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1. WO2008152394 - PHARMACEUTICAL COMPOUNDS

Publication Number WO/2008/152394
Publication Date 18.12.2008
International Application No. PCT/GB2008/002023
International Filing Date 12.06.2008
IPC
C07D 491/048 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
491Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/-C07D459/290
02in which the condensed system contains two hetero rings
04Ortho-condensed systems
044with only one oxygen atom as ring hetero atom in the oxygen-containing ring
048the oxygen-containing ring being five-membered
C07D 519/00 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
519Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/ or C07D455/257
A61K 31/33 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
A61P 35/00 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
CPC
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
C07D 491/048
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
491Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
02in which the condensed system contains two hetero rings
04Ortho-condensed systems
044with only one oxygen atom as ring hetero atom in the oxygen-containing ring
048the oxygen-containing ring being five-membered
C07D 519/00
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
519Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Applicants
  • F.HOFFMANN-LA ROCHE AG [CH]/[CH] (AllExceptUS)
  • HANCOX, Timothy, Colin [GB]/[GB] (UsOnly)
  • PEGG, Neil, Anthony [GB]/[GB] (UsOnly)
  • NADIN, Alan, John [GB]/[GB] (UsOnly)
  • PRICE, Stephen [GB]/[GB] (UsOnly)
Inventors
  • HANCOX, Timothy, Colin
  • PEGG, Neil, Anthony
  • NADIN, Alan, John
  • PRICE, Stephen
Agents
  • KEEN, Celia, Mary
Priority Data
0711346.712.06.2007GB
0715675.510.08.2007GB
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) PHARMACEUTICAL COMPOUNDS
(FR) COMPOSÉS PHARMACEUTIQUES
Abstract
(EN) Furanopyrimidines of formula (I): wherein W represents a furan ring; R1 and R2 form, together with the N atom to which they are attached, a group of the following formula (IIa): in which A is selected from: (a) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being fused to a second ring selected from a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, a 5- to 12-membered unsaturated heterocyclic ring, a 5- to 7-membered saturated O-containing heterocyclic ring, a 3- to 12- membered saturated carbocyclic ring and an unsaturated 5- to 12- membered carbocyclic ring to form a heteropolycyclic ring system, the heteropolycyclic ring system being unsubstituted or substituted; (b) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and which further comprises, linking two constituent atoms of the ring, a bridgehead group selected from -(CR'2)n- and -(CR'2)r-O-(CR'2)s- wherein each R' is independently H or C1 - C6 alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted; and (c) a group of formula (IIb): wherein ring B is a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and ring B' is a 3- to 12- membered saturated carbocyclic ring, a 5- to 7- membered saturated O-containing heterocyclic ring or a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, each of B and B' being unsubstituted or substituted; m is 0, 1 or 2; R3 is H or C1-C6 alkyl; R4 is an indole group which is unsubstituted or substituted; and Ra is selected from R, halo, CN, C(O)NR2, halo(C1-C6)alkyl, SO2R, SO2NR2, NRSO2R, NRC(O)R, NRC(O)OR and NRC(O)NR2 wherein each R is independently H or C1-C6 alkyl; and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
(FR) La présente invention concerne des furanopyrimidines de formule (I) où W représente un composé cyclique de furanne ; R1 et R2 forment, avec l'atome N auquel ils sont liés, un groupe de formule suivante (IIa) : où A est choisi parmi : (a) un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O, ledit composé étant fusionné à un second composé cyclique choisi parmi un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N tel que défini précédemment, un composé hétérocyclique insaturé comportant de 5 à 12 chaînons, un composé hétérocyclique saturé comportant de 5 à 7 chaînons contenant O, un composé carbocyclique saturé comportant de 3 à 12 chaînons et un composé carbocyclique insaturé comportant de 5 à 12 chaînons pour former un système de composés hétéropolycycliques, ledit système étant non substitué ou substitué ; (b) un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O, et qui comprend également, liant deux atomes constitutifs du composé cyclique, un groupe en tête de pont choisi parmi -(CR'2)n- et -(CR'2)r-O-(CR'2)s- où chaque R' est indépendamment H ou C1 - C6 alkyle, n est 1, 2 ou 3, r est 0 ou 1 et s est 0 ou 1, les positions cycliques restantes étant non substituées ou substituées ; et (c) un groupe de formule (IIb) : où B est un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O et B' est un composé carbocyclique saturé comportant de 3 à 12 chaînons, un composé hétérocyclique saturé comportant de 5 à 7 chaînons contenant O ou un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N tel que défini précédemment, B et B' étant non substitués ou substitués ; m est 0, 1 ou 2 ; R3 est H ou C1-C6 alkyle ; R4 est un groupe d'indole qui est non substitué ou substitué ; et Ra est choisi parmi R, halo, CN, C(O)NR2, halo(C1-C6)alkyle, SO2R, SO2NR2, NRSO2R, NRC(O)R, NRC(O)OR et NRC(O)NR2 où chaque R est indépendamment H ou C1-C6 alkyle. Les sels pharmaceutiquement acceptables correspondants sont des inhibiteurs de PI3K et sont sélectifs de l'isoforme p110δ, une PI3 kinase de classe Ia, sur les deux autres kinases de classe Ia et de classe Ib. Les composés peuvent être utilisés dans le traitement de maladies et de troubles provoqués par un développement cellulaire, une fonction ou un comportement anormal associé à une kinase PI3, tel qu'un cancer, des désordres immuns, une maladie cardiovasculaire, une infection virale, une inflammation, des troubles fonctionnels du métabolisme/endocriniens et des troubles neurologiques.
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