfonamid. Svi ovi ostaci iz predlijekova mogu uključivati grupe koje uključuju, ali se time ne ograničuju, eterske, aminske i karboksilno kiselinske funkcionalnosti.
Detaljni opis izuma
Dobivanje spojeva iz ovog izuma prikazano je u slijedećim Shemama.
Shema 1
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Shema 2
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Shema 2 (nastavak)
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Shema 2 (nastavak)
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Shema 3
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Dobivanje spojeva iz ovog izuma prikazano je na prethodnim shemama. Polazni materijali i/ili konačni spojevi formule 1 gdje R10 je ostatak različit od etila, unutar definicije R10 navedene gore, može se dobiti kao što je opisano u PCT patentnim prijavama objavljenim kao WO 98/01571 (Biotica Tech. Ltd. i Pfizer Inc.) i WO 98/01546 (dodijeljena Biotica Tech. Ltd.). Druge specifične postupke koji se odnose na sintezu spojeva iz ovog izuma navodi se u PCT patentnoj prijavi objavljenoj kao WO 98/38199 (objavljena 3. rujna 1998.), PCT patentnog prijavi objavljenoj kao WO 98/56800 (objavljena 17. prosinca 1998.), US privremenoj patentnoj prijavi br. 60/101,263 (prijavljena 22. rujna 1998.), US privremenoj patentnoj prijavi br. 60/111,728 (prijavljena 10. prosinca 1998.), Evropskoj patentnoj prijavi EP 487.411, i Evropskoj patentnoj prijavi EP 799.833. Na prethodnim shemama, svi supstituenti odgovaraju definiciji formule 1 navedenoj gore, izuzev ako nije drugačije navedeno.
Polazni materijali mogu ili ne moraju zahtijevati odgovarajuću zaštitu funkcionalne grupe prije raznih modifikacija, te uklanjanje zaštite nakon dovršenja traženih modifikacija. Najčešće upotrebljavane zaštitne grupe za amino ostatke makrolidnih spojeva iz ovog izuma su benziloksikarbonilna (Cbz) i t-butiloksikarbonilna (Boc) grupa. Hidroksilne grupe se općenito zaštićuje kao acetate, Cbz karbonate ili trialklilsililnom grupom. C-2' hidroksilna grupa je potencijalno reaktivna hidroksilna grupa između brojnih hidroksilnih grupa ovdašnjih makrolidnih spojeva ovdje zahtjevanog tipa. C-2' hidroksilnu grupu selektivno se zaštićuje reakcijom spoja s 1 ekvivalentom acetanhidrida u diklormetanu, u odsustvu vanjske alkalije. Ovaj proces selektivno prevodi C-2' hidroksilnu grupu u odgovarajući acetat. Zaštitnu grupu za hidroksil može se ukloniti reakcijom spoja s metanolom, na temperaturi raspona od oko 0-40 °C do 65 °C, tijekom 10-48 sati. Drugi postupci selektivnog zaštićivanja te uklanjanja zaštite poznati su stručnjacima.
U pogledu Sheme 1, spoj formule 5, gdje R11 je halo grupa, a svi drugi supstituenti odgovaraju gore navedenoj definiciji, može se dobiti reakcijom spoja formule 4 s alkalijom poput natrij hidrida, kalij hidrida, kalij heksametildisilazida (KHMDS), piridina, natrij karbonata ili litij diizopropilamida, po mogućnosti, KHMDS, te halogenirajućim agensom, poput N-fluorbenzensufoimida, SELECTFLUORTM-a (proizvodi Air Products and Chemicals, Inc., Allentown, Pennsilvania, USA) radi fluoriranja, piridinij tribromida ili cijanogen bromida radi bromiranja ili heksakloretanom radi kloriranja, u otapalu poput N,N-dimetilformamida (DMF), tetrahidrofurana (THF), CH2Cl2 ili N-metilpirolidona ili smjesi prethodno navedenih otapala, po mogućnosti, DMF. Reakcijska temperatura, koja jako ovisi o upotrijebljenom reagensu, može biti od –78 °C do 60 °C. U ovom koraku, R8 je, po mogućnosti, zaštitna grupa za hidroksi, poput acetilne grupe, benzilne grupe, ili trialkilsililne grupe. Kako bi se dobilo spoj formule 6, uklanjanje zaštite s C-2' hidroksi može se provesti metanolom, ako R8 je acetilna grupa, hidrogeniranjem ako R8 je benzilna grupa, ili fluoridnim anionom, poput tetrabutilamonij fluoridom, ako R8 je trialkilsililna grupa. Spoj formule 6 odgovara spoju formule 1, gdje R8 je H.
Shema 2 prikazuje postupak dobivanja spojeva iz ovog izuma uvođenjem R11 grupe u ranom koraku u sintezi konačnih spojeva. U koraku 1 Sheme 2, R11 halo grupu se muže uvesti u osnovi istim postupkom, opisnim gore u shemi 1. U koraku 2 Sheme 2, spoj formule 9 može se dobiti reakcijom spoja formule 8 s alkalijom, poput 1,8-diazabiciklo[5,4,0]undec-7-ena (diazabicyclo[5,4,0]undec-7-ene, DBU) i 1,1'-karbonil-diimidazola (1,1'-carbonyl-diimidazole,CDI) u metilen kloridu. Reakcija spoja formule 9 s hidrazinom u acetonitrilu, na oko 60 °C, daje ciklički karbazat formule 10. Reakcija spoja formula 10 s O–aikilhidroksiaminom etanolu daje oksim formule 11. Reduktivna aminacija s odgovarajućim aldehidom formule R2–C(O)H, te uklanjanje zaštite, ako se traži, s C-2' hidroksi grupe daje spoj formule 12, koji odgovara spoju formule 1, gdje X1 je –NH–, a X2 je =NOR1. Spoj formule 10 također se može prevesti u spoj formule 14, gdje X1 je –NH–, kao što je navedeno gore u koraku 4' Sheme 2, reakcijom spoja formule 10 s odgovarajućim heterocilom, poput supstituiranog imidazola, i α,β-nezasićenim aldehidom, poput akroleina, u octenoj kiselini, nakon čega slijedi redukcija natrij borhidridom.
Shema 3 prikazuje dobivanje spojeva formule 13 koji odgovaraju spojevima formule 1, gdje X2 je =O. U ovom procesu, spoj formule 9 može se dobiti kao što je opisano gore. Spoj formule 9 može se prevesti u spoj formule 13, gdje X1 je O, CR4R5 ili NR4, reakcijom spoja formule 9 s NH2–X1–R2, gdje X1 je O, CR4R5 ili NR4.
Spojevi iz ovog izuma mogu imati asimetrične atome ugljika. Takve dijastereomerne smjese može se razdvojiti na pojedine dijastereomere na osnovu njihovih fizikalnokemijskih razlika, postupcima poznatim stručnjacima, primjerice, kromatografijom ili frakcijskom kristalizacijom. Enantiomere se može razdvojiti prevođenjem enantiomernih smjesa u dijastereomernu smjesu reakcijom s odgovarajućim optički aktivnim spojem (npr. alkoholom), razdvajanjem dijastereomera i prevođenjem (npr. hidrolizom) pojedinih dijastereomera u odgovarajuće čiste enantiomere. Sve takve izomere, koji uključuju diastereomerne smjese i čiste enantiomere smatra se dijelom ovog izuma.
Spojevi formule 1 alkalne prirode mogu tvoriti široki raspon različitih soli s različitim anorganskim i organskim kiselinama. Iako takve soli moraju biti farmaceutski pogodne za primjenu na životinjama, često je u praksi poželjno najprije izdvojiti spoj formule I iz reakcijske smjese kao farmaceutski neprihvatljivu sol, koju se reakcijom s alkalnim reagensom jednostavno natrag prevede u slobodni alkalni spoj, a zatim istu slobodnu alkaliju u farmaceutski prihvatljivu kiselu adicijsku sol. Kisele adicijske soli alkalnih spojeva iz ovog izuma lako se dobije reakcijom alkalnog spoja s, u osnovi, ekvivalentnom količinom odabrane mineralne ili organske kiseline u mediju vodenog otapala ili u pogodnom organskom otapalu, poput metanola ili etanola. Nakon pažljivog otparavanja otapala, lako se dobije traženu krutu sol. Traženu kiselu sol također se može istaložiti iz otopine slobodne alkalije u organskom otapalu dodavanjem u otopinu pogodne mineralne ili organske kiseline.
Spojevi formule 1 kisele prirode mogu tvoriti alkalne soli s različitim farmakološki prihvatljivim kationima. Primjeri takvih soli uključuju soli alkalnih i zemnoalkalnih metala, a osobito soli natrija i kalija. Ove soli može se dobiti konvencionalnim tehnikama. Kemijske alkalije koje se upotrebljava kao reagense u dobivanju farmaceutski prihvatljivih alkalnih soli iz ovog izuma su one koje tvore neotrovne alkalne soli s kiselim spojevima formule 1. Takve neotrovne alkalne soli uključuju one derivirane iz farmakološki prihvatljivih kationa poput natrija, kalija, kalcija i magnezija itd. Ove soli može se dobiti reakcijom odgovarajućih kiselih spojeva s vodenom otopinom koja sadrži tražene farmakološki prihvatljive katione, a zatim otparavanjem dobivene otopine do suhog, po mogućnosti, pod sniženim tlakom. Alternativno, također ih se može dobiti miješanjem nižih alkanolnih otopina kiselih spojeva s onim alkoksida traženih metala, a zatim otparavanjem dobivene otopine do suhog na isti način kao ranije. U oba slučaja, po mogućnosti se upotrebljava stehiometrijske količine reagensa, radi osiguranja potpunosti reakcije i dobivanja maksimalnih prinosa traženog konačnog produkta.
Aktivnost spojeva iz ovog izuma protiv bakterijskih i protozojskih patogena prikazana je sposobnošću spoja da inhibira rast definiranih sojeva patogena kod ljudi (Test I) ili životinja (Testovi II i III).
Test I
Test I, opisan niže, upotrebljava konvencionalnu metodologiju i kriterije interpretacije i zamišljen je kako bi se ustanovio pravac kemijskih modifikacija koje mogu dovesti do spojeva koji zaobilaze definirane mehanizme otpornosti na makrolide. U Testu I, načinjen je panel bakterijskih sojeva kako bi se uključilo mnoštvo patogenih vrsta, koje uključuju karakterizirane predstavnike mehanizama otpornosti na makrolide. Upotreba ovog panela omogućuje određivanje odnosa između kemijske strukture i aktivnosti, s obzirom na potentnost, spektar i elemente strukture ili modifikacije koje mogu biti nužne u sprječavanju mehanizama otpornosti. Bakterijski patogeni koje sadrži pregledni panel prikazani su u tablici, niže. U mnogo slučajeva, dostupni su i roditeljski soj osjetljiv na makrolide i iz njega izvedeni soj, kako bi se omogućilo precizniju procjenu sposobnosti soja da zaobiđe mehanizam otpornosti. Sojevi koji sadrže gen označen kao ermA/ermB/ermC otporni su na makrolidne, linkozamidne i streptogramin B antibiotike zbog modifikacija (metilacije) 23S rRNA molekula Erm metilazom (erythromycin resistance methylation), sprječavajući tako sve tri klase struktura. Opisana su dva tipa efluksa makrolida (mehanizma izbacivanja); msrA (macrolide and streptogramin resistance) kodira komponentu sustava efluksa kod stafilokoka koja priječi ulazak makrolida i streptogramina, dok mefA/E (macrolide efflux) kodira transmembranski protein koji očito izbacuje samo makrolide. Inaktivacija makrolidnih antibiotika može se desiti i biti posredovana bilo fosforilacijom 2'-hidroksila (mph = macrolide phosphorilation) ili cijepanjem makrocikličkog laktona (esteraza). Sojeve se može karakterizirati konvencionalnom tehnologijom lančane reakcije polimeraze (polymerase chain reaction, PCR) i/ili sekvenciranjem determinante otpornosti. upotreba tehnologije PCR-a u ovoj prijavi opisana je u članku J. Sutcliffe i drugi: "Detection Of Erythromycin-Resistant Determinants By PCR", Antimicrobial Agents and Chemotherapy, 40(11), 2562-2566 (1996.). Test se provodi u mikrotitarskim posudicama i interpretira u skladu sa Standardima provođenja testova osjetljivosti na diskove od antimikrobnih tvari -6. izdanje: Odobreni standard (Performance Standards for Antimicrobial Disk susceptibility Tests - Sixth Edition: Approved Standard), objavljen u Smjernicama Nacionalnog komiteta za kliničke laboratorijske standarde (National Committee for Clinical Laboratory Standards (NCCLS) guidelines); u uspoređivanju sojeva upotrebljava se minimalnu inhibicijsku koncentraciju (minimal inhibition concentration, MIC). Spojeve se najprije otopi u dimetilsulfoksidu (dimethylsulfoxide, DMSO) kao 40 mg/ml matične otopine.
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Test II upotrebljava se u testiranju aktivnosti protiv bakterije Pasteurella multocida, a Test III upotrebljava se u testiranju aktivnosti protiv bakterije Pasteurella haemolytica.
Test II
Ovaj test temelji se na postupku tekućinskog razrjeđivanja u mikrolitarskom formatu. Jednu koloniju bakterije P. multocida (soj 59A067) nasadi se u 5 ml moždano-srčanog infuzijskog bujona (brain heart infusion, BHI). Ispitne spojeve se priredi otapanjem 1 mg spoja u 125 µl dimetilsulfoksida (DMSO). Razrjeđenja ispitnog spoja dobije se na nenasađenom BHI bujonu. Koncentracije ispitnog spoja bile su raspona od 200-0,098 µg/ml, dobivene dvostrukim serijskim razrjeđivanjem. BHI nasađen bakterijom P. multocida razrijedi se nenasađenim BHI bujonom kako bi se dobilo suspenziju od 104 stanica po 200 µl. BHI stanične suspenzije pomiješa se s odgovarajućim razrjeđenjima ispitnog spoja, zatim 18 sati inkubira na 37 °C. Minimalna inhibicijska koncentracija (MIC) je koncentracija spoja, koja 100 % inhibira rast bakterije P. multocida, što se odredi uspoređivanjem s nenasađenom kontrolom.
Test III
Ovaj test temelji se na postupku agarskog razrjeđivanja pomoću Steers-ovog replikatora. Dvije do pet kolonija izoliranih s agarske ploče nasadi se u BHI bujon i inkubira preko noći na 37 °C uz trešenje (200 okretaja u minuti). Iduće jutro, 300 µl narasle predkulture bakterije P. haemolytica nasadi se u 3 ml svježeg BHI bujona i inkubira na 37 °C uz trešenje (200 okretaja u minuti). Odgovarajuće količine ispitnih spojeva otopi se u etanolu te se načini niz dvostrukih serijskih razrjeđenja. Po 2 ml odgovarajućeg serijskog razrjeđenja pomiješa se s 18 ml rastaljenog BHI agara, i zatim skrutne. Kada nasađena kultura bakterije P. haemolytica dosegne 0,5 standardne gustoće po McFarland-u, oko 5 µl kulture bakterije P. haemolytica nasadi se na ploče BHI agara, koje sadrže različite koncentracije ispitnog spoja, uz pomoć Steers-ovog replikatora, te 18 sati inkubira na 37 °C. Početne koncentracije ispitnog spoja raspona su od 100-200 µg/ml. MIC je koncentracija ispitnog spoja koja 100 % inhibira rast bakterije P. haemolytica, što se odredi uspoređivanjem s nenasađenom kontrolom.
In vivo aktivnost spojeva formule 1 može se odrediti konvencionalnim ispitivanjima zaštite životinja dobro poznatim stručnjacima, koje se obično provodi na miševima.
Miševe se raspodijeli po kavezima (10 po kavezu) po njihovom dolasku, a zatim ih se pusti neka se prilagode barem 48 sati prije nego ih se upotrijebi. Životinje se intraperitonealno inokulira s 0,5 ml 3 × 103 CFU/ml (colony forming unit = jedinica kolonizacije) bakterijske suspenzije (P. multocida soj 59A006). U svakom eksperimentu su barem 3 neliječene kontrolne grupe, koje uključuju jednu inficiranu s 0,1 × doze izazova te dvije inficirane s 1 × doze izazova; također se može upotrijebiti i podatke iz grupe s 10 × izazovom. Općenito, sve miševe u danoj studiji može se izazvati unutar 30-90 minuta, osobito ako se za primjenu izazova upotrijebi ponavljajuća injekcijska šprica (Cornwll® šprica). Prvi tretman spojem izvrši se 30 minuta nakon početka izazova. Ako sve životinje nisu izazvane unutar 30 minuta može biti potrebno da i druga osoba počne primjenjivati doziranje spoja. Načini primjene su potkožne i oralne doze. Potkožne doze primjenjuje se u labavu kožu na stražnjem dijelu vrata, dok se oralne doze daje iglom za hranjenje. U oba slučaja, upotrijebi se volumen od 0,2 ml po mišu. Spojeve se primjenjuje 30 minuta, 4 sata i 24 sata nakon izazova. U svaki test uključen je kontrolni spoj poznate djelotvornosti, primijenjen na isti način. Životinje se promatra dnevno, te se zabilježi broj preživjelih u svakoj grupi. Promatranje P. multocida modela traje 96 sati (4 dana) nakon izazova.
PD50 je izračunata doza kod koje ispitni spoj štiti 50 % grupe miševa od smrti izazvane bakterijskom infekcijom, koja bi bila smrtonosna u odsustvu tretmana lijekom.
Spojeve formule 1, i njihove farmaceutski prihvatljive soli i solvate (nadalje "aktivni spojevi"), može se primijeniti oralnim, parenteralnim, topikalnim ili rektalnim načinom u tretmanu ili sprječavanju bakterijske ili protozojske infekcije. Općenito, ove spojeve se najpoželjnije primjenjuje u doziranjima raspona od oko 0,2 mg/kg tjelesne težine dnevno (mg/kg/dan) do oko 200 mg/kg/dan, u jednoj ili podijeljenim dozama (tj. od 1-4 doze dnevno), iako su varijacije nužno moguće, ovisno o vrsti, težini i stanju tretiranog subjekta, a osobito odabranom načinu primjene. Međutim, razina doziranja, koja je raspona od oko 4-50 mg/kg/dan je najpoželjnija prilikom upotrebe. Varijacije su, ipak, moguće, ovisno o vrsti sisavca, ribe ili ptice koje se tretira, te njihovom individualnom odgovoru na navedeni lijek, kao i tipu odabrane farmaceutske formulacije i vremenskom periodu i intervalu u kojem se takvu primjenu provodi. U izvjesnim slučajevima, razine doziranja niže od gore navedenog raspona mogu biti i više no dovoljne, dok u drugim slučajevima može se upotrebljavati čak i veće doze bez izazivanja bilo kakve štetne nuspojave, uz uvjet da se takve veće doze najprije podijeli u nekoliko manjih, radi primjene tijekom dana.
Aktivne spojeve može se primijeniti same ili u kombinaciji s farmaceutski prihvatljivim podlogama ili razrjeđivačima gore navedenim načinima, a takvu primjenu može se provesti u jednoj ili više doza. Specifičnije, aktivne spojeve može se primijeniti u širokom rasponu različitih oblika doziranja, tj. može ih se kombinirati s različitim farmaceutski prihvatljivim inertnim podlogama u obliku tableta, kapsula, pilula, pastila, tvrdih bombona, praškova, sprejeva, krema, pomada, supozitorija, želea, gelova, pasta, losiona, masti, vodenih suspenzija, otopina za injiciranje, ljekovitih napitaka, sirupa i slično. Takve podloge uključuju krute razrjeđivače ili punila, sterilne vodene medije i različita neotrovna organska otapala itd. Osim toga, oralne farmaceutske pripravke može se pogodno zasladiti i/ili aromatizirati. Općenito, aktivni spojevi dolaze u takvim oblicima doziranja u razinama koncentracije raspona od oko 5,0-70 %, težinski.
Prilikom oralne primjene, tablete koje sadrže različite ekscipijense, poput mikrokristalne celuloze, natrij citrata, kalcij karbonata, dikalcij fosfata i glicina, može se upotrebljavati s različitim dezintegransima, poput škroba (po mogućnosti, kukuruznog, krumpirovog ili tapiokinog škroba), alginske kiseline i izvjesnih složenih silikata, skupa s granulacijskim vezivima poput polivinilpirolidona, saharoze, želatine i agacije. Osim toga, maziva, poput magnezij stearata, natrij lauril sulfata i talka su često vrlo korisna u tabletiranju. Krute pripravke sličnog tipa također se može upotrijebiti kao punila u želatinskim kapsulama; poželjni materijali u vezi s tim također uključuju laktozu ili mliječni šećer, kao i visokomolekulske polietilen glikole. Kada se želi oralno primijeniti vodene suspenzije i/ili vodene napitke, aktivni spoj se može kombinirati s različitim aromama ili sladilima, bojama ili bojilima, te, ako se želi, emulgatorima i/ili suspendirajućim tvarima, kao i skupa s razrjeđivačima poput vode, etanola, propilen glikola, glicerina i različitim njihovim smjesama.
Prilikom parenteralne primjene, može se upotrebljavati otopine aktivnog spoja bilo u sezamovom ili kikirikijevim ulju, ili u vodenoj otopini propilen glikola. Vodene otopine treba po potrebi pogodno puferirati (po mogućnosti pH > 8), a vodeno otapalo se najprije izotonizira. Ove vodene otopine pogodne su za intravensko injiciranje. Uljne otopine pogodne su za intraartikularno, intramuskularno i potkožno injiciranje. Dobivanje svih tih otopina pod sterilnim uvjetima se lako postiže standardnim farmaceutskim tehnikama i bit će poznato stručnjacima.
Osim toga, aktivne spojeve iz ovog izuma također je moguće primijeniti topikalno, a to se može postići putem krema, želea, gelova, pasta, flastera, masti i slično, u skladu sa standardnom farmaceutskom praksom.
Za primjenu na životinjama različitim od ljudi, poput stoke ili domaćih životinja, aktivne spojeve može se primijeniti u životinjskom krmivu ili oralno, kao tekući pripravak.
Aktivne spojeve također se može primijeniti u obliku liposomskih sustava unošenja, poput malih jednoslojnih vezikula, velikih jednoslojnih vezikula i višeslojnih vezikula. Liposome se može dobiti iz niza fosfolipida, poput kolesterola, stearilamina ili fosfatidilkolina.
Aktivne spojeve također se može vezati na topive polimere kao ciljane nosače lijekova. Takvi polimeri mogu uključiti polivinilpirolidon, piranski kopolimer, polihidroksipropilmetakrilamid fenil, polihidroksietilaspartamid-fenol, ili polietilenoksid-polilizin supstituiran palmitoilnim ostacima. Osim toga, aktivne spojeve se može vezati na klasu biorazgradivih polimera, korisnih u postizanju kontroliranog otpuštanja lijeka, primjerice, polimliječnu kiselinu, poliglikolnu kiselinu, kopolimere polimliječne i poliglikolne kiseline, poliepsilon kaprolakton, polihidroksi maslačnu kiselinu, poliortoestere, poliacetale, polidihidropirane, policijanoakrilate i umrežene ili amfipatske blok kopolimere hidrogelova.
Niže iznijeti Primjeri prikazuju specifična ostvarenja ovog izuma, no ovaj izum se ne ograničuje na specifično iznijete primjere.
Niže iznijeti primjer prikazuje specifično ostvarenje ovog izuma, no ovaj izum se ne ograničuje na specifično iznijeti Primjer. U slijedećem primjeru, "Ac" je acetilna grupa, "Me" je metilna grupa, a "Et" je etilna grupa.
[image]
Primjer 1
U otopinu koja sadrži spoj gornji formule 30 (gdje "Ac" je acetilna grupa) (513 mg, 0,58 mmol) u 5,8 ml DMF-a doda se na –78 °C 1,74 ml 0,5 M otopine KHMDS-a u toluenu (0,87 mmol). SELECTFLUORTM (proizvodi Air Products and Chemicals, Inc., Allentown, Pennsilvania, USA) (236 mg, 0,87 mmol) doda se u tu otopinu nakon 30 minuta miješanja na –78 °C. Svježi SELECTFLUORTM (27 mg, 0,076 mmol) doda se nakon 30 minuta miješanja na –78 °C. Nakon još 30 minuta miješanja na istoj temperaturi, reakcijsku smjesu se razrijedi s EtOAc (etil acetat) i ispere vodom i slanom vodom. Sušenje iznad natrij sulfata i uklanjanje otapala daje 477 mg (93 %) spoja prema gornjoj formuli 31, s tim što je C-2' hidroksi zaštićen acetilnom grupom.
Ovaj materijal otopi se u 50 ml MeOH i grije na 50 °C preko noći. Otparavanje otapala i kromatografija na SiO2 daje spoj formule 31 (koji odgovara spoju formule 2 navedenom gore, gdje R12, R13, R14 i R15 su svaki H).
NMR (CDCl3, δ) 8,93 (1H,d), 8,42 (1H, dd), 8,04 (1H, dd), 7,57 (1H, s), 7,35 (1H, d), 7,24 (1H, dd), 6,03 (1H, s), 4,89 (1H, dd), 4,28 (1H, d), 4,09 (2H, m), 4,07 (1H, d); 3,69 (3H, s), 3,66 (1H, s), 3,56 (1H, m), 3,48 (1H, m), 3,41 (1H, m), 3,24 (1H, m), 2,76 (1H, m), 2,60 (2H, m), 2,57 (3H, s), 2,36 (6H, s), 1,93 (2H, m), 1,74 (3H, d), 1,76-1,20 (6H, m), 1,49 (3H, s), 1,34 (3H, s), 1,27 (3H, d), 1,22 (3H, d), 1,01 (3H, d), 0,98 (3H, d), 0,83 (3H, t).
Primjer 2
Prema postupcima opisanim gore u Shemi 2 dobije se spoj prema formuli 1, gdje X1 je –CH(CH3)(CH2)2–, X2 je =NOCH3, R8 je H, R9 je CH3, R10 je CH2CH3, R11 je F, a R12 je 4-(piridin-3-il)-imidazol-1-il.
MS 874 (M+1).
[image]
Slijedeće primjere, gdje svaki ima strukturu u skladu s gornjom formulom 32, dobije se postupkom opisanim niže, koji opisuje dobivanje spoja iz Primjera 3. Primjere 4-10 dobije se istim postupkom uz upotrebu odgovarajućeg heterocikličkog spoja umjesto fenil imidazola.
Primjer 3
U otopinu spoja 10 (100 mg, 0,055 mmol) fenil imidazola (67,0 mg, 0,465 mmol) u 1,5 ml octene kiseline doda se 12,7 µl 90 % akroleina (0,071 mmol). Dobivenu smjesu se preko noći miješa na sobnoj temperaturi. Zatim se doda natrij cijanborhidrid (46,7 mg, 0,775 mmol), a otopinu se preko noći miješa na sobnoj temperaturi. Otopinu se razrijedi vodom, a pH joj se podesi na 10 pomoću 40 % vodene otopine NaOH. Vodenu otopinu se ekstrahira metilen kloridom. prikupljeni metilen kloridni sloj osuši se iznad natrij sulfata, a otapalo se ukloni pod sniženim tlakom. Ostatak se pročisti TLC-om (89 % metilen klorid-10 %metanol-1 % amonij hidroksid), kako bi se dobilo 6 mg (prinos 5 %) iz Primjera 3.
[image] [image]
Claims (9)
1. Spoj formule
[image]
,
ili njegova farmaceutski prihvatljiva sol ili solvat, naznačen time što:
X1 je O, –CR4R5– ili –NR4–;
X2 je =O ili =NOR1;
R1 je H ili C1-C10 alkil, gdje je 1-3 ugljika navedenog alkila izborno zamijenjeno heteroatomom odabranim između O, S i –N(R4)–, a navedeni alkil je izborno supstituiran s 1-3 supstituenta neovisno odabrana iz grupe koju čine –C(O)O(C1-C10 alkil), C1-C10 alkoksi, C1-C10 alkanoil, halo, nitro, cijano, 4-10-eročlani heterociklil, C1-C10 alkil, –NR4R5, C6-C10 aril, –S(O)n(C1-C10 alkil), gdje n je cijeli broj raspona od 0-2, i –SO2NR4R5;
R2 je –(CR4R5)n(4-10-eročlani heterocikl) ili –(CR4R5)n(C6-C10 aril), gdje n je cijeli broj od 0-6, a od 1-3 R4 ili R5 grupe –(CR4R5)n- ostatka prethodno navedenih R2 grupa izborno je zamijenjeno halo supstituentom, i heterociklički i arilni ostaci prethodno navedenih R2 grupa su izborno supstituirani s 1-4 R3 grupe;
svaki R3 neovisno je odabran između halo, cijano, nitro, trifluormetoksi, trifluormetila, azido, hidroksi, C1-C6 alkoksi, C1-C10 alkila, C2-C6 alkenila, C2-C6 alkinila, –C(O)R6, –C(O)OR6, –OC(O)R6, –NR6C(O)R7, –NR5C(O)NR1R7, –NR6C(O)OR7, –C(O)NR6R7, –NR6R7, –NR6OR7, –SO2NR6R7, –S(O)j(C1-C6 alkil), gdje j je cijeli broj od 0-2, –(CR1R2)t(C6-C10 arila), –(CR4R5)t(4-10-eročlanog heterocikla), –(CR4R5)qC(O)(CR4R5)t(C6-C10 arila), –(CR4R5)qC(O)(CR4R5)t(4-10-eročlanog heterocikla), –(CR4R5)t(CR4R5)q(C6-C10 arila), –(CR4R5)t(CR4R5)q(4-10-eročlanog heterocikla), –(CR4R5)qSO2(CR4R5)t(C6-C10 aril) i –(CR4R5)qSO2(CR4R5)t(4-10-eročlanog heterocikla), gdje q i t su svaki neovisno cijeli broj od 0-5, a 1 ili 2 ugljikova atoma iz prstena heterocikličkih ostataka prethodno navedenih R10 grupa su izborno supstituirani okso (=O) ostatkom, i alkilni, alkenilni, alkinilni, arilni i heterociklički ostaci prethodno navedenih R10 grupa su izborno supstituirani s 1-3 supstituenta neovisno odabrana između halo, cijano, nitro, trifluormetila, trifluormetoksi, azido, –OR6, –C(O)R6, –C(O)OR6, –OC(O)R6, –NR6C(O)R7, –C(O)NR6R7, –NR6R7, –NR6OR7, C1-C6 alkila, C2-C6 alkenila, C2-C6 alkinila, –(CR4R5)t(C6-C10 aril) i –(CR4R5)t(4-10-eročlanog heterocikla), gdje t je cijeli broj od 0-5;
svaki R4 i R5 neovisno je odabran između H i C1-C6 alkila;
svaki R6 i R7 neovisno je odabran između H, C1-C6 alkila, –(CR4R5)t(C6-C10 arila) i –(CR4R5)t(4-10-eročlanog heterocikla), gdje t je cijeli broj od 0-5, a 1 ili 2 ugljikova atoma iz prstena heterocikličke grupe izborno su supstituirani s okso (=O) ostatkom, i alkilni, arilni i heterociklički ostaci prethodno navedenih R6 i R7 grupa su, izborno, supstituiran s 1-3 supstituenta neovisno odabrana između halo, cijano, nitro, –NR4R5, trifluormetila, trifluormetoksi, C1-C6 alkila, C2-C6 alkenila, C2-C6 alkinila, hidroksi i C1-C6 alkoksi;
R8 je H, –C(O)(C1-C6 alkil), benzil, benziloksikarbonil ili (C1-C6 alkil)3silil;
R9 je C1-C6 alkil;
R10 je H ili C1-C10 alkil; i
R11 se bira između klora, broma, joda, fluora i cijano;
uz uvjet da gdje X2 je =O, R11 je cijano ili od 1-3 R4 ili R5 grupe –(CR4R5)n– ostatka R2 gore navedenih grupa su bilo C1-C6 alkil ili su zamijenjeni halo supstituentom.
2. Spoj formule
[image]
,
ili njegova farmaceutski prihvatljiva sol ili solvat, naznačen time što R12, R13, R14 i R15 se svakog neovisno bira između H, halo, metila i etila.
3. Spoj prema zahtjevu 2, naznačen time što R14 i R15 su oba H, a R12 i R13 se svakog neovisno bira između H i metila.
4. Spoj prema zahtjevu 2, naznačen time što R12, R13, R14 i R15 su svaki H.
5. Spoj formule
[image]
ili njegova farmaceutski prihvatljiva sol ili solvat, naznačen time što R12, R13, R14 i R15 se svakog neovisno bira između H, halo, metila i etila, uz uvjet da barem jedan od R12, R13, R14 i R15 nije H.
6. Spoj prema zahtjevu 5, naznačen time što R14 i R15 su oba H, R12 je metil, i R13 se bira između H i metila.
7. Farmaceutski pripravak za tretman poremećaja odabranog između bakterijske infekcije, protozojske infekcije i poremećaja povezanog s bakterijskom infekcijom ili protozojskom infekcijom kod sisavca, ribe ili ptice, naznačen time što sadrži terapeutski djelotvornu količinu spoja prema zahtjevu 1 i farmaceutski prihvatljivu podlogu.
8. Postupak tretiranja poremećaja odabranog između bakterijske infekcije, protozojske infekcije i poremećaja povezanog s bakterijskom infekcijom ili protozojskom infekcijom kod sisavca, ribe ili ptice, naznačen time što se sastoji u primjeni na navedenom sisavcu, ribi ili ptici terapeutski djelotvorne količine spoja prema zahtjevu 1.
9. Postupak dobivanja spoja prema zahtjevu 1, gdje R11 je halo grupa, naznačen time što se sastoji u reakciji spoja formule
[image]
gdje R8, R9, R10, X1, X2 i R2 odgovaraju definiciji u zahtjevu 1, s halogenirajućim agensom.
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Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AP1060A (en) | 1998-01-02 | 2002-04-23 | Pfizer Prod Inc | Novel erythromycin derivatives. |
AU1675400A (en) | 1999-01-27 | 2000-08-18 | Pfizer Products Inc. | Ketolide antibiotics |
WO2000062783A2 (en) | 1999-04-16 | 2000-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
US6514944B2 (en) | 1999-04-16 | 2003-02-04 | Kosan Biosciences, Inc. | Macrolide antiinfective agents |
JP2003523938A (ja) | 1999-04-16 | 2003-08-12 | コーサン バイオサイエンシーズ, インコーポレイテッド | マクロライド系抗感染剤 |
US6939861B2 (en) | 1999-04-16 | 2005-09-06 | Kosan Biosciences, Inc. | Amido macrolides |
US6451768B1 (en) | 1999-04-16 | 2002-09-17 | Kosan Biosciences, Inc. | Macrolide antiinfective agents |
US6590083B1 (en) | 1999-04-16 | 2003-07-08 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
PL352720A1 (en) | 1999-05-24 | 2003-09-08 | Pfizer Products Inc. | 13-methyl-erythromycin derivatives |
TR200401847T4 (tr) | 2000-06-30 | 2004-09-21 | Pfizer Products Inc. | Makrolit antibiyotikler. |
US20020115621A1 (en) | 2000-08-07 | 2002-08-22 | Wei-Gu Su | Macrolide antibiotics |
AU1727702A (en) * | 2000-12-21 | 2002-07-01 | Glaxo Group Ltd | Macrolide antibiotics |
WO2003022289A1 (fr) * | 2001-09-05 | 2003-03-20 | Hokuriku Seiyaku Co., Ltd. | Medicament contenant de l'erythromycine pour traiter ou prevenir la tuberculose |
WO2004080391A2 (en) | 2003-03-10 | 2004-09-23 | Optimer Pharmaceuticals, Inc. | Novel antibacterial agents |
JP2008508322A (ja) * | 2004-07-28 | 2008-03-21 | ランバクシー ラボラトリーズ リミテッド | 抗菌剤としてのケトライド誘導体 |
PL1836211T3 (pl) | 2004-12-21 | 2010-07-30 | Pfizer Prod Inc | Makrolidy |
WO2007129646A1 (ja) * | 2006-05-01 | 2007-11-15 | Taisho Pharmaceutical Co., Ltd. | マクロライド誘導体 |
CN101917850B (zh) | 2007-10-25 | 2016-01-13 | 森普拉制药公司 | 大环内酯类抗菌剂的制备方法 |
EP2358379B1 (en) | 2008-10-24 | 2015-12-16 | Cempra Pharmaceuticals, Inc. | Biodefenses using triazole-containing macrolides |
US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
AU2010292010B2 (en) | 2009-09-10 | 2016-01-07 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and MAC diseases |
KR20180101643A (ko) | 2010-03-22 | 2018-09-12 | 셈프라 파마슈티컬스, 인크. | 매크로라이드의 결정 형태들 및 그 용도들 |
BR112012029586A2 (pt) | 2010-05-20 | 2016-08-02 | Cempra Pharmaceuticals Inc | processos para preparar macrolídeos e cetolídeos e intermediários dos mesmos |
JP6042334B2 (ja) | 2010-09-10 | 2016-12-14 | センプラ ファーマシューティカルズ,インコーポレイテッド | 疾患治療のための水素結合形成フルオロケトライド |
RU2658050C2 (ru) | 2012-03-27 | 2018-06-19 | Семпра Фармасьютикалз, Инк. | Парентеральные составы для введения макролидных антибиотиков |
CA2905975A1 (en) | 2013-03-14 | 2014-09-25 | Cempra Pharmaceuticals, Inc. | Methods for treating respiratory diseases and formulations therefor |
JP6675973B2 (ja) | 2013-03-15 | 2020-04-08 | センプラ ファーマシューティカルズ,インコーポレイテッド | マクロライド抗菌薬を調製するための集束的な方法 |
JP6332266B2 (ja) | 2013-03-28 | 2018-05-30 | 不二製油株式会社 | 緑豆蛋白ゲル状組成物及びチーズ様食品 |
CN106518939B (zh) * | 2015-09-14 | 2019-12-31 | 江苏奥赛康药业有限公司 | 一种制备Solithromycin化合物的方法 |
EP3522896A4 (en) * | 2016-10-04 | 2020-06-17 | Biopharmati SA | KETOLID WITH ANTIBACTERIAL EFFECT |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI8110592A8 (en) | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
US4474768A (en) | 1982-07-19 | 1984-10-02 | Pfizer Inc. | N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor |
US5141926A (en) | 1990-04-18 | 1992-08-25 | Abbott Laboratories | Erythromycin derivatives |
IL99995A (en) | 1990-11-21 | 1997-11-20 | Roussel Uclaf | Erythromycin derivatives, their preparation and pharmaceutical compositions containing them |
US5527780A (en) | 1992-11-05 | 1996-06-18 | Roussel Uclaf | Erythromycin derivatives |
FR2697524B1 (fr) | 1992-11-05 | 1994-12-23 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
FR2719587B1 (fr) * | 1994-05-03 | 1996-07-12 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
FR2727969B1 (fr) * | 1994-12-09 | 1997-01-17 | Roussel Uclaf | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
US5747466A (en) | 1995-11-08 | 1998-05-05 | Abbott Laboratories | 3-deoxy-3-descladinose derivatives of erythromycins A and B |
FR2742757B1 (fr) * | 1995-12-22 | 1998-01-30 | Roussel Uclaf | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
FR2745290B1 (fr) | 1996-02-28 | 1998-04-03 | Roussel Uclaf | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
FR2748746B1 (fr) | 1996-05-14 | 1998-08-14 | Hoechst Marion Roussel Inc | Nouveau procede d'isomerisation du radical methyle en 10 de derives de l'erythromycine |
EP0910633B1 (en) | 1996-07-05 | 2009-12-09 | Biotica Technology Limited | Hybrid polyketide synthase I gene |
FR2751656B1 (fr) | 1996-07-24 | 1998-10-16 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
UA51730C2 (uk) | 1996-09-04 | 2002-12-16 | Ебботт Лабораторіз | 6-o-заміщені кетоліди з антибактеріальною активністю, спосіб їх одержання (варіанти), фармацевтична композиція та спосіб регулювання бактеріальної інфекції у ссавців |
FR2757168B1 (fr) | 1996-12-12 | 1999-06-11 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
FR2760017B1 (fr) | 1997-02-27 | 1999-04-30 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erytromycine, leur procede de preparation et leur application comme medicaments |
AU4472897A (en) | 1997-03-10 | 1998-09-29 | Taisho Pharmaceutical Co., Ltd. | Erythromycin a derivatives |
US20020025937A1 (en) | 2000-03-20 | 2002-02-28 | Yong-Jin Wu | 9-oxime erythromycin derivatives |
ZA987689B (en) | 1997-09-02 | 1999-02-24 | Abbott Lab | 3-descladinose 6-O substituted erythromycin derivatives |
HN1998000159A (es) | 1997-10-29 | 1999-02-09 | Monsanto Co | Derivados de 9- amino - 3 ceto eritromicina |
JP2003527301A (ja) | 1997-10-29 | 2003-09-16 | 大正製薬株式会社 | エリスロマイシンa誘導体 |
FR2771008B1 (fr) * | 1997-11-17 | 2000-04-28 | Hoechst Marion Roussel Inc | Utilisation des ketolides pour la preparation de compositions pharmaceutiques destinees a prevenir les complications thrombotiques arterielles liees a l'atherosclerose |
WO1999025385A1 (en) | 1997-11-17 | 1999-05-27 | Imarx Pharmaceutical Corp. | A method of increasing nucleic acid synthesis with ultrasound |
AP1060A (en) | 1998-01-02 | 2002-04-23 | Pfizer Prod Inc | Novel erythromycin derivatives. |
FR2777282B1 (fr) | 1998-04-08 | 2001-04-20 | Hoechst Marion Roussel Inc | Nouveaux derives de la 2-fluoro 3-de((2,6-dideoxy 3-c-methyl 3-0-methyl-alpha-l-ribohexopyranosyl) oxyl) 6-o-methyl 3-oxo erythromycine, leur procede de preparation et leur application a la synthese de principes actifs de medicaments |
AU5299499A (en) | 1998-09-22 | 2000-04-10 | Pfizer Products Inc. | Carbamate and carbazate ketolide antibiotics |
US6100240A (en) | 1998-10-09 | 2000-08-08 | Pfizer Inc | Macrolide derivatives |
FR2785612A1 (fr) | 1998-11-10 | 2000-05-12 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
AP2001002131A0 (en) | 1998-11-03 | 2001-06-30 | Pfizer Prod Inc | Novel macrolide antibiotics. |
FR2786188B1 (fr) | 1998-11-24 | 2002-10-31 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur applicaion comme medicaments |
DE69933897T2 (de) | 1998-12-10 | 2007-03-15 | Pfizer Products Inc., Groton | Carbamat- und Carbazatketolid-Antibiotika |
AU1675400A (en) | 1999-01-27 | 2000-08-18 | Pfizer Products Inc. | Ketolide antibiotics |
FR2789392B1 (fr) | 1999-02-04 | 2001-10-05 | Hoechst Marion Roussel Inc | Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments |
JP2003523938A (ja) | 1999-04-16 | 2003-08-12 | コーサン バイオサイエンシーズ, インコーポレイテッド | マクロライド系抗感染剤 |
WO2000062783A2 (en) | 1999-04-16 | 2000-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
US6355620B1 (en) | 1999-05-14 | 2002-03-12 | Abbott Laboratories | C-2 modified erythromycin derivatives |
PL352720A1 (en) | 1999-05-24 | 2003-09-08 | Pfizer Products Inc. | 13-methyl-erythromycin derivatives |
EP1114826A3 (en) | 1999-12-29 | 2001-10-31 | Pfizer Products Inc. | Novel antibacterial and prokinetic macrolides |
EP1122261A3 (en) | 2000-01-31 | 2001-09-26 | Pfizer Products Inc. | 13 and 14-membered antibacterial macrolides |
US20020061856A1 (en) | 2000-04-24 | 2002-05-23 | Yong-Jin Wu | Novel tricyclic erythromycin derivatives |
TR200401847T4 (tr) | 2000-06-30 | 2004-09-21 | Pfizer Products Inc. | Makrolit antibiyotikler. |
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