DK2125822T3 - Substituerede pyrazoloquinazolinderivater, fremgangsmåde til fremstilling deraf og anvendelse deraf som kinasehæmmere - Google Patents

Substituerede pyrazoloquinazolinderivater, fremgangsmåde til fremstilling deraf og anvendelse deraf som kinasehæmmere Download PDF

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DK2125822T3
DK2125822T3 DK07857726.9T DK07857726T DK2125822T3 DK 2125822 T3 DK2125822 T3 DK 2125822T3 DK 07857726 T DK07857726 T DK 07857726T DK 2125822 T3 DK2125822 T3 DK 2125822T3
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methyl
compound
dihydro
pyrazolo
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Michele Caruso
Italo Beria
Maria Gabriella Brasca
Ron Ferguson
Barbara Valsasina
Helena Posteri
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Nerviano Medical Sciences Srl
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Claims (15)

1. Forbindelse med formlen (I):
(!) hvor R1 er en orffro-substitueret arylaminogruppe med formlen:
ELLER
hvor R'4 og R"4 er uafhængigt valgt fra en gruppe bestående af halogen, nitro, cyano, (CrC6)-alkyl, polyfluoreret alkyl, polyfluoreret alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, (C3-C6)-cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylendioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkylidenaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonat og alkylphosphonat; R2 er hydrogen eller en eventuelt substitueret gruppe valgt blandt ligekædet eller forgrenet (Ci-C6)-alkyl, ligekædet eller forgrenet (C2-C6)-alkenyl, ligekædet eller forgrenet (C2-C6)-alkynyl, (C3-C6)-cycloalkyl og heterocyclyl; R3 er CO-OR' eller CO-NR'R", hvor R' og R" hver uafhængigt er hydrogen eller en eventuelt substitueret gruppe valgt blandt ligekædet eller forgrenet (CrC6)-alkyl, (C3-C6)-cycloalkyl og heterocyclyl, eller R' og R" taget sammen med det nitrogenatom, hvortil de er bundet, kan udgøre en eventuelt substitueret heterocyclylgruppe, som eventuelt indeholder ét yderligere heteroatom valgt blandt N, O og S; og isomerer, tautomerer, hydrater, solvater, N-oxider og farmaceutisk acceptable salte deraf.
2. Forbindelse med formlen (I) ifølge krav 1, hvor: R3 er CO-OH eller CO-NR'R", hvor R' og R" er som defineret i krav 1.
3. Forbindelse med formlen (I) ifølge krav 1 eller 2, hvor: R2 er en eventuelt substitueret ligekædet eller forgrenet (CrC6)-alkyl-eller (C2-C6)-alkenylgruppe.
4. Forbindelse med formlen (I) ifølge krav 1 til 3, hvor: R3 er CO-NR'R", hvor R' og R" er som defineret i krav 1.
5. Forbindelse eller farmaceutisk acceptabelt salt deraf, som er valgt fra gruppen bestående af: 8-[2-acetyl-5-(4-methyl-piperazin-1-yl)-phenylamino]-1-methyl-4,5-dihydro-1 FI-pyrazolo[4,3-h]quinazolin-3-carboxannid (A39B1C1Z); 8-[2-acetyl-5-(4-methyl-piperazin-1-yl)-phenylamino]-1-(2-fluor-ethyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A39B2C1Z); 1-methyl-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B1C1Z); ethyl-1-methyl-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxylat (A51B1C2Z); 1 -methyl-8-[2-methoxy-5-(4-methyl-piperazin-1 -yl)-phenylamino]-1 - methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A85B1C1Z); 8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylamino]-1-(2-fluor- ethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B2C1Z); 1-methyl-8-[4-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A48B1C1Z); 1-methyl-8-(2-trifluormethoxy-5-piperazin-1-yl-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A97B1C1Z); 1-methyl-8-[2-methyl-5-(4-methyl-piperazin-1-yl)-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A98B1C1Z); 1 -methyl-8-[5-(4-pyrrolidin-1 -yl-piperidin-1 -yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A99B1C1Z); 1-methyl-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]- 4.5- dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxylsyre-methylamid (A51B1C4Z); 1-methyl-8-[5-(4-methyl-piperazin-1-yl)-2-methoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxylsyre-methylannid (A85B1C4Z); 1-methyl-8-[2-methyl-5-(4-methyl-piperazin-1-carbonyl)-phenylamino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A87B1C1Z); 1-methyl-8-[2-methyl-4-(4-methyl-piperazin-1-carbonyl)-phenylamino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A86B1C1Z); 1-methyl-8-{2-trifluormethoxy-5-[(1-methyl-piperidin-4-carbonyl)-amino]- phenylamino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A82B1C1Z); kalium-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]-1- methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxylat (A51B1C3Z); 1-ethyl-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B7C1Z); 1-methyl-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxylsyre(2,2,2-trifluor-ethyl)-amid (A51B1C7Z); 1-((2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy- phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxannid (A51B5C1Z); 8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylamino]-1-vinyl-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B10C1Z); 1-((2-chlor-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B9C1Z); 8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylannino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A51B8C1Z); kalium-1 -(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1 -yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxylat (A51B5C3Z); ethyl-1-(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxylat (A51B5C2Z); 1 -methyl-8-[5-(1 -methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluormethoxy-phenylamino]-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A113B1C1Z); 1-methyl-8-[5-(1-methyl-piperidin-4-yl)-2-trifluormethoxy-phenylannino]- 4.5- dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A114B1C1Z); 8-((5-brom-2-trifluormethoxy-phenylamino)-1 -methyl-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A49B1C1Z) og 8-((5-brom-2-trifluormethoxy-phenylamino)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinazolin-3-carboxamid (A49B8C1Z).
6. Fremgangsmåde til fremstilling af en forbindelse med formlen (I) ifølge krav 1, hvilken fremgangsmåde omfatter: trin 1) omsætning af forbindelsen med formlen (II):
(I!) med et hydrazinderivat med formlen (III):
(III) hvor R2 er som defineret i krav 1, i nærværelse af eddikesyre til opnåelse afen forbindelse med formlen (IV):
(IV) hvor R2 er som defineret ovenfor; eventuelt alkylering afen forbindelse med formlen (IV), hvor R2 er hydrogen, med forbindelserne med formlen (V):
(V) hvor Y er en egnet leaving-gruppe, såsom mesyl, tosyl, halogen, og R2 er som defineret ovenfor, men ikke hydrogen, til opnåelse af en forbindelse med formlen (IV), hvor R2 er som defineret ovenfor, men ikke hydrogen; trin 2) omsætning af forbindelsen med formlen (IV) med dimethylformamid-di-ferf-butylacetal eller dimethylformamid-diisopropylacetal til opnåelse afen forbindelse med formlen (VI):
(VI) hvor R2 er som defineret ovenfor; og trin 3) omsætning af forbindelsen med formlen (VI) ifølge et hvilket som helst af de alternative trin (trin 3a) eller (trin 3b): trin 3a) med guanidin til opnåelse afen forbindelse med formlen (VII), hvor R2 er som defineret ovenfor; omdannelse af aminogruppen i den resulterende forbindelse med formlen (VII) til iod og derpå omsætning af det resulterende iodderivat med formlen (VIII) med en ortho-substitueret arylamin med formlen R1-H (IX), hvor R1 er som defineret i krav 1, til opnåelse af en forbindelse med formlen (I):
(vin (viii) cj hvor R1 og R2 er som defineret ovenfor; trin 3b) med et guanidinderivat med formlen (X):
(X) hvor R1 er som defineret ovenfor, til opnåelse af en forbindelse med formlen (I):
(1} hvor R1 og R2 er som defineret ovenfor, og eventuelt omdannelse af den til andre derivater med formlen (I) og/eller til farmaceutisk acceptable salte deraf.
7. Fremgangsmåde til fremstilling af en forbindelse med formlen (I) ifølge krav 6, kendetegnet ved, at forbindelsen med formlen (I) fremstilles ifølge en fremgangsmåde, som omfatter: trin 4) omdannelse af ethoxycarbonylgruppen i forbindelsen med formlen (VIII) ifølge krav 6 til en forbindelse med formlen (XIII) eller tilsvarende salt ved hjælp af sur eller basisk hydrolyse; omdannelse af den resulterende forbindelse med formlen (XIII) eller tilsvarende salt til forbindelsen med formlen (XIV) ved hjælp af omsætning under basiske betingelser, og i nærværelse af et egnet kondenseringsmiddel, med en amin med formlen R'R"-NH (XI), hvor R' og R" er som defineret i krav 1; omsætning af forbindelsen med formlen (XIV) med en orffto-substitueret arylamin med formlen R1-H (IX), hvor R1 er som defineret i krav 1, til opnåelse afen forbindelse med formlen (I):
hvor R1, R2, R' og R" er som defineret ovenfor, og eventuelt omdannelse af den til andre derivater med formlen (I) og/eller til farmaceutisk acceptable salte deraf.
8. Fremgangsmåde til fremstilling af en forbindelse med formlen (I) ifølge krav 6 eller 7, kendetegnet ved, at den eventuelle omdannelse af en forbindelse med formlen (I) til en anden forbindelse med formlen (I) udføres ved en eller flere af følgende reaktioner: a) omdannelse af en forbindelse med formlen (I), hvor R3 er ethoxycarbonyl, til en forbindelse med formlen (I), hvor R3 er aminocarbonyl, ved behandling med ammoniumhydroxid:
(i) (o b) omdannelse af en forbindelse med formlen (I), hvor R3 er ethoxycarbonyl, til en forbindelse med formlen (I), hvor R3 er en CO-NR'R"-gruppe, ved behandling med en amin med formlen R'R"-NH (XI), hvor R' og R" er som defineret i krav 1:
(i) (i) c) omdannelse af en forbindelse med formlen (I), hvor R3 er ethoxycarbonyl, til en forbindelse med formlen (I), hvor R3 er en CO-OH-gruppe, eller tilsvarende salt ved hjælp af sur eller basisk hydrolyse:
(i) (l) d) omdannelse af en forbindelse med formlen (I), hvor R3 er CO-OH, eller tilsvarende salt til en forbindelse med formlen (I), hvor R3 er en CO-NR'R"-gruppe, ved hjælp af omsætning med en amin med formlen R'R"-NH (XI) under basiske betingelser og i nærværelse af et egnet kondenseringsmiddel, hvor R' og R" er som defineret ovenfor:
(0 (i) e) omdannelse af en forbindelse med formlen (I), hvor R2 er trityl, til en forbindelse med formlen (I), hvor R2 er hydrogen, under sure betingelser:
(I) (!) f) omdannelse af en forbindelse med formlen (I), hvor R2 er hydrogen, til en forbindelse med formlen (I), hvor R2 er som defineret i krav 1, men ikke hydrogen, ved hjælp af omsætning med en alkohol med formlen R2-OH (XII), hvor R2 er som defineret ovenfor, men ikke hydrogen:
(!) 0) g) omdannelse afen forbindelse med formlen (I), hvor R2 er hydrogen, til en forbindelse med formlen (I), hvor R2 er som defineret i krav 1, men ikke hydrogen, ved hjælp af omsætning med en forbindelse med formlen R2-X (XV), hvor R2 er som defineret ovenfor, men ikke hydrogen, og X er halogen:
(I) 0) h) omdannelse af en forbindelse med formlen (I), hvor R2 er en halogenethylgruppe, til en forbindelse med formlen (I), hvor R2 er vinyl: («)
0) i) omdannelse af en forbindelse med formlen (I), hvor R1 er en ortho-substitueret arylaminogruppe med formlen: ELLER
hvor R'4 eller R"4 er brom, til en forbindelse med formlen (I), hvor R'4 eller R"4 er en -NR'R"-gruppe, ved behandling med en amin med formlen R'R"-NH (XI), hvor R' og R" er som defineret i krav 1.
9. Bibliotek med to eller flere forbindelser med formlen (I):
(l) hvor R1 er en o/ffto-substitueret arylaminogruppe med formlen:
hvor R'4 og R"4 er uafhængigt valgt fra en gruppe bestående af halogen, nitro, cyano, (Ci-Ce)-alkyl, polyfluoreret alkyl, polyfluoreret alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, (C3-C6)-cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylendioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkylidenaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonat og alkylphosphonat; R2 er hydrogen eller en eventuelt substitueret gruppe valgt blandt ligekædet eller forgrenet (Ci-Ce)-alkyl, ligekædet eller forgrenet (C2-C6)- alkenyl, ligekædet eller forgrenet (C2-C6)-alkynyl, (C3-C6)-cycloalkyl og heterocyclyl; R3 er CO-OR' eller CO-NR'R", hvor R' og R" hver uafhængigt er hydrogen eller en eventuelt substitueret gruppe valgt blandt ligekædet eller forgrenet (Ci-C6)-alkyl, (C3-C6)-cycloalkyl og heterocyclyl, eller R' og R" taget sammen med det nitrogenatom, hvortil de er bundet, kan udgøre en eventuelt substitueret heterocyclylgruppe, som eventuelt indeholder ét yderligere heteroatom valgt blandt N, O og S; og isomerer, tautomerer, hydrater, solvater, N-oxider og farmaceutisk acceptable salte deraf.
10. Farmaceutisk sammensætning, som omfatter en terapeutisk effektiv mængde af en forbindelse med formlen (I) eller et farmaceutisk acceptabelt salt deraf ifølge krav 1 og mindst én farmaceutisk acceptabel excipiens, bærer og/eller diluent.
11. Produkt eller kit, som omfatter en forbindelse med formlen (I) eller et farmaceutisk acceptabelt salt deraf ifølge krav 1 eller farmaceutiske sammensætninger deraf ifølge krav 10 og et eller flere kemoterapeutiske midler som et kombineret præparat til samtidig, separat eller sekventiel anvendelse ved anticancerbehandling.
12. Forbindelse med formlen (I) eller farmaceutisk acceptabelt salt deraf ifølge krav 1 til anvendelse som lægemiddel.
13. Forbindelse med formlen (I) eller farmaceutisk acceptabelt salt deraf ifølge krav 1 til anvendelse ved en fremgangsmåde til behandling af cancer.
14. Anvendelse afen forbindelse med formlen (I) eller et farmaceutisk acceptabelt salt deraf ifølge krav 1 til fremstilling af et lægemiddel med anticancer-aktivitet.
15. Mellemprodukt med formlen (X'):
(X') hvor R1' er ELLER
ELLER eller har formlen (IX'): R1'-H (IX') hvor R1' er ELLER
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HUE024105T2 (hu) 2016-02-29
AU2007336281A1 (en) 2008-06-26
PL2125822T3 (pl) 2015-04-30
EP2125822A1 (en) 2009-12-02
KR20090101942A (ko) 2009-09-29
PT2125822E (pt) 2015-01-30
EA200970611A1 (ru) 2009-12-30
SI2125822T1 (sl) 2015-01-30
ES2527696T3 (es) 2015-01-28
TWI418560B (zh) 2013-12-11
AU2007336281A2 (en) 2009-09-03
SG177911A1 (en) 2012-02-28
AR064608A1 (es) 2009-04-15
BRPI0720588B8 (pt) 2021-05-25

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