FI115399B - Förfarande för framställning av terapeutiskt användbara metylfosfonsyraestrar - Google Patents
Förfarande för framställning av terapeutiskt användbara metylfosfonsyraestrar Download PDFInfo
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- FI115399B FI115399B FI956341A FI956341A FI115399B FI 115399 B FI115399 B FI 115399B FI 956341 A FI956341 A FI 956341A FI 956341 A FI956341 A FI 956341A FI 115399 B FI115399 B FI 115399B
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Claims (6)
1. Förfarande för framställning av sadana före-ningar som har formeln (I), 5 /'°W * — CH—, (I) r o väri Y är en OH-, SH-, OAc- eller SAc-grupp, i vilka Ac 10 = Ci-18-acylgrupp, som är eventuellt 1 - 3-faldigt omättad, R' är en aryl-, heteroaryl- eller alkylgrupp, W är en farmaceutiskt verksam 5'-, 3'- eller 2'- nukleosidanalog, R är tili betydelsen sarana som grupp W, varvid R 15 och W kan vara lika eller olika, eller R är en eventuellt substituerad alkylgrupp eller W och R bildar tillsammans med en fosfonatgrupp, tili vilken de är bundna, en oligonukleotid, varvid W är en grupp enligt formel (II) och R är en grupp enligt for- .
2 0 mel (II ' ) , » · ::*f *' ' \sKj : o o i1 ‘ · . ' 1 1 . , F- —f--C----; v fc F -F-0—--1 , 6 · 11 —| *' /hl - 0 J. w r|. 0, OR * :. (ID (HT) i vilka X är en oxi-, sulfandiyl- eller metylen- : grupp, . » ! grupp B är oberoende en nukleotidbas, 25 n är oberoende ett heltal 0 - 50, ,* vardera gruppen R1 och R2 är oberoende en H-atom, Ci^ig-acylgrupp eller en grupp med formeln 66 115399 O r4-p-or5
5 I väri R4 är en O"-, S”-, CH3- eller CHYR'-grupp, väri R' och Y är ovan definierade grupper och R5 är en eventuellt substituerad alkylgrupp med 1-18 kolatomer, 10 var och en av grupperna R3 är oberoende en H-atom, OCi-is-alkyl- eller OCi_18-acylgrupp, F- eller Cl-atom eller N3-, NH2- eller NHRe-grupp, väri R6 är en Ci^-alkyl- eller -acylgrupp, och klammertecknen anger att grupp R3 och intilliggan-15 de fosfonylgrupp kan vara i 2'- eller 3'-ställning, kän-netecknat av att a) en förening enligt formel (III) bringas att re-agera med en förening enligt formel (IV), H n\ * ^ . 0 X0R X0 • * i* (m) (iv) ;;r; 20 t l eller ♦ - » ; b) en förening enligt formel (V) bringas i önskad ordning och genom användning av ett kondenseringsmedel att 25 reagera med föreningar enligt formel (VI) eller c) en förening enligt formel (V) bringas i önskad ! ordning och genom användning av ett kondenseringsmedel att reagera med föreningar enligt formel (VI) och formel ,'i (vii), • » 67 115399 o li/0K R \ /’’v · WÖM * i0H X-'" X0H D - S 5 (V) (VI) (VII) varvid SG är en skyddsgrupp, som för framställning av föreningen enligt formel (I) eventuellt bortspjälkes, eller 5 en nukleotidenhet med en 3 ' (2')-terminal H-fosfo- natgruppering och en skyddad 5'-hydroxylgrupp bringas att reagera med en andra nukleotidenhet med en fri 5'-hydroxylgrupp och en skyddad 3’ (2')-hydroxylgrupp i närvaro av ett aktiveringsmedel tili en H-fosfonatdinukleosid och 10 denna kondenseras med en aldehyd tili dinukleosid-a-hydroxialkyl(aryl)fosfonat, som efter att ha reagerat tili sinä aktiverade derivat reagerar med övriga (oligo)nukleo-tidfragment tili oligonukleotider, varvid de tillfälliga skyddsgrupperna avlägsnas, eller 15 a) en nukleotidenhet med en 3 ' (2')-terminal fos forini)- eller fosfor(V)-gruppering bringas att reagera med en andra nukleotidenhet eller en växande oligonukleo- I ‘ I t tidkedjas fria 5'-hydroxylgrupp i närvaro av ett kondense- • · * ringsmedel eller • · » • ’.· 20 b) med deras aktiverade derivat, eller bildas oligonukleotidanaloger fragmentvis pä samma sätt, bortspjälkes i enlighet med punkt (a) eller (b) de i de framställda oligonukleotiderna för skydd av övriga funktionella grupper tillfälligt tillsatta skyddsgrupperna 25 och ändras de sälunda erhällna oligonukleotidanalogerna med formel (I), väri W är en grupp enligt formel (II) och R är en grupp enligt formel (II1), eventuellt tili sitt ; fysiologiskt godtagbara sait. : 2. Förfarande enligt patentkrav 1, känneteck- 30 nat av att en förening framställs, väri . Y är en OH-, SH-, OAc- eller SAc-grupp, i vilka Ac = Ci-i8-acylgrupp, som är eventuellt 1 - 3-faldigt omättad, 68 115399 R' ar en arylgrupp med 6-14 C-atomer och som är eventuellt substituerad med högst tre av varandra oberoen-de grupper, vilka väljs bland följande: en Ci-5-alkylgrupp, halogenatom och N02-, CN-, Ci_6-alkoxyl -, amino-, Ci-4-al-5 kylamino- och Ci-8-dialkylaminogrupper, varvid i arylgrup-pen även kan vara kondenserad en C3-a-alkylengrupp, väri en CH2-grupp även kan vara ersatt med en oxigrupp; en hetero-arylgrupp med 3-13 C-atomer och högst tre heteroatomer som skall valjas bland N-, O- och S-atomer; en förgrenad 10 eller rakkedjad, mättad eller 1 - 3-faldigt omättad Ci-i6-alkylgrupp, som är eventuellt substituerad med högst tre av varandra oberoende substituenter som väljs bland halo-genatomer och CN-, N02- och Ci-3-alkoxylgrupper, W är en farmaceutiskt verksam 5'-, 3'- eller 2'- 15 nukleosidanalog, R är till betydelsen samma som grupp W, varvid R och W kan vara lika eller olika, eller R är en Cx^-alkyl-grupp, som kan vara förgrenad eller rakkedjad och är eventuellt substituerad med högst tre av varandra oberoende 20 grupper, vilka väljs bland halogenatomer och CN-, Ci_i8-acyloxi- och Ci-i8-alkoxylgrupperna, eller '"· W och R bildar tillsammans med en fosfonatgrupp, tili vilken de är bundna, en oligonukleotid, varvid W är : · : en grupp enligt formel (II) och R är en grupp enligt for- : 25 mel (II'), : väri X är en oxi- eller sulfandiylgrupp, ·. grupp B är oberoende en nukleotidbas, ♦ n är oberoende ett heitai 0 - 30, vardera gruppen R1 och R2 är oberoende en H-atom, ; 30 Ci_12-acylgrupp eller en grupp med formeln : : o • ; il r4-p-or5 '! 35 | 69 115399 väri R4 är en O- eller S-atom eller CH3- eller CHYR'-grupp, väri R' och Y är ovan definierade grupper och R5 är en eventuellt substituerad alkylgrupp med 1-12 kolatomer, 5 var och en av grupperna R3 är oberoende en H-atom, OCi-12-alkyl- eller OCi-i2-acylgrupp, Cl-atom eller N3-, NH2-eller NHR6-grupp, väri R6 är en Ci-3-alkyl eller -acyl-grupp, och klammertecknen anger att grupp R3 och intilliggan-10 de fosfonylgrupp kan vara i 2'- eller 31-ställning.
3. Förfarande enligt patentkrav 1 eller 2, kän-netecknat av att en förening framställs, väri Y är en OH-, SH-, OAc- eller SAc-grupp, i vilka Ac = Ci-3-acylgrupp, som är eventuellt 1 - 3-faldigt omättad,
15 R' är en arylgrupp med 6-14 C-atomer och som är eventuellt substituerad med högst tre av varandra oberoende grupper, vilka väljs bland följande: en Ci_3-alkylgrupp, F- och Cl-atomer och N02-, CN-, Ci_4-alkoxyl-, amino-, Ci-3-alkylamino- och Ci-6-dialkylaminogrupper, varvid i aryl-20 gruppen även kan vara kondenserad en C3_8-alkylengrupp, väri en CH2-grupp även kan vara ersatt med en oxigrupp; en heteroarylgrupp med 3-6 C-atomer och högst tre hetero-·’ atomer som skall väljas bland N-, O- och S-atomer; en för- ' : grenad eller rakkedjad, mättad eller 1 - 3-faldigt omättad ; *; 25 Ci_8-alkylgrupp, som är eventuellt substituerad med högst : *. tre av varandra oberoende substituenter som väljs bland * ; · ·, Cl-atomer och CN-, N02- och Ci-3-alkoxylgrupper, • · W är en 5'-, 3'- eller 2'-nukleosidanalog, R är tili betydelsen samma som grupp W eller en * S » ·;;; 30 C^s-alkylgrupp, som kan vara förgrenad eller rakkedjad och är eventuellt substituerad med högst tvä grupper, vilka ; · : väljs bland halogenatomer och CN-, C3-6-acyloxi- och C8_18- • · alkoxylgrupperna, eller 70 115399 W och R bildar tillsammans med en fosfonatgrupp, till vilken de är bundna, en oligonukleotid, varvid W är en grupp enligt formel (II) och R är en grupp enligt forme 1 (II 1 ) , 5 väri X är en oxigrupp, grupp B är oberoende en nukleotidbas, n är oberoende ett heltal 0-20, vardera gruppen R1 och R2 är oberoende en H-atom, Ci_8-acylgrupp eller en grupp med formeln 10 0 r4-p-or5 15 väri R4 är en 0- eller S-atom eller CH3- eller CHYR'-grupp, väri R' och Y är ovan definierade grupper och R5 är en eventuellt substituerad alkylgrupp med 1-8 kolatomer, 20 var och en av grupperna R3 är oberoende en H-atom, OCi-s-alkyl- eller OCi_8-acylgrupp, Cl-atom eller N3-grupp, , och > · ' I klammertecknen anger att grupp R3 och intilliggan- : ** de f osf onylgrupp kan vara i 2'- eller 3 '-ställning. ’ .· 25
4. Förfarande enligt ett eller flera av patentkra- i, * ven 1 - 3, kännetecknat av att en förening fram- » t : : ställs, väri Y är en OH-grupp, • R' är en arylgrupp med 6 C-atomer och som är even- .* 30 tuellt substituerad med högst tre av varandra oberoende grupper, vilka väljs bland följande: en Ci-3-alkylgrupp, F-’* * och Cl-atomer och N02-, CN-, Ci_4-alkoxyl-, amino-, Ci-3- • alkylamino- och Ci_6-dialkylaminogrupper, varvid i aryl- '· gruppen även kan vara kondenserad en C3-6-alkylengrupp, 3. väri en CH2-grupp även kan vara ersatt med en oxigrupp; en heteroarylgrupp med 3-6 C-atomer och högst tre hetero- 71 115399 atomer som skall valjas bland N-, O- och S-atomer; en för-grenad eller rakkedjad, mättad eller 1 - 3-faldigt omät-tad, företrädesvis konjugerat omättad, Ci_8-alkylgrupp in-nehällande en omättad bindning i alfa-ställning, som är 5 eventuellt substituerad med högst tre av varandra oberoen-de substituenter som väljs bland Cl-atomer och CN-, N02- och Cx-3-alkoxylgrupper, W är en 5'- eller 3'-nukleosidanalog, R är till betydelsen samma som grupp W eller en 10 Ci_4-alkylgrupp, som kan vara förgrenad eller rakkedjad, eller W och R bildar tillsammans med en fosfonatgrupp, till vilken de är bundna, en oligonukleotid, varvid W är en grupp enligt formel (II) och R är en grupp enligt for-15 mel (II ' ) , väri X är en oxigrupp, grupp B är oberoende en nukleotidbas, n är oberoende ett heitai 0 - 15, vardera gruppen R1 och R2 är oberoende en H-atom,
20 Ci-4-acylgrupp eller en grupp med formeln * * · O , I* ii r4-p-or5 ;.· 25 I : väri R4 är en 0- eller S-atom eller CH2- eller CHYR'-grupp, väri R' och Y är ovan definierade grupper och ·. R5 är en eventuellt substituerad alkylgrupp med 1-3 ·. 3 0 kolatomer, var och en av grupperna R3 är oberoende en H-atom, OCi-3-alkyl- eller OCi_3-acylgrupp, Cl-atom eller N3-grupp, * och klammertecknen anger att grupp R3 och intilliggan- ; 35 de f osf onylgrupp kan vara i 2'- eller 3 ' - ställning . 72 115399
5. Förfarande enligt patentkrav ett eller flera av patentkraven 1 - 4, kännetecknat av att en förening framställs, väri Y är en OH-grupp,
5 W är en 5'- eller 3'-nukleosidanalog, R är till betydelsen samma som grupp W eller en Ci-4-alkylgrupp, som kan vara förgrenad eller rakkedjad, R1 är en arylgrupp med
6 C-atomer och som är even-tuellt substituerad med högst tre av varandra oberoende 10 grupper, som väljs bland följande: en Cl-atom och NO2-, CN-, Ci-3-alkoxyl-, amino- och Ci-3-alkylaminogrupper. t * * » • · ψ · • » · • i m * · * * • » · * * · * > % • · *
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DE4321946A DE4321946A1 (de) | 1993-07-01 | 1993-07-01 | Methylphosphonsäureester, Verfahren zu deren Herstellung und deren Verwendung |
DE4321946 | 1993-07-01 | ||
PCT/EP1994/002121 WO1995001363A1 (de) | 1993-07-01 | 1994-06-29 | Methylphosphonsäureester, verfahren zu deren herstellung und deren verwendung |
EP9402121 | 1994-06-29 |
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DE4338704A1 (de) * | 1993-11-12 | 1995-05-18 | Hoechst Ag | Stabilisierte Oligonucleotide und deren Verwendung |
DE19502912A1 (de) * | 1995-01-31 | 1996-08-01 | Hoechst Ag | G-Cap Stabilisierte Oligonucleotide |
ATE206131T1 (de) * | 1995-03-13 | 2001-10-15 | Aventis Pharma Gmbh | Phosphonomonoesternnukleinsäuren, verfahren zu ihrer herstellung und ihre verwendung |
US5821354A (en) * | 1996-11-26 | 1998-10-13 | Angiogene Inc. | Radiolabeled DNA oligonucleotide and method of preparation |
US6248878B1 (en) | 1996-12-24 | 2001-06-19 | Ribozyme Pharmaceuticals, Inc. | Nucleoside analogs |
WO1998028317A2 (en) * | 1996-12-24 | 1998-07-02 | Ribozyme Pharmaceuticals, Inc. | Synthesis of nucleosides and polynucleotides |
US7776343B1 (en) | 1999-02-17 | 2010-08-17 | Csl Limited | Immunogenic complexes and methods relating thereto |
DE19935303A1 (de) | 1999-07-28 | 2001-02-08 | Aventis Pharma Gmbh | Oligonukleotide zur Inhibierung der Expression von humanem eg5 |
WO2002066092A2 (en) * | 2001-02-23 | 2002-08-29 | Angiogene Inc. | Drug eluting device for treating vascular diseases |
GB0110732D0 (en) * | 2001-05-02 | 2001-06-27 | Psl Technology Ltd | Apparatus and method |
AR040996A1 (es) | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
JP2006515277A (ja) | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ, リミテッド | C型肝炎ウィルス感染の処置および予防に関する方法および製品 |
JP2007526253A (ja) | 2004-02-19 | 2007-09-13 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 免疫刺激性ウイルスrnaオリゴヌクレオチド |
US20060287263A1 (en) | 2004-07-18 | 2006-12-21 | Csl Limited | Methods and compositions for inducing antigen-specific immune responses |
US20080045473A1 (en) | 2006-02-15 | 2008-02-21 | Coley Pharmaceutical Gmbh | Compositions and methods for oligonucleotide formulations |
PT2078080E (pt) | 2006-09-27 | 2015-09-18 | Coley Pharm Gmbh | Análogos dos oligonucleotídeos cpg que contêm análogos t hidrofóbicos com atividade imunoestimulante potenciada |
MX2009012482A (es) * | 2007-05-17 | 2009-12-02 | Coley Pharm Group Inc | Oligonucleotidos de clase a con potencia inmunoestimuladora. |
RU2010112771A (ru) | 2007-10-09 | 2011-11-20 | Коули Фармасьютикал ГмбХ (DE) | Иммуностимулирующие аналоги олигонуклеотидов, содержащие модифицированные сахарные группировки |
ES2672526T3 (es) * | 2008-06-26 | 2018-06-14 | Prolynx Llc | Profármacos y conjugados de fármaco-macromolécula que presentan velocidades de liberación de fármaco controladas |
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ES2622562T3 (es) | 2008-12-09 | 2017-07-06 | Pfizer Vaccines Llc | Vacuna de péptido CH3 de IgE |
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DK2575878T3 (en) | 2010-05-28 | 2018-08-13 | Zoetis Belgium S A | VACCINES INCLUDING CHOLESTEROL AND CPG AS THE ONLY ADJUVENT CARRIER MOLECULES |
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LT3240801T (lt) | 2014-12-31 | 2021-02-25 | Checkmate Pharmaceuticals, Inc. | Kombinuota navikų imunoterapija |
WO2024127215A2 (en) | 2022-12-13 | 2024-06-20 | Pfizer Inc. | Immunogenic compositions and methods for eliciting an immune response against clostridioides (clostridium) difficile |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993010140A1 (en) * | 1991-11-21 | 1993-05-27 | Pharmagenics, Inc. | Oligonucleotides having modified anionic moieties |
-
1993
- 1993-07-01 DE DE4321946A patent/DE4321946A1/de not_active Withdrawn
-
1994
- 1994-06-29 DE DE59409880T patent/DE59409880D1/de not_active Expired - Fee Related
- 1994-06-29 WO PCT/EP1994/002121 patent/WO1995001363A1/de active IP Right Grant
- 1994-06-29 US US08/578,686 patent/US6028182A/en not_active Expired - Fee Related
- 1994-06-29 AT AT94919670T patent/ATE206130T1/de not_active IP Right Cessation
- 1994-06-29 JP JP50326995A patent/JP3831407B2/ja not_active Expired - Fee Related
- 1994-06-29 EP EP94919670A patent/EP0707591B1/de not_active Expired - Lifetime
- 1994-06-29 CA CA002165971A patent/CA2165971C/en not_active Expired - Fee Related
- 1994-06-29 DK DK94919670T patent/DK0707591T3/da active
- 1994-06-29 ES ES94919670T patent/ES2165391T3/es not_active Expired - Lifetime
- 1994-06-29 PT PT94919670T patent/PT707591E/pt unknown
- 1994-06-29 AU AU70735/94A patent/AU698928B2/en not_active Ceased
-
1995
- 1995-12-29 FI FI956341A patent/FI115399B/sv active IP Right Grant
- 1995-12-29 NO NO19955352A patent/NO319860B1/no unknown
Also Published As
Publication number | Publication date |
---|---|
WO1995001363A1 (de) | 1995-01-12 |
DE59409880D1 (de) | 2001-10-31 |
NO955352D0 (no) | 1995-12-29 |
DE4321946A1 (de) | 1995-01-12 |
DK0707591T3 (da) | 2002-01-21 |
EP0707591B1 (de) | 2001-09-26 |
FI956341A0 (sv) | 1995-12-29 |
ATE206130T1 (de) | 2001-10-15 |
NO955352L (no) | 1996-02-14 |
PT707591E (pt) | 2002-03-28 |
NO319860B1 (no) | 2005-09-26 |
CA2165971C (en) | 2006-05-30 |
JP3831407B2 (ja) | 2006-10-11 |
AU698928B2 (en) | 1998-11-12 |
FI956341A (sv) | 1996-02-19 |
ES2165391T3 (es) | 2002-03-16 |
JPH08512039A (ja) | 1996-12-17 |
AU7073594A (en) | 1995-01-24 |
US6028182A (en) | 2000-02-22 |
EP0707591A1 (de) | 1996-04-24 |
CA2165971A1 (en) | 1995-01-12 |
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