RU2008141770A - INTERACTION INHIBITORS BETWEEN MDM2 AND P53 - Google Patents

Abstract

 1. The compound of formula (I),! ! its N-oxide form, an addition salt or a stereochemically isomeric form, where! m is 0, 1 or 2, and when m is 0, a direct relationship is implied; ! n is 0, 1, 2, 3, or 4, and when n is 0, a direct relationship is implied; ! p is 0 or 1, and when p is 0, a direct relationship is implied; ! s is 0 or 1, and when s is 0, a direct relationship is implied; ! t is 0 or 1, and when t is 0, a direct relationship is implied; ! R1 and R2 are each independently hydrogen, halo, C1-6alkyl, C1-6alkyloxy, aryl C1-6alkyloxy, heteroaryl C1-6alkyloxy, 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! ! ! ! ! ! ! ! ! ! ! where R4 and R5 are each independently selected from hydrogen, halogen, C1-6 alkyl, polyhaloC1-6 alkyl, cyano, cyanoC1-6 alkyl, hydroxyC1-6 alkyl, hydroxy, amino, C1-6alkyloxy, C1-6 alkylcarbonyl, methylsulfonylamino, aryl or heteroaryl; ! Z is a radical selected from! ! ! where R6 and R7 are each independently selected from hydrogen, halogen, hydroxy, amino, C1-6 alkyl, nitro, polyhalogen C1-6 alkyl, cyano, cyano C1-6 alkyl, tetrazolo C1-6 alkyl, aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-6 alkyl, aryl ( hydroxy) C1-6alkyl, heteroaryl (hydroxy) C1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C1-6alkylcarbonyl, aryl C1-6alkylcarbonyl, heteroarylC1-6alkylcarbonyl, C1-6alkyloxy, C3-7cycloalkylcarbonyl, C3-7cycloalkyl (hydroxy) C1-6 6alkyloxyC1-6alkyl, C1-6alkyloxyC1-6alkyloxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alk

Claims (10)

1. The compound of formula (I),

its N-oxide form, an addition salt or a stereochemically isomeric form, where m is 0, 1 or 2, and when m is 0, a direct relationship is implied; n is 0, 1, 2, 3, or 4, and when n is 0, a direct relationship is implied; p is 0 or 1, and when p is 0, a direct relationship is implied; s is 0 or 1, and when s is 0, a direct relationship is implied; t is 0 or 1, and when t is 0, a direct relationship is implied; R ¹ and R ² each independently represent hydrogen, halogen, C _1-6 alkyl, C _1-6 alkyloxy, arilC _1-6 alkyloxy geteroarilC _1-6 alkyloxy, phenylthio, hydroxyC _1-6 alkylcarbonyl, C _1-6 alkyl substituted with a substituent selected from amino, aryl and heteroaryl; or C _3-7 cycloalkyl substituted with a substituent selected from amino, aryl and heteroaryl; A represents a radical selected from

wherein R ⁴ and R ^{5 are} each independently selected from hydrogen, halogen, C _1-6 alkyl, polyhaloC _1-6 alkyl, cyano, tsianoC _1-6 alkyl, hydroxyC _1-6 alkyl, hydroxy, amino, C _1-6 alkyloxy, C _1-6 alkylcarbonyl, methylsulfonylamino, aryl or heteroaryl; Z represents a radical selected from

where R ⁶ and R ^{7 are} each independently selected from hydrogen, halogen, hydroxy, amino, C _1-6 alkyl, nitro, polyhalo C _1-6 alkyl, cyano, cyanoC _1-6 alkyl, tetrazoloC _1-6 alkyl, aryl, heteroaryl, arilC _1-6 alkyl, geteroarilC _1-6 alkyl, aryl (hydroxy) C _1-6 alkyl, heteroaryl (hydroxy) C _1-6 alkyl, arylcarbonyl, heteroarylcarbonyl, C _1-6 alkylcarbonyl, arilC _1-6 alkylcarbonyl, geteroarilC _{1 -6} alkylcarbonyl, C _1-6 alkyloxy, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl (hydroxy) C _1-6 alkyl, arylC _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkyloxyC _{1 -6} alkyl, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkiloksikarbonilC _1-6 alkyl, hydroxyC _1-6 alkyloxyC _1-6 alkyl, C _1-6 alkiloksikarbonilC _2-6 alkenylC _1-6 alkyloxyC _1-6 alkyl, C _{1 -6} alkyloxycarbonyl, C _1-6 alkylcarbonyloxy, aminocarbonyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C _1-6 alkyl and - (CH ₂ ) _v - (C (= O) _r ) - (CHR ¹⁰ ) _u -NR ⁸ R ⁹ , Where v is 0, 1, 2, 3, 4, 5, or 6, and when v is 0, a direct relationship is implied; r is 0 or 1, and when r is 0, a direct relationship is implied; u is 0, 1, 2, 3, 4, 5, or 6, and when u is 0, a direct relationship is implied; R ¹⁰ represents hydrogen or C _1-6 alkyl; R ⁸ and R ^{9 are} each independently selected from hydrogen, C _1-12 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, aryl C _1-6 alkylcarbonyl, C _3-7 cycloalkyl, C _3-7 cycloalkylcarbonyl, - (CH ₂ ) _k -NR ¹¹ R ¹² , C _1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C _1-6 alkyloxycarbonyl, C _1-6 alkyloxy, aryl or heteroaryl; or C _3-7 cycloalkyl substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, amino, aryl C _1-6 alkyl, heteroaryl or heteroaryl C _1-6 alkyl; or R ⁸ and R ⁹ 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 _1-6 alkyl, arilC _1-6 alkyl, _1-6 alkyloxycarbonyl arilC heteroaryl C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 cycloalkyl C _1-6 alkyl, Where k is 0, 1, 2, 3, 4, 5, or 6, and when k is 0, a direct relationship is implied; R ¹¹ and R ¹² are each independently selected from hydrogen, C _1-6 alkyl, arilC _1-6 alkyloxycarbonyl, C _3-7 cycloalkyl, C _1-12 alkyl substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, and heteroaryl; and C _3-7 cycloalkyl substituted with a substituent selected from hydroxy, C _1-6 alkyloxy, aryl, aryl C _1-6 alkyl, heteroaryl and heteroaryl C _1-6 alkyl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached may optionally form morpholinyl, piperazinyl or piperazinyl substituted with C _1-6 alkyloxycarbonyl; 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, hydroxyC _1-6 alkyl, C _1-6 alkyl, amino, polyhaloC _1-6 alkyl and C _1-6 alkyloxy ; and each phenyl or naphthalenyl optionally may 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 may optionally be substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, C _1-6 alkyl, amino, polyhaloC _1-6 alkyl, aryl, arilC _1-6 alkyl or C _1-6 alkyloxy; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl may optionally be substituted with a bivalent radical selected from methylenedioxy and ethylenedioxy. 2. The compound according to claim 1, where m is 0; n is 0 or 2; p is 1; s is 0; t is 0; R ¹ and R ² each independently represent hydrogen; A represents a radical selected from (a-15), (a-21), (a-30), (a-39) or (a-40); R ⁴ and R ^{5 are} each independently selected from hydrogen or C _1-6 alkyloxy; Z represents a radical (b-2); or R ⁶ and R ^{7 are} each independently selected from hydrogen. 3. The compound according to claim 1, where m is 0; n is 2; p is 1; s is 0; t is 0; R ¹ and R ² each independently represent hydrogen; A represents a radical selected from (a-21), (a-39) or (a-40); R ⁴ and R ^{5 are} each independently selected from hydrogen or C _1-6 alkyloxy; Z represents a radical (b-2); or R ⁶ and R ^{7 are} each independently selected from hydrogen. 4. The compound according to claim 1, where the compound is a compound No. 2, a compound No. 3 or a compound No. 5.

Connection Number 2 Connection Number 3

Connection Number 5 5. The compound according to claims 1, 2, 3 or 4 for use as a medicine. 6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and, as an active component, a compound according to claims 1-4 in a therapeutically effective amount. 7. The method of obtaining the pharmaceutical composition according to claim 6, where the pharmaceutically acceptable carriers and the compound according to claims 1-4 are directly mixed. 8. The use of a compound according to claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of a disorder caused by p53-MDM2 interaction. 9. The combination of anti-cancer agents and compounds according to claims 1, 2, 3 or 4. 10. A method of obtaining a compound according to claim 1, comprising a) the interaction of an intermediate compound of formula (II) with an intermediate compound of formula (III), where W represents an appropriate leaving group, such as, for example, halogen,

b) converting an intermediate of formula (IV) into a compound of formula (I), where p is 1, referred to herein as a compound of formula (I-a), in the presence of lithium aluminum hydride in a suitable solvent

c) reacting the corresponding 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 the corresponding carboxaldehyde of formula (VII) to form a compound of formula (I), where t is 1, referred to herein as a compound of formula (I-b), or

e) reacting an intermediate of formula (VIII) with lithium aluminum hydride in a suitable solvent to form a compound of formula (I), where s is 1, referred to herein as a compound of formula (I-c)