HRP20150489T1 - Imidazo[4,5-c]kinolini kao inhibitori dna-pk - Google Patents

Imidazo[4,5-c]kinolini kao inhibitori dna-pk Download PDF

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HRP20150489T1
HRP20150489T1 HRP20150489TT HRP20150489T HRP20150489T1 HR P20150489 T1 HRP20150489 T1 HR P20150489T1 HR P20150489T T HRP20150489T T HR P20150489TT HR P20150489 T HRP20150489 T HR P20150489T HR P20150489 T1 HRP20150489 T1 HR P20150489T1
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Thomas Fuchss
Werner Mederski
Frank Zenke
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Merck Patent Gmbh
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/42—Nitrogen atoms attached in position 4
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
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    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
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    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/11—Protein-serine/threonine kinases (2.7.11)
    • C12Y207/11001—Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase

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Claims (15)

1. Spojevi s formulom (I) [image] naznačeni time da R1 označava Y ili -(CY2)n-Ar, R2 označava Y, -(CY2)p-(C[YR6])s-R7 ili -Alk-R7, R3 označava Y ili CN, R4 označava Y, Hal, -(CY2)p-COOY ili -(CY2)p-CO-NYY, R5 označava A, Hal, -(CY2)p-OY, -(CY2)p-NYY, -(CY2)p-COOY, -(CY2)p-CO-NYY ili -(CY2)p-NY-COY, R6 označava Y, Hal, -(CY2)n-NYY, -(CY2)n-NY-COO-(CY2)n-SiA3, -(CY2)n-COOY, -CO-NYY, -CO-NY-(CY2)n-OY, -CO-NY-(CY2)n-NYY ili SO2A, R7 označava -(CY2)p-Ar ili -(CY2)p-Het1, X označava CH2, O, S ili jednostruku vezu, Y označava H ili A, A označava nerazgranati ili razgranati alkil koji ima 1, 2, 3, 4, 5, 6, 7, 8, 9 ili 10 C atoma, gdje 1, 2, 3, 4, 5, 6 ili 7 H atoma može biti zamijenjeno, međusobno neovisno, s Hal, Alk označava alkilen koji ima 1, 2, 3, 4, 5 ili 6 C atoma, Ar označava fenil koji je nesupstituiran ili jednostruko-, dvostruko- ili trostruko- supstituiran s Hal, A, CN, -(CY2)p-OY, -(CY2)p-NYY, -(CY2)p-COOY, -(CY2)p-CO-NYY ili -(CY2)p-NY-COY, Het1 označava mono- ili biciklički aromatski heterocikal koji ima 2, 3, 4, 5, 6, 7, 8 ili 9 C atoma i 1, 2, 3 ili 4 N, O i/ili S atoma, koji mogu biti nesupstituirani ili jednostruko-, dvostruko- ili trostruko- supstituirani s Hal, A, CN, -(CY2)p-OY, -(CY2)p-NYY, -(CY2)p-COOY, -(CY2)p-CO-NYY, -(CY2)p-NY-COY ili -SO2-Het2, Het2 označava monociklički zasićeni heterocikal koji ima 2, 3, 4, 5, 6 ili 7 C atoma i 1, 2, 3 ili 4 N, O i/ili S atoma, koji mogu biti nesupstituirani ili jednostruko supstituirani sa A, Hal označava F, Cl, Br ili I, m označava 0, 1, 2, 3 ili 4, i n, p, s, međusobno neovisno, označavaju 0, 1, 2, 3, 4, 5 ili 6, i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
2. Spojevi prema zahtjevu 1 koji imaju pod-formulu (IA) [image] naznačeni time da R2 označava Y ili -(CY2)p-C(YR6)-R7, R5 označava Y ili Hal, R6 označava Y, -(CY2)n-NYY, -CO-NYY ili -CO-NY-(CY2)n-OY, R7 označava Ar ili Het1, Y označava H ili A, A označava nerazgranati ili razgranati alkil koji ima 1, 2, 3 ili 4 C atoma, gdje 1, 2 ili 3 H atoma može biti zamijenjeno, međusobno neovisno, s Hal, Ar označava fenil koji je nesupstituiran ili jednostruko- ili dvostruko- supstituiran s Hal, Het1 označava mono- ili biciklički aromatski heterocikal koji ima 2, 3, 4, 5, 6, 7, 8 ili 9 C atoma i 1, 2 ili 3 N i/ili S atoma, koji mogu biti nesupstituirani ili jednostruko- ili dvostruko- supstituirani s Hal, A, OY ili -SO2-Het2, Het2 označava monociklički zasićeni heterocikal koji ima 3, 4 ili 5 C atoma i 1 ili 2 N i/ili O atoma, Hal označava F, Cl, Br ili I, te n, p, međusobno neovisno, označavaju 0, 1, 2 ili 3, i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
3. Spojevi prema zahtjevu 1 koji imaju pod-formulu (IB) [image] naznačeni time da R2 označava R7, -Alk-Ar ili -Alk-Het1, R5 označava Y ili Hal, R7 označava -(CY2)p-Ar ili -(CY2)p-Het1, Y označava H ili A, A označava nerazgranati ili razgranati alkil koji ima 1, 2, 3 ili 4 C atoma, gdje 1, 2 ili 3 H atoma može biti zamijenjeno, međusobno neovisno, s Hal, Alk označava alkilen koji ima 1, 2 ili 3 C atoma, Ar označava fenil koji je nesupstituiran ili jednostruko- ili dvostruko- supstituiran s Hal, Het1 označava mono- ili biciklički aromatski heterocikal koji ima 2, 3, 4, 5, 6, 7, 8 ili 9 C atoma i 1, 2 ili 3 N i/ili S atoma, koji mogu biti nesupstituirani ili jednostruko- ili dvostruko- supstituirani s Hal, A, OY ili -SO2-Het2, Het2 označava monociklički zasićeni heterocikal koji ima 3, 4 ili 5 C atoma i 1 ili 2 N i/ili O atoma, Hal označava F, Cl, Br ili I, te p označava 0, 1, 2 ili 3, i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
4. Spojevi prema zahtjevu 3 koji imaju pod-formulu (IB-1) [image] naznačeni time da R2 označava R7, -Alk-Ar ili -Alk-Het1, R5 označava Hal, R7 označava Ar ili Het1, A označava nerazgranati ili razgranati alkil koji ima 1, 2, 3 ili 4 C atoma, gdje 1, 2 ili 3 H atoma može biti zamijenjeno, međusobno neovisno, s Hal, Alk označava alkilen koji ima 1 ili 2 C atoma, Ar označava fenil koji je nesupstituiran ili jednostruko supstituiran s Hal, Het1 označava mono- ili biciklički aromatski heterocikal koji ima 2, 3, 4, 5, 6, 7, 8 ili 9 C atoma i 1, 2 ili 3 N i/ili S atoma, koji mogu biti nesupstituirani ili jednostruko- ili dvostruko- supstituirani s Hal ili A, i Hal označava F, Cl, Br ili I, i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
5. Spojevi prema jednom zahtjevu od 1 do 4, naznačeni time da su odabrani iz skupine: [image] [image] [image] [image] [image] [image] [image] [image] [image] i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
6. Intermedijarni spojevi formule (II) [image] naznačeni time da R3 označava CN, R8 označava NO2 ili NYY, te R1, R2, R5, Y i m imaju značenje navedeno u zahtjevu 1, i/ili njihove soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
7. Intermedijarni spojevi prema zahtjevu 6 naznačeni time da R1 označava A, R2 označava A ili -(CH2)p-(CH2)s-Ar, R3 označava CN, R5 označava Hal, R8 označava NH2, A označava nerazgranati ili razgranati alkil koji ima 1, 2, 3 ili 4 C atoma, gdje 1, 2 ili 3 H atoma može biti zamijenjeno, međusobno neovisno, s Hal, Ar označava fenil koji je nesupstituiran ili jednostruko- ili dvostruko- supstituiran s Hal, Hal označava F, Cl, Br ili I, i m, p, s, međusobno neovisno, označavaju 0, 1 ili 2, i/ili njihove soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima.
8. Postupak za dobivanje spojeva s formulom (I) prema zahtjevu 1, njihovih pod-formula i/ili njihovih fiziološki prihvatljivih soli, tautomera i/ili stereoizomera, uključujući njihove smjese u svim omjerima, naznačen time da sadrži slijedeće korake: (a) reakciju spoja formule (II) [image] u kojoj R1, R2, R3, R5, R8 i m imaju značenje navedeno u zahtjevu 7, sa halidom karboksilne kiseline i s organskom bazom u otapalu, da se dobiju spojevi pod-formule (IC) [image] u kojoj R1, R2, R3, R5 i m imaju značenje navedeno u zahtjevu 7, te proizvoljno (b') reakciju spojeva pod-formule (IC) sa spojem Hal-R4, u kojem R4 i Hal imaju značenje navedeno u zahtjevu 1, da se dobiju spojevi pod-formule (ID) [image] [image] u kojoj R1, R2, R3, R5 i m imaju značenje navedeno u zahtjevu 7, i R4 ima značenje navedeno u zahtjevu 1, (b") pretvaranje R1, -O-R2, R3, R4 i/ili R5 spojeva pod-formule (ID) i/ili dodavanje barem jednog R5 koji ima značenje navedeno u zahtjevu 1 na fenilni prsten spojeva pod-formule (ID) da se dobiju spojevi formule (I) [image] u kojoj R1, R2, R3, R4, R5, X i m imaju značenje navedeno u zahtjevu 1, i/ili (b"') pretvaranje baze ili kiseline spojeva formule (I) ili pod-formule (IC) ili (ID) u jednu od njihovih fiziološki prihvatljivih soli.
9. Postupak za dobivanje intermedijarnih spojeva formule (II) prema zahtjevu 6 i/ili njihovih soli, tautomera i/ili stereoizomera, uključujući njihove smjese u svim omjerima, naznačen time da sadrži slijedeće korake: (a) reakciju spoja formule (III) [image] u kojoj Hal označava F, Cl, Br ili I, i R1, R2 i R8 imaju značenje navedeno u zahtjevu 6, sa spojem formule (IV) [image] u kojoj R3, R5 i m imaju značenje navedeno u zahtjevu 6, da se dobiju spojevi formule (II) [image] u kojoj R1, R2, R3, R5, R8 i m imaju značenje navedeno u zahtjevu 6, te proizvoljno (b) pretvaranje baze ili kiseline spojeva formule (II) u jednu od njihovih soli.
10. Uporaba spojeva prema jednom od zahtjeva 1 do 5 i/ili njihovih fiziološki prihvatljivih soli, tautomera i/ili stereoizomera, uključujući njihove smjese u svim omjerima, naznačena time da je za in vitro inhibiciju serin/treonin protein kinaza, poželjno PIKK i/ili ATM, naročito poželjno DNA-PK.
11. Uporaba najmanje jednog spoja prema jednom od zahtjeva 1 do 5 i/ili njihovih fiziološki prihvatljivih soli, tautomera i/ili stereoizomera, uključujući njihove smjese u svim omjerima, naznačena time da je za senzibilizaciju stanica raka na sredstvo protiv raka i/ili ionizirajuće zračenje, uz uvjet da se senzibilizacija ne provodi na ljudskom ili životinjskom tijelu.
12. Medikament naznačen time da sadrži najmanje jedan spoj prema jednom od zahtjeva 1 do 5 i/ili njihove fiziološki prihvatljive soli, tautomere i/ili stereoizomere, uključujući njihove smjese u svim omjerima.
13. Farmaceutski pripravak naznačen time da sadrži, kao aktivni spoj, učinkovitu količinu najmanje jednog spoja prema jednom od zahtjeva 1 do 5 i/ili njegove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima, zajedno s farmaceutski podnošljivom pomoćnom tvari, u kombinaciji s najmanje jednim sredstvom protiv raka.
14. Spojevi prema jednom od zahtjeva 1 do 5 i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima, naznačeni time da su za uporabu za sprečavanje, terapiju i/ili kontrolu napredovanja raka, tumora, metastaza i/ili poremećaja angiogeneze, u kombinaciji s radioterapijom i/ili s najmanje jednim sredstvom protiv raka.
15. Spojevi prema jednom od zahtjeva 1 do 5 i/ili njihove fiziološki prihvatljive soli, tautomeri i/ili stereoizomeri, uključujući njihove smjese u svim omjerima, naznačeni time da su za uporabu za senzibilizaciju stanica raka na sredstvo protiv raka i/ili na ionizirajuće zračenje.
HRP20150489TT 2010-08-28 2015-05-07 Imidazo[4,5-c]kinolini kao inhibitori dna-pk HRP20150489T1 (hr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102010035744A DE102010035744A1 (de) 2010-08-28 2010-08-28 Imidazolonylchinoline
EP11748260.4A EP2609082B1 (de) 2010-08-28 2011-07-26 Imidazo[4,5-c]chinoline als dna-pk-inhibitoren
PCT/EP2011/003744 WO2012028233A1 (de) 2010-08-28 2011-07-26 Imidazo [4,5-c]chinoline als dna-pk-inhibitoren

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HRP20150489T1 true HRP20150489T1 (hr) 2015-06-05

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HUE025692T2 (en) 2016-04-28
PT2609082E (pt) 2015-06-05
EP2609082A1 (de) 2013-07-03
BR112013004613A2 (pt) 2017-04-04
IL224903A (en) 2016-02-29
US20150203491A1 (en) 2015-07-23
AU2011298013A1 (en) 2013-04-11
US20170166567A1 (en) 2017-06-15
JP5882329B2 (ja) 2016-03-09
ES2536313T3 (es) 2015-05-22
PL2609082T3 (pl) 2015-07-31
EP2609082B1 (de) 2015-02-18
WO2012028233A1 (de) 2012-03-08
US9000153B2 (en) 2015-04-07
US20130172337A1 (en) 2013-07-04
CY1116281T1 (el) 2017-02-08
KR20130106367A (ko) 2013-09-27
DE102010035744A1 (de) 2012-03-01
AU2011298013B2 (en) 2015-01-29
SG187954A1 (en) 2013-04-30
MX338150B (es) 2016-04-05
CA2809553C (en) 2019-02-26
EA022095B1 (ru) 2015-10-30
KR101912475B1 (ko) 2018-10-26
CN103068803A (zh) 2013-04-24
SI2609082T1 (sl) 2015-06-30
BR112013004613B1 (pt) 2021-08-03
MX2013002259A (es) 2013-05-09
CN103068803B (zh) 2016-01-20
US9598408B2 (en) 2017-03-21
CA2809553A1 (en) 2012-03-08
RS54038B1 (en) 2015-10-30
HK1184154A1 (zh) 2014-01-17
DK2609082T3 (en) 2015-05-11
AR082728A1 (es) 2012-12-26
EA201300288A1 (ru) 2013-08-30
AU2011298013B9 (en) 2015-08-20
JP2013536256A (ja) 2013-09-19

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