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WO2003076437A1 - 2-heteroaryle-pyrimidines inhibitrices de la kinase dependante des cyclines, leur production et leur utilisation comme medicaments - Google Patents

2-heteroaryle-pyrimidines inhibitrices de la kinase dependante des cyclines, leur production et leur utilisation comme medicaments Download PDF

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Publication number
WO2003076437A1
WO2003076437A1 PCT/EP2003/001995 EP0301995W WO03076437A1 WO 2003076437 A1 WO2003076437 A1 WO 2003076437A1 EP 0301995 W EP0301995 W EP 0301995W WO 03076437 A1 WO03076437 A1 WO 03076437A1
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Prior art keywords
alkyl
alkoxy
cycloalkyl
halogen
hydroxy
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PCT/EP2003/001995
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German (de)
English (en)
Inventor
Ulrich LÜCKING
Martin Krüger
Rolf Jautelat
Olaf Prien
Gerd Siemeister
Alexander Ernst
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Bayer Pharma AG
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Schering AG
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Priority claimed from DE2002112100 external-priority patent/DE10212100A1/de
Priority claimed from DE10255984A external-priority patent/DE10255984A1/de
Application filed by Schering AG filed Critical Schering AG
Priority to AU2003212282A priority Critical patent/AU2003212282A1/en
Priority to EP03708151A priority patent/EP1483260A1/fr
Priority to JP2003574654A priority patent/JP2005526765A/ja
Publication of WO2003076437A1 publication Critical patent/WO2003076437A1/fr
Anticipated expiration legal-status Critical
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • CDK inhibitory 2-heteroaryl-pyrimidines their preparation and use as drugs
  • the present invention relates to 2-heteroaryl-pyrimidine derivatives, their preparation and their use as a medicament for the treatment of various diseases.
  • the CDKs (cyclin-dependent kinase) is an enzyme family that plays an important role in the regulation of the cell cycle and thus is a particularly interesting target for the development of small inhibitory molecules.
  • Selective inhibitors of CDKs can be used to treat cancer or other diseases that cause cell proliferation disorders.
  • Pyrimidines and analogues have already been described as active ingredients such as, for example, the 2-anilino-pyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for the treatment of neurological or neurodegenerative diseases (WO 99/19305).
  • pyrimidine derivatives for example bis (anilino) pyrimidine derivatives (WO 00/12486), 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano Pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N, N-dimethylaminopropoxypyrimidines (WO 00/39101).
  • bis (anilino) pyrimidine derivatives WO 00/12486
  • 2-amino-4-substituted pyrimidines WO 01/14375
  • purines WO 99/02162
  • 5-cyano Pyrimidines WO 02/04429
  • anilinopyrimidines WO 00/12486
  • 2-hydroxy-3-N, N-dimethylaminopropoxypyrimidines WO 00/39101
  • the object of the present invention is to provide compounds which have better properties than the already known inhibitors.
  • the substances described here are more effective since they already inhibit in the nanomolar range and are thus distinguishable from other already known CDK inhibitors such as olomoucine and roscovitine. It has now been found that compounds of the general formula I compounds of the general formula I
  • D, E, G, L, M and T are each independently carbon, oxygen, nitrogen or sulfur, wherein at least one heteroatom must be contained in the ring,
  • R 1 is hydrogen, halogen, CC 6 alkyl, CC 6 alkynyl .
  • -NH- or -N (C 1 -C 3 -alkyl) - or X and R 2 together denote a C 3 -C- form o-cycloalkyl ring which may optionally contain one or more heteroatoms and optionally mono- or polysubstituted by hydroxy, C 1 -C 6 -alkyl, hydroxyC-
  • Alkyl or halogen can be substituted, A and B are each independently hydrogen,
  • Groups may be interrupted in the ring and / or optionally one or more possible double bonds may be contained in the ring
  • R 5 is hydroxy, benzoxy, CC 6 alkyl, CC 6 alkylthio or CC 6 alkoxy
  • R 6 is a optionally mono- or polysubstituted, identical or different, with halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or -SO 2 NR 3 R 4 -substituted benzylthio, phenyloxy or C 3 -C 7 -cycloalkyl ring, where the C 3 -C 7 -cycloalkyl ring has the meaning given for R 2 , R 7 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl,
  • C 3 -C 7 -cycloalkyl where the C 3 -C 7 -cycloalkyl ring has the meaning given under R 2 , or represents the group -NR 3 R 4 , or optionally mono- or polysubstituted, identical or different with hydroxy, C ⁇ -C6 alkoxy, halogen, phenyl, -NR 3 R 4 or phenyl, which itself optionally mono- or polysubstituted identically or differently with halogen, hydroxy, -C 6 - alkyl, C ⁇ -C6 alkoxy, halo -CRC 6 alkyl, halo-C C 6 - alkoxy may be substituted, substituted C 1 -C 10 - alkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ 0 alkynyl, or C 3 -C 7 -
  • Halogen, and mean, and their isomers, diastereomers, enantiomers and salts overcome the known disadvantages.
  • Alkyl is in each case a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl or decyl to understand.
  • alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl or decyl to understand.
  • Alkoxy is in each case a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. Butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy. Cycloalkyl is in each case to be understood as meaning cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • ring systems which may optionally contain one or more possible double bonds in the ring are, for example, cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl to understand the attachment can be done both on the double bond as well as the single bonds ,
  • Halogen is in each case fluorine, chlorine, bromine or iodine.
  • alkenyl substituents are in each case straight-chain or branched, where the following are, for example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl , But-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1 -ene-1-yl, But 1-en-3-yl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, but-3-en-1-yl , Allyl.
  • alkynyl substituents are in each case straight-chain or branched, where the following radicals are for example meant: propargyl, propyn-1-yl, propyn-2-yl, but-1-yn-1-yl, but-1-yn-2-yl , But-2-yn-1-yl, but-2-yn-2-yl, 2-methyl-prop-2-yn-1-yl, 2-methyl-prop-1-yn-1-yl, But 1-yn-3-yl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl ,
  • Aryl is an aryl radical having in each case 6 to 12 carbon atoms, for example naphthyl, biphenyl and in particular phenyl.
  • heteroaryl is meant a heteroaryl radical which may also be benzo-fused in each case.
  • heteroaryl radical which may also be benzo-fused in each case.
  • 5-ring heteroaromatics thiophene, furan, oxazole, thiazole, imidazole, pyrazole, triazole, thia-4H-pyrazole and benzo derivatives thereof and as 6-ring heteroaromatic pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.
  • suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethylglucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
  • organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethylglucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, amino
  • physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.
  • L, M and T are each independently carbon
  • R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkynyl,
  • R 2 is hydrogen, C -C 0 alkyl, C 2 -C ⁇ 0 alkenyl, C is 2 -C ⁇ 0 -
  • X is halogen, oxygen, sulfur or the group
  • X and R 2 together form a C 3 -C 10 -cycloalkyl ring which may optionally contain one or more heteroatoms and optionally mono- or polysubstituted by hydroxy, C ⁇ C 8 alkyl, hydroxy ⁇ -C 6 alkyl or Halogen may be substituted,
  • a and B are each independently hydrogen
  • R 3 and R 4 are each independently of one another hydrogen,
  • R 7 is -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl,
  • C 3 -C 7 -cycloalkyl where the C 3 -C -cycloalkyl ring has the meaning given under R 2 , or represents the group -NR 3 R 4 , or represents optionally mono- or polysubstituted, identical or different, with hydroxyl, d-Ce-alkoxy, halogen, phenyl, -NR 3 R 4 or phenyl which is itself, mono- or polysubstituted or differently or different with halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 6 C alkyl, halo-C C 6 -alkoxy, substituted Ci-do alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C 10 alkynyl or C 3 -C 7 - cycloalkyl, or is phenyl which itself may optionally be monosubstituted or polysubstituted, identically
  • L, M and T are each independently of one another carbon, oxygen, nitrogen or sulfur, where at least one heteroatom must be present in the ring,
  • R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkynyl,
  • Alkyl) 2 -SO (C 1 -C 6 -alkyl), -SO 2 (C 1 -C 6 -alkyl), CC 6 -alkanoyl, -CONR 3 R 4 , -COR 5 , C 1 -C 6 -alkyl OAc, phenyl or with the group R 6 substituted d-Cio-alkyl, C 2 -C ⁇ o-alkenyl, C 2 -C ⁇ o-alkynyl, aryl, heteroaryl or C 3 -C -cycloalkyl, the ring of C 3 -C 7 -
  • Alkyl or halogen can be substituted, A and B are each independently hydrogen,
  • R 3 and R 4 are each independently of one another hydrogen,
  • R 5 is hydroxy, benzoxy, C 1 -C 6 -alkyl, C 6 -C 6 -alkylthio or C 1 -C 6 -alkoxy
  • R 6 is an optionally mono- or polysubstituted, identical or different, with halogen, hydroxy, C 1 -C 6 -alkyl , Ci-C ⁇ -alkoxy or -SO 2 NR 3 R 4 substituted
  • C 3 -C -cycloalkyl where the C 3 -C 7 -cycloalkyl ring has the meaning given under R 2 , or represents the group -NR 3 R 4 , or represents mono- or polysubstituted, identical or different, with hydroxyl, dC 6 -alkoxy,
  • Halogen and their isomers, diastereomers, enantiomers and salts.
  • L, M and T are each independently carbon
  • R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, CC 6 -alkynyl,
  • R 2 is hydrogen, C 2 -C ⁇ o-alkynyl, C 3 -C 7 -cycloalkyl or optionally mono- or polysubstituted, identically or differently, with hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 7 - Cycloalkyl, -N (-CC 6 -alkyl) 2 , -NHC 3 -C 7 - cycloalkyl, -COR 5 , phenyl or substituted with the group R 6 d-Cio-alkyl, phenyl or C 3 -C 7 - cycloalkyl , wherein the C 3 -C -cycloalkyl ring, the under
  • X is halogen, oxygen, sulfur or the group -NH- or -N (-CC 3 alkyl) - or X and R 2 together form a C3-C-
  • Alkyl or halogen can be substituted, A and B are each independently hydrogen,
  • Halogen, hydroxy or for the group -SR 7 , -S (O) R 7 , -SO 2 R 7 , R 3 and R 4 are each independently of one another hydrogen,
  • R 5 is hydroxy, benzoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio or C 1 -C 6 -alkoxy
  • R 6 represents an optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or -SO 2 NR 3 R 4 -benzylthio, phenyloxy or C 3 -C 7 -cycloalkyl- Ring, wherein the C 3 -C 7 cycloalkyl ring has the meaning given under R 2 of claims 1 to 3,
  • R 7 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, benzyl,
  • D, E, G, L, M and T are each independently carbon
  • R 1 is halogen
  • R 2 is hydrogen, C 2 -C ⁇ 0 alkynyl or optionally mono- or polysubstituted, identical or different with hydroxy, Ci -Ce-alkyl, CC 6 -alkoxy, COR 5 , C 3 -C 7 -cycloalkyl, -N (-CC 6 -alkyl) 2 , -NHC 3 -C 7 - cycloalkyl or phenyl-substituted d-Cio-alkyl .
  • Phenyl or C 3 -C 7 cycloalkyl said C 3 -C 7 - cycloalkyl ring having under R 2 in claim 1 to 3 meaning indicated, and phenyl or C 3 -C - cycloalkyl may be optionally substituted with hydroxy,
  • X is halogen, oxygen, sulfur or the group
  • -NH- or -N (-CC 3 -alkyl) - or X and R 2 together is a C3-C- form o-cycloalkyl ring which may optionally contain one or more heteroatoms and may optionally be mono- or polysubstituted by hydroxy, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl or halogen,
  • a and B are each independently of one another Hydrogen, halogen or for the group -SR 7 , -S (O) R 7 or
  • R 3 and R 4 are each independently hydrogen or
  • R 6 is substituted C 1 -C 6 -alkyl
  • R 5 is C 1 -C -alkyl
  • R 6 represents an optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or -SO 2 NR 3 R 4
  • Halogen and their isomers, diastereomers, enantiomers and salts.
  • Q is pyridine, thiophene, 1, 3,4-thiadiazole, 1, 2,4-triazole, R 1 is bromine or chlorine,
  • R 2 is hydrogen, C 2 0 -C ⁇ -alkynyl or optionally mono- or polysubstituted, identically or differently, with hydroxy, -C 6 alkyl, -C 6 alkoxy, COR 5, C 3 -C 7 cycloalkyl, -N (C 1 -C 6 -alkyl) 2 , -NHC 3 -C 7 -cycloalkyl or phenyl-substituted C 1 -C 10 -alkyl, phenyl or C 3 -C -cycloalkyl, where the C 3 -C -cycloalkyl ring is the same as under R 2 of claims 1 to 3 given meaning, and phenyl or C 3 -C -cycloalkyl are optionally substituted by hydroxy, X is chlorine, oxygen, sulfur or the group - NH- or -N (-C -C 3 -alkyl) - stands or X and R 2 together form a
  • a and B are each independently hydrogen
  • Chlorine or for the group -SR 7 , -S (0) R 7 or -SO 2 R 7 , R 3 and R 4 are each independently hydrogen or optionally mono- or polysubstituted, identical or different, with hydroxy, dC 6 alkoxy, dC 6 - alkylthio, -N (C ⁇ -C6 alkyl) 2, the group R 6 or -N (C Ce-alkyl) - R 6 substituted C ⁇ -C 6 alkyl, R 5 is C 1 -C 6 -alkyl,
  • R 6 is an optionally mono- or polysubstituted by identical or different halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or -SO 2 NR 3 R 4 -substituted C 3 -C 7 -cycloalkyl, where the C 3 -C 7 -cycloalkyl ring under
  • L, M and T are each independently carbon
  • Oxygen, nitrogen or sulfur are, wherein at least one heteroatom must be present in the ring, R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkynyl,
  • R 2 is hydrogen, CVCio-alkyl. C 2 0 -C ⁇ alkenyl, C2 -C ⁇ 0 -
  • C 1 -C 6 -alkoxy or may be substituted by the group -CF 3 or -OCF 3
  • X is halogen, oxygen, sulfur or the group -NH- or -N ( C 1 -C 3 -alkyl) - or X and R 2 together represent a C 3 -C- form o-cycloalkyl ring, optionally one or more heteroatoms and optionally may be mono- or polysubstituted by hydroxy, C 1 -C 6 -alkyl, hydroxyC-CQ-alkyl or halogen
  • a and B are each independently hydrogen, hydroxy, halogen or -SR 7 , -
  • R 5 is hydroxy, benzoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio or C 1 -C 6 -alkoxy,
  • R 6 is an optionally mono- or polysubstituted by identical or different substituents with C 1 -C 6 -alkyl or hydroxy, C 3 -C -cycloalkyl ring, wherein the ring has the meaning given above, R 7 is Ci-Ce-alkyl , C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, benzyl,
  • C 3 -C 7 -cycloalkyl as defined above or for the group -NR 3 R 4 , or for mono- or polysubstituted by identical or different hydroxy, d-Ce-alkoxy, halogen, phenyl, -NR 3 R 4 or phenyl, which itself, a-or 6 alkoxy may be substituted more than once, identically or differently with halogen, hydroxy, Ci-Ce-alkyl, dC 6 -alkoxy, halo-CrC 6 alkyl, halo-C C, substituted d- Cio-alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, or C 3 -C 7 - cycloalkyl, or is phenyl, which turns itself or polysubstituted, identically or differently with halogen, hydroxy , C 1 -C 6 -alkyl or C 1 -C 6 -alk
  • L, M and T jjeewweeiillss independently of one another are carbon, oxygen, nitrogen or sulfur, wherein at least one hetero atom contained in the ring must be, R 1 represents halogen, R 2 is hydrogen, C 2 0 -C ⁇ alkynyl, C 3 - C 7 -cycloalkyl or mono- or polysubstituted, identically or differently, with hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, COR 5 , -N (CC 6 -alkyl) 2 , -NHC 3 -C 7 - Cycloalkyl or C 3 -C 7 -cycloalkyl-substituted C 1 -C 10 -alkyl or C 3 -C 7 -cycloalkyl
  • a or B may each independently be hydrogen, halogen or the group -SR 7 , -S (O) R 7 or
  • R 7 , R 3 and R 4 are each independently hydrogen
  • R 5 is Ci-Ce-alkyl
  • R 6 is an optionally mono- or polysubstituted by identical or different CC 6 alkyl or hydroxy-substituted C 3 -C -cycloalkyl ring, where the ring has the abovementioned meaning,
  • R 7 is C 1 -C 6 -alkyl, benzyl or the group -NR 3 R 4 , and their isomers, diastereomers, enantiomers and salts.
  • L, M and T are each independently of one another carbon, oxygen, nitrogen or sulfur, where at least one heteroatom must be present in the ring,
  • R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkynyl,
  • Ce-alkyl C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, -NHC-C 6 -alkyl, -N (C 1 -C 6 -alkyl) 2 , -SO (CC 6 - Alkyl) , -SO 2 (C 1 -C 6 -alkyl), C 1 -C 6 -alkanoyl, -CONR 3 R 4 , -COR 5 , C 1 -C 6 -alkyl OAc, phenyl or C 1 -C 10 -alkyl substituted with the group -R 6 , C 2 0 -C ⁇ alkenyl, C2 -C ⁇ 0 -
  • Halogen C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, amino, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl alkyl, -NHC C 6 alkyl, -N (dC 6 - alkyl) 2, -SO (d-Ce-alkyl), -S0 2 (C ⁇ -C6 alkyl), CC 6 - alkanoyl, -CONR 3 R 4 , -COR 5 , CC 6 alkylOAc,
  • Phenyl or may be substituted with the group R 6 , wherein the phenyl itself optionally one or more times, same or different with halogen, hydroxy, -CC 6 alkyl, dC 6 alkoxy, or with the group -CF 3 or -OCF 3 can be substituted,
  • R 3 and R 4 are each independently hydrogen
  • R 5 is hydroxy, benzoxy, -CC 6 alkylthio or Ci-Ce-
  • R 6 is a C 3 -C cycloalkyl ring, wherein the ring has the meaning indicated above, R 7 is Ci-Ce-alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , Benzyl,
  • C 3 -C 7 cycloalkyl with the above Meaning or for the group -NR 3 R 4 , or for one or more times, same or different with hydroxy, Ci-Ce-alkoxy, halogen, phenyl, -NR 3 R 4 or phenyl, which itself, one or more times identical or different with halogen, hydroxy,
  • Halogen, hydroxy, dC 6 alkyl or Ci-Ce-alkoxy, halo-d-Ce-alkyl, halo-dC 6 alkoxy may be substituted, as well as their isomers, diastereomers, enantiomers and salts effective.
  • L, M and T are each independently carbon
  • R 1 is halogen
  • R 3 and R 4 are hydrogen, R 7 is C 1 -C 6 -alkyl, benzyl or the group -NR 3 R 4 , and their isomers,
  • the compounds of the present invention substantially inhibit cyclic-dependent kinases, as well as their anti-cancer effects such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapeutic-induced alopecia and mucositis, cardiovascular diseases such as strictures, atherosclerosis and restenosis, infectious diseases such. As caused by unicellular parasites such as Trypanosoma, Toxoplasma or Plasmodium, or by fungi, nephrological diseases such.
  • Glomerulonephritis chronic neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS, dementia and Alzheimer's disease, acute neurodegenerative diseases such as ischaemias of the brain and neurotrauma, viral infections such as. B.
  • Cytomegalovirus infections herpes, hepatitis B and C, and HIV related disorders.
  • the eukaryotic cell division cycle ensures the duplication of the genome and its distribution to the daughter cells by undergoing a coordinated and regulated sequence of events.
  • the cell cycle is divided into four consecutive phases: the G1 phase represents the time before DNA replication in which the cell grows and is susceptible to external stimuli.
  • the S phase the cell replicates its DNA
  • the G2 phase it prepares for entry into mitosis.
  • mitosis M phase
  • the replicated DNA is separated and cell division is performed.
  • the cyclin-dependent kinases CDKs
  • CDKs a family of serine / threonine kinases whose members require the binding of a cyclin (Cyc) as a regulatory subunit to their activation, drive the cell through the cell cycle.
  • CDK / CycD, CDK2 / CycE, CDK2 / CycA, CDK1 / CycA and CDK1 / CycB are important for the basic function of the cell cycle.
  • Some members of the CDK enzyme family have a regulatory function by affecting the activity of the aforementioned cell cycle CDKs, while other members of the CDK enzyme family have not yet been assigned a particular function.
  • CDK5 is characterized by the fact that it has an atypical, non-cyclic regulatory subunit (p35), and its activity in the brain is highest.
  • Rb retinoblastoma protein
  • HDAC histone deacetylases
  • Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI / SNF and Rb-hSWI / SNF, Cell 101, 79-89).
  • the phosphorylation of Rb by CDKs releases bound E2F transcription factors and leads to transcriptional activation of genes whose products are required for DNA synthesis and progression through S phase.
  • Rb phosphorylation causes the dissolution of the Rb-HDAC complexes, thereby activating additional genes.
  • the phosphorylation of Rb by CDKs is equivalent to crossing the "restriction point".
  • CDK2 / CycE and CDK2 / CycA complexes necessary, e.g., the activity of E2F-type transcription factors is turned off by CDK2 / CycA phosphorylation as soon as the cells enter S-phase.
  • CDK1 complexed with CycA or CycB controls the entry and passage of G2 and M ( Figure 1).
  • the cycle is strictly regulated and controlled.
  • the enzymes necessary for the progression through the cycle must be activated at the right time, and also shut down once the appropriate phase has passed.
  • Corresponding control points arrest the progression through the cell cycle if DNA damage is detected, or the DNA replication, or the structure of the spindle apparatus has not yet ended.
  • the activity of the CDKs is directly controlled by various mechanisms, such as cyclone synthesis and degradation, complexing of the CDKs with the corresponding cyclins, phosphorylation and dephosphorylation of regulatory threonine and tyrosine residues, and binding of natural inhibitory proteins.
  • CDK activating kinases Thr160 / 161 of CDK1
  • CDK activating kinases Thr160 / 161 of CDK1
  • Wee1 / Myt1 kinases inactivate CDK1 by phosphorylation of Thr14 and Tyr15.
  • CDK / Cyc complexes very important is the regulation of the activity of the CDK / Cyc complexes by two families of natural CDK inhibitor proteins (CKIs), the p21 gene family protein products (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19).
  • CKIs CDK inhibitor proteins
  • p21, p27, p57 CDK inhibitor proteins
  • p16 gene family p15, p16, p18, p19.
  • Members of the p21 family bind to cyclin complexes of CDKs 1, 2,4,6, but only inhibit complexes containing CDK1 or CDK2.
  • Members of the p16 family are specific inhibitors of the CDK4 and CDK6 complexes.
  • Control points allow the cell to track the orderly progress of each phase during the cell cycle.
  • the key control points are at the junction of G1 to S and G2 to M.
  • the G1 checkpoint ensures that the cell will not begin DNA synthesis if it is not properly nourished, correctly interacts with other cells or the substrate, and its DNA is intact.
  • the G2 / M checkpoint ensures complete replication of the DNA and assembly of the mitotic spindle before the cell enters mitosis.
  • the G1 control point is activated by the gene product of the p53 tumor suppressor gene.
  • p53 is activated upon detection of changes in the metabolism or genomic integrity of the cell, and may either trigger a halt in cell cycle progression or apoptosis.
  • the transcriptional activation of the expression of the CDK inhibitor protein p21 by p53 plays a decisive role.
  • a second branch of the G1 control point involves activation of the ATM and Chk1 kinases following DNA damage by UV light or ionizing radiation, and finally phosphorylation and subsequent proteolytic degradation of cdc25A phosphatase (Milan N. et al., 2000) of human cdc25A in response to DNA damage, Science 288, 1425-1429). This results in a locking of the Zelizyklusses, since the inhibitory phosphorylation of the CDKs is not removed.
  • both mechanisms are similarly involved in halting progression through the cell cycle.
  • Loss of regulation of the cell cycle and loss of control point function are characteristics of tumor cells.
  • the CDK-Rb signaling pathway is affected by mutations in over 90% of human tumor cells. These mutations, eventually leading to inactivating phosphorylation of RB include overexpression of D and E cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of p16-type CDK inhibitors, as well as increased (p27) or decreased (CycD) protein degradation ,
  • the second set of genes hit by mutations in tumor cells encodes components of the control points.
  • p53 which is essential for the G1 and G2 / M control points, is the most frequently mutated gene in human tumors (approximately 50%).
  • CDK2 / Cyc complexes occupy a crucial position during cell cycle progression: (1) Both dominant-negative forms of CDK2 and transcriptional repression of CDK2 expression by anti-sense oligonucleotides cause cell cycle progression to stop. (2) The inactivation of the CycA gene in mice is lethal. (3) Disturbance of the function of the CDK2 / CycA complex in cells by cell-permeable peptides led to tumor cell-selective apoptosis (Chen YNP et al., 1999. Selective killing of transformed cells by cyclin / cyclin-dependent kinase 2 antagonists. Proc. Natl. Acad. See U.S.A. 96, 4325-4329).
  • Cyclin-dependent kinase inhibitors useful targets in cell cycle regulation.
  • a pharmaceutical preparation in addition to the active ingredient for enteral or parenteral administration suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
  • suitable pharmaceutical, organic or inorganic inert carrier materials such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
  • the pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they also contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer.
  • adjuvants such as preserv
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • carrier systems are surface-active adjuvants such as salts of bile acids or animal or vegetable phospholipids, but also Mixtures thereof as well as liposomes or their constituents are used.
  • tablets, dragees or capsules with talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
  • talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
  • the application can also take place in liquid form, for example as juice, which may be accompanied by a sweetener.
  • enteral, parenteral and oral applications are also the subject of the present invention.
  • the dosage of the active ingredients may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease being treated, and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, which dose may be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the present invention is the use of the compounds of the general formula I or I f for the preparation of a medicament for the treatment of cancer, autoimmune diseases, cardiovascular diseases, chemotherapeutic-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, including cancerous tumors and leukemia, autoimmune psoriasis, alopecia and multiple sclerosis, cardiovascular disease, stenosis, arteriosclerosis and restenosis, infectious diseases caused by unicellular parasite diseases, nephrology glomerulonephritis, chronic neurodegenerative diseases Huntington's disease , amyotrophic lateral sclerosis, Parkinson's disease, AIDS, dementia and Alzheimer's disease, in acute neurodegenerative diseases Brain ischemias and neurotrauma, and viral infections include cytomegalovirus infections, herpes, hepatitis B or C, and HIV disorders.
  • medicaments for the treatment of the abovementioned disorders which contain at least one compound according to the general formula I or If, as well as medicaments with suitable formulating and carrier substances.
  • the compounds of general formula I or I f according to the invention are, inter alia, outstanding inhibitors of cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, and glycogen synthase kinase (GSK). 3R).
  • cyclin-dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, and glycogen synthase kinase (GSK). 3R).
  • the preparation of the salts is carried out in a customary manner by adding a solution of the compound of formula I or I f with the equivalent amount or an excess of a base or acid, optionally in solution, and separating the precipitate or working up in the solution usually ,
  • R ' is C1-C3-alkyl in consistency with formula I.
  • a solution of 11.3 g (49.6 mmol) of a mixture of 4-nitro-thiophene-2-sulfonyl chloride and 5-nitro-thiophene-2-sulfonyl chloride (ratio: 1.4 / 1.0) in acetone is added with stirring to a saturated solution of ammonia 170 ml of acetone at -35 ° C given. After 30 minutes, the batch is filtered and concentrated. The crude product is dissolved in 100 ml of ethanol without further purification. It is mixed with 6 g of Raney nickel and hydrogenated for 8 h under low pressure at room temperature. The mixture is filtered and concentrated.
  • the present invention thus also relates to compounds of the general formula Ia
  • a further subject of the present invention are compounds of general formula Ib
  • R 1 and R 2 have the meanings given in the general formula (I) or (I f ) and their use as intermediates for the preparation of the compound of the general formula I.
  • Another object of the invention relates to compounds of general formula Ic
  • X is halogen or NH 2 and Y is hydrogen and Z is NH 2 or NO 2 or
  • Y is NH 2 or NO 2 and Z is hydrogen, and their use as
  • the agents according to the invention can also be used for the treatment of cancer, autoimmune diseases, cardiovascular diseases, chemotherapeutic-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, solid tumors and leukemia under cancer, autoimmune diseases psoriasis, alopecia and multiple sclerosis, cardiovascular diseases, stenoses, atherosclerosis and restenosis, diseases caused by unicellular parasite infectious diseases, nephrological diseases glomerulonephritis, chronic neurodegenerative diseases Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases brain ischemia and neurotrauma, and viral infections Cytomegalus infections, herpes, hepatitis B o the C, and HIV disorders are used.
  • CDK2 and CycE GST fusion proteins purified from baculovirus-infected insect cells were purchased from Proquinase, Freiburg. Histone IIIS, which was used as a kinase substrate, was purchased from Sigma.
  • CDK2 / CycE (50 ng / measuring point) was incubated for 15 min at 22 ° C in the presence of various concentrations of test substances (0 ⁇ M, as well as within the range 0.01-100 ⁇ M) in assay buffer [50 mM Tris / HCl pH8.0, 10 mM MgCl 2 , 0.1 mM Na ortho-vanadate, 1.0 mM dithiothreitol, 0.5 ⁇ M adenosine trisphosphate (ATP), 10 ⁇ g / measurement point histone IIIS, 0.2 ⁇ Ci / measurement point 33 P-gamma ATP, 0, 05% NP40, 12.5% dimethylsulfoxide].
  • assay buffer 50 mM Tris / HCl pH8.0, 10 mM MgCl 2 , 0.1 mM Na ortho-vanadate, 1.0 mM dithiothreitol, 0.5 ⁇ M adenosine trisphosphate (ATP
  • Cultured human tumor cells (as indicated) were plated at a density of 5000 cells / measuring point in a 96-well multi-well plate in 200 ⁇ l of the appropriate growth medium. After 24 hours, the cells of one plate (zero point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 ⁇ l) containing the test substances at various concentrations (0 ⁇ M and in the range 0.01 - 30 ⁇ M, the final concentration of the solvent dimethylsulfoxide was 0.5%) were added replaced. The cells were incubated for 4 days in the presence of the test substances. Cell proliferation was determined by staining the cells with crystal violet.

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Abstract

La présente invention concerne des dérivés de 2-hétéroaryl-pyrimidine de la formule générale (I) ou (If) utilisés comme inhibiteurs de la kinase dépendante des cyclines. L'invention concerne également la production et l'utilisation de ces dérivés comme médicaments pour traiter différentes maladies.
PCT/EP2003/001995 2002-03-11 2003-02-26 2-heteroaryle-pyrimidines inhibitrices de la kinase dependante des cyclines, leur production et leur utilisation comme medicaments Ceased WO2003076437A1 (fr)

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AU2003212282A AU2003212282A1 (en) 2002-03-11 2003-02-26 Cdk inhibiting 2-heteroaryl pyrimidine, the production thereof, and use thereof as a medicament
EP03708151A EP1483260A1 (fr) 2002-03-11 2003-02-26 2-heteroaryle-pyrimidines inhibitrices de la kinase dependante des cyclines, leur production et leur utilisation comme medicaments
JP2003574654A JP2005526765A (ja) 2002-03-11 2003-02-26 Ｃｄｋ−阻害性２−ヘテロアリール−ピリミジン類、それらの生成及び医薬としての使用

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