HRP20211034T1 - 2-amino-n-(piperidin-1-il-piridin-3-il)pirazolo[1,5alfa]pirimidin-3-karboksamid kao inhibitor atr kinaze - Google Patents
2-amino-n-(piperidin-1-il-piridin-3-il)pirazolo[1,5alfa]pirimidin-3-karboksamid kao inhibitor atr kinaze Download PDFInfo
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- HRP20211034T1 HRP20211034T1 HRP20211034TT HRP20211034T HRP20211034T1 HR P20211034 T1 HRP20211034 T1 HR P20211034T1 HR P20211034T T HRP20211034T T HR P20211034TT HR P20211034 T HRP20211034 T HR P20211034T HR P20211034 T1 HRP20211034 T1 HR P20211034T1
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- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 claims 1
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- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 claims 1
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Claims (30)
1. Spoj, koji ima formulu I-B:
[image]
ili njegova farmaceutski prihvatljiva sol, naznačeno time,
u kojem (I):
R1 je neovisno odabran od fluoro, kloro ili -C(J1)2CN;
J1 je neovisno odabran od H ili C1-2alkila; ili
dvije pojave J1, skupa s atomom ugljika za kojeg su vezani, tvore po izboru supstituirani 3-4-eročlani karbociklički prsten;
R3 je neovisno odabran od H; kloro; fluoro; C1-4alkila po izboru supstituiranog s 1-3 pojavljivanja halo; C3-4cikloalkila;
-CN; ili C1-3alifatskog lanca pri čemu se do dvije jedinice metilena iz alifatskog lanca po izboru mogu zamijeniti sa -O-, -NR-, -C(O)- ili -S(O)n;
L1 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L1 je po želji supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
L2 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L2 je po izboru supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabranih između kisika, dušika ili sumpora; ili
L1 i L2, zajedno s dušikom na koji su vezani, čine prsten D; prsten D je po izboru supstituiran s 0-5 pojavljivanja JG;
prsten D se neovisno bira između 3-7-eročlanog heterociklilnog prstena koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-člani potpuno zasićeni ili djelomično nezasićeni biciklički prsten s 1-5 heteroatoma odabrana između kisika, dušika ili sumpora;
JG je neovisno odabran između halo; -N (R°) 2; 3-6-eročlanog karbociklila; 3-6-eročlanog heterociklila koji ima 1-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-4alkilni lanac u kojem do dvije metilenske jedinice alkilnog lanca se po izboru zamjenjuju sa -O-, -NR-, -C (O) - ili -S (O)n;
svaki JG je po izboru supstituiran s 0-2 pojavljivanja JK,
dva pojavljivanja JG na istom atomu, zajedno s atomom kojem su vezani, čine 3-6-eročlani prsten s 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; dvije pojave JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prestenski sustav;
JK je 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika, ili sumpora;
L3 je neovisno odabran između H; klor; fluoro; C1-4alkila po izboru supstituiranog sa 1-3 pojavljivanja halo; -CN; ili C1-3alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po želji zamijenjene sa - O-, -NR-, -C (O) - ili -S (O)n;
N je 0, 1 ili 2; i
R i R° su H ili C1-4alkil; ili:
u kojem (II):
R1 je neovisno odabran od fluoro, kloro ili -C (J1)2CN;
J1 je neovisno odabran između H ili C1-2alkila; ili dva pojavljivanja J1, zajedno s atomom ugljika na koji su vezani, tvore poželji supstituirani 3-4-eročlani karbociklički prsten;
R3 je neovisno odabran između H; klor; fluoro; C1-4alkila po izboru supstituiranog s 1-3 pojavljivanja halo; C3-4cikloalkila; -CN; ili C1-3alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n;
L1 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L1 je po izboru supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlanim ne-aromatskim prstenom koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
L2 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L2 je po izboru supstituiran s C1-4alifatom;
-CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; ili
L1 i L2, zajedno s dušikom na koji su vezani čine prsten D; prsten D je po izboru supstituiran s 0-5 pojavljivanja JG;
L3 je H; C1-3alifat; ili CN;
prsten D je neovisno odabran između 3-7-eročlanog heterociklilnog prstena koji ima 1-2 heteroatoma odabrana
od kisika, dušika ili sumpora; ili 7-12-eročlani potpuno zasićeni ili djelomično nezasićeni biciklički prsten s 1-5 heteroatoma odabrana između kisika, dušika ili sumpora;
JG je neovisno odabran između halo; -CN; -N (R°)2; → O; 3-6-eroeročlani karbociklil; 3-6-eročlani heterociklil koji ima 1-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-4alkilni lanac u kojem
do dvije metilenske jedinice alkilnog lanca se po izboru zamjenjuju sa -O-, -NR-, -C (O) - ili -S (O)n; svaki
JG je po izboru supstituiran s 0-2 pojavljivanja JK, dva pojavljivanja JG na istom atomu, zajedno s atomom za kojeg su vezani, čine 3-6-eročlani prsten s 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
dva pojavljivanja JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prstenski sustav;
JK je 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora;
n je 0, 1 ili 2; i
R i R° su H ili C1-4alkil; ili:
u kojem (III):
R1 je neovisno odabran između fluoro, kloro ili -C (J1)2CN;
J1 je neovisno odabran između H ili C1-2alkila; ili
dva pojavljivanja J1, zajedno s atomom ugljika na koji su vezani, tvore po želji supstituirani 3-4-eročlani karbociklički prsten;
R3 je neovisno odabran između H; klor; fluoro; C1-4alkila po izboru supstituiranog s 1-3 pojavljivanja halo; C3-4cikloalkil; -CN; ili C1-3alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n;
L1 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L1 je po želji supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlanim ne-aromatskim prstenom koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
L2 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C (O) - ili -S (O)n; svaki L2 je po izboru supstituiran s C1-4alifatom;
-CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; ili
L1 i L2, zajedno s dušikom na koji su vezani, čine prsten D; prsten D je po izboru supstituiran s 0-5 pojavljivanja JG;
prsten D se neovisno bira između 3-7-eročlanog heterociklilnog prstena koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlanog potpuno zasićenog ili djelomično nezasićenog bicikličkog prstena koji ima 1-5 heteroatoma odabrana između kisika, dušika ili sumpora;
JG je neovisno odabran između halo; -CN; -N (R°)2; 3-6-eročlanog karbociklila; 3-6-eročlanog heterociklila koji
ima od 1-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-4alkilnog lanca pri čemu gore navedene do dvije metilenske jedinice alkilnog lanca se po izboru zamjenjuju sa -O-, -NR-, -C (O) - ili -S(O)n;
svaki JG je po želji supstituiran s 0-2 pojavljivanja JK,
dva pojavljivanja JG na istom atomu, zajedno s atomom kojem su pridruženi, tvore 3-6-eročlani prsten s 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
dva pojavljivanja JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prestenski sustav;
JK je 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika, ili sumpora;
n je 0, 1 ili 2; i
R i R° su H ili C1-4alkil; ili:
u kojem (IV):
R1 je neovisno odabran između fluoro, kloro ili -C(J1)2CN;
J1 je neovisno odabran između H ili C1-2alkila; ili dva pojavljivanja J1, zajedno s atomom ugljika na koji su vezani, tvore po izboru supstituirani 3-4-eročlani karbociklički prsten;
R3 je neovisno odabran između H; klor; fluoro; C1-4alkila po izboru supstituiranog s 1-3 pojavljivanja halo; C3-4cikloalkila; -CN; ili C1-3alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene sa -O-, -NR-, -C(O) - ili -S(O)n;
L1 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O) - ili -S(O)n; svaki L1 je po izboru supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora;
L2 je H; 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; ili C1-6alifatski lanac u kojem su do dvije metilenske jedinice alifatskog lanca po izboru zamijenjene s -O-, -NR-, -C(O)- ili -S(O)n; svaki L2 je po izboru supstituiran s C1-4alifatom; -CN; halo; -OH; ili 3-6-eročlani ne-aromatski prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; ili L1 i L2, zajedno s dušikom na koji su vezani, čine prsten D; prsten D je po izboru supstituiran s 0-5 pojavljivanja JG;
prsten D se neovisno bira između 3-7-eročlanog heterociklilnog prstena koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; ili 7-12-eročlanog potpuno zasićenog ili djelomično nezasićenog bicikličkog prstena s 1-5 heteroatoma odabranih između kisika, dušika ili sumpora;
JG je neovisno odabran između halo; -N(R°)2; 3-6-eročlanog karbociklila; 3-6-eročlanog heterociklila koji ima 1-2 heteroatoma odabrana između kisika dušika ili sumpora; ili halkilni lanac u kojem do dvije metilenske jedinice alkilnog lanca se po izboru szamjenjuju s -O-, -NR-, -C(O)- ili -S(O)n; svaki JG je po izboru supstituiran s 0-2 pojavljivanja JK,
dva pojavljivanja JG na istom atomu, zajedno s atomom kojem su pridruženi, čine 3-6-eročlani prsten s 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; dva pojavljivanja JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prestenski sustav;
JK je 3-7-eročlani aromatski ili ne-aromatski prsten koji ima 0-2 heteroatoma odabrana od kisika, dušika ili sumpora;
n je 0, 1 ili 2; i
R i R° su H ili C1-4alkil; ili:
u kojem (V):
R1 je neovisno odabran između fluoro, kloro ili -C (J1)2CN;
J1 je neovisno odabran između H ili C1-2alkila; ili dva pojavljivanja J1, zajedno s atomom ugljika na koji su vezani, tvore po želji supstituirani 3-4-eročlani karbociklički prsten;
R3 je neovisno odabran između H; klor; fluoro; C1-4alkila po izboru supstituiranog s 1-3 pojavljivanja halo; C3-4cikloalkil; ili -CN;
L1 je po izboru supstituirani C1-6alifat;
L2 je po izboru supstituirani C1-6alifat; ili
L1 i L2, zajedno s dušikom na koji su vezani, čine prsten D; prsten D je po izboru supstituiran s 0-5 pojavljivanja JG; prsten D je neovisno odabran između 3-7-eročlanog heterociklilnog prstena koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora; ili 8-12-eročlanog potpuno zasićenog ili djelomično nezasićenog bicikličkog prstena s 0-5 heteroatoma odabrana između kisika, dušika ili sumpora;
JG je neovisno odabran između C1-4alkila, -N (R°)2 ili 3-5-eročlanog karbociklila; ili dva pojavljivanja JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prstenski sustav; i
R° je H ili C1-4alkil.
2. Spoj u skladu s bilo kojim od patentnih zahtjeva 1(I) do 1(IV), naznačeno time,
u kojem je (I) R1 fluoro; ili:
u kojem je (II) R1 -CH2CN; ili:
u kojem je (III) R1 kloro.
3. Spoj u skladu s patentnim zahtjevom 1 do 2(II), naznačeno time, što je R3 neovisno odabran od H, kloro, fluoro, ciklopropila ili C1-4alkila.
4. Spoj u skladu s patentnim zahtjevom 3, naznačeno time, što je (I) R3 neovisno odabran od H, kloro ili fluoro; ili:
u kojem je (II) R3 H; ili:
u kojem je (III) R3 kloro; ili:
u kojem je (IV) R3 fluoro.
5. Spoj u skladu s patentnim zahtjevom 4, naznačeno time, što su L1 i L2 H; -(C1-3alkil)O(C1-2alkil); -(C1-3alkil)N(C1-2alkil)2; C1-4alkil; azetidinil; piperidinil; oksitanil ili pirolidinil.
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 2 do 4, naznačeno time, što L1 and L2 zajedno s dušikom za kojeg su vezani, tvore prsten D.
7. Spoj u skladu s patentnim zahtjevom 6, naznačeno time, što je prsten D 3-7-eročlani heterociklički prsten koji ima 1-2 heteroatoma odabrana od kisika, dušika ili sumpora.
8. Spoj u skladu s patentnim zahtjevom 7, naznačeno time, što je (I) prsten D neovisno odabran između piperazinila, piperidinila, morfolinila, tetrahidropiranila, azetidinila, pirolidinila ili 1,4-diazepanila; po izboru gdje je prsten D piperazinil, piperidinil, 1,4-diazepanil, pirolidinil ili azetidinil; po izboru pri čemu je prsten D piperazinil ili piperidinil; ili: gdje je (II) prsten D 8-12-eročlani potpuno zasićeni ili djelomično nezasićeni biciklički prsten koji ima 0-5 heteroatoma odabrana između kisika, dušika ili sumpora; po izboru gdje je prsten D oktahidropirolo[1,2-a] pirazin ili oktahidropirolo [3,4-c] pirol.
9. Spoj u skladu s bilo kojim od patentnih zahtjeva 7 i 8, naznačeno time, što JG je halo, C1-4alkil, -O (C1-3alkil), C3-6cikloalkil, 3-6-eročlani heterociklil, -NH (C1-3alkil), -OH ili -N (C1-4alkil)2; po izboru gdje JG je metil, -N(C1-4alkil)2, etil, -O(C1-3alkil), ciklopropil, oksetanil, ciklobutil, pirolidinil, piperidinil ili azetidinil; po izboru pri čemu je JG metal, -O (C1-3alkil), oksetanil, pirolidinil, piperidinil ili azetidinil; po izboru pri čemu je JG metil.
10. Spoj u skladu s patentnim zahtjevom 8, naznačeno time, što dva pojavljivanja JG, zajedno s prstenom D, tvore 6-10-eročlani zasićeni ili djelomično nezasićeni premošteni prstenski sustav; proizvoljno pri čemu je premošteni prstenski sustav 1,4-diazabiciklo[3.2.2]nonan, 1,4-diazabiciklo[3.2.1] oktan ili 2,5-diazabiciklo [2.2.1] heptan.
11. Spojevi u skladu s bilo kojim patentnim zahtjevom 7 i 8 (I), naznačeno time, što dva pojavljivanja JG na istom atomu, zajedno s atomom kojem su pridruženi, tvore 3-6-eročlani prsten koji ima 0-2 heteroatoma odabrana između kisika, dušika ili sumpora; po izboru pri čemu se prsten koji nastaje dvjema pojavama JG na istom atomu bira između oksetanila ili ciklopropila.
12. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 11, naznačeno time, što je neovisno odabran između:
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ili odabran od:
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ili njegova farmaceutski prihvatljiva sol.
13. Farmaceutski pripravak, naznačeno time, što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 12 i farmaceutski prihvatljiv nosač.
14. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačeno time, što se koristi u liječenju karcinoma kod pacijenta.
15. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, koji se koristi u skladu s patentnim zahtjevom 14, naznačeno time, što uporaba nadalje obuhvaća davanje navedenom pacijentu dodatnog terapijskog sredstva neovisno odabranog između sredstva koje oštećuje DNA; pri čemu je navedeno dodatno terapijsko sredstvo prikladno za bolest koja se liječi; i navedeno dodatno terapijsko sredstvo daje se zajedno sa rečenim spojem u obliku jednog doziranja ili odvojeno od rečenog spoja kao dio višestrukog oblika doziranja; po izboru:
pri čemu je (I) spomenuto sredstvo koje oštećuje DNA odabrano liječenjem kemoterapijom ili zračenjem; po izboru gdje je sredstvo za oštećenje DNA sredstvo za alkiliranje odabrano od Temozolomida; ili:
u kojem je (II) navedeno sredstvo za oštećivanje DNA neovisno odabrano između ionizirajućeg zračenja, radiomimetičkog neokarzinostatina, platinirajućeg sredstva, inhibitora Topo I, inhibitora Topo II, antimetabolita, alkilirajućeg sredstva, alkil sulfonata ili antibiotika; po izboru pri čemu je (i) navedeno sredstvo za oštećivanje DNA neovisno odabrano između ionizirajućeg zračenja, sredstva za platinizaciju, inhibitora Topo I, inhibitora Topo II ili antibiotika; ili:
pri čemu je (ii) navedeno sredstvo za oštećivanje DNA neovisno odabrano između ionizirajućeg zračenja, sredstva za platiniranje, inhibitora Topo I, inhibitora Topo II, antimetabolita, sredstva za alkiliranje ili alkil sulfonati; po izboru:
pri čemu (a) je navedeno sredstvo za platiniranje neovisno odabrano između Cisplatina, Oksaliplatina, Karboplatina, Nedaplatina, Lobaplatina, Triplatin tetranitrata, pikoplatina, satraplatina, ProLindaca i Aroplatina; navedeni inhibitor Topo I odabran je između Camptothecina, Topotecana, Irinotecan / SN38, Rubitecana i Belotecana; navedeni inhibitor Topo II odabran je između Etopozida, Daunorubicina, Doksorubicina, Aclarubicina, Epirubicina, Idarubicina, Amrubicina, Pirarubicina, Valrubicina, Zorubicina i Tenipozida; navedeni antimetabolit je odabran između Aminopterina, Metotreksata, Pemetrekseda, Raltitrekseda, Pentostatina, Kladribina, Klofarabina, Fludarabina, Tioguanina, Merkaptopurina, Fluorouracila, Kapecitabina, Tegafura, Carmofura, Floxuridinacita, Citridekitara, Gemidrata, Klorafurina navedeno alkilirajuće sredstvo odabrano je iz mehloretamina, ciklofosfamida, ifosfamida, trofosfamida, klorambucila, melfalana, prednimustina, bendamustina, uramustina, estramustina, karmustina, Lomustina, Semustina, Fotemustina, Nimustina, Treptomansulfana, Ranimustfanola, Ranimustfan Triazikiona, Trietilenmelamina, Procarbazina, Dacarbazina, Temozolomida, Altretamina, Mitobronitola, Actinomycina, Bleomycina, Mitomycina i Plicamycina; po izboru:
pri čemu (aa) navedeno sredstvo za platiniranje je neovisno odabrano između Cisplatina, Oksaliplatina, Karboplatina, Nedaplatina ili Satraplatina; navedeni inhibitor Topo I odabran je između kamptotecina, topotekana, irinotekana / SN38, rubitekana; spomenuti inhibitor Topo II odabran je između Etopozida; navedeni antimetabolit je odabran između metotreksata, pemetrekseda, tioguanina, fludarabina, kladribina, citarabina, gemcitabina, 6-merkaptopurina ili 5-fluorouracila; spomenuto sredstvo za alkiliranje odabire se između dušične gorušice, nitroso-uree, triazena, alkil sulfonata, prokarbazina ili aziridina; a spomenuti antibiotik odabran je iz obitelji Hydroxyurea, Anthracyclines, Anthracenediones ili Streptomyces; ili:
pri čemu se (bb) navedeno sredstvo za oštećenje DNA neovisno bira između sredstva za platiniranje ili
ionizirajućeg zračenja; proizvoljno gdje je dodatno terapijsko sredstvo Gemcitabin a tumor je karcinom gušterače; ili:
pri čemu je (cc) kemoradijacija gemcitabin i zračenje; ili:
pri čemu (b) je antimetabolit Gemcitabin; ili:
pri čemu (c) sredstvo koje oštećuje DNA je ionizirajuće zračenje; ili:
pri čemu (d) sredstvo za oštećenje DNA je sredstvo za platiniranje neovisno odabrano između Cisplatina ili Carboplatina;ili:
pri čemu (e) sredstvo koje oštećuje DNA je inhibitor Topo II odabran između Etopozida; ili:
pri čemu (f) sredstvo za oštećivanje DNA neovisno se bira između jednog ili više od sljedećeg:
Cisplatin, Carboplatin, Gemcitabin, etopozida, temozolomida ili ionizirajuće zračenje; po izboru
pri čemu su dodatna terapijska sredstva odabrana između jednog ili više od sljedećeg: Gemcitabin, Cisplatin ili Carboplatin i etopozid.
16. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim patentnim zahtjevom od 1 do 12, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, koji se koristi u skladu s patentnim zahtjevom 14 ili patentnim zahtjevom 15, naznačeno time, što je navedeni karcinom čvrsti tumor odabran od sljedećih karcinoma: oralno: usna šupljina, usne, jezik, usta, ždrijelo; srčani: sarkom (angiosarkom, fibrosarkom, rabdomiosarkom, liposarkom), miksom, rabdomiom, fibrom, lipom i teratom; pluća: bronhogeni karcinom (skvamozni ili epidermoidni, nediferencirane male stanice, nediferencirane velike stanice, adenokarcinom), alveolarni (bronhiolarni) karcinom, bronhijalni adenom, sarkom, limfom, hondromatozni hamartom, mezoteliom; gastrointestinalni: jednjak (skvamozni karcinom, grkljan, adenokarcinom, leiomiosarkom, limfom), želudac (karcinom, limfom, leiomiosarkom), gušterača (duktalni adenokarcinom, inzulin, glukagonom, gastrinom, karcinoidni tumori, tanki čvor, vipoma karcinom, limfom, karcinoidni tumori, Karposijev sarkom, leiomiom, hemangiom, lipom, neurofibroma, fibrom), crijevo ili debelo crijevo (adenokarcinom, tubularni adenom, vilozni adenom, hamartom, leiomiom), debelo crijevo, debelo crijevo-rektum, kolorektalni, rectum; genitourinarni trakt: bubreg (adenokarcinom, Wilmov tumor [nefroblastom], limfom), mokraćni mjehur i uretra (karcinom skvamoznih stanica, karcinom prijelaznih stanica, adenokarcinom), prostata (adenokarcinom, sarkom), testisi (seminom, teratom, embrionalni karcinom, teratokarcinom , horiokarcinom, sarkom, karcinom intersticijskih stanica, fibroma, fibroadenom, adenomatoidni tumori, lipomi); jetra: hepatom (hepatocelularni karcinom), kolangiokarcinom, hepatoblastom, angiosarkom, hepatocelularni adenom, hemangiom, bilijarni prolazi; Kosti: osteogeni sarkom (osteosarkom), fibrosarkom, maligni fibrozni histiocitom, hondrosarkom, Ewingov sarkom, maligni limfom (sarkom retikulumskih stanica), multipli mijelom, kordom malignog tumora divovskih stanica, osteokronfroma (osteokartilagični kostomandomagijski kostondomagijski kostomandomagijski kosto-bronhomagijski kosto-bronhomagijski kosto-bronhomagijski kosto-bronhomagijski kosto-magni kostoni bronhomani kosti tumori osteoma i divovskih stanica; živčani sustav: lubanja (osteom, hemangiom, granulom, ksantom, osteitis deformans), moždane ovojnice (meningioma, meningiosarkom, gliomatoza), mozak (astrocitom, meduloblastom, gliom, ependimom, germinom [pinealoma], glioblaligoma genomblastomoma multiformni glioblastomahnom, glioblastomahni multiform kongenitalni tumori), neurofibrom leđne moždine, meningiom, gliom, sarkom); ginekološki / ženski: maternica (karcinom endometrija), cerviks (karcinom vrata maternice, predtumorska cervikalna displazija), jajnici (karcinom jajnika [serozni cistadenokarcinom, mucinozni cistadenokarcinom, neklasificirani karcinom], tumori granulosatekalnih stanica, tumori Sertoli-Leydigoma, maligni tumori ćelija teratom), vulve (karcinom skvamoznih stanica, intraepitelna karcinom, adenokarcinom, fibrosarkom, melanom), vaginu (karcinom jasno stanica, karcinom skvamoznih stanica, botrioid sarkoma (embrionalni rabdomiosarkoma), jajovodi (karcinom), dojke, kože: maligni melanom, bazalni stanični karcinom, skvamozni karcinom, Karposijev sarkom, keratoakantom, molsni displastični nevusi, lipomi, angiomi, dermatofibromi, keloidi, psorijaza, štitnjača: papilarni karcinom štitnjače, folikularni karcinom štitnjače; tip 2B, obiteljski medularni karcinom štitnjače, feokromocitom, paragangliom i nadbubrežna glava nds: neuroblastoma: po izboru: pri čemu je spomenuti tumor odabran od karcinoma pluća ili gušterače; po izboru:
pri čemu je spomenuti tumor karcinom pluća; proizvoljno:
pri čemu je karcinom pluća ne-malih stanica ili karcinom pluća malih stanica; proizvoljno:
pri čemu je (I) karcinom pluća malih stanica, a dodatna terapijska sredstva su cisplatin i etopozid; ili
pri čemu (II) je karcinom pluća ne-malih stanica, a dodatna terapijska sredstva su gemcitabin i cisplatin; proizvoljno:
pri čemu (i) je rak pluća ne-malih stanica stanični karcinom pluća nemalih stanica; ili:
pri čemu (ii) je terapija karcinomom gemcitabin i zračenje.
17. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, ili farmaceutski pripravak u skladu s patentnim zahtjevom zahtjevu 13, namijenjen upotrebi u skladu s patentnim zahtjevom 14 ili patentnim zahtjevom 15, naznačeno time, što je (I) navedeni karcinom odabran od karcinoma pluća, carcinoma glave i vrata, karcinoma gušterače, karcinoma želuca ili mozga; ili:
pri čemu je (II) spomenuti karcinom odabran od karcinoma pluća ne-malih stanica, karcinoma pluća malih stanica, karcinoma gušterače, carcinoma žučnog trakta, karcinoma glave i vrata, karcinoma mokraćnog mjehura, karcinoma debelog crijeva, glioblastom, karcinoma jednjaka, karcinoma dojke, hepatocelularnog karcinoma ili karcinoma jajnika; po izboru pri čemu je tumor karcinoma dojke i dodatno terapijsko sredstvo je cisplatin; po izboru pri čemu je tumor trostruko negativni karcinom dojke.
18. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačeno time, što u kombinaciji s dodatnim terapijskim sredstvom odabranim od Gemcitabina, terapije zračenjem ili zajedno s Gemcitabinom i terapijom zračenjem, služi za uporabu u liječenju raka gušterače.
19. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačeno time, što se koristi u liječenju koje povećava osjetljivost stanica raka gušterače na terapiju karcinoma odabranu između kemoterapije ili zračenja; po želji:
pri čemu je (I) kemoterapija gemcitabin; ili:
pri čemu je (II) terapija karcinoma gemcitabin; ili:
pri čemu je (III) terapija karcinoma zračenje.
20. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačeno time, što u kombinaciji s Gemcitabinom (100 nM) i / ili zračenjem (6 Gy) se koristi u liječenju koje inhibira fosforilaciju Chk1 (Ser 345) u stanici raka gušterače.
21. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačeno time, što se koristi u liječenju koje senzibilizira stanice raka gušterače na kemoterapiju u kombinaciji s kemoterapijom.
22. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačeno time, što se koristi u liječenju koji sadrži (I) radiosenzibilizirajuće hipoksične stanice raka gušterače u kombinaciji s terapijom zračenjem; ili: sadrži (II) senzibilizirajuće hipoksične stanice raka gušterače u kombinaciji s kemoterapijom.
23. Spoj, ili njegova farmaceutski prihvatljiva sol, za uporabu u skladu s patentnim zahtjevima 21 ili 22, naznačeno time, što je spomenuta stanica karcinoma PSN-1, MiaPaCa-2 ili PancM stanica karcinoma.
24. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 1 do 12, naznačeno time, što se koristi u liječenju koje obuhvaća narušavanje kontrolnih točaka staničnog ciklusa uzrokovanih oštećenjem u kombinaciji s terapijom zračenjem i / ili Gemcitabinom.
25. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s patentnim zahtjevima 1 do 12, naznačeno time, što se koristi u liječenju koje obuhvaća inhibiranje popravka oštećenja DNA rekombinacijom hemoglobina u stanici karcinoma gušterače u kombinaciji s terapijom zračenjem i / ili Gemcitabinom.
26. Spoj ili njegova farmaceutski prihvatljiva sol, za uporabu u skladu s patentnim zahtjevima 22 do 25, naznačeno time, što se spoj primjenjuje na stanicu raka gušterače; proizvoljno pri čemu su stanice raka gušterače izvedene iz stanične linije gušterače odabrane između PSN-1, MiaPaCa-2 ili Panc-1.
27. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačeno time, što se koristi u liječenju koje obuhvaća
(I) liječenje karcinoma pluća ne-malih stanica u kombinaciji s jednim ili više sljedećih dodatnih terapijskih sredstava: Cisplatin ili Carboplatin , Etopozid i ionizirajuće zračenje; ili:
(II) promicanje stanične smrti u stanicama raka; ili:
(III) sprječavanje reparacije stanica od oštećenja DNA; ili:
(IV) inhibiranje ATR u biološkom uzorku koji obuhvaća korak dovođenja u kontakt spoja prema bilo kojem od zahtjeva 1do 12 s navedenim biološkim uzorkom; proizvoljno pri čemu je navedeni biološki uzorak stanica; ili:
(V) senzibilizaciju stanica na sredstva koji oštećuju DNA.
28. Spoj prema bilo kojem od zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, ili farmaceutski pripravak u skladu s patentnim zahtjevom zahtjevu 13, za uporabu skladu s patentnim zahtjevima 15 do 27, naznačeno time, što je (I) navedena stanica stanica raka koja ima nedostatke u ATM signalnoj kaskadi; po izboru:
pri čemu (i) je navedeni nedostatak promijenjeni izraz ili aktivnost ili jedan ili više ili slijedeće: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP ili SMC1; ili:
pri čemu je (ii) spomenuti nedostatak promijenjena ekspresija ili aktivnost jednog ili više od sljedećeg: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 ili H2AX.
pri čemu (II) rečeni karcinom, stanica raka, ili stanica ima nedostatak na proteinu za popravak bazne ekscizije; proizvoljno pri čemu proteini za popravak bazne ekscizije su: UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glikozilaze); APE1, APEX2 (AP endonukleaze); LIG1, LIG3 (DNA ligaze I i III); XRCC1 (dodatak LIG3); PNK, PNKP (polinukleotid kinaza i fosfataza); PARP1, PARP2 (poli (ADP-ribozne) polimeraze); PolB, PolG (polimeraze); FEN1 (endonukleaza) ili Aprataxin; po izboru, pri čemu je protein za popravak bazne ekscizije PARP1, PARP2 ili PolB; po izboru pri čemu je protein za popravak bazne ekscizije PARP1 ili PARP2.
29. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, koji se koristi u skladu s patentnim zahtjevima 14 do 27, naznačeno time, što je navedena stanica, tumorska stanica koja eksprimira onkogene koji oštećuju DNA; proizvoljno pri čemu je spomenuta tumorska stanica promijenila ekspresiju ili aktivnost jednog ili više od sljedećeg: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Ciklin E, Ciklin A i Rb.
30. Spoj prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, ili farmaceutski pripravak u skladu s patentnim zahtjevom 13, koji se koristi u skladu s patentnim zahtjevima 15 do 27, naznačeno time, što se nadalje sastoji od primjene na pacijenta dodatnog terapijskog sredstva u kojem navedeno sredstvo inhibira ili modulira protein za popravak bazne ekscizije; proizvoljno
u kojem je protein za popravak bazne ekscizije odabran od UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylases); APE1, APEX2 (AP endonukleaze); LIG1, LIG3 (DNA ligaze I and III); XRCC1 (dodatak LIG3); PNK, PNKP (polinukleotid kinaza i fosfataza); PARP1, PARP2 (Poli(ADP-Riboza) Polimeraza); PolB, PolG (polimeraze); FEN1 (endonukleaza) ili Aprataksin; po izobru
pri čemu je protein za popravak bazne ekscizije odabran između PARP1, PARP2 ili PolB; po izboru, pri čemu je protein za popravak bazne ekscizije odabran između PARP1 ili PARP2; po izboru, pri čemu je navedeno sredstvo odabrano od Olapariba (također poznatog kao AZD2281 ili KU-0059436), Inipariba (također poznatog kao BSI-201 ili SAR240550), Velipariba (također poznatog kao ABT-888), Rucapariba (također poznatog kao PF-01367338 ), CEP-9722, INO-1001, MK-4827, E7016, BMN673 ili AZD2461.
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WO2015187451A1 (en) | 2014-06-05 | 2015-12-10 | Vertex Pharmacetucals Incorporated | Radiolabelled derivatives of a 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]- pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof |
LT3157566T (lt) | 2014-06-17 | 2019-08-12 | Vertex Pharmaceuticals Incorporated | Vėžio gydymo būdas, panaudojant chk1 ir atr inhibitorių derinį |
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