Claims for Patent: 7,834,016

Summary for Patent: 7,834,016

Title:	Inhibitors of the interaction between MDM2 and p53
Abstract:	The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds of formula (I) ##STR00001## wherein n, m, p, s, t, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, Y, Q and Z have defined meanings.
Inventor(s):	Lacrampe; Jean Fernand Armand (Le Mesnil-Esnard, FR), Meyer; Christophe (Les Authieux sur le Port Saint Ouen, FR), Ligny; Yannick Aime Eddy (Sotteville-les-Rouen, FR), Csoka; Imre Christian Francis (Louviers, FR), Van Hijfte; Luc (Belbeuf, FR), Arts; Janine (Breda, NL), Schoentjes; Bruno (Bois-Guillaume, FR), Wermuth; Camille Georges (Strasbourg, FR), Giethlen; Bruno (Altorf, FR), Contreras; Jean-Marie (Benfeld, FR), Joubert; Muriel (Illkirch, FR)
Assignee:	Janssen Pharmaceutica NV (Beerse, BE)
Application Number:	11/575,552
Patent Claims:	1. A compound of formula (I), ##STR00393## a N-oxide form, an addition salt or a stereochemically isomeric form thereof, wherein m is 0, 1, or 2 and when m is 0 then a direct bond is intended; n is 0, 1, 2, or 3 and when n is 0 then a direct bond is intended; p is 0, or 1 and when p is 0 then a direct bond is intended; s is 0, or 1 and when s is 0 then a direct bond is intended; t is 0 or 1 and when t is 0 then a direct bond is intended; X is CHR.sup.8; wherein R.sup.8 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, --C(.dbd.O)--NR.sup.17R.sup.18, hydroxycarbonyl, arylC.sub.1-6alkyloxycarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylC.sub.1-6alkyloxycarbonyl, piperazinylcarbonyl, pyrrolidinyl, piperidinylcarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with a substituent selected from hydroxy, amino, aryl, and heteroaryl; C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl, and heteroaryl; piperazinylcarbonyl substituted with hydroxy, hydroxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl; pyrrolidinyl substituted with hydroxyC.sub.1-6alkyl; or piperidinylcarbonyl substituted with one or two substituents selected from hydroxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyl(dihydroxy)C.sub.1-6alkyl or C.sub.1-6alkyloxy(hydroxy)C.sub.1-6alkyl; R.sup.17 and R.sup.18 are each independently selected from hydrogen, C.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, arylC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl(C.sub.1-6alkyl) or hydroxyC.sub.1-6alkyl(arylC.sub.1-6alkyl); ##STR00394## s is --CR.sup.9.dbd.C< and then the dotted line is a bond, --C(.dbd.O)--CH<, --CHR.sup.9--CH<or --CHR.sup.9--N<; wherein each R.sup.9 is independently hydrogen or C.sub.1-6alkyl; R.sup.1 is hydrogen, aryl, heteroaryl, C.sub.1-6alkyloxycarbonyl, C.sub.1-12alkyl, or C.sub.1-12alkyl substituted with one or two substituents independently selected from hydroxy, aryl, heteroaryl, amino, C.sub.1-6alkyloxy, mono- or di(C.sub.1-6alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C.sub.1-6alkylpiperazinyl, arylC.sub.1-6alkylpiperazinyl, heteroarylC.sub.1-6alkylpiperazinyl, C.sub.3-7cycloalkylpiperazinyl and C.sub.3-7cycloalkylC.sub.1-6alkylpiperazinyl; R.sup.2 is hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy, heteroarylC.sub.1-6alkyloxy, phenylthio, hydroxyC.sub.1-6alkylcarbonyl, C.sub.1-6alkyl substituted with a substituent selected from amino, aryl and heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl; R.sup.3 is hydrogen, C.sub.1-6alkyl, heteroaryl, C.sub.3-7cycloalkyl, C.sub.1-6alkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; R.sup.4 and R.sup.5 are each independently hydrogen, halo, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, hydroxy, amino or C.sub.1-6alkyloxy; or R.sup.4 and R.sup.5 together can optionally form a bivalent radical selected from methylenedioxy or ethylenedioxy; R.sup.6 is hydrogen, C.sub.1-6alkyloxycarbonyl or C.sub.1-6alkyl; when p is 1 then R.sup.7 is hydrogen, arylC.sub.1-6alkyl, hydroxy or heteroarylC.sub.1-6alkyl; Z is a radical selected from ##STR00395## ##STR00396## wherein each R.sup.10or R.sup.11 are each independently selected from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl, nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, tetrazoloC.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl, heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C.sub.1-6alkylcarbonyl, arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxy, C.sub.3-7cycloalkylcarbonyl, C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl, arylC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyC.sub.2-6alkenyl C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl and --(CH.sub.2).sub.v--(C(.dbd.O).sub.r)--(CHR.sup.19).sub.u--NR.sup.13R.sup- .14; wherein v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bond is intended; r is 0, or 1 and when r is 0 then a direct bond is intended; u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond is intended; R.sup.19 is hydrogen or C.sub.1-6alkyl; R.sup.12 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyl substituted with a substituent selected from hydroxy, amino, C.sub.1-6alkyloxy and aryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and C.sub.1-6alkyloxy; R.sup.13 and R.sup.14 are each independently selected from hydrogen, C.sub.1-12alkyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkylsulfonyl, arylC.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkylcarbonyl, --(CH.sub.2).sub.k--NR.sup.15R.sup.16, C.sub.1-12alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyloxy, aryl or heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, amino, arylC.sub.1-6alkyl, heteroaryl or heteroarylC.sub.1-6alkyl; or R.sup.13 and R.sup.14 together with the nitrogen to which they are attached can optionally form a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or piperazinyl substituted with a substituent selected from C.sub.1-6alkyl, arylC.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl, heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl and C.sub.3-7cycloalkylC.sub.1-6alkyl; wherein k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended; R.sup.15 and R.sup.16 are each independently selected from hydrogen, C.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyl, C.sub.1-12alkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl, and heteroarylC.sub.1-6alkyl; or R.sup.15 and R.sup.16 together with the nitrogen to which they are attached can optionally form a morpholinyl, a piperazinyl or a piperazinyl substituted with C.sub.1-6alkyloxycarbonyl; aryl is phenyl or naphthalenyl; each phenyl or naphthalenyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, amino, polyhaloC.sub.1-6alkyl and C.sub.1-6alkyloxy; and each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from methylenedioxy and ethylenedioxy; heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl; each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, amino, polyhaloC.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl or C.sub.1-6alkyloxy; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy; with the proviso that when m is 1; the substituents on the phenyl ring other than R.sup.2 are in the meta position; s is 0; and t is 0; then Z is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8) or (a-9). 2. A compond according to claim 1 wherein ##STR00397## is --CR.sup.9.dbd.C< and then the dotted line is a bond, --CHR.sup.9--CH< or --CHR.sup.9--N<. 3. A compound according to claim 2 wherein X is CHR.sup.8 wherein R.sup.8 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aminocarbonyl, mono- or di(C.sub.1-6alkyl) aminocarbonyl, hydroxycarbonyl, arylC.sub.1-6alkyloxycarbonyl, heteroarylC.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with a substituent selected from hydroxy, amino, aryl, and heteroaryl or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; R.sup.1 is hydrogen, aryl, heteroaryl, C.sub.1-12alkyl, or C.sub.1-12alkyl substituted with one or two substituents independently selected from hydroxy, aryl, heteroaryl, amino, C.sub.1-6alkyloxy, mono- or di(C.sub.1-6alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C.sub.1-6alkylpiperazinyl, arylC.sub.1-6alkylpiperazinyl,heteroarylC.sub.1-6alkylpiperazinyl, C.sub.3-7cycloalkylpiperazinyl and C.sub.3-7cycloalkylC.sub.1-6alkylpiperazinyl; R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyl substituted with a substituent selected from hydroxy, amino, aryl, and heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; R.sup.4 and R.sup.5 are each independently hydrogen, halo, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, hydroxy, amino or C.sub.1-6alkyloxy; R.sup.4 and R.sup.5 together can optionally form a bivalent radical selected from methylenedioxy or ethylenedioxy; R.sup.6 is hydrogen or C.sub.1-6alkyl; when p is 1 then R.sup.7 is hydrogen, arylC.sub.1-6alkyl or heteroarylC.sub.1-6alkyl; Z is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5) and (a-6); each R.sup.10 or R.sup.11 are each independently selected from hydrogen, hydroxy, amino, C.sub.1-6alkyl, nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, tetrazoloC.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl, heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl, heteroarylcarbonyl, arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl and --(CH.sub.2).sub.v--(C(.dbd.O).sub.r)--(CH.sub.2).sub.u--NR .sup.13R.sup.14; R.sup.13 R and R.sup.14 are each independently selected from hydrogen, C.sub.1-12alkyl, C.sub.3-7cycloalkyl, --(CH.sub.2).sub.k--NR.sup.15R.sup.16, C.sub.1-12alkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl and heteroarylC.sub.1-6alkyl; R.sup.13 and R.sup.14 together with the nitrogen to which they are attached can optionally form a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or piperazinyl substituted with a substituent selected from C.sub.1-6alkyl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl, and C.sub.3-7cycloalkylC.sub.1-6alkyl; R.sup.15 and R.sup.16 are each independently selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-12alkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and C.sub.3-7cycloalkyl substituted with a substituent selected from hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl and heteroarylC.sub.1-6alkyl; heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C.sub.1-6alkyl, amino, polyhaloC.sub.1-6alkyl and C.sub.1-6alkyloxy, or each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy. 4. A compound according to claim 2 wherein; R.sup.8 is hydrogen, --C(.dbd.O)--NR.sup.17R.sup.18, arylC.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with hydroxy, piperazinylcarbonyl substituted with hydroxy, hydroxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl, pyrrolidinyl substituted with hydroxyC.sub.1-6alkyl or piperidinylcarbonyl substituted with one or two substituents selected from hydroxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyl(dihydroxy)C.sub.1-6alkyl or C.sub.1-6alkyloxy(hydroxy)C.sub.1-6alkyl; R.sup.17 and R.sup.18 are each independently selected from hydrogen, C.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, arylC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl or hydroxyC.sub.1-6alkyl; ##STR00398## is --CR.sup.9.dbd.C< and then the dotted line is a bond, --CHR.sup.9--CH< or --CHR.sup.9--N<; R.sup.1 is hydrogen, heteroaryl, C.sub.1-6alkyloxycarbonyl, C.sub.1-12alkyl or C.sub.1-12alkyl substituted with heteroaryl; R.sup.2 is hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy or phenylthio; R.sup.3 is hydrogen, C.sub.1-6alkyl or heteroaryl; R.sup.4 and R.sup.5 are each independently hydrogen, halo, C.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, hydroxy or C.sub.1-6alkyloxy; when p is 1 then R.sup.7 is arylC.sub.1-6alkyl or hydroxy; Z is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-8), (a-9), (a-10) and (a-11); each R.sup.10or R.sup.11 are each independently selected from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl, nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, tetrazoloC.sub.1-6alkyl, aryl, heteroaryl, heteroarylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl, C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl, arylC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyC.sub.2-6alkenyl, C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, aminocarbonyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl and --(CH.sub.2).sub.v--(C(.dbd.O).sub.r)--(CHR.sup.19).sub.u--NR.sup.13R.sup- .14; v is 0 or 1; u is 0 or 1; R.sup.12 is hydrogen or C.sub.1-6alkyl; R.sup.13 and R.sup.14 are each independently selected from hydrogen, C.sub.1-12alkyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkylsulfonyl, arylC.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl, --(CH.sub.2).sub.k--NR.sup.15R.sup.16, C.sub.1-12alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C.sub.1-6alkyloxycarbonyl or aryl; R.sup.13 and R.sup.14 together with the nitrogen to which they are attached can optionally form a morpholinyl, pyrrolidinyl, piperazinyl or piperazinyl substituted with a substituent selected from C.sub.1-6alkyl or arylC.sub.1-6alkyloxycarbonyl; k is 2; R.sup.15 and R.sup.16 are each independently selected from hydrogen, C.sub.1-6alkyl or arylC.sub.1-6alkyloxycarbonyl; k is 2; R.sup.15 and R.sup.16 are each independently selected from hydrogen, C.sub.1-6alkyl or arylC.sub.1-6alkyloxycarbonyl; R.sup.15 and R.sup.16 together with the nitrogen to which they are attached can optionally form a morpholinyl or piperazinyl, or a piperazinyl substituted with C.sub.1-6alkyloxycarbonyl; aryl is phenyl or phenyl substituted with halo; heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl can optionally be substituted with one substituent selected from C.sub.1-6alkyl, aryl or arylC.sub.1-6alkyl. 5. A compound according to claim 4 wherein m is 0; n is 1; p is 0; s is 0; t is 0. 6. A compound according to claim 5 wherein X is CHR.sup.8 and R.sup.8 is hydrogen. 7. A compound according to claim 2 wherein ##STR00399## is --CR.sup.9.dbd.C< and R.sup.9 is hydrogen. 8. A compound according to claim 2 wherein R.sup.1 is hydrogen; R.sup.3 is hydrogen; R.sup.6 is hydrogen. 9. A compound according to claim 2 wherein R.sup.4 and R.sup.5 are each independently hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy. 10. A compound according to claim 2 wherein Z is a radical selected from (a-1), (a-2), (a-3) or (a-4). 11. A compound according to claim 2 wherein R.sup.10 or R.sup.11 are each independently selected from hydrogen, hydroxy or hydroxyC.sub.1-6alkyl. 12. A compound according to claim 2 wherein R.sup.2 is hydrogen or C.sub.1-6alkyloxy. 13. A compound according to claim 2 wherein m is 0; n is 1; p is 0; s is 0; t is 0; X is CHR.sup.8; R.sup.8 is hydrogen; ##STR00400## is --CR.sup.9.dbd.C<; each R.sup.9 is hydrogen; R.sup.1 is hydrogen; R.sup.2 is hydrogen or C.sub.1-6alkyloxy; R.sup.3 is hydrogen; R.sup.4 and R.sup.5 are each independently hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy; R.sup.6 is hydrogen; Z is a radical selected from (a-1), (a-2), (a-3) or (a-4); and R.sup.10 or R.sup.11 are each independently selected from hydrogen, hydroxy or hydroxyC.sub.1-6alkyl. 14. A compound according to claim 1 wherein the compound is selected from the group consisting of: ##STR00401## ##STR00402## and the N-oxide form, the addition salt or the stereochemically isomeric form thereof. 15. A compound according to claim 13 which is ##STR00403## or the pharmaceutically acceptable salt thereof. 16. A compound according to claim 13 which is ##STR00404## 17. A combination of an anti-cancer agent and a compound claimed in claim 1. 18. The combination according to claim 17 wherein the anti-cancer agent is selected from the group consisting of platinum coordination compounds cisplatin, carboplatin or oxalyplatin; taxane compounds paclitaxel or docetaxel; topoisomerase I inhibitors; camptothecin compounds irinotecan or topotecan; topoisomerase II inhibitors, anti-tumour podophyllotoxin derivatives etoposide or teniposide; anti-tumour vinca alkaloids vinblastine, vincristine or vinorelbine; anti-tumour nucleoside derivatives 5-fluorouracil, gemcitabine or capecitabine; alkylating agents nitrogen mustard or nitrosourea, cyclophosphamide, chlorambucil, carmustine or lomustine; anti-tumour anthracycline derivatives daunorubicin, doxorubicin, idarubicin or mitoxantrone; HER2 antibodies trastuzumab; estrogen receptor antagonists or selective estrogen receptor modulators tamoxifen, toremifene, droloxifene, faslodex or raloxifene; aromatase inhibitors exemestane, anastrozole, letrazole and vorozole; differentiating agents, retinoids, vitamin D and retinoic acid metabolism blocking agents, (RAMBA), accutane; DNA methyl transferase inhibitors, azacytidine; kinase inhibitors flavoperidol, imatinib mesylate or gefitinib; farnesyltransferase inhibitors; HDAC inhibitors; inhibitors of the ubiquitin-proteasome pathway, velcade; and yondelis. 19. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1. 20. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 2. 21. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 13. 22. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 16. 23. A method for the treatment of a disorder mediated by a p53-MDM2 interaction in a subject in need of treatment, said method comprising administering to said subject a therapeutically effective amount of a compound as claimed in claim 1. 24. A method for the treatment of a disorder mediated by a p53-MDM2 interaction in a subject in need of treatment, said method comprising administering to said subject a therapeutically effective amount of a compound as claimed in claim 4. 25. A method for the treatment of a disorder mediated by a p53-MDM2 interaction in a subject in need of treatment, said method comprising administering to said subject a therapeutically effective amount of a compound as claimed in claim 13. 26. A method for the treatment of a disorder mediated by a p53-MDM2 interaction in a subject in need of treatment, said method comprising administering to said subject a therapeutically effective amount of a compound as claimed in claim 14. 27. A method for the treatment of cancer in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound as claimed in claim 1, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, and colon cancer. 28. The method of claim 27 wherein the cancer is breast cancer. 29. The method of claim 28 wherein the cancer is prostate cancer. 30. A composition which is a combination of an anti-cancer agent and a compound according to claim 1, wherein the anti-cancer agent treats breast cancer, prostate cancer, and colon cancer. 31. A composition of claim 30 as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer, wherein the cancer is elected from the group consisting of breast cancer, prostate cancer, and colon cancer. 32. A process for preparing a compound as claimed in claim 1, said process comprising the steps of: a) reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W is an appropriate leaving group such as, for example, halo, ##STR00405## wherein the variables are as defined in claim 1; b) converting a compound of formula (I) wherein X is C(.dbd.O), herein referred to as compounds of formula (I-b), into compounds of formula (I), wherein X is CH.sub.2, herein referred to as compounds of formula (I-a), in the presence of lithium aluminium hydride in a suitable solvent, ##STR00406## wherein the variables are as defined in claim 1; c) reacting an appropriate carboxaldehyde of formula (IV), with an intermediate of formula (V), in the presence of an appropriate reagent, in a suitable solvent, ##STR00407## wherein the variables are as defined in claim 1; d) reacting an intermediate of formula (II) with an appropriate carboxaldehyde of formula (VI) with the formation of a compound of formula (I), wherein t is 1, herein referred to as compounds of formula (I-c), ##STR00408## wherein the variables are as defined in claim 1; e) reacting an intermediate of formula (VII) with lithium aluminium hydride in a suitable solvent, with the formation of a compound of formula (I), wherein s is 1, herein referred to as compounds of formula (I-d) ##STR00409## wherein the variables are as defined in claim 1. 33. The method of claim 28 wherein the cancer is colon cancer. 34. The composition of claim 31, wherein the cancer is breast cancer. 35. The composition of claim 31, wherein the cancer is prostate cancer. 36. The composition of claim 31, wherein the cancer is colon cancer.

Details for Patent 7,834,016

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2024-09-22
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2024-09-22
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2024-09-22