Macrocyclic pyrimidines, their production and use as pharmaceutical agents
Macrocyclic pyrimidine derivatives of general formula I in which R 1 to R 5 , X, Y, A, B, m and n have the meanings that are contained in the description, as inhibitors of the cyclin-dependent kinase, their processes for production as well as their use as medications for treating various diseases are described.
1. Compounds of formula I
in which
A stands for phenylene,
B stands for a bond or for C 1 -C 12 -alkylene, C 2 -C 12 -alkenylene, C 2 -C 12 -alkinylene, C 3 -C 8 -cycloalkylene, or phenylene that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, cyano, nitro, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 1 -C 6 -hydroxyalkyl, —(CH 2 ) p SO 3 R 8 , or with the group —NR 8 R 9 , —NR 8 COR 9 , —NR 8 CSR 9 , —NR 8 SOR 9 , —NR 8 SO 2 R 9 , —NR 8 CONR 8 R 9 , —NR 8 COOR 9 , —NR 8 C(NH)NR 9 R 10 , —NR 8 CSNR 9 R 10 , —NR 8 SONR 9 R 10 , —NR 8 SO 2 NR 9 R 10 , —COR 8 , —CSR 8 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —SO 3 R 8 , —CO 2 R 8 , —CONR 8 R 9 , —CSNR 8 R 9 , —SR 8 or —CR 8 (OH)—R 9 ,
X and Y, in each case independently of one another, stand for oxygen, sulfur or for the group —NR 11 , —NR 11 (CH 2 )—, —NR 11 O—, —ONR 11 —, ═CR 6 R 7 , ═C═O, ═C═S, ═SO, ═SO 2 , —C(O)O—, —OC(O)—, —S(O)O—, —OS(O)—, —S(O) 2 O—, —OS(O) 2 —, —CONR 8 —, —N(COR 8 )—, —N(COOR 8 )—, —N(CONR 8 R 9 )—, —NR 8 CO—, —OCONR 8 —, —NR 8 C(O)O—, —CSNR 8 —, —NR 8 CS—, —OCSNR 8 —, —NR 8 CSO—, —SONR 8 —, —NR 8 SO—, —SO 2 NR 8 —, —S(O) 2 N(COR 8 )—, —NR 8 SO 2 —, —NR 8 CONR 9 —, —NR 8 CSNR 9 —, —NR 8 SONR 9 —, —NR 8 SO 2 NR 9 —, —NR 8 C(O)NR 9 — or —NR 8 C(S)NR 9 —,
R 1 and R 5 , in each case independently of one another, stand for hydrogen, hydroxy, halogen, nitro, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, the group —C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyloxy, —(CH 2 ) p PO 3 (R 10 ) 2 , —NR 8 R 9 , —NR 8 COR 9 , —NR 8 CSR 9 , —NR 8 SOR 9 , —NR 8 SO 2 R 9 , —NR 8 CONR 9 R 10 , —NR 8 COOR 9 , —NR 8 C(NH)NR 9 R 10 , —NR 8 CSNR 9 R 10 , —NR 8 SONR 9 R 10 , —NR 8 SO 2 NR 9 R 10 —, —COR 8 , —CSR 8 , —S(O)R 8 , —S(O)(NH)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —S(O) 2 N═CH—NR 8 R 9 —, SO 3 R 8 , —CO 2 H, —CO 2 R 8 , —CONR 8 R 9 , —CSNR 8 R 9 , —SR 8 or —CR 8 (OH)—R 9 , or for C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl, or C 3 -C 10 -cycloalkyl, that is substituted in one or more places in the same way or differently with hydroxy, C 1 -C 6 -alkoxy, halogen, phenyl or with the group —NR 3 R 4 , and the phenyl, C 3 -C 10 -cycloalkyl, C 3 -C 12 -aryl, and —(CH 2 ) p —C 3 -C 18 -heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, or with the group —CF 3 or —OCF 3 —,
R 2 stands for hydrogen or C 1 -C 10 -alkyl,
R 3 stands for hydrogen, halogen, nitro, cyano, C 1 -C 10 -alkyl, halo-C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl, C 3 -C 10 -cycloalkyl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, amino, —NH—(CH 2 ) p —C 3 -C 10 -cycloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —NHC 1 -C 6 -alkyl, —N(C 1 -C 6 -alkyl) 2 , —SO(C 1 -C 6 -alkyl), —SO 2 (C 1 -C 6 -alkyl), C 1 -C 6 -alkanoyl, —CONR 8 R 9 , —COR 10 , C 1 -C 6 -alkylOAc, carboxy, or for the group —NR 8 R 9 , or for C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl, or C 3 -C 10 -cycloalkyl, that is substituted in one or more places in the same way or differently with hydroxy, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, amino, cyano, C 1 -C 6 -alkyl, —NH—(CH 2 ) p —C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl, C 1 -C 6 -hydroxyalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —NHC 1 -C 6 -alkyl, —N(C 1 -C 6 -alkyl) 2 , —SO(C 1 -C 6 -alkyl), —SO 2 (C 1 -C 6 -alkyl), C 1 -C 6 -alkanoyl, —CONR 8 R 9 , —COR 10 , C 1 -C 6 -alkylOAc, carboxy, —(CH 2 ) p PO 3 (R 10 ) 2 or with the group —NR 8 R 9 ,
R 4 stands for hydrogen, halogen or C 1 -C 4 -alkyl,
R 6 , R 7 , R 8 ,
R 9 , R 10
and R 11 , in each case independently of one another, stand for hydrogen or for C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl, C 3 -C 10 -cycloalkyl,
m stands for 0 to 8, and
n and p stand for 0 to 6, or isomers, diastereomers, enantiomers and salts thereof.
2. Compounds of formula (I),
in which
A stands for phenylene,
B stands for a bond or for C 1 -C 12 -alkylene, C 3 -C 8 -cycloalkylene, or phenylene or thiophenylene that is optionally substituted in one or more places in the same way or differently with hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl or —(CH 2 ) p SO 3 R 8 ,
X and Y, in each case independently of one another, stand for oxygen, or for the group —NR 11 —, —NR 11 (CH 2 )—, —CONR 8 —, —SO 2 NR 8 — or —NR 8 CONR 9 —,
R 1 and R 5 , in each case independently of one another, stand for hydrogen, halogen, nitro, C 1 -C 6 -alkyl, or for —NR 8 R 9 , —C 1 -C 6 -alkyloxy-C 1 C 6 -alkyloxy or —S(O) 2 NR 8 R 9 ,
R 2 stands for hydrogen,
R 3 stands for hydrogen, halogen, cyano, C 1 -C 10 -alkyl or —CONR 8 R 9 ,
R 4 stands for hydrogen,
R 8 ,
R 9 ,
and R 11 , in each case independently of one another, stand for hydrogen or for C 1 -C 10 -alkyl,
n stands for 0 to 6,
m stands for 0 to 4, and
p stands for 0 to 6,
or isomers, diastereomers, enantiomers and salts thereof.
3. Compounds of formula (I), according to claim 2 , in which
A stands for phenylene,
B stands for a bond or for C 1 -C 12 -alkylene, cyclohexylene or phenylene that is optionally substituted in one or more places in the same way or differently with hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl or —(CH 2 )SO 3 R 8 ,
X stands for oxygen or for the group —CONR 8 —, —SO 2 NR 8 — or —NR 8 CONR 9 —,
Y stands for oxygen or for the group —NR 11 —,
R 1 and R 5 , in each case independently of one another, stand for hydrogen, amino, halogen, nitro, C 1 -C 6 -alkyl, or for the group —NR 8 R 9 , —C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyloxy or —S(O) 2 NR 8 R 9 ,
R 2 stands for hydrogen,
R 3 stands for hydrogen, halogen, cyano, C 1 -C 10 -alkyl, or —CONR 8 R 9 ,
R 4 stands for hydrogen,
R 8 , R 9 and R 11 , in each case independently of one another, stand for hydrogen or for methyl or isobutyl,
m stands for 0 to 4, and
p stands for 0 to 6,
as well as isomers, diastereomers, enantiomers, and salts thereof.
4. Compounds of formula (I), according to claim 2 , in which
A stands for phenylene,
B stands for a bond or for C 1 -C 12 -alkylene that is optionally substituted in one or more places in the same way or differently with hydroxy, C 1 -C 6 -hydroxyalkyl or —(CH 2 )SO 3 R 8 ,
X stands for oxygen or for the group —SO 2 NR 8 — or —NR 8 CONR 9 —,
Y stands for the group —NR 11 —,
R 1 and R 5 , in each case independently of one another, stand for hydrogen, amino, halogen, nitro or for the group —S(O) 2 NR 8 R 9 ,
R 2 stands for hydrogen,
R 3 stands for halogen or cyano,
R 4 stands for hydrogen,
R 8 , R 9 and R 11 in each case stand for hydrogen, and
m stands for 0 to 4,
or isomers, diastereomers, enantiomers and salts thereof.
5. Process for the production of the compounds of formula I according to claim 1 , wherein either
a) compounds of formula VIII
in which R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, A, B, m and n have the meanings that are indicated in formula I, and L stands for a leaving group, are cyclized with a an acid to compounds of formula I, or
b) the acyclic precursors of formula (IX)
in which R 1 , R 3 , R 4 , R 5 , X, Y, A, B, m and n have the meanings that are indicated in formula I, and L stands for a leaving group, are first reduced to amine in a solvent and a reducing agent at 0° C. until reflux takes place and then the intermediately formed amine is cyclized to the compounds of formula I.
6. A method for the treatment of hormone-independent human breast cancer, human nonsmall-cell lung cancer, human colon cancer, hormone-independent human prostate cancer, or hormone-independent, multiple pharmaceutical agent-resistant human breast cancer, comprising administering to a host in need thereof a compound of formula I according to claim 1 .
7. A pharmaceutical composition, comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition, comprising compound according to claim 2 and suitable formulation substances and vehicles.
9. Compounds of formula I
in which
A stands for phenylene,
B stands for C 1 -C 12 -alkylene, C 3 -C 8 -cycloalkylene, or phenylene that is optionally substituted in one or more places in the same way or differently with hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, or —(CH 2 ) p SO 3 R 8 ,
X and Y, in each case independently of one another, stand for oxygen, sulfur or for the group —NR 11 —, —NR 11 (CH 2 )—, —CONR 8 —, —SO 2 NR 8 , —S(O) 2 N(COR 8 )—, —NR 8 SO 2 —, or —NR 8 CONR 9 —,
R 1 and R 5 , in each case independently of one another, stand for hydrogen, halogen, nitro, C 1 -C 6 -alkyl or for the group —C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyloxy, —NR 8 R 9 , —NR 8 COR 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 N═CH—NR 8 R 9 , —CO 2 H, —CO 2 R 8 , —CONR 8 R 9 ,
R 2 stands for hydrogen,
R 3 stands for hydrogen, halogen, cyano, C 1 -C 10 -alkyl, —CONR 8 R 9 ,
R 4 stands for hydrogen,
R 6 , R 7 , R 8 ,
R 9 , R 10
and R 11 , in each case independently of one another, stand for hydrogen or for C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, —N(C 1 -C 6 -alkyl) 2 , or —SO(C 1 -C 6 -alkyl),
m stands for 0 to 8,
p stands for 0 to 6, and
n stands for 1
or diastereomers, enantiomers or salts thereof.