1-92. (canceled)
93. A recording medium wherein the following are recorded:
enciphered contents information; and
processor readable management information that includes access positions on the recording medium, the recording medium access positions indicating addresses on the recording medium corresponding to a time stamp in the contents information.
94. A medium containing processor readable instructions for causing an information processor to execute a plurality of steps comprising:
inputting content information;
extracting access positions for the inputted content information;
creating management information showing one or more access positions for the content information; and
writing the inputted content information and the management information on the medium.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of formula (I),
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, 3 or 4 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;
R1 and R2 are each independently hydrogen, halo, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyloxy, heteroarylC1-6alkyloxy, phenylthio, hydroxyC1-6alkylcarbonyl, C1-6alkyl substituted with a substituent selected from amino, aryl and heteroaryl; or C3-7cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl;
A is a radical selected from
wherein
R4 and R5 are each independently selected from hydrogen, halo, C1-6alkyl, polyhaloC1-6alkyl, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, hydroxy, amino, C1-6alkyloxy,
C1-6alkylcarbonyl, methylsulfonylamino, aryl or heteroaryl;
Z is a radical selected from
wherein
R6 or R7 are each independently selected from hydrogen, halo, hydroxy, amino, C1-6alkyl, nitro, polyhaloC1-6alkyl, cyano, cyanoC1-6alkyl, tetrazoloC1-6alkyl, aryl, heteroaryl, arylC1-6alkyl, heteroarylC1-6alkyl, aryl(hydroxy)C1-6alkyl, heteroaryl(hydroxy)C1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C1-6alkylcarbonyl, arylC1-6alkylcarbonyl, heteroarylC1-6alkylcarbonyl, C1-6alkyloxy, C3-7cycloalkylcarbonyl, C3-7cycloalkyl(hydroxy)C1-6alkyl, arylC1-6alkyloxyC1-6alkyl, C1-6alkyloxyC1-6alkyloxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC2-6alkenyl C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC1-6alkyl, aminoC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl and \u2014(CH2)v\u2014(C(\u2550O)r)\u2014(CHR10)u\u2014NR8R9; 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;
R10 is hydrogen or C1-6alkyl;
R8 and R9 are each independently selected from hydrogen, C1-12alkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, arylC1-6alkylcarbonyl, C3-7cycloalkyl, C3-7cycloalkylcarbonyl, \u2014(CH2)k\u2014NR11R12, C1-2alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C1-6alkyloxycarbonyl, C1-6alkyloxy, aryl or heteroaryl; or
C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, amino, arylC1-6alkyl, heteroaryl or heteroarylC1-6alkyl; or
R8 and R9 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 C1-6alkyl, arylC1-6alkyl, arylC1-6alkyloxycarbonyl, heteroarylC1-6alkyl, C3-7cycloalkyl and C3-7cycloalkylC1-6alkyl; wherein
k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended
\u2003R11 and R12 are each independently selected from hydrogen, C1-6alkyl, arylC1-6alkyloxycarbonyl, C3-7cycloalkyl, C1-12alkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, and heteroaryl;
\u2003and C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, arylC1-6alkyl, heteroaryl, and
\u2003heteroarylC1-6alkyl; or
\u2003R11 and R12 together with the nitrogen to which they are attached can optionally form a morpholinyl, a piperazinyl or a piperazinyl substituted with C1-6alkyloxycarbonyl;
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, hydroxyC1-6alkyl, C1-6alkyl, amino, polyhaloC1-6alkyl and C1-6alkyloxy; 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, C1-6alkyl, amino, polyhaloC1-6alkyl, aryl, arylC1-6alkyl or C1-6alkyloxy; and
each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy.
2. A compound according to claim 1 wherein;
m is 0; n is 0 or 2; p is 1; s is 0; t is 0; R1 and R2 are each independently hydrogen; A is a radical selected from (a-15), (a-21), (a-30), (a-39) or (a-40);
R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z is the radical (b-2); or R6 and R7 are each independently selected from hydrogen.
3. A compound according to claim 1 wherein
m is 0; n is 2; p is 1; s is 0; t is 0; R1 and R2 are each independently hydrogen; A is a radical selected from (a-21), (a-39) or (a-40);
R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy;
Z is the radical (b-2); or R6 and R7 are each independently selected from hydrogen.
4. A compound selected from the group consisting of:
5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.
6. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 are intimately mixed.
7. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, wherein the disorder is tumour growth.
8. A combination of an anti-cancer agent and a compound according to claim 1.
9. 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,
b) converting an intermediate of formula (IV) into compounds of formula (I), wherein p is 1, herein referred to as compounds of formula (I-a), in the presence of lithium aluminum hydride in a suitable solvent,
c) reacting an appropriate carboxaldehyde of formula (VI), with an intermediate of formula (V), in the presence of an appropriate reagent, in a suitable solvent,
d) reacting an intermediate of formula (II) with an appropriate carboxaldehyde of formula (VII) with the formation of a compound of formula (I), wherein t is 1, herein referred to as compounds of formula (I-b), or
e) reacting an intermediate of formula (VIII) with lithium aluminum 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-c).
10. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 4.
11. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 4 are intimately mixed.
12. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier, wherein the disorder is tumour growth.
13. A combination of an anti-cancer agent and a compound according to claim 4.
14. A compound according to claim 2 wherein
m is 0; n is 2; p is 1; s is 0; t is 0; R1 and R2 are each independently hydrogen; A is a radical selected from (a-21), (a-39) or (a-40);
R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy;
Z is the radical (b-2); or R6 and R7 are each independently selected from hydrogen.
15. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 14.
16. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 14 are intimately mixed.
17. A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier, wherein the disorder is tumour growth.