HRP990148A2 - Purine l-nucleosides, analogs and uses thereof - Google Patents
Purine l-nucleosides, analogs and uses thereof Download PDFInfo
- Publication number
- HRP990148A2 HRP990148A2 HRP990148A HRP990148A2 HR P990148 A2 HRP990148 A2 HR P990148A2 HR P990148 A HRP990148 A HR P990148A HR P990148 A2 HRP990148 A2 HR P990148A2
- Authority
- HR
- Croatia
- Prior art keywords
- aralkyl
- alkynyl
- alkyl
- alkenyl
- acetyl
- Prior art date
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- 239000002777 nucleoside Substances 0.000 title claims description 40
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims description 73
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000000304 alkynyl group Chemical group 0.000 claims description 44
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 229910052794 bromium Inorganic materials 0.000 claims description 39
- 229910052740 iodine Inorganic materials 0.000 claims description 35
- 229910052801 chlorine Inorganic materials 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 32
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 28
- -1 COOR' Chemical group 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 208000015181 infectious disease Diseases 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 206010061217 Infestation Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 239000002212 purine nucleoside Substances 0.000 claims description 3
- 229910014288 N-N Inorganic materials 0.000 claims description 2
- 229910014320 N—N Inorganic materials 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- YWBULOYFCXZCGF-UHFFFAOYSA-N [1,3]thiazolo[4,5-d]pyrimidine Chemical compound C1=NC=C2SC=NC2=N1 YWBULOYFCXZCGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 2
- 125000000716 hydrazinylidene group Chemical group [*]=NN([H])[H] 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims 1
- 238000012544 monitoring process Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
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- 229940029575 guanosine Drugs 0.000 description 53
- 239000007787 solid Substances 0.000 description 45
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- 235000019439 ethyl acetate Nutrition 0.000 description 13
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
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- OOOBGFAUGXVKGI-UHFFFAOYSA-N 5,6-dihydropyrazolo[3,4-d]pyrimidin-4-one Chemical compound O=C1NCN=C2N=NC=C12 OOOBGFAUGXVKGI-UHFFFAOYSA-N 0.000 description 9
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- PYMYPHUHKUWMLA-MROZADKFSA-N aldehydo-L-ribose Chemical compound OC[C@H](O)[C@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-MROZADKFSA-N 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 7
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
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- 229910000069 nitrogen hydride Inorganic materials 0.000 description 5
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- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
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Description
Područje izuma Field of invention
Ovaj izum je iz područja organske kemije i biokemije, odnosi se na znanstveno područje koje se bavi L-nukleozidima. This invention is from the field of organic chemistry and biochemistry, it refers to the scientific field that deals with L-nucleosides.
Stanje izuma State of the art
Posljednjih nekoliko desetljeća uloženi su značajni napori da se istraži mogućnost uporabe D-nukleozidnih analoga kao antivirusnih sredstava. Nešto od ovog rada urodilo je plodom, te se određen broj nukleozidnih analoga sada nalazi na tržištu kao antivirusna sredstva, uključujući inhibitore HIV reverzne transkriptaze (AZT, ddI, ddC, d4T i 3TC). In the last few decades, considerable efforts have been made to investigate the possibility of using D-nucleoside analogues as antiviral agents. Some of this work has borne fruit, and a number of nucleoside analogs are now on the market as antiviral agents, including HIV reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC).
U potrazi za imuno-modulatorima također su ispitani različiti analozi purinskih D-nukleozida. Guanozinski analozi koji imaju supstituente na 7- i/ili 8-položaju, primjerice, pokazalo se da stimuliraju imunološki sustav (za pregled, vidi: Weigle, W.O. CRC Crit. Rev. Immunol. 1987, 7, 285; Lin et al. J. Med. Chem. 1985, 28, 1194-1198; Reitz, et al. J. Med. Chem. 1994, 37, 3561-3578, Michael et al. J. Med. Chem. 1993, 36, 3431-3436). Neki 3-β-D-ribofuranozil-tiazolo[4,5-d]pirimidini također su pokazali određenu imunološku aktivnost, uključujući staničnu proliferaciju mišje slezene i in vitro aktivnost protiv Semliki Forest virusa (Nagahara, et al. J. Med. Chem. 1990, 33, 407-415; Robins et al. U.S. Patent 5,041,426). U drugim istraživanjima, 7-deazaguanozin i analozi, nađeno je, pokazuju značajnu antivirusnu aktivnost u miševa glede različitih RNA virusa, premda u staničnoj kulturi spojevi nemaju antivirusnih svojstava. 3-Deazaguanin nukleozidi i nukleotidi također pokazuju značajno široki spektar antivirusne aktivnosti prema određenim DNA i RNA virusima (Revankar et al. J. Med Chem. 1984, 27, 1389-1396). Određeni 7- i 9-deazaguaninski C-nukleozidi pokazuju sposobnost da zaštite miševe u odnosu na smrtonosne Semliki Forest viruse (Girgis et al. J. Med Chem. 1990, 33, 2750-2755). Neki 6-sulfenamidski i 6-sulfinamidski purinski nukleozidi pokazali su značajnu antitumorsku aktivnost (Robins et al. U.S. Patent 4,328,336). Neki pirimido[5,4-D]pirimidinski nukleozidi bili su učinkoviti u liječenju protiv L1210 u BDF1 miševa (Robins et al. U.S. Patent 5,041,542), te nadalje, antivirusna i antitumorska aktivnost gore navedenih nukleozida pretpostavlja se da je rezultat njihove uloge kao imunomodulatora (Bonnet et al. J Med. Chem. 1993, 36, 63 5653). Various analogs of purine D-nucleosides were also tested in the search for immunomodulators. Guanosine analogs having substituents at the 7- and/or 8-position, for example, have been shown to stimulate the immune system (for review, see: Weigle, W.O. CRC Crit. Rev. Immunol. 1987, 7, 285; Lin et al. J . Med. Chem. 1985, 28, 1194-1198; Reitz, et al. J. Med. Chem. 1994, 37, 3561-3578, Michael et al. J. Med. Chem. 1993, 36, 3431-3436) . Some 3-β-D-ribofuranosyl-thiazolo[4,5-d]pyrimidines have also shown some immunological activity, including mouse spleen cell proliferation and in vitro activity against Semliki Forest virus (Nagahara, et al. J. Med. Chem. 1990, 33, 407-415; Robins et al. U.S. Patent 5,041,426). In other studies, 7-deazaguanosine and analogues were found to show significant antiviral activity in mice against various RNA viruses, although in cell culture the compounds have no antiviral properties. 3-Deazaguanine nucleosides and nucleotides also exhibit a significantly broad spectrum of antiviral activity against certain DNA and RNA viruses (Revankar et al. J. Med Chem. 1984, 27, 1389-1396). Certain 7- and 9-deazaguanine C-nucleosides show the ability to protect mice against the lethal Semliki Forest viruses (Girgis et al. J. Med Chem. 1990, 33, 2750-2755). Some 6-sulfenamide and 6-sulfinamide purine nucleosides have shown significant antitumor activity (Robins et al. U.S. Patent 4,328,336). Some pyrimido[5,4-D]pyrimidine nucleosides were effective in treatment against L1210 in BDF1 mice (Robins et al. U.S. Patent 5,041,542), and furthermore, the antiviral and antitumor activity of the above nucleosides is thought to result from their role as immunomodulators (Bonnet et al. J Med. Chem. 1993, 36, 63 5653).
Jedan od mogućih ciljeva imunomoduliranja uključuje stimuliranje ili supresiju Th1 i Th2 limfokina. Stanice tipa I (Th1) proizvode interleukin 2 (IL-2), faktor tumorske nekroze (TNFa) i gama-interferon (IFNγ) i njima se primarno stanični imunitet kao što je hiperosjetljivost odgođenog tipa i antivirusni imunitet. Stanice tipa 2 (Th2) proizvode interleukine, IL4, IL-5, LL-6, IL-9, IL-10 i IL-13 i primarno su uključene kao pomoć pri odgovoru humoralnog imuniteta kao što su oni koji se mogu vidjeti kao odgovor na alergene, npr. IgE i IgG4 izotipska promjena antitijela (Mosmann, 1989, Annu Rev Immunol, 7:145-173). D-guanozinski analozi, pokazalo se, pokazuju različito djelovanje na limfokine IL-1, IL-6, IFNα i TNFα (posredno) in vitro (Goodman, 1988, Int J Immunopharrnacol, 10, 579-88) i in vivo (Smee et al., 1991, Antiviral Res 15: 229). Međutim, sposobnost D-guanozinskih analoga kao što je 7- tio-8-oksoguanozin, da moduliraju citokine tipa I ili tipa II izravno u T-stanicama bila je nedjelotvorna ili nije bila opisana. One of the possible targets of immunomodulation involves the stimulation or suppression of Th1 and Th2 lymphokines. Type I (Th1) cells produce interleukin 2 (IL-2), tumor necrosis factor (TNFa) and gamma-interferon (IFNγ) and are primarily involved in cellular immunity such as delayed-type hypersensitivity and antiviral immunity. Type 2 (Th2) cells produce interleukins, IL4, IL-5, LL-6, IL-9, IL-10, and IL-13, and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, eg IgE and IgG4 isotype change of antibodies (Mosmann, 1989, Annu Rev Immunol, 7:145-173). D-guanosine analogues have been shown to exhibit differential effects on the lymphokines IL-1, IL-6, IFNα and TNFα (indirectly) in vitro (Goodman, 1988, Int J Immunopharrnacol, 10, 579-88) and in vivo (Smee et al. al., 1991, Antiviral Res 15: 229). However, the ability of D-guanosine analogs such as 7-thio-8-oxoguanosine to modulate type I or type II cytokines directly in T-cells has been ineffective or has not been described.
Dakle, postoji potreba da se načine novi D-nukleozidni analozi, uključujući nove analoge L-nukloezida. Posebno postoji potreba za novim purinskim L-nukleozidima koji su aktivni glede imunomoduliranja, a posebice za novim purinskim L-nukleozidima koji moduliraju aktivnost Th1 i Th2. Thus, there is a need to develop new D-nucleoside analogs, including new L-nucleoside analogs. In particular, there is a need for new purine L-nucleosides that are active in terms of immunomodulation, and especially for new purine L-nucleosides that modulate Th1 and Th2 activity.
Kratak opis izuma Brief description of the invention
Ovaj izum odnosi se na nove purinske L-nukleozidne spojeve, njihovu terapeutsku uporabu i sintezu. This invention relates to novel purine L-nucleoside compounds, their therapeutic use and synthesis.
U jednom aspektu izuma, dobiveni su purinski L-nukleozidni analozi formule 1. In one aspect of the invention, purine L-nucleoside analogs of formula 1 are provided.
[image] [image]
Formula I Formula I
gdje R1, R2, R3, R4, R5, R2' i R3' su neovisno odabrani iz skupa kojega sačinjavaju H, OH, NH2, F, Cl, Br, I, N3, -CN, -OR', -NR'2, -SR', -NHNH2, -NHOH, CHO, COOR', CONR'2, alkil, alkenil, alkinil, aril, aralkil, supstituirani alkil, supstituirani alkenil, supstituirani alkinil, supstituirani aril, supstituirani aralkil, gdje je supstituent odabran iz skupa kojega sačinjavaju F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, COOR", CONR"2 i gdje R' i R" su H, alkil, alkenil, alkinil, aril, aralkil; where R1, R2, R3, R4, R5, R2' and R3' are independently selected from the group consisting of H, OH, NH2, F, Cl, Br, I, N3, -CN, -OR', -NR'2 , -SR', -NHNH2, -NHOH, CHO, COOR', CONR'2, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, wherein the substituent is selected from set consisting of F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, COOR", CONR"2 and where R' and R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl;
W = O, S, CH2, Se; W = O, S, CH2, Se;
Z1, Z2 su neovisno odabrani između N, C, CH; Z1, Z2 are independently selected from N, C, CH;
Z3, Z4, Z5 su neovisno odabrani iz skupa kojega sačinjavaju -CR-, -NR-, -O-, -S-, -Se-, -C=O, -C=S, -S=O, -CR=CR-, -CR=N-, -N=N-, gdje je R odabran iz skupa kojega sačinjavaju H, F, C1, Br, I, N3, -CN, -OR', -NR'2, -SR', -NHNH2, -NHOH, -NO2, CHO, COOR', CONH2, -C(O)-NH2, -C(S)-NH2, -C(NH)-NH2, -C(NOH)-NH2, =O, =NH, =NOH, =NR, alkil, alkenil, alkinil, aril, aralkil, supstituirani alkil, supstituirani alkenil, supstituirani alkinil, supstituirani aril, supstituirani aralkil, gdje je supstituent odabran iz skupa kojega sačinjavaju H, -OH, NH2, F, Cl, Br, I, N3, -CN, -COOR", -CONR"2, -OR", -NR"2, -SR", -NHNH2, -NHOH, -NO2 i R', R" su H, alkil, alkenil, alkinil, aril, aralkil, acetil, acil, sulfonil; Z3, Z4, Z5 are independently selected from the group consisting of -CR-, -NR-, -O-, -S-, -Se-, -C=O, -C=S, -S=O, -CR= CR-, -CR=N-, -N=N-, where R is selected from the group consisting of H, F, C1, Br, I, N3, -CN, -OR', -NR'2, -SR' , -NHNH2, -NHOH, -NO2, CHO, COOR', CONH2, -C(O)-NH2, -C(S)-NH2, -C(NH)-NH2, -C(NOH)-NH2, = O, =NH, =NOH, =NR, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from the group consisting of H, -OH, NH2 , F, Cl, Br, I, N3, -CN, -COOR", -CONR"2, -OR", -NR"2, -SR", -NHNH2, -NHOH, -NO2 and R', R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl;
kemijska veza između Z3 i Z4 ili Z4 i Z5 odabrana je između C-C, C=C, C-N, C=N, N-N, N=N, C-S, N-S; the chemical bond between Z3 and Z4 or Z4 and Z5 is selected from C-C, C=C, C-N, C=N, N-N, N=N, C-S, N-S;
X i Y su neovisno odabrani iz skupa kojega sačinjavaju H, OH, NH2, F, CI, Br, I, N3, -S-NH2, -S(O)-NH2, -S(O2)-NH2, -CN, -COOR', -CONR'2, -OR', -NR'2, -SR', NHNH2, -NHOH, alkil, alkenil, alkinil, aril, aralkil, supstituirani alkil, supstituirani alkenil, supstituirani alkinil, supstituirani aril, supstituirani aralkil, gdje je supstituent odabran iz skupa kojega sačinjavaju F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, a R', R" su H, alkil, alkenil, alkinil, aril, aralkil. X and Y are independently selected from the group consisting of H, OH, NH2, F, CI, Br, I, N3, -S-NH2, -S(O)-NH2, -S(O2)-NH2, -CN, -COOR', -CONR'2, -OR', -NR'2, -SR', NHNH2, -NHOH, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from the group consisting of F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, and R', R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl.
U daljnjem aspektu ovog izuma, farmaceutski kompozit uključuje terapeutski učinkovitu količinu spoja formule I ili farmaceutski prihvatljivi ester ili njegovu sol koja je pomiješana bar s jednim farmaceutski prihvatljivim nosačem. In a further aspect of the present invention, the pharmaceutical composition includes a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable ester or salt thereof in admixture with at least one pharmaceutically acceptable carrier.
U daljnjem aspektu ovog izuma, spoj sukladno formuli I koristi se u obradi stanja koja odgovaraju pozitivno na primjenu spoja, te sukladno bilo kojoj formulaciji i protokolu kojim se postiže pozitivan odgovor. Između ostalog, smatra se da se spojevi formule I mogu koristiti u liječenju infekcija, infestacija, karcinoma, tumora ili ostalih neoplazmi ili autoimunih bolesti. In a further aspect of this invention, a compound according to formula I is used in the treatment of conditions that respond positively to the application of the compound, and according to any formulation and protocol that achieves a positive response. Among other things, it is believed that the compounds of formula I can be used in the treatment of infections, infestations, cancers, tumors or other neoplasms or autoimmune diseases.
Kratak opis crteža Brief description of the drawing
Slike 1-6 (sheme 1-6) opisuju stupnjeve kemijske sinteze koji se mogu rabiti da se sintetiziraju spojevi sukladno ovom izumu. Sheme koje se odnose na sintezu određenog spoja navedene su u primjerima koji su ovdje navedeni. Figures 1-6 (Schemes 1-6) describe the chemical synthesis steps that can be used to synthesize the compounds of the present invention. Schemes relating to the synthesis of a particular compound are provided in the examples provided herein.
Slika 7 je grafički opis L-gunozidnog analoga na Th1 i Th2. Figure 7 is a graphical description of the L-gunoside analog on Th1 and Th2.
Detaljni opis Detailed description
Tamo gdje se sljedeći pojmovi koriste u ovoj specifikaciji, oni se rabe sukladno definiciji koja je niže navedena. Where the following terms are used in this specification, they are used as defined below.
Pojam “nukleozid” odnosi se na spojeve koji su sastavljeni od neke pentozne ili modificirane pentozne specije koja je vezana na specifičan položaj hetecikličkog prstena ili na prirodni položaj purina (položaj 9) ili pirimidina (položaj 1) ili na ekvivalentan položaj u nekom analogu. The term "nucleoside" refers to compounds that are composed of a pentose or modified pentose species that is attached to a specific position of the hetecyclic ring or to the natural position of a purine (position 9) or pyrimidine (position 1) or to an equivalent position in an analog.
Pojam “nukleotid” odnosi se na fosfatni ester koji je supstituiran na 5’-položaju nukleozida. The term "nucleotide" refers to a phosphate ester that is substituted at the 5'-position of the nucleoside.
Pojam “heterociklički spoj” odnosi se na jednovalentni zasićeni ili nezasićeni ugljikov ciklički radikal koji ima bar jedan hetero-atom, kao što su N, O, S, Se ili P, a unutar prstena svaki raspoloživi položaj koji može biti proizvoljno supstituiran, neovisno, npr. s hidroksi, okso, amino, imino, nižim alkilom, bromom, klorom i/ili cijano skupinom. Obuhvaćeni unutar ove klase supstituenata su purini, pirimidini. The term "heterocyclic compound" refers to a monovalent saturated or unsaturated carbon cyclic radical that has at least one heteroatom, such as N, O, S, Se or P, and any available position within the ring that can be arbitrarily substituted, independently, eg with hydroxy, oxo, amino, imino, lower alkyl, bromine, chlorine and/or cyano group. Included within this class of substituents are purines, pyrimidines.
Pojam “purin” odnosi se na dušikove bicikličke heterocikličke spojeve. The term "purine" refers to nitrogen bicyclic heterocyclic compounds.
Pojam "pirimidin" odnosi se dušikove monocikličke heterocikličke spojeve. The term "pyrimidine" refers to nitrogen monocyclic heterocyclic compounds.
Pojam "D-nukleozidi" koji se koristi u ovom izumu opisuje nukleozidne spojeve koji imaju kao ugljikohidratni dio D-ribozu (npr. adenozin). The term "D-nucleosides" as used herein describes nucleoside compounds having D-ribose (eg, adenosine) as a carbohydrate moiety.
Pojam "L-nukleozidi" koji se rabi u ovom izumu opisuje nukleozidne spojeve koji imaju kao ugljikohidratni dio L-ribozu. The term "L-nucleosides" used in this invention describes nucleoside compounds having L-ribose as a carbohydrate moiety.
Pojam "L-konfiguracija" koji se ovdje koristi u ovom izumu opisuje kemijsku konfiguraciju ribofuranozilnog dijela spojeva koji je vezan za nukleinsku bazu. L-konfiguracija ugljikohidratnog dijela spojeva u ovom izumu u suprotnosti je s D-konfiguracijom ugljikohidratnog dijela - riboze u prirodnim nukleozidima kao što su citidin, adenozin, timidin, guanozin i uridin. The term "L-configuration" as used herein in this invention describes the chemical configuration of the ribofuranosyl portion of the compounds which is attached to the nucleic base. The L-configuration of the carbohydrate moiety of the compounds of this invention contrasts with the D-configuration of the carbohydrate moiety - ribose in naturally occurring nucleosides such as cytidine, adenosine, thymidine, guanosine and uridine.
Pojam "C-nukleozidi" koji se koristi u ovoj publikaciji opisuje tip veze između ugljikohidratnog dijela – riboze i heterocikličke baze. U C-nukleozidima, veza polazi od C-1 položaja ugljikohidratnog dijela – riboze i veže se na ugljik heterocikličke baze. Veza koja postoji u C-nukleozidima je ugljik-ugljik tipa. The term "C-nucleosides" used in this publication describes the type of linkage between the carbohydrate moiety - ribose and the heterocyclic base. In C-nucleosides, the bond starts from the C-1 position of the carbohydrate part - ribose and is attached to the carbon of the heterocyclic base. The bond that exists in C-nucleosides is carbon-carbon type.
Pojam "N-nukleozidi" koristi u ovoj publikaciji opisuje tip veze između ugljikohidratnog dijela – riboze i heterocikličke baze. U N-nukleozidima, veza polazi od C-1 položaja ugljiko-hidratnog dijela – riboze i veže se za ugljik heterocikličke baze. Veza koja postoji u N-nukleozidima je ugljik-dušik tipa. The term "N-nucleosides" used in this publication describes the type of bond between the carbohydrate moiety - ribose and the heterocyclic base. In N-nucleosides, the bond starts from the C-1 position of the carbohydrate part - ribose and binds to the carbon of the heterocyclic base. The bond that exists in N-nucleosides is of the carbon-nitrogen type.
Pojam “zaštitna skupina” odnosi se na kemijsku skupinu koja je vezana za kisikov ili dušikov atoma da se spriječi daljnja reakcija tijekom stvaranja derivata ili drugih specija u molkuli u kojoj se nalazi kisik ili dušik. Poznat je cijeli niz kisikovih ili dušikovih zaštitnih skupina, što je poznato onima koji se bave organskom sintezom. The term "protecting group" refers to a chemical group that is attached to an oxygen or nitrogen atom to prevent further reaction during the formation of derivatives or other species in the molecule containing the oxygen or nitrogen. A whole series of oxygen or nitrogen protecting groups is known, which is known to those involved in organic synthesis.
Pojam "niži alkil" odnosi se metil, etil, n-propil, izopropil, n-butil, t-butil, i butil ili n-heksil. Pojam se nadalje odnosi na cikličke, razgranate ili nerazgranate lance od jednog do šest ugljikovih atoma. The term "lower alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and butyl or n-hexyl. The term further refers to cyclic, branched or unbranched chains of one to six carbon atoms.
Pojam “aril” odnosi se na jednovalentni nezasićeni aromatski ugljikov ciklički radikal koji ima jedan prsten (npr. fenil) ili dva kondenzirana prstena (npr. naftil), koji može proizvoljno biti supstituiran hidroksilom, nižim alkilom, klorom i/ili cijano skupinom. The term "aryl" refers to a monovalent unsaturated aromatic carbon cyclic radical having one ring (eg, phenyl) or two fused rings (eg, naphthyl), which may be optionally substituted with hydroxyl, lower alkyl, chlorine, and/or cyano.
Pojam “heterociklički spoj” odnosi se na jednovalentni zasićeni ili nezasićeni ugljikov ciklički radikal koji ima bar jedan hetero-atom, kao što su N, O, S, Se ili P, a unutar prstena svaki raspoloživi položaj koji može biti proizvoljno supstituiran ili nesupstituiran, neovisno, npr. s hidroksi, okso, amino, imino, nižim alkilom, bromom, klorom i/ili cijano skupinom. The term "heterocyclic compound" refers to a monovalent saturated or unsaturated carbon cyclic radical that has at least one hetero-atom, such as N, O, S, Se or P, and any available position within the ring that can be arbitrarily substituted or unsubstituted, independently, eg with hydroxy, oxo, amino, imino, lower alkyl, bromine, chlorine and/or cyano group.
Pojam "monociklički spoj" odnosi se na jednovalentni zasićeni ugljikov ciklički radikal koji ima bar jedan hetero-atom, kao što su N, O, S, Se ili P, a unutar prstena svaki raspoloživi položaj koji može biti proizvoljno supstituiran, neovisno, ugljikohidratnim dijelom ili nekom drugom skupinom kao što su klor, brom i/ili cijano skupina, tako da je monociklički prsten eventualno aromatiziran (npr. timidin; 1-(2'-deoksi-β-D-eritro-pentofuranozil)timin). The term "monocyclic compound" refers to a monovalent saturated carbon cyclic radical having at least one heteroatom, such as N, O, S, Se or P, and any available position within the ring that can be arbitrarily substituted, independently, by a carbohydrate moiety or some other group such as chlorine, bromine and/or cyano group, so that the monocyclic ring is optionally aromatized (eg thymidine; 1-(2'-deoxy-β-D-erythro-pentofuranosyl)thymine).
Pojam "imunomodulatori" odnosi se na prirodne ili sintetske produkte koji mogu promijeniti normalne ili nenormalne imunološke sustave putem stimuliranja ili supresije. The term "immunomodulators" refers to natural or synthetic products that can alter normal or abnormal immune systems through stimulation or suppression.
Pojam "učinkovita količina" odnosi se na količinu spoja formule (I) koji može obnoviti imunološke funkcije na normalnu razinu, ili povećati imunološku funkciju iznad normalnih razina da se ukloni infekcija. The term "effective amount" refers to an amount of a compound of formula (I) that can restore immune function to normal levels, or increase immune function above normal levels to clear an infection.
Spojevi formule I i I-A do I-F mogu imati višestruke asimetrične centre. Sukladno tome, oni se mogu prirediti kao optički aktivni oblik ili kao racemička smjesa. Doseg izuma kao što je opisano i u zahtjevima navedeno uključuje pojedine optičke izomere ili njihove neracemičke smjese kao i racemičke oblike spojeva formule I. Compounds of formula I and I-A to I-F may have multiple asymmetric centers. Accordingly, they can be prepared as an optically active form or as a racemic mixture. The scope of the invention as described and stated in the claims includes individual optical isomers or their non-racemic mixtures as well as racemic forms of the compounds of formula I.
Pojmovi "α" and "β" odnose se na specifičnu stereokemijsku konfiguraciju supstituenta na simetričnom ugljikovom atomu u kemijskoj strukturi kao što je prikazano. Spojevi koji su ovdje opisani su svi konfiguracije L-furanozila. The terms "α" and "β" refer to the specific stereochemical configuration of the substituent on the symmetrical carbon atom in the chemical structure as shown. The compounds described herein are all of the L-furanosyl configuration.
Pojam "enantiomeri" odnosi se na par stereoizomera koji su međusobno nisu zrcalne slike koje se ne mogu prekriti. Smjesa para enantiomera, u 1:1 odnosu je “racemička” smjesa. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in a 1:1 ratio is a "racemic" mixture.
Pojam "izomeri" odnosi se na različite spojeve koji svi imaju identičnu formulu. The term "isomers" refers to different compounds that all have an identical formula.
“Stereoizomeri” su izomeri koji se razlikuju samo načinom na koji su atomi raspoređeni u prostoru. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.
“Farmaceutski prihvatljiva sol” može biti bilo koja sol koja je izvedena iz anorganske ili organske kiseline ili baze. "Pharmaceutically acceptable salt" can be any salt derived from an inorganic or organic acid or base.
Spojevi Dates
Spojevi ovog izuma općenito su opisani formulom I. Postoji, međutim, nekoliko podskupova spojeva koji su od posebnog interesa, uključujući spojeve sukladno formulama I-A do I-F, niže. The compounds of this invention are generally described by formula I. There are, however, several subsets of compounds of particular interest, including compounds according to formulas I-A through I-F, below.
Spojevi formule I-A su 8-supstituirani α- ili β-L-guanozinski analozi sljedeće strukture: The compounds of formula I-A are 8-substituted α- or β-L-guanosine analogues of the following structure:
[image] [image]
Formula I-A Formula I-A
gdje je X odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, -CHO, -CONH2, -COOR i –L-A; gdje je R odabran da bude alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; L je sveza koja je odabrana da bude alkil, alkenil, alkinil i aralkil; a A je odabran između H, -OR', -SR', -NR'2, -NHNR'2, -CHO, -COOR', -CONR'2, gdje je R' odabran između H, Me, Et, alil, acetil, -COCF3; wherein X is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, -CHO, -CONH2, -COOR and -L-A; wherein R is selected from alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl; L is a bond selected from alkyl, alkenyl, alkynyl and aralkyl; and A is selected from H, -OR', -SR', -NR'2, -NHNR'2, -CHO, -COOR', -CONR'2, where R' is selected from H, Me, Et, allyl , acetyl, -COCF3;
Y je odabran između H, R, F, Cl, Br, I, N3, CN, OR, SR, NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, CN, OR, SR, NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl;
Z je N ili CH; i Z is N or CH; and
R1, R2 i R3 su neovisno odabrani između H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Spojevi formule IB su 7-supstituirani-8-okso-α- ili β- L-guanozinski analozi sljedeće strukture: The compounds of formula IB are 7-substituted-8-oxo-α- or β-L-guanosine analogues of the following structure:
[image] [image]
Formula I-B Formula I-B
gdje je X odabran između H, R, -NH2, -CHO, -COOR, -L-A, gdje je R odabran da bude alkil, alkenil, alkinil i aralkil; L je veza koja je odabrana da bude alkil, alkenil, alkinil i aralkil; A je odabran između H, F, Cl, Br, I, -OR', -SR', -NR'2, -NHNH2, -NHOH, N3, -CHO, -CONH2, -COOR', -CN, gdje je R' odabran između Me, Et, alil, acetil, COCF3; wherein X is selected from H, R, -NH2, -CHO, -COOR, -L-A, wherein R is selected from alkyl, alkenyl, alkynyl and aralkyl; L is a bond selected from alkyl, alkenyl, alkynyl and aralkyl; A is selected from H, F, Cl, Br, I, -OR', -SR', -NR'2, -NHNH2, -NHOH, N3, -CHO, -CONH2, -COOR', -CN, where R' selected from Me, Et, allyl, acetyl, COCF3;
Y je odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl ;
Z je N ili CH; Z is N or CH;
R1, R2 i R3 su neovisno odabrani H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected H, -OH, -OAc, -OBz, -OP(O2)OH.
Spojevi formule I-C su 7-deaza-7,8-mono- ili disupstituirani α- ili β- L-guanozinski analozi sljedeće strukture: Compounds of formula I-C are 7-deaza-7,8-mono- or disubstituted α- or β-L-guanosine analogs of the following structure:
[image] [image]
Formula I-C Formula I-C
gdje su X1 i X2 neovisno odabrani između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, -CHO, -CONH2, -COOR i -L-A; gdje je R odabran da bude alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; L je veza koja je odabrana da bude alkil, alkenil, alkinil i aralkil; a A je odabran između H, -OR', SR', -NR'2, -NHNR'2, -CHO, -COOR', -CONR'2, gdje je R' odabran između H, Me, Et, alil, acetil, -COCF3; where X1 and X2 are independently selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, -CHO, -CONH2, -COOR and - LA; wherein R is selected from alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl; L is a bond selected from alkyl, alkenyl, alkynyl and aralkyl; and A is selected from H, -OR', SR', -NR'2, -NHNR'2, -CHO, -COOR', -CONR'2, where R' is selected from H, Me, Et, allyl, acetyl, -COCF3;
Y je odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl ;
Z je N ili CH; Z is N or CH;
R1, R2 i R3 su neovisno odabrani između H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Spojevi formule I-D su 7-deaza-8-aza-7-supstituirani α- ili β-L-guanozinski analozi sljedeće strukture: Compounds of formula I-D are 7-deaza-8-aza-7-substituted α- or β-L-guanosine analogs of the following structure:
[image] [image]
Formula I-D Formula I-D
gdje je X odabran između H, R, -NH2, -CHO, -COOR, -L-A, gdje je R odabran da bude alkil, alkenil, alkinil i aralkil; L je veza koja je odabrana da bude alkil, alkenil, alkinil i aralkil; A je odabran između H, F, CI, Br, I, -OR', -SR', -NR'2, -NHNH2, -NHOH, N3, -CHO, -CONH2, -COOR', -CN, gdje je R' odabran između Me, Et, alil, acetil, COCF3; wherein X is selected from H, R, -NH2, -CHO, -COOR, -L-A, wherein R is selected from alkyl, alkenyl, alkynyl and aralkyl; L is a bond selected from alkyl, alkenyl, alkynyl and aralkyl; A is selected from H, F, CI, Br, I, -OR', -SR', -NR'2, -NHNH2, -NHOH, N3, -CHO, -CONH2, -COOR', -CN, where R' selected from Me, Et, allyl, acetyl, COCF3;
Y je odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl ;
Z je N ili CH; Z is N or CH;
R1, R2 i R3 su neovisno odabrani H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected H, -OH, -OAc, -OBz, -OP(O2)OH.
Spojevi formule I-E su tiazolo[4,5-d]pirimidin α- ili β-L-nukleozidi sljedeće strukture: Compounds of formula I-E are thiazolo[4,5-d]pyrimidine α- or β-L-nucleosides of the following structure:
[image] [image]
Formula I-E Formula I-E
X1 = O, S, =NH, =NNH2, =NHOH, =NR gdje je R odabran između alkil, alkienil, alkinil i aralkil, acil; X1 = O, S, =NH, =NNH2, =NHOH, =NR where R is selected from alkyl, alkyenyl, alkynyl and aralkyl, acyl;
X2 je S, O ili Se X 2 is S, O or Se
Y je odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl ;
Z je N ili CH; Z is N or CH;
R1, R2 i R3 su neovisno odabrani između H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Spojevi formule I-F su β-L-purinski nukleozidi sljedeće strukture: Compounds of formula I-F are β-L-purine nucleosides of the following structure:
[image] [image]
Formula I-F Formula I-F
X je odabran između H, R, -SNH2, -S(O)NH2, -SO2NH2, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran da bude H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; X is selected from H, R, -SNH2, -S(O)NH2, -SO2NH2, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected to be H , alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl;
Y je odabran između H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, gdje je R odabran između H, alkil, alkenil, alkinil i aralkil, acetil, acil, sulfonil; Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl ;
Z1, Z2 i Z3 su neovisno odabrani između C, N i CH; Z 1 , Z 2 and Z 3 are independently selected from C, N and CH;
R1, R2 i R3 su neovisno odabrani između H, -OH, -OAc, -OBz, -OP(O2)OH. R1, R2 and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Primjena Application
Podrazumijeva se da će se spojevi ovog izuma koristiti za liječenje cijelog niza stanja, zapravo za svako stanje koje ima pozitivan odgovor na primjenu jednog ili više ovih spojeva. Između ostalog, posebice se podrazumijeva da se spojevi ovog izuma mogu koristiti za liječenje infekcije, infestacije, karcinoma ili tumora ili autoimune bolesti. It is to be understood that the compounds of this invention will be used to treat a wide range of conditions, in fact any condition that has a positive response to the administration of one or more of these compounds. Among other things, it is particularly understood that the compounds of this invention can be used for the treatment of infection, infestation, cancer or tumor or autoimmune disease.
Infekcije za koje se podrazumijeva da se mogu liječiti spojevima ovog izuma uključuju respiratorni sincitijalni virus (RSV), virus hepatitisa B (HBV), virus hepatitisa C (HCV), herpes simpleks tipa 1 i 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, virus humane imunodeficijencije (HIV), virus influence A, hantanski virus (hemoragična groznica), humani papiloma virus (HPV), ospice i fungus. Infections contemplated to be treatable by the compounds of this invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex types 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, Hantan virus (hemorrhagic fever), human papilloma virus (HPV), measles and fungus.
Infestacije za koje se smatra da se mogu liječiti spojevima ovog izuma su infestacije protozoima, kao i helmintima i ostale parazitne zaraze. Infestations believed to be treatable with the compounds of this invention are protozoan infestations as well as helminths and other parasitic infections.
Karcinomi i tumori za koje se smatra da se mogu liječiti uključuju one koji su uzrokovani virusom, te učinak može uključivati inhibiranje pretvorbe stanica zaraženih virusom u neoplastično stanje, inhibiranje širenja virusa iz promijenjenih stanica u ostale normalne stanice i/ili zaustavljanje rasta virusno promijenjenih stanica. Carcinomas and tumors thought to be treatable include those caused by a virus, and the effect may include inhibiting the conversion of virus-infected cells to a neoplastic state, inhibiting the spread of the virus from the altered cells to other normal cells, and/or stopping the growth of the virally altered cells.
Autoimune i ostale bolesti za koje se smatra da se mogu liječiti su artritis, psorijaza, trbušne bolesti, juvenilni dijabetes, mutipla skleroza, podagra i podagrin artritis, reumatoidni artritis, odbacivanje presađenog organa, alergija i astma. Autoimmune and other diseases considered to be treatable include arthritis, psoriasis, stomach ailments, juvenile diabetes, multiple sclerosis, gout and gouty arthritis, rheumatoid arthritis, organ transplant rejection, allergy and asthma.
Daljnja podrazumijevana uporaba spojeva iz ovog izuma uključuje njihovu uporabu kao intermedijera u kemijskoj sintezi ostalih nukleozidnih ili nukleotidnih analoga koji su, opet, korisni kao terapeutska sredstva za ostale namjene. Further implied uses of the compounds of this invention include their use as intermediates in the chemical synthesis of other nucleoside or nucleotide analogs which, again, are useful as therapeutic agents for other purposes.
U daljnjem aspektu, metoda liječenja sisavaca uključuje primjenu terapeutski i/ili profilaktički učinkovite količine farmaceutika koji sadrži spoj ovog izuma. Glede ovog aspekta, učinak može biti povezan s moduliranjem nekog dijela imunološkog sustava sisavca, osobito s moduliranjem profila limfokina Th1 i Th2. Kada dođe do moduliranja Th1 i Th2 limfokina, smatra se da moduliranje može uključiti stimuliranje Th1 i Th2, stimuliranje bilo Th1 ili Th2 te supresiju onog drugog, ili bimodalno moduliranje pri čemu se učinak na Th1/Th2 razine (kao što je generalizirana supresija) događa pri nižoj koncentraciji, dok se drugi efekt (kao što je stimuliranje bilo Th1 ili Th2 i supresija onog drugog) događa pri višoj koncentraciji. In a further aspect, the method of treating a mammal includes administering a therapeutically and/or prophylactically effective amount of a pharmaceutical comprising a compound of the present invention. Regarding this aspect, the effect may be related to the modulation of some part of the mammalian immune system, in particular to the modulation of Th1 and Th2 lymphokine profiles. When modulation of Th1 and Th2 lymphokines occurs, it is thought that the modulation may involve stimulation of Th1 and Th2, stimulation of either Th1 or Th2 and suppression of the other, or bimodal modulation whereby an effect at Th1/Th2 levels (such as generalized suppression) occurs at a lower concentration, while another effect (such as stimulation of either Th1 or Th2 and suppression of the other) occurs at a higher concentration.
Općenito, najpoželjnije primjene sukladno ovom izumu su one kada su aktivni spojevi relativno manje citotoksični u odnosu na neciljane stanice domaćina i razmjerno aktivnije u odnosu na cilj. Glede toga, također ima prednosti ako su L-nukleozidi povećane postojanosti u odnosu na D-nukleozide, što može dovesti do bolje farmakokinetike. Ovaj se rezultat može postići jer L-nukleozide ne mogu prepoznati enzimi, te prema tome oni mogu biti duljeg poluživota. In general, the most preferred applications according to the present invention are those where the active compounds are relatively less cytotoxic to non-targeted host cells and relatively more active to the target. In this regard, it is also advantageous if L-nucleosides are of increased stability compared to D-nucleosides, which may lead to better pharmacokinetics. This result can be achieved because L-nucleosides cannot be recognized by enzymes, and therefore they can have a longer half-life.
Podrazumijeva se da će spojevi sukladno ovom izumu biti primijenjeni u bilo kojoj odgovarajućoj farmaceutskoj formulaciji te pod bilo kojim dogovarajućim protokolom. Prema tome, primjena može biti oralna, parenteralna (uključujući supkutane injekcije, intravenske, intramuskularne, intrasternalne injekcije ili tehniku infuzije), sprejem za inhaliranje ili rektalno, topički itd., te u jediničnom doznim formulacijama koje sadrže pogodne netoksične farmaceutski prihvatljive nosače, adjuvante i pokretače. It is understood that the compounds of this invention will be administered in any suitable pharmaceutical formulation and under any agreed protocol. Accordingly, administration may be oral, parenteral (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technique), inhalation spray or rectally, topically, etc., and in unit dose formulations containing suitable non-toxic pharmaceutically acceptable carriers, adjuvants and drivers.
Kao primjer, podrazumijeva se da se spojevi ovog izuma mogu formulirati u smjesi s farmaceutski prihvatljivim nosačem. Primjerice, spojevi ovog izuma mogu se primijeniti oralno kao farmaceutski prihvatljive soli. Budući da su spojevi ovog izuma većinom topljivi u vodi, oni se mogu primijeniti intravenski u fiziološkoj otopini (npr. puferirani na pH oko 7.2 do 7.5). Za ovu namjenu mogu se koristiti uobičajeni puferi kao što su fosfati, bikarbonati ili citrati. Naravno, onaj tko poznaje ovo područje može promijeniti formulacije unutar odrednica specifikacije da se dobiju brojne formulacije za određeni put primjene pri čemu se kompoziti ovog izuma ne smiju učiniti nepostojanim niti se to smije odraziti na njihovu terapeutsku aktivnost. Točnije, promjene ovih spojeva s namjerom da se načine topljivijima u vodi ili drugom sredstvu, na primjer, mogu se jednostavno postići malenim promjenama (sastavom soli, esterificiranjem itd.) koje su dobro poznate onima koji poznaju ovo područje. Također je poznato, unutar standardnih tehnika ovog područja, kako se može promijeniti put primjene ili režim doziranja za određeni spoj da bi se moglo upravljati farmakokinetikom ovih spojeva u cilju postizanja maksimuma blagotvornog učinka u bolesnika. By way of example, it is understood that the compounds of the present invention may be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of this invention can be administered orally as pharmaceutically acceptable salts. Since the compounds of this invention are mostly water soluble, they can be administered intravenously in saline (eg, buffered to a pH of about 7.2 to 7.5). Common buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skill in the art can vary the formulations within the specifications to obtain numerous formulations for a particular route of administration without rendering the composites of this invention unstable nor affecting their therapeutic activity. In particular, modifications of these compounds with the intention of making them more soluble in water or another medium, for example, can be easily achieved by minor changes (salt composition, esterification, etc.) which are well known to those skilled in the art. It is also known, within the standard techniques of the art, how the route of administration or dosage regimen for a particular compound can be changed to manage the pharmacokinetics of these compounds in order to achieve maximum beneficial effect in the patient.
Za određene farmaceutske oblike doziranja, oblik pro-lijeka spojeva, posebice onaj koji uključuje acilirane (acetilirane ili druge) derivate, poželjni su piridinski esteri i različiti oblici soli ovih spojeva. Oni koji poznaju ovo područje znaju kako se mogu jednostavno promijeniti ovi spojevi u oblike pro-lijeka da se olakša unošenje aktivnih spojeva na ciljano mjesto unutar organizma domaćina ili bolesnika. Oni koji poznaju ovo područje mogu također iskoristiti prednosti povoljnih farmakokinetičkih parametara oblika pro-lijeka, pri primjeni, pri unosu ovog spoja na ciljano mjesto unutar organizma domaćina ili bolesnika, da se učini maksimalnim željeni učinak spoja. For certain pharmaceutical dosage forms, the prodrug form of the compounds, especially that which includes acylated (acetylated or other) derivatives, pyridine esters and various salt forms of these compounds are preferred. Those skilled in the art know how to easily change these compounds into pro-drug forms to facilitate delivery of the active compounds to the target site within the host or patient organism. Those skilled in the art may also take advantage of the favorable pharmacokinetic parameters of the pro-drug form upon administration of the compound to a target site within the host or patient to maximize the desired effect of the compound.
Nadalje, spojevi sukladno ovom izumu mogu se primijeniti sami ili u kombinaciji s drugim tvarima u liječenju gore navedenih infekcija ili stanja. Kombinirane terapije sukladno ovom izumu uključuju primjenu bar jednog spoja ovog izuma ili njegova funkcijskog derivata i bar jedan drugi farmaceutski aktivan dodatak. Količina aktivnog dodatka (dodataka) i farmaceutski aktivne tvari te relativna vremena primjene bit će odabrani tako da se postigne željeni terapeutski učinak. Poželjno kombinirana terapija uključuje primjenu jednog spoja ovog izuma ili njegova funkcionalnog derivata te jedno sredstvo koje je niže navedeno. Furthermore, the compounds according to the present invention can be used alone or in combination with other substances in the treatment of the above-mentioned infections or conditions. Combined therapies according to the present invention include the administration of at least one compound of the present invention or its functional derivative and at least one other pharmaceutically active supplement. The amount of active additive(s) and pharmaceutical active substance and the relative times of administration will be selected so as to achieve the desired therapeutic effect. Preferably, the combination therapy includes the administration of one compound of the present invention or a functional derivative thereof and one agent listed below.
Daljnji primjeri takvih terapeutskih sredstava koja su učinkovita u moduliranju imunološkog sustava ili povezanih stanja uključuju takve kao što su AZT, 3TC, 8-supstituirani guanozinski analozi, 2',3'-dideoksinukleozidi, interleukin II, interferoni kao što su γ-interferon, tukarezol, levamisole isoprinozin i ciklolignani. Neki spojevi sukladno ovom izumu mogu biti učinkoviti za pojačanje biološke aktivnosti određenih sredstava sukladno ovom izumu smanjenjem metabolizma ili deaktiviranjem ostalih spojeva, te se kao takvi oni paralelno primjenjuju za ovaj željeni učinak. Further examples of such therapeutic agents effective in modulating the immune system or related conditions include such as AZT, 3TC, 8-substituted guanosine analogs, 2',3'-dideoxynucleosides, interleukin II, interferons such as γ-interferon, tucaresol , levamisole isoprinosine and cyclolignans. Some compounds according to this invention may be effective for enhancing the biological activity of certain agents according to this invention by reducing metabolism or deactivating other compounds, and as such they are applied in parallel for this desired effect.
Glede doziranja, onaj tko poznaje ovo područje zna da terapeutski učinkovita količina varira i ovisi o infekciji ili stanju koje se liječi, njegovoj uznapredovalosti, režimu tretmana koji se primjenjuje, o farmakokinetici sredstva koje se koristi, kao i o bolesniku (životinja ili čovjek) koji se liječi. Učinkovita doza može biti u rasponu od 1 mg/kg tjelesne težine, ili manje, do 25 mg/kg tjelesne težine ili više. Općenito, terapeutski učinkovita doza ovog spoja u dozirajućem obliku obično je u rasponu od nešto manje od 1 mg/kg do oko 25 mg/kg za bolesnika, ovisno o spoju koji se koristi, stanju ili infekciji koja se liječi, te o putu primjene. Ovaj dozirajući raspon obično daje učinkovitu razinu koncentracije aktivnog spoja u krvi u rasponu od oko 0.04 do oko 100 mikrogram/ccm krvi bolesnika. Podrazumijeva se, međutim, da se može ostvariti odgovarajući režim primjenom malene količine, te povećavanjem količine sve dok sporedni učinci ne postanu nepoželjno štetni, ili je postignut željeni učinak. Regarding dosage, one skilled in the art knows that the therapeutically effective amount varies and depends on the infection or condition being treated, its advanced stage, the treatment regimen being used, the pharmacokinetics of the agent being used, and the patient (animal or human) being treated. heals. An effective dose may range from 1 mg/kg body weight, or less, to 25 mg/kg body weight or more. In general, a therapeutically effective dose of this compound in a dosage form typically ranges from slightly less than 1 mg/kg to about 25 mg/kg for a patient, depending on the compound being used, the condition or infection being treated, and the route of administration. This dosage range usually provides an effective blood concentration level of the active compound in the range of about 0.04 to about 100 micrograms/cc of the patient's blood. It is understood, however, that an adequate regimen can be achieved by applying a small amount, and increasing the amount until the side effects become undesirably harmful, or the desired effect is achieved.
Primjena aktivnog spoja može varirati od kontinuirane primjene (intravenski unos kapanjem) do nekoliko oralnih unosa dnevno (primjerice, Q.I.D.) te može uključivati oralnu, topikalnu, parenteralnu, intramuskularnu, supkutanu, transdermalnu (koja može uključiti sredstvo za pospješenje prodiranja) i bukalnu primjenu, te primjenu supozitorija, među ostalim putevima primjene. Administration of the active compound may vary from continuous administration (intravenous drip) to several oral administrations per day (eg, Q.I.D.) and may include oral, topical, parenteral, intramuscular, subcutaneous, transdermal (which may include a penetration enhancer) and buccal administration, and the use of suppositories, among other routes of administration.
Da se prirede farmaceutski kompoziti sukladno ovom izumu, terapeutski učinkovita količina jednog ili više spojeva sukladno ovom izumu poželjno se dobro pomiješa s farmaceutski prihvatljivim nosačem sukladno uobičajenim farmaceutskim tehnikama vezanja da se načini doza. Nosač može biti u cijelom nizu oblika, ovisno o obliku pripravka koji je poželjan za primjenu, npr. oralnu ili parenteralnu. Pri priređivanju farmaceutskih kompozita za oralnu primjenu, može se koristiti bilo koji od uobičajenih farmaceutskih medija. Prema tome, za tekuće oralne pripravke kao što su suspenzije, eliksiri i otopine, odgovarajući nosači i aditivi uključuju vodu, glikole, ulja, alkohole, sredstva za poboljšanje okusa, konzervanse, sredstva na obojenje i slično. Za krute oralne pripravke kao što su prašci, tablete, kapsule i za krute pripravke kao što su supozitorije, odgovarajući nosači i aditivi uključuju škrob, ugljikohidratne nosače kao što su dekstroza, manitol, laktoza i srodni nosači, diluente, sredstva za granuliranje, lubrikante, sredstva za razlaganje i slična. Po želji, tablete ili kapsule mogu biti crijevne – prevučene ili s odgođenim otpuštanjem, pomoću standardnih tehnika. To prepare pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more compounds according to the present invention is preferably well mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical binding techniques to form a dosage. The carrier can be in a variety of forms, depending on the form of preparation desired for administration, eg oral or parenteral. When preparing pharmaceutical composites for oral administration, any of the usual pharmaceutical media can be used. Accordingly, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as powders, tablets, capsules and for solid preparations such as suppositories, suitable carriers and additives include starch, carbohydrate carriers such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, agents for decomposition and the like. If desired, tablets or capsules can be enteric-coated or delayed-release, using standard techniques.
Za parenteralne formulacije, nosač se obično sastoji iz sterilne vode ili vodene otopine natrijeva klorida, premda se mogu dodati i ostali dodaci, uključujući one koji pomažu disperziju. naravno, ako se koristi sterilna voda i održava se sterilnom, onda kompozite i nosače treba također sterilizirati. Suspenzije za injiciranje mogu se također prirediti, pa se u tom slučaju mogu koristiti odgovarajući tekući nosači, sredstva za suspendiranje i slično. For parenteral formulations, the carrier usually consists of sterile water or aqueous sodium chloride, although other additives, including those that aid dispersion, may be added. of course, if sterile water is used and kept sterile, then composites and supports should also be sterilized. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used.
Rezultati ispitivanja test results
In vitro testovi provedeni su s devet L-guanozinskih spojeva, a rezultati su niže opisani. Tih devet spojeva su sljedeći: In vitro tests were performed with nine L-guanosine compounds, and the results are described below. Those nine connections are as follows:
17316 8-merkapto-L-guanozin 17316 8-mercapto-L-guanosine
17317 2-amino-9 β-L-ribofuranzilpurin-6-sulfenamid 17317 2-amino-9 β-L-ribofuranzylpurine-6-sulfenamide
17318 2-amino-9 β-L-ribofuranzilpurin-6-sulfinamid 17318 2-amino-9 β-L-ribofuranzylpurine-6-sulfinamide
17319 2-amino-9 β-L-ribofuranzilpurin-6-sulfonamid 17319 2-amino-9 β-L-ribofuranylpurine-6-sulfonamide
17320 7-deaza-8-aza-β-L-guanozin 17320 7-deaza-8-aza-β-L-guanosine
17321 7-deaza-8-aza-7-amino-β-L-guanozin 17321 7-deaza-8-aza-7-amino-β-L-guanosine
17322 7-deaza-8-aza-7-brom-β-L-guanozin 17322 7-deaza-8-aza-7-bromo-β-L-guanosine
17323 8-amino-1-β-L-ribofuranoziltiazolo 4,3-dipirimidin-2,7(3H,6H)-dion 17323 8-amino-1-β-L-ribofuranosylthiazolo 4,3-dipyrimidine-2,7(3H,6H)-dione
17324 8-aliloksi-β-L-guanozin 17324 8-allyloxy-β-L-guanosine
U prvom nizu eksperimenata, izolirane su periferne krvne mononuklearne stanice (peripheral blood mononuclear cells, PBMCs) nakon čega je 60 ml krvi zdravih davalaca podvrgnuto Ficoll-Hypaque centrifugiranju gradijentne gustoće. T-stanice su zatim očišćene od PBMC koristeći Lymphokwik limfocitni izolacijski reagens koji je specifičan za T-stanice (LK-25T, One Lambda, Canoga Park CA). Prosječna količina od 40-60×106 T-stanica zatim je inkubirana preko noći na 37°C u 20-30 ml RPMI-APS (RPMI-1640 medij (ICN, Costa Mesa, CA) koji sadrži 20 mM HEPES pufera, pH 7.4, 5% autologne plazme, 1% L-glutamina, 1% penicilin/streptomicin i 0.05% 2-merkaptoetanol) da se uklone stanice s adherentnom nečistoćom. U svim eksperimentima, T-stanice isprane su s RPMI-APS i zatim postavljene na mikro-titarsku ploču s 96-jačica pri staničnoj koncentraciji od 1 × 106 stanica/ml. In the first series of experiments, peripheral blood mononuclear cells (PBMCs) were isolated, after which 60 ml of blood from healthy donors was subjected to Ficoll-Hypaque density gradient centrifugation. T cells were then purified from PBMCs using Lymphokwik T-cell-specific lymphocyte isolation reagent (LK-25T, One Lambda, Canoga Park CA). An average of 40-60×106 T-cells were then incubated overnight at 37°C in 20-30 ml RPMI-APS (RPMI-1640 medium (ICN, Costa Mesa, CA) containing 20 mM HEPES buffer, pH 7.4 , 5% autologous plasma, 1% L-glutamine, 1% penicillin/streptomycin, and 0.05% 2-mercaptoethanol) to remove cells with adherent debris. In all experiments, T cells were washed with RPMI-APS and then plated in a 96-well microtiter plate at a cell concentration of 1 × 10 6 cells/ml.
T-stanice su aktivirane dodatkom 500 ng ionomicina i 10 ng forbol 12-miristata 13-acetata (PMA) (Calbiochem, La Jolla, CA) te inkubirane tijekom 48-72 h na 37°C. T-stanice aktivirane PMA/ionomicinom obrađene su s 0.5-50 pM L-guanozina koji je ispitan, ili s 250-10000 U/ml kontrolnog antivirusa, interferona-alfa (Accurate, Westbury, NY) neposredno nakon aktiviranja i ponovne obrade nakon 24 sata. Za imunofluorescentnu analizu korištene su T-stanice sa svake ploče, a za izvanstanična mjerenja citokina korišten je supernatant. Nakon aktiviranja, preneseno je 900 μl staničnog supernatanta sa svake mikroploče u sljedeću mikroploču za analizu stanične proizvodnje citokina. Stanice su zatim korištene za imunofluorescentnu analizu razine unutarstaničnog citokina i ekspresiju citokinskog receptora. T-cells were activated by the addition of 500 ng of ionomycin and 10 ng of phorbol 12-myristate 13-acetate (PMA) (Calbiochem, La Jolla, CA) and incubated for 48-72 h at 37°C. PMA/ionomycin-activated T-cells were treated with 0.5-50 pM of the L-guanosine tested, or with 250-10000 U/ml of the control antiviral, interferon-alpha (Accurate, Westbury, NY) immediately after activation and retreated after 24 an hour. T-cells from each plate were used for immunofluorescence analysis, and the supernatant was used for extracellular cytokine measurements. After activation, 900 μl of cell supernatant from each microplate was transferred to the next microplate for analysis of cellular cytokine production. Cells were then used for immunofluorescence analysis of intracellular cytokine levels and cytokine receptor expression.
Stanično izvedene koncentracije humanog citokina određene su u staničnim supernatantima svake mikroploče. Aktiviranjem izazvane promjene u razini interleukina-2 (IL-2) određene su komercijalno dostupnim ELISA priborom (R&D systems Quantikine kit, Minneapolis, MN) ili biološkom analizom koristeći IL-2 ovisnu staničnu liniju, CTLL-2 (ATCC, Rockville, MD). Aktiviranjem izazvane promjene interleukina-4 (IL-4), faktora tumorske nekroze (TNFα) interleukina-8 (IL-8) (R & D systems (Quantikine kit, Minneapolis, MN) i razine interferona-gama (IFN-γ) (Endogen (Cambridge, MA) određene su korištenjem ELISA pribora. Svi ELISA rezultati su izraženi u pg/ml te CTLL-2 biološke analize kao impulsi u minuti što predstavlja IL-2-zavisnu staničnu ugradnju 3H-timidina (ICN, Costa Mesa, CA) pomoću CTLL-2 stanica. Cell-derived human cytokine concentrations were determined in the cell supernatants of each microplate. Activation-induced changes in interleukin-2 (IL-2) levels were determined by a commercially available ELISA kit (R&D systems Quantikine kit, Minneapolis, MN) or by bioassay using an IL-2-dependent cell line, CTLL-2 (ATCC, Rockville, MD). . Activation induced changes in interleukin-4 (IL-4), tumor necrosis factor (TNFα) interleukin-8 (IL-8) (R & D systems (Quantikine kit, Minneapolis, MN), and interferon-gamma (IFN-γ) levels ( Endogen (Cambridge, MA) were determined using an ELISA kit All ELISA results are expressed in pg/ml and CTLL-2 bioassays as pulses per minute representing IL-2-dependent cellular incorporation of 3H-thymidine (ICN, Costa Mesa, CA ) using CTLL-2 cells.
Rezultati za svaki od devet L-guanozinskih analoga na razine IL,-2 TNFα, IF'N-γ, IL-4 i IL-5 prikazani su na slikama 7. The results for each of the nine L-guanosine analogs on levels of IL,-2 TNFα, IF'N-γ, IL-4, and IL-5 are shown in Figures 7 .
Sinteza Synthesis
Spojevi ovog izuma mogu se prirediti sukladno sintetskim metodama koje su pojedinačno dobro poznate onima koji se bave tim područjem. Općenito, spojevi ovog izuma mogu se sintetizirati stapanjem odgovarajuće nukleozidne baze s potrebnim ugljikohidratnim sintonom da se dobije zaštićeni L-nukleozid koji nakon naknadnih zahvata i uklanjanja hidroksilne zaštitne skupine konačno daje nukleozidni analog koji ima željeni robofuranozilni dio L-konfiguracije. The compounds of this invention may be prepared according to synthetic methods which are individually well known to those skilled in the art. In general, the compounds of this invention can be synthesized by fusing the appropriate nucleoside base with the required carbohydrate synthon to give a protected L-nucleoside which, after subsequent manipulations and removal of the hydroxyl protecting group, finally yields a nucleoside analog having the desired robofuranosyl moiety of the L-configuration.
Shema 1 prikazuje sintezu nekih 7- i 8-supstituiranih L-guanozinskih analoga. L-riboza 1 je metilirana na C-1 i dobiveni produkt 2 benzoiliran da se dobije spoj 3, koji je preveden u 4 obradom s acetanihidridom i u prisutnosti sumporne kiseline. Reakcija 4 i sililirani N2-acetil guanin u psiutnosti in the presence of trimetilsilil triflata daje spoj 5 sukladno opće korištenom postupku (Vorbrüggen et al. Chem. Ber., 1981, 14, 1234). 5 je preveden u 6 s amonijakom u metanolu. Bromiranje 5 daje 8-brom derivat 7, koje je preveden u 8-aliloksi-derivat 8 obradom s alilnim alkoholom i natrijevim hidridom. 8 je grijan u voda-metanolu da se dobije 7-alil-8-okso derivat 9, koji je hidrogeniran da se dobije 7-propil-8-okso-L-guanozin 10. Scheme 1 shows the synthesis of some 7- and 8-substituted L-guanosine analogs. The L-ribose of 1 was methylated at C-1 and the resulting product 2 benzoylated to give compound 3, which was converted to 4 by treatment with acetic anhydride and in the presence of sulfuric acid. The reaction of 4 and silylated N2-acetyl guanine in the presence of trimethylsilyl triflate gives compound 5 according to the generally used procedure (Vorbrüggen et al. Chem. Ber., 1981, 14, 1234). 5 was converted to 6 with ammonia in methanol. Bromination of 5 gives the 8-bromo derivative 7, which is converted to the 8-allyloxy derivative 8 by treatment with allyl alcohol and sodium hydride. 8 was heated in water-methanol to give the 7-allyl-8-oxo derivative 9, which was hydrogenated to give 7-propyl-8-oxo-L-guanosine 10.
Shema 2 prikazuje sintezu N2-acetil-3-deaza-L-guanozina. 3-deazaguanin 11 (Cook et al. J. Med. Chem. 1976, 27, 1389) obrađen je s acetanihidridom u piridinu da se dobije N2-acetil-3-deazaguanin 12, koji je sililiran i vezan s 1-acetil-2,3,5-O-tribenzoil-L-ribozom da se dobije spoj 13. Uklanjanje benzoilne skupine s amonijačnim metanolom daje N2-acetil-3-deaza-L-guanozin 14. Scheme 2 shows the synthesis of N2-acetyl-3-deaza-L-guanosine. 3-Deazaguanine 11 (Cook et al. J. Med. Chem. 1976, 27, 1389) was treated with acetic anhydride in pyridine to give N2-acetyl-3-deazaguanine 12, which was silylated and coupled with 1-acetyl-2 ,3,5-O-tribenzoyl-L-ribose to give compound 13. Removal of the benzoyl group with ammonia methanol gives N2-acetyl-3-deaza-L-guanosine 14.
Shema 3 prikazuje sintezu 6-merkapto-L-guanozina i derivata. N2-acetil-2',3',S'-O-tribenzoil-β-L-guanozin 5 preveden je obradom s fosfornim pentoksidom (Fox, et al. J. Am. Chem. Soc. 1958, 80, 1669) u 6-merkapto derivat 15, s kojega se uklonjena zaštita da se dobije 6-merkapto-β-L-guanozin 16. Sulfenamidski derivat 17 priređen je reakcijom 16 s NH2-Cl koji je produciran in situ. The sulfenamid 17 oksidiran je s MCPBA u sulfinamid 18 i sulfonamid 19 kontrolom količine reagensa (Revankar et al. J. Med Chem. 1990, 33, 121). Scheme 3 shows the synthesis of 6-mercapto-L-guanosine and derivatives. N2-acetyl-2',3',S'-O-tribenzoyl-β-L-guanosine 5 was converted by treatment with phosphorus pentoxide (Fox, et al. J. Am. Chem. Soc. 1958, 80, 1669) into 6-mercapto derivative 15, which was deprotected to give 6-mercapto-β-L-guanosine 16. Sulfenamide derivative 17 was prepared by reacting 16 with NH2-Cl produced in situ. The sulfenamide 17 was oxidized with MCPBA to sulfinamide 18 and sulfonamide 19 by controlling the amount of reagent (Revankar et al. J. Med Chem. 1990, 33, 121).
Shema 4 prikazuje sintezu 1-β-L-ribofuranozilpiranzolo[3,4-d]pirimidin-4(5H)-ona i derivata. Komercijalno dostupan 4-hidroksipiranzolo[3,4-d]pirimidin 20 vezan je sa zaštićenom L-ribozom da se dobije zaštićeni nukleozid 21, s kojega je uklonjena zaštita da se dobije 1-β-L-ribofuranozilpiranzolo[3,4-d]pirimidin-4(5H)-on 22. Slično, 3-brom-4-hidroksipiranzolo[3,4-d]pirimidin 23 (Cottam et al. J. Med Chem. 1984, 27, 1119) vezan je s L-ribozom da se dobije zaštićeni nukleozid 24, s kojega je uklonjena zaštita da se dobije 3-brom-1-β-L-ribofuranozilpiranzolo[3,4-d]pirimidin-4(5H)-on 25. Obrada 24 amonijakom u prisutnosti bakra i bakrenog klorida na 100°C daje 3-amino derivat 26. Scheme 4 shows the synthesis of 1-β-L-ribofuranosylpyranzolo[3,4-d]pyrimidin-4(5H)-one and derivatives. Commercially available 4-hydroxypyranzolo[3,4-d]pyrimidine 20 was coupled with protected L-ribose to give protected nucleoside 21, which was deprotected to give 1-β-L-ribofuranosylpyranzolo[3,4-d] pyrimidine-4(5H)-one 22. Similarly, 3-bromo-4-hydroxypyranzolo[3,4-d]pyrimidine 23 (Cottam et al. J. Med Chem. 1984, 27, 1119) is linked with L-ribose to give protected nucleoside 24, which was deprotected to give 3-bromo-1-β-L-ribofuranosylpyranzolo[3,4-d]pyrimidin-4(5H)-one 25. Treatment of 24 with ammonia in the presence of copper and of copper chloride at 100°C gives the 3-amino derivative 26.
Shema 5 prikazuje sintezu 8-aza-7-deaza-L-guanozinskih analoga. 3,6-dibrompirazolo[3,4-d]pirimidin-4(5H)-on 27 (Petrie III et al. J. Med Chem. 1985, 28, 1010) vezan je sa zaštićenom L-ribozom da se dobije nukleozid 28, koji je obrađen s amonijakom da se dobije 8-aza-3-brom-7-deaza-β-L-guanozin 29. Obrada 28 s amonijakom na 120°C daje 3-amino derivat 30. Hidrogeniranje 29 na Pd/C dalo je 8-aza-7-deaza-β-L-guanozin 31. Scheme 5 shows the synthesis of 8-aza-7-deaza-L-guanosine analogs. 3,6-Dibromopyrazolo[3,4-d]pyrimidin-4(5H)-one 27 (Petrie III et al. J. Med Chem. 1985, 28, 1010) was coupled with a protected L-ribose to give nucleoside 28 , which was treated with ammonia to give 8-aza-3-bromo-7-deaza-β-L-guanosine 29. Treatment of 28 with ammonia at 120°C gave the 3-amino derivative 30. Hydrogenation of 29 over Pd/C gave is 8-aza-7-deaza-β-L-guanosine 31.
Shema 6 prikazuje sintezu 5-amino-3-[3-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-diona i analoga. 5-aminotiazolo[4,5-d]pirimidin-2,7(3H, 6H)-dion 32 (Baker et al. J. Chem. Soc. C 1970, 2478) vezan je za ribozu kojoj je uklonjena zaštita da se dobije nukleozid 33, s kojega je uklonjena zaštita da se dobije 5-amino-3-β-L-ribofuranoziltiazolo[4,S-d]pirimidin-2,7(6H)-dion 34. Spoj 33 može se zaštititi s nitrofenetilnom skupinom i zatim obrađen s butil nitritom i fluorovodikom u piridinu da se dobije fluoridni derivat 35. Obradom 33 s t-butil nitritom (Nagahara et al. J. Med. Chem. 1990, 33, 407) u THF može se zamijeniti amino skupina vodikom da se dobije 36. Scheme 6 shows the synthesis of 5-amino-3-[3-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione and analogs. 5-Aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione 32 (Baker et al. J. Chem. Soc. C 1970, 2478) was attached to the deprotected ribose to give nucleoside 33, which was deprotected to give 5-amino-3-β-L-ribofuranosylthiazolo[4,S-d]pyrimidine-2,7(6H)-dione 34. Compound 33 can be protected with a nitrophenethyl group and then worked up with butyl nitrite and hydrogen fluoride in pyridine to give the fluoride derivative 35. Treatment of 33 with t-butyl nitrite (Nagahara et al. J. Med. Chem. 1990, 33, 407) in THF can replace the amino group with hydrogen to give 36 .
Shema 7 prikazuje sintezu 3-deaza-L-guanozina i derivata. Idimazolni derivat 37 je sililiran i reagirao je s 4 da se dobije 38, koji cikliziranjem daje 39. Bromiranje 39 daje 40. Scheme 7 shows the synthesis of 3-deaza-L-guanosine and derivatives. The imidazole derivative 37 was silylated and reacted with 4 to give 38, which cyclized to give 39. Bromination of 39 gave 40.
Spojevi opisani u shemama 1-6 su β-L-guanozinski analozi. Odgovarajući L-analozi mogu se prirediti na sličan način, ali s L-ribozom koja ima različite zaštitne skupine. 1-acetil-2,3,5-O-tribenzoil-L-ribofuranoza može se zamijeniti derivatima 1-brom-β-L-riboze kao reagensom, koji će većinom dati α-L-nukleozide. The compounds described in Schemes 1-6 are β-L-guanosine analogs. The corresponding L-analogs can be prepared in a similar manner, but with L-ribose having different protecting groups. 1-Acetyl-2,3,5-O-tribenzoyl-L-ribofuranose can be replaced by 1-bromo-β-L-ribose derivatives as a reagent, which will mostly give α-L-nucleosides.
Primjeri Examples
U sljedećem poglavlju izneseni su eksperimentalni primjeri koji su načinjeni u laboratoriju podnositelja. Nastojalo se da primjeri budu općeniti, ali ne i sažeti. Eksperimentalni rad koji je načinjen obuhvaća sve primjere koji su dolje opisani, ali nije ograničen na ove primjere. In the next chapter, experimental examples that were made in the applicant's laboratory are presented. An effort was made to make the examples general, but not concise. The experimental work that has been done includes all the examples described below, but is not limited to these examples.
Primjer 1 Example 1
1-O-metil-L-ribofuranoza 2 1-O-methyl-L-ribofuranose 2
Hladna otopina klorovodične kiseline (4.4 g, 0.12 mol) u metanolu (100 mL) polako je dodana otopini L-(+)-riboze 1 (50 g, 0.33 mol) u metanolu (1000 mL) na sobnoj temperaturi. Nakon dodatka, otopina je miješana tijekom 2.5 h i prigušena piridinom (100 mL). Smjesa je miješana tijekom 10 min i otapalo je upareno. A cold solution of hydrochloric acid (4.4 g, 0.12 mol) in methanol (100 mL) was slowly added to a solution of L-(+)-ribose 1 (50 g, 0.33 mol) in methanol (1000 mL) at room temperature. After the addition, the solution was stirred for 2.5 h and quenched with pyridine (100 mL). The mixture was stirred for 10 min and the solvent was evaporated.
Rezidue su otopljene u piridinu (100 mL) i dobivena otopina je koncentrirana do suhog da se dobije 1-O-metil-L-ribofuranoza 2 kao blijedožuti sirup. The residue was dissolved in pyridine (100 mL) and the resulting solution was concentrated to dryness to give 1-O-methyl-L-ribofuranose 2 as a pale yellow syrup.
Primjer 2 Example 2
1-O-metil-2',3',5'-O-tribenzoil-L-ribofuranoza 3 1-O-methyl-2',3',5'-O-tribenzoyl-L-ribofuranose 3
Benzoil klorid (154.5 g, 1.1 mol) dokapavanjem je dodavan tijekom 10 min otopini 1-O-metil-L-ribofuranoze 2 (0.33 mol) u piridinu (350 mL) na 0°C. Nakon dodatka, otopina je ostavljena na sobnoj temperaturi tijekom 14 h i reakcija je zaustavljena miješanjem s vodom (50 mL) na 0°C tijekom 1 h. Vodeni sloj je ekstrahiran s CH2Cl2 (2×100 mL) i sjedinjeni organski slojevi su koncentrirani. Rezidue su otopljene u CH2Cl2 (500 mL), isprane uzastopno sa zasićenom otopinom NaHCO3 (3 x 100 mL), vodom (200 mL), slanom otopinom (200 mL), osušene iznad Na2SO4, filtrirane i uparene s toluenom (2×300 mL). Naknadno sušenje pod vakuumom dalo je 1-O-metil-2',3',5'-O-tribenzoil-L-ribofuranozu 3 u obliku žutog sirupa (80 g, 0.17 mol). Benzoyl chloride (154.5 g, 1.1 mol) was added dropwise over 10 min to a solution of 1-O-methyl-L-ribofuranose 2 (0.33 mol) in pyridine (350 mL) at 0°C. After the addition, the solution was left at room temperature for 14 h and the reaction was quenched by stirring with water (50 mL) at 0 °C for 1 h. The aqueous layer was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were concentrated. The residues were dissolved in CH2Cl2 (500 mL), washed successively with saturated NaHCO3 solution (3 x 100 mL), water (200 mL), brine (200 mL), dried over Na2SO4, filtered and evaporated with toluene (2×300 mL ). Subsequent drying under vacuum afforded 1-O-methyl-2',3',5'-O-tribenzoyl-L-ribofuranose 3 as a yellow syrup (80 g, 0.17 mol).
Primjer 3 Example 3
1-O-acetil-2',3',5'-O-tribenzoil-L-ribofuranoza 4 1-O-acetyl-2',3',5'-O-tribenzoyl-L-ribofuranose 4
1-O-metil-2',3',5'-O-tribenzoil-L-ribofuranoza 3 (80 g, 0.17 mol) otopljena je na sobnoj temperaturi u smjesi octene kiseline (354 mL) i acetanhidrida (36 mL). Dobivena otopina ohlađena je na 0°C i dokapavanjem je dodana sumporna kiselina (96%, 8.23 g, 0.084 mol). Nakon dodatka, reakcijska smjesa je ostavljena na sobnoj temperaturi tijekom 18 h, stavljena na led (500 g) i miješana sve dok se led nije rastalio. Dodan je EtOAc (1.2 L) pa voda (1 L). Organski sloj je ispran smjesom voda/slana otopina (4/1 odnos), zasićenom otopinom NaHCO3 (500 mL), slanom otopinom (500 mL), filtriran kroz sloj silika-gela i koncentriran da se dobije sirovi produkt u obliku žute krutine. Rekristaliziranje iz smjese heksan/EtOAc (300 mL/100 mL odnos) daje 1-O-acetil-2',3',5'-O-tribenzoil-L-ribofuranozu 4 u obliku bijelih iglica (50 g, 59.6% ukupni prinos iz L-riboze). 1-O-methyl-2',3',5'-O-tribenzoyl-L-ribofuranose 3 (80 g, 0.17 mol) was dissolved at room temperature in a mixture of acetic acid (354 mL) and acetic anhydride (36 mL). The resulting solution was cooled to 0°C and sulfuric acid (96%, 8.23 g, 0.084 mol) was added dropwise. After the addition, the reaction mixture was left at room temperature for 18 h, placed on ice (500 g) and stirred until the ice melted. EtOAc (1.2 L) was added followed by water (1 L). The organic layer was washed with water/brine (4/1 ratio), saturated NaHCO3 solution (500 mL), brine (500 mL), filtered through a pad of silica gel, and concentrated to give the crude product as a yellow solid. Recrystallization from hexane/EtOAc (300 mL/100 mL ratio) gave 1-O-acetyl-2',3',5'-O-tribenzoyl-L-ribofuranose 4 as white needles (50 g, 59.6% overall yield from L-ribose).
Primjer 4 Example 4
N2-acetil-2',3',5'-O-tribenzoil-β-L-guanozin 5 N2-acetyl-2',3',5'-O-tribenzoyl-β-L-guanosine 5
N2-acetilguanin (4.125 g, 21.35 mmol) suspendiran je u piridinu (50 mL) na 80°C tijekom 25 min i zatim je pod visokim vakuumom uparen piridin. Jednaki postupak je ponovljen još jednom. Dobivena tvar je osušena pod vakuumom preko noći i sililirana grijanjem uz suvišak HMDS (50 mL), piridina (10 mL) i TMSCl (150 mL) pod argonom tijekom 2.5 sati. Nakon toga je reakcijska smjesa ohlađena na sobnu temperaturu, te je otapalo upareno pod vakuumom. Ostatni HMDS i piridin su upareni zajedno s ksilenom (2×40 mL). Sililirana baza suspendirana je u dikloretanu (70 mL) i spojena s dikloretanskom (182 mL) otopinom 1-acetil-2,3,5-O-tribenzoil-L-riboze (9.71g, 19.22 mmol). N2-Acetylguanine (4.125 g, 21.35 mmol) was suspended in pyridine (50 mL) at 80°C for 25 min and then the pyridine was evaporated under high vacuum. The same procedure was repeated once more. The obtained substance was dried under vacuum overnight and silylated by heating with excess HMDS (50 mL), pyridine (10 mL) and TMSCl (150 mL) under argon for 2.5 hours. After that, the reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The remaining HMDS and pyridine were co-evaporated with xylene (2×40 mL). The silylated base was suspended in dichloroethane (70 mL) and combined with a dichloroethane (182 mL) solution of 1-acetyl-2,3,5-O-tribenzoyl-L-ribose (9.71 g, 19.22 mmol).
Dobivena suspenzija je miješana pod argonom na temperaturi refluksa tijekom 10 min. dikloretanska otopina (35 mL) TMS-triflata (4.50 mL, 23.276 mmol) dodana je dokapavanjem (20 min.). Dobivena smjesa je miješana pod refluksom 1.5 h, ohlađena na sobnu temperaturu i razrijeđena metilen kloridom (500 ml). Organska otopina isprana je otopinom NaHCO3 (5% aq., 2×150 mL), slanom otopinom (150 mL), osušena (Na2SO4) i uparena do suhog. Reakcijska smjesa je pročišćena “flash” kromatografijom (400 g silika-gel, eluent: 28% EtOAc, 2% EtOH u CH2Cl2, v/v) da se dobije 5.60 g (46%) N2-acetil-2',3',5'-O-tribenzoil-β-L-guanozina. The resulting suspension was stirred under argon at reflux temperature for 10 min. dichloroethane solution (35 mL) of TMS-triflate (4.50 mL, 23.276 mmol) was added dropwise (20 min.). The resulting mixture was stirred under reflux for 1.5 h, cooled to room temperature and diluted with methylene chloride (500 ml). The organic solution was washed with NaHCO3 solution (5% aq., 2×150 mL), brine (150 mL), dried (Na2SO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (400 g silica gel, eluent: 28% EtOAc, 2% EtOH in CH2Cl2, v/v) to give 5.60 g (46%) of N2-acetyl-2',3', 5'-O-tribenzoyl-β-L-guanosine.
Primjer 5 Example 5
β-L-guanozin 6 β-L-guanosine 6
Otopina N2-acetil-2',3',5'-O-tribenzoil-L-guanozina 5 u zasićenom amonijačnom metanolu stajala je na sobnoj temperaturi tijekom dva dana. Amonijak i metanol su upareni i sirovi produkt je otopljen u vodi i kloroformu (dva sloja). Vodeni sloj je ispran kloroformom tri puta i koncentriran. Sirovi produkt je pročišćen kristaliziranjem iz voda-metanola da se dobije β-L-guanozin 6 u obliku bezbojne krutine. A solution of N2-acetyl-2',3',5'-O-tribenzoyl-L-guanosine 5 in saturated ammonia methanol stood at room temperature for two days. Ammonia and methanol were evaporated and the crude product was dissolved in water and chloroform (two layers). The aqueous layer was washed with chloroform three times and concentrated. The crude product was purified by crystallization from water-methanol to give β-L-guanosine 6 as a colorless solid.
Primjer 6 Example 6
8-brom-β-L-guanozin 7 8-bromo-β-L-guanosine 7
Suspenziji L-guanozina 6 (1.24 g) u vodi (7.5 mL) dodano je u obrocima 35 mL zasićene bromne vode koja sadrži 0.35 mL broma. Krutina je otfiltrirana, uzastopno isprana hladnom vodom, hladnim acetonom i osušena. Kristaliziranje iz vode dalo je čisti 8-brom-L-guanozin 7 u obliku bezbojne krutine. To the suspension of L-guanosine 6 (1.24 g) in water (7.5 mL) was added in portions 35 mL of saturated bromine water containing 0.35 mL of bromine. The solid was filtered off, washed successively with cold water, cold acetone and dried. Crystallization from water gave pure 8-bromo-L-guanosine 7 as a colorless solid.
Primjer 7 Example 7
8-aliloksi-β-L-guanozin 8 8-allyloxy-β-L-guanosine 8
Uz miješanje, smjesi NaH (984 mg) u bezvodnom DMSO (30 mL) dokapavanjem je dodan alilni alkohol (10 mL), nakon čega je dodan 8-brom-L-guanozin 7 (1.78 g, 4.92 mmol) u DMSO (10 mL). Dobivena reakcijska smjesa miješana je na 60°C preko noći, ohlađena na sobnu temperaturu i razrijeđena etileterom (350 mL). Dobiveni talog je filtriran, otopljen u vodi (18 mL) i neutraliziran octenom kiselinom. Nastali talozi su filtrirani i rekristalizirani iz vode/metanola da se dobije 836 mg 8-aliloksi-L-guanozina 8 u obliku slabo žute krutine. With stirring, allyl alcohol (10 mL) was added dropwise to a mixture of NaH (984 mg) in anhydrous DMSO (30 mL), followed by 8-bromo-L-guanosine 7 (1.78 g, 4.92 mmol) in DMSO (10 mL) ). The resulting reaction mixture was stirred at 60°C overnight, cooled to room temperature and diluted with ethyl ether (350 mL). The precipitate obtained was filtered, dissolved in water (18 mL) and neutralized with acetic acid. The resulting precipitate was filtered and recrystallized from water/methanol to give 836 mg of 8-allyloxy-L-guanosine 8 as a pale yellow solid.
Primjer 8 Example 8
7-alil-8-okso-β-L-guanozin 9 7-allyl-8-oxo-β-L-guanosine 9
Smjesa 8-aliloksiguanozina 8 (560 mg) u metanol-vodi (50 mL, 1:1, v/v) miješana je pod refluksom i nakon dva sata nastala je bistra otopina. Otopina je refluksirana daljnjih 5 h i ohlađena na sobnu temperaturu. Smeđi talog (sporedni produkt) je filtriran i filtrat je koncentriran da se dobije sirovi produkt. Kristaliziranje iz vode-etanola dalo je 83 mg naslovnog spoja u obliku slabo smeđe krutine. Filtrat je koncentriran i rezidue su kromatografirane na silika-gelu s 5% Et3N i 20% MeOH u metilen kloridu da se dobije 260 mg 7-alil-8-okso-β-L-guanozina 9 u obliku bezbojne krutine. A mixture of 8-allyloxyguanosine 8 (560 mg) in methanol-water (50 mL, 1:1, v/v) was stirred under reflux and after two hours a clear solution was formed. The solution was refluxed for a further 5 h and cooled to room temperature. The brown precipitate (by-product) was filtered off and the filtrate was concentrated to give the crude product. Crystallization from water-ethanol gave 83 mg of the title compound as a pale brown solid. The filtrate was concentrated and the residue was chromatographed on silica gel with 5% Et3N and 20% MeOH in methylene chloride to give 260 mg of 7-allyl-8-oxo-β-L-guanosine 9 as a colorless solid.
Primjer 9 Example 9
8-okso-7-propil-β-L-guanozin 10 8-oxo-7-propyl-β-L-guanosine 10
Suspenzija 120 mg 7-alil-8-okso-β-L-guanozina 9 i 80 mg 10% paladija na ugljiku je mućkana u uređaju za hidrogeniranje na sobnoj temperaturi pod 55 psi vodika tijekom 2 h. Paladijev katalizator je filtriran i filtrat je koncentriran. Sirovi produkt je kristaliziran iz vode-etanola da se dobije 75 mg 8-okso-7-propil-β-L-guanozina 10 u obliku blijedožute krutine. A suspension of 120 mg of 7-allyl-8-oxo-β-L-guanosine 9 and 80 mg of 10% palladium on carbon was shaken in a hydrogenator at room temperature under 55 psi of hydrogen for 2 h. The palladium catalyst was filtered off and the filtrate was concentrated. The crude product was crystallized from water-ethanol to give 75 mg of 8-oxo-7-propyl-β-L-guanosine 10 as a pale yellow solid.
Primjer 10 Example 10
N2-acetil-3-deazaguanin 12 N2-acetyl-3-deazaguanine 12
Suspenziji 3-aeazaguanina 11 (2.0 g) u bezvodnom piridinu (30 mL) dodan je acetanhidrid (5 mL) i dobivena reakcijska smjesa zagrijana je na 90°C. Krutina je postepeno otapana i nastala je smeđa otopina. Nakon 10 minuta ponovo je nastao talog. Smjesa je miješana na 90°C daljnjih 90 minuta i ohlađena na 50°C. Precipitat je filtriran i ispran acetonitrolm, vodom i ponovo acetonitrilom da se dobije 1.79 g N2-acetil-3-deazaguanina 12 u obliku svijetlosmeđe krutine. Acetic anhydride (5 mL) was added to a suspension of 3-aazaguanine 11 (2.0 g) in anhydrous pyridine (30 mL) and the resulting reaction mixture was heated to 90°C. The solid was gradually dissolved and a brown solution was formed. After 10 minutes, the precipitate formed again. The mixture was stirred at 90°C for a further 90 minutes and cooled to 50°C. The precipitate was filtered and washed with acetonitrile, water and again with acetonitrile to give 1.79 g of N2-acetyl-3-deazaguanine 12 as a light brown solid.
Primjer 11 Example 11
N2-acetil-3-deaza-β-L-guanozin 14 N2-acetyl-3-deaza-β-L-guanosine 14
Suspenzija N2-acetil-3-deazaguanina 12 (576 mg, 3.0 mmol), heksametildisilazana (HMDS, 15 mL), piridina (2 mL) i amonijeva sulfata (10 mg) miješana je pod refluksom i uz isključenu vlagu tijekom 2.5 h. Otapala su isparena i rezidue su osušene pod vakuumom tijekom 2 h da se dobije pjenasti sirup. Rezidue su otopljene u metilen kloride (bezvodni, 30 mL) i dodana je 1-acetil-2,3,5-tribenzoil-L-riboza (1.51 g, 3.0 mmol), nakon čega je polako dodavan trimetilsilil triflat (4.5 mmol, 0.81 mL). Dobivena otopina je refluksirana tijekom 20 h. Otapalo je upareno i rezidue su otopljene u atilacetatu, isprane s 5% NaHCO3, osušene (Na2SO4) i koncentrirane. A suspension of N2-acetyl-3-deazaguanine 12 (576 mg, 3.0 mmol), hexamethyldisilazane (HMDS, 15 mL), pyridine (2 mL), and ammonium sulfate (10 mg) was stirred under reflux with moisture excluded for 2.5 h. The solvents were evaporated and the residue was dried under vacuum for 2 h to give a foamy syrup. The residues were dissolved in methylene chloride (anhydrous, 30 mL) and 1-acetyl-2,3,5-tribenzoyl-L-ribose (1.51 g, 3.0 mmol) was added, after which trimethylsilyl triflate (4.5 mmol, 0.81 mL). The resulting solution was refluxed for 20 h. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with 5% NaHCO 3 , dried (Na 2 SO 4 ) and concentrated.
Kromatografija na silika-gelu s 5% Et3N i 2-10% etanola u metilen kloridu dala je tri glavna produkta: 340 mg produkta s višim Rf, 368 mg produkta sa srednjim Rf i 335 mg produkta sa nižim, a svi su slabo žute krutine. Chromatography on silica gel with 5% Et3N and 2-10% ethanol in methylene chloride gave three major products: 340 mg of higher Rf product, 368 mg of intermediate Rf product, and 335 mg of lower Rf product, all as pale yellow solids. .
Otopina produkta 13 sa srednjim Rf (350 mg) u zasićenom amonijak-metanolu stajala je na sobnoj temperaturi tijekom dva dana. Amonijak i metanol su upareni i rezidue su kromatografirane na silika-gelu s 5% Et3N i 20% etanola u metilen kloridu da se dobije 114 mg N2-acetil-3-deaza-β-L-guanozina kao 14 u obliku bijele krutine. A solution of medium Rf product 13 (350 mg) in saturated ammonia-methanol was allowed to stand at room temperature for two days. Ammonia and methanol were evaporated and the residue was chromatographed on silica gel with 5% Et3N and 20% ethanol in methylene chloride to give 114 mg of N2-acetyl-3-deaza-β-L-guanosine as 14 as a white solid.
Primjer 12 Example 12
N2-acetil-6-merkapto-2',3',5'-O-tribenzoil-β-L-guanozin 15 N2-acetyl-6-mercapto-2',3',5'-O-tribenzoyl-β-L-guanosine 15
Uz miješanje, suspenziji N2-acetil-2',3',5'-O-tribenzoil-L-guanozina 5 (5.608, 8.78 mmol) i fosforna pentasulfida (8.0 g, 36.0 mmol) u piridinu (210 mL) dokapavanjem je dodana voda (590 mL) i nastala reakcijska smjesa grijana je na temperaturi refluksa tijekom 8 h. Svaki puta kada je tekućina počela gubiti svoju mutnoću, dodano je nekoliko kapi vode. Na kraju perioda refluksiranja, uparen je piridin da se dobije gusti sirup koji je zatim polako dodan u energično mješanu, kipuću vodu (1000 mL). Dobivena smjesa je miješana tijekom 45 minuta i ekstrahirana s EtOAc (3×250 mL). Organski sloj je ispran slanom otopinom (2×200 mL), vodom (2×100 mL), osušen (Na2SO4) i uparen do suhog. Kromatografija na silika-gelu (400 g) s 23% EtOAc, 2% EtOH u CH2Cl2 (v/v) dala je 3.538 (61.5%) N2-acetil-6-merkapto-2',3',5'-O-tribenzoil-β-L-guanozina 15 u obliku bezbojna krutine. With stirring, a suspension of N2-acetyl-2',3',5'-O-tribenzoyl-L-guanosine 5 (5.608, 8.78 mmol) and phosphorus pentasulfide (8.0 g, 36.0 mmol) in pyridine (210 mL) was added dropwise water (590 mL) and the resulting reaction mixture was heated at reflux temperature for 8 h. Every time the liquid began to lose its turbidity, a few drops of water were added. At the end of the reflux period, the pyridine was evaporated to give a thick syrup which was then slowly added to vigorously stirred boiling water (1000 mL). The resulting mixture was stirred for 45 min and extracted with EtOAc (3×250 mL). The organic layer was washed with brine (2×200 mL), water (2×100 mL), dried (Na2SO4) and evaporated to dryness. Chromatography on silica gel (400 g) with 23% EtOAc, 2% EtOH in CH2Cl2 (v/v) gave 3.538 (61.5%) N2-acetyl-6-mercapto-2',3',5'-O- tribenzoyl-β-L-guanosine 15 in the form of a colorless solid.
Primjer 13 Example 13
6-merkapto-β-L-guanozin 16 6-mercapto-β-L-guanosine 16
Otopina N2-acetil-6-merkapto-2',3',5'-O-tribenzoil-L-guanozina 15 (3.53 g, 5.40 mmol) u zasićenom amonijačnom metanolu (200 mL) miješana je na sobnoj temperaturi tijekom 62 sata. Amonijak i metanol su upareni i rezidue su razmuljene kloroformom. Talog je filtriran i ispran toplim kloroformom (50 mL), ponovo otopljen u razrijeđenom amonijaku, te zakiseljen octenom kiselinom. Dobiveni talog je filtriran i osušen u vakuumu da se dobije 1.48 g (91.6%) 6-merkapto-β-L-guanozina 16 u obliku bezbojne krutine. A solution of N2-acetyl-6-mercapto-2',3',5'-O-tribenzoyl-L-guanosine 15 (3.53 g, 5.40 mmol) in saturated ammonia methanol (200 mL) was stirred at room temperature for 62 hours. Ammonia and methanol were evaporated and the residue triturated with chloroform. The precipitate was filtered and washed with warm chloroform (50 mL), redissolved in dilute ammonia, and acidified with acetic acid. The resulting precipitate was filtered and dried in vacuo to give 1.48 g (91.6%) of 6-mercapto-β-L-guanosine 16 as a colorless solid.
Primjer 14 Example 14
2-amino-9-(β-L-ribofuranozil)purin-6-sulfonamid 17 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfonamide 17
Uz miješanje, vodenoj otopini natrijeva hipoklorita (5.25%, 2.25 mL, 1.725 mmol) ohlađenoj na 0°C u ledenoj kupelji dodan je amonijev hidroksid (1.4 M, 6 mL, 8.4 mmol) ohlađen na 0°C. Nastala smjesa je miješana na 0°C tijekom 15 minuta i dodana je hladna (0°C) otopina 6-merkapto-L-guanozina 16 (450 mg, 1.5 mmol) u 2M KOH (750 mL). Reakcijska smjesa je miješana 2 h sve dok se nije zagrijala na sobnu temperaturu. With stirring, ammonium hydroxide (1.4 M, 6 mL, 8.4 mmol) cooled to 0°C was added to an aqueous solution of sodium hypochlorite (5.25%, 2.25 mL, 1.725 mmol) cooled to 0°C in an ice bath. The resulting mixture was stirred at 0°C for 15 min and a cold (0°C) solution of 6-mercapto-L-guanosine 16 (450 mg, 1.5 mmol) in 2M KOH (750 mL) was added. The reaction mixture was stirred for 2 h until it warmed to room temperature.
Nastali talog je otfiltriran, ispran hladnim EtOH, filtriran i osušen da se dobije 240 mg (51%) 2-amino-9-(β-L-ribofuranozil)purin-6-sulfenamida 17 u obliku bezbojne krutine. The resulting precipitate was filtered off, washed with cold EtOH, filtered and dried to give 240 mg (51%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfenamide 17 as a colorless solid.
Primjer 15 Example 15
2-amino-9-(β-L-ribofuranozil)purin-6-sulfinamid 18 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfinamide 18
Smjesa 2-amino-9-(β-L-ribofuranozil)purin-6-sulfenamida 17 (200 mg, 0.637 mmol), etanola (90 mL) i vode (6.4mL) snažno je miješana na -10°C u kupelji sol-voda. Dokapavanjem je dodana otopina MCPBA (80%, 137.0 mg, 0.637 mmol) u etanolu, 5.5 mL, tijekom 15 minuta. Smjesa je ostavljena da se miješa i grije kako se tali led (8 h), te je miješana do sobne temperature daljnjih 14 h. Mala količina taloga je otfiltrirana i filtrat je uparen na 23°C do suhoga. Rezidue su razmuljene s etileterom (30 mL) i krutina je sakupljena filtriranjem, te isprana etileterom (10 mL). Krutina je ponovo suspendirana u etileteru (25 mL), filtrirana i osušena da se dobije 182 mg (87%) 2-amino-9-(β-L-ribofuranozil)purin-6-sulfinamid 18 u obliku bezbojne krutine. A mixture of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfenamide 17 (200 mg, 0.637 mmol), ethanol (90 mL), and water (6.4 mL) was vigorously stirred at -10°C in a salt bath -water. A solution of MCPBA (80%, 137.0 mg, 0.637 mmol) in ethanol, 5.5 mL, was added dropwise over 15 minutes. The mixture was allowed to stir and heat as the ice melted (8 h), and was stirred to room temperature for a further 14 h. A small amount of precipitate was filtered off and the filtrate was evaporated to dryness at 23°C. The residue was triturated with ethyl ether (30 mL) and the solid was collected by filtration and washed with ethyl ether (10 mL). The solid was resuspended in ethyl ether (25 mL), filtered and dried to give 182 mg (87%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfinamide 18 as a colorless solid.
Primjer 16 Example 16
2-amino-9-(β-L-ribofuranozil)purin-6-sulfonamid 19 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfonamide 19
Uz miješanje, otopini 2-amino-9-(β-L-ribofuranozil)purin-6-sulfonamid 17 (150 mg, 0.478 mmol) u etanolu (28.5 mL) i vode (2.8 mL) na sobnoj temperaturi dodana je u obrocima tijekom 1 h otopina MCPBA (80%, 412.0 mg, 1.91 mmol) u etanolu (2.8 mL). Reakcijska otopina je postala bistra nakon 3 h. Otopina je miješana tijekom daljnjih 15 h na temperaturi okoline i postala je zamućena. Reakcijska smjesa je koncentrirana na sobnoj temperaturi do suhoga. rezidue su razmuljene s etileterom (30 mL) i krutina je sakupljena filtriranjem. Sirovi produkt je otopljen u smjesi metanol/voda i adsorbiran na silika-gel (2.0 g). Otapalo je ispareno i silika-gel koji nosi produkt nanesen je na “flash” kolonu silika-gela (100 g) koja je pakirana u metilen kloridu. Kolona je eluirana s 20% MeOH u CH2Cl2 (v/v) da se dobije 87 mg (52.6%) 2-amino-9-(β-L-ribofuranozil)purin-6-sulfonamida 19 u obliku bezbojne krutine. With stirring, a solution of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfonamide 17 (150 mg, 0.478 mmol) in ethanol (28.5 mL) and water (2.8 mL) at room temperature was added portionwise over 1 h solution of MCPBA (80%, 412.0 mg, 1.91 mmol) in ethanol (2.8 mL). The reaction solution became clear after 3 h. The solution was stirred for a further 15 h at ambient temperature and became cloudy. The reaction mixture was concentrated to dryness at room temperature. the residue was triturated with ethyl ether (30 mL) and the solid was collected by filtration. The crude product was dissolved in a methanol/water mixture and adsorbed on silica gel (2.0 g). The solvent was evaporated and the silica gel carrying the product was applied to a "flash" column of silica gel (100 g) packed in methylene chloride. The column was eluted with 20% MeOH in CH2Cl2 (v/v) to give 87 mg (52.6%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfonamide 19 as a colorless solid.
Primjer 17 Example 17
1-( 2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-djpirimidin-4(5H)-on 21 1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-dpyrimidin-4(5H)-one 21
Smjesa 4-hidroksipirazolo[3,4-d]pirimidina 20 (100 mg, 0.74 mmol), 1,1,1,3,3,3-heksametildisilazana (HMDS, 10 mL) i (NH4)2SO4 (10 mg, o.076 mmol) grijana je pod refluksom 3 h da se dobije bistra otopina. Suvišak HMDS je uparen da se dobije žuta krutina, koja je sušena pod vakuumom tijekom 15 min. Dodana je 1-O-acetil-2',3',5'-O-tribenzoil-L-ribofuranoza (370 mg, 0.74 mmol), zatim je dodan acetonitril (bezvodni, 5 mL). Trimetilsilil trifluoromethanesulfonat (245 mg, 1.1 mmol) je dodan dokapavanjem gore navedenoj kaši na sobnoj temperaturi. Nakon dodatka, bistra otopina ostavljena je stajati na sobnoj temperaturi 14 h. Otapalo je ispareno i žute rezidue su otopljene u EtOAc (50 mL), isprane zasićenom otopinom NaHCO3 (2×20 mL), vodom (3×20 mL), osušene iznad Na2SO4, te koncentrirane. “Flash” kromatografija na silika-gelu (5% metanol u metilen kloridu) dala je 1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-on 21 u obliku bijele krutine (177 mg, 41.5%). A mixture of 4-hydroxypyrazolo[3,4-d]pyrimidine 20 (100 mg, 0.74 mmol), 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 10 mL) and (NH4)2SO4 (10 mg, o .076 mmol) was heated under reflux for 3 h to obtain a clear solution. Excess HMDS was evaporated to give a yellow solid, which was dried under vacuum for 15 min. 1-O-acetyl-2',3',5'-O-tribenzoyl-L-ribofuranose (370 mg, 0.74 mmol) was added, followed by acetonitrile (anhydrous, 5 mL). Trimethylsilyl trifluoromethanesulfonate (245 mg, 1.1 mmol) was added dropwise to the above slurry at room temperature. After the addition, the clear solution was left to stand at room temperature for 14 h. The solvent was evaporated and the yellow residue was dissolved in EtOAc (50 mL), washed with saturated NaHCO3 solution (2×20 mL), water (3×20 mL), dried over Na2SO4, and concentrated. Flash chromatography on silica gel (5% methanol in methylene chloride) gave 1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidine- 4(5H)-one 21 as a white solid (177 mg, 41.5%).
Primjer 18 Example 18
1-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 22 1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 22
1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-on 21 (152 mg, 0.26 mmol) otopljen je u MeOH koji je zasićen s NH3 na 0°C (75 mL). Dobivena otopina je ostavljena na sobnoj temperaturi 24 h i koncentrirana. Rezidue su otopljene u vodi (30 mL), isprane s EtOAc (3×15 mL). Nakon isparavanja vode, kristalna krutina natopljena je acetonitrilom (2 mL), filtrirana i osušena pod vakuumom da se dobije 1-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 22 kao bijela kristalna krutina (70 mg, 99%). 1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 21 (152 mg, 0.26 mmol) was dissolved in MeOH which is saturated with NH3 at 0°C (75 mL). The resulting solution was left at room temperature for 24 h and concentrated. The residue was dissolved in water (30 mL), washed with EtOAc (3×15 mL). After evaporation of the water, the crystalline solid was taken up in acetonitrile (2 mL), filtered and dried under vacuum to give 1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 22 as a white crystalline solid ( 70 mg, 99%).
Primjer 19 Example 19
3-brom-1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d] pirimidin-4(5H)-on 24 3-bromo-1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24
Acetonitril (30 mL) je dodan smjesi 3-brompirazolo[3,4-d]pirimidin-4(5H)-ona 23 (1.08 g, 4.0 mmol) i 1-O-acetil-2',3',5'-O-tribenzoil-β-L-ribofuranoze (3.02 g, 6.0 mmol). Nastala kaša je grijana do refluksa i dokapavanjem je dodan trifluoroboran eterat (851 mg, 6.0 mmol). Nastala otopina je grijana pod refluksom preko noći. Otapalo je ispareno, rezidue su otopljene u EtOAc (100 mL), nastala otopina je isprana zasićenom otopinom NaHCO3, vodom, osušena iznad Na2SO4 i koncentrirana. “Flash” kromatografija na silika-gelu (5% aceton u metilen kloridu) dala je 3-brom-1-(2',3',5'-O-tribenzoil-β-L-ribofurano-zil)pirazolo[3,4-d]pirimidin-4(5H)-on 24 u obliku blijedožute krutine (1.1 g, 41 .7%). Acetonitrile (30 mL) was added to a mixture of 3-bromopyrazolo[3,4-d]pyrimidin-4(5H)-one 23 (1.08 g, 4.0 mmol) and 1-O-acetyl-2',3',5'- O-tribenzoyl-β-L-ribofuranose (3.02 g, 6.0 mmol). The resulting slurry was heated to reflux and trifluoroborane etherate (851 mg, 6.0 mmol) was added dropwise. The resulting solution was heated under reflux overnight. The solvent was evaporated, the residue was dissolved in EtOAc (100 mL), the resulting solution was washed with saturated NaHCO3 solution, water, dried over Na2SO4 and concentrated. Flash chromatography on silica gel (5% acetone in methylene chloride) gave 3-bromo-1-(2',3',5'-O-tribenzoyl-β-L-ribofurano-syl)pyrazolo[3, 4-d]pyrimidin-4(5H)-one 24 as a pale yellow solid (1.1 g, 41.7%).
Primjer 20 Example 20
3-brom-l-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 25 3-bromo-l-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 25
3-brom-1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-on 24 (280 mg, 0.43 mmol) otopljen je u MeOH zasićenom s NH3 na 0°C (25 mL). Otopina je u zataljenom autoklavu od nehrđajućeg čelika grijana na 100°C tijekom 6 h. Nakon hlađenja su amonijak i metanol ispareni. Rezidue su otopljene u vodi (40 mL), isprane s EtOAc (4×20 mL) i koncentrirane. Rezidue su natopljene acetonitrilom i dobivena krutina je filtrirana, osušena pod vakuumom da se dobije 3-brom-1-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 25 u obliku bijele krutine (140 mg, 95%). 3-bromo-1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24 (280 mg, 0.43 mmol) was dissolved in MeOH saturated with NH3 at 0°C (25 mL). The solution was heated to 100°C for 6 hours in a sealed stainless steel autoclave. After cooling, ammonia and methanol were evaporated. The residue was dissolved in water (40 mL), washed with EtOAc (4×20 mL) and concentrated. The residue was taken up with acetonitrile and the resulting solid was filtered, dried under vacuum to give 3-bromo-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 25 as a white solid (140 mg , 95%).
Primjer 21 Example 21
3-amino-1-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 26 3-amino-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 26
3-brom-1-(2',3',S'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-on 24 (714 mg, 1.08 mmol) otopljen je u MeOH zasićenom s NH3 na 0°C (30 mL). Dodana je tanka bakrena žica (21 mg, 0.33 mmol) i bakreni klorid (33 mg, 0.33 mmol). Otopina je u zataljenom autoklavu od nehrđajućeg čelika grijana na 100°C tijekom 16 h. Nakon hlađenja, reakcijskoj smjesi dodan je silika-gel (2 g) i otapalo je ispareno Silika-gel s apsorbiranim sirovim produktom nanesen je na kolonu silika-gela i eluiran s 5% Et3N, 17% MeOH u CH2Cl2). Produkt je naknadno pročišćen rekristaliziranjem (95% EtOH) da se dobije 3-amino-1-β-L-ribofuranozilpirazolo[3,4-d]pirimidin-4(5H)-on 26 u obliku bijelih iglica (110 mg, 36%). 3-bromo-1-(2',3',S'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24 (714 mg, 1.08 mmol) was dissolved in MeOH saturated with NH3 at 0°C (30 mL). Thin copper wire (21 mg, 0.33 mmol) and copper chloride (33 mg, 0.33 mmol) were added. The solution was heated to 100°C for 16 hours in a sealed stainless steel autoclave. After cooling, silica gel (2 g) was added to the reaction mixture and the solvent was evaporated. The product was subsequently purified by recrystallization (95% EtOH) to give 3-amino-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 26 as white needles (110 mg, 36% ).
Primjer 22 Example 22
3,6-dibrom-1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo(3,4-d]pirimidin-4(5H)-on 28 3,6-dibromo-1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo(3,4-d]pyrimidin-4(5H)-one 28
Acetonitril (80 mL) je dodan smjesi 3,6-dibrompirazolo[3,4-d]pirimidin-4(5H)-ona 27 (1.18 g, 4.0 mmol) i 1-O-acetil-2',3',5'-O-tribenzoil-L-ribofuranoze (3.02 g, 6.0 mmol). Kaša je zagrijana do refluksa, nakon toga je polako dodan trifluoroboran eterat (851 mg, 6.0 mmol). Reakcijska smjesa je grijana pod refluksom tijekom 6 h. Nakon uklanjanja otapala, rezidue su otopljene u EtOAc (200 mL), isprane zasićenom otopinom NaHCO3 (2×50 mL), vodom (2×50 mL), osušene (Na2SO4) i koncentrirane. Sirovi produkt je pročišćen “flash” kromatografijom na silika-gelu (5% aceton u metilen kloridu) da se dobije (1.49 g, 50.5%) 3,6-dibrom-1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-ona 28 u obliku žute pjene. Acetonitrile (80 mL) was added to a mixture of 3,6-dibromopyrazolo[3,4-d]pyrimidin-4(5H)-one 27 (1.18 g, 4.0 mmol) and 1-O-acetyl-2',3',5 of '-O-tribenzoyl-L-ribofuranose (3.02 g, 6.0 mmol). The slurry was heated to reflux, after which trifluoroborane etherate (851 mg, 6.0 mmol) was slowly added. The reaction mixture was heated under reflux for 6 h. After removal of the solvent, the residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO3 solution (2×50 mL), water (2×50 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (5% acetone in methylene chloride) to give (1.49 g, 50.5%) 3,6-dibromo-1-(2',3',5'-O- tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 28 as a yellow foam.
Primjer 23 Example 23
3-brom-7-deaza-8-aza-β-L-guanozin 24 3-bromo-7-deaza-8-aza-β-L-guanosine 24
3,6-dibrom-1-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)pirazolo(3,4-d]pirimidin-4(5H)-on (260 mg, 0.35 mmol) 28 otopljen je u MeOH zasićenom s NH3 na 0°C (20 mL). Otopina je u zataljenom autoklavu od nehrđajućeg čelika grijana na 120°C tijekom 16 h. Nakon hlađenja i uklanjanja otapala, rezidue su otopljene u vodi (100 mL), isprane s CH2Cl2 (5×15 mL), te koncentrirane da se dobije žuta krutina. Krutina je otopljena u smjesi metanola i metilen klorida (1:1 ) te propuštena kroz sloj silika-gela. Filtrat je koncentriran i krute rezidue otopljene u MeOH (5 mL), nakon čega je polako dodan dietileter (40 mL). Nastali talog je filtriran, ispran dietileterom (2×2 mL), te osušen pod vakuumom da se dobije 3-brom-7-deaza-8-aza-β-L-guanozin 29 u obliku prljavobijele krutine (102.2 mg, 80.2%). 3,6-dibromo-1-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)pyrazolo(3,4-d]pyrimidin-4(5H)-one (260 mg, 0.35 mmol ) 28 was dissolved in MeOH saturated with NH3 at 0°C (20 mL). The solution was heated in a sealed stainless steel autoclave at 120°C for 16 h. After cooling and removing the solvent, the residues were dissolved in water (100 mL) , washed with CH2Cl2 (5×15 mL), and concentrated to give a yellow solid. The solid was dissolved in a mixture of methanol and methylene chloride (1:1) and passed through a pad of silica gel. The filtrate was concentrated and the solid residue was dissolved in MeOH (5 mL), after which diethyl ether (40 mL) was slowly added. The resulting precipitate was filtered, washed with diethyl ether (2×2 mL), and dried under vacuum to give 3-bromo-7-deaza-8-aza-β -L-guanosine 29 in the form of an off-white solid (102.2 mg, 80.2%).
Primjer 24 Example 24
3-amino-7-deaza-8-aza-L-guanozin 25 3-amino-7-deaza-8-aza-L-guanosine 25
3,6-dibrom-1-(2',3',5'-0-tribenzoil-β-L-ribofuranozil)pirazolo[3,4-d]pirimidin-4(5H)-on 28 (500 mg, 0.68 mmol) otopljen je u MeOH zasićenom s NH3 na 0°C (50 mL), nakon čega je dodana tanka bakrena žica (21.5 mg, 0.34 mmol) i bakreni klorid (19.8 mg, 0.20 mmol). Otopina je u zataljenom autoklavu od nehrđajućeg čelika grijana na 120°C tijekom 16 h. Nakon hlađenja i uklanjanja otapala rezidue su otopljene u MeOH, krutina je filtrirana i filtrat je koncentriran. Pročišćavanje “flash” kromatografijom na silika-gelu (20% MeOH u CH2Cl2) daje 3-amino-7-deaza-8-aza-L-guanozin 30 u obliku bijele krutine (62 mg, 30.9%). 3,6-dibromo-1-(2',3',5'-0-tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 28 (500 mg, 0.68 mmol) was dissolved in MeOH saturated with NH3 at 0°C (50 mL), after which thin copper wire (21.5 mg, 0.34 mmol) and copper chloride (19.8 mg, 0.20 mmol) were added. The solution was heated to 120°C for 16 hours in a sealed stainless steel autoclave. After cooling and removing the solvent, the residue was dissolved in MeOH, the solid was filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (20% MeOH in CH2Cl2) gave 3-amino-7-deaza-8-aza-L-guanosine 30 as a white solid (62 mg, 30.9%).
Primjer 25 Example 25
7-deaza-8-aza-L-guanozin 26 7-deaza-8-aza-L-guanosine 26
3-brom-7-deaza-8-aza-β-L-guanozin 29 (246 mg, 0.68 mmol) otopljen je u EtOH (50%, 60 mL), nakon čega je dodan 10% Pd/C (67 mg). Smjesa je mućkana na 50 psi vodika na sobnoj temperaturi tijekom 6 h. Paladijev katalizator je filtriran i filtrat je koncentriran. Sirovi produkt je otopljen u MeOH, a zatim je dodan silika-gel (2 g). Nakon uklanjanja metanola, silika-gel adsorbiran sa sirovim produktom nanesen je na kolonu silika-gela koja je eluirana sa 17% MeOH u CH2Cl2) da se dobije 7-deaza-8-aza-β-L-guanozin 31 u obliku bijele krutine (102.4 mg, 53.2%). 3-Bromo-7-deaza-8-aza-β-L-guanosine 29 (246 mg, 0.68 mmol) was dissolved in EtOH (50%, 60 mL), after which 10% Pd/C (67 mg) was added. . The mixture was shaken at 50 psi hydrogen at room temperature for 6 h. The palladium catalyst was filtered off and the filtrate was concentrated. The crude product was dissolved in MeOH and then silica gel (2 g) was added. After removal of methanol, silica gel adsorbed with the crude product was applied to a silica gel column eluted with 17% MeOH in CH2Cl2) to give 7-deaza-8-aza-β-L-guanosine 31 as a white solid ( 102.4 mg, 53.2%).
Primjer 26 Example 26
5-amino-3-β-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-dion 34 5-amino-3-β-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione 34
5-aminotiazolo[4,5-d]pirimidin-2,7(6H)-dion 32 (400 mg, 2.71 mmol) suspendiran je u acetonitrilu (16 mL) i heksametildisilazanu (0.96 mL), te su dodani trimetilklorosilan (0.55 mL) i trimetilsilil triflat (0.9 mL). Smjesa je miješana pod refluksom 3.5 h. Dokapavanjem je dodana otopina trimetilsilil triflata (0.45 mL) u acetonitrilu (1.0 mL) i miješanje sa zagrijavanjem nastavljeno je daljnjih 30 min. Dodana je kaša 1-O-acetil-2,3,5-O-tribenzoil-L-ribofuranoze (1.22 g, 2.28 mmol) u acetonitrilu (4.1 mL) i smjesa je miješana pod refluksom tijekom 30 min. Reakcijska smjesa je ohlađena i polako ulivena uz snažno miješanje u smjesu natrijeva bikarbonata (2.81 g) i vode (96 mL), nakon čega je nastala ljepljiva krutina. Dodan je tilacetat, te je smjesa miješana sve dok nije otopljena krutina. Vodeni sloj je dva puta ekstrahiran etilacetatom i sjedinjeni organski sloj ispran je natrijevim bikarbonatom, osušen (Na2SO4) i koncentriran. Sirvoi produkt pročišćen je kromatografijom na silika-gelu s 5% Et3N i 5% etanolom u metilen kloridu da se dobije 1.10 g 5-amino-3-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)tiazolo[4,5-d]pirimidin-2,7(6H)-diona 33 u obliku bijele krutine. 5-Aminothiazolo[4,5-d]pyrimidine-2,7(6H)-dione 32 (400 mg, 2.71 mmol) was suspended in acetonitrile (16 mL) and hexamethyldisilazane (0.96 mL), and trimethylchlorosilane (0.55 mL) was added ) and trimethylsilyl triflate (0.9 mL). The mixture was stirred under reflux for 3.5 h. A solution of trimethylsilyl triflate (0.45 mL) in acetonitrile (1.0 mL) was added dropwise and stirring with heating was continued for a further 30 min. A slurry of 1-O-acetyl-2,3,5-O-tribenzoyl-L-ribofuranose (1.22 g, 2.28 mmol) in acetonitrile (4.1 mL) was added and the mixture was stirred under reflux for 30 min. The reaction mixture was cooled and slowly poured with vigorous stirring into a mixture of sodium bicarbonate (2.81 g) and water (96 mL), after which a sticky solid was formed. Thylacetate was added and the mixture was stirred until the solid was dissolved. The aqueous layer was extracted twice with ethyl acetate and the combined organic layer was washed with sodium bicarbonate, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel with 5% Et3N and 5% ethanol in methylene chloride to give 1.10 g of 5-amino-3-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl )thiazolo[4,5-d]pyrimidine-2,7(6H)-dione 33 as a white solid.
5-amino-3-(2',3',5'-O-tribenzoil-β-L-ribofuranozil)tiazolo[4,5-d]pirimidin-2,7(6H)-dion 33 (1.09 g, 1.717 mmol) otopljen je u metanolu (25 mL) i dodan je natrijev metoksid (5.4 M u metanolu, 0.64 mL). Otopina je stajala na sobnoj temperaturi tijekom 64 h. Većina metanola je isparila te su dodani voda (20 mL) i Amberlite H-oblik (1.0 g). Suspenzija je blago miješana tijekom 20 min i ostatak je filtriran sisanjem, te ispran vodom (2×10 mL). Filtrat je koncentriran i sirovi produkt je pročišćen kristaliziranjem iz metana da se dobije 368 mg 5-amino-3-β-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-diona 34 u obliku bezbojne krutine. 5-amino-3-(2',3',5'-O-tribenzoyl-β-L-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(6H)-dione 33 (1.09 g, 1.717 mmol) was dissolved in methanol (25 mL) and sodium methoxide (5.4 M in methanol, 0.64 mL) was added. The solution stood at room temperature for 64 h. Most of the methanol evaporated and water (20 mL) and Amberlite H-form (1.0 g) were added. The suspension was gently stirred for 20 min and the residue was filtered by suction and washed with water (2×10 mL). The filtrate was concentrated and the crude product was purified by crystallization from methane to give 368 mg of 5-amino-3-β-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione 34 as a colorless solid.
Primjer 27 Example 27
3-β-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-dion 36 3-β-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione 36
Otopini 5-amino-3-β-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-diona 34 (1.40 g, 2.22 mmol) u bezvodnom THF (50 mL) na sobnoj temperaturi dokapavanjem je dodan t-butil nitrit (15.05 mmol, 1.72 mL). Nastala otopina miješana je na sobnoj temperaturi 1 h na 50°C tijekom 14 h. Otapalo je upareno i rezidue kromatografirane na silika-gelu s 20-30% etilacetatom u metilen kloridu da se dobije 612 mg deaminiranog produkta u obliku pjene. A solution of 5-amino-3-β-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione 34 (1.40 g, 2.22 mmol) in anhydrous THF (50 mL) at room temperature was added dropwise t-butyl nitrite (15.05 mmol, 1.72 mL). The resulting solution was stirred at room temperature for 1 h at 50°C for 14 h. The solvent was evaporated and the residue chromatographed on silica gel with 20-30% ethyl acetate in methylene chloride to give 612 mg of the deaminated product as a foam.
500 mg deaminiranog produkta otopljeno je u metanolu (15 mL) i dodan je 30% amonijev hidroksid (75 mL). Nastala otopina stajala je na sobnoj temperaturi preko noći. Otapalo je ispareno i rezidue su kromatografirane na silika-gelu s 10-20% metanolom u metilen kloridu da se dobije 184 mg 3-β-L-ribofuranoziltiazolo[4,5-d]pirimidin-2,7(6H)-diona 36 u obliku bezbojne krutine. 500 mg of the deaminated product was dissolved in methanol (15 mL) and 30% ammonium hydroxide (75 mL) was added. The resulting solution stood at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel with 10-20% methanol in methylene chloride to give 184 mg of 3-β-L-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione 36 in the form of a colorless solid.
Primjer 28 Example 28
Metil 5-cijanometil-1-(2,3,5-O-tribenzoil-L-ribofuranozil)imidazol-4-karboksilat 38 Methyl 5-cyanomethyl-1-(2,3,5-O-tribenzoyl-L-ribofuranosyl)imidazole-4-carboxylate 38
Metil 5-cijanometilimidazol-4-karboksilat 37 (Robins et al. J. Org. Chem. 1963, 28, 3041, 500 mg, 3.02 mmol) refluksiran je u bezvodnim uvjetima tijekom 12 h s HMDS (8 mL) i amonijevim sulfatom (30 mg). Suvišak HMDS je uklnjen destiliranjem pod sniženim tlakom da se dobije trimetilsilil derivat u obliku žutosmeđeg ulja. Ulje je otopljeno u 1,2-dikloretanu (20 mL) i dodana je 1-O-acetil-2,3,5-O-tribenzoilribofuranoza (1.53 g, 3.03 mmol), nakon čega je dodan kositreni klorid (516 mL, 4.39 mmol). Reakcijska smjesa je miješana na temperaturi okoline tijekom 18 h te stavljena u hladnu vodenu otopinu 5% NaHCO3 (50 mL). Talog je filtriran kroz celit i filtrat je ekstrahiran kloroformom (3×50 mL). Ekstrakti su osušeni (Na2SO4) i upareni pod sniženim tlakom da se dobije pjena svijetlo bež boje (1.8 g). Ova tvar je pročišćena kromatografijom na silika-gelu s heksan-etilacetatom (1:1) da se dobije 1.65 g (89%) metil 5-cijanometil-1-(2,3,5-O-tribenzoil-L-ribofuranozil)imidazol-4-karboksilat 38 u obliku bezbojne krutine. Methyl 5-cyanomethylimidazole-4-carboxylate 37 (Robins et al. J. Org. Chem. 1963, 28, 3041, 500 mg, 3.02 mmol) was refluxed under anhydrous conditions for 12 h with HMDS (8 mL) and ammonium sulfate (30 mg). Excess HMDS was removed by distillation under reduced pressure to give the trimethylsilyl derivative as a tan oil. The oil was dissolved in 1,2-dichloroethane (20 mL) and 1-O-acetyl-2,3,5-O-tribenzoylribofuranose (1.53 g, 3.03 mmol) was added, followed by stannous chloride (516 mL, 4.39 mmol). The reaction mixture was stirred at ambient temperature for 18 h and placed in a cold aqueous solution of 5% NaHCO3 (50 mL). The precipitate was filtered through celite and the filtrate was extracted with chloroform (3×50 mL). The extracts were dried (Na2SO4) and evaporated under reduced pressure to give a light beige foam (1.8 g). This material was purified by chromatography on silica gel with hexane-ethyl acetate (1:1) to give 1.65 g (89%) of methyl 5-cyanomethyl-1-(2,3,5-O-tribenzoyl-L-ribofuranosyl)imidazole. -4-carboxylate 38 as a colorless solid.
Primjer 29 Example 29
3-deaza-β-L-guanozin 39 3-deaza-β-L-guanosine 39
Metil 5-cijanometil-1-(2,3,5-O-tribenzoil-L-ribofuranozil)imidazole-4-karboksilat 38 (1.03 g, 1.69 mmol) otopljen je u metanolu (60 mL) i zasićen bezvodnim amonijakom na 0°C. Reakcijska smjesa je stavljena u zataljen čelični autoklav i držana na 100°C 18 h. Smjesa je ohlađena na sobnu temperaturu i uparena do suhog. Rezidue su suspendirane u toplom kloroformu, te je preostala krutina filtrirana, isprana kloroformom (5×10 ml) i osušena. Sirovi produkt je rekristaliziran iz vode da se dobije 320 mg (70%) 3-deaza-β-L-guanozin 39 u obliku bezbojne krutine. Methyl 5-cyanomethyl-1-(2,3,5-O-tribenzoyl-L-ribofuranosyl)imidazole-4-carboxylate 38 (1.03 g, 1.69 mmol) was dissolved in methanol (60 mL) and saturated with anhydrous ammonia at 0° C. The reaction mixture was placed in a sealed steel autoclave and kept at 100°C for 18 h. The mixture was cooled to room temperature and evaporated to dryness. The residues were suspended in warm chloroform, and the remaining solid was filtered, washed with chloroform (5×10 ml) and dried. The crude product was recrystallized from water to give 320 mg (70%) of 3-deaza-β-L-guanosine 39 as a colorless solid.
Primjer 30 Example 30
3-brom-3-deaza-β-L-guanozin 40 3-bromo-3-deaza-β-L-guanosine 40
Uz miješanje, otopini 3-deaza-β-L-guanozina 39 (200 mg, 0.708 mmol) u 8 mL vode/metanola (1:1) dodan je brom (20 mL, 0.39 mmol). Nakon miješanja tijekom 15 min. reakcijska smjesa je uparena do suhog. Sirova tvar suspendirana je u kloroformu, filtrirana i osušena da se dobije 210 mg (82%) 3-brom-3-deaza-β-L-guanozina 40 u obliku bezbojne krutine. With stirring, bromine (20 mL, 0.39 mmol) was added to a solution of 3-deaza-β-L-guanosine 39 (200 mg, 0.708 mmol) in 8 mL of water/methanol (1:1). After mixing for 15 min. the reaction mixture was evaporated to dryness. The crude material was suspended in chloroform, filtered and dried to give 210 mg (82%) of 3-bromo-3-deaza-β-L-guanosine 40 as a colorless solid.
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