HRP20010742A2 - Pyrazolobenzodiazepines as cdk2 inhibitors - Google Patents
Pyrazolobenzodiazepines as cdk2 inhibitors Download PDFInfo
- Publication number
- HRP20010742A2 HRP20010742A2 HR20010742A HRP20010742A HRP20010742A2 HR P20010742 A2 HRP20010742 A2 HR P20010742A2 HR 20010742 A HR20010742 A HR 20010742A HR P20010742 A HRP20010742 A HR P20010742A HR P20010742 A2 HRP20010742 A2 HR P20010742A2
- Authority
- HR
- Croatia
- Prior art keywords
- benzodiazepine
- pyrazolo
- chlorophenyl
- nitro
- methyl
- Prior art date
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- QBCJSMSLBBCZGU-UHFFFAOYSA-N pyrazolo[3,4-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=NN=C3C=CC2=C1 QBCJSMSLBBCZGU-UHFFFAOYSA-N 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 3
- 101150073031 cdk2 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 199
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 19
- 150000002367 halogens Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000000651 prodrug Chemical group 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- -1 5-(2-chlorophenyl)-7-amino-pyrazolo[3,4][1,4]benzodiazepine 5-phenyl-7-chloro-pyrazolo[3,4][1,4]benzodiazepine Chemical compound 0.000 claims description 14
- 210000001072 colon Anatomy 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 210000000481 breast Anatomy 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000002207 metabolite Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- PHTNFRNPQIUWKC-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-cyclopropyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1C1CC1 PHTNFRNPQIUWKC-UHFFFAOYSA-N 0.000 claims description 3
- JJGGQXHWUMXVAS-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-methyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical group N=1C(C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl JJGGQXHWUMXVAS-UHFFFAOYSA-N 0.000 claims description 3
- IZGJNHSAHZFTKD-UHFFFAOYSA-N 7-iodo-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(I)C=C2C=1C1=CC=CC=C1 IZGJNHSAHZFTKD-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000023958 prostate neoplasm Diseases 0.000 claims description 3
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 2
- CGJDUGAFOYIHTB-UHFFFAOYSA-N 1-[5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepin-3-yl]-n,n-dimethylmethanamine Chemical compound N=1C(CN(C)C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl CGJDUGAFOYIHTB-UHFFFAOYSA-N 0.000 claims description 2
- XTWNGXKBMHZIER-UHFFFAOYSA-N 3-benzyl-5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1CC1=CC=CC=C1 XTWNGXKBMHZIER-UHFFFAOYSA-N 0.000 claims description 2
- HSFQXDXHXDMILT-UHFFFAOYSA-N 3-butan-2-yl-5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C(C)CC)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl HSFQXDXHXDMILT-UHFFFAOYSA-N 0.000 claims description 2
- UHLHKEDGAYUSTO-UHFFFAOYSA-N 3-methyl-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 UHLHKEDGAYUSTO-UHFFFAOYSA-N 0.000 claims description 2
- OFWRSDREYGYKGJ-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-(1h-imidazol-5-yl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1C1=CNC=N1 OFWRSDREYGYKGJ-UHFFFAOYSA-N 0.000 claims description 2
- WNDSNMARKFKCIF-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-(2-methylpropyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(CC(C)C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl WNDSNMARKFKCIF-UHFFFAOYSA-N 0.000 claims description 2
- XULTYYGWUDIBIW-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-(methoxymethyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(COC)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl XULTYYGWUDIBIW-UHFFFAOYSA-N 0.000 claims description 2
- KMXPHGKNZQNROX-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-ethenyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=C(C=C)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1Cl KMXPHGKNZQNROX-UHFFFAOYSA-N 0.000 claims description 2
- BGAWSOWJMONNFD-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-ethyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(CC)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl BGAWSOWJMONNFD-UHFFFAOYSA-N 0.000 claims description 2
- QPEVVQRRJHXGRY-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=CC=C2C=1C1=CC=CC=C1Cl QPEVVQRRJHXGRY-UHFFFAOYSA-N 0.000 claims description 2
- SFYHCLIBZXPRMU-UHFFFAOYSA-N 5-(2-chlorophenyl)-3-propan-2-ylpyrazolo[3,4-i][1,4]benzodiazepin-7-amine Chemical compound N=1C(C(C)C)=CN=C2C3=CN=NC3=C(N)C=C2C=1C1=CC=CC=C1Cl SFYHCLIBZXPRMU-UHFFFAOYSA-N 0.000 claims description 2
- MPKKGHVTTPSQPL-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-methoxypyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C(OC)=CC2=C1C1=CC=CC=C1Cl MPKKGHVTTPSQPL-UHFFFAOYSA-N 0.000 claims description 2
- KVWPQZLDEBQZSC-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-(1h-pyrazol-5-yl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1C=1C=CNN=1 KVWPQZLDEBQZSC-UHFFFAOYSA-N 0.000 claims description 2
- JWGAEBZTHFZGKM-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-(1h-pyrrol-2-yl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1C1=CC=CN1 JWGAEBZTHFZGKM-UHFFFAOYSA-N 0.000 claims description 2
- HOKRLOYXSZZVKP-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-(2-phenylethyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1CCC1=CC=CC=C1 HOKRLOYXSZZVKP-UHFFFAOYSA-N 0.000 claims description 2
- LXVBZQKLBLFLDJ-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-(trifluoromethyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=C(C(F)(F)F)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1Cl LXVBZQKLBLFLDJ-UHFFFAOYSA-N 0.000 claims description 2
- HPJMNQBJIUWWHZ-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1C1=CC=CC=C1 HPJMNQBJIUWWHZ-UHFFFAOYSA-N 0.000 claims description 2
- WYVODKLLIDDJIN-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-propan-2-ylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C(C)C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl WYVODKLLIDDJIN-UHFFFAOYSA-N 0.000 claims description 2
- PGYWEBOUEIOXHG-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-propylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(CCC)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl PGYWEBOUEIOXHG-UHFFFAOYSA-N 0.000 claims description 2
- GTNNJCPSLJCCLP-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitro-3-pyrazol-1-ylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C(=CC=CC=2)Cl)N=C1N1C=CC=N1 GTNNJCPSLJCCLP-UHFFFAOYSA-N 0.000 claims description 2
- JSOYSJVRPOLDIB-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1Cl JSOYSJVRPOLDIB-UHFFFAOYSA-N 0.000 claims description 2
- AMPXSKXWAJDCAY-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine-3-carbaldehyde Chemical compound N1=C(C=O)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1Cl AMPXSKXWAJDCAY-UHFFFAOYSA-N 0.000 claims description 2
- FSHHPYCWHJMLSC-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine-3-carbonitrile Chemical compound N1=C(C#N)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1Cl FSHHPYCWHJMLSC-UHFFFAOYSA-N 0.000 claims description 2
- HPDUBBCFARSERL-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine-3-carboxamide Chemical compound N=1C(C(=O)N)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl HPDUBBCFARSERL-UHFFFAOYSA-N 0.000 claims description 2
- CQCCAQYYDLMFBY-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-(hydroxymethyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carbonitrile Chemical group N=1C(CO)=CN=C2C3=CN=NC3=C(C#N)C=C2C=1C1=CC=CC=C1F CQCCAQYYDLMFBY-UHFFFAOYSA-N 0.000 claims description 2
- DCCPWWJJFVJDKB-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-methyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F DCCPWWJJFVJDKB-UHFFFAOYSA-N 0.000 claims description 2
- YQGSZJOIADOUQX-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine-7-carbonitrile Chemical group N=1C(C)=CN=C2C3=CN=NC3=C(C#N)C=C2C=1C1=CC=CC=C1F YQGSZJOIADOUQX-UHFFFAOYSA-N 0.000 claims description 2
- ZHAYIETWSBKSID-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine-7-carboxamide Chemical group N=1C(C)=CN=C2C3=CN=NC3=C(C(N)=O)C=C2C=1C1=CC=CC=C1F ZHAYIETWSBKSID-UHFFFAOYSA-N 0.000 claims description 2
- ZOYUTSBNHKSWFH-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-iodo-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(I)C=C2C=1C1=CC=CC=C1F ZOYUTSBNHKSWFH-UHFFFAOYSA-N 0.000 claims description 2
- DSCKBFOEVNZHSD-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-iodopyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(I)=C1N=NC=C12 DSCKBFOEVNZHSD-UHFFFAOYSA-N 0.000 claims description 2
- YMWYFETZSIACMI-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1F YMWYFETZSIACMI-UHFFFAOYSA-N 0.000 claims description 2
- BINAVSWISHYZAV-UHFFFAOYSA-N 5-(2-fluorophenyl)-n,n-bis(2-hydroxyethyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carboxamide Chemical compound N1=CC=NC2=C3C=NN=C3C(C(=O)N(CCO)CCO)=CC2=C1C1=CC=CC=C1F BINAVSWISHYZAV-UHFFFAOYSA-N 0.000 claims description 2
- GFKQOJBRLPAZIM-UHFFFAOYSA-N 5-(2-fluorophenyl)-n-(2-hydroxyethyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carboxamide Chemical compound N1=CC=NC2=C3C=NN=C3C(C(=O)NCCO)=CC2=C1C1=CC=CC=C1F GFKQOJBRLPAZIM-UHFFFAOYSA-N 0.000 claims description 2
- XTHFLXPPCJCRCV-UHFFFAOYSA-N 5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC=C1N=NC=C12 XTHFLXPPCJCRCV-UHFFFAOYSA-N 0.000 claims description 2
- NKKYOHGUIFRIGR-UHFFFAOYSA-N 5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carbonitrile Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(C#N)=C1N=NC=C12 NKKYOHGUIFRIGR-UHFFFAOYSA-N 0.000 claims description 2
- ANSFKHHLWMGXOS-UHFFFAOYSA-N 5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C=CC2=C1C1=CC=CC=C1 ANSFKHHLWMGXOS-UHFFFAOYSA-N 0.000 claims description 2
- VDFDWUJTYQVVKI-UHFFFAOYSA-N 7-bromo-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Br)C=C2C=1C1=CC=CC=C1 VDFDWUJTYQVVKI-UHFFFAOYSA-N 0.000 claims description 2
- MKDASOXGVVGWEJ-UHFFFAOYSA-N 7-chloro-5-(2,4-dichlorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound ClC1=CC(Cl)=CC=C1C1=NC=CN=C2C1=CC(Cl)=C1N=NC=C12 MKDASOXGVVGWEJ-UHFFFAOYSA-N 0.000 claims description 2
- NRIUOAGROAIQFX-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Cl)C=C2C=1C1=CC=CC=C1Cl NRIUOAGROAIQFX-UHFFFAOYSA-N 0.000 claims description 2
- ZHWNRINMEYNKEO-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound ClC1=CC=CC=C1C1=NC=CN=C2C1=CC(Cl)=C1N=NC=C12 ZHWNRINMEYNKEO-UHFFFAOYSA-N 0.000 claims description 2
- VIRZTGGBXATKRK-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Cl)C=C2C=1C1=CC=CC=C1F VIRZTGGBXATKRK-UHFFFAOYSA-N 0.000 claims description 2
- HQYMNMKHMKIDEA-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(Cl)=C1N=NC=C12 HQYMNMKHMKIDEA-UHFFFAOYSA-N 0.000 claims description 2
- YYNADVCNWNNESS-UHFFFAOYSA-N 7-fluoro-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(F)C=C2C=1C1=CC=CC=C1 YYNADVCNWNNESS-UHFFFAOYSA-N 0.000 claims description 2
- HNNKBZNZOZXPSW-UHFFFAOYSA-N 7-fluoro-5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(F)C=C2C=1C1=CC=CC=C1F HNNKBZNZOZXPSW-UHFFFAOYSA-N 0.000 claims description 2
- SAYYEHPNKHRUPG-UHFFFAOYSA-N 7-fluoro-5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(F)=C1N=NC=C12 SAYYEHPNKHRUPG-UHFFFAOYSA-N 0.000 claims description 2
- CQKGSXJJMDROBJ-UHFFFAOYSA-N 7-methylsulfonyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C(S(=O)(=O)C)=CC2=C1C1=CC=CC=C1 CQKGSXJJMDROBJ-UHFFFAOYSA-N 0.000 claims description 2
- JOVGYUXQTZHZEA-UHFFFAOYSA-N 7-nitro-5-[2-(trifluoromethyl)phenyl]pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1C(F)(F)F JOVGYUXQTZHZEA-UHFFFAOYSA-N 0.000 claims description 2
- VYCSQLMGSOJUFC-UHFFFAOYSA-N 7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1 VYCSQLMGSOJUFC-UHFFFAOYSA-N 0.000 claims description 2
- QGGINYQQBSKSKP-UHFFFAOYSA-N CC1=CN=C2C(=CC(=C3C2=CN=N3)N)C(=N1)C4=CC=CC=C4F Chemical compound CC1=CN=C2C(=CC(=C3C2=CN=N3)N)C(=N1)C4=CC=CC=C4F QGGINYQQBSKSKP-UHFFFAOYSA-N 0.000 claims description 2
- XEXRYRHHVLPJOB-UHFFFAOYSA-N FC1=C(C=CC=C1)C=1N=CC=NC=2C=1C=C(C=1C=2C=NN=1)C(=O)N1CCOCC1 Chemical compound FC1=C(C=CC=C1)C=1N=CC=NC=2C=1C=C(C=1C=2C=NN=1)C(=O)N1CCOCC1 XEXRYRHHVLPJOB-UHFFFAOYSA-N 0.000 claims description 2
- UKCJZRZZXIYXEW-UHFFFAOYSA-N [5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepin-3-yl]methanol Chemical compound N=1C(CO)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl UKCJZRZZXIYXEW-UHFFFAOYSA-N 0.000 claims description 2
- IVPBZCJMGMVVGV-UHFFFAOYSA-N [O-][N+](C(C1=NN=CC1=C1N=C2)=CC1=C(C1=CC=CC=C1Cl)N=C2[S+]1C=NC=C1)=O Chemical compound [O-][N+](C(C1=NN=CC1=C1N=C2)=CC1=C(C1=CC=CC=C1Cl)N=C2[S+]1C=NC=C1)=O IVPBZCJMGMVVGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- WJSCPXNAFJEGED-UHFFFAOYSA-N ethyl 5-(2-chlorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine-3-carboxylate Chemical compound N=1C(C(=O)OCC)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1Cl WJSCPXNAFJEGED-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/22—Sulfur atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Predloženi izum odnosi se na nove pirazolobenzodiazepine koji inhibiraju kinaze ovisne o ciklinu (CDK), a posebno CDK2. Ti spojevi i njihove farmaceutski prihvatljive soli i predlijekovi navedenih spojeva su antiproliferacijska sredstva korisna u liječenju ili kontroli staničnih proliferacijskih poremećaja, naročito karcinoma. Izum se također odnosi na farmaceutske pripravke koji sadrže takve spojeve te na metode liječenja i/ili sprječavanja karcinoma, ponajprije u liječenju ili kontroli solidnih tumora. Spojevi ovog izuma naročito su korisni u liječenju i kontroli tumora dojke, debelog crijeva, pluća i prostate. Izum se također odnosi na intermedijare korisne u pripravljanju gornjih antiproliferacijskih sredstava.
Nekontrolirana stanična proliferacija je odlika karcinoma. Stanice kanceroznog tumora tipično imaju neki oblik oštećenja gena koji izravno ili neizravno reguliraju ciklus stanične diobe.
Kinaze ovisne o ciklinu (CDK) su enzimi koji su presudni za kontrolu staničnog ciklusa. Ti enzimi reguliraju prijelaze između različitih faza staničnog ciklusa, kao što je napredovanje od G1-faze do S-faze (period aktivne DNA sinteze), ili napredovanje od G2-faze do M-faze, u kojoj dolazi do mitoze i diobe stanice.
CDK-ovi se sastoje od katalitičke CDK podjedinice i regulatorne ciklinske podjedinice. Ciklinska podjedinica je ključni regulator djelovanja CDK, gdje svaki CDK međusobno djeluje s određenom podskupinom ciklina: npr. ciklin A (CDK1, CDK2). Različiti parovi kinaze/ciklina reguliraju napredovanje kroz određene faze staničnog ciklusa.
Odstupanja u sustavu kontrole staničnog ciklusa povezana su s nekontroliranim rastom tumorskih stanica. Postoji znatna količina literature koja potvrđuje primjenu spojeva inhibitora CDK-ova kao antiproliferacijskih terapeutskih sredstava.
Predloženi izum odnosi se na pirazolobenzodiazepine koji mogu inhibirati djelovanje jedne ili više CDK, a naročito CDK2. Takvi spojevi korisni su za liječenje karcinoma, ponajprije solidnih tumora. Spojevi predloženog izuma su posebno korisni u liječenju ili kontroli karcinoma dojke, debelog crijeva i prostate. Izum se također odnosi na intermedijarne spojeve korisne u pripravljanju gore navedenih pirazolobenzodiazepina.
Spojevi predloženog izuma su spojevi donje formule I
[image]
u kojima
R1 je vodik, -NO2, -CN, -halogen, -OR5, -R6OR7, -COOR7, -CONR8R9, -NR10R11, -NHCOR12, -NHSO2R13, ili niži alkil ravnog lanca koji se može supstituirati s hidroksi i/ili halogenom;
svaki R2 i R4 neovisno predstavljaju vodik, -halogen, -NO2, -CF3 ili niži alkil ravnog lanca;
R3 je vodik, -cikloalkil, -aril, -heterocikl, -heteroaril, -COOR7-CN, -alkenil, -CONR8R9, -alkinil, ili niži alkil koji se može supstituirati s hidroksi, -OR9, F, i/ili alkilom;
R5 je niži alkil koji se može supstituirati s halogenom;
R6 je niži alkil;
R7 je vodik ili niži alkil;
svaki od R8 i R9 neovisno predstavlja vodik i/ili niži alkil koji se sam može supstituirati s hidroksi i/ili -NH2; alternativno, R8 i R9 mogu oblikovati 5- ili 6-člani heterocikl koji se može supstituirati s hidroksi, -NH2 i/ili nižim alkilom;
svaki od R10, R11 i R12 neovisno predstavlja vodik ili niži alkil;
R13 je niži alkil koji se može supstituirati s halogenom i/ili -NR14R15; a
svaki od R14 i R15 neovisno predstavlja vodik ili niži alkil koji se mogu supstituirati s halogenom, ili alternativno, -NR14R15 je heterocikl.
Izum se nadalje odnosi na predlijekove i farmaceutski aktivne metabolite spojeva formule I te farmaceutski prihvatljive soli navedenih spojeva.
Predloženi izum je dalje usmjeren prema primjeni spojeva formule I, ili predlijekova ili farmaceutski aktivnih metabolita spojeva formule I te farmaceutski prihvatljivih soli navedenih spojeva kao lijekova; te prema farmaceutskim pripravcima koji sadrže farmaceutski učinkovitu količinu bilo kojeg ili više gore opisanih spojeva, ili njihovih farmaceutski prihvatljivih soli ili predlijekova te farmaceutski prihvatljiv nosač ili pomoćnu tvar.
Predloženi izum također se odnosi na uporabu spojeva formule I, predlijekova ili farmaceutski aktivnih metabolita spojeva formule I, ili farmaceutski prihvatljivih soli navedenih spojeva za proizvodnju lijeka za liječenje solidnih tumora, posebno tumora dojke, debelog crijeva i prostate, a naročito tumora dojke i debelog crijeva.
Kako se ovdje rabe, sljedeći pojmovi imaju sljedeće definicije.
"Aril" znači aromatsku skupinu s 5 do 10 atoma i 1 ili 2 prstena. Primjeri arilnih skupina uključuju fenil i 1- ili 2-naftil.
"Alkenil" znači supstituiran ili nesupstituiran alifatski nezasićeni ugljikovodik ravnog ili razgranatog lanca s 2 do 6, ponajprije 2 do 4 ugljikova atoma koji ima dvostruke veze. Tipične alkenilne skupine uključuju etilen, propilen, izopropilen, butilen i slično. Poželjne alkenilne skupine su skupine ravnog lanca.
"Alkinil" znači supstituiran ili nesupstituiran alifatski nezasićeni ugljikovodik ravnog ili razgranatog lanca s 2 do 6, ponajprije 2 do 4 ugljikova atoma koji ima trostruke veze. Tipične alkenilne skupine uključuju acetilen i slično. Poželjne alkinilne skupine su skupine ravnog lanca.
"Cikloalkil" znači nearomatsku, djelomično ili potpuno zasićenu cikličku, alifatsku ugljikovodičnu skupinu s 3 do 8 atoma. Primjeri cikloalkilnih skupina obuhvaćaju ciklopropil, ciklobutil, ciklopentil i cikloheksil.
"Učinkovita količina" znači količinu od najmanje jednog spoja formule I, ili njegove farmaceutski prihvatljive soli ili predlijeka ili metabolita koja značajno inhibira proliferaciju tumorskih stanica, uključujući stanične linije humanih tumora.
"Halogen" znači fluor, klor, brom ili jod. Poželjni halogeni su fluor i klor.
"Heteroarilne skupine" su aromatske skupine s 5 do 10 atoma, jednim ili dva prstena te sadrže jedan ili više heteroatoma. Primjeri heteroarilnih skupina su 2-, 3-, ili 4-piridil, tetrazolil, oksadiazolil, pirazinil, kinolil, pirolil i imidazolil.
"Heteroatom" znači atom izabran između N, O i S.
"Heterocikl" znači 3- do 10-članu nearomatsku, djelomično ili potpuno zasićenu ugljikovodičnu skupinu, kao što je tetrahidrokinolil koja ima jedan ili dva prstena te najmanje jedan heteroatom.
"IC50" se odnosi na koncentraciju određenog pirazolobenzodiazepina potrebnu za inhibiranje 50% određenog izmjerenog djelovanja. IC50 se između ostalog može mjeriti kako je opisano u Primjeru 4, ispod.
"Niži alkil" označava zasićeni ili nezasićeni alifatski ugljikovodik ravnog ili razgranatog lanca s 1 do 6, ponajprije 1 do 4 ugljikova atoma. Tipični niži alkili su metil, etil, propil, izopropil, butil, t-butil, 2-butil, pentil, heksil i slično.
"Farmaceutski prihvatljive soli" se odnose na uobičajene kiselinske adicijske soli ili bazične adicijske soli koje zadržavaju biološku učinkovitost i svojstva spojeva formule I te su oblikovane iz odgovarajućih organskih ili anorganskih kiselina ili organskih ili anorganskih baza.
Primjeri kiselinskih adicijskih soli obuhvaćaju one dobivene iz anorganskih kiselina kao što je klorovodična kiselina, bromovodična kiselina, jodovodična kiselina, sulfatna kiselina, sulfamska kiselina, fosforna kiselina i dušična kiselina te one dobivene iz organskih kiselina kao što je p-toluensulfonska, salicilna, metansulfonska, oksalna, sukcinska, limunska, 2-hidroksibutan-dikiselina, mliječna, fumarna kiselina i slično. Primjeri bazičnih adicijskih soli obuhvaćaju one dobivene iz amonijevog, kalijevog, natrijevog i kvaternog amonijevog hidroksida, kao što je na primjer trimetilamonijev hidroksid.
"Farmaceutski prihvatljiv" kao što je farmaceutski prihvatljiv nosač, pomoćna tvar, predlijek itd. znači farmakološki prihvatljiv i u biti netoksičan subjektu kojem se određeni spoj daje.
"Farmaceutski aktivni metabolit" znači, produkt metabolizma spoja formule I koji je farmaceutski prihvatljiv i učinkovit.
"Predlijek" se odnosi na spoj koji se u fiziološkim uvjetima ili solvolizom može pretvoriti u bilo koji od spojeva formule I ili u farmaceutski prihvatljivu sol spoja formule I. Predlijek kada se daje subjektu može biti neaktivan, ali se in vivo pretvara u aktivni spoj formule I.
"Supstituirani" kao supstituirani alkil, znači da može doći do supstitucije na jednoj ili više pozicija i, osim ako nije drugačije navedeno, da se supstituenti na svakom od mjesta supstitucije neovisno biraju između navedenih mogućnosti.
Spojevi
U jednom ostvarenju se predloženi izum odnosi na spojeve formule:
[image]
te na predlijekove i farmaceutski aktivne metabolite spojeva formule I, i farmaceutski prihvatljive soli navedenih spojeva, u kojima su R1 do R15 kako su gore definirani.
U poželjnom ostvarenju spojeva formule I, R1 je vodik, NO2, CN, CONH2, halogen i nesupstituirani niži alkil. Poželjni niži alkili su metil i etil. R1 je naročito NO2, CN ili CONH2. R1 je ponajprije na položaju 7 ili 8.
U drugom poželjnom ostvarenju spojeva formule I, R2 je na položaju 2' te predstavlja ili vodik ili halogen.
U još jednom poželjnom ostvarenju spojeva formule I, R3 je nesupstituirani niži alkil, hidroksi niži alkil, cikloalkil, heterocikl ili heteroaril. Poželjne skupine nižih alkila su metil, etil i hidroksimetil. Poželjne cikloalkilne skupine su nesupstituirani C3-C5.
U drugom poželjnom, ostvarenju spojeva formule I, R4 je na položaju 4' i predstavlja vodik ili halogen, a nadasve poželjno vodik.
U daljnjem poželjnom ostvarenju spojeva formule I, R5 i R6 neovisno predstavljaju metil ili etil, od kojih se svaki može supstituirati halogenom. R5 je ponajprije trifluorometil.
U još jednom poželjnom ostvarenju spojeva formule I, R je vodik, metil ili etil.
U drugom poželjnom ostvarenju spojeva formule I, svaki od R8 i R9 neovisno predstavlja vodik, metil, etil ili hidroksietil. Kada R8 i R9 oblikuju heterocikl, poželjne heterocikličke skupine su 6-eročlane, nesupstituirane skupine koje ponajprije uključuju dva heteroatoma. Najpoželjniji heteroatomi biraju se između O i N.
U drugom poželjnom ostvarenju spojeva formule I, svaki od R10, R11 i R12 neovisno predstavljaju vodik, metil i etil.
U drugom poželjnom ostvarenju spojeva formule I, R13 je niži alkil koji se može supstituirati halogenom, a R13 je ponajprije metil, etil ili trifluorometil.
U daljnjem poželjnom ostvarenju spojeva formule I, svaki od R14 i R15 neovisno predstavlja vodik, metil, etil ili heterocikl. Poželjni heterocikli su 3-7-eročlani prstenovi koji uključuju barem jedan dušik.
Sljedeći intermedijari također su primjeri dodatnih poželjnih spojeva u skladu s predloženim izumom:
[image]
pri čemu su R1, R2 i R4 kao što su gore definirani;
[image]
[image]
pri čemu, u svakoj od gore navedenih formula, svaki je od R1, R2, R3 i R4 kao što je prethodno ovdje definiran. Ti intermedijari korisni su u sintezi spojeva formule I.
Ovdje izneseni i gornjim formulama prikazani spojevi pokazuju tautomerizam ili strukturalni izomerizam. Namjera je da izum obuhvati bilo koji tautomerni ili strukturalno izomerni oblik ovih spojeva ili smjese takvih oblika, a nije ograničen na pojedini tautomerni ili strukturalno izomerni oblik koji se rabi u gore prikazanim formulama.
Sinteza spojeva Formule I
Spojevi predloženog izuma mogu se pripraviti u struci poznatim postupcima. Prikladni postupci za sintezu ovih spojeva prikazani su u primjerima. Ovi spojevi općenito se mogu pripraviti sukladno dolje prikazanim shemama sinteze.
Shema 1
R3=H
[image]
a) Lawesson-ov reagens (reakcija poznata za većinu supstitucija)
b) reakcija s Me2N-CH (OEt)2
c) reakcija s hidrazinom.
Spoj 1 je ili komercijalno dostupan ili sintetiziran u struci poznatim metodama.
Shema 2
R3 nije H
[image]
a) Lawesson-ov reagens (reakcija poznata za većinu supstitucija)
b) reakcija s R3-CHO, uz dodatak baze, ponajprije piperidina
c) reakcija s hidrazinom
d) oksidacija dihidropirazola u pirazol (uporaba zraka u DMSO RT-150°C, ili uz dodatak zraka i baze (Cs2CO3/DMF)).
Shema 3
Alternativna shema kada R3 nije H
[image]
a) Lawesson-ov reagens (reakcija poznata za većinu supstitucija)
f) reakcija s R3-CHO uz dodatak baze ponajprije diazabicikloundekana ili 2,2,6,6-tetrametilpiperidina.
g) dehidracija obradom sa slabom bazom (piridinij p-toluensulfonat, piridinij-acetat itd.) ili s klorotrimetilsilanom u piridinu na refluksu
c) reakcija s hidrazinom
e) oksidacija dihidropirazola u pirazol (uporaba zraka u DMSO
RT-150°C, ili uz dodatak zraka i baze (Cs2CO3/DMF)).
Shema 4
Transformacija R1 ili R3 funkcionalnih skupina
[image]
pri čemu R1' može biti bilo koja od opcija za R1 kako je gore definirano, a sukladno tome, R3' može biti bilo koja od opcija za R3 kako je gore definirano.
Kemijskom modifikacijom postojećih funkcionalnih skupina može se, primjenjujući poznate metode kako je gore prikazano u shemi 4, dobiti nekoliko supstitucija. Na primjer, kada je željeni R1=NH2 ta se supstitucija može dobiti redukcijom odgovarajuće nitro skupine. Sukladno tome, kada je željeni R1=NHR' (gdje je R'=-COR12, -SO2R13, ili -R10R11), ta se supstitucija može dobiti reakcijom odgovarajućeg R1=NH2 spoja s kiselim halidom ili anhidridom. Kada je željeni R1=CONRR" (gdje je R= vodik ili niži alkil, a R"= niži alkil), ta se supstitucija može dobiti reakcijom odgovarajućeg spoja u kojem je R1=I, s ugljikovim monoksidom i primarnim ili sekundarnim aminom uz dodatak paladija kao katalizatora.
Dodatno, ako je R3 u početnom materijalu CO2Et, može se primijeniti standardna kemijska modifikacija za proizvodnju spojeva sa sljedećim odgovarajućim R3 skupinama:
CH2OH (redukcija); CHO (djelomična redukcija); CH2NMe2 (reduktivna aminacija aldehida); CH2OMe (alkilacija alkohola); CH=CH2 (olefinacija aldehida); CONRR" (gdje je R=H ili niži alkil, a R''=H ili niži alkil, aminoliza s odgovarajućim aminom HNRR" pri čemu je R=H ili niži alkil, a R"=h ili niži alkil); CONHNHR (gdje je R=H, niži alkil ili aril) (hidrazinoliza-reakcija s hidrazinom); CN (dehidracija amida CONH2).
U prethodnim shemama, spoj formule I ili je komercijalno dostupan, na primjer u Sigma-i, ili se može jednostavno sintetizirati u struci poznatim metodama. Stoga se spoj 2 pripravlja iz odgovarajućeg laktama (spoj 1) postupkom Sternbacha et al., J. Org. Chem. 29:231 (1964) ili reakcijom s Lawesson-ovim reagensom.
Pripravci/Formulacije
U alternativnom ostvarenju, predloženi izum se odnosi na farmaceutske pripravke koji sadrže najmanje jedan spoj formule I ili njegov predlijek ili farmaceutski prihvatljivu sol spoja formule I ili predlijek takvog spoja.
Ti farmaceutski pripravci mogu se davati oralno, na primjer u obliku tableta, presvučenih tableta, dražeja, krutih ili mekanih želatinoznih kapsula, otopina, emulzija ili suspenzija. Također se mogu davati rektalno, na primjer u obliku supozitorija, ili parenteralno, na primjer u obliku injekcijskih otopina.
Farmaceutski pripravci predloženog izuma koji sadrže spojeve formule I, predlijekove takvih spojeva ili njihove soli mogu se proizvesti na način poznat u struci, npr. postupcima uobičajenog miješanja, stavljanja u kapsule, otapanja, granuliranja, emulzifikacije, entrapping, pravljenja dražeja ili liofilizacije. Ti farmaceutski pripravci mogu se formulirati s terapeutski inertnim anorganskim ili organskim nosačima. Laktoza, kukuruzni škrob i njegovi derivati, talk, stearinska kiselina i njezine soli mogu se upotrijebiti kao takvi nosači za tablete, presvučene tablete, dražeje i krute želatinozne kapsule. Prikladni nosači za mekane želatinozne kapsule uključuju biljna ulja, voskove i masti. Ovisno o prirodi aktivne tvari, u slučaju mekanih želatinoznih kapsula općenito nisu potrebni nosači. Nosači prikladni za proizvodnju otopina i sirupa su voda, polioli, saharoza, invertni šećer i glukoza. Nosači odgovarajući za injektiranje su voda, alkoholi, polioli, glicerin, biljna ulja, fosfolipidi i surfakanti. Nosači prikladni za supozitorije su prirodna ili očvrsnuta ulja, voskovi, masti i polutekući polioli. Farmaceutski pripravci također mogu sadržavati konzervanse, sredstva za otapanje, stabilizatore, sredstva za vlaženje, sredstva za emulziranje, sladila, boje, arome, soli za podešavanje osmotskog tlaka, pufere, sredstva za presvlačenje ili antioksidanse. Oni također mogu sadržavati druge terapeutski vrijedne tvari, uključujući dodatne aktivne sastojke koji nisu formule I.
Doziranja
Kako je gore navedeno, spojevi formule I, njihovi predlijekovi te njihove soli i pripravci koji sadrže te spojeve korisni su u liječenju ili kontroli staničnih proliferacijskih poremećaja, posebno onkoloških poremećaja. Ti spojevi i formulacije koje sadrže te spojeve posebno su korisni u liječenju i kontroli solidnih tumora, kao što su na primjer tumori dojke i debelog crijeva.
Terapeutski učinkovita količina spoja u skladu s ovim izumom znači količinu spoja koji je učinkovit u zaštiti, ublažavanju ili poboljšanju simptoma bolesti ili koji produljuje život pacijenta kojeg se liječi. Određivanje terapeutski učinkovite količine spada u vještinu primjene stručnog znanja.
Terapeutski učinkovita količina ili doziranje spoja formule I može varirati unutar širokog raspona te se podešava sukladno individualnim potrebama u svakom posebnom slučaju. Općenito, u slučaju oralnog ili parenteralnog davanja odraslim ljudima mase otprilike 70 kg, trebala bi odgovarati dnevna doza od oko 10 mg do oko 10,000 mg, ponajprije od oko 200 mg do oko 1,000 mg premda se gornja granica može povećati po potrebi. Dnevna doza se može davati odjednom ili u podijeljenim dozama, ili se za parenteralnu uporabu može davati kao kontinuirana infuzija.
Primjeri
Spojevi predloženog izuma mogu se sintetizirati u skladu s poznatim metodama, kao što su, primjerice, gore prikazane opće sheme. Sljedeći primjeri ilustriraju poželjne metode sintetiziranja spojeva i formulacija predloženog izuma.
U sljedećim primjerima NMR podaci su dani u ppm relativno prema trimetilsilanu, s otapalom i frekvencijom spektrometra kako je navedeno.
Primjer 1: Pirazoli pripravljeni u skladu sa shemom l
Korak a: Reakcija Laktama (spoj 1) s Lawesson-ovim reagensom kako bi se oblikovao Tiolaktam (spoj 2):
1.1. Spoj Al: R1=H, R2=F, R4=H
Otopini od 5.085 g (20 mmol) laktama 1 (u kojem je R1=H, R2=F, R4=H) u 50 ml dimetoksietana na 75°C doda se 8.9 g (22 mmol) Lawesson-ovog reagensa (2,4-bis(4-metoksifenil)-1,3-ditia-2,4-difosfetan-2,4-disulfid; Pedersen, B.S.; Scheibye, S.; Nilsson, N.H.; Lawesson, S.-O., Buli. Soc. Chim. Belg., 1978, 87:223). Smjesa se miješa 30 minuta, ohladi, a zatim izlije u 10%-tnu vodenu otopinu natrijevog hidrogenkarbonata. Vodena smjesa se ekstrahira s metilen-kloridom, a ekstrakti se isperu s vodom, isuše s bezvodnim natrijevim sulfatom, profiltriraju i koncentriraju pod smanjenim tlakom. Talog prekristalizira iz metilen-klorida-metanola dajući 4.0 g Spoja Al (tiolaktam 2).
1H nmr: (DMSO-d6, 300 mHz) 12.56 (s, 1H, NH) , 7.10-7.65 (m, 8H), 4.59 (s, 2H).
1.2 Spoj A2: R1=F, R2=R4=H
Spoj A2 se pripravlja na isti način kako je opisano za spoj A1. 1H nmr: (DMSO-d6, 300 mHz) 12.50 (s, 1H, NH), 7.37-7.56 (m, 7H) , 7.06 (dd, J=3.9 Hz, 1H), 4.60 (br s, 2H).
1.3 Spoj A3: R1=Cl, R2=Cl, R4=H
Otopina od 0.999 g (3.1 mmol) tiolaktama 2 (R1=Cl, R2=Cl, R4=H), 10 mL suhog tetrahidrofurana i 10 mL dimetilformamid-dietilacetata se 2 sata miješa na sobnoj temperaturi. Pod smanjenim tlakom se uklone volatili, a ostane crveno-narančasti kruti talog. Kristalizacija iz heksan-etil acetata daje 0.716 g Spoja A3 (derivat 3 u kojem je R1=Cl, R2=Cl, R4=H) kao crvene krutine, tt 196-198°C. 1H nmr: (DMSO-d6, 400 mHz) 10.21 (s, 1H), 7.84 (s, 1H), 7.43-7.56 (m, 4H), 7.32 (dd, J=3.9 Hz, 1H), 7.00 (d, J=9 Hz, 1H), 6.60 (d, J=3 Hz, 1H), 3.27 (s, 6H).
Korak c: Pretvaranje derivata 3 dimetilaminometilena u pirazol 4:
1.4 Spoj A4: R1=Cl, R2=Cl, R3=R4=H
5-(2-klorofenil)-7-kloro-pirazolo[3,4] [1,4]benzodiazepin
Otopini od 0.265 g (0.71 mmol) u 10 mL suhog metilen-klorida doda se oko 39.8 mikrolitara (1.27 mmol) bezvodnog hidrazina. Smjesa se miješa u atmosferi argona 85 min., a zatim otopi u metilen-kloridu te ispere s vodom, isuši s bezvodnim natrijevim sulfatom, profiltrira te koncentrira pod smanjenim tlakom dajući 0.219 g Spoja A4 (pirazol u kojem je R1=Cl, R2=Cl, R4=H) kao svijetlosmeđu krutinu. Analitički uzorak se profiltrira kroz tanki sloj silikagela, eluirajući s etil-acetatom, a zatim prekristalizira iz etil-acetata. tt>300°C. 1H nmr: (DMSO-d6, 400 mHz) 12.07 (s, 1H, NH), 8.03 (s, 1H, NH), 7.58 (s, 1H), 7.4-7.5 (m, 4H), 7.17 (dd, J=2,9 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 6.25 (s, 1H).
Sljedeći pirazoli (spoj 4) pripravljeni su prema shemi 1 i kako je gore opisano u koracima a-c:
1.5 Spoj A5: R1=NO2, R2=Cl, R3=H, R4=H
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 9.16 (s, 1H, NH), 7.90 (dd, J=2.8 Hz, 1H), 7.4-7.6 (m, 5H), 7.08 (d, J=2 Hz, 1H), 6.75 (d, J=8 Hz, 1H).
1.6 Spoj A6: R1=Cl, R2=H, R3=H, R4=H
5-fenil-7-kloro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 200 mHz) 7.97 (s, 1H, NH) , 7.62 (s, 1H), 7.35-7.60 (m, 5H), 7.29 (dd, J=2,9 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.60 (d, J=9 Hz, 1H).
1.7 Spoj A7: R1=Cl, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.10 (s, 1H, NH) , 8.01 (s, 1H), 7.60 (s, 1H), 7.5 (m, 2H), 7.18-7.33 (m, 3H), 6.83 (d, J=8 Hz, 1H), 6.47 (s, 1H).
1.8 Spoj A8: R1=Cl, R2=Cl, R3=H, R4=Cl
5-(2,4-diklorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.09 (s, 1H, NH) , 8.05 (s, 1H, NH), 7.68 (s, 1H), 7.56 (s, 1H), 7.52 (d, J=10 Hz, 1H), 7.48 (d, J=10 Hz, 1H), 7.19 (dd, J=2,9 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 6.27 (d, J=2 Hz, 1H).
1.9 Spoj A9: R1=H, R2=H, R3=H, R4=H
5-fenil-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.04 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.32-7.47 (m, 5H), 7.22 (dt, J=2.8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 6.67 (dd, J=1.8 Hz, 1H).
1.10 Spoj A10: R1=H, R2=F, R3=H, R4=H
5-(2-fluorofenil)-pirazolo[3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 200 mHz) 12.00 (s, 1H, NH) , 7.79 (s, 1H), 7.32-7.56 (m, 3H), 7.00-7.32 (m, 3H), 6.78 (d, J=6 Hz, 1H), 6.64 (t, J=6 Hz, 1H), 6.48 (d, J=6 Hz, 1H).
1.11 Spoj Ali: R1=F, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-fluoro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 200 mHz) 12.10 (s, 1H, NH), 7.85 (s, 1H), 7.47-7.7 (m, 3H), 7.18-7.39 (m, 2H), 7.05 (m, 1H), 6.86 (m, 1H), 6.26 (br d, J=8 Hz, 1H).
1.12 Spoj A12: R1=CH3O, R2=Cl, R3=H, R4=H
5-(2-klorofenil)-7-metoksi-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 200 mHz) 12.00 (s, 1H, NH) , 7.35-7.60 (m, 5H), 6.81 (d, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 5.89 (s, 1H), 3.46 (s, 3H).
1.13 Spoj A13: R1=NO2, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.14 (s, 1H, NH), 9.06 (s, 1H, NH), 7.89 (dd, J=2,9 Hz, 1H), 7.55 (s, 1H), 7.4-7.5 (m, 2H), 6.76 (d, J=9 Hz, 1H).
1.14 Spoj A14: R1=CH3SO2, R2=H, R3=H, R4=H
5-fenil-7-metansulfonil-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.18 (s, 1H, NH), 8.54 (s, 1H, NH), 7.72 (dd, J=2,9 Hz, 1H), 7.64 (s, 1H), 7.43 (m, 5H), 7.14 (d, J=2 Hz, 1H), 7.06 (d, J=9 Hz, 1H), 3.01 (s, 3H).
1.15 Spoj A15: R1=CN, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-cijano-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.16 (s, 1H, NH), 8.63 (s, 1H, NH), 7.59 (s, 1H), 7.4-7.58 (m, 3H), 7.2-7.37 (m, 2H), 6.82 (dd, J=2.8 Hz, 1H), 6.78 (s, 1H).
1.16 Spoj A16: R1=NO2, R2=H, R3=H, R4=H
5-fenil-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.19 (s, 1H, NH), 8.96 (s, 1H, NH), 8.03 (dd, J=2,9 Hz, 1H), 7.62 (s, 1H), 7.35-7.5 (m, 6H), 6.94 (d, J=9 Hz, 1H).
1.17 Spoj A17: R1=NO2, R2=CF3, R3=H, R4=H
5-(2-trifluorometilfenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.15 (s, 1H, NH), 8.42 (s, 1H, NH), 7.78 (dd, J=2,9 Hz, 1H), 7.62 (s, 1H), 7.35-7.45 (m, 5H), 7.29 (d, J=2 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 3.66 (s, 3H).
1.18 Spoj A18: R1=CO2CH3, R2=H, R3=H, R4=H
5-fenil-7-karbometoksi-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.15 (s, 1H, NH), 8.42 (s, 1H, NH), 7.78 (dd, J=2,9 Hz, 1H), 7.62 (s, 1H), 7.35-7.45 (m, 5H), 7.29 (d, J=2 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 3.66 (s, 3H).
1.19 Spoj A19: R1=I, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-jodo-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.09 (s, 1H, NH) , 7.99 (s, 1H, NH), 7.58 (s, 1H), 7.4-7.55 (m, 3H), 7.19-7.35 (m, 2H), 6.76 (s, 1H), 6.62 (d, J=8 Hz, 1H).
1.20 Spoj A20: R1=CO2Et, R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-karboetoksi-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 rnHz) 12.08 (s, 1H, NH) , 8.50 (s, 1H, NH), 7.62 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.4-7.5 (m, 2H), 7.18-7.35 (m, 2H), 7.14 (s, 1H), 6.80 (d, J=8 Hz, 1H), 4.15 (q, J=6 Hz, 2H), 1.17 (t, J=6 Hz, 3H).
1.21 Spoj A21: R1=H, R2=Cl, R3=H, R4=H
5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.95 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 7.38-7.48 (m, 4H), 7.09 (t, J=8 Hz,
IH), 6.78 (d, J=8 Hz, 1H), 6.61 (t, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H).
Primjer 2: Pretvaranje tiolaktama 2 u supstituirani pirazol 7 prema shemama 213
2.1 Spoj B1: R1=NO2, R2=Cl, R3=2-pirolil, R4=H; Shema 2
3-(2-pirolil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin
Smjesa od 0.995 g (3 mmol) tiolaktama 2 (R1=NO2, R2=Cl, R3=2-pirolil, R4=H), 0.571 g (6 mmol) pirol-2-karboksaldehida, 0.383 g (4.5 mmol) (Aldrich) piperidina i 10 mL dimetoksietana miješa se u atmosferi argona 2 sata. Smjesa se otopi u etil-acetatu te redom ispere s 0.1 M sulfatnom kiselinom, vodom, a zatim s lugom, isuši s bezvodnim natrijevim sulfatom, profiltrira te koncentrira pod smanjenim tlakom. Odgovarajući olefin 5 se izolira kromatografijom preko silikagela (eluiranje s heksanom/etil-acetatom (1:1)) kao žuta krutina (0.309 g) te direktno upotrijebi u sljedećem koraku. Olefin 5 (0.309 g) se otopi u 6 mL dimetil-sulfoksida te reagira s 72.5 mg (2.2 mmol) hidrazina u atmosferi argona. Nakon 20 minuta, smjesa se otopi u etil-acetatu i redom ispere s vodom i lugom, isuši s bezvodnim natrijevim sulfatom, profiltrira i koncentrira pod smanjenim tlakom dajući smjesu dihidropirazola 6 (0.296 g). Smjesa od 6 se otopi u dimetil-sulfoksidu te zagrije u prisutnosti zraka na 130°C 2 sata, ohladi, otopi u etil-acetatu te redom ispere s vodom i lugom. Ekstrakt se isuši s bezvodnim natrijevim sulfatom, profiltrira te koncentrira pod smanjenim tlakom. Produkt, Spoj BI, 7 pročisti se kromatografijom preko silikagela (eluiranje s heksan-etil-acetatom 25/75).
1H nmr: (DMSO-d6, 400 m.Hz) 12.12 (s, 1H, NH) , 10.39 (s, 1H, NH), 9.07 (s, 1H, NH), 7.96 (dd, J=2.8 Hz, 1H), 7.45-7.65 (m, 4H), 7.15 (d, J=2 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8 Hz, 1H), 6.48 (s, 1H), 6.12 (d, J=2 Hz, 1H).
2.2 Spoj B2: R1=NO2, R2=Cl, R3=CO2Et, R4=H; Shema 3
3-karboetoksi-5-(2-klorofenil)-7-nitro-pirazolo [3,4][1,4]benzodiazepin
Smjesa od 5.0 g (15.1 mmol) tiolaktama 2 (R1=NO2, R2=Cl), 6 mL 50%-tne otopine etil-glikoksilata u toluenu, 4.5 mL (31 mmol) diazabicikloundekana i 100 mL dimetoksietana miješa se u atmosferi argona 30 minuta na sobnoj temperaturi. Smjesa se zakiseli s 0.005 M H2SO4, ekstrahira s etil-acetatom. Kombinirani ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju i koncentriraju pod smanjenim tlakom. Kromatografijom preko silikagela (eluiranje s heksan-etil-acetatom 60/40) dobije se aldol 8 kao smjesa diastereomera (5.6 g).
Smjesa od 4.7 g (10.8 mmol) gore dobivenog aldola 8, 100 ml piridina i 6.9 mL (54.4 mmol) klorotrimetilsilana miješa se 10 minuta na sobnoj temperaturi, a zatim zagrijava na 120°C 1.5 sati. Smjesa se ohladi, otopi u 1 1 etil-acetata i redom ispere s vodom i lugom, a etil-acetatni sloj se isuši s bezvodnim natrijevim sulfatom. Nakon filtracije i uparavanja volatila pod smanjenim tlakom, sirovi talog se profiltrira preko silikagela, eluirajući s heksan-etil-acetatom (1:1), dajući 4.3 g olefina 5.
Otopina od 4.3 g gore dobivenog olefina 5 u 210 mL diklorometana se miješa s 0.68 mL (21.6 mmol) bezvodnog hidrazina 30 min. Smjesa se zatim razdijeli između vode, a vodena faza ekstrahira s diklorometanom. Kombinirani ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju te koncentriraju pod smanjenim tlakom. Talog, koji sadrži smjesu dihidropirazola 6, se otopi u 50 mL dimetilsulfoksida te na zraku zagrijava na 130°C 3 sata. Reakcijska smjesa se ohladi, otopi u etil-acetatu i ispere s vodom. Organski sloj se isuši s bezvodnim natrijevim sulfatom, profiltrira i koncentrira pod smanjenim tlakom. Produkt se izolira kromatografijom preko silikagela eluirajući s heksan-etil-acetatom (40/60) dajući 0.580 g Spoja B2 (R1=NO2, R2=Cl, R3=CO2Et, R4=H).
1H nmr: (DMSO-d6, 400 rnHz) 13.33 (s, 1H), 9.15 (s, 1H), 8.02 (dd, J=2,9 Hz, 1H), 7.46-7.55 (m, 4H), 7.18 (d, J=2 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 4.25 (q, J=7 Hz, 2H), 1.27 (t, J=7 Hz, 3H).
Sljedeći pirazoli (spoj 7) pripravljeni su prema shemi 2 ili 3 kako je gore opisano:
2.3 Spoj B3: R1=NO2, R2=Cl, R3=CH3, R4=H; (Shema 2) 3-metil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.85 (s, 1H, NH), 9.04 (s, 1H, NH), 7.83 (dd, J=2,9 Hz, 1H), 7.32-7.52 (m, 4H), 7.05 (d, J=2 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 1.98 (s, 3H).
2.4 Spoj B4: R1=NO2, R2=Cl, R3=CH2CH3, R4=H; (Shema 2)
3-etil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.91 (s, 1H, NH), 9.05 (s, 1H, NH), 7.85 (dd, J=2.8 Hz, 1H), 7.35-7.58 (m, 4H), 7.04 (d, J=2 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 2.41 (q, J=7 Hz, 2H), 1.06 (t, J=7 Hz, 3H).
2.5 Spoj B5: R1=NO2, R2=Cl, R3=CH2CH2Ph, R4=H; (Shema 2)
3-(2-feniletil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 200 mHz) 11.95 (s, 1H, NH), 9.05 (s, 1H, NH), 7.82 (dd, J=2.8 Hz, 1H), 7.05-7.60 (m, 10 H), 6.70 (d, J=8 Hz, 1H), 2.82 (m, 2H), 2.64 (m, 2H).
2.6 Spoj B6: R1=NO2, R2=Cl, R3=i-Pr, R4=H; (Shema 2)
3-(1-metiletil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.90 (s, 1H, NH), 9.02 (s, 1H, NH), 7.84 (dd, J=2,9 Hz, 1H), 7.35-7.55 (m, 4H), 7.04 (d, J=2 Hz, IH), 6.74 (d, J=9 Hz, 1H), 2.86 (sept, J=9 Hz, 1H), 1.14 (d, J=9 Hz, 6H).
2.7 Spoj B7: R1=CN, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karbonitril
1H nmr: (DMSO-d6, 300 mHz) 12.05 (s, 1H, NH), 8.55 (s, 1H, NH), 7.45 (m, 3H) , 7.25 (m, 2H) , 6.78 (d, J=8 Hz, 1H), 6.71 (s, 1H), 2.03 (s, 3H).
2.8 Spoj B8: R1=NO2, R2=Cl, R3=CH2Ph, R4=H; (Shema 2)
3-(fenilmetil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.08 (s, 1H, NH), 9.08 (s, 1H), 7.85 (d, J=9 Hz, 1H), 7.40-7.56 (m, 4H), 7.16-7.34 (m, 5H), 7.06 (br s, 1H), 6.71 (d, J=9 Hz, 1H), 3.71 (s, 2H).
2.9 Spoj B9: R1=CO2Et, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-7-karboetoksi-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J=2,9 Hz, 1H), 7.39-7.51 (m, 2H), 7.16-7.31 (m, 2H), 7.09 (s, 1H), 6.74 (d, J=9 Hz, 1H), 4.08 (q, J=7 Hz, 2H), 2.04 (s, 3H) , 1.12 (t, J=7 Hz, 3H).
2.10 Spoj B10: R1=NO2, R2=Cl, R3=5-(4-Me)-pirazolil, R4=H; (Shema 2)
3-(4-metilpirazol-5-il)-5-(2-klorofenil)-7-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.58 (s, 1H), 9.26 (s, 1H), 8.75 (br s, 1H), 7.95 (d, J=8 Hz, 1H), 7.42-7.6 (m, 5H), 7.12 (s, 1H), 6.81 (d, J=8 Hz, 1H), 2.32 (s, 3H).
2.11 Spoj B11: R1=NO2, R2=Cl, R3=CH2-iPr, R4=H; (Shema 2)
3-(2-metilpropil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 11.91 (s, 1H), 9.06 (s, 1H), 7.87 (dd, J=2,9 Hz, 1H), 7.4-7.56 (m, 4H), 7.08 (d, J=2 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 2.28 (d, J=7 Hz, 2H), 1.89 (n, J=7 Hz, 1H), 0.88 (d, J=7 Hz, 6H).
2.12 Spoj B12: R1=NO2, R2=Cl, R3=CF3, R4=H; (Shema 3)
3-trifluorometil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (CDCl3+DMSO-d6, 300 mHz) 7.98 (dd, J=2,9 Hz, 1H), 7.2-7.6 (m, 6H), 7.02 (br s, 1H), 6.62 (d, J=9 Hz, 1H).
2.13 Spoj B13: R1=NOa, R2=Cl, R3=1-tiazolil, R4=H; (Shema 3)
3-(1-tiazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 13.08 (s, 1H), 9.21 (s, 1H), 7.88-7.92 (m, 2H), 7.84 (d, J=3 Hz, 1H), 7.42-7.62 (m, 4H), 7.12 (d, J=2 Hz, 1H), 6.79 (d, J=8 Hz, 1H).
2.14 Spoj B14: R1=NO2, R2=Cl, R3=4-imidazolil, R4=H; (Shema 2)
3-(4-imidazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.33 (s, 1H), 12.29 (s, 1H), 9.07 (s, 1H), 7.90 (dd, J=2,9 Hz, 1H), 7.76 (s, 1H), 7.44-7.63 (m, 4H) , 7.35 (s, 1H), 7.11 (d, J=2 Hz, 1H), 6.78 (d, J=9 Hz, 1H).
2.15 Spoj B15: R1=NO2, R2=Cl, R3=2-pirazolil, R4=H; (Shema 2)
3-(2-pirazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 13.11 (s, 1H), 12.48 (s, 1H), 9.12 (s, 1H), 7.93 (d, J=9 Hz, 1H), 7.76 (s, 1H), 7.39-7.60 (m, 4H), 7.11 (s, 1H), 6.78 (d, J=9 Hz, 1H), 6.59 (s, 1H).
2.16 Spoj B16: R1=NO2, R2=Cl, R3=3-pirazolil, R4=H; (Shema 2)
3-(3-pirazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 13.09 (s, 1H), 12.31 (s, 1H), 9.13 (s, 1H), 7.80-8.05 (m, 4H), 7.40-7.62 (m, 3H), 7.13 (s, 1H), 6.78 (d, J=9 Hz, 1H).
2.17 Spoj B17: R1=NO2, R2=Cl, R3=CH (Me) CH2Me, R4=H; (Shema 2)
3-(1-metilpropil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.90 (s, 1H), 9.04 (s, 1H), 7.85 (dd, J=2,9 Hz, 1H), 7.38-7.55 (m, 4H), 7.05 (d, J=2 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 2.65 (m, 1H), 1.52 (m, 2H) , 1.13 (d, J=7 Hz, 3H), 0.79 (t, J=8 Hz, 3H).
2.18 Spoj B18: R1=MeO, R2=Cl, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.69 (s, 1H), 7.34-7.50 (m, 5H), 6.77 (dd, J=2,9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.86 (d, J=9 Hz, 1H), 5,86 (d, J=2 Hz, 1H), 3.44 (s, 3H), 2.05 (s, 3H).
2.19 Spoj B19: R1=Cl, R2=H, R3=CH3, R4=H; (Shema 2)
3-metil-5-fenil-7-kloro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 11.85 (s, 1H), 7.90 (s, 1H), 7.46-7.52 (m, 2H), 7.39-7.44 (m, 3H), 7.29 (dd, J=2,9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 2.16 (s, 3H).
2.20 Spoj B20: R1=Cl, R2=Cl, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-klorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.78 (s, 1H), 7.95 (s, 1H), 7.38-7.55 (m, 4H), 7.17 (dd, J=2,9 Hz, 1H), 6.75 (d, J=9 Hz, 1H), 6.22 (d, J=2 Hz, 1H), 2.03 (s, 3H).
2.21 Spoj B21: R1=H, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.75 (s, 1H), 7.69 (s, 1H), 7.36-7.52 (m, 2H), 7.04-7.30 (m, 3H), 6.77 (d, J=8 Hz, 1H), 6.63 (t, J=8 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 2.07 (s, 3H).
2.22 Spoj B22: R1=F, R2=H, R3=CH3, R4=H; (Shema 2)
3-metil-5-fenil-7-fluoro-pirazolo[3,4][1,4]benzodiazepin 1H nmr: (DMSO-d6, 300 mHz) 11.85 (s, 1H), 7.70 (s, 1H), 7.46-7.55 (m, 2H), 7.35-7.43 (m, 2H), 7.11 (dt, J=3,9 Hz, 1H), 6.92 (dd, J=5,9 Hz, 1H), 6.41 (dd, J=3,10 Hz, 1H), 2.14 (s, 3H).
2.23 Spoj B23: R1=NO2, R2=Cl, R3=fenil, R4=H; (Shema 2)
3-fenil-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 12.65 (s, 1H), 9.18 (s, 1H), 7.95 (dd, J=2,9 Hz, 1H), 7.78 (d, J=8 Hz, 2H), 7.32-7.63 (m, 7H), 7.14 (d, J=2 Hz, 1H), 6.85 (d, J=9 Hz, 1H).
2.24 Spoj B24: R1=NO2, R2=Cl, R3=n-propil, R4=H; (Shema 2)
3-propil-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 11.91 (s, 1H), 9.06 (s, 1H), 7.86 (d, J=8 Hz, 1H), 7.41-7.53 (m, 4H) , 7.08 (s, 1H), 6.72 (d, J=8 Hz, 1H), 2.38 (t, J=8 Hz, 2H), 1.54 (tq, J=8,7 Hz, 2H), 0.88 (t, J=7 Hz, 3H).
2.25 Spoj B25: R1=NO2, R2=Cl, R3=ciklopropil, R4=H; (Shema 2)
3-ciklopropil-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 400 mHz) 11.72 (s, 1H), 9.05 (s, 1H), 7.87 (dd, J=2,9 Hz, 1H), 7.41-7.55 (m, 4H), 7.08 (d, J=2 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 1.79 (p, J=7 Hz, 1H), 0.88 (d, J=7 Hz, 4H).
2.26 Spoj B26: R1=F, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-7-fluoro-pirazolo [3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.82 (s, 1H), 7.76 (s, 1H), 7.41-7.58 (m, 2H), 7.18-7.35 (m, 2H), 7.05 (dt, J=3,9 Hz, 1H), 6.84 (dd, J=6,9 Hz, 1H), 6.25 (dd, J=3,9 Hz, 1H), 2.08 (s, 3H).
2.27 Spoj B27: R1=NO2, R2=Cl, R3=CH3, R4=H; (Shema 2)
3-metil-5-fenil-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
2.28 Spoj B28: R1=H, R2=H, R3=CH3, R4=H;
(Shema 2) 3-metil-5-fenil-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.78 (s, 1H), 7.66 (s, 1H), 7.47 (m, 2H), 7.39 (m, 3H), 7.20 (dt, J=l,8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 6.68 (dt, J=l,8 Hz, 1H), 2.14 (s, 3H).
2.29 Spoj B29: R1=I, R2=F, R3=CF3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-7-jodo-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 7.90 (s, 1H), 7.39-7.57 (m, 3H), 7.18-7.36 (m, 2H) , 6.75 (s, 1H), 6.59 (d, J=9 Hz, 1H), 2.07 (s, 3H).
2.30 Spoj B30: R1=H, R2=Cl, R3=CH3, R4=H;
(Shema 2) 3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin
2.31 Spoj B31: R1=NO2, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.90 (s, 1H), 9.00 (s, 1H), 7.87 (dd, J=3,9 Hz, 1H), 7.47 (m, 2H), 7.18-7.32 (m, 3H), 6.73 (d, J=9 Hz, 1H), 2.02 (s, 3H).
2.32 Spoj B32: R1=Cl, R2=F, R3=CH3, R4=H; (Shema 2)
3-metil-5-(2-fluorofenil)-7-kloro-pirazolo [3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 7.96 (s, 1H), 7.40-7.55 (m, 2H), 7.17-7.32 (m, 3H), 6.79 (d, J=9Hz, 1H), 6.42 (s, 1H), 2.08 (s, 3H).
2.33 Spoj B33: R1=I, R2=H, R3=CH3, R4=H; (Shema 2)
3-metil-5-fenil-7-jodo-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.82 (s, 1H), 7.85 (s, 1H), 7.36-7.55 (m, 6H), 6.91 (d, J=2 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 2.15 (s, 3H).
2.34 Spoj B34: R1=Br, R2=H, R3=CH3, R4=H; (Shema 2)
3-metil-5-fenil-7-bromo-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 7.89 (s, 1H), 7.49 (m, 2H), 7.38 (m, 4H), 6.85 (d, J=9 Hz, 1H), 6.74 (d, J=2 Hz, 1H), 2.15 (s, 3H).
2.35 Spoj B35: R1=CN, R2=F, R3=-CH2OH, R4=H; (Shema 3)
3-hidroksimetil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karbonitril.
Primjer 3: Modifikacija funkcionalnih skupina prema Shemi 4
Kako je gore navedeno s obzirom na Shemu 4, određeni spojevi mogu se jednostavno dobiti transformacijom postojećih funkcionalnih skupina. Nekoliko tih transformacija je dolje prikazano.
A. Supstitucija jodos karbonilom: R1=I do R1=CONRR'
3.1 Spoj Cl: R1=CON(CH2CH2-O-CH2CH2-), R2=F, R3=H, R4=H
5-(2-fluorofenil)-7-morfolinilkarbonil-pirazolo [3,4] [1,4]benzodiazepin
Smjesa od 0.0712 g (0.17 mmol) pirazola 4 (R1=I, R2=F, R3=H, R4=H), 0.0082 g (0.0012 mmol) bis-trifenilfosfin-paladij-diklorida kao katalizatora, 1 mL morfolina miješa se i zagrijava (75°C) u atmosferi ugljik-monoksida 90 minuta. Smjesa se ohladi, a zatim pročisti kromatografijom reverznih faza preko silikagela (gradijentno eluiranje s vodom-acetonitrilom) dajući 0.06 g Spoja Cl (pirazol 4 u kojem je R1=CON (CH2CH2-O-CH2CH2-), R2=F, R3=H, R4=H).
1H nmr: (DMSO-d6, 300 mHz) 12.05 (s, 1H, NH), 8.18 (s, 1H, NH), 7.59 (s, 1H), 7.4-7.5 (m, 2H), 7.18-7.35 (m, 3H), 6.84 (d, J=9 Hz, 1H), 3.25 (m, 8H).
Sljedeći spojevi su pripravljeni primjenom gornje metode A:
3.2 Spoj C2: R1=CONHCH2CH2OH, R2=F, R3=H, R4=H
N-(2-hidroksietil)-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid
1H nmr: (DMSO-d6, 300 mHz) 12.08 (s, 1H, NH), 8.20 (s, 1H, NH), 8.16 (m, 1H, NH), 7.61 (d, J=9 Hz, 1H), 7.57 (s, 1H), 7.4-7.5 (m, 2H), 7.14-7.3 (m, 2H), 7.11 (s, 1H), 6.89 (d, J=9 Hz, 1H), 4.63 (m, 1H, OH), 3.40 (m, 2H), 3.18 (m, 2H).
3.3 Spoj C3: R1=CON (CH2CH2OH)2, R2=F, R3=H, R4=H
N,N-bis-(2-hidroksietil)-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid
1H nmr: (DMSO-d6, 300 mHz) 12.10 (s, 1H, NH), 8.11 (s, 1H, NH), 7.59 (s, 1H), 7.4-7.52 (m, 2H), 7.15-7.3 (m, 3H), 6.80 (d, J=9 Hz, 1H), 6.58 (s, 1H), 4.65 (m, 2H, OH), 3.30 (m, 8H).
B. Redukcija ni tro u amino: Ri=NO2 do R1=NH2
3.4 Spoj C4: R1=NH2, R2=Cl, R3=CH3, R4=H
3-metil-5-(2-fluorofenil)-7-amino-pirazolo[3,4][1,4]benzodiazepin
Otopina od 0.20 g (0.57 mmol) pirazola 7 (R1=NO2, R2=Cl, R3=CH3, R4=H) u 8 mL etanola se miješa na sobnoj temperaturi u atmosferi vodika s Raney-ovim niklom (0.5 mL 50% mulja u vodi, isprano s etanolom neposredno prije uporabe). Nakon 4 sata, smjesa se profiltrira i koncentrira pod smanjenim tlakom dajući 0.177 g Spoja C4 (amino derivat 7 u kojem je R1=NO2, R2=Cl, R3=CH3, R4=H). tt. 260-263°C.
lH nmr: (DMSO-d6, 300 mHz) 11.62 (s, 1H), 7.38-7.47 (m, 4H) , 7.07 (s, s, 1H), 6.53 (d, J=8 Hz, 1H), 6.38 (dd, J=2,9 Hz, 1H), 5.74 (d, J=2 Hz, 1H), 4.52 (s, 2H), 2.06 (s, 3H).
Sljedeći spojevi su pripravljeni primjenom gornje metode B:
3.5 Spoj C5: R1=NH2, R2=Cl, R3=H, R4=H
3-(1-metiletil)-5-(2-klorofenil)-7-amino-pirazolo[3,4][1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 11.65 (2, 1H), 7.38-7.4 (m, 4H), 7.08 (s, 1H), 6.75 (d, J=8 Hz, 1H), 6.39 (dd, J=2,8 Hz, 1H), 5.74 (d, J=2 Hz, 1H), 2.98 (sept, J=7 Hz, 1H), 1.18 (d, J=7 Hz, 6H).
C. Izvođenje amino spojeva R1=NH2 do R1=NHR' (kako je definirano u Shemi 4 gore)
3.7 Spoj C7: R1=NHAc, R2=Cl, R3=CH3, R4=H
N-(3-metil-5-(2-klorofenil)-pirazolo [3,4] [l, 4]benzodiazepin-7-il)-acetamid
Suspenzija od 0.323 g (1 mmol) pirazola 7 (R1=NH2, R2=Cl, R3=CH3, R4=H) u 20 mL diklorometana reagira s 0.112 g (1.1 mmol) anhidrida octene kiseline u inertnoj atmosferi na sobnoj temperaturi 2 sata. Smjesa se zatim razrijedi s etil-acetatom te redom ispere s vodom i lugom. Vodeni slojevi se ekstrahiraju s etil-acetatom, a kombinirani ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju te koncentriraju pod smanjenim tlakom. Produkt se izolira kromatografijom preko silikagela eluirajući s heksan-etil-acetatom (30/70) dajući 0.175 g Spoja C7.
lH nmr: (DMSO-d6, 300 mHz) 11.71 (s, 1H), 9.56 (s, 1H), 7.56 (s, 1H), 7.38-7.57 (m, 5H), 6.67 (d, J=8 Hz, 1H), 6.57 (d, J=2 Hz, 1H), 2.05 (s, 3H), 1.83 (s, 3H).
Sljedeći spojevi su pripravljeni analogno Spoju C7 prema metodi C gore:
3.8 Spoj C.8: R1=AkrilolilNH, R2=Cl, R3=CH3, R4=H
N-(3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-2-propenamid
1H nmr: (DMSO-d6, 300 mHz) 11.71 (s, 1H), 9.78 (s, 1H), 7.63 (s, 1H), 7.52 (dd, J=2,9 Hz, 1H), 7.35-7.50 (m, 4H), 6.71 (d, J=9 Hz, 1H), 6.69 (d, J=2 Hz, 1H), 6.23 (dd, J=10,18 Hz, 1H), 6.08 (dd, J=2,18 Hz, 1H), 5.60 (dd, J=2,10 Hz, 1H), 2.05 (s, 3H).
3.9 Spoj C9: R1=CH3SO2NH R2=Cl, R3=CH3, R4=H
N-(3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-metansulfonamid
Smjesa od 0.323 g (1 mmol) pirazola 7 (R1=NH2, R2=Cl, R3=CH3, R4=H), 0.122 g (1 mmol) 4-dimetilaminopiridina i 5 mL tetrahidrofurana miješa se u inertnoj atmosferi na sobnoj temperaturi 2 sata. Smjesa se razrijedi s etil-acetatom te redom ispere s vodom i lugom, s ponovnom ekstrakcijom vodene faze s etil-acetatom. Kombinirani etil-acetatni ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju te koncentriraju pod smanjenim tlakom. Produkt se izolira kromatografijom preko silikagela eluirajući s heksan-etil-acetatom (10/90) dajući 0.244 g Spoja C9 (pirazol 7 u kojem je R1=CH3SO2NH R2=Cl, R3=CH3, R4=H) (prekristalizacija iz etil-acetata) tt 196-198°C.
1H nmr: (DMSO-d6, 300 m.Hz) 11.74 (s, 1H), 9.12 (s, 1H), 7.71 (s, 1H), 7.36-7.46 (m, 4H), 6.94 (dd, J=2,8 Hz, 1H), 6.72 (d, J=8 Hz, 1H), 6.31 (d, J=2 Hz, 1H), 2.70 (s, 3H), 2.05 (s, 3H).
D. Aminoliza R3=CO2Et u R3=CONRR'
3.10 Spoj CIO: R1=NO2, R2=Cl, R3=CONH2, R4=H
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karboksamid
0.15 g (0.36 mmol) pirazola 7 (R1=NO2, R2=Cl, R3=CO2Et, R4=H) miješa se s otopinom amonijaka (15 mL) u etanolu (50 mL) na sobnoj temperaturi 48 sati. Volatili se uklone pod smanjenim tlakom, a produkt pročisti kromatografijom preko silikagela. Eluiranje s etil-acetat-izopropanolom (95/5) daje 0.074 g Spoja C10 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CONH2, R4=H) kao krutinu. tt>340°C (prekristalizacija iz etil-acetata).
1H nmr: (DMSO-d6, 400 mHz) 12.95 (br s, 1H), 9.23 (br s, 1H), 7.92 (d, J=8 Hz, 1H), 7.81 (s, 1H), 7.45-7.61 (m, 4H), 7.21 (s, 1H), 7.08 (s, 1H), 6.75 (d, J=8 Hz, 1H).
Sljedeći spojevi su pripravljeni analogno Spoju CIO primjenom gornje metode D:
3.11 Spoj C11: R1=NO2, R2=Cl, R3=CONMe2, R4=H N,N-dimetil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin-3-karboksamid
1H nmr: (DMSO-d6, 300 mHz) 12.65 (s, 1H), 9.18 (s, 1H), 7.91 (d, J=9 Hz, 1H), 7.41-7.55 (m, 4H) , 7.08 (s, 1H), 6.75 (d, J=9 Hz, 1H), 3.01 (s, 3H), 2.88 (s, 3H).
3.12 Spoj C12: R1=NO2, R2=Cl, R3=CONHNH2, R4=H
N-amino-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karboksamid
1H nmr: (DMSO-d6, 300 mHz) 13.02 (s, 1H), 9.19 (s, 1H), 8.58 (t, J=5 Hz, 1H), 7.91 (dd, J=2,9 Hz, 1H), 7.41-7.62 (m, 4H), 7.09 (d, J=2 Hz, 1H), 6.75 (d, J=9 Hz, 1H), 4.54 (d, J=5 Hz, 2H).
E. Redukcija R3=CO2Et do R3=CHO i R3=CH2OH
3.13 Spoj C13: R1=NO2, R2=Cl, R3=CHO, R4=H i Spoj C14: R1=NO2, R2=Cl, R3=CH2OH, R4=H
Smjesa od 0.48 g (1.17 mmol) pirazola 7 (R1=NO2, R2=Cl, R3=CO2Et, R4=H) i 30 mL tetrahidrofurana na -15°C u inertnoj atmosferi se 30 minuta obrađuje s 1.52 mL IM otopinom litij-aluminij-hidrida u tetrahidrofuranu. Smjesa se zatim razrijedi s etil-acetatom te redom ispere s vodenom otopinom natrij -kalij-sulfata i lugom, a organski ostaci ispiranja se ponovo ekstrahiraju s etil-acetatom. Kombinirani etil-acetatni ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju te koncentriraju pod smanjenim tlakom. Pročišćavanje kromatografijom preko silikagela, eluirajući s heksan-etil-acetatom, daje 0.21 g Spoja C13 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CHO, R4=H) kao crvenu krutinu, i 0.11 g Spoja C14 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CH2OH, R4=H) kao crvenu krutinu.
Spoj Cl3:
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karboksaldehid
lH nmr: (DMSO-d6, 300 mHz) 13.29 (s, 1H), 9.66 (s, 1H), 9.27 (s, 1H), 7.96 (dd, J=2,9 Hz, 1H), 7.45-7.59 (m, 4H) , 7.13 (d, J=2 Hz, 1H), 6.79 (d, J=9 Hz, 1H).
Spoj C14: R1=NO2, R2=Cl, R3=CONH2, R4=H
3-hidroksimetil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin
1H nmr: (DMSO-d6, 300 mHz) 12.11 (s, 1H), 9.08 (s, 1H), 7.85 (dd, J=2,9 Hz, 1H), 7.42-7.50 (m, 4H), 7.06 (d, J=2 Hz, 1H), 6.71 (d, J=9 Hz, 1H), 5.23 (t, J=5 Hz, 1H), 4.27 (d, J=5 Hz, 2H).
F. Reduktivna aminacija aldehida: R3=CHO do R3=CH2NR2
3.14 Spoj C. 15: R1=NO2, R2=Cl, R3=CH2Nme2, R4=H
3-(N,N-dimetilaminometil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin
Suspenzija od 0.142 g (0.39 mmol) pirazola 7 (R1=NO2, R2=Cl, R3=CHO, R4=H), 0.0631 g (0.78 mmol) dimetilamin-hidroklorida, 0.11 mL (0.78 mmol) trietilamina, 0.165 g (1 mmol) natrijevog triacetoksiborohidrida, 0.2 4A molekularnih sita i 20 mL diklorometana se 3 h miješa u inertnoj atmosferi. Smjesa se profiltrira, razrijedi s etil-acetatom te redom ispere s vodom i lugom, ponovno ekstrahirajući vodene faze s etil-acetatom. Kombinirani etil-acetatni ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju te koncentriraju pod smanjenim tlakom. Pročišćavanje kromatografijom reverznih faza preko silikagela (gradijentno eluiranje s vodom-acetonitrilom-trifluorooctenom kiselinom) daje 0.147 g Spoja C15 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CH2Nme2, R4=H) kao trifluoroacetatnu sol.
1H nmr: (DMSO-d6, 300 mHz) 12.54 (s, 1H), 9.92 (s, 1H), 9.25 (s, 1H), 7.91 (dd, J=2,8 Hz, 1H), 7.45-7.55 (m, 4H), 7.10 (d, J=2 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 4.08 (s, 2H), 2.75 (s, 6H).
G. Alkilacija alkohola R3=CH2OH do R3=CH2OCH3
3.15 Spoj C16: R1=NO2, R2=Cl, R3=CH2OCH3, R4=H 3-metoksimetil-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin
Smjesa od 0.075 g pirazola 7 (R1=NO2, R2=Cl, R3=CH2OH, R4=H), 0.2 g silikagela i 20 mL tetrahidrofurana miješa se s otopinom diazometana u eteru (50 mL, oko 9.2 mmol). Smjesa se nakon 2 sata profiltrira, koncentrira pod smanjenim tlakom. Produkt se pročisti kromatografijom na koloni silikagela, eluirajući s heksan-etil-acetatom dajući spoj C16 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CH2OCH3, R4=H) kao crvenu krut inu.
1H nmr: (DMSO-d6, 300 mHz) 12.27 (s, 1H), 9.11 (s, 1H), 7.86 (dd, J=2,9 Hz, 1H), 7.43-7.50 (m, 4H), 7.06 (d, J=2 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 4.20 (s, 2H), 3.25 (s, 3H).
F. Metilenacija aldehida: R3=CHO do R3=CHCH2
3.16 Spoj C17: R1=NO2, R2=Cl, R3=CH2CH2, R4=H 3-etenil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin
Otopini metilen-trifenilfosforana, pripravljenoj reakcijom 0.109 g (0.31 mmol) metiltrifenilfosfonij-bromida u 5 mL tetrahidrofurana i 0.29 mL 1M otopine kalijevog tert-butoksida u tetrahidrofuranu, na -78°C u inertnoj atmosferi, doda se 0.080 g (0.22 mmol) pirazola 7 (R1=NO2, R2=Cl, R3=CHO, R4=H). Smjesa se zagrije do refluksa te miješa preko noći, a zatim se ohladi na sobnu temperaturu, razrijedi s etil-acetatom te redom ispere s vodom i lugom. Etil-acetatni ekstrakt se isuši s bezvodnim natrijevim sulfatom, profiltrira te koncentrira pod smanjenim tlakom. Pročišćavanje kromatografijom preko silikagela, eluirajući s heksan-etil-acetatom (70/30) daje 0.043 g spoja C17 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CHCH2, R4=H) kao crvenu krutinu.
lH nmr: (DMSO-d6, 300 mHz) 12.33 (s, 1H), 9.11 (s, 1H), 7.88 (dd, J=2,9 Hz, 1H), 7.40-7.50 (m, 4H), 7.08 (d, J=2 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 6.40 (dd, J=12,18 Hz, 1H), 5.85 (d, J=18 Hz, 1H), 5.36 (d, J=12 Hz, 1H).
I. Dehidracija amida: R3=CONH2 do R3=CN
3.17 Spoj C18: R1=NO2, R2=Cl, R3=CN, R4=H
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karbonitril
Smjesa od 0.47 g (1.23 mino l) pirazola 7 (R1=NO2, R2=Cl, R3=CONH2, R4=H), 0.34 g (2.46 mmol) kalijevog karbonata, 0.94 g (6.15 mmol) fosfor-oksiklorida i 20 mL acetonitrila se u inertnoj atmosferi zagrijava do refluksa 4 sata. Smjesa se ohladi na sobnu temperaturu, razrijedi s etil-acetatom te redom ispere s zasićenom vodenom otopinom natrij -hidrogenkarbonata, vodom i lugom, ponovno ekstrahirajući vodene faze s etil-acetatom. Kombinirani etil-acetatni ekstrakti se isuše s bezvodnim natrijevim sulfatom, profiltriraju i koncentriraju pod smanjenim tlakom. Talog se kromatografira preko silikagela eluirajući s heksan-etil-acetatom (70/30) dajući 0.24 g Spoja C18 (pirazol 7' u kojem je R1=NO2, R2=Cl, R3=CN, R4=H) kao narančaste krutine (prekristalizacija iz diklorometana} . tt 193-196 C.
IR (KBr) 2240 cm-1. 1H nmr: (DMSO-d6, 300 mHz) 9.36 (s, 1H), 7.96 (dd, J=2,9 Hz, 1H), 7.48-7.58 (m, 4H), 7.11 (d, J=2 Hz, 1H), 6.77 (d, J=9 Hz, 1H).
J. Hidroliza nitrila: R3=CN do R3=CN
3.18 Spoj C. 19: R1=CONH2, R2=F, R3=CN, R4=H
3-metil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid
Otopini od 0.5 g (1.6 mmol) pirazola 7 (R1=CN, R2=F, R3=CH3, R4=H) u 79 mL dimetilsulfoksida doda se 47 mL ledeno hladnog vodikovog peroksida (30%-tna vodena otopina) i 24 mL 1M natrijevog hidroksida. Nakon završetka reakcije smjesa se ekstrahira s etil-acetatom, a ekstrakti redom isperu s vodom, lugom, a zatim isuše s bezvodnim natrijevim sulfatom. Smjesa se profiltrira i koncentrira pod smanjenim tlakom. Pročišćavanje kromatografijom preko silikagela (eluiranje s etil-acetatom/metanolom (95:5)) daje 0.5 g Spoja C19 (pirazol 7 ukojem je R1=CONH2, R2=F, R3=CH3, R4=H) kao žute krutine. tt 323-324°C.
1H nmr: (DMSO-d6, 300 mHz) 11.79 (s, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 7.58 (dd, J=2,9Hz, 1H), 7.38-7.52 (m, 2H), 7.02-7.30 ' (m, 4H), 6.73 (d, J=9 Hz, 1H), 2.05 (s, 3H).
Dodatni spojevi koji nisu posebno navedeni u Primjerima 1-3 pripravljeni su primjenom gore opisanih metoda. Ti spojevi, označeni s "D" uključeni su dolje u Tablice I-IV.
Primjer 4: Antiproliferacijsko djelovanje
Antiproliferacijsko djelovanje spojeva predloženog izuma pokazano je dolje. Ti učinci ukazuju da su spojevi predloženog izuma korisni u liječenju karcinoma, posebno solidnih tumora kao što su tumori dojke i debelog crijeva.
CDK2 FlashPlate Istraživanje
Kako bi se odredila inhibicija djelovanja CDK2, pročišćeni rekombinantni retinoblastom (Rb) protein se presvuče na FlashPlates pločama od 96 jažica (New England Nuclear, Boston, MA). Rb je prirodni supstrat za fosforil.aciju CDK2 (Herwing i Strauss Eurr. J. Biochem., Vol 246 (1997) pp. 581-601 kao i reference u njemu). Rekombinantni aktivni humani Ciklinski E/CDK2 kompleksi djelomično se pročiste od ekstrakata stanica insekata. Aktivni Ciklin E/CDK2 se doda Rb-om presvučenim Flash Plates pločama zajedno s 33P-ATP-om i razrjedenjima ispitivanih spojeva. Mikrotitarske pločice se inkubiraju 25 minuta na sobnoj temperaturi uz tresenje, a zatim isperu i prebroje u Topcount scintilacijskom brojaču (Packard Instrument Co., Downers Grove, IL). Razrjeđenja ispitivanih spojeva se dvostruko testiraju u svakom ispitivanju. Postotak inhibicije Rb fosforilacije, koji je mjera inhibicije CDK2 aktivnosti, određuje se prema sljedećoj formuli:
100x[1- (ispitivani spoj-nespecifičan)/(ukupno-nespecifično)]
gdje se "ispitivani spoj" odnosi na prosječan broj prebrojavanja po minuti test duplikata, "nespecifičan" se odnosi na prosječan broj prebrojavanja po minuti kada nije dodan Ciklin E/CDK2, a "ukupno" se odnosi na odnosi na prosječan broj prebrojavanja po minuti kada nije dodan spoj.
Rezultati navedenih in vitro eksperimenata izloženi su u Tablicama IA do 1C ispod.
TABLICA 1A
Inhibicija Cdk2-IC50 raspon od 0.01-0.99 μM
[image] [image] [image]
*Ako drugačije nije navedeno.
** Pozicija 3'.
U ostalim tablicama pozicija je supstituiranih R1, R2, R3 i R4 kao što je prikazana gore u Tablici IA.
TABLICA IB
Inhibicija Cdk2-IC50 raspon od 1-9.99 μM
[image] [image]
TABLICA IC
Inhibicija Cdk2-IC50 raspon od 10-30 μM
[image]
Stanično temeljena ispitivanja
Stanična linija epitelnog karcinoma dojke s negativnim receptorima estrogena (MDA-MB-435) nabavljena u American Type Cell Culture Collection (ATCC; Rockville, MD), raste u mediju preporučenom od ATCC. Za analizu učinka testnih spojeva na rast tih stanica, stanice se stave na 2000 stanica po jažici na ploči za kulture tkiva od 96 jažica te se inkubiraju preko noći na 37°C s 5% CO2. Sljedeći dan se testni spojevi otope u 100%-tnom dimetil-sulfoksidu (DMSO) dajući 10 mM štok otopine. Svaki spoj se razrijedi sa sterilnim sredstvom na 1 mM u dovoljnoj količini da se dobije konačna koncentracija od 120 μM. Spojevi se zatim serijski razrijede u sredstvu s 1.2% DMSO. Jedna četvrtina konačnog volumena razrijeđenih spojeva se prenese na ploče od 96 jažica. Testni spojevi se dvostruko ispituju. U redak "kontrolnih stanica" doda se DMSO tako da je konačna koncentracija DMSO u svakoj jažici 0.3%. Jažice u koje nisu dodane stanice služile su kao "slijepe". Jažice u koje nije dodan inhibitor služe kao "kontrola bez inhibitora". Jažice se vrate u inkubator i nakon 5 dana od dodavanja testnog spoja analiziraju kako je dolje opisano.
3-(4,5-Dimetiltiazol-2-il)-2,5-difenil-2H-tetrazolij-bromid (tiazolil plavi; MTT) doda se u svaku jažicu dajući konačnu koncentraciju od 1 mg/mL. Ploče se zatim inkubiraju na 37°C 3 sata, a zatim centrifugiraju na 1000 o/min 5 minuta prije aspiracije sredstva koje sadrži MTT. Sredstvo koje sadrži MTT se zatim ukloni te se u svaku jažicu doda 100 μL 100%-tnog etanola kako bi se otopio rezultirajući formazan metabolit. Kako bi se osiguralo potpuno otapanje, ploče se tresu 15 minuta na sobnoj temperaturi. Na čitaču mikrotitarske ploče (Molecular Dynamics) očitavaju se apsorpcije na valnoj dužini od 570 nm s 650 nm referencom. Postotak inhibicije se izračuna oduzimanjem apsorpcije "slijepe" jažice (bez stanica) od svih jažica, a zatim oduzimanjem od 1.00 kvocijenta prosječne apsorbcije svakog testnog duplikata s prosječnom od kontrola. Inhibitorne koncentracije (IC50) određuju se iz linearne regresije grafa logaritma koncentracije naspram postotka inhibiranja.
Rezultati navedenih MDA-MB-435 stanično temeljenih ispitivanja prikazani su u Tablicama IIA-IIC ispod.
TABLICA IIA
Ispitivanje antiproliferacijskog djelovanja MDA-MB435 (dojka)
- raspon IC50 0.01-1 μM
[image]
TABLICA IIB
Ispitivanje antiproliferacijskog djelovanja MDA-MB435 (dojka) - raspon IC50 1.1-9.99 μM
[image]
TABLICA IIC
Ispitivanje antiproliferacijskog djelovanja MDA-MB435 (dojka) - raspon IC50 10-30 μM
[image]
Iz ATCC su također dobivene stanična linija adenokarcinoma SW480 i stanična linija karcinoma debelog crijeva HCT-116 te testirane u skladu s istim protokolom gore navedenim za MDA-MB-435 stanično temeljena ispitivanja sa sljedećim modifikacijama. Stanična linija SW480 smještena je na 1000 stanica po jažici i analizirana 6 dana nakon dodavanja testnog spoja. Stanična linija HCT-116 smještena je na 1000 stanica po jažici i analizirana 4 dana nakon dodavanja testnog spoja.
Rezultati navedenih SW480 (debelo crijevo) i HCT-116 (debelo crijevo) temeljenih ispitivanja redom su prikazani u Tablicama IIIA-IIIC i IVA-IVC.
TABLICA IIIA
Ispitivanje antiproliferacijskog djelovanja SW480 (debelo crijevo) - raspon IC50 0.01-1 μM
[image]
TABLICA IIIB
Ispitivanje antiproliferacijskog djelovanja SW480 (debelo crijevo) - raspon IC50 1.1-9.99 μM
[image]
TABLICA IIIC
Ispitivanje antiproliferacijskog djelovanja SW480 (debelo crijevo) - raspon IC50 10-30 μM
[image] TABLICA IVA
Ispitivanje antiproliferacijskog djelovanja HCT 116 (debelo crijevo) - raspon IC50 0.01-1 μM
[image]
TABLICA IVB
Ispitivanje antiproliferacijskog djelovanja HCT 116 (debelo crijevo) - raspon IC50 1.1-9.99 μM
[image]
TABLICA IVC
Ispitivanje antiproliferacijskog djelovanja HCT 116 (debelo crijevo) - raspon IC50 10-30 μM
[image] [image]
Primjer 5: Oblikovanje tablete
[image] Spoj 1 predstavlja spoj iz izuma
Postupak izrade:
1. Miješati stavke 1, 2 i 3 u odgovarajućem mikseru 15 minuta.
2. Granulirati praškastu mješavinu iz Koraka 1 s 20% otopine Povidona K30 (stavka 4).
3. Sušiti granulat iz Koraka 2 na 50°C.
4. Propustiti granulat iz Koraka 3 kroz odgovarajući mlin.
5. Dodati Stavak 5 mljevenom granulatu iz Koraka 4 te miješati 5 minuta.
6. Prešati granulat iz Koraka 5 u odgovarajućoj preši.
Primjer 6: Oblikovanje kapsule
[image] * Spoj 1 predstavlja spoj iz izuma
Postupak izrade:
1. Miješati Stavke l, 2 i 3 u odgovarajućem mikseru 15 minuta.
2. Dodati Stavke 4&5 te miješati 3 minute.
3. Napuniti u odgovarajuće kapsule.
Primjer 7: Pripravljanje Injekcijske Otopine/Emulzije
[image] * Spoj 1 predstavlja spoj iz izuma
Postupak izrade:
1. Otopiti Stavak 1 u Stavku 2.
2. Dodati Stavke 3,4 i 5 u Stavak 6 te miješati dok se ne dispergiraju, zatim homogenizirati.
3. Dodati otopinu iz koraka 1 u smjesu iz koraka 2 i homogenizirati sve dok disperzija ne postane prozirna.
4. Sterilno filtrirati kroz O.2 um filter i puniti u fijale.
Primjer 8: Pripravljanje Injekcijske Otopine/Emulzije
[image] * Spoj 1 predstavlja spoj iz izuma
Postupak izrade:
1. Otopiti Stavak 1 u Stavku 2.
2. Dodati Stavke 3,4 i 5 u Stavak 6 te miješati dok se ne dispergiraju, zatim homogenizirati.
3. Dodati otopinu iz koraka 1 u smjesu iz koraka 2 i homogenizirati sve dok disperzija ne postane prozirna.
4. Sterilno filtrirati kroz 0.2 um filter i puniti i fijale.
Premda je izum ilustriran kroz određena i poželjna ostvarenja, stručnjak će uočiti varijacije i modifikacije koje se mogu postići uobičajenim eksperimentiranjem i praktičnom primjenom izuma. Nije, dakle, mišljeno da izum bude ograničen prethodnim opisom, nego da bude definiran dodanim zahtjevima i njihovim ekvivalentima.
Claims (20)
1. Spoj formule
[image]
naznačen time, da je
R1 vodik, -N02, -CN, -halogen, -OR5, -R6OR7, -COOR7, -CONR8R9, -NR10Rn, -NHCOR12, -NHS02R13, ili niži alkil ravnog lanca koji se može supstituirati s hidroksi i/ili halogenom;
svaki od R2 i R4 neovisno predstavlja vodik, -halogen, -NO2, -CF3 ili niži alkil ravnog lanca;
R3 je vodik, -cikloalkil, -aril, -heterocikl, -heteroaril, -COOR7-CN, -alkenil, -CONR8R9, -alkinil, ili niži alkil koji se može supstituirati s hidroksi, -OR9, F, i/ili aril;
R5 je niži alkil koji se može supstituirati s halogenom;
R6 je niži alkil;
R7 je vodik ili niži alkil;
svaki od R8 i R9 neovisno predstavlja vodik ili niži alkil koji se sam može supstituirati s hidroksi i/ili -NH2;
alternativno, R8 i R9 mogu oblikovati 5- ili 6-člani heterocikl koji se može supstituirati s hidroksi, -NH2 i/ili nižim alkilom;
svaki od R10, R11 i R12 neovisno predstavlja vodik ili niži alkil;
R13 je niži alkil koji se može supstituirati halogenom i/ili -NR14R15; a
svaki od R14 i R15 neovisno predstavlja vodik ili niži alkil koji se mogu supstituirati s halogenom, ili alternativno, -NR14R15 je heterocikl
i predlijekovi i farmaceutski aktivni metaboliti spojeva formule I, i farmaceutski prihvatljive soli navedenih spojeva.
2. Spoj iz zahtjeva 1, naznačen time, da je R1 vodik, NO2, CN CONH2, halogen ili niži alkil.
3. Spoj iz zahtjeva 1 ili 2, naznačen time, da je R1 NO2, CN ili CONH2.
4. Spoj iz bilo kojeg od zahtjeva 1 do 3, naznačen time, da je R2 na poziciji 2' te da je ili vodik ili halogen.
5. Spoj iz bilo kojeg od zahtjeva 1 do 4, naznačen time, da je R3 niži alkil, hidroksi niži alkil, cikloalkil, heterocikl ili heteroaril.
6. Spoj iz bilo kojeg od zahtjeva 1 do 4, naznačen time, da je R3 metil, etil ili hidroksimetil.
7. Spoj, naznačen time, da je 3-metil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin.
8. Spoj, naznačen time, da je 3-metil-5-(2-fluorofenil)-pirazolo [3,4] [1,4]benzodiazepin-7-karbonitril.
9. Spoj, naznačen time, da je 3-metil-5-(2-fluorofenil)-pirazolo [3,4] [1,4]benzodiazepin-7-karboksamid.
10. Spoj, naznačen time, da je 3-hidroksimetil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karbonitril.
11. Spoj formule I iz zahtjeva 1, naznačen time, da je
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-klorofenil)-7-amino-pirazolo[3,4][1,4]benzodiazepin
5-fenil-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-fluorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-klorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
5-(2,4-diklorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
5-fenil-pirazolo [3,4] [1,4]benzodiazepin,
5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin,
5-(2-fluorofenil)-7-fluoro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-klorofenil)-7-metoksi-pirazolo[3,4][1,4]benzodiazepin,
5-(2-fluorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
5-fenil-7-metansulfonil-pirazolo[3,4][1,4]benzodiazepin,
5-(2-fluorofenil)-7-cijano-pirazolo[3,4][1,4]benzodiazepin,
5-fenil-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
5-(3-nitrofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-trifluorometilfenil)-7-nitro-pirazolo [3, 4 ] [1,4]benzodiazepin,
5-fenil-7-karbometoksi-pirazolo[3,4][1,4]benzodiazepin natrijeva sol
(5-fenil-pirazolo [3,4] [1,4]benzodiazepin-7-il)-karboksilne kiseline,
5-(2-fluorofenil)-7-jodo-pirazolo[3,4][1,4]benzodiazepin,
5-(2-fluorofenil)-7-karboetoksi-pirazolo [3,4] [1,4]benzodiazepin,
N-(2-hidroksietil)-5-(2-fluorofenil)-pirazolo [3,4] [1,4]benzodiazepin-7-karboksamid,
5-(2-fluorofenil)-7-morfolinilkarbonil-pirazolo [3,4] [1,4]benzodiazepin,
N,N-bis-(2-hidroksietil)-5-(2-fluorofenil)-pirazolo [3,4] [1,4]benzodiazepin-7-karboksamid,
(5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-karboksilna kiselina,
5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid, ili
5-(2-klorofenil)-7-karboetoksi-pirazolo [3,4] [1,4]benzodiazepin,
12. Spoj formule I iz zahtjeva 1, naznačen time, da je
3-etil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-feniletil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(1-metiletil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(1-metiletil)-5-(2-klorofenil)-7-amino-pirazolo[3,4] [1,4]benzodiazepin,
3-(fenilmetil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-karboetoksi-pirazolo[3,4][1,4]benzodiazepin,
3-(2-metilpropil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-trifluorometil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-hidroksimetil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
N-(2-hidroksietil)-3-metil-5-(2-fluorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid,
3-(N,N-dimetilaminometil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(1-metilpropil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-metoksimetil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-etenil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-klorofenil)-7-metoksi-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-klorofenil)-7-amino-pirazolo [3,4] [1,4]benzodiazepin
3-metil-5-fenil-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-klorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-amino-pirazolo[3,4][1,4]benzodiazepin,
N-(3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-acetamid,
N-(3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-metansulfonamid,
N-(3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-il)-2-propenamid,
3-metil-5-fenil-7-fluoro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-klorofenil)-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-fenil-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-jodo-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-morfolinilkarbonil-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-fenil-7-jodo-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-kloro-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-trifluorometilfenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
N'-(3-metil-5-(2-klorofenil)-pirazolo[3,4] [1,4]benzodiazepin-7-il)-4-N,N-dimetilaminsulfonamid,
N'-(3-metil-5-(2-klorofenil)-pirazolo[3,4] [1,4]benzodiazepin-7-il)-4-N-klorometilaminsulfonamid,
N'-(3-metil-5-(2-klorofenil)-pirazolo[3,4] [1,4]benzodiazepin-7-il)-4-morfolinsulfonamid,
N-[2-(4-morfolinil)etil]-3-metil-5-(2-fluorofenil)-pirazolo[3,4][1,4]benzodiazepin-7-karboksamid,
3-metil-5-fenil-7-jodo-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-fenil-7-bromo-pirazolo[3,4][1,4]benzodiazepin,
3-metil-5-(2-fluorofenil)-7-fluoro-pirazolo[3,4][1,4]benzodiazepin,
3-ciklopropil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-ciklopropil-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin, ili
3-propil-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin.
13. Spoj formule I iz zahtjeva 1, naznačen time, da je
3-karboetoksi-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karboksamid,
N,N-dimetil-5-(2-klorofenil)-7-nitro-pirazolo [3,4][1,4]benzodiazepin-3-karboksamid
N-amino-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin-3-karboksamid,
5-(2-klorofenil)-7-nitro-pirazolo[3, 4] [1,4]benzodiazepin-3-karboksaldehid, ili
5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin-3-karbonitril.
14. Spoj formule I iz zahtjeva 1, naznačen time, da je
3-(4-metilfenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(4-dimetilaminofenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4][1,4]benzodiazepin,
3-(2-cijanofenil)-5-(2-klorofenil)-7-nitro-pirazplo[3,4][1,4]benzodiazepin,
3-fenil-5-(2-klorofenil)-7-nitro-pirazolo [3,4][1,4]benzodiazepin,
3-(2-metilfenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-nitrofenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-trifluorometilfenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4][1,4]benzodiazepin,
3-(3-trifluorometilfenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(1-naftil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4 ] [1,4]benzodiazepin,
3-(2-metoksifenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(4-(metiltio)fenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(4-trifluorometoksilfenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(4-hidroksi-2-metoksifenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-hidroksifenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-((1,1'-bifenil)-4-il)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(2-naftil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-nitrofenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-fenoksifenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-cijanofenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-etoksifenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-metilfenil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin, ili
3- (2-fluorofenil)-5-fenil-7-nitro-pirazolo[3,4][1,4]benzodiazepin.
15. Spoj formule I iz zahtjeva 1, naznačen time, da je
3-(4-metilpirazol-5-il)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(1-tiazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(1,3,4-oksadiazol-2-il)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(4-imidazolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(2-pirazolil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(3-pirazolil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-tienil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3- (2-furanil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(3-metiltien-2-il)-5-(2-klorofenil)-7-nitro-pirazolo[3,4][1,4]benzodiazepin,
3-(3-metiltien-2-il)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(indol-2-il)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(l-metil-lH-pirol-2-il)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(3-piridinil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(4-piridinil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(4(1-pirolil)fenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-pirolil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(4-izokinolil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(2-benzofuranil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(3-tienil)-5-(2-klorofenil)-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(5-metiltien-2-il)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2-imidazolil)-5-fenil-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(3-piridinil)-5-fenil-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(l,3-benzodioksol-5-il)-5-fenil-7-nitro-pirazolo[3,4] [1,4]benzodiazepin,
3-(2,3-dihidro-l,4-benzodioksin-6-il)-5-fenil-7-nitro-pirazolo [3,4] [1,4]benzodiazepin,
3-(2,3-metilendioksifenil)-5-(2-klorofenil)-7-nitro-pirazolo [3,4] [1,4]benzodiazepin, ili
3-(3-etilfuran-2-il)-5-fenil-7-nitro-pirazolo[3,4] [1,4]benzodiazepin.
16. Spoj formula
[image]
ili
[image]
naznačen time, da su R1 do R4 kao u zahtjevu 1.
17. Farmaceutski pripravak, naznačen time, da sadrži spoj iz bilo kojeg od zahtjeva 1 do 15 kao aktivni sastojak i farmaceutski prihvatljiv nosač ili pomoćno sredstvo.
18. Spojevi iz bilo kojeg od zahtjeva 1 do 15, naznačeni time, da služe kao lijek.
19. Uporaba spoja iz bilo kojeg od zahtjeva 1 do 15, naznačena time, da je za proizvodnju lijeka za liječenje ili kontrolu tumora dojke, debelog crijeva, pluća i prostate.
20. Novi spojevi, pripravci i primjena, naznačeni time, da kako su gore opisani, posebno s obzirom na Primjere.
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US13037099P | 1999-04-21 | 1999-04-21 | |
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FR2847253B1 (fr) * | 2002-11-19 | 2007-05-18 | Aventis Pharma Sa | Nouveaux derives de pyridazinones a titre de medicaments et compositions pharmaceutiques les renfermant |
PL378116A1 (pl) * | 2003-02-27 | 2006-03-06 | Abbott Laboratories | Heterocykliczne inhibitory kinazy |
PL1802625T3 (pl) * | 2004-10-13 | 2008-12-31 | Hoffmann La Roche | Dwupodstawione pirazolobenzodiazepiny użyteczne jako inhibitory CDK2 i angiogenezy oraz w leczeniu raka sutka, okrężnicy, płuca i gruczołu krokowego |
CN101287469A (zh) * | 2005-10-14 | 2008-10-15 | 霍夫曼-拉罗奇有限公司 | 5-(2-氯苯基)-1,2-二氢-7-氟-8-甲氧基-3-甲基-吡唑并[3,4-b][1,4]苯并二氮杂䓬的给药方案 |
DE602007009128D1 (de) | 2006-07-10 | 2010-10-21 | Paion Uk Ltd | Benzodiazepinsalze mit kurzzeitwirkung und polymorphe formen davon |
KR20100073454A (ko) * | 2008-12-23 | 2010-07-01 | 국립암센터 | 트란스글루타미나제 억제제로 사용되는 신규한 피라졸로디아제핀계 화합물, 이의 제조방법 및 이를 포함하는 조성물 |
EP2305647A1 (en) | 2009-09-18 | 2011-04-06 | PAION UK Limited | Process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4 H-imidazo[1,2-a][1,4]benzodiazepine-4-yl] propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
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CN102603743B (zh) * | 2012-02-24 | 2014-05-28 | 南京天易生物科技有限公司 | 抗肿瘤的氮杂苯并[f]薁衍生物其制备方法及其用途 |
CN103288828A (zh) * | 2012-02-24 | 2013-09-11 | 中国科学院大连化学物理研究所 | 一种合成手性二氢-6H-吲哚并[2,1-c][1,4]-苯并二氮杂卓的方法 |
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