SK118798A3 - Pharmaceutically useful compounds - Google Patents
Pharmaceutically useful compounds Download PDFInfo
- Publication number
- SK118798A3 SK118798A3 SK1187-98A SK118798A SK118798A3 SK 118798 A3 SK118798 A3 SK 118798A3 SK 118798 A SK118798 A SK 118798A SK 118798 A3 SK118798 A3 SK 118798A3
- Authority
- SK
- Slovakia
- Prior art keywords
- pyrazolo
- hydroxy
- formula
- bond
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 285
- 238000000034 method Methods 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 199
- 150000003839 salts Chemical class 0.000 claims description 177
- 125000000217 alkyl group Chemical group 0.000 claims description 118
- -1 NR 16 R 17 Chemical group 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 23
- UTKNBHYJLFLZRD-UHFFFAOYSA-N isoquinolin-2-ium;hydroxide Chemical compound [OH-].C1=[NH+]C=CC2=CC=CC=C21 UTKNBHYJLFLZRD-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 11
- GYPOFOQUZZUVQL-UHFFFAOYSA-N 2h-isoquinolin-3-one Chemical compound C1=CC=C2C=NC(O)=CC2=C1 GYPOFOQUZZUVQL-UHFFFAOYSA-N 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- ZDQCLDBVVQUHDH-UHFFFAOYSA-N 6h-isoquinolin-5-one Chemical compound N1=CC=C2C(=O)CC=CC2=C1 ZDQCLDBVVQUHDH-UHFFFAOYSA-N 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-O isoquinolin-2-ium Chemical compound C1=[NH+]C=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-O 0.000 claims description 8
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- DKAKOSUOWJVWSD-UHFFFAOYSA-N COc1ccc(Cn2c3c(O)n(nc3c3ccccc3c2=O)-c2ccc(cc2)C(F)(F)F)cc1 Chemical compound COc1ccc(Cn2c3c(O)n(nc3c3ccccc3c2=O)-c2ccc(cc2)C(F)(F)F)cc1 DKAKOSUOWJVWSD-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- PVFTVWLLJSNYFC-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].C1=CC(OC)=CC=C1CN1C2=C(O)N(C=3C=CC(=CC=3)C(F)(F)F)[NH2+]C2=C2C=CC=CC2=C1 PVFTVWLLJSNYFC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- AHFMOFVTPSIFDG-UHFFFAOYSA-N 4-methyl-5-methylsulfanyl-2-[4-(trifluoromethyl)phenyl]-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C(SC)=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C(F)(F)F)C=C1 AHFMOFVTPSIFDG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000000269 nucleophilic effect Effects 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- OOVMRUNJTOSPNP-UHFFFAOYSA-N 2-(4-chlorophenyl)-4-(2-methylsulfanylethyl)-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(CCSC)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(Cl)C=C1 OOVMRUNJTOSPNP-UHFFFAOYSA-N 0.000 claims description 3
- YLICKAKYJGCYNI-UHFFFAOYSA-N 4-(2-methylsulfanylethyl)-2-[4-(trifluoromethyl)phenyl]-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(CCSC)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C(F)(F)F)C=C1 YLICKAKYJGCYNI-UHFFFAOYSA-N 0.000 claims description 3
- ZCQJCHZBLNLFJY-UHFFFAOYSA-N 4-methyl-2-(4-methylthiophen-2-yl)-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC(C)=CS1 ZCQJCHZBLNLFJY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- KQRHWMBVDDGFJH-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C=1N(C=C1C=CC=CC=21)CC1=CC=C(C=C1)OC)C=1C=NC2=CC=CC=C2C=1 Chemical compound [OH-].OC=1N([NH2+]C=2C=1N(C=C1C=CC=CC=21)CC1=CC=C(C=C1)OC)C=1C=NC2=CC=CC=C2C=1 KQRHWMBVDDGFJH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- WISWOBVOXDOJLV-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)-4-methyl-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(Cl)C(Cl)=C1 WISWOBVOXDOJLV-UHFFFAOYSA-N 0.000 claims description 2
- WHNDAYMYILZNGT-UHFFFAOYSA-N 2-(4-bromophenyl)-4-methyl-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(Br)C=C1 WHNDAYMYILZNGT-UHFFFAOYSA-N 0.000 claims description 2
- IXPCPXXOAVXTCX-UHFFFAOYSA-N 2-(4-chlorophenyl)-3a,4-dimethyl-5h-pyrazolo[4,3-c]isoquinolin-3-one Chemical compound O=C1C2(C)N(C)CC3=CC=CC=C3C2=NN1C1=CC=C(Cl)C=C1 IXPCPXXOAVXTCX-UHFFFAOYSA-N 0.000 claims description 2
- XRYAOHFWRNRGHB-UHFFFAOYSA-N 2-(4-chlorophenyl)-4,5-dimethyl-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].[NH2+]1C2=C3C=CC=CC3=C(C)N(C)C2=C(O)N1C1=CC=C(Cl)C=C1 XRYAOHFWRNRGHB-UHFFFAOYSA-N 0.000 claims description 2
- ROMNEYAQUBNRLR-UHFFFAOYSA-N 2-(4-hydroxybiphenyl-3-yl)-4-methyl-1h-isoindole-1,3(2h)-dione Chemical compound O=C1C=2C(C)=CC=CC=2C(=O)N1C(C(=CC=1)O)=CC=1C1=CC=CC=C1 ROMNEYAQUBNRLR-UHFFFAOYSA-N 0.000 claims description 2
- RDZKPSLCQMHEMV-UHFFFAOYSA-N 2-(4-iodophenyl)-4-methyl-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(I)C=C1 RDZKPSLCQMHEMV-UHFFFAOYSA-N 0.000 claims description 2
- HSKNESSXMAUTOB-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-4-methyl-1H-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C(C)(C)C)C=C1 HSKNESSXMAUTOB-UHFFFAOYSA-N 0.000 claims description 2
- MLAYZCMWRNQKQX-UHFFFAOYSA-N 2-hydroxy-1h-isoquinoline Chemical compound C1=CC=C2C=CN(O)CC2=C1 MLAYZCMWRNQKQX-UHFFFAOYSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- BDCYLEDBRGCNIA-UHFFFAOYSA-N 4-(3-hydroxy-4-methyl-1h-pyrazolo[4,3-c]isoquinolin-1-ium-2-yl)benzoic acid;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C(O)=O)C=C1 BDCYLEDBRGCNIA-UHFFFAOYSA-N 0.000 claims description 2
- JHFCMQCVAAGCCH-UHFFFAOYSA-N 4-methyl-2-(4-methylphenyl)-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C)C=C1 JHFCMQCVAAGCCH-UHFFFAOYSA-N 0.000 claims description 2
- UHMJRIYVFOEEKI-UHFFFAOYSA-N 4-methyl-2-(4-methylsulfinylphenyl)-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(S(C)=O)C=C1 UHMJRIYVFOEEKI-UHFFFAOYSA-N 0.000 claims description 2
- CMSFBHOWFRNPJY-UHFFFAOYSA-N 4-methyl-2-(4-nitrophenyl)-1H-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C([N+]([O-])=O)C=C1 CMSFBHOWFRNPJY-UHFFFAOYSA-N 0.000 claims description 2
- MYDOMCZZXQMLSS-UHFFFAOYSA-N 4-methyl-2-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol hydroxide Chemical compound [OH-].OC1=C2N(C)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C)N=C1 MYDOMCZZXQMLSS-UHFFFAOYSA-N 0.000 claims description 2
- FJJRSCAHJXBCJU-UHFFFAOYSA-N 4-methyl-5-piperazin-1-yl-2-[4-(trifluoromethyl)phenyl]-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].CN1C2=C(O)N(C=3C=CC(=CC=3)C(F)(F)F)[NH2+]C2=C2C=CC=CC2=C1N1CCNCC1 FJJRSCAHJXBCJU-UHFFFAOYSA-N 0.000 claims description 2
- QYJOUBPYPKRTDS-UHFFFAOYSA-N 4-phenyl-2-[4-(trifluoromethyl)phenyl]-1h-pyrazolo[4,3-c]isoquinolin-1-ium-3-ol;hydroxide Chemical compound [OH-].OC1=C2N(C=3C=CC=CC=3)C=C3C=CC=CC3=C2[NH2+]N1C1=CC=C(C(F)(F)F)C=C1 QYJOUBPYPKRTDS-UHFFFAOYSA-N 0.000 claims description 2
- PQLUVPOJYXZXKA-UHFFFAOYSA-N CC(C)n1c2c(O)n(nc2c2ccccc2c1=O)-c1ccc(cc1)C(F)(F)F Chemical compound CC(C)n1c2c(O)n(nc2c2ccccc2c1=O)-c1ccc(cc1)C(F)(F)F PQLUVPOJYXZXKA-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- HSXCYGJGXAAURQ-UHFFFAOYSA-N [OH-].C(C)C=1N(C=2C(=C3C=CC=CC13)[NH2+]N(C2O)C2=CC=C(C=C2)C(F)(F)F)C Chemical compound [OH-].C(C)C=1N(C=2C(=C3C=CC=CC13)[NH2+]N(C2O)C2=CC=C(C=C2)C(F)(F)F)C HSXCYGJGXAAURQ-UHFFFAOYSA-N 0.000 claims description 2
- HJQAANGFUHVFRL-UHFFFAOYSA-N [OH-].C(C)N1C=C2C=CC=CC2=C2C1=C(N([NH2+]2)C2=CC=C(C=C2)C(F)(F)F)O Chemical compound [OH-].C(C)N1C=C2C=CC=CC2=C2C1=C(N([NH2+]2)C2=CC=C(C=C2)C(F)(F)F)O HJQAANGFUHVFRL-UHFFFAOYSA-N 0.000 claims description 2
- RSVNVYFYIHNDRN-UHFFFAOYSA-N [OH-].C1(CC1)N1C=C2C=CC=CC2=C2C1=C(N([NH2+]2)C=2SC=C(C2)C)O Chemical compound [OH-].C1(CC1)N1C=C2C=CC=CC2=C2C1=C(N([NH2+]2)C=2SC=C(C2)C)O RSVNVYFYIHNDRN-UHFFFAOYSA-N 0.000 claims description 2
- YPDMCSDSADTGGW-UHFFFAOYSA-N [OH-].ClC1=C(C=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)C)=C1O)C(F)(F)F Chemical compound [OH-].ClC1=C(C=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)C)=C1O)C(F)(F)F YPDMCSDSADTGGW-UHFFFAOYSA-N 0.000 claims description 2
- CMWNUFVTYZYHFW-UHFFFAOYSA-N [OH-].ClC1=C(C=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)C2CC2)=C1O)C(F)(F)F Chemical compound [OH-].ClC1=C(C=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)C2CC2)=C1O)C(F)(F)F CMWNUFVTYZYHFW-UHFFFAOYSA-N 0.000 claims description 2
- CYLSDUHKDBQAQL-UHFFFAOYSA-N [OH-].ClC1=CC=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CCS(=O)C)=C1O Chemical compound [OH-].ClC1=CC=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CCS(=O)C)=C1O CYLSDUHKDBQAQL-UHFFFAOYSA-N 0.000 claims description 2
- LZPGGCKOJSZMSH-UHFFFAOYSA-N [OH-].ClC1=CC=C(C=N1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CC2=CC=C(C=C2)OC)=C1O Chemical compound [OH-].ClC1=CC=C(C=N1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CC2=CC=C(C=C2)OC)=C1O LZPGGCKOJSZMSH-UHFFFAOYSA-N 0.000 claims description 2
- CRVSEQIRJPWAQK-UHFFFAOYSA-N [OH-].FC(C1=CC=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CC(=O)OCC)=C1O)(F)F Chemical compound [OH-].FC(C1=CC=C(C=C1)N1[NH2+]C=2C(N(C=C3C=CC=CC23)CC(=O)OCC)=C1O)(F)F CRVSEQIRJPWAQK-UHFFFAOYSA-N 0.000 claims description 2
- LQAZGVCPDKIGMG-UHFFFAOYSA-N [OH-].FC=1C2=C3C(N(C(=C2C=CC1)C)CC1=CC=C(C=C1)OC)=C(N([NH2+]3)C3=CC=C(C=C3)C(F)(F)F)O Chemical compound [OH-].FC=1C2=C3C(N(C(=C2C=CC1)C)CC1=CC=C(C=C1)OC)=C(N([NH2+]3)C3=CC=C(C=C3)C(F)(F)F)O LQAZGVCPDKIGMG-UHFFFAOYSA-N 0.000 claims description 2
- FWOYHGSMHOOUCK-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C1N(C(=C1C=CC=CC21)N2CCOCC2)C)C2=CC=C(C=C2)C(F)(F)F Chemical compound [OH-].OC=1N([NH2+]C=2C1N(C(=C1C=CC=CC21)N2CCOCC2)C)C2=CC=C(C=C2)C(F)(F)F FWOYHGSMHOOUCK-UHFFFAOYSA-N 0.000 claims description 2
- KVKVNRULGGTDFO-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C(C)C)C2=CC(=CC=C2)C(F)(F)F Chemical compound [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C(C)C)C2=CC(=CC=C2)C(F)(F)F KVKVNRULGGTDFO-UHFFFAOYSA-N 0.000 claims description 2
- NZLSLVKJSPNIKJ-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C(C)C)C2=CC=C(C=C2)C(F)(F)F Chemical compound [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C(C)C)C2=CC=C(C=C2)C(F)(F)F NZLSLVKJSPNIKJ-UHFFFAOYSA-N 0.000 claims description 2
- FVZUJMMJOPFHHD-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C)C2=CC=C(C=C2)C(C)C Chemical compound [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)C)C2=CC=C(C=C2)C(C)C FVZUJMMJOPFHHD-UHFFFAOYSA-N 0.000 claims description 2
- PYIJULHKKBJYIL-UHFFFAOYSA-N [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)CC2=CC=C(C=C2)OC)C2=CC=CC=C2 Chemical compound [OH-].OC=1N([NH2+]C=2C1N(C=C1C=CC=CC21)CC2=CC=C(C=C2)OC)C2=CC=CC=C2 PYIJULHKKBJYIL-UHFFFAOYSA-N 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- 150000001989 diazonium salts Chemical class 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000007280 thionation reaction Methods 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 2
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- 239000004296 sodium metabisulphite Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Farmaceutický užitočné zlúčeniny a spôsob ich prípravyPharmaceutically useful compounds and processes for their preparation
Oblasť technikyTechnical field
Tento vynález sa týka farmaceutický užitočných zlúčenín, spôsobov ich prípravy, ich použitia ako liečiv a farmaceutických formulácií, ktoré ich obsahujú.The present invention relates to pharmaceutically useful compounds, processes for their preparation, their use as medicaments and pharmaceutical formulations containing them.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Niektoré pyrazolo[4,3-c]izochinolín-3-óny sú známe z J. Chem. Soc. 599 (1959) (Hinton a kol.). Ich použitie ako liečiv sa neuvádza. Syntéza a schopnosť istých pyrazolo[4,3-c]izochinolín-3-olov inhibovať viazanie na benzodiazepínové receptory bola podrobne opísaná v J. Med. Chem. , 368 (1992) (Alien a koľ). Niektoré ďalšie pyrazolo[4,3-c]izochinolín-3-oly sú uvedené v Gaodeng Xuexiao Huaxue Xuebao 1991, , 1620-1622 (Qian Jian-hua a kol.). Nespomína sa žiadne farmaceutické využitie týchto zlúčenín.Some pyrazolo [4,3-c] isoquinolin-3-ones are known from J. Chem. Soc. 599 (1959) (Hinton et al.). Their use as medicaments is not mentioned. The synthesis and ability of certain pyrazolo [4,3-c] isoquinolin-3-oles to inhibit binding to benzodiazepine receptors has been described in detail in J. Med. Chem. , 368 (1992) (Alien et al.). Some other pyrazolo [4,3-c] isoquinolin-3-oles are disclosed in Gaodeng Xuexiao Huaxue Xuebao 1991, 1620-1622 (Qian Jianhui et al.). No pharmaceutical use of these compounds is mentioned.
Podstata vynálezuSUMMARY OF THE INVENTION
Teraz sa zistilo, že 2-arylpyrazolizochinolínové a cinolinónové deriváty vykazujú antialergickú a protizápalovú aktivitu. Z prvého hľadiska teda vynález poskytuje zlúčeninu vzorca I alebo jej farmaceutický prijateľný derivát na použitie ako liečivo:It has now been found that the 2-arylpyrazoloisoquinoline and cinolinone derivatives exhibit antiallergic and anti-inflammatory activity. Thus, in a first aspect, the invention provides a compound of formula I or a pharmaceutically acceptable derivative thereof for use as a medicament:
(I) kde:(I) where:
• B, D, E a G každé predstavuje CH, CA alebo N s tým, že nie viac ako jedno z B, D, E a G predstavuje CA a nie viac ako jedno z B, D, E a G predstavuje N;• B, D, E and G each represents CH, CA or N, with not more than one of B, D, E and G representing CA and no more than one of B, D, E and G representing N;
• X predstavuje C=O, C=S, C=NR15, CR3R6 alebo NR4;• X represents C = O, C = S, C = NR 15 , CR 3 R 6 or NR 4 ;
• Y predstavuje N alebo N+R7 alebo CR18;• Y represents N or N + R 7 or CR 18 ;
, · Z predstavuje OR8 alebo O’;Z represents OR 8 or O ';
• R1 predstavuje OH alebo Ci-6 alkyl, alebo tvorí väzbu s jedným z R2 alebo R5;R 1 represents OH or C 1-6 alkyl, or forms a bond with one of R 2 or R 5 ;
.· R2 predstavuje H, Ci_6 alkyl (voliteľne substituovaný fenylom, COOR9, NR10R11, OR12 alebo F) alebo C3.7 cykloalkyl, alebo tvorí väzbu s jedným z R1, R3 alebo R4;R 2 represents H, C 1-6 alkyl (optionally substituted with phenyl, COOR 9 , NR 10 R 11 , OR 12 or F) or C 3-7 cycloalkyl, or forms a bond with one of R 1 , R 3 or R 4 ;
• R3 predstavuje H alebo väzbu s R2;R 3 represents H or a bond with R 2 ;
• R4 predstavuje C^e alkyl alebo väzbu s R2;R 4 represents C 1-6 alkyl or a bond with R 2 ;
® R5 predstavuje väzbu s R1 alebo R8;R 5 represents a bond with R 1 or R 8 ;
• R6 predstavuje H, Ci-6 alkyl (voliteľne substituovaný fenylom), C3-7 cykloalkyl, fenyl, halogén, Ci_6 alkoxy, Ci.6 alkyltio, Ci_6 alkylsulfinyl, kyano alebo NR13R14;R 6 represents H, C 1-6 alkyl (optionally substituted with phenyl), C 3-7 cycloalkyl, phenyl, halogen, C 1-6 alkoxy, C 1-6 alkyl; 6 alkylthio, C 1-6 alkylsulfinyl, cyano or NR 13 R 14 ;
• R7 predstavuje Ci.6 alkyl (voliteľne substituovaný fenylom) alebo C3.7 cykloalkyl, z ktorých každý môže byť voliteľne substituovaný halogénom, hydroxylom, Ci_6 alkoxy, Ci-6 alkyltio, Ci-6 alkylsulfinyl, NR16R17, COOH, COO(Ci.6 alkyl) alebo kyano;R 7 represents C 1-6 alkyl (optionally substituted with phenyl) or C 3-7 cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, NR 16 R 17 , COOH, COO (C 1-6 alkyl) or cyano;
• alebo R6 a R7 spolu predstavujú C3.5 alkylén, X a Y pritom tvoria 5-7 členný kruh;Or R 6 and R 7 together represent C 3 . 5 alkylene, X and Y form a 5-7 membered ring;
• R8 predstavuje H, Ci-6 alkyl alebo väzbu s R5;R 8 represents H, C 1-6 alkyl or a bond with R 5 ;
• R9, R10, R11, R12, R15, R16, R17 a R18 nezávisle predstavujú C^e alkyl alebo H;R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 and R 18 independently represent C 1-6 alkyl or H;
• R13 a R14 sú nezávisle C1.6 alkyl, H alebo spolu s atómom dusíka, ku ktorému sú pripojené, tvoria 3-7 členný nasýtený kruh voliteľne obsahujúci ďalší atóm kyslíka alebo atóm dusíka voliteľne substituovaný Ci-6 alkylom;R 13 and R 14 are independently C 1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom optionally substituted with C 1-6 alkyl;
• Ar1 predstavuje fenyl, pyrídyl, pyrimidinyl, 2-benzotiazolyl, 2- alebo 3-chinolyl alebo 2-chinoxalinyl, z ktorých všetky sú voliteľne substituované jedným alebo viacerými substituentami vybranými z nasledujúcich: halogén, nitro, kyano, fenyl, fenylsulfonyl, Cve alkyl, Ci_6 alkoxy, Ci_6 alkyltio, Ci-6 alkylsulfinyl, COOH, C00(Ci-6 alkyl), Ci-6 alkyl substituovaný fenylom alebo fenyl, v ktorom akékoľvek alkylové, alkoxylové, alkyltio a alkylsulfinyl skupiny môžu byť voliteľne substituované fluórom; a • A predstavuje halogén, kyano, amino, nitro, Ci^ alkyl alebo Ci.6 alkoxy;Ar 1 represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, phenylsulfonyl, Cve alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, COOH, C00 (C 1-6 alkyl), C 1-6 alkyl substituted with phenyl or phenyl, wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with fluorine ; and A represents halogen, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkyl. 6 alkoxy;
v ktorých fenylové skupiny, ktoré sa nachádzajú v R2, R6, R7 alebo ako substituenty na Ar1, môžu byť voliteľne substituované Ci.6 alkylom, halogénom alebo Ci.6 alkoxylom;wherein the phenyl groups found in R 2 , R 6 , R 7, or as substituents on Ar 1 , may be optionally substituted with C 1-6 alkyl; 6 alkyl, halogen or C. 6 alkoxy;
s výhradami, že:with the proviso that:
(i) keď X predstavuje C=O, C=S alebo C=NR15, potom Y predstavuje N;(i) when X represents C = O, C = S or C = NR 15 , then Y represents N;
(ii) keď R4 predstavuje väzbu s R2, potom Y predstavuje N+R7;(ii) when R 4 represents a bond with R 2 , then Y represents N + R 7 ;
(iii) keď Y predstavuje N+R7, potom Z predstavuje O’, R2 predstavuje väzbu s R3 alebo R4 a R1 a R5 tvoria väzbu;(iii) when Y represents N + R 7 , then Z represents O ', R 2 represents a bond with R 3 or R 4 and R 1 and R 5 form a bond;
(iv) keď Y predstavuje N, potom Z predstavuje OR8;(iv) when Y is N, then Z is OR 8 ;
(v) keď R1 predstavuje OH, potom X predstavuje C=O, Y predstavuje N, Z predstavuje OR8 a R5 predstavuje väzbu s R8;(v) when R 1 represents OH, then X represents C = O, Y represents N, Z represents OR 8 and R 5 represents a bond with R 8 ;
(vi) keď R1 predstavuje alkyl, potom R5 predstavuje väzbu s R8, Y predstavuje N, R2 nepredstavuje väzbu a X nepredstavuje NR4;(vi) when R 1 represents alkyl, then R 5 represents a bond with R 8 , Y represents N, R 2 does not represent a bond and X does not represent NR 4 ;
(vii) keď R1 predstavuje väzbu s R2, potom R5 a R8 tvoria väzbu, a ak X predstavuje NR4, potom R4 predstavuje alkyl;(vii) when R 1 represents a bond with R 2 , then R 5 and R 8 form a bond, and when X represents NR 4 , then R 4 represents alkyl;
I (viii) keď R6 predstavuje aryl, halogén, alkoxy, tioalkyl, potom R2 a R3 tvoria väzbu;(Viii) when R 6 represents aryl, halogen, alkoxy, thioalkyl, then R 2 and R 3 form a bond;
(ix) keď Y predstavuje N alebo N+R7 a R2 je substituované ktorýmkoľvek z NR10R11, OR12 alebo F, potom substituent a dusík kruhu z Y nesmie byť pripojený na ten istý atóm uhlíka z R2;(ix) when Y represents N or N + R 7 and R 2 is substituted by any one of NR 10 R 11 , OR 12 or F, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R 2 ;
(x) keď R7 je substituovaný ktorýmkoľvek z NR1SR17, OR12 alebo halogénom, potom substituent a dusík kruhu z Y nesmú byť pripojené na ten istý atóm uhlíka z R7;(x) when R7 is substituted by any of DB 1 S R 17, OR 12 or halogen, the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R7;
(xi) keď jedno z B, D, E a G predstavuje N, potom X nepredstavuje NR4;(xi) when one of B, D, E and G is N, then X is not NR 4 ;
(xii) · keď Y predstavuje CR18, potom X predstavuje CR3R6;(xii) · when Y is CR 18 , then X is CR 3 R 6 ;
i · · s tou ďalšou výhradou, že:with the further proviso that:
« keď B, D, E a G všetky predstavujú CH, X predstavuje CHR3, Y predstavuje dusík, R1 a R5 tvoria väzbu, R8 predstavuje H a R2 a R3 spolu predstavujú väzbu, potom Ar1 nepredstavuje nesubstituovaný fenyl, 4-chlórfenyl, 4-fluórfenyl aleboWhen B, D, E and G all represent CH, X represents CHR 3 , Y represents nitrogen, R 1 and R 5 form a bond, R 8 represents H and R 2 and R 3 together represent a bond, then Ar 1 is not unsubstituted phenyl , 4-chlorophenyl, 4-fluorophenyl or
4-metoxyfenyl.4-methoxyphenyl.
Niektoré zo zlúčenín vzorca (I) sú nové. V rámci vynálezu sa ďalej uvádza zlúčenina vzorca I:Some of the compounds of formula (I) are new. The invention further provides a compound of formula I:
(l)(L)
kde:where:
• B, D, E a G každé predstavuje CH, CA alebo N za predpokladu, že nie viac ako jedno z B, D, E a G predstavuje CA a nie viac ako jedno z B, D, E a G predstavuje N;• B, D, E and G each represents CH, CA or N provided that no more than one of B, D, E and G represents CA and no more than one of B, D, E and G represents N;
• X predstavuje C=O, C=S, C=NR15, CR3R6 alebo NR4;• X represents C = O, C = S, C = NR 15 , CR 3 R 6 or NR 4 ;
• Y predstavuje N alebo N+R7 alebo CR18;• Y represents N or N + R 7 or CR 18 ;
• Z predstavuje OR8 alebo 0‘;Z represents OR 8 or O ';
• R1 predstavuje OH alebo Ci.6 alkyl, alebo s tvorí väzbu buď s R2 alebo R5;R 1 represents OH or C 1-6; 6 alkyl, or forms a bond with either R 2 or R 5;
« R2 predstavuje H, Ci.6 alkyl (voliteľne substituovaný fenylom, COOR9, NR10R11, OR12 alebo F) alebo C3-7 cykloalkyl, alebo tvorí väzbu buď s R1, R3 alebo R4;"R 2 is H, C. 6 alkyl (optionally substituted by phenyl, COOR 9, NR 10 R 11, OR 12, or F) or C3-7 cycloalkyl, or forms a bond with either R 1, R 3 or R 4;
• R3 predstavuje H alebo väzbu s R2;R 3 represents H or a bond with R 2 ;
• R4 predstavuje Ci-6 alkyl alebo väzbu s R2;R 4 represents C 1-6 alkyl or a bond with R 2 ;
• R5 predstavuje väzbu s R1 alebo R8;• R 5 represents a bond with R 1 or R 8 ;
• R6 predstavuje H, Cve alkyl (voliteľne substituovaný fenylom), C3-7 cykloalkyl, fenyl, halogén, Ci.6 alkoxy, Ci_6 alkyltio, Cv6 alkylsulfinyl, kyano alebo NR13R14;R 6 represents H, C 1-6 alkyl (optionally substituted with phenyl), C 3-7 cycloalkyl, phenyl, halogen, C 1-6 alkyl; 6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, cyano or NR 13 R 14 ;
• R7 predstavuje Ci.6 alkyl (voliteľne substituovaný fenylom) alebo C3.7 cykloalkyl, z ktorých každý môže byť voliteľne substituovaný halogénom, hydroxylom, C^e' alkoxy, Ci-e alkyltio, C1.6 alkylsulfinyl, NR16R17, COOH, COO(Ci.6 alkyl) alebo kyano;R 7 represents C 1-6 alkyl (optionally substituted with phenyl) or C 3-7 cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, NR 16 R 17 , COOH, COO (C 1-6 alkyl) or cyano;
• alebo R6 a R7 spolu predstavujú C3.5 alkylén, X a Y pritom tvoria 5-7 členný kruh;Or R 6 and R 7 together represent C 3-5 alkylene, X and Y being a 5-7 membered ring;
• R8 predstavuje H, Ci-6 alkyl alebo väzbu s R5;R 8 represents H, C 1-6 alkyl or a bond with R 5 ;
• R9, R10, R11, R12, R15, R16, R17 a R18 nezávisle predstavujú Ci-6 alkyl alebo H;R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 and R 18 independently represent C 1-6 alkyl or H;
• R13 a R14 sú nezávisle Ci.6 alkyl, H alebo spolu s atómom dusíka, ku ktorému sú pripojené, tvoria 3-7 členný nasýtený kruh voliteľne obsahujúci ďalší atóm kyslíka alebo atóm dusíka voliteľne substituovaný Ci_6 alkylom;R 13 and R 14 are independently C 1-6. C 1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom optionally substituted with C 1-6 alkyl;
• Ar1 predstavuje fenyl, pyridyl, pyrimidinyl, 2-benzotiazolyl, 2- alebo 3-chinolyl alebo 2-chinoxalinyl, z ktorých všetky sú voliteľne substituované jedným alebo viacerými substituentami vybranými z nasledujúcich: halogén, nitro, kyano, fenyl, fenylsulfonyl, Ci_6 alkyl, Ci-6 alkoxy, Ci_6 alkyltio, Ci_6 alkylsulfinyI, COOH, COO(Ci-S alkyl), C(1.6 alkyl substituovaný fenylom alebo fenyl, v ktorom akékoľvek alkylové, alkoxylové, alkyltio a alkylsulfinyl skupiny môžu byť voliteľne substituované fluórom; a • A predstavuje halogén, kyano, amino, nitro, Ci-s alkyl alebo Ci.6 alkoxy;Ar 1 represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, phenylsulfonyl, C 1-8; 6 alkyl, C 6 alkoxy, C 6 alkylthio, C 6 alkylsulfinyI, COOH, COO (C alkyl), C (first 6 alkyl, phenyl or substituted phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be and A represents halogen, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
v ktorých fenylové skupiny, ktoré sa nachádzajú v R2, R6, R7 alebo ako substituenty na Ar1, môžu byť voliteľne substituované Ci.6 alkylom, halogénom alebo C1-6 alkoxylom;wherein the phenyl groups found in R 2 , R 6 , R 7, or as substituents on Ar 1 , may be optionally substituted with C 1-6 alkyl; C 1-6 alkyl, halogen or C 1-6 alkoxy;
s výhradami, že:with the proviso that:
(i) keď X predstavuje C=O, C=S alebo C=NR15, potom Y predstavuje N;(i) when X represents C = O, C = S or C = NR 15 , then Y represents N;
(ii) keď R4 predstavuje väzbu s R2, potom Y predstavuje N+R7;(ii) when R 4 represents a bond with R 2 , then Y represents N + R 7 ;
(iii) keď Y predstavuje N+R7, potom Z predstavuje 0-, R2 predstavuje väzbu s R3 alebo R4 a R1 a R5 tvoria väzbu;(iii) when Y represents N + R 7 , then Z represents O-, R 2 represents a bond with R 3 or R 4 and R 1 and R 5 form a bond;
(iv) keď Y predstavuje N, potom Z predstavuje OR8;(iv) when Y is N, then Z is OR 8 ;
(v) keď R1 predstavuje OH, potom X predstavuje 0=0, Y predstavuje N, Z predstavuje OR8 a R5 predstavuje väzbu s R8;(v) when R 1 represents OH, then X represents O = O, Y represents N, Z represents OR 8 and R 5 represents a bond with R 8 ;
(vi) keď R1 predstavuje alkyl, potom R5 predstavuje väzbu s R8, Y predstavuje N, R2 nepredstavuje väzbu a X nepredstavuje NR4;(vi) when R 1 represents alkyl, then R 5 represents a bond with R 8 , Y represents N, R 2 does not represent a bond and X does not represent NR 4 ;
(vii) keď R1 predstavuje väzbu s R2, potom R5 a R8 tvoria väzbu, a ak X predstavuje NR4, potom R4 predstavuje alkyl;(vii) when R 1 represents a bond with R 2 , then R 5 and R 8 form a bond, and when X represents NR 4 , then R 4 represents alkyl;
(viii) keď R6 predstavuje aryl, halogén, alkoxy, tioalkyl, potom R2 a R3 tvoria väzbu;(viii) when R 6 represents aryl, halogen, alkoxy, thioalkyl, then R 2 and R 3 form a bond;
(ix) keď Y predstavuje N alebo N+R7 a R2 je substituované ktorýmkoľvek z NR10R11, OR12 alebo F, potom substituent a dusík kruhu z Y nesmie byť pripojený na ten istý atóm uhlíka z R2;(ix) when Y represents N or N + R 7 and R 2 is substituted by any one of NR 10 R 11 , OR 12 or F, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R 2 ;
(x) keď R7 je substituovaný ktorýmkoľvek z NR16R17, OR12 alebo halogénom, potom substituent a dusík kruhu z Y nesmú byť pripojené na ten istý atóm uhlíka z R7;(x) when R 7 is substituted with any of NR 16 R 17 , OR 12 or halogen, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R 7 ;
(xi) keď jedno z B, D, E a G predstavuje N, potom X nepredstavuje NR4;(xi) when one of B, D, E and G is N, then X is not NR 4 ;
(xii) keď Y predstavuje CR18, potom X predstavuje CR3R6;(xii) when Y is CR 18 , then X is CR 3 R 6 ;
s tými ďalšími výhradami, že:with those further reservations that:
(a) keď B, D, E a G všetky predstavujú CH, X predstavuje CHR3, Y predstavuje N, R1 a R5 tvoria väzbu, R8 predstavuje H a R2 a R3 spolu predstavujú väzbu, . potom Ar1 nepredstavuje nesubstituovanýfenyl, 4-chlórfenyl, 4-fluórfenyl alebo 4-metoxyfenyl;(a) when B, D, E and G all represent CH, X represents CHR 3 , Y represents N, R 1 and R 5 form a bond, R 8 represents H and R 2 and R 3 together represent a bond,. then Ar 1 is not unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl;
(b) keď B, D, E a G všetky prestavujú CH, X predstavuje CHR3, Y predstavuje N+R7, R1 a R5 tvoria väzbu, R2 a R3 predstavujú väzbu, R8 predstavuje H a R7 predstavuje metyl, potom Ar1 nepredstavuje nesubstituovaný fenyl;(b) when B, D, E and G all represent CH, X represents CHR 3 , Y represents N + R 7 , R 1 and R 5 form a bond, R 2 and R 3 represent a bond, R 8 represents H and R 7 represents methyl, then Ar 1 is not unsubstituted phenyl;
(c) keď B, D, E a G všetky predstavujú CH, X predstavuje CH21 Y predstavuje N, R1 a R5 tvoria väzbu, R8 predstavuje H a R2 predstavuje izopropyl, potom Ar1 nepredstavuje nesubstituovaný fenyl alebo 4-brómfenyl; a (d) keď B, D, E a G všetky predstavujú CH, X a Y predstavujú CH2 a R1 a R5 tvoria väzbu, potom Ar1 nepredstavuje nesubstituovaný fenyl.(c) when B, D, E and G are all CH, X is CH 21 Y is N, R 1 and R 5 form a bond, R 8 is H and R 2 is isopropyl, then Ar 1 is not unsubstituted phenyl or 4- bromophenyl; and (d) when B, D, E and G all represent CH, X and Y represent CH 2 and R 1 and R 5 form a bond, then Ar 1 is not unsubstituted phenyl.
alebo ich farmaceutický prijateľný derivát. 1 'or a pharmaceutically acceptable derivative thereof. 1 '
Ar1 s výhodou predstavuje fenyl alebo pyridyl, s najväčšou výhodou fenyl. Fenylová skupina Ar1 má s výhodou substituent v para polohe, s väčšou výhodou Cl, Br, CF3, C2F5, OCF3 alebo SCH3 substituent v para polohe, najmä CF3, C2F5, OCF3 alebo SCH3 substituent v para polohe.Ar 1 is preferably phenyl or pyridyl, most preferably phenyl. The phenyl group Ar 1 preferably has a substituent in the para position, more preferably Cl, Br, CF 3 , C 2 F 5 , OCF 3 or SCH 3 a substituent in the para position, especially CF 3 , C 2 F 5 , OCF 3 or SCH 3 substituent in para position.
Y s výhodou predstavuje N+R7 a X predstavuje CR3R6, v ktorom R3 tvorí väzbu s R2, a R6 predstavuje alkyl. V takom prípade R6 s výhodou predstavuje . rozvetvený alkyl. Alternatívne môže X predstavovať NR4, v ktorom R4 predstavuje väzbu s R2, a Y predstavuje N+R7.Y preferably represents N + R 7 and X represents CR 3 R 6 , wherein R 3 forms a bond with R 2 , and R 6 represents alkyl. In such a case, R 6 preferably represents. branched alkyl. Alternatively, X may be NR 4 , wherein R 4 is a bond with R 2 , and Y is N + R 7 .
B s výhodou predstavuje CA. V takom prípade A s výhodou predstavuje F.B preferably represents CA. In such a case, A preferably represents F.
V prípade, kedy jedno z B, D, E a G predstavuje N, potom to, ktoré predstavuje N, je s výhodou D alebo G.In the case where one of B, D, E and G is N, then that which is N is preferably D or G.
R1 s výhodou predstavuje väzbu s R2 alebo R5 V takom prípade R1 s výhodou predstavuje väzbu s R5.R 1 preferably represents a bond with R 2 or R 5 In which case R 1 preferably represents a bond with R 5 .
-7Medzi osobitne výhodné zlúčeniny podľa vynálezu patria zlúčeniny, na ktoré sú tu uvedené príklady, vrátane ich voľnej formy a všetkých ich solí a solvátov.Particularly preferred compounds of the invention include those exemplified herein, including their free form and all salts and solvates thereof.
Medzi farmaceutický prijateľné deriváty patria solváty a soli. Medzi konkrétne soli, ktoré možno spomenúť, ; patrí hydrochlorid, hydrobromid, benzénsulfônát, tozylát a metánsulfonát.Pharmaceutically acceptable derivatives include solvates and salts. Among the specific salts that may be mentioned ; include hydrochloride, hydrobromide, benzenesulfonate, tosylate and methanesulfonate.
Zlúčeniny vzorca I môžu vykazovať tautomerizmus. Všetky ich tautomérne formy a zmesi sú zahrnuté do rozsahu vynálezu. Zlúčeniny vzorca I môžu tiež obsahovať jeden alebo viacero asymetrických atómov uhlíka a môžu preto vykazovať optickú izomériu a/alebo diastereoizomériu. Všetky diastereoizoméry možno oddeliť pomocou konvenčných techník, napríklad chromatografiou alebo frakčnou kryštalizáciou. Rôzne optické izoméry možno izolovať rozdelením racemických alebo iných zmesí zlúčenín pomocou konvenčných techník, napríklad frakčnou kryštalizáciou alebo HPLC. Alternatívne možno požadované optické izoméry pripraviť reakciou príslušných opticky aktívnych východiskových látok za podmienok, ktoré nespôsobia racemizáciu, alebo derivatizáciou, napríklad homochirálnou kyselinou, s následným oddelením diastereomérnych derivátov konvenčnými prostriedkami (napríklad HPLC, chromatografiou na oxide kremičitom). Všetky stereoizoméry sú zahrnuté v rozsahu vynálezu.Compounds of formula I may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism and / or diastereoisomerism. All diastereoisomers can be separated by conventional techniques, for example chromatography or fractional crystallization. The various optical isomers may be isolated by resolution of racemic or other mixtures of compounds using conventional techniques, for example, fractional crystallization or HPLC. Alternatively, the desired optical isomers may be prepared by reacting the appropriate optically active starting materials under conditions that do not cause racemization or derivatization, for example with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means (for example, HPLC, silica chromatography). All stereoisomers are included within the scope of the invention.
Alkylové skupiny, ktoré môžu predstavovať R1, R2, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 a R18, alebo ktoré môžu byť substituované jedným alebo viacerými aromatickými kruhmi tvoriacimi súčasť Ar1, môžu byť nasýtené alebo nenasýtené a môžu mať lineárny alebo rozvetvený reťazec. C3.7 cykloalkyl, Cve alkoxy, C^e alkyltio,' Ci-6 alkylsulfinyl, 000(^.6 alkyl) a C3-5 alkyléri treba interpretovať v súlade s tým.Alkyl groups which may represent R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 , or which may be substituted with one or more aromatic rings forming part of Ar 1 , may be saturated or unsaturated and may be linear or branched. C 3-7 cycloalkyl, C 1-4 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, 000 (C 1-6 alkyl), and C 3-5 alkylers are to be interpreted accordingly.
V rámci vynálezu sa tiež uvádza postup prípravy zlúčenín vzorca I, ktorý pozostáva z nasledujúcich krokov:The invention also provides a process for the preparation of compounds of formula I which comprises the following steps:
(a) príprava zlúčenín vzorca I, kde X predstavuje CH2 alebo C=0, Y predstavuje(a) preparing compounds of formula I wherein X is CH 2 or C = O, Y is
N, Z predstavuje OR8, R5 a R8 tvoria väzbu a R1 a R2 tvoria väzbu, oxidáciou príslušnej zlúčeniny vzorca I, kde R1 aj R2 predstavujú H a B, D, E, G, X, Y, Z, Ar1 a R5 majú vyššie uvedený význam, napríklad pri laboratórnej teploteN, Z is OR 8 , R 5 and R 8 form a bond and R 1 and R 2 form a bond by oxidation of the corresponding compound of formula I, wherein R 1 and R 2 both represent H and B, D, E, G, X, Y, Z, Ar 1 and R 5 are as defined above, for example at room temperature
-8pomocou vhodného oxidačného činidla (napríklad oxidu manganičitého) a vhodného organického rozpúšťadla;Using a suitable oxidizing agent (e.g., manganese dioxide) and a suitable organic solvent;
(b) príprava zlúčenín vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje amino, redukciou príslušnej zlúčeniny vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje nitro a zvyšok B, D, E a G, a X, Y, Z, Ar1, R1, R2 a R5 majú vyššie uvedený význam, napríklad s práškovým železom a chloridom amónnym v refluxujúcom etanole;(b) preparing compounds of formula I wherein one of B, D, E and G is CA where A is amino by reduction of the corresponding compound of formula I wherein one of B, D, E and G is CA where A is nitro and residue B, D, E and G, and X, Y, Z, Ar 1 , R 1 , R 2 and R 5 are as defined above, for example with iron powder and ammonium chloride in refluxing ethanol;
(c) príprava zlúčenín vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje halogén, diazotáciou príslušnej zlúčeniny vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje amino a zvyšok B, D, E a G, a X, Y, Z, Ar1, R1, R2 a R5 majú vyššie uvedený význam, a rozkladom diazóniovej soli v prítomnosti halogenidového aniónu alebo (pre fluór) tetrafluórborátu sodného v dichlórbenzéne za refluxu;(c) preparing compounds of formula I wherein one of B, D, E and G is CA where A is halogen by diazotizing the corresponding compound of formula I wherein one of B, D, E and G is CA where A is amino and residue B, D, E and G, and X, Y, Z, Ar 1 , R 1 , R 2 and R 5 are as defined above, and by decomposing the diazonium salt in the presence of a halide anion or (for fluorine) sodium tetrafluoroborate in dichlorobenzene to reflux;
(d) príprava zlúčenín vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje kyano, reakciou príslušnej zlúčeniny vzorca I, kde jedno z B, D, E a G predstavuje CA, kde A predstavuje bróm a zvyšok B, D, E a G, a X, Y, Z, Ar1, R1, R2 a R5 majú vyššie uvedený význam, reakciou s kyanidom med’ným, napríklad pri refluxe v N-metylpyrolidóne;(d) preparing compounds of formula I wherein one of B, D, E and G is CA where A is cyano by reacting a corresponding compound of formula I wherein one of B, D, E and G is CA where A is bromo and residue B, D, E and G, and X, Y, Z, Ar 1 , R 1 , R 2 and R 5 are as defined above, by reaction with cuprous cyanide, for example at reflux in N-methylpyrrolidone;
(e) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O', R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje alkyltio, substitučnou reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje CR3R6, kde R6 predstavuje metyltio alebo halogén a B, D, E, G, Y, Z, Ar1, R1, R2, R3 a R5 majú vyššie uvedený význam, so zlúčeninou vzorca II:(e) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O ', R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkylthio, a substituent by reacting an appropriate compound of formula I wherein X is CR 3 R 6 , wherein R 6 is methylthio or halogen and B, D, E, G, Y, Z, Ar 1 , R 1 , R 2 , R 3 and R 5 have the above with the compound of formula II:
R6axSxH (II) kde RSa predstavuje Ci-6 alkyl, v prítomnosti bázy, napríklad hydridu sodného, vo vhodnom rozpúšťadle, napríklad DMF; XSx R 6a H (II) wherein R is C was 6 alkyl, in the presence of a base such as sodium hydride, in a suitable solvent such as DMF;
(f) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O’, R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje alkoxy, substitučnou reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje CR3R6, kde R6 predstavuje metyltio alebo halogén a B, D, E, G, Y, Z, Ar1, R1, R2, R3 a R5 majú vyššie uvedený význam, so zlúčeninou vzorca III:(f) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O ', R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkoxy, substituent by reacting an appropriate compound of formula I wherein X is CR 3 R 6 , wherein R 6 is methylthio or halogen and B, D, E, G, Y, Z, Ar 1 , R 1 , R 2 , R 3 and R 5 have the above as defined above, with a compound of formula III:
(g) (h) (i)(g) (h) (i)
G)G)
R6ax^H π (III) kde R6a má vyššie uvedený význam, v prítomnosti bázy, napríklad hydridu sodného, vo vhodnom rozpúšťadle, napríklad DMF;R 6a x 1 H π (III) wherein R 6a is as defined above, in the presence of a base, for example sodium hydride, in a suitable solvent, for example DMF;
príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O; R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje NR13R14, substitučnou reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje CR3R6, kde R6 predstavuje metyltio alebo halogén a B, D, E, G, Y, Z, Ar1, R1, R2, R3 a R5 majú vyššie uvedený význam, so zlúčeninou vzorca IV:preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O; R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents NR 13 R 14 , by a substitution reaction of the corresponding compound of formula I wherein X represents CR 3 R 6 wherein R 6 represents methylthio or halogen and B, D , E, G, Y, Z, Ar 1 , R 1 , R 2 , R 3 and R 5 are as defined above, with a compound of formula IV:
R13 (IV) kde R13 a R14 majú vyššie uvedený význam, v prítomnosti bázy, napríklad hydrogenuhličitanu sodného, vo vhodnom rozpúšťadle, napríklad DMF, pri 100 °C;R 13 (IV) wherein R 13 and R 14 are as defined above, in the presence of a base, for example sodium bicarbonate, in a suitable solvent, for example DMF, at 100 ° C;
príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O’, R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje metyltio, reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje C=S, Y predstavuje N, Z predstavuje OH a B, D, E, G, Ar1, R1, R2 a R5 majú vyššie uvedený význam, s metylačným činidlom, napríklad metyljodidom, napríklad blízko refluxu;the preparation of compounds of formula I wherein X represents CR 3 R 6 , Y represents N + R 7 , Z represents O ', R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents methylthio, by reacting the corresponding compound of formula Where X is C = S, Y is N, Z is OH and B, D, E, G, Ar 1 , R 1 , R 2 and R 5 are as defined above, with a methylating agent, for example methyl iodide, for example near reflux;
príprava zlúčenín vzorca I, kde X predstavuje C=S, Y predstavuje N, Z predstavuje OH a R1 predstavuje väzbu s R5, reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje C=O a B, D, E, G, Y, Z, Ar1, R1, R2 á R5 majú vyššie uvedený význam, tionáciou, napríklad pomocou Lawessonovho činidla, vo vhodnom rozpúšťadle, napríklad v dioxáne pri refluxe;preparing compounds of formula I wherein X is C = S, Y is N, Z is OH and R 1 is a bond with R 5 by reacting the corresponding compound of formula I wherein X is C = O and B, D, E, G, Y Z, Ar 1 , R 1 , R 2, and R 5 are as defined above, by thionation, for example using Lawesson's reagent, in a suitable solvent, for example dioxane at reflux;
príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje 0' a R6 predstavuje halogén, reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje C=O, Y predstavuje N, Z predstavuje OR8, R8 prestavuje väzbu s R5 a B, D, E, G, Ar1, R1 a R2 majú vyššie uvedený význam, halogenáciou, napríklad oxyhalogenidom fosforečným, napríklad blízko 100 °C;preparation of compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O 'and R 6 is halogen, by reacting the corresponding compound of formula I wherein X is C = O, Y is N, Z is OR 8 , R 8 represents a bond with R 5 and B, D, E, G, Ar 1 , R 1 and R 2 are as defined above, by halogenation, for example phosphorus oxyhalide, for example near 100 ° C;
-10(k) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O’, R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje alkyl, reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje C=O, Y predstavuje N, Z predstavuje OH, R1 prestavuje väzbu s R5, B, D, E, G a Ar1 majú vyššie uvedený význam a R2 predstavuje skupinu zodpovedajúcu vyššie definovanému R7, reakciou s nukleofilným alkylačným činidlom, napríklad zlúčeninou vzorca V:-10 (k) preparation of compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O ', R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkyl , reacting the corresponding compound of formula I wherein X is C = O, Y is N, Z is OH, R 1 is a bond with R 5 , B, D, E, G and Ar 1 are as defined above and R 2 is a group corresponding to R 7 as defined above, by reaction with a nucleophilic alkylating agent, for example a compound of formula V:
Hal (VI) kde R6 má vyššie uvedený význam a Hal predstavuje halogén, napríklad v prítomnosti meďnej soli, napríklad bromidu meďného, vo vhodnom rozpúšťadle, napríklad v dimetoxyetáne, napríklad pri refluxe;Hal (VI) wherein R 6 is as defined above and Hal represents halogen, for example in the presence of a copper salt, for example copper (I) bromide, in a suitable solvent, for example in dimethoxyethane, for example at reflux;
(I) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje O, R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 prestavuje alkyl, reakciou príslušnej zlúčeniny vzorca I, kde X predstavuje CR3R6, kde R6 predstavuje H, a B, D, E, G, Y, Z, Ar1, R1, R2 a R5 majú vyššie uvedený i(I) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O, R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 is alkyl, by reaction of the appropriate compounds of formula I wherein X is CR 3 R 6 , wherein R 6 is H, and B, D, E, G, Y, Z, Ar 1 , R 1 , R 2 and R 5 have the above
význam, s nukleofilným alkylačným činidlom, napríklad zlúčeninou vzorca V podľa vyššie uvedenej definície, vo vhodnom rozpúšťadle, napríklad v THF, napríklad pri 0 °C;with a nucleophilic alkylating agent, for example a compound of formula V as defined above, in a suitable solvent, for example THF, for example at 0 ° C;
(m) príprava zlúčenín vzorca I, kde X predstavuje C=O, Y predstavuje N, Z predstavuje OR8, R1 predstavuje väzbu s R5 a R8 predstavuje alkyl, reakciou príslušnej zlúčeniny vzorca I, kde Z predstavuje OR8, kde R8 predstavuje H, a B, D, E, G, X, Y, Ar1, R1, R2 a R5 majú vyššie uvedený význam, so zlúčeninou vzorca VI:(m) preparing compounds of formula I wherein X represents C = O, Y represents N, Z represents OR 8 , R 1 represents a bond with R 5 and R 8 represents alkyl, by reacting the corresponding compound of formula I wherein Z represents OR 8 , wherein R 8 represents H, and B, D, E, G, X, Y, Ar 1 , R 1 , R 2 and R 5 are as defined above, with the compound of formula VI:
R8Hal (VI) kde R8 a Hal majú vyššie uvedený význam, napríklad v prítomnosti bázy, napríklad hydridu sodného, vo vhodnom rozpúšťadle, napríklad DMF;R 8 Hal (VI) wherein R 8 and Hal are as defined above, for example in the presence of a base such as sodium hydride in a suitable solvent such as DMF;
(n) príprava zlúčenín vzorca I, kde R1 predstavuje OH, X predstavuje C=O, Y predstavuje N, Z predstavuje OR8 a R5 predstavuje väzbu s R8, reakciou príslušnej zlúčeniny vzorca I, kde Z predstavuje O', R1 a R5 tvoria väzbu a B, D, E, G, X, Y, Ar1 a R2 majú vyššie uvedený význam, pôsobením oxidačného činidla, napríklad dusičnanu amónno ceričitého, vo vhodnom rozpúšťadle, napríklad v acetonitrile, napríklad pri laboratórnej teplote;(n) preparing compounds of formula I wherein R 1 is OH, X is C = O, Y is N, Z is OR 8 and R 5 is a bond with R 8 , by reacting the corresponding compound of formula I wherein Z is O ', R 1 and R 5 form a bond and B, D, E, G, X, Y, Ar 1 and R 2 are as defined above by treating with an oxidizing agent such as ammonium cerium nitrate in a suitable solvent such as acetonitrile such as room temperature ;
-11 (o) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje 0‘, R3 a R2 tvoria väzbu a R1 a R5 tvoria väzbu, reakciou príslušnej zlúčeniny vzorca I, kde Y predstavuje N, Z predstavuje OH a B, D, E, G, X, Ar1, R1, R2 a R5 majú vyššie uvedený význam, so zlúčeninou vzorca IX: ,,-11 (o) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O ', R 3 and R 2 form a bond and R 1 and R 5 form a bond, by reacting the corresponding compound of formula Where Y is N, Z is OH and B, D, E, G, X, Ar 1 , R 1 , R 2 and R 5 are as defined above, with a compound of formula IX: ,,
R7Hal (IX) kde R7 a Hal majú vyššie uvedený význam, a bázou, napríklad hydridom sodným, vo vhodnom rozpúšťadle, napríklad DMF, napríklad pri laboratórnej teplote;R 7 Hal (IX) wherein R 7 and Hal are as defined above, and with a base, for example sodium hydride, in a suitable solvent, for example DMF, for example at room temperature;
(p) príprava zlúčenín vzorca I, kde X predstavuje C=O, R2 nepredstavuje H, Y predstavuje N, Z predstavuje OH a R1 predstavuje väzbu s R5, reakciou príslušnej zlúčeniny vzorca I, kde R2 predstavuje H a B, D, E, G, X, Y, Z, Ar1, R1 a R5 majú vyššie uvedený význam, s bázou, napríklad hydridom sodným, a zlúčeninou vzorca VII:(p) preparing compounds of formula I wherein X is C = O, R 2 is not H, Y is N, Z is OH and R 1 is a bond with R 5 , by reacting the corresponding compound of formula I wherein R 2 is H and B, D, E, G, X, Y, Z, Ar 1 , R 1 and R 5 are as defined above, with a base such as sodium hydride and a compound of formula VII:
R2Hal (VII) kde R2, ktoré nepredstavuje H, a Hal majú vyššie uvedený význam, vo vhodnom rozpúšťadle, napríklad DMF, napríklad pri teplote miestnosti;R 2 Hal (VII) wherein R 2 , which is not H, and Hal are as defined above, in a suitable solvent, for example DMF, for example at room temperature;
(q) príprava zlúčenín vzorca I, kde B, D, E a G predstavujú CH alebo CA, X predstavuje NR4, Y prestavuje N+R7, Z prestavuje O', R4 a R2 tvoria väzbu a R1 a R5 tvoria väzbu, reakciou zlúčeniny vzorca VIII:(q) preparing compounds of formula I wherein B, D, E and G are CH or CA, X is NR 4 , Y is N + R 7 , Z is O ', R 4 and R 2 form a bond and R 1 and R 5 form a bond, by reacting a compound of formula VIII:
(VIII) kde A a Ar1 majú vyššie uvedený význam, s bázou, napríklad hydridom sodným, a zlúčeninou vzorca IX s vyššie uvedeným významom, vo vhodnom rozpúšťadle, napríklad DMF, napríklad pri teplote miestnosti;(VIII) wherein A and Ar 1 are as defined above, with a base such as sodium hydride and a compound of formula IX as defined above, in a suitable solvent such as DMF, e.g. at room temperature;
(r) príprava zlúčenín vzorca I, kde B, D, E a G predstavujú CH alebo CA, X predstavuje NR4, Y predstavuje N, Z predstavuje OR8, R2 a R1 tvoria väzbu a R5 a R8 tvoria väzbu, reakciou zlúčeniny vzorca VIII s vyššie uvedeným významom s bázou, napríklad hydridom sodným, a zlúčeninou vzorca X:(r) preparing compounds of formula I wherein B, D, E and G are CH or CA, X is NR 4 , Y is N, Z is OR 8 , R 2 and R 1 form a bond and R 5 and R 8 form a bond by reacting a compound of formula VIII as defined above with a base, for example sodium hydride, and a compound of formula X:
-12R4Hal (X) kde R4 a Hal majú vyššie uvedený význam, vo vhodnom rozpúšťadle, napríklad DMF, napríklad pri laboratórnej teplote;-12R 4 Hal (X) wherein R 4 and Hal are as defined above, in a suitable solvent, for example DMF, for example at room temperature;
(s) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N, Z predstavuje OH, R3 a R2 tvoria väzbu a R1 predstavuje väzbu s R5, pôsobením kyseliny, napríklad kyseliny trifluóroctovej, na príslušnú zlúčeninu vzorca I, kde Y predstavuje N+R7, Z predstavuje O', R7 prestavuje CH2C6H40alkyl a B, D, E, G, X, Ar1, R1, R2 a R5 majú vyššie uvedený význam, napríklad pri refluxe;(s) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N, Z is OH, R 3 and R 2 form a bond, and R 1 is a bond with R 5 , by treatment with an acid such as trifluoroacetic acid of formula I wherein Y is N + R 7 , Z is O ', R 7 is CH 2 C 6 H 40 alkyl and B, D, E, G, X, Ar 1 , R 1 , R 2 and R 5 have the this meaning, for example at reflux;
(t) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N, Z predstavuje OH, R3 a R2 tvoria väzbu a R1 predstavuje väzbu s R5, reakciou príslušnej zlúčeniny vzorca I, kde Y predstavuje N+R7, Z predstavuje O', R7 predstavuje CH2fenyl (voliteľne substituovaný Ci.6 alkylom alebo Ci.6 alkoxylom) a B, D, E, G, X, Ar1, R1 a R5 majú vyššie uvedený význam, s vodíkom v prítomnosti katalyzátora, napríklad paládia na uhlíku;(t) preparing compounds of formula I wherein X represents CR 3 R 6 , Y represents N, Z represents OH, R 3 and R 2 form a bond and R 1 represents a bond with R 5 , by reacting the corresponding compound of formula I wherein Y represents N + R 7 , Z is O ', R 7 is CH 2 phenyl (optionally substituted with C 1-6 alkyl or C 1-6 alkoxy) and B, D, E, G, X, Ar 1 , R 1 and R 5 have the above with hydrogen in the presence of a catalyst such as palladium on carbon;
(u) príprava zlúčenín vzorca I, kde X predstavuje C=O, Y predstavuje N, Z predstavuje OH, R2 predstavuje H a R1 predstavuje väzbu s R5, reakciou príslušnej zlúčeniny vzorca I, kde Y prestavuje N+R7, Z predstavuje 0‘, R7 predstavuje CH2C6H40alkyl a B, D, E, G, X, Ar1, R1, R2 a R5 majú vyššie uvedený význam, s kyselinou, napríklad kyselinou trifluóroctovou, napríklad pri refluxe;(u) preparing compounds of formula I wherein X is C = O, Y is N, Z is OH, R 2 is H and R 1 is a bond with R 5 , by reacting the corresponding compound of formula I wherein Y is N + R 7 , Z is O ', R 7 is CH 2 C 6 H 40 alkyl, and B, D, E, G, X, Ar 1 , R 1 , R 2 and R 5 are as defined above, with an acid such as trifluoroacetic acid e.g. at reflux;
(v) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje N+R7, Z predstavuje 0‘, R3 a R2 tvoria väzbu, R1 a R5 tvoria väzbu a R6 predstavuje H, reakciou zlúčeniny vzorca XI;(v) preparing compounds of formula I wherein X is CR 3 R 6 , Y is N + R 7 , Z is O ', R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents H, by reaction compounds of formula XI;
(XI) kde X predstavuje CH2, R1 predstavuje H, R2 predstavuje skupinu zodpovedajúcu R7 s vyššie významom uvedeným v zlúčenine vzorca I, B, D,(XI) wherein X represents CH 2 , R 1 represents H, R 2 represents a group corresponding to R 7 as defined above for a compound of formula I, B, D,
E a G majú vyššie uvedený význam a R je alkyl, so zlúčeninou vzorca XII: Ar1NHNH2 (XII) kde Ar1 má vyššie uvedený význam, napríklad v xyléne pri refluxe;E and G are as defined above and R is alkyl, with a compound of formula XII: Ar 1 NHNH 2 (XII) wherein Ar 1 is as defined above, for example in xylene at reflux;
- 13(w) príprava zlúčenín vzorca I, kde X predstavuje C=O, R2 nepredstavuje H, Y predstavuje N, Z predstavuje OH a R1 predstavuje väzbu s R5, reakciou zlúčeniny vzorca XI s vyššie uvedeným významom, kde X predstavuje C=O, R1 predstavuje H, R2 má vyššie uvedený význam a B, D, E, G a R majú vyššie uvedený význam, so zlúčeninou vzorca XII s vyššie uvedeným významom, kde Ar1 má vyššie uvedený význam, napríklad v xyléne pri refluxe;(W) preparing compounds of formula I wherein X is C = O, R 2 is not H, Y is N, Z is OH and R 1 is a bond with R 5 , by reacting a compound of formula XI as defined above, wherein X is C = O, R 1 is H, R 2 is as defined above and B, D, E, G and R are as defined above, with a compound of formula XII as defined above, wherein Ar 1 is as defined above, e.g. in xylene at reflux;
(x) príprava zlúčenín vzorca I, kde X predstavuje CH2, Y predstavuje N, Z predstavuje OR8, R8 a R5 tvoria väzbu a R1 predstavuje alkyl, reakciou zlúčeniny vzorca XI s vyššie uvedeným významom, kde X predstavuje CH2, R1 predstavuje alkyl a B, D, E, G, R2 a R majú vyššie uvedený význam, so zlúčeninou vzorca XII s vyššie uvedeným významom, kde Ar1 má vyššie uvedený význam, napríklad v xyléne pri refluxe; alebo (y) príprava zlúčenín vzorca I, kde X predstavuje C=O, Y predstavuje N, Z predstavuje OR8, R8 a R5 tvoria väzbu a R1 predstavuje alkyl, reakciou zlúčeniny XI s vyššie uvedeným významom, kde X predstavuje C=O, R1 predstavuje alkyl, R2 predstavuje H alebo alkyl, a B, D, E, G a R majú vyššie uvedený význam, so zlúčeninou vzorca XII s vyššie uvedeným významom, kde Ar1 má vyššie uvedený význam, napríklad v xyléne pri refluxe;(x) preparing compounds of formula I wherein X represents CH 2 , Y represents N, Z represents OR 8 , R 8 and R 5 form a bond and R 1 represents alkyl, by reacting a compound of formula XI as defined above, wherein X represents CH 2 R 1 is alkyl and B, D, E, G, R 2 and R are as defined above, with a compound of formula XII as defined above, wherein Ar 1 is as defined above, for example in xylene at reflux; or (y) preparing compounds of formula I wherein X represents C = O, Y represents N, Z represents OR 8 , R 8 and R 5 form a bond and R 1 represents alkyl, by reacting compound XI as defined above, wherein X represents C = O, R 1 is alkyl, R 2 is H or alkyl, and B, D, E, G and R are as defined above, with a compound of formula XII as defined above, wherein Ar 1 is as defined above, e.g. in xylene at reflux;
(z) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje CR18, Z predstavuje OH, R1 a R5 tvoria väzbu a R2 a R3 tvoria väzbu, oxidáciou príslušnej zlúčeniny vzorca I, kde X predstavuje CR3R6, Y predstavuje CR18, Z predstavuje OH, R2 a R3 predstavujú H, R1 a R5 tvoria väzbu a B, D, E, G, Ar1, R6 a R18 majú vyššie uvedený význam; alebo (aa) príprava zlúčenín vzorca I, kde X predstavuje CR3R6, Y predstavuje CR18, Z predstavuje OH, R2 a R3 predstavujú H a R1 a R5 tvoria väzbu, reakciou zlúčeniny vzorca XII s vyššie uvedeným významom so zlúčeninou vzorca XX:(z) preparing compounds of formula I wherein X represents CR 3 R 6 , Y represents CR 18 , Z represents OH, R 1 and R 5 form a bond and R 2 and R 3 form a bond by oxidation of the corresponding compound of formula I wherein X represents CR 3 R 6 , Y represents CR 18 , Z represents OH, R 2 and R 3 represent H, R 1 and R 5 form a bond and B, D, E, G, Ar 1 , R 6 and R 18 are as defined above ; or (aa) preparing compounds of formula I wherein X is CR 3 R 6 , Y is CR 18 , Z is OH, R 2 and R 3 are H and R 1 and R 5 form a bond, by reacting a compound of formula XII as defined above with a compound of formula XX:
kde B, D, E, G, R6, R18 a R majú vyššie uvedený význam.wherein B, D, E, G, R 6 , R 18 and R are as defined above.
-14Zlúčeniny vzorca I, kde X predstavuje CHR3, R2 a R3 spolu predstavujú väzbu, R1 a R5 tvoria väzbu a buď:The compounds of formula I wherein X is CHR 3 , R 2 and R 3 together represent a bond, R 1 and R 5 form a bond and either:
«> Y predstavuje N+R7 a Z predstavuje 0‘, alebo » Y predstavuje N a Z predstavuje OH, možno pripraviť analogicky ako v spôsoboch opísaných v J. Med. Chem. , 368 (1992). Zlúčeniny vzorca VIII sú známe z európskej patentovej prihlášky č. EPA-187551 alebo ich možno pripraviť analogicky podľa spôsobov tam opísaných. Zlúčeniny vzorca XI možno pripraviť reakciou zlúčeniny vzorca XIII:?> Y represents N + R 7 and Z represents O ', or »Y represents N and Z represents OH, can be prepared analogously to the methods described in J. Med. Chem. 368 (1992). Compounds of formula VIII are known from European patent application no. EPA-187551 or may be prepared analogously to the methods described therein. Compounds of formula XI can be prepared by reacting a compound of formula XIII:
COOR (xiii) kde B, D, E, G, R, R2 a X majú vyššie uvedený význam a R’, je alkyl, s bázou, napríklad hydridom sodným, napríklad v DMSO pri 60 °C v prítomnosti alkoholu. Zlúčeniny vzorca XI, kde X predstavuje C=O a R2 predstavuje H, sú známe z japonskej preskúmanej patentovej publikácie č. JP-B-82 54,152, alebo ich možno pripraviť analogicky so spôsobmi tam opísanými.COOR (xiii) wherein B, D, E, G, R 2, R 2 and X are as defined above and R 1 is alkyl, with a base, for example sodium hydride, for example in DMSO at 60 ° C in the presence of an alcohol. Compounds of formula XI, wherein X is C = O and R2 is H are known from Japanese examined patent publication no. JP-B-82 54,152, or may be prepared analogously to the methods described therein.
Zlúčeniny vzorca Xlll, kde X predstavuje C=O, možno pripraviť reakciou zlúčeniny vzorca XVI:Compounds of formula XIII wherein X represents C = O may be prepared by reacting a compound of formula XVI:
COOR (XVI) kde B, D, E, G, R a R2 majú vyššie uvedený význam, alkyláciou, napríklad zlúčeninou vzorca XVII:COOR (XVI) wherein B, D, E, G, R, and R 2 are as defined above, by alkylation, for example, a compound of formula XVII:
(RO)2SO2 (XVII)(RO) 2 SO 2 (XVII)
-15kde R’ má vyššie uvedený význam, v prítomnosti bázy, napríklad uhličitanu draselného, napríklad v acetóne pri 50 °C.- where R is as defined above, in the presence of a base, for example potassium carbonate, for example in acetone at 50 ° C.
Zlúčeniny vzorca XIII, kde X predstavuje CH2, možno pripraviť reakciou zlúčeniny vzorca XIV: ' . , .3. . COOFiCompounds of formula XIII wherein X is CH 2 may be prepared by reaction of a compound of formula XIV:. , .3. . COOFi
DD
(XIV) kde B, D, E, G a R majú vyššie uvedený význam, so zlúčeninou vzorca XV:(XIV) wherein B, D, E, G and R are as defined above, with a compound of Formula XV:
(XV) kde R1, R2 a R’ majú vyššie uvedený význam, v prítomnosti bázy, napríklad trietylamínu, vo vhodnom rozpúšťadle, napríklad v éteri pri refluxe.(XV) wherein R 1 , R 2 and R 'are as defined above, in the presence of a base such as triethylamine in a suitable solvent such as ether at reflux.
Zlúčeniny vzorca XIV možno pripraviť reakciou zlúčeniny vzorca XVIII:Compounds of formula XIV may be prepared by reacting a compound of formula XVIII:
(XVIII) kde B, D, E, G a R majú vyššie uvedený význam, s bromačným činidlom, napríklad NBS, napríklad v dichlórmetáne pri refluxe s fotolytickým žiarením.(XVIII) wherein B, D, E, G and R are as defined above, with a brominating agent, for example NBS, for example in dichloromethane at reflux with photolytic radiation.
**
Zlúčeniny vzorca XVI možno pripraviť reakciou zlúčeninv vzorca XIX:Compounds of formula XVI may be prepared by reaction of compounds of formula XIX:
(XIX) kde B, D, E a G majú vyššie uvedený význam, so zlúčeninou vzorca av s vyššie uvedeným významom, kde R1, R2 a R’ majú vyššie uvedený význam, vo vhodnom rozpúšťadle, napríklad v acetóne pri 50 °C.(XIX) wherein B, D, E and G are as defined above, with a compound of formula and as defined above, wherein R 1 , R 2 and R 'are as defined above, in a suitable solvent, e.g. acetone at 50 ° C .
-16Zlúčeniny vzorca II, III, IV, V, VI, VII, IX, X, XII, XV, XVI, XVII, XVIII a XX sú buď komerčne dostupné alebo známe z literatúry, alebo sú dostupné pomocou známych techník.Compounds of formula II, III, IV, V, VI, VII, IX, X, XII, XV, XVI, XVII, XVIII and XX are either commercially available or known from the literature, or are available by known techniques.
Odborníkom v danej oblasti bude zrejmé, že v krokoch postupu opísaných vyššie môžu funkčné skupiny medziproduktov vyžadovať ochranu chrániacimi skupinami. Ochrana funkčných skupín sa môže uskutočniť pred ktorýmkoľvek krokom vyššie opísaného postupu. Napríklad dusíkový atóm zlúčenín vzorca XI, XIII a XVI možno chrániť pred ďalšou reakciou pomocou vhodnej chrániacej skupiny, napríklad benzylovej skupiny alebo s výhodou 4-metoxyfenylmetyl skupiny. Chrániace skupiny možno odstrániť po reakčnom kroku alebo na konci reakčného procesu pomocou techník, ktoré sú odborníkom známe (napríklad kyselinovou hydrolýzou).It will be apparent to those skilled in the art that in the process steps described above, functional groups of intermediates may require protection by protecting groups. Functional group protection may be performed prior to any step of the above-described procedure. For example, the nitrogen atom of the compounds of formulas XI, XIII and XVI may be protected from further reaction with a suitable protecting group, for example benzyl or preferably 4-methoxyphenylmethyl. The protecting groups may be removed after the reaction step or at the end of the reaction process by techniques known to those skilled in the art (for example by acid hydrolysis).
Zlúčeniny podľa vynálezu sú užitočné, majú farmakologickú aktivitu a sú preto indikované ako liečivá užitočné v terapii.The compounds of the invention are useful, have pharmacological activity and are therefore indicated to be useful in therapy.
V rámci vynálezu sa ďalej uvádza zlúčenina vzorca I s vyššie uvedeným významom, ale bez výhrady (c), na použitie ako liečivo.The present invention further provides a compound of formula I as defined above, but without limitation (c), for use as a medicament.
Zlúčeniny podľa vynálezu majú konkrétne antialergickú a protizápalovú aktivitu, ako je napríklad ukázané v ďalej opísaných testoch. Zlúčeniny podľa vynálezu sú teda indikované na použitie v liečbe alergických a zápalových chorôb dýchacích ciest, ako je napríklad astma (napríklad bronchiálna astma, alergická astma, intrinzická astma, extrinzická astma a prachová astma), najmä chronická alebo'ťažká astma (napríklad čerstvá astma a hyperreaktívríosť dýchacích ciest), bronchitída a podobne. Ďalej sú zlúčeniny podľa vynálezu indikované v liečbe chorôb vrátane zápalov alebo alergií ako rinitída, vrátane všetkých stavov charakterizovaných zápalom nosnej sliznice, ako je napríklad akútna rinitída, alergická rinitída, atropická rinitída, chronická rinitída vrátane rhinitis caseosa, hypertrofická rinitída, rhinitis purulenta a rhinitis sicca, rhinitis medicamentosa, membránová rinitída vrátane krupóznej, fibrínovej a pseudomembránovej rinitídy, skrofulóznej rinitídy, sezónnej rinitídy vrátane rhinitis nervosa (senná nádcha) a vazomotorickej rinitídy.In particular, the compounds of the invention have antiallergic and anti-inflammatory activity, as shown, for example, in the assays described below. Thus, the compounds of the invention are indicated for use in the treatment of allergic and inflammatory diseases of the airways, such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), in particular chronic or severe asthma (e.g. airway hyperreactivity), bronchitis and the like. Further, the compounds of the invention are indicated in the treatment of diseases including inflammation or allergies such as rhinitis, including all conditions characterized by inflammation of the nasal mucosa such as acute rhinitis, allergic rhinitis, atropic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis sinusitis, rhinitis sinusitis, , rhinitis medicamentosa, membrane rhinitis including crupous, fibrin and pseudomembrane rhinitis, scrofulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.
-17Zlúčeniny podľa vynálezu sú tiež indikované na použitie v liečbe chronických alergických porúch, atopickej dermatitídy, kutánnej eozinofílie, eozinofilnej fascitídy, hyper IgE syndrómu, jarnej konjunktivitídy, systémovej lupus erythematosis, thyroiditis, lepromatóznej lepry, sezárneho syndrómu, chronickej choroby štep verzus hostiteľ, myasthenia gravis, idiopatickej trombocytopénie purpura a podobne.The compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilia, eosinophilic fascitis, hyper IgE syndrome, spring conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous leprosy, mycosis, vertebral disease gravis, idiopathic purpura thrombocytopenia, and the like.
Zlúčeniny podľa vynálezu môžu mať aktivitu aj v profylaktickej aj terapeutickej liečbe syndrómu získanej imunitnej nedostatočnosti (AIDS), prevencii chronického odmietania aloimplantátov sprostredkovaného humorálnou imunitou a v liečbe autoimunitných chorôb ako skleróza multiplex a reumatoidná artritída.The compounds of the invention may have activity in both prophylactic and therapeutic treatment of Acquired Immune Deficiency Syndrome (AIDS), prevention of chronic allograft rejection mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
Predmetom osobitného záujmu spomedzi vyššie uvedených indikácií je použitie zlúčenín podľa vynálezu pri astme, najmä v profylaxii astmy, a v rinitíde, najmä alergickej rinitíde a sezónnej rinitíde vrátane rhinitis nervosa (senná nádcha).Of particular interest among the above indications is the use of the compounds of the invention in asthma, particularly in the prophylaxis of asthma, and in rhinitis, especially allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).
Ako ďalší aspekt predloženého vynálezu sa uvádza spôsob liečby alebo profylaxie alergickej alebo zápalovej poruchy, ktorý spôsob zahŕňa podanie terapeuticky účinného množstva zlúčeniny vzorca I s vyššie uvedeným významom, ale bez výhrad (b) alebo (c), alebo jej farmaceutický prijateľného derivátu, osobe trpiacej takou chorobou alebo vnímavej na ňu.A further aspect of the present invention provides a method of treating or prophylaxis of an allergic or inflammatory disorder, which method comprises administering to a person suffering from a therapeutically effective amount of a compound of formula I as hereinbefore defined, but without reservation of (b) or (c), such a disease or susceptible to it.
Podanie zlúčenín podľa vynálezu môže byť lokálne (napríklad inhaláciou do pľúc). Zlúčeniny podľa vynálezu možno inhalovať ako suchý prášok, ktorý môže byť aerosólový alebo neaérosólový.Administration of the compounds of the invention may be topical (e.g., by inhalation into the lung). The compounds of the invention may be inhaled as a dry powder, which may be aerosol or non-aerosol.
Pri neaerosólových práškových kompozíciách možno použiť jemne mletú aktívnu zložku v zmesi s farmaceutický prijateľným nosičom väčšej veľkosti častíc. Kompozíciu možno alternatívne pripraviť ako aerosól a môže obsahovať stlačený plyn, napríklad dusík, alebo skvapalnené plynné výtlačné médium. V takých aerosólových kompozíciách je aktívna zložka s výhodou jemne mletá. Aerosólová kompozícia môže obsahovať aj povrchovo aktívne činidlo. Aerosólové kompozície možno pripravovať konvenčnými metódami.For non-aerosol powder compositions, the finely divided active ingredient can be used in admixture with a pharmaceutically acceptable carrier of larger particle size. Alternatively, the composition may be prepared as an aerosol and may contain a pressurized gas such as nitrogen or a liquefied gaseous dispensing medium. In such aerosol compositions, the active ingredient is preferably finely ground. The aerosol composition may also contain a surfactant. Aerosol compositions can be prepared by conventional methods.
-18Zlúčeniny podľa vynálezu možno podávať systémovo (napríklad orálnym podaním do gastrointestinálneho traktu). Aktívna zložka môže byť formulovaná spolu so známymi adjuvans, riedidlami alebo nosičmi pomocou konvenčných techník, čím sa zhotovia tablety alebo kapsule na orálne podanie do gastrointestinálneho traktu. Medzi príklady na vhodné adjuvans, riedidlá alebo nosiče na orálne podanie vo forme tabliet, kapsúl a dražé patrí mikrokryšťalická celulóza, fosforečnan vápenatý, kremelina, cukor ako napríklad laktóza, dextróza alebo mantel, talkum, kyselina stearová, škrob, hydrogenuhličitan sodný a/alebo želatína.The compounds of the invention may be administered systemically (e.g., by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers by conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract. Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugar such as lactose, dextrose or mantel, talc, stearic acid, starch, sodium bicarbonate and / or gelatin .
Ako ďalší aspekt predloženého vynálezu sa uvádza farmaceutická kompozícia obsahujúca zlúčeninu vzorca I s vyššie uvedeným významom, ale bez výhrady (c), alebo jej farmaceutický prijateľný derivát, v zmesi s farmaceutický prijateľným adjuvans, riedidlom alebo nosičom.As a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I as defined above, but not limited to (c), or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Vhodné dávky na lokálne alebo orálne podanie sú v rozmedzí 0,01 až 30 mg.kg'1.deň1, napríklad 0,3 mg.kg'1.deň1.Suitable doses for topical or oral administration are in the range of 0.01 to 30 mg.kg -1 day 1 , for example 0.3 mg.kg -1 day 1 .
Odborníkom v danej oblasti bude zrejmé, že niektoré funkčné skupiny v zlúčeninách podľa vynálezu môžu byť chránené pomocou vhodných chrániacich skupín, čím sa vytvoria “chránené deriváty” zlúčenín podľa vynálezu. Bude tiež zrejmé, že hoci také chránené deriváty nemusia mať farmakologickú aktivitu ako také, môžu sa podávať a potom metabolizovať v tele za vzniku zlúčeniny podľa vynálezu, ktorá je farmakologicky aktívna. Také deriváty možno preto opísať ako “prekurzory liečiv”. Všetky chránené deriváty a prekurzory zlúčenín vzorca I sú zahrnuté v rozsahu tohto vynálezu.It will be apparent to those skilled in the art that some functional groups in the compounds of the invention may be protected with suitable protecting groups to form "protected derivatives" of the compounds of the invention. It will also be appreciated that although such protected derivatives may not have pharmacological activity per se, they may be administered and then metabolized in the body to produce a compound of the invention that is pharmacologically active. Such derivatives can therefore be described as "prodrugs". All protected derivatives and prodrugs of the compounds of formula I are included within the scope of this invention.
Vynález je ilustrovaný nasledujúcimi príkladmi.The invention is illustrated by the following examples.
-19Príklady uskutočnenia vynálezu19 Examples
Všeobecné poznámky:General remarks:
Stĺpcová chromatografia sa robila na oxide kremičitom (35 - 70 pm) pod tlakom plynu, väčšinou 0,5 baru. Nasledujúce hydrazíny boli použité ako intermediáty v nasledujúcich príkladoch:Column chromatography was performed on silica (35-70 µm) under gas pressure, mostly 0.5 bar. The following hydrazines were used as intermediates in the following examples:
5-Hydrazino-2-metylpyridín5-hydrazino-2-methylpyridine
Roztok dusitanu sodného (0,3 g) vo vode (2 ml) sa pridal do studeného roztoku 5-amino-2-metylpyridínu (J. Chem. Soc. (C)., 1971, 3257) (3,61 g) vo vode (6 ml) a koncentrovanej kyseline chlorovodíkovej (1 ml), pričom teplota sa udržiavala pod 5 °C. Zmes sa miešala pri 0 °C 15 minút a potom sa ďalej ochladila na -10 °C. Potom sa po kvapkách pridal roztok chloridu cínatého (2,53 g) v koncentrovanej kyseline chlorovodíkovej (5 ml). Po miešaní pri -10 °C počas 10 minút sa roztok nechal ohriať na teplotu miestnosti a pridával sa bezvodý uhličitan draselný, až kým sa nevytvorila hustá suspenzia. Suspenzia sa rozmiešala s etylacetátom a organická fáza sa dekantovala a odparila na olej. Suspenzia sa potom zriedila vodou a extrahovala dichlórmetánom (trikrát). Organická fáza sa vysušila nad síranom sodným, prefiltrovala a odparila, a potom spojila s vyššie uvedeným olejom. Čistením stĺpcovou chromatografiou, elúciou zmesou dichlórmetánu a metanolu (20 : 1) sa získala titulná zlúčenina ako béžová tuhá látka (0,09 g), 1.1. 68 - 70 °C.A solution of sodium nitrite (0.3 g) in water (2 mL) was added to a cold solution of 5-amino-2-methylpyridine (J. Chem. Soc. (C)., 1971, 3257) (3.61 g) in water. water (6 mL) and concentrated hydrochloric acid (1 mL) while maintaining the temperature below 5 ° C. The mixture was stirred at 0 ° C for 15 minutes and then further cooled to -10 ° C. A solution of stannous chloride (2.53 g) in concentrated hydrochloric acid (5 ml) was then added dropwise. After stirring at -10 ° C for 10 minutes, the solution was allowed to warm to room temperature and anhydrous potassium carbonate was added until a thick suspension formed. The suspension was stirred with ethyl acetate and the organic phase was decanted and evaporated to an oil. The suspension was then diluted with water and extracted with dichloromethane (three times). The organic phase was dried over sodium sulfate, filtered and evaporated, and then combined with the above oil. Purification by column chromatography, eluting with dichloromethane: methanol (20: 1) afforded the title compound as a beige solid (0.09 g), m.p. Mp 68-70 ° C.
. 1H NMR (CDCIa): δ 2.47 (3H, s), 3.60 (2H, br s), 5.13(1 H, br s), 7.03 (1H, d), 7.12 (1H, dd), 8.12 (1H, d). 1 H NMR (CDCl 3): δ 2.47 (3H, s), 3.60 (2H, br s), 5.13 (1H, br s), 7.03 (1H, d), 7.12 (1H, dd), 8.12 (1H, d)
4-(Pentafluóretyl)fenyl hydrazín4- (Pentafluoroethyl) phenyl hydrazine
Pripravený podľa spôsobu použitého pre 5-hydrazino-2-metylpyridín s použitím 4-(pentafluóretyl)anilínu (J. Chem. Soc., Perkin Trans. , 1990, 2293). MS (El) 226 (M+) 1H NMR (CDCI3) δ 4,15 (2H, br), 6,87 (2H, d), 7,45 (1H, br)Prepared according to the method used for 5-hydrazino-2-methylpyridine using 4- (pentafluoroethyl) aniline (J. Chem. Soc., Perkin Trans., 1990, 2293). MS (EI) 226 (M +) 1 H NMR (CDCl3) δ 4.15 (2H, br), 6.87 (2H, d), 7.45 (1H, br)
2-Hydrazino-5-metylpyridín (J. Org. Chem., 1966,, 251)2-Hydrazino-5-methylpyridine (J. Org. Chem., 1966, 251)
2- Chlór-5-hydrazinopyridín (Atti R. Accad. dei Lincei, Rím, 1925,, 125); Chem. Zent. 1926, I, 6722-Chloro-5-hydrazinopyridine (Atti R. Accad. Dei Lincei, Rome, 1925, 125); Chem. Zent. 1926, 1, 672
II
Hydrazinopyrimidín J. Chem. Soc. 1955, 3478Hydrazinopyrimidine J. Chem. Soc. 1955, 3478
Príklad 1Example 1
3- Hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2A/-pyrazolo-[4,3cjizochinolín hydroxid, vnútorná soľ (a) Metyl 2-[A/-(metoxykarbonylmetyl)-A/-(4-metoxyfenyl)metyl)amino]metylbenzoát3-Hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinoline hydroxide, inner salt (a) Methyl 2- [N - (methoxycarbonylmethyl) - A / - (4-methoxyphenyl) methyl) amino] methylbenzoate
Metyl 2-brómmetylbenzoát (23,47 g; pripravený analogicky so spôsobom opísaným pre etylester v J. Med. Chem., 1992, , 368) a trietylamín (15,7 ml) sa rozpustili v suchom dietyléteri (200 ml) pod dusíkovou atmosférou. Po kvapkách sa pridal metyl /V-[(4-metoxyfenyl)metyl]glycinát (23,6 g; J. Am. Chem. Soc., 1993, , 536). Zmes sa zahrievala na reflux počas 16 hodín a nechala sa ochladiť na laboratórnu teplotu. Pridala sa voda a organická fáza sa oddelila. Vodná fáza sa potom extrahovala etylacetátom (trikrát). Spojená organická fáza sa premyla soľankou a vysušila nad síranom sodným. Filtráciou a odparením roztoku s následným čistením zvyškov stĺpcovou chromatografiou elúciou zmesou etylacetátu a izohexánu (1 : 9) sa získala titulná zlúčenina ako olej (27,85 g);Methyl 2-bromomethylbenzoate (23.47 g; prepared analogously to the method described for the ethyl ester in J. Med. Chem., 1992, 368) and triethylamine (15.7 mL) were dissolved in dry diethyl ether (200 mL) under a nitrogen atmosphere. . Methyl N - [(4-methoxyphenyl) methyl] glycinate (23.6 g; J. Am. Chem. Soc., 1993, 536) was added dropwise. The mixture was heated to reflux for 16 hours and allowed to cool to room temperature. Water was added and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (three times). The combined organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation of the solution followed by purification of the residue by column chromatography eluting with a 1: 9 mixture of ethyl acetate and isohexane gave the title compound as an oil (27.85 g);
MS (APCI) 358 ((M + H)+) 1H NMR (CDCh): δ 3.23 (2H, s), 3.66 (3H, s), 3.71 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.8 (2H, d), 7.2 (2H, d), 7.3 (1H, td), 7.45 (1H, td), 7.6 (1H, dd), 7.75(1 H, dd) (b) Metyl 1,2,3,4-tetrahydro-2-(4-metoxyfenyl)metyl-4-oxo-3-izochinolínkarboxylátMS (APCI) 358 ((M + H) + ) 1 H NMR (CDCl 3): δ 3.23 (2H, s), 3.66 (3H, s), 3.71 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.16 (2 H, s), 6.8 (2 H, d), 7.2 (2 H, d), 7.3 (1 H, td), 7.45 (1 H, td), 7.6 (1 H, dd), 7.75 ( 1 H, dd) (b) Methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl 4-oxo-3-isoquinolinecarboxylate
Metyl 2-[/V-(metoxykarbonylmetyl)-A/-(4-metoxyfenyl)metyl)amino]metylbenzoát (27,85 g; z vyššie uvedeného kroku (a)) sa rozpustil v suchom toluéne (150 ml) a pridal sa po kvapkách do refluxujúcej suspenzie oleja zbaveného hydridu sodného (od 4,37 g 60 % hydridu sodného) v suchom toluéne (300 ml) a 2metylpropán-2-ole (2,0 ml). Zahrievanie pokračovalo 12 hodín. Zmes sa nechala ochladiť na teplotu miestnosti a potom sa vyliala do nasýteného roztoku chloridu amónneho a extrahovala sa etylacetátom (trikrát). Spojená organická fáza sa potom premyla soľankou a vysušila nad síranom sodným. Filtráciou a odparením s následným čistením stĺpcovou chromatografiou elúciou zmesou dietyléteru a izohexánu (1 : 4) sa získala titulná zlúčenina ako olej (20,41 g). 1H NMR (CDCI3) (hlavná zložka - enolický tautomér) δ 3,60 (2H, s), 3,81 (3H, s), 3,91 (5H, s) 6,86 (2H, d), 7,09 (1H, d), 7,25 (2H, d), 7,35 - 7,43 (2H, m), 7,77 (1H, d) a 11,58 (1H, s).Methyl 2 - [N - (methoxycarbonylmethyl) - N - (4-methoxyphenyl) methyl) amino] methylbenzoate (27.85 g; from step (a) above) was dissolved in dry toluene (150 mL) and added dropwise to a refluxing suspension of sodium hydride-free oil (from 4.37 g of 60% sodium hydride) in dry toluene (300 mL) and 2-methylpropan-2-ol (2.0 mL). Heating was continued for 12 hours. The mixture was allowed to cool to room temperature and then poured into saturated ammonium chloride solution and extracted with ethyl acetate (3 times). The combined organic phase was then washed with brine and dried over sodium sulfate. Filtration and evaporation followed by purification by column chromatography eluting with diethyl ether: isohexane (1: 4) afforded the title compound as an oil (20.41 g). 1 H NMR (CDCl 3 ) (major component - enolic tautomer) δ 3.60 (2H, s), 3.81 (3H, s), 3.91 (5H, s) 6.86 (2H, d), 7.09 (1H, d), 7.25 (2H, d), 7.35-7.43 (2H, m), 7.77 (1H, d) and 11.58 (1H, s).
(c) 3-Hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo-[4,3cjizochinolínium hydroxid, vnútorná soľ(c) 3-Hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
Metyl 1,2,3,4-tetrahydro-2-(4-metoxyfenyl)metyl-4-oxo-3-izochinolínkarboxylát (1,0 g; z vyššie uvedeného kroku (b)), 4-(trifluórmetyl)fenylhydrazín (1,08 g) a katalytické množstvo kyseliny 4-toluénsulfónovej sa spolu tavili pri 150 °C 10 minút. Potom sa pridal xylén (20 ml) a zahrievanie pokračovalo ďalšiu hodinu. Po ochladení na teplotu miestnosti sa rozpúšťadlo odparilo. Tuhý zvyšok sa rozotrel s dietyléterom, čím sa získala titulná zlúčenina ako červená tuhá látka (0,5 g), t. t. 220-221 °C.Methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl-4-oxo-3-isoquinolinecarboxylate (1.0 g; from step (b) above), 4- (trifluoromethyl) phenylhydrazine (1 , 08 g) and a catalytic amount of 4-toluenesulfonic acid were melted together at 150 ° C for 10 minutes. Then xylene (20 mL) was added and heating was continued for an additional hour. After cooling to room temperature, the solvent was evaporated. The solid residue was triturated with diethyl ether to give the title compound as a red solid (0.5 g), m.p. t. Mp 220-221 ° C.
MS (APCI) 450 ((M + H)+) 1H NMR ( d6-DMSO) δ 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m), 7.7 (2H, m),MS (APCI) 450 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m), 7.7 (2H, m) .
7.8 (3H, m), 7.95 (1H, td), 8.15 (1H, d), 8.35 (1H, d), 8.6 (2H, d), 8.96 (1H, s).7.8 (3H, m), 7.95 (1 H, td), 8.15 (1 H, d), 8.35 (1 H, d), 8.6 (2 H, d), 8.96 (1 H, s).
Príklad 2Example 2
2-(4-Trifluórmetylfenyl)-2/-/-pyrazolo[4,3-c]izochinolín-3-ol ,3-Hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo-[4,3cjizochinolínium hydroxid, vnútorná soľ (0,26 g; z vyššie uvedeného kroku (c) sa zahrieval na reflux v trifluóroctovej kyseline (2 ml) pod dusíkovou atmosférou počas 16 hodín. Po ochladení na teplotu miestnosti sa rozpúšťadlo odparilo. K zvyšku sa pridal toluén a potom sa odparil (dvakrát). Pridal sa metanol, odparil sa a červený zvyšok sa rozotrel s etylacetátom. Rekryštalizáciou z etanolu sa získala titulná zlúčenina ako červená tuhá látka (14 mg), 1.1. > 250 °C.2- (4-Trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol, 3-Hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) - 2 H -pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.26 g; from step (c) above, was heated to reflux in trifluoroacetic acid (2 mL) under a nitrogen atmosphere for 16 hours. Toluene was added to the residue and then evaporated (twice), methanol was added, evaporated, and the red residue was triturated with ethyl acetate, and recrystallized from ethanol to give the title compound as a red solid (14 mg), m.p. ≫ 250 ° C.
MS (APCI) 330 ((M + H)+) 1H NMR (ds-DMSO) δ 7.9 (3H, m), 8.0 (1H, t), 8.3 (4H, m), 9.03 (1H, bs).MS (APCI) 330 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.9 (3H, m), 8.0 (1H, t), 8.3 (4H, m), 9.03 (1H, bs).
Príklad 3Example 3
2-(4-Chlórfenyl)-2,5-dihydro-5-metyl-3/7-pyrazolo[4,3-c]cinolín-3-ón2- (4-Chlorophenyl) -2,5-dihydro-5-methyl-3/7-pyrazolo [4,3-c] cinnoline-3-one
2-(4-Chlórfenyl)-2,5-dihydro-pyrazolo[4,3-c]cino!ín-3-ón (0,33 g; európska patentová prihláška EP-A-0187551) sa pridal po častiach do miešanej suspenzie olej neobsahujúceho hydridu sodného (od 49 mg 60 % disperzie) v suchom dimetylformamide (5 ml) pod dusíkovou atmosférou. Po kvapkách sa pridal jódmetán (0,076 ml) po 0,5 h a získaný roztok sa miešal pri teplote miestnosti počas 2 hodín.· Roztok . sa vylial do solänky a extrahoval sa zmesou dichlórmetán/metanol (trikrát). Organická fáza sa premyla 2 M kyselinou chlorovodíkovou a soľankou a potom sa vysušila nad síranom sodným, prefiltrovala a nakoncentrovala, čím sa získala červená tuhá látka. Čistením stĺpcovou chromatografiou (etylacetát a hexán 3 : 2) s následnou rekryštalizáciou z dimetylformamidu sa získala titulná zlúčenina vo forme červených kryštálov (55 mg), 1.1. > 250 °C.2- (4-Chlorophenyl) -2,5-dihydro-pyrazolo [4,3-c] quinolin-3-one (0.33 g; European Patent Application EP-A-0187551) was added in portions to a stirred a suspension of oil free of sodium hydride (from 49 mg of 60% dispersion) in dry dimethylformamide (5 mL) under a nitrogen atmosphere. Iodomethane (0.076 mL) was added dropwise over 0.5 h and the resulting solution was stirred at room temperature for 2 hours. The mixture was poured into brine and extracted with dichloromethane / methanol (three times). The organic phase was washed with 2M hydrochloric acid and brine and then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (ethyl acetate and hexane 3: 2) followed by recrystallization from dimethylformamide gave the title compound as red crystals (55 mg), m.p. ≫ 250 ° C.
MS (El) 310, 312 (M+) 1H NMR (CDCI3) Ô 4.33 (3H, s), 7.4 (2H, dd), 7.65 (2H, t), 7.75 (1 H, td), 8.20 (2H, dd), 8.35 (1H, d).MS (EI) 310, 312 (M + ) 1 H NMR (CDCl 3 )? 4.33 (3H, s), 7.4 (2H, dd), 7.65 (2H, t), 7.75 (1H, td), 8.20 ( 2H, dd), 8.35 (1 H, d).
Príklad 4Example 4
2-(4-Chlórfenyl)-2,3a,4,5-tetrahydro-3a,4-dimetylpyrazolo[4,3-c]izochinolín-3-ón (a) Metyl 2-(((1 -metoxykarbonyl)etyl)metylamino]metylbenzoát2- (4-Chlorophenyl) -2,3a, 4,5-tetrahydro-3a, 4-dimethylpyrazolo [4,3-c] isoquinolin-3-one (a) Methyl 2 - (((1-methoxycarbonyl) ethyl)) amino] methylbenzoate
Metyl 2-brómmetylbenzoát (3,51 g) a diizopropyletylamín (5,86 ml) sa rozpustili v suchom dietyléteri (30 ml) pod dusíkovou atmosférou a roztok sa ochladil na 0 °C. Po kvapkách sa pridala soľ metylesteru /V-metylalanínu s kyselinou trifluóroctovou (3,89 g) rozpustená v suchom dietyléteri (10 ml) a suchom dichlórmetáne (5 ml) a zmes sa nechala ohriať cez noc na laboratórnu teplotu. Potom sa pridala voda a organická fáza sa oddelila, premyla soľankou a vysušila nad síranom sodným. Filtráciou a odparením s následnou stĺpcovou chromatografiou (etylacetát a hexán 1 : 9) sa získala titulná zlúčenina (2,87 g).Methyl 2-bromomethylbenzoate (3.51 g) and diisopropylethylamine (5.86 mL) were dissolved in dry diethyl ether (30 mL) under a nitrogen atmosphere and the solution was cooled to 0 ° C. N-Methylalanine methyl ester salt with trifluoroacetic acid (3.89 g) dissolved in dry diethyl ether (10 mL) and dry dichloromethane (5 mL) was added dropwise and the mixture was allowed to warm to room temperature overnight. Water was then added and the organic phase was separated, washed with brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (ethyl acetate and hexane 1: 9) gave the title compound (2.87 g).
MS (El) 265 (M+) (b) Metyl 1,2,3,4-tetrahydro-2,3-dimetyl-4-oxo-3-izochinolín karboxylátMS (EI) 265 (M < + > ) (b) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate
Metyl 2-(((1-metoxykarbonyl)etyl)metylamino]metylbenzoát (2 g) v suchom toluéne (10 ml) sä po kvapkách, pridal do refluxujúcej suspenzie olej neobsahujúceho hydridu sodného (od 0,42 g 60 % disperzie) v suchom toluéne (30 ml) a 2-metyl-2-propanole (5 kvapiek) pod dusíkovou atmosférou. Po zahrievaní na reflux 45 minút sa roztok ochladil v ľade a vylial sa do nasýteného roztoku chloridu amónneho, ktorý sa extrahoval etylacetátom (trikrát). Organická fáza sa premyla soľankou a vysušila nad síranom sodným. Filtráciou a odparením s následnou stĺpcovou chromatografiou (etylacetát a hexán 1 : 4) sa získala titulná zlúčenina ako žltý olej (0,95 g).Methyl 2 - (((1-methoxycarbonyl) ethyl) methylamino] methylbenzoate (2 g) in dry toluene (10 mL) is added dropwise, to the refluxing suspension, sodium hydride-free oil (from 0.42 g 60% dispersion) in dry toluene (30 mL) and 2-methyl-2-propanol (5 drops) under a nitrogen atmosphere After heating at reflux for 45 min, the solution was cooled in ice and poured into a saturated ammonium chloride solution which was extracted with ethyl acetate (3 times). phase was washed with brine and dried over sodium sulfate, filtered and evaporated followed by column chromatography (ethyl acetate and hexane 1: 4) to give the title compound as a yellow oil (0.95 g).
-24MS (El) 234 (M+) (c) 2-(4-Chlórfenyl)-2,3a,4,5-tetrahydro-3a,4-dimetylpyrazolo[4,3-c]izochinolín-3-ón-24MS (EI) 234 (M + ) (c) 2- (4-Chlorophenyl) -2,3a, 4,5-tetrahydro-3a, 4-dimethylpyrazolo [4,3-c] isoquinolin-3-one
Metyl 1,2,3,4-tetrahydro-2,3-dimetyl-4-oxo-3-izochinolín karboxylát (0,84 g),Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate (0.84 g),
4-chlórfenylhydrazín (1,54 g) a kyselina 4-toluénsulfónová (20 mg) sa spolu tavili pri 150 °C počas 10 minút pod dusíkovou atmosférou. Potom sa pridal xylén (10 ml) a zmes sa zahrievala na 150 °C ďalších 6 hodín. Po ochladení na laboratórnu teplotu sa rozpúšťadlo odstránilo a zvyšok sa rozpustil v dichlórmetáne s metanolom. Roztok sa premyl 2M kyselinou chlorovodíkovou a soľankou a vysušil sa nad síranom sodným. Filtráciou a odparením s následnou stĺpcovou chromatografiou (metanol a dichlórmetán 1 : 99) sa získala titulná zlúčenina ako bezfarebná tuhá látka (50 mg), 1.1. 128-129 °C.4-Chlorophenylhydrazine (1.54 g) and 4-toluenesulfonic acid (20 mg) were melted together at 150 ° C for 10 minutes under a nitrogen atmosphere. Then xylene (10 mL) was added and the mixture was heated at 150 ° C for an additional 6 hours. After cooling to room temperature, the solvent was removed and the residue was dissolved in dichloromethane with methanol. The solution was washed with 2M hydrochloric acid and brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (methanol and dichloromethane 1:99) gave the title compound as a colorless solid (50 mg), m.p. 128-129 [deg.] C.
MS (El) 325, 327 (M+)MS (EI) 325, 327 (M < + > )
Príklad 6Example 6
2-(4-Chlórfenyl)-2,4-dihydro-3-hydroxy-4-metylpyrazolo[4,3-c]izochinolín-5-ón2- (4-Chlorophenyl) -2,4-dihydro-3-hydroxy-4-methyl-pyrazolo [4,3-c] isoquinolin-5-one
Metyl 1,2-dihydro-4-hydroxy-2-metyl-1-oxo-3-izochinolínkarboxylát (JP 82 54, 152; 0,5 g), 4-chlórfenylhydrazín (0,91 g) a kyselina 4-toluénsulfónová (10 mg) sa spolu tavili pri 150 °C 10 minút pod dusíkovou atmosférou. Potom sa pridal xylén (5 ml) a zmes sa zahrievala na 150 °C 5 hodín. Po ochladení na laboratórnu teplotu sa filtráciou oddelila žltá zrazenina, ktorá sa premyla dietyléterom.. Čistením stĺpcovou chromatografiou (metanol a dichlórmetán 1, : 49) 1 s’ následnou rekryštalizáciou z etanolu sa získala titulná zlúčenina ako béžová tuhá látka (0,1 g), 1.1. >250 °C.Methyl 1,2-dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylate (JP 82 54, 152; 0.5 g), 4-chlorophenylhydrazine (0.91 g) and 4-toluenesulfonic acid ( 10 mg) were melted together at 150 ° C for 10 minutes under a nitrogen atmosphere. Then xylene (5 mL) was added and the mixture was heated at 150 ° C for 5 hours. After cooling to room temperature, the yellow precipitate collected by filtration, which was washed with diethyl ether .. Purification by column chromatography (dichloromethane, methanol, and 1, 49) with a 1 "followed by recrystallization from ethanol gave the title compound as a beige solid (0.1 g) , 1.1. ≫ 250 ° C.
MS (El) 325, 327 (M+)MS (EI) 325, 327 (M < + > )
-25Príklad 7-25Example 7
3-Hydroxy-4-[(4-metoxyfenyl)metyl]-2-(3-chinolyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ3-Hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 3-hydrazinochinolínu. T. t. 232 - 233 °C.The title compound was prepared according to the method described in Example 1 (c) using 3-hydrazinoquinoline. T. t. Mp 232-233 ° C.
MS (APCI) 433 ((M + H)+)MS (APCI) 433 ((M + H) < + > )
NMR (d6-DMSO) δ 3.7 (3H, s), 6.1 (2H, s), 6.7 (2H, d), 7.65 (1 H, t), 7.70 (3H, m), 7.80 (1H, t), 8.05 (3H, m), 8.20 (1 H, d), 8.40 (1H, d), 9.00 (1H, s), 9.20 (1H, d), 9.90 (1H, d).NMR (d 6 -DMSO) δ 3.7 (3H, s), 6.1 (2H, s), 6.7 (2H, d), 7.65 (1H, t), 7.70 (3H, m), 7.80 (1H, t) 8.05 (3H, m), 8.20 (1H, d), 8.40 (1H, d), 9.00 (1H, d), 9.20 (1H, d), 9.90 (1H, d).
Príklad 8Example 8
2-(3-Chinolyl)-2H-pyrazolo[4,3-c]izochinolín-3-ol2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina (0,21 g) bola pripravená podľa spôsobu opísaného, v príklade 2 s použitím 3-hydroxy-4-[(4-metoxyfenyl)metyl]-2-(3-chinolyl)-2Hpyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,66 g). T. t. 247 - 248 °C.The title compound (0.21 g) was prepared according to the method described in Example 2 using 3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide inner salt (0.66 g). T. t. Mp 247-248 ° C.
MS (APCI) 313 ((M + H)+) 1H NMR (d6-DMSO) δ 7.70 (1H, td), 7.80 (1H, td), 7.90 (1H, bt), 8.00 (1H, t),MS (APCI) 313 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.70 (1H, td), 7.80 (1H, td), 7.90 (1H, bt), 8.00 (1H, t) .
8.15 (2H, m), 8.35 (2H, m), 8.90 (1 H, d), 9.05 (1H), 9.70 (1 H, d), 12.20 (1 H, bs).8.15 (2H, m), 8.35 (2H, m), 8.90 (1H, d), 9.05 (1H), 9.70 (1H, d), 12.20 (1H, bs).
Príklad 9Example 9
2-(3,4-Dichlórfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ2- (3,4-Dichlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1 (c) s použitím 3,4-dÍchlórfenylhydrazínu. T. t. 239 - 240 °C.The title compound was prepared according to the method described in Example 1 (c) using 3,4-dichlorophenylhydrazine. T. t. Mp 239-240 ° C.
-26MS (APCI) 448, 450, 452 ((M + H)+) 1H NMR (d6-DMSO) δ 3.72 (3H, s), 6.06 (2H, s), 6.69 (2H, d), 7.70 (3H, m),-26MS (APCI) 448, 450, 452 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 3.72 (3H, s), 6.06 (2H, s), 6.69 (2H, d), 7.70 (3H, m)
7.79 (1H, t), 7.97 (1H, t), 8.16 (1H, d), 8.37 (2H, m), 8.72 (1H, d), 8.97 (1H, s).7.79 (1 H, t), 7.97 (1 H, t), 8.16 (1 H, d), 8.37 (2 H, m), 8.72 (1 H, d), 8.97 (1 H, s).
Príklad 10Example 10
2-(3,4-Dichlórfenyl)-2H-pyrazolo[4,3-c]izochinolín-3-ol2- (3,4-Dichlorophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina (0,028 g) bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 2-(3,4-dichlórfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2/-/pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,26 g). T. t. >230 °C.The title compound (0.028 g) was prepared according to the method described in Example 2 using 2- (3,4-dichlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2 H -pyrazolo [4,3- b] -c] isoquinolinium hydroxide, inner salt (0.26 g). T. t. Mp > 230 ° C.
MS (APCI) 330, 332, 334 ((M + H)+) 1H NMR (d5-DMSO) δ 7.82 (1H, d), 7.86 (1H, t), 7.97 (1 H, t), 8.13 (1H, dd), 8.24 (1H, d), 8.32 (1H, d), 8.42 (1H, d), 8.94 (1H, s).MS (APCI) 330, 332, 334 ((M + H) + ) 1 H NMR (d 5 -DMSO) δ 7.82 (1H, d), 7.86 (1H, t), 7.97 (1H, t), 8.13 (1H, dd), 8.24 (1 H, d), 8.32 (1 H, d), 8.42 (1 H, d), 8.94 (1 H, s).
Príklad 11Example 11
2-((1, ľ-Bifenyl]-4-yl)-2H-pyrazolo[4,3-c]izochinolín-3-ol (a) 2-([ 1,1 ,-Bifenyl]-4-yl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2H-pyrazolo-[4,3cjizochinolínium hydroxid, vnútorná soľ2 - ((1 ' -biphenyl] -4-yl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol (a) 2 - ([1,1'-biphenyl] -4-yl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím [1 ,ľ-bifenyl]-4-ylhýdrazínu (pozrite J. Chem. Soc., Perkin Trans. , (1975) 1280).The title compound was prepared according to the method described in Example 1 (c) using [1,1'-biphenyl] -4-yl-hydrazine (see J. Chem. Soc., Perkin Trans., (1975) 1280).
(b) 2-([1 ,ľ-Bifenyl]-4-yl)“2H-pyrazolo[4,3-c]izochinolín-3-ol(b) 2 - ([1,1'-Biphenyl] -4-yl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina (0,082 g) bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 2-([1,ľ-bifenyl]-4-yl)-3-hydroxy-4-[(4-metoxyfenyl)metyljThe title compound (0.082 g) was prepared according to the method described in Example 2 using 2 - ([1,1'-biphenyl] -4-yl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl]
-27 2/7-pyrazolo-[4,5-c]izochinolínium hydroxidu, vnútornej soli (0,29 g; z vyššie uvedeného kroku (a)). T. t. > 220 °C (s rozkladom).2- [2- (7-pyrazolo [4,5- c] isoquinolinium hydroxide, inner salt) (0.29 g; from step (a) above). T. t. ≫ 220 ° C (with decomposition).
MS (APCI) 338 ((M + H)+) 1H NMR (d6-DMSO) δ 7.37 (1H, m), 7.51 (2H, m), 7.75 (2H, m), 7.89 (3H, m), 7.98 (1H, m), 8.05 (2H, m), 8.31 (2H, m), 9.02 (1H, s, br).MS (APCI) 338 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.37 (1H, m), 7.51 (2H, m), 7.75 (2H, m), 7.89 (3H, m) 7.98 (1 H, m), 8.05 (2 H, m), 8.31 (2 H, m), 9.02 (1 H, s, br).
Príklad 12Example 12
3-Hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-metylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ3-Hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 4-metylfenylhydrazínu. T. t. > 100 °C (rozkl.)The title compound was prepared according to the method described in Example 1 (c) using 4-methylphenylhydrazine. T. t. > 100 ° C (dec.)
MS (APCI) 396 ((M + H)+) 1H NMR (d6-DMSO) δ 2.34 (3H, s), 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, m), 7.26 (2H, m), 7.74 (3H, m), 7.94 (1H, m), 8.13 (1H, d), 8.23 (2H, d), 8.33 (1H, d), 8.89(1 H, s).MS (APCI) 396 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.34 (3H, s), 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, m) 7.26 (2H, m); 7.74 (3H, m); 7.94 (1H, m); 8.13 (1H, d); 8.23 (2H, d); 8.33 (1H, d); 8.89 (1H, s) .
Príklad 13Example 13
2-(4-Metylfenyl)-2/-/-pyrazolo[4,3-c]izochinolín-3-ol2- (4-methylphenyl) -2 / - / - pyrazolo [4,3-c] isoquinolin-3-ol
Titulná 'zlúčenina (0,043 g) bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 3-hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-metylfenyl)-2/-/pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,20 g). T. t. 202 - 209 °C (rozkl.)The title compound (0.043 g) was prepared according to the method described in Example 2 using 3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-methylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide inner salt (0.20 g). T. t. 202 - 209 ° C (dec.)
MS (APCI) 276 ((M + H)+) 1H NMR (d6-DMSO) δ 2.37 (3H, s), 7.37 (2H, d), 7.88 (3H, m), 7.94 (1H, m),MS (APCI) 276 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.37 (3H, s), 7.37 (2H, d), 7.88 (3H, m), 7.94 (1H, m) .
8.29 (2H, m), 9.02 (1 H, br), 11.90 (1 H, br).8.29 (2H, m), 9.02 (1H, br), 11.90 (1H, br).
Príklad 14Example 14
2-(4-Brómfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2H-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4-Bromophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 4-brómfenylhydrazínu. T. t. > 220 °C (rozkl.)The title compound was prepared according to the method described in Example 1 (c) using 4-bromophenylhydrazine. T. t. > 220 ° C (dec.)
MS (APCl) 460, 462 ((M + H)+) 1H NMR (de-DMSO) δ 3.70 (3H, s), 6.08 (2H, s), 6.96 (2H, m), 7.66 (2H, m),MS (APCl) 460, 462 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 3.70 (3H, s), 6.08 (2H, s), 6.96 (2H, m), 7.66 (2H, m) )
7.76 (2H, m), 7.77 (1 H, t), 7.96 (1 H, m), 8.15 (1 H, d), 8.36 (3H, m), 8.94 (1H, s).7.76 (2H, m), 7.77 (1H, t), 7.96 (1H, m), 8.15 (1H, d), 8.36 (3H, m), 8.94 (1H, s).
Príklad 15Example 15
2-(4-Brómfenyl)-2/7-pyrazolo[4,3-c]izochinolín-3-ol2- (4-Bromo-phenyl) -2 / 7-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina (0,053 g) bola pripravená podľa metódy opísanej v príklade 2 s. použitím 2-(4-brómfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2/-/pyrazolo[4,3-c]-izochinolínium hydroxidu, vnútornej soli (0,164 g). T. t. > 250 °C.The title compound (0.053 g) was prepared according to the method described in Example 2 sec. using 2- (4-bromophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt (0.164 g). T. t. ≫ 250 ° C.
MS (APCl) 340, 342 ((M + H)+) 1H NMR (ds-DMSO) δ 7.76 (2H, d), 7.89 (1H, m), 8.02 (3H, m), 8.31 (2H, m), 9.07(1 H, br), 11.92(1 H, br).MS (APCl) 340, 342 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.76 (2H, d), 7.89 (1H, m), 8.02 (3H, m), 8.31 (2H, m) ), 9.07 (1H, br), 11.92 (1H, br).
ís
Príklad 16 'Example 16 '
2-(3-Trifluórmetylfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (3-Trifluoromethylphenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 3-trifluórmetylfenylhydrazínu, čím sa získal olej, ktorý bol čistený dvakrát chromatografiou, elúciou najprv etylacetátom a druhýkrát zmesami éteru a etylacetátu, čím sa získala titulná zlúčenina ako olej.The title compound was prepared according to the method described in Example 1 (c) using 3-trifluoromethyl-phenylhydrazine to give an oil which was purified twice by chromatography, eluting first with ethyl acetate and secondly with ether-ethyl acetate mixtures to give the title compound as an oil.
-29MS (APCI) 450 ((M + H)+) 1H NMR (CDCI3) δ 3.81 (3H, s), 6.19 (2H, s), 6.96 (2H, d), 7.45 (1H, m), 7.54 (3H, m), 7.79 (2H, m), 7.86 (1 H, t), 8.52 (1 H, d), 8.68 (1 H, d), 8.72 (1 H, s).-29MS (APCI) 450 ((M + H) + ) 1 H NMR (CDCl 3 ) δ 3.81 (3H, s), 6.19 (2H, s), 6.96 (2H, d), 7.45 (1H, m), 7.54 (3H, m), 7.79 (2H, m), 7.86 (1H, t), 8.52 (1H, d), 8.68 (1H, d), 8.72 (1H, s).
Príklad 17Example 17
2-(3-Trifluórmetylfenyl)-2/-/-pyrazolo[4,3-c]izochinolín-3-ol2- (3-trifluoromethylphenyl) -2 / - / - pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 2-(3-trifluórmetylfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2/-/-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli. T. t. 250 °C (rozkl.).The title compound was prepared according to the method described in Example 2 using 2- (3-trifluoromethyl-phenyl) -3-hydroxy-4 - [(4-methoxy-phenyl) -methyl] -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide , inner salt. T. t. 250 ° C (dec.).
MS (APCI) 330 ((M + H)+) 1H NMR (dg-DMSO) δ 7.67 (1H, d), 7.81 (1 H, t), 7.88 (1 H, t), 7.99 (1H, t), 8.42 (3H, m), 8.48 (1 H, s), 9.01 (1 H, s).MS (APCI) 330 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.67 (1H, d), 7.81 (1H, t), 7.88 (1H, t), 7.99 (1H, t 8.42 (3H, m), 8.48 (1H, s), 9.01 (1H, s).
Príklad 18Example 18
2-(4-(1,1-Dimetyletyl)fenyl]-2/-/-pyrazolo[4,3-c]izochinolín-3-ol (a) 3-Hydroxy-2-(4-(1,1-dimetyletyl)fenyl]-4-[(4-metoxyfenyl)metyl]-2H-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4- (1,1-Dimethylethyl) phenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol (a) 3-Hydroxy-2- (4- (1,1- dimethylethyl) phenyl] -4 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 4-((1,1-dimetylfenyl)fenyl]hydrazínu a bola použitá bež ďalšieho čistenia v nasledujúcom kroku.The title compound was prepared according to the method described in Example 1 (c) using 4 - ((1,1-dimethylphenyl) phenyl] hydrazine, and was used for the next purification in the next step.
(b) 2-(4-(1,1 -D i mety lety l)fenyl]-2/-/-pyrazolo[4,3-c]izochinol ίη-3-ol(b) 2- (4- (1,1-Dimethylamino) phenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 3-hydroxy-2-[4-(1,1 -dimetyletyl)fenyl]-4-(4-metoxyfenylmetyl)-2/-/-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli. T. t. > 210 °C (rozkl.)The title compound was prepared according to the method described in Example 2 using 3-hydroxy-2- [4- (1,1-dimethylethyl) phenyl] -4- (4-methoxyphenylmethyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt. T. t. > 210 ° C (dec.)
-30MS (APCI) 318 ((Μ + Η)+) 1H NMR (ds-DMSO) δ 1.33 (9H, s), 7.51 (2H, d), 7.75 (1H, t), 7.84 (1H, t), 8.01 (2H, d), 8.12 (1 H, d), 8.25 (1H, d), 8.74 (1H, s).-30MS (APCI) 318 ((Μ + Η) + ) 1 H NMR (d with -DMSO) δ 1.33 (9H, s), 7.51 (2H, d), 7.75 (1 H, t), 7.84 (1 H, t) ), 8.01 (2H, d), 8.12 (1H, d), 8.25 (1H, d), 8.74 (1H, s).
Príklad 19Example 19
2-(4-Trifluórmetoxyfenyl)-2/-/-pyrazolo[4,3-c]izochinolín-3-ol (a) 2-(4-Trifluórmetoxyfenyl)-3-hydroxy-2-[(4-metoxyfenyl)metyl]-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4-Trifluoromethoxyphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol (a) 2- (4-Trifluoromethoxyphenyl) -3-hydroxy-2 - [(4-methoxyphenyl) methyl ] -2 / - / - pyrazolo [4,3-cisoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 1(c) s použitím 4-trifluórmetoxyfenylhydrazínu a použila sa bez ďalšieho čistenia v nasledujúcom kroku.The title compound was prepared according to the method described in Example 1 (c) using 4-trifluoromethoxyphenylhydrazine, and was used in the next step without further purification.
(b) 2-(4-Trifluórmetoxyfenyl)-2H-pyrazolo[4,3-c]izochinolín-3-ol(b) 2- (4-Trifluoromethoxyphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 2 s použitím 2-(4-trifluórmetoxyfenyl)-3-hydroxy-2-[(4-metoxyfenyl)metyl]-2H-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli. T. t. > 230 °C.The title compound was prepared according to the method described in Example 2 using 2- (4-trifluoromethoxyphenyl) -3-hydroxy-2 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt . T. t. Mp > 230 ° C.
MS (APCI) 346 ((M + H)+) 1H NMR (d6-DMSO) δ 7.58 (2H, d), 7.91 (1H, t), 7.99 (1H, t), 8.14 (2H, d),MS (APCI) 346 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.58 (2H, d), 7.91 (1H, t), 7.99 (1H, t), 8.14 (2H, d) .
8.29 (2H, m), 9.03(1 H, br). ' ,8.29 (2H, m), 9.03 (1H, br). ',
Príklad 20Example 20
2-(4-Chlórfenyl)-3-hydroxy-4-metyl-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ2- (4-Chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Metyl 1,2,3,4-tetrahydro-2-metyl-4-oxo-3-izochinolínkarboxylát (0,5 g) (I. G. Hinton a F. G. Mann, J. Chem. Soc. 1959, 599), 4-chlórfenylhydrazín (0,98 g) aMethyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.5 g) (IG Hinton and FG Mann, J. Chem. Soc. 1959, 599), 4-chlorophenylhydrazine ( 0.98 g) a
-31 kyselina 4-toluénsulfónová (10 mg) sa spolu tavili pri 150 °C počas desiatich minút pod dusíkovou atmosférou. Potom sa pridal xylén (10 ml) a zmes sa zahrievala ďalších 6 hodín na 150 °C. Reakčná zmes sa ochladila a získaná červená zrazenina sa odfiltrovala a premyla dietyléterom. Rekryštalizáciou z metanolu sa získala titulná zlúčenina (0,27 g). T. t. 247 - 248 °C.-31 4-Toluenesulfonic acid (10 mg) was melted together at 150 ° C for ten minutes under a nitrogen atmosphere. Then xylene (10 mL) was added and the mixture was heated at 150 ° C for a further 6 hours. The reaction mixture was cooled and the resulting red precipitate was filtered off and washed with diethyl ether. Recrystallization from methanol gave the title compound (0.27 g). T. t. Mp 247-248 ° C.
MS (El) 309, 311 ((M + H)+) 1H NMR (d6-DMSO) δ 4.5 (3H, s), 7.5 (2H, d), 7.75 (1 H, t), 7.95 (1 H, t), 8.1 (1 H, d), 8.3 (1H, d), 8.4 (2H, d), 8.6 (1H, s).MS (EI) 309, 311 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 4.5 (3H, s), 7.5 (2H, d), 7.75 (1H, t), 7.95 (1 H, t), 8.1 (1H, d), 8.3 (1H, d), 8.4 (2H, d), 8.6 (1H, s).
Príklad 21Example 21
2-(4-Chlórfenyl)-3-hydroxy-4-metyl-2/-/-pyrazolo[4,3-c]cinolínium hydroxid, vnútorná soľ2- (4-Chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] cinolinium hydroxide, inner salt
2-(4-Chlórfeny|)-2,5-dihydro-pyrazolo[4,3-c]cinolín-3-ón (0,33 g) (európska patentová prihláška EP-A-0187551) sa pridal po častiach do miešanej suspenzie olej neobsahujúceho hydridu sodného (od 49 mg 60 % disperzie) v suchom dimetylformamide (5 ml) pod dusíkovou atmosférou. Po 0,5 h sa pridal jódmetán (0,076 ml) a získaný roztok sa miešal pri teplote miestnosti počas 2 hodín. Roztok sa vylial do soľanky a extrahoval sa zmesou dichlórmetánu a metanolu (trikrát). Organická fáza sa premyla 2 N kyselinou chlorovodíkovou a soľankou a vysušila sa nad síranom sodným, prefiltrovala a nakoncentrovala, čím sa získala červená tuhá látka. Čistením stĺpcovou chromatografiou (etylacetát a hexán 2 : 3) s následnou rekryštalizáciou z dimetylformamidu sa získala titulná zlúčenina vo forme fialových kryštálov (65 mg). T. t. 249 - 250 °C.2- (4-Chlorophenyl) -2,5-dihydro-pyrazolo [4,3-c] cinolin-3-one (0.33 g) (European patent application EP-A-0187551) was added in portions to the stirred a suspension of oil free of sodium hydride (from 49 mg of 60% dispersion) in dry dimethylformamide (5 mL) under a nitrogen atmosphere. After 0.5 h, iodomethane (0.076 mL) was added and the resulting solution was stirred at room temperature for 2 hours. The solution was poured into brine and extracted with a mixture of dichloromethane and methanol (three times). The organic phase was washed with 2 N hydrochloric acid and brine and dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (ethyl acetate and hexane 2: 3) followed by recrystallization from dimethylformamide gave the title compound as violet crystals (65 mg). T. t. Mp 249-250 ° C.
MS (El) 310, 312((M + H)+) 1H NMR (CDCI3) 4.81 (3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (1 H, dd), 8.25 (2H, d), 8.35(1 H, dd).MS (EI) 310, 312 ((M + H) + ) 1 H NMR (CDCl 3 ) 4.81 (3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (1H, dd) 8.25 (2H, d); 8.35 (1H, dd).
-32Príklad 22-32Example 22
2-(4-Chlórfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4-Chlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Titulná zlúčenina bola pripravená podľa spôsobu opísaného v príklade 20 z metyl 1,2,3,4-tetrahydro-2-(4-metoxyfenyl)metyl-4-oxo-3-izochinolínkarboxylátu (ktorý bol pripravený analogicky so spôsobom opísaným v I. G. Hinton a F. G. Mann, J. Chem. Soc. 1959, 599). T. t. 227 - 228 °C.The title compound was prepared according to the method described in Example 20 from methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl-4-oxo-3-isoquinolinecarboxylate (which was prepared analogously to the method described in IG Hinton and FG Mann, J. Chem. Soc. 1959, 599). T. t. Mp 227-228 ° C.
MS (El) 416, 418((M + H)+) 1H NMR (d6-DMSO) 3.70 (3H, s), 6.08 (2H, s), 6.95 (2H, d), 7.50 (2H, d),MS (EI) 416, 418 ((M + H) + ) 1 H NMR (d 6 -DMSO) 3.70 (3H, s), 6.08 (2H, s), 6.95 (2H, d), 7.50 (2H, d) )
7.70 (2H, d), 7.75 (1H, t), 7.95 (1H, t), 8.15 (1 H, d), 8.35 (1H, d), 8.40 (2H, d), 8.93 (1H,s).7.70 (2H, d), 7.75 (1 H, t), 7.95 (1 H, t), 8.15 (1 H, d), 8.35 (1 H, d), 8.40 (2 H, d), 8.93 (1 H, s).
Nasledujúce zlúčeniny, príklady 23 - 56, boli pripravené spôsobmi analogickými s príkladmi 20 a 22:The following compounds, Examples 23-56, were prepared by methods analogous to Examples 20 and 22:
Príklad 57Example 57
3-Hydroxy-2-(4-jódfenyl)-4-metyl-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ >3-Hydroxy-2- (4-iodophenyl) -4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt>
Metyl 1,2(3,4-tetrahydro-2-metyl-4-oxo-3-izochinolínkarboxylát (0,485 g) a 4jódfenylhydrazín (1,053 g) sa zmiešali v etanole (15 ml) a zahrievali sa na reflux počas 20 hodín. Pri ochladení vypadla tuhá látka, ktorá sa prekryštalizovala z etanolu a potom z 2-propanolu, čím sa získala titulná zlúčenina (0,054 g). T. t. > 260 °C.Methyl 1,2 ( 3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.485 g) and 4-iodophenylhydrazine (1.053 g) were combined in ethanol (15 mL) and heated to reflux for 20 hours. On cooling, a solid precipitated which was recrystallized from ethanol and then from 2-propanol to give the title compound (0.054 g), mp> 260 ° C.
MS (+ve ESI) 402 ((M + H)+) 1H NMR (dé-DMSO) 5 4.50 (3H, s), 7.76 (1H, t), 7.77 (2H, d), 7.94 (1H, t), 8.09 (1H, d), 8.19 (2H, d), 8.32 (1H, d), 8.62 (1H, s).MS (+ ve ESI) 402 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 4.50 (3H, s), 7.76 (1H, t), 7.77 (2H, d), 7.94 (1H, t) 8.09 (1 H, d), 8.19 (2 H, d), 8.32 (1 H, d), 8.62 (1 H, s).
Nasledujúce zlúčeniny, príklady 58 - 60, boli pripravené analogickým spôsobom ako v príklade 2:The following compounds, Examples 58-60, were prepared in an analogous manner to Example 2:
Nasledujúce zlúčeniny, príklady 61 - 68, boli pripravené analogickým spôsobom ako v príklade 6:The following compounds, Examples 61-68, were prepared in an analogous manner to Example 6:
Príklad 69Example 69
2,4-Dihydro-3-hydroxy-2-(4-trifluórmetylfenyl)-5/-/-pyrazolo[4,3-c]izochinolín-5-ón2,4-dihydro-3-hydroxy-2- (4-trifluoromethyl-phenyl) -5 / - / - pyrazolo [4,3-c] isoquinolin-5-one
Kyselina trifluóroctová (4 ml) sa pridala do 2,4-dihydro-3-hydroxy-4(metoxyfenylmetyl)-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-c]izochinolín-5-ónu (príklad 66) (425 mg) a zmes sa zahrievala na reflux počas 12 hodín. Po ochladení na teplotu miestnosti sa rozpúšťadlo odstránilo a získaný zvyšok sa rekryštalizoval zo zmesi metanol/voda, čím sa získala žltá tuhá látka, ktorá sa ďalej vyčistila rozotrením s izohexánom, čím sa získala titulná zlúčenina (150 mg). T. t. > 200 °C.Trifluoroacetic acid (4 mL) was added to 2,4-dihydro-3-hydroxy-4- (methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (Example 66). (425 mg) and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the solvent was removed and the obtained residue was recrystallized from methanol / water to give a yellow solid which was further purified by trituration with isohexane to give the title compound (150 mg). T. t. ≫ 200 ° C.
MS (APCI) 346 ((M + H)+) 1H NMR (de-DMSO) δ 7.76 (1H, t), 7.92 (3H, m), 8.02 (1H, d), 8.18 (2H, d), 8.34(1 H, d), 11.20 (1H, s).MS (APCI) 346 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.76 (1H, t), 7.92 (3H, m), 8.02 (1H, d), 8.18 (2H, d), 8.34 (1H, d), 11.20 (1 H, s).
-40Nasledujúce zlúčeniny boli pripravené analogicky ako v príklade 69:The following compounds were prepared analogously to Example 69:
Príklad 72Example 72
2-(4-chlórfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-5-metyl-2H-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4-chlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
M roztok metylmagnézium bromidu v dietyléteri (2.0 ml) sa pridal po kvapkách do ľadom chladenej suspenzie 2-(4-chlórfenyl)-3-hydroxy-4-[(4metoxyfenyl)metyl]-2H-pyrazolo[4,3-c]izochinolín hydroxidu, vnútornej soli (príklad 22) (0,5 g) a bromidu meďného (17 mg) v suchom tetrahydrofuráne (20 ml). Zmes sa miešala s chladením počas 1 hodiny a pridal sa nasýtený vodný roztok chloridu amónneho a etylacetát. Táto zmes sa miešala pri laboratórnej teplote 16 hodín a potom sa vodná fáza extrahovala etylacetátom (trikrát). Organická fáza sa premyla soľankou, vysušila nad síranom sodným, prefiltrovala a odparila. Tuhý zvyšok sa prečistil stĺpcovou chromatografiou (dichlórmetán a metanol 99 : 1), čím sa získala fialová tuhá látka (0,38 g). Vzorka (0,1 g) sa rekryštalizovala z etanolu, čím sa získala titulná zlúčenina (31 mg). T. t. 212 - 216 °CM solution of methylmagnesium bromide in diethyl ether (2.0 mL) was added dropwise to an ice-cooled suspension of 2- (4-chlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinoline hydroxide, inner salt (Example 22) (0.5 g) and copper (I) bromide (17 mg) in dry tetrahydrofuran (20 mL). The mixture was stirred with cooling for 1 hour and saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was stirred at room temperature for 16 hours and then the aqueous phase was extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column chromatography (dichloromethane and methanol 99: 1) to give a violet solid (0.38 g). A sample (0.1 g) was recrystallized from ethanol to give the title compound (31 mg). T. t. Mp 212-216 ° C
MS (APCI) 430, 432 ((M + H)+) 1H NMR (d6-DMSO) δ 2.88 (3H, s), 3.71 (3H, s), 6.50 (2H, br s), 6.93 (2H, d), 7.32 (2H, d), 7.51 (2H, d), 7.76 (1H, t), 7.98 (1 H, t), 8.32 (1H, d), 8.43 (3H, m).MS (APCI) 430, 432 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.88 (3H, s), 3.71 (3H, s), 6.50 (2H, br s), 6.93 (2H d, 7.32 (2H, d), 7.51 (2H, d), 7.76 (1H, t), 7.98 (1H, t), 8.32 (1H, d), 8.43 (3H, m).
-41 Príklad 73-41 Example 73
2-(4-Chlórfenyl)-5-metyl-2/7-pyrazolo[4,3-c]izochinolín-2-ol2- (4-Chloro-phenyl) -5-methyl-2/7-pyrazolo [4,3-c] isoquinoline-2-ol
2-(4-Chlórfenyl)-3-hydroxy-4-[(4-metoxyfenyl)metyl]-5-metyl-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ (0,29 g) sa rozpustila v kyseline trifluóroctovej(10 ml) a zahrievala sa na reflux v dusíkovej atmosfére počas 2 hodín. Po ochladení na laboratórnu teplotu sa rozpúšťadlo odparilo a zvyšok bol odparený spolu s toluénom (trikrát). Čistením stĺpcovou chromatografiou (dichlórmetán a metanol 20 : 1) s následným rozotrením s metanolom sa získala titulná zlúčenina ako oranžová tuhá látka (0,07 g). T. t. > 250 °C2- (4-Chlorophenyl) -3-hydroxy-4 - [(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.29 g) was dissolved in trifluoroacetic acid (10 mL) and heated to reflux under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the solvent was evaporated and the residue was co-evaporated with toluene (three times). Purification by column chromatography (dichloromethane and methanol 20: 1) followed by trituration with methanol gave the title compound as an orange solid (0.07 g). T. t. ≫ 250 ° C
MS (APCI)310, 312 ((M + H)+) 1H NMR (d6-DMSO) δ 2.77 (3H, s), 7.47 (2H, d), 7.68 (1H, t), 7.77 (1H, t),MS (APCI) 310, 312 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.77 (3H, s), 7.47 (2H, d), 7.68 (1 H, t), 7.77 (1 H, t),
8.10 (1H, d), 8.25 (1H, d), 8.31 (2H, d).8.10 (1 H, d), 8.25 (1 H, d), 8.31 (2 H, d).
Nasledujúce zlúčeniny boli pripravené podľa spôsobu z príkladu 72:The following compounds were prepared according to the method of Example 72:
-42Príklad 76Example 42
2-(4-Chlórfenyl)-3-hydroxy-4,5-dimetyl-2H-pyrazolo[4,3-c]izochinolinium hydroxid, vnútorná soľ2- (4-Chlorophenyl) -3-hydroxy-4,5-dimethyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
2-(4-Chlórfenyl)-2,4-dihydro-3-hydroxy-4-metylpyrazolo[4,3-c]izochinolín-5ón (0,48 g) (príklad 6) bol suspendovaný v suchom 1,2-dimetoxyetáne (50 ml). Pridal sa roztok metylmagnézium bromidu (3 ml 3 M roztoku v éteri) a zahrievanie pokračovalo 3 hodiny. Reakčná zmes sa nechala ochladiť na laboratórnu teplotu a potom sa neutralizovala pomalým pridaním zriedenej kyseliny chlorovodíkovej. Zmes sa upravila na bázické pH vodným roztokom hydrogenuhličitanu sodného a extrahovala sa etylacetátom (trikrát). Organická vrstva sa premyla soľankou a vysušila nad síranom horečnatým, prefiltrovala a odparila. Čistením zvyšku chromatografiou (oxid kremičitý, dichlórmetán a metanol 97 : 3 - 95 : 5) sa získala červená tuhá látka, ktorá sa rozotrela s éterom, čím sa získala titulná zlúčenina (0,060 g). T. t. > 250 ’C.2- (4-Chlorophenyl) -2,4-dihydro-3-hydroxy-4-methylpyrazolo [4,3-c] isoquinolin-5-one (0.48 g) (Example 6) was suspended in dry 1,2-dimethoxyethane (50 mL). A solution of methylmagnesium bromide (3 mL of a 3M solution in ether) was added and heating was continued for 3 hours. The reaction mixture was allowed to cool to room temperature and then neutralized by the slow addition of dilute hydrochloric acid. The mixture was basified with aqueous sodium bicarbonate and extracted with ethyl acetate (3 times). The organic layer was washed with brine and dried over magnesium sulfate, filtered and evaporated. Purification of the residue by chromatography (silica, dichloromethane and methanol 97: 3 - 95: 5) gave a red solid which was triturated with ether to give the title compound (0.060 g). T. t. > 250 ’C.
MS (APCI) 324/326 ((M + H)+) 1H NMR (d6-DMSO) δ 2.90 (3H, s), 4.63 (3H, s), 7.49 (2H, d), 7.77 (1H, t), 7.95(1 H, t), 8.39 (4H, m).MS (APCI) 324/326 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.90 (3H, s), 4.63 (3H, s), 7.49 (2H, d), 7.77 (1H, t), 7.95 (1H, t), 8.39 (4H, m).
Nasledujúce zlúčeniny boli pripravené podľa spôsobu z príkladu 76:The following compounds were prepared according to the method of Example 76:
Príklad 81Example 81
5-Chlór-2-(4-trifluórmetylfenyl)-2F/-pyrazolo[4,3-c]izochinolín-3-ol5-Chloro-2- (4-trifluoromethylphenyl) -2F / -pyrazolo [4,3-c] isoquinolin-3-ol
Oxychlorid fosforečný (5 ml) sa pridal do 2,4-dihydro-3-hydroxy-4-(4metoxyfenylmetyl)-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-c]izochinolín-5-ónu (príklad 66) (350 mg) a zahrieval sa na reflux počas 1 hodiny. Po ochladení na laboratórnu teplotu sa rozpúšťadlo odstránilo a zvyšok sa vyčistil stĺpcovou chromatografiou elúciou zmesou izohexán, etylacetát, kyselina octová (80 : 20 : 2) s následným rozotrením s acetonitrilom, čím sa získala titulná zlúčenina (25 mg). T. t. >250 °C (rozkl.).Phosphorus oxychloride (5 mL) was added to 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (Example 66) (350 mg) and heated to reflux for 1 hour. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography eluting with isohexane, ethyl acetate, acetic acid (80: 20: 2) followed by trituration with acetonitrile to give the title compound (25 mg). T. t. > 250 ° C (dec.).
MS (APCI) 364/366 ((M + H)+) 1H NMR (d6-DMSO) δ 7.96 (5H, m), 8.07 (1 H, t), 8.25 (1 H, d), 8.43 (1 H, d).MS (APCI) 364/366 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.96 (5H, m), 8.07 (1H, t), 8.25 (1H, d), 8.43 ( 1 H, d).
-44Príklad 82-44Example 82
3a,4-Dihydro-3a-hydroxy-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo[4l3-c]izochinolín-3,5dión3, 4-dihydro-3-hydroxy-2- (4-trifluoromethylphenyl) -2 / - / - pyrazolo [l 3 4-c] isoquinoline-3,5-dione
Dusičnan ce'ričito-amónny (700 mg) sá pridal do suspenzie 2,4-dihydro-3hydroxy-4-(4-metóxyfeny!metyl)-2-(4-trifluórmetylfenyl)-5/-/-pyrazolo[4,3-c]izochinolín-5-ónu (príklad 66) (200 mg) v acetonitrile (4 ml) a vode (1 ml) pri teplote miestnosti. Po 2 hodinách sa zmes adsorbovala na silikagél a vyčistila sa stĺpcovou chromatografiou elúciou izohexánom a 2-propanolom (9 : 1) a potom HPLC elúciou izohexánom a etylacetátom (4 : 1), čím sa získala titulná zlúčenina (50 mg). T. t. 175-185 °CTertiary ammonium nitrate (700 mg) was added to a suspension of 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-d] -c] isoquinolin-5-one (Example 66) (200 mg) in acetonitrile (4 mL) and water (1 mL) at room temperature. After 2 hours the mixture was adsorbed onto silica gel and purified by column chromatography eluting with isohexane and 2-propanol (9: 1) followed by HPLC eluting with isohexane and ethyl acetate (4: 1) to give the title compound (50 mg). T. t. 175-185 ° C
MS (El) 360 ((M + H)+) 1H NMR (d6-DMSO) δ 7.7 až 8.0 (5H, m), 8.08 až 8.12 (4H, m), 9.78(1 H, s).MS (EI) 360 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.7-8.0 (5H, m), 8.08-8.12 (4H, m), 9.78 (1H, s).
Príklad 83Example 83
214-Dihydro-3-metoxy-4-metyl-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-2 1 4-Dihydro-3-methoxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-
c]izochinolín-5-ónc] isoquinolin-5-one
2,4-Dihydro-3-hydroxy-4-metyl-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-c]izochinolín-5-ón (0,2 g) (príklad 63) v suchom dimetylformamide (5 ml) sa pridal po kvapkách do miešanej suspenzie olej neobsahujúceho hydridu sodného (od 0,022 g 60 % disperzie) v suchom dimetylformamide (1 ml) pri 0 °C. Po 0,5 h sa pridal metyljodid (0,038 ml). Miešanie pokračovalo 16 hodín. Zmes sa zriedila vodou, okyslila zriedenou kyselinou chlorovodíkovou a extrahovala etylacetátom (trikrát). Organická fáza sa premyla soľankou (sedem krát) a potom vysušila nad síranom horečnatým, prefiltrovala a nakoncentrovala. Čistením chromatografiou (etylacetát, dichlórmetán 25 : 75 - 50 : 50 a potom etylacetát, izohexán 30 : 70) sa získala titulná zlúčenina ako bezfarebná tuhá látka (0,015 g). T. t. 163-164 °C2,4-Dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (0.2 g) (Example 63) in dry dimethylformamide (5 mL) was added dropwise to a stirred suspension of sodium hydride-free oil (from 0.022 g 60% dispersion) in dry dimethylformamide (1 mL) at 0 ° C. After 0.5 h, methyl iodide (0.038 mL) was added. Stirring was continued for 16 hours. The mixture was diluted with water, acidified with dilute hydrochloric acid and extracted with ethyl acetate (three times). The organic phase was washed with brine (seven times) and then dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (ethyl acetate, dichloromethane 25: 75 - 50: 50 and then ethyl acetate, isohexane 30: 70) gave the title compound as a colorless solid (0.015 g). T. t. 163-164 [deg.] C
MS (APCI) 374 ((M + H)+)MS (APCI) 374 ((M + H) < + > )
-451H NMR (CDCh): δ 3.78 (3H, s), 3.83 (3H, s), 7.60 (1H, td), 7.74 (1 H, td),-45 1 H NMR (CDCl 3): δ 3.78 (3H, s), 3.83 (3H, s), 7.60 (1 H, td), 7.74 (1 H, td),
7.80 (2H, d), 8.04 (2H, d), 8.27 (1 H, dd), 8.48 (1H, dd).7.80 (2 H, d), 8.04 (2 H, d), 8.27 (1 H, dd), 8.48 (1 H, dd).
Príklad 84 t ' IExample 84 t 'I
2- (4-ChlórŤenyl)-4-{2-(/V,A/-dimetylamino)etyl}-3-hydroxy-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ2- (4-Chloro-phenyl) -4- {2 - (N, N -dimethylamino) -ethyl} -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
2- (4-Chlórfenyl)-2H-pyrazolo[4,3-c]izochinolín-3-ol (0,3 g) sa pridal do miešanej suspenzie olej neobsahujúceho hydridu sodného (od 81 mg 60 % disperzie) v suchom dimetylformamide (5 ml) pod dusíkovou atmosférou. Po 30 minútach sa pridal hydrochlorid 2-dimetylaminoetyl chloridu (0,15 g) a zmes sa miešala pri teplote miestnosti 16 hodín. Zmes sa zriedila vodou a extrahovala etylacetátom (trikrát). Organická fáza sa premyla soľankou a potom vysušila nad síranom sodným, prefiltrovala a nakoncentrovala, čím sa získala fialová tuhá látka. Čistením stĺpcovou chromatografiou (dichlórmetán, etanol 20 : 1) s následnou rekryštalizáciou zo zmesi cyklohexánu a etylacetátu 4 : 1 sa získala titulná látka ako červená tuhá látka (125 mg). T. t. 173 - 174 °C.2- (4-Chlorophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol (0.3 g) was added to a stirred suspension of sodium hydride-free oil (from 81 mg 60% dispersion) in dry dimethylformamide ( 5 ml) under a nitrogen atmosphere. After 30 minutes, 2-dimethylaminoethyl chloride hydrochloride (0.15 g) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine and then dried over sodium sulfate, filtered and concentrated to give a violet solid. Purification by column chromatography (dichloromethane, ethanol 20: 1) followed by recrystallization from cyclohexane / ethyl acetate 4: 1 gave the title compound as a red solid (125 mg). T. t. Mp 173-174 ° C.
MS (APCI) 367, 369 ((M + H)+) 1H NMR (d6-DMSO) δ 2.32 (6H, s), 3.02 (2H, t), 5.03 (2H, t), 7.4 (2H, d),MS (APCI) 367, 369 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.32 (6H, s), 3.02 (2H, t), 5.03 (2H, t), 7.4 (2H, d),
7.65 (1H, t), 7.85 (3H, m), 8.30 (2H, d), 8.50 (1H, d).7.65 (1 H, t), 7.85 (3 H, m), 8.30 (2 H, d), 8.50 (1 H, d).
Príklad 85Example 85
3- Hydroxy-4-metyl-2-(4-metylsulfinylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ3-Hydroxy-4-methyl-2- (4-methylsulfinylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
3- Hydroxy-4-metyl-2-(4-metyltiofenyl)-2/-/-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ (0,10 g) (príklad 41), sa rozpustila v dichlórmetáne (15 ml) a ochladila na -78 °C. Pridala sa kyselina 3-chlórperbenzoová (0,055) a zmes sa miešala 10 minút, vyliala sa do vodného disiričitanu sodného a extrahovala sa etylacetátom (trikrát). Spojené extrakty sa pretrepali s vodným hydrogenuhličitanom sodným, vysušili sa síranom sodným a odparili. Získaný zvyšok sa vyčistil stĺpcovou chromatografiou (etylacetát, metanol 3 : 2), čím sa získala titulná zlúčenina vo forme červeného prášku. T. t. > 230 °C.3-Hydroxy-4-methyl-2- (4-methylthiophenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt (0.10 g) (Example 41) was dissolved in dichloromethane ( 15 mL) and cooled to -78 ° C. 3-Chloroperbenzoic acid (0.055) was added and the mixture was stirred for 10 minutes, poured into aqueous sodium metabisulfite and extracted with ethyl acetate (three times). The combined extracts were shaken with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The obtained residue was purified by column chromatography (ethyl acetate, methanol 3: 2) to give the title compound as a red powder. T. t. Mp > 230 ° C.
MS (APCl) 338 ((M + H)+) 1H NMR (d6-DMSO) δ 2.77 (3H, s), 4.52 (3H, s), 7.80 (3H, m), 7.96 (1H, t), 8.13 (1H, d), 8.37 (1 H, d), 8.57 (2H, d), 8.64 (1 H, s).MS (APCl) 338 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.77 (3H, s), 4.52 (3H, s), 7.80 (3H, m), 7.96 (1 H, t) 8.13 (1H, d), 8.37 (1H, d), 8.57 (2H, d), 8.64 (1H, s).
Príklad 86Example 86
2-(4-Chlórfenyl)-3-hydroxy-4-[2-(metylsulfinyl)etyl]-2H-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ2- (4-Chlorophenyl) -3-hydroxy-4- [2- (methylsulfinyl) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Kyselina 3-chlórperbenzoová (0,86 g) sa rozpustila v dichlórmetáne (20 ml). 6 ml získaného roztoku sa po kvapkách pridalo do roztoku 2-(4-chlórfenyl)-3hydroxy-4-[2-(metyltio)etyl]-2W-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (príklad 46) (0,43, g) v dichlórmetáne (20 ml) pri -78 °C. Po 30 minútach sa pridal vodný roztok disiričitanu sodného a reakčná zmes sa potom rozdelila medzi vodu a dichlórmetán. Organická vrstva sa premyla vodným roztokom hydroxidu sodného a potom vysušila (síran horečnatý), prefiltrovala a odparila. Zvyšok bol podrobený chromatografii pomocou metanolu (2 - 6 % obj.) v dichlórmetáne ako eluentu, čím sa získala fialová tuhá látka (0,46 g). T. t. 228 - 230 °C.3-Chloroperbenzoic acid (0.86 g) was dissolved in dichloromethane (20 mL). 6 ml of the obtained solution was added dropwise to a solution of 2- (4-chlorophenyl) -3-hydroxy-4- [2- (methylthio) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (Example 46) (0.43, g) in dichloromethane (20 mL) at -78 ° C. After 30 minutes, aqueous sodium metabisulphite solution was added and the reaction mixture was then partitioned between water and dichloromethane. The organic layer was washed with aqueous sodium hydroxide solution and then dried (magnesium sulfate), filtered and evaporated. The residue was chromatographed using methanol (2-6% v / v) in dichloromethane as eluent to give a violet solid (0.46 g). T. t. Mp 228-230 ° C.
MS (APCI+) 386, 388 ((M + H)+) 1H NMR (d6-DMSO) δ 2Ό9 (3H, s), 3.47 (1H, m),‘3.64(1H, m), 5.11 (1H, m), 5.34 (1H, m), 7.50 (2H, m), 7.79 (1H, m), 7.99 (1H, m), 8.17 (1H, d), 8.38 (3H, m), 8.83(1 H, s).MS (APCI +) 386, 388 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2-9 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H , m), 5.34 (1 H, m), 7.50 (2 H, m), 7.79 (1 H, m), 7.99 (1 H, m), 8.17 (1 H, d), 8.38 (3 H, m), 8.83 (1 H) , with).
Príklad 87Example 87
3-Hydroxy-4-[2-(metylsulfinyl)etyl]-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ3-Hydroxy-4- [2- (methylsulfinyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Pripravený z 3-hydroxy-4-[2-(metyltio)etyl]-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (príklad 47), podľa spôsobu príkladu 86 za vzniku titulnej zlúčeniny ako fialovej tuhej látky. T. t. 241 - 243 °C.Prepared from 3-hydroxy-4- [2- (methylthio) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (Example 47), according to the method of Example 86 after formation of the title compound as a violet solid. T. t. Mp 241-243 ° C.
MS (APCI+) 420 ((M + H)+) ’ 1H NMR (d6-DMSO) δ 2.70 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H, m), 5.36 (1H, m), 7.81 (3H, m), 8.01 (1H, m), 8.19 (1H, d), 8.38 (1H, d), 8.60 (2H, d), 8.86(1 H, s).MS (APCI +) 420 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.70 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H, m) ), 5.36 (1H, m), 7.81 (3H, m), 8.01 (1H, m), 8.19 (1H, d), 8.38 (1H, d), 8.60 (2H, d), 8.86 (1H, s) ).
Príklad 88Example 88
5-[2-(4-Metoxyfenyl)etyl]-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolín-3-pl, sodná soľ5- [2- (4-Methoxyphenyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-pl, sodium salt
Metylmagnézium bromid (3 M v éteri, 8,6 ml) sa pridal pomaly do miešanej suspenzie 2,4-dihydro-3-hydroxy-4-(4-metoxyfenylmetyl)-2-(4-trifluórmetylfenyl)5H-pyrazolo[4,3-c]izochinolín-5-ónu (príklad 66) (500 mg) a bromidu med’ného (15 mg) v 1,2-dimetoxyetáne (50 ml) a potom sa zahrieval na 100 °C 24 hodín. Po vychladnutí na teplotu miestnosti sa zmes vyliala do studenej zriedenej kyseliny chlorovodíkovej a pH sa upravilo na bázické pomocou hydrogenuhličitanu sodného a hydroxidu sodného. Vodná fáza sa extrahovala etylacetátom. Spojená organická fáza sa premyla soľankou a vysušila nad síranom horečnatým. Filtráciou a odparením roztoku s následným čistením stĺpcovou chromatografiou elúciou postupne zmesou izohexánu a etylacetátu (1 : 1), etylacetátom a zmesou etylacetátu a metanolu (9 : 1) sa získala titulná zlúčenina ako červená tuhá látka (90 mg). T. t. > 200 °C (rozkl.).Methylmagnesium bromide (3 M in ether, 8.6 mL) was added slowly to a stirred suspension of 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4] 3-c] isoquinolin-5-one (Example 66) (500 mg) and copper (I) bromide (15 mg) in 1,2-dimethoxyethane (50 mL) and then heated at 100 ° C for 24 hours. After cooling to room temperature, the mixture was poured into cold dilute hydrochloric acid and the pH was made basic with sodium bicarbonate and sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate. Filtration and evaporation of the solution followed by purification by column chromatography eluting sequentially with isohexane / ethyl acetate (1: 1), ethyl acetate, and ethyl acetate / methanol (9: 1) afforded the title compound as a red solid (90 mg). T. t. > 200 ° C (dec.).
MS (APCI) 464 ((M + H)+)MS (APCI) 464 ((M + H) < + > )
-481H NMR (d6-DMSO/TFA) δ 3.08 (2H, t), 3.59 (2H, t), 3.73 (3H, s), 6.87 (2H,-48 @ 1 H NMR (d6 -DMSO / TFA) .delta. 3.08 (2H, t), 3.59 (2H, t), 3.73 (3H, s), 6.87 (2H,
d), 7.25 (2H, d), 7.92 (3H, m), 8.05 (1 H. t), 8.33 (2H, d), 8.40 (1 H, d), 8.50 (1H, d), 12.05 (TFA/voda/1H).d), 7.25 (2H, d), 7.92 (3H, m), 8.05 (1H, t), 8.33 (2H, d), 8.40 (1H, d), 8.50 (1H, d), 12.05 (TFA) / water / 1 H).
iand
Príklad 89Example 89
2-Fluór-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ (a) 2,6-Difluór-/V-(2-hydroxy-1,1-dimetyletyl)benzamid2-Fluoro-3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt of (a) 2,6-Difluoro- / V- (2-hydroxy-1,1-dimethyl-ethyl) -benzamide
Roztok 2,6-difluórbenzoylchloridu (20 g) v suchom dichlórmetáne (100 ml) sa pridal po kvapkách do ľadom chladeného roztoku 2-amino-2-metylpropanolu (20,2 g) v suchom dichlórmetáne (150 ml) pod dusíkovou atmosférou, pričom teplota sa udržiavala pod 5 °C. Po skončení pridávania sa ľadový kúpeľ odstránil a miešanie pokračovalo ďalších 16 hodín pri laboratórnej teplote. Organická fáza sa zriedila vodou a oddelila. Vodná fáza sa potom extrahovala dichlórmetánom (dvakrát). Spojená organická fáza sa premyla soľankou, vysušila nad síranom sodným, prefiltrovala a odparila. Rozotrením s hexánom sa získala titulná zlúčenina (24,65 g).A solution of 2,6-difluorobenzoyl chloride (20 g) in dry dichloromethane (100 mL) was added dropwise to an ice-cooled solution of 2-amino-2-methylpropanol (20.2 g) in dry dichloromethane (150 mL) under nitrogen. the temperature was kept below 5 ° C. After the addition was complete, the ice bath was removed and stirring was continued for another 16 hours at room temperature. The organic phase was diluted with water and separated. The aqueous phase was then extracted with dichloromethane (twice). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. Trituration with hexane gave the title compound (24.65 g).
MS (APCI) 230 ((M + H)+) 1H NMR (CDCIa) δ 1.41 (6H, s), 3.70 (2H, d), 3.95 (1H, t), 6.00 (1 H, br s), 6:95 (2H, m), 7.38 (i H, m). , (b) 2-(2,6-Difluórfenyl)-4,5-dihydro-4,4-dimetyloxazolMS (APCI) 230 ((M + H) + ) 1 H NMR (CDCl 3) δ 1.41 (6H, s), 3.70 (2H, d), 3.95 (1H, t), 6.00 (1H, br s), 6:95 (2H, m); 7.38 (1H, m). (b) 2- (2,6-Difluorophenyl) -4,5-dihydro-4,4-dimethyloxazole
Tionylchlorid (12,6 ml) sa pridal po kvapkách do ľadom chladeného roztokuThionyl chloride (12.6 mL) was added dropwise to an ice-cooled solution
2,6-difluór-A/-(2-hydroxy-1,1-dimetyletyl)benzamidu (24,65 g) v suchom dichlórmetáne (100 ml) pod dusíkovou atmosférou. Po pridávaní sa ľadový kúpeľ odstránil a miešanie pokračovalo 1 hodinu pri laboratórnej teplote. Rozpúšťadlo sa potom odparilo a zvyšok sa rozotrel s dietyléterom. Získaná tuhá látka sa rozpustila v minimálnom množstve vody (80 ml) a pH sa upravilo na bázické pomocou tabliet hydroxidu sodného. Bázická fáza sa potom extrahovala etylacetátom (trikrát). Organické extrakty sa spojili a potom premyli soľankou, vysušili nad síranom sodným, prefiltrovali a odparili. Získaný olej sa vyčistil stĺpcovou chromatografiou (hexán a etylacetát 4:1), čím sa získala titulná zlúčenina (20,86 g).2,6-Difluoro-N- (2-hydroxy-1,1-dimethylethyl) benzamide (24.65 g) in dry dichloromethane (100 mL) under a nitrogen atmosphere. After the addition, the ice bath was removed and stirring was continued for 1 hour at room temperature. The solvent was then evaporated and the residue was triturated with diethyl ether. The solid obtained was dissolved in a minimum amount of water (80 ml) and the pH was adjusted to basic with sodium hydroxide tablets. The basic phase was then extracted with ethyl acetate (three times). The organic extracts were combined and then washed with brine, dried over sodium sulfate, filtered and evaporated. The obtained oil was purified by column chromatography (hexane and ethyl acetate 4: 1) to give the title compound (20.86 g).
I II I
MS (El) 211 (M+) 1H NMR (CDCI3) δ 1.42 (6H, s), 4.14 (2H, s), 6.95 (2H, m), 7.40 (1 H, m).MS (EI) 211 (M + ) 1 H NMR (CDCl 3 ) δ 1.42 (6H, s), 4.14 (2H, s), 6.95 (2H, m), 7.40 (1H, m).
(c) 4,5-Dihydro-2-(2-fluór-6-metylfenyl)-4,4-dimetyloxazol(c) 4,5-Dihydro-2- (2-fluoro-6-methylphenyl) -4,4-dimethyloxazole
M roztok metylmagnézium chloridu v tetrahydrofuráne (86 ml) sa pridal po kvapkách do roztoku 2-(2,6-difluórfenyl)-4,5-dihydro-4,4-dimetyloxazolu (18,23 g) v suchom tetrahydrofuráne (60 ml) pri 0 °C pod dusíkovou atmosférou. Roztok sa miešal pri 0 °C hodinu a potom sa nechal ohriať na laboratórnu teplotu v priebehu 16 hodín. Do reakčnej zmesi sa opatrne pridal nasýtený roztok chloridu amónneho. Zmes sa potom extrahovala etylacetátom (trikrát). Organické extrakty sa premyli soľankou, vysušili nad síranom sodným, prefiltrovali a odparili, čím sa získala titulná zlúčenina ako svetložltý olej (18,18 g).A solution of methylmagnesium chloride in tetrahydrofuran (86 mL) was added dropwise to a solution of 2- (2,6-difluorophenyl) -4,5-dihydro-4,4-dimethyloxazole (18.23 g) in dry tetrahydrofuran (60 mL). at 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for one hour and then allowed to warm to room temperature over 16 hours. Saturated ammonium chloride solution was carefully added to the reaction mixture. The mixture was then extracted with ethyl acetate (three times). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound as a pale yellow oil (18.18 g).
MS (APCI) 208 ((M + H)+ 1H NMR (CDCI3) δ 1.42 (6H, s), 2.40 (3H, s), 4.12 (2H, s), 6.93 (1H, t), 7.00 (1H, d), 7.26 (1H, m).MS (APCI) 208 ((M + H) + 1 H NMR (CDCl 3 ) δ 1.42 (6H, s), 2.40 (3H, s), 4.12 (2H, s), 6.93 (1 H, t), 7.00 ( 1 H, d), 7.26 (1 H, m).
(d) Kyselina 2-fluór-6-metylbenzoová(d) 2-Fluoro-6-methylbenzoic acid
4,5-Dihydro-2-(2-fluór-6-metylfenyl)-4,4-dimetyloxazol (18,18 g) a nadbytok jódmetánu (20 ml) sa zahrievali na reflux v acetonitrile (150 ml) počas 4 hodín a potom sa nechali vychladnúť na laboratórnu teplotu. Rozpúšťadlo sa odparilo a tuhý zvyšok sa rozotrel s dietyléterom. Získaná tuhá látka sa potom rozpustila v zmesi metanolu (80 ml) a 10 % roztoku hydroxidu sodného (80 ml) a zahrievala sa na reflux 4 hodiny. Reakčná zmes sa nechala ochladiť na teplotu miestnosti a potom sa metanol odparil. Vodné zvyšky sa premyli etylacetátom (trikrát) a potom sa okyslili zriedenou kyselinou chlorovodíkovou na pH 1. Kyslá fáza sa extrahovala etylacetátom (trikrát). Organické extrakty sa premyli soľankou, vysušili nad síranom sodným, prefiltrovali a odparili, čím sa získala kyselina 2-fluór-6-metylbenzoová (10,85 g). Vzorka (0,27 g) sa rekryštalizovala zo zmesi hexánu a etylacetátu 4:1, čím sa získala titulná zlúčenina (0,15 g). T. t. 123 -124 °C.4,5-Dihydro-2- (2-fluoro-6-methylphenyl) -4,4-dimethyloxazole (18.18 g) and excess iodomethane (20 mL) were heated to reflux in acetonitrile (150 mL) for 4 hours and then allowed to cool to room temperature. The solvent was evaporated and the solid residue was triturated with diethyl ether. The solid obtained was then dissolved in a mixture of methanol (80 ml) and 10% sodium hydroxide solution (80 ml) and heated at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and then the methanol was evaporated. The aqueous residues were washed with ethyl acetate (three times) and then acidified with dilute hydrochloric acid to pH 1. The acidic phase was extracted with ethyl acetate (three times). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give 2-fluoro-6-methylbenzoic acid (10.85 g). A sample (0.27 g) was recrystallized from 4: 1 hexane: ethyl acetate to give the title compound (0.15 g). T. t. Mp 123-124 ° C.
MS (El) 154 (M+) 1H NMR (CDCI3) δ 2.52 (3H, s), 7.02 (2H, m), 7.35 (1H, m).MS (EI) 154 (M + ) 1 H NMR (CDCl 3 ) δ 2.52 (3H, s), 7.02 (2H, m), 7.35 (1H, m).
(e) Metyl 2-fluór-6-metylbenzoát(e) Methyl 2-fluoro-6-methylbenzoate
Uhličitan cézny (16 g) a jódmetán (4,6 ml) sa pridali do miešaného roztoku kyseliny 2-fluór-6-metylbenzoovej (3,78 g) v suchom dimetylformamide (25 ml), pod dusíkovou atmosférou. Miešanie pokračovalo pri teplote miestnosti počas 16 hodín a potom sa reakčná zmes zriedila vodou a extrahovala etylacetátom (trikrát). Organická fáza sa postupne premyla zriedenou kyselinou chlorovodíkovou, nasýteným roztokom hydrogenuhličitanu sodného a soľankou, vysušila sa nad síranom sodným, prefiltrovala a odparila, čím sa získala titulná zlúčenina ako žltý olej (4,07 g).Cesium carbonate (16 g) and iodomethane (4.6 mL) were added to a stirred solution of 2-fluoro-6-methylbenzoic acid (3.78 g) in dry dimethylformamide (25 mL), under a nitrogen atmosphere. Stirring was continued at room temperature for 16 hours and then the reaction mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (4.07 g).
MS (El) 168 (M+) ' ·. , 1H NMR (CDCI3) δ 2.40 (3H, s), 3.94 (3H, s), 6.94 (1H, t), 7.01 (1H, d), 7.30 (1H, m).MS (EI) 168 (M < + > ). , 1H NMR (CDCl3) δ 2:40 (3H, s), 3.94 (3H, s), 6.94 (1H, t), 1.7 (1 H, d), 7.30 (1 H, m).
(f) Metyl 2-(brómmetyl)-6-fluórbenzoát(f) Methyl 2- (bromomethyl) -6-fluorobenzoate
Suspenzia metyl 2-fluór-6-metylbenzoátu (35,53 g), N-brómsukcínimidu (37,6 g) a azobis(izobutyronitrilu) (2 g) v suchom dichlórmetáne (150 ml) sa ožarovala (100 W halogénová lampa) pod dusíkovou atmosférou 4 hodiny. ZískanýA suspension of methyl 2-fluoro-6-methylbenzoate (35.53 g), N-bromosuccinimide (37.6 g) and azobis (isobutyronitrile) (2 g) in dry dichloromethane (150 mL) was irradiated (100 W halogen lamp) under nitrogen atmosphere for 4 hours. acquired
-51 roztok sa vylial do 10% roztoku hydroxidu sodného a extrahoval sa dichlórmetánom (trikrát). Organická fáza sa premyla soľankou, vysušila sa nad síranom sodným, prefiltrovala a odparila, čím sa získala zmes titulnej zlúčeniny a východiskovej látky (52,33 g) ako žltý olej.The 5151 solution was poured into 10% sodium hydroxide solution and extracted with dichloromethane (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give a mixture of the title compound and the starting material (52.33 g) as a yellow oil.
MS (EI) 246/248 (M+) , ’H NMR (CDCI3) δ 3.99 (3H, s), 4.66 (2H, s), 7.06 (1H, t), 7.23 (1H, d), 7.40 (1H, m).MS (EI) 246/248 (M + ), 1 H NMR (CDCl 3 ) δ 3.99 (3H, s), 4.66 (2H, s), 7.06 (1 H, t), 7.23 (1 H, d), 7.40 ( 1 H, m).
(g) Metyl 2-fluór-6-{[(2-metoxy-2-oxoetyl)-(4-metoxyfenylmetyl)amino]metyl}benzoát(g) Methyl 2-fluoro-6 - {[(2-methoxy-2-oxoethyl) - (4-methoxyphenylmethyl) amino] methyl} benzoate
Metylester A/-(4-metoxyfenylmetyl)glycínu (10,2 g) sa pridal po kvapkách do miešaného roztoku metyl 2-(brómmetyl)-6-fluórbenzoátu (11 g) a trietylamínu (6,8 ml) v suchom dietyléteri (50 ml). Zmes sa zahrievala na reflux v dusíkovej atmosfére 16 hodín. Reakčná zmes sa nechala ochladiť a potom sa zriedila vodou a extrahovala etylacetátom (trikrát). Organická fáza sa premyla soľankou, vysušila nad síranom sodným, prefiltrovala a odparila. Zvyšok sa vyčistil stĺpcovou chromatografiou (hexán a etylacetát 20 : 1), čím sa získala titulná zlúčenina ako bezfarebný olej (8,82 g).N- (4-methoxyphenylmethyl) glycine methyl ester (10.2 g) was added dropwise to a stirred solution of methyl 2- (bromomethyl) -6-fluorobenzoate (11 g) and triethylamine (6.8 mL) in dry diethyl ether (50 mL). ml). The mixture was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool and then diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (hexane and ethyl acetate 20: 1) to give the title compound as a colorless oil (8.82 g).
MS (APCI) 376 ((M + H)+) 1H NMR (CDCIa): δ 3.21 (2H, s), 3.67 (3H, s), 3.68 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.01 (2H, s), 6.82 (2H, d), 7.05 (1H, t), 7.18 (3H, m), 7.35 (1 H, m).MS (APCI) 376 ((M + H) + ) 1 H NMR (CDCl 3): δ 3.21 (2H, s), 3.67 (3H, s), 3.68 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.01 (2 H, s), 6.82 (2 H, d), 7.05 (1 H, t), 7.18 (3 H, m), 7.35 (1 H, m).
(h) Metyl 5-f luór-1,2,3,4-tetrahydro-2-(4-metoxyfenylmetyl)-4-oxo-3- izochinolínkarboxylát(h) Methyl 5-fluoro-1,2,3,4-tetrahydro-2- (4-methoxyphenylmethyl) -4-oxo-3-isoquinolinecarboxylate
Roztok metyl 2-fluór-6-[[(2-metoxy-2-oxoetyl)-(4-metoxyfenylmetyl)amino]metyl}benzoátu (8,82 g) v suchom toluéne (50 ml) sa pridal po kvapkách do suspenzie hydridu sodného (1,32 g 60% disperzie zbavenej oleja) a tercbutylalkoholu (1 ml) v suchom toluéne (100 ml) zahrievanej na reflux v dusíkovej atmosfére. Zahrievanie pokračovalo ďalších 12 hodín a potom sa reakčná zmes nechala vychladnúť na laboratórnu teplotu. Zmes sa vyliala doA solution of methyl 2-fluoro-6 - [[(2-methoxy-2-oxoethyl) - (4-methoxyphenylmethyl) amino] methyl} benzoate (8.82 g) in dry toluene (50 mL) was added dropwise to the hydride suspension. sodium (1.32 g of a 60% de-oiled dispersion) and tert-butyl alcohol (1 mL) in dry toluene (100 mL) heated to reflux under a nitrogen atmosphere. Heating was continued for a further 12 hours and then the reaction mixture was allowed to cool to room temperature. The mixture was poured into
-52nasýteného vodného roztoku chloridu amónneho a extrahovala sa etylacetátom (trikrát). Organická fáza sa premyla soľankou, vysušila nad síranom sodným, odfiltrovala a odparila, čím sa získala titulná zlúčenina (7,96 g). MS (APCI) 344 (M+H)+).Saturated aqueous ammonium chloride solution and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (7.96 g). MS (APCI) 344 (M + H) < + > ).
! 1H NMR (CDCI3): δ 3.60 (2H, s), 3.81 (3H, s), 3.89 (2H, s), 3.92 (3H, s), 6.86 (3H, m), 7.05 (1 H, m), 7.22 (2H, m), 7.38 (1 H, m), 11.83 (1 H, s). ! 1 H NMR (CDCl 3 ): δ 3.60 (2H, s), 3.81 (3H, s), 3.89 (2H, s), 3.92 (3H, s), 6.86 (3H, m), 7.05 (1H, m) 7.22 (2H, m), 7.38 (1H, m), 11.83 (1H, s).
(i) 9-Fluór-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2/-/pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ(i) 9-Fluoro-3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
Metyl 5-fluór-1,2,3,4-tetrahydro-2-(4-metoxyfenylmetyl)-4-oxo-3-izochinolínkarboxylát (1,0 g), 4-trifluórmetylfenylhydrazín (1,03 g) a kyselina p-toluénsulfónová (20 mg) sa spolu tavili pri 150 °C pod dusíkovou atmosférou 15 minút. Pridal sa xylén (20 ml) a zahrievanie pokračovalo ďalšie 2 hodiny. Po ochladení na teplotu miestnosti sa rozpúšťadlo odparilo a tuhý zvyšok sa vyčistil stĺpcovou chromatografiou (dichlórmetán a metanol 99 : 1), čím sa získala titulná zlúčenina vo forme fialových ihličiek (0,425 g).Methyl 5-fluoro-1,2,3,4-tetrahydro-2- (4-methoxyphenylmethyl) -4-oxo-3-isoquinolinecarboxylate (1.0 g), 4-trifluoromethylphenylhydrazine (1.03 g) and p- toluenesulfonic acid (20 mg) was melted together at 150 ° C under a nitrogen atmosphere for 15 minutes. Xylene (20 mL) was added and heating was continued for another 2 hours. After cooling to room temperature, the solvent was evaporated and the solid residue was purified by column chromatography (dichloromethane and methanol 99: 1) to give the title compound as purple needles (0.425 g).
MS (APCI) 468 ((M + H)+) 1H NMR (d6-DMSO) δ 3.72 (3H, s), 6.10 (2H, s), 6.69 (2H, d), 7.70 (2H, d),MS (APCI) 468 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 3.72 (3H, s), 6.10 (2H, s), 6.69 (2H, d), 7.70 (2H, d) .
7.80 (4H, m), 8.00 (1 H, dd), 8.59 (2H, d), 8.98 (1H, s).7.80 (4H, m); 8.00 (1H, dd); 8.59 (2H, d); 8.98 (1H, s).
Príklad 90Example 90
9-Fluór-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolín-3-ol9-Fluoro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
9-Fluór-3-hydroxy-4-[(4-metoxyfenyl)metyl]-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxid, vnútorná soľ (0,43 g), sa rozpustila v kyseline trifluóroctovej (5 ml) a zahrievala sa na reflux v dusíkovej atmosfére počas 16 hodín. Po ochladení na laboratórnu teplotu sa rozpúšťadlo odparilo a zvyšok sa odparil spolu s toluénom (trikrát). Zvyšok sa postupne rozotrel s metanolom a9-Fluoro-3-hydroxy-4 - [(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.43 g), dissolved in trifluoroacetic acid (5 mL) and heated to reflux under nitrogen for 16 hours. After cooling to room temperature, the solvent was evaporated and the residue was co-evaporated with toluene (three times). The residue was successively triturated with methanol and
-53potom s dietyléterom a nakoniec sa rekryštalizoval z etylacetátu, čím sa získala titulná zlúčenina ako červená tuhá látka (0,08 g). T. t. > 250 °C.It was recrystallized from ethyl acetate to give the title compound as a red solid (0.08 g). T. t. ≫ 250 ° C.
MS (APCI) 348 ((M + H)+) 1H NMR (d6-DMSO) δ 7.86 (2H, m), 7.95 (2H, d), 8.14 (1 H, d), 8.24 (2H, br d), 9.09(1 H, br d), 11.85 (1H, br s).MS (APCI) 348 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.86 (2H, m), 7.95 (2H, d), 8.14 (1H, d), 8.24 (2H, br) d), 9.09 (1H, br d), 11.85 (1H, br s).
Nasledujúce zlúčeniny boli pripravené analogicky ako v príklade 90:The following compounds were prepared analogously to Example 90:
Nasledujúce zlúčeniny (príklady 98 - 100) boli pripravené podľa postupov z príkladu 2:The following compounds (Examples 98-100) were prepared according to the procedures of Example 2:
Nasledujúce zlúčeniny boli pripravené podľa postupov z príkladu 69:The following compounds were prepared according to the procedures of Example 69:
Nasledujúce zlúčeniny boli pripravené podľa postupov z príkladu 2:The following compounds were prepared according to the procedures of Example 2:
Príklad 105Example 105
2,4-Dihydro-3-hydroxy-4-metyl-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethyl-phenyl) -5 H -pyrazolo [4,3-
c]izochinolín-5-tiónc] isoquinoline-5-thione
Roztok 2,4-dihydro-3-hydroxy-4-metyl-2-(4-trifluórmetylfenyl)-5H-pyrazolo[4,3-c]izochinolín-5-ónu (príklad 63) (0,25 g) a Lawessonovho činidla (0,7 g) v dioxáne (20 ml) sa miešal a zahrieval na reflux počas 18 hodín. Získaná zmes sa ochladila a adsorbovala na silikagél. Čistením chromatografiou (metanolA solution of 2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (Example 63) (0.25 g) and Lawesson's of reagent (0.7 g) in dioxane (20 mL) was stirred and heated to reflux for 18 hours. The resulting mixture was cooled and adsorbed onto silica gel. Purification by chromatography (methanol
-56s dichlórmetánom 1 : 99 - 3 : 97) sa získala titulná zlúčenina, ktorá vykryštalizovala z etanolu na žlté kryštály (0,075 g). T. t. 255 - 259 °C.-56 with dichloromethane 1: 99 - 3: 97) gave the title compound, which crystallized from ethanol to yellow crystals (0.075 g). T. t. 255-259 ° C.
MS (APCI) 376 ((M + H)+) 1H NMR (D2O/NaOD),ô 8.47 (1H, d), 7.71 (2H, d), 7.60 (3H, m), 7.34 (1H, t), 7.22(1 H, t), 4.08 (3H, s).MS (APCI) 376 ((M + H) + ) 1 H NMR (D 2 O / NaOD), δ 8.47 (1H, d), 7.71 (2H, d), 7.60 (3H, m), 7.34 (1H, t), 7.22 (1H, t), 4.08 (3H, s).
Príklad 106Example 106
3-Hydroxy-4-metyl-5-metyltio-2-(4-trifluórmetylfenyl)-2/7-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ3-Hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2,7-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt
Roztok 2,4-dihydro-3-hydroxy-4-metyl-2-(4-trifluórmetylfenyl)-5/7-pyrazolo[4,3-c]izochinolín-5-tiónu (0,46 g) (príklad 105) a jódmetánu (0,095 ml) v acetóne (50 ml) sa miešal a zahrieval na reflux počas 4 hodín. Pridal sa uhličitan draselný (0,170 g) a zmes sa zahrievala na reflux ďalšie 2 hodiny. Zmes sa nakoncentrovala vo vákuu. Čistením zvyšku chromatografiou (metanol s dichlórmetánom 2 : 98) sa získala titulná zlúčenina ako fialová tuhá látka (0,375 g).A solution of 2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5,7-pyrazolo [4,3-c] isoquinoline-5-thione (0.46 g) (Example 105) and iodomethane (0.095 mL) in acetone (50 mL) was stirred and heated to reflux for 4 hours. Potassium carbonate (0.170 g) was added and the mixture was heated at reflux for an additional 2 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol with dichloromethane 2: 98) gave the title compound as a violet solid (0.375 g).
MS (APCI) 390 ((M + H)+) 1H NMR (CDCh) δ 8.54 (4H, m), 7.86 (1H, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 (3H, s).MS (APCI) 390 ((M + H) + ) 1 H NMR (CDCl 3) δ 8.54 (4H, m), 7.86 (1H, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 ( 3H, s).
Príklad 107 l ,Example 107 l,
2- (4-Trifluórmetylfenyl)-2,4-dihydro-5-imino-4-metyl-5/-/-pyrazolo[4,3-c]izochinolín-2- (4-Trifluoromethylphenyl) -2,4-dihydro-5-imino-4-methyl-5 H -pyrazolo [4,3- c] isoquinoline-
3- ol3- ol
Suspenzia 3-hydroxy-4-metyl-5-metyltio-2-(4-trifluórmetylfenyl)-2/7-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,013 g) (príklad 106) v etanole (7 ml) a roztoku amoniaku (merná hmotnosť 0,880; 15 ml) sa miešala pri 20 °C počas 24 hodín. Zmes sa zriedila vodou a extrahovala sa etylacetátom. OrganickáA suspension of 3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2,7-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.013 g) (Example 106) in ethanol (7). ml) and ammonia solution (specific gravity 0.880; 15 ml) were stirred at 20 ° C for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. organic
-57fáza sa premyla soľankou, vysušila nad síranom horečnatým a nakoncentrovala vo vákuu. Čistením zvyšku chromatografiou (metanol s dichlórmetánom 5 : 95 - 10 : 90) sa získala titulná zlúčenina ako oranžová tuhá látka (0,043 g). T. t. 253 255 °CThe 5757 phase was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by chromatography (methanol with dichloromethane 5: 95 - 10: 90) gave the title compound as an orange solid (0.043 g). T. t. 253 255 ° C
MS (APCI) 717 ((2M + H)+), 359 ((M + H)+) 1H NMR (d6-DMSO) δ 8.60 (2H, d), 8.46 (1H, d), 8.29 (3H, m), 7.90 (1H, t),MS (APCI) 717 ((2M + H) + ), 359 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 8.60 (2H, d), 8.46 (1H, d), 8.29 (3H) m) 7.90 (1 H, t),
7.71 (3H, m), 4.19 (3H, s).7.71 (3 H, m), 4.19 (3 H, s).
Príklad 108Example 108
3-Hydroxy-4-(4-metoxyfenyl)metyl-2-(4-trifluórmtylfenyl)-2/-/-pyrazolo[3,4-f][1,7]nafthydrínium hydroxid, vnútorná soľ (a) Metyl 2-(brómmetyl)nikotinát3-Hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2 H -pyrazolo [3,4- f] [1,7] naphthydrinium hydroxide, inner salt (a) Methyl 2- (bromomethyl) nicotinate
Metyl 2-metylnikotinát (10,0 g) a /V-brómsukcínimid (14,9 g) sa zmiešali v 1,2-dichlóretáne (80 ml). Pridala sa kyselina octová (3,8 ml) a potom 2,2’azobis(2-metylpropionitril) (1,0 g) a zmes sa zahrievala na reflux, pričom sa ožarovala 500 W lampou. Po 2 hodinách sa reakčná zmes nechala vychladnúť a potom sa vyliala na roztok hydrogenuhličitanu sodného. Organická fáza sa oddelila a premyla dvakrát soľankou, potom sa vysušila, prefiltrovala a odparila, čím sa získal olej (18,2 g), ktorý sa bezprostredne použil v nasledujúcom kroku.Methyl 2-methylnicotinate (10.0 g) and N -bromosuccinimide (14.9 g) were mixed in 1,2-dichloroethane (80 mL). Acetic acid (3.8 mL) was added followed by 2,2'azobis (2-methylpropionitrile) (1.0 g) and the mixture was heated to reflux while irradiated with a 500 W lamp. After 2 hours, the reaction mixture was allowed to cool and then poured onto sodium bicarbonate solution. The organic phase was separated and washed twice with brine, then dried, filtered and evaporated to give an oil (18.2 g) which was used immediately in the next step.
(b) Metylester /V-[(4-metoxyfenyl)metyl]-/V-[(3-metoxykarbonyl-2-pyridyl)metyl]glycín(b) N - [(4-Methoxyphenyl) methyl] - N - [(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester
Pripravený podľa spôsobu z príkladu 1, stupeň (a) s použitím metyl 2(brómmetyl)nikotinátu (9,10 g), metyl /V-(4-metoxyfenyl)metylglycínu (10,2 g) a trietylamínu (5,5 ml) v dietyléteri (100 ml), čím sa získala titulná zlúčenina (3,20 g).Prepared according to the method of example 1, step (a) using methyl 2 (bromomethyl) nicotinate (9.10 g), methyl N- (4-methoxyphenyl) methylglycine (10.2 g) and triethylamine (5.5 ml) in diethyl ether (100 mL) to give the title compound (3.20 g).
MS (DESC SI) 358 (M+)MS (DESC SI) 358 (M < + > )
-581H NMR (d6-DMSO) 3.17 (s, 2H), 3.34 (s, 3H), 3.58 (s, 2H), 3.71 (s, 3H), 3.82 (s, 3H), 4.23 (s, 2H), 6.82 (d, 2H), 7.04 (d, 2H), 7.43 (dd, 1H), 8.03 (dd, 1H), 8.61 (dd, 1H).-58 1 H NMR (d 6 -DMSO) 3.17 (s, 2H), 3:34 (s, 3H), 3:58 (s, 2H), 3.71 (s, 3H), 3.82 (s, 3H), 4.23 (s, 2H), 6.82 (d, 2H), 7.04 (d, 2H), 7.43 (dd, 1 H), 8.03 (dd, 1 H), 8.61 (dd, 1 H).
(c) Metyl 7,8-dihydro-5'-hydroxy-7-(4-metoxyfenyl)metyl[1,7]naftyridín-6-karboxylát(c) Methyl 7,8-dihydro-5'-hydroxy-7- (4-methoxyphenyl) methyl [1,7] naphthyridine-6-carboxylate
Pripravený podľa spôsobu z príkladu 1, krok (b), s použitím metylesteru Λ/[(4-metoxyfenyl)metyl]-A/-[(3-metoxykarbonyl-2-pyridyl)metyl]glycínu (1,00 g), hydridu sodného (60% disperzia v oleji) (160 mg), 2-metylpropán-2-olu (0,10 ml) a toluénu (15 ml), čím sa získala titulná zlúčenina (790 mg).Prepared according to the method of example 1, step (b), using N / [(4-methoxyphenyl) methyl] - N - [(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester (1.00 g) hydride sodium (60% dispersion in oil) (160 mg), 2-methylpropan-2-ol (0.10 mL) and toluene (15 mL) to give the title compound (790 mg).
MS (APCI) 327 ((M + H)+) 1H NMR (d6-DMSO) 3.65 až 3.97 (m, 10H), 6.79 (m, 2H), 7.11 až 7.39 (m, 3H), 7.86 až 8.25 (m, 1 H), 8.52 až 8.75 (m, 1 H), 11.25 (s, 1 H).MS (APCI) 327 ((M + H) + ) 1 H NMR (d 6 -DMSO) 3.65-3.97 (m, 10H), 6.79 (m, 2H), 7.11-7.39 (m, 3H), 7.86-8.25 (m, 1H), 8.52-8.75 (m, 1H), 11.25 (s, 1H).
(d) 3-Hydroxy-4-(4-metoxyfenyl)metyl-2-(4-trifluórmetylfenyl)-2A/-pyrazolo[3,4/][1,7]nafthydrínium hydroxid, vnútorná soľ(d) 3-Hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4 /] [1,7] naphthyrdrinium hydroxide, inner salt
Pripravený podľa spôsobu z príkladu 1, krok (c), s použitím metyl 7,8-dihydro-5-hydroxy-7-(4-metoxyfenyl)metyl-1,7-nafthydrín-6-karboxylátu (200 mg), 4trifluórmetylfenylhydrazínu (1,00 g) a etanolu (3 ml), čím sa získala titulná zlúčenina (21 mg). T. t. 201 - 203 °C.Prepared according to the method of example 1, step (c), using methyl 7,8-dihydro-5-hydroxy-7- (4-methoxyphenyl) methyl-1,7-naphthyridine-6-carboxylate (200 mg), 4-trifluoromethylphenylhydrazine ( 1.00 g) and ethanol (3 mL) to give the title compound (21 mg). T. t. Mp 201-203 ° C.
MS (APCI) 451 ((M + H)+) 1H NMR (de-DMSO) 3.72 (s, 3H), 6.13 (s, 2H), 6.96 (d, 2H), 7.76 (d, 2H),MS (APCI) 451 ((M + H) + ) 1 H NMR (d 6 -DMSO) 3.72 (s, 3H), 6.13 (s, 2H), 6.96 (d, 2H), 7.76 (d, 2H),
7.84 (d, 2H), 7.88 (dd, 1H), 8.59 (d, 2H), 8.72 (dd, 1H), 9.00 (s, 1H), 9.05 (dd, 1H).7.84 (d, 2H), 7.88 (dd, 1 H), 8.59 (d, 2 H), 8.72 (dd, 1 H), 9.00 (s, 1 H), 9.05 (dd, 1 H).
-59Príklad 109Example 59
2-(4-Trifluórmetylfenyl)-2H-pyrazolo[3,4-/][1,7]nafthydrín-3-ol2- (4-trifluoromethylphenyl) -2 H pyrazolo [3,4 - /] [1,7] naphthyridine-3-ol
Pripravený podľa spôsobu z príkladu 2 s použitím 3-hydroxy-4-(4metoxyfenyl)metyl-2-(4-trifluórmetylfenyl)-2H-pyrazolo[3,4-/][1,7]nafthydrínium hydroxidu, vnútornej soli (135 mg) a kyseliny trifluóroctovej (5 ml), čím sa získala titulná zlúčenina (19 mg). T. t. 239 - 241 °C (rozkl.).Prepared according to the method of example 2 using 3-hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4- f] [1,7] naphthyrdrinium hydroxide, inner salt (135 mg) ) and trifluoroacetic acid (5 mL) to give the title compound (19 mg). T. t. Mp 239-241 ° C (dec.).
MS (APCI) 331 ((M + H)+) 1H NMR (d6-DMSO) 7.94 (d, 2H), 7.95 (m, 1H), 8.28 (d, 2H), 8.74 (d, 1H), 9.01 (br, 1 H), 9.16 (s, 1H).MS (APCI) 331 ((M + H) + ) 1 H NMR (d 6 -DMSO) 7.94 (d, 2H), 7.95 (m, 1H), 8.28 (d, 2H), 8.74 (d, 1H), 9.01 (br. 1H), 9.16 (s, 1H).
Nasledujúce zlúčeniny boli pripravené analogicky podľa príkladu 109 s použitím metyl 2-(brómmetyl)nikotinátu, metylésteru sarkozínu a príslušného hydrazínu:The following compounds were prepared analogously to Example 109 using methyl 2- (bromomethyl) nicotinate, sarcosine methyl ether and the corresponding hydrazine:
-60Príklad 112-60Example 112
3-Hydroxy-4-metyl-5-(dimetylamino)-2-(4-trifluórmetylfenyl)-2/-/-pyražolo[4,3cjizochinolínium hydroxid, vnútorná soľ3-Hydroxy-4-methyl-5- (dimethylamino) -2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
Roztok 3-hydroxy-4-metyl-5-metyltio-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,39 g) (príklad 106), v acetóne (10 ml) a 40 % vodného roztoku dimetylamínu (2 ml) sa miešal pri 20 °C počas 24 hodín. Zmes sa nakoncentrovala vo vákuu. Čistením zvyšku chromatografiou (metanol a dichlórmetán, 1 : 99 - 2,5 : 97,5) sa získala titulná zlúčenina ako červená tuhá látka (0,129 g). T. t. 256 - 259 °C.A solution of 3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.39 g) (Example 106), in acetone ( 10 ml) and 40% aqueous dimethylamine solution (2 ml) were stirred at 20 ° C for 24 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol and dichloromethane, 1: 99-2.5: 97.5) gave the title compound as a red solid (0.129 g). T. t. 256-259 ° C.
MS (APCI) 387 ((M + H)+) 1H NMR (CDCIs) δ 3.19 (6H, s), 4.52 (3H, s), 7.64 (3H, m), 7.84 (1H, td), 7.95(1 H, d), 8.54 (3H, d).MS (APCI) 387 ((M + H) + ) 1 H NMR (CDCl 3) δ 3.19 (6H, s), 4.52 (3H, s), 7.64 (3H, m), 7.84 (1H, td), 7.95 ( 1 H, d), 8.54 (3 H, d).
Príklad 113Example 113
3-Hydroxy-4-metyl-5-morfolinyl-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ3-Hydroxy-4-methyl-5-morpholinyl-2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
Roztok 3-hydroxy-4-metyl-5-metyltio-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,520 g) (príklad 106), v suchom tetrahydrofuráne (7 ml) a morfolínu (2,3 ml) sa zahrieva! na 70 °C počas 12 hodín a potom na 95 °C počas 2 hodín. Zmes sa nakoncentrovala vo vákuu. Čistením zvyšku chromatografiou (metanol a dichlórmetán, 5 : 95) sa získala titulná zlúčenina ako Červená tuhá látka (0,165 g). T. t. 278 - 281 °C.A solution of 3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.520 g) (Example 106), in dry tetrahydrofuran (7 ml) and morpholine (2.3 ml) are heated! at 70 ° C for 12 hours and then at 95 ° C for 2 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol and dichloromethane, 5:95) gave the title compound as a red solid (0.165 g). T. t. Mp 278-281 ° C.
MS (APCI) 429 ((M + H)+) 1H NMR (d6-DMSO) δ 3.49 (4H, m), 3.87 (4H, m), 4.49 (3H, s), 7.77 (2H, m), 7.94 (1 H, t), 8.28 (1H, d), 8.38 (1H, d), 8.59 (2H, d).MS (APCI) 429 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 3.49 (4H, m), 3.87 (4H, m), 4.49 (3H, s), 7.77 (2H, m) 7.94 (1H, t), 8.28 (1 H, d), 8.38 (1 H, d), 8.59 (2 H, d).
-61 Príklad 114-61 Example 114
3-Hydroxy-4-metyl-5-piperazinyl-2-(4-trifluórmetylfenyl)-2/-/-pyrazolo[4,3cjizochinolínium hydroxid, vnútorná soľ3-Hydroxy-4-methyl-5-piperazinyl-2- (4-trifluoromethylphenyl) -2 H -pyrazolo [4,3- c] isoquinolinium hydroxide, inner salt
I 'I '
Roztok 3-hydroxy-4-metyl-5-metyltio-2-(4-trifluórmetylfenyl)-2H-pyrazolo[4,3-c]izochinolínium hydroxidu, vnútornej soli (0,29 g) (príklad 106), v toluéne (20 ml) sa pridal po kvapkách do miešaného roztoku piperazínu (1,28 g) v toluéne (50. ml) zahrievaného na 110 °C. Získaný roztok sa miešal pri 110 °C 6 hodín a potom pri teplote miestnosti 16 hodín. Zmes sa nakoncentrovala vo vákuu. Čistením zvyšku chromatografiou (metanol a dichlórmetán, 5 : 95 - 10 : 90) s následnou kryštalizáciou z etanolu sa získala titulná zlúčenina ako červená tuhá látka (0,107 g). T. t. 260 - 262 °C.A solution of 3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner salt (0.29 g) (Example 106), in toluene ( 20 mL) was added dropwise to a stirred solution of piperazine (1.28 g) in toluene (50 mL) heated to 110 ° C. The resulting solution was stirred at 110 ° C for 6 hours and then at room temperature for 16 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol and dichloromethane, 5: 95-10: 90) followed by crystallization from ethanol gave the title compound as a red solid (0.107 g). T. t. Mp 260-262 ° C.
MS (APCI) 428 ((M + H)+) 1H NMR (DMSO) δ 2.96 (4H, m), 3.37 (4H, m), 4.44 (3H, s), 7.76 (3H, m), 7.93 (1 H, t), 8.27 (1 H, d), 8.37 (1 H, d), 8.59 (2H, d).MS (APCI) 428 ((M + H) + ) 1 H NMR (DMSO) δ 2.96 (4H, m), 3.37 (4H, m), 4.44 (3H, s), 7.76 (3H, m), 7.93 ( 1 H, t), 8.27 (1H, d), 8.37 (1H, d), 8.59 (2H, d).
Príklad 115Example 115
4,5-Dihydro-2-[4-(trifluórmetyl)fenyl]-2H-benz[g]indazol-3-ol4,5-Dihydro-2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazole-3-ol
Metylester kyseliny 1-oxotetrahydronaftalén-2-karboxylovej (Mander, L. N. a Sethi, S. P.; Tetrahedron Lett. 1983, 24, 5425-8) (2,0 g) a 4trifluórmetylfenylhydrazín (3,47 g) sa zahrieval v xyléne (15 ml) na reflux počas 8 hodín. Reakčná zmes sa nechala vychladnúť a produkt sa odfiltroval. Tuhá látka sa premyla dietyléterom, vysušila a rekryštalizovala z toluénu, čím sa získala titulná zlúčenina vo forme bezfarebných kryštálov (1,45 g). T. t. 189- 190 °C.1-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (Mander, LN and Sethi, SP; Tetrahedron Lett. 1983, 24, 5425-8) (2.0 g) and 4-trifluoromethylphenylhydrazine (3.47 g) were heated in xylene (15 ml) ) to reflux for 8 hours. The reaction mixture was allowed to cool and the product was filtered off. The solid was washed with diethyl ether, dried and recrystallized from toluene to give the title compound as colorless crystals (1.45 g). T. t. Mp 189-190 ° C.
MS (APCI) 331 ((M + H)+) 1H NMR (de-DMSO) δ 2.67 (2H, m), 2.90 (2H, m), 7.29 (3H, m), 7.75 (1H, m),MS (APCI) 331 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.67 (2H, m), 2.90 (2H, m), 7.29 (3H, m), 7.75 (1H, m),
7.84 (2H, d), 8.10 (2H, d), 11.70 (1 H, s, br).7.84 (2H, d), 8.10 (2H, d), 11.70 (1H, s, br).
-62Príklad 116-62Example 116
4,5-Dihydro-2-(5-metyl-2-pyridinyl)-2H-benz[g]indazol-3-ol4,5-Dihydro-2- (5-methyl-2-pyridinyl) -2H-benz [g] indazole-3-ol
Metylester kyseliny 1-oxotetrahydronaftalén-2-karboxylovej (2,18 g) a 2hydrazino-5-metylpyridín (2,85 g) sa spolu zahrievali v xyléne (15 ml) na reflux počas 6 hodín. Reakčná zmes sa nechala vychladnúť a produkt sa potom odfiltroval a vysušil. Rekryštalizáciou zo zmesi dietyléteru a izohexánu sa získala titulná zlúčenina ako svetlohnedé ihličky (0,69 g). T. t. 112 °C.1-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2.18 g) and 2hydrazino-5-methylpyridine (2.85 g) were heated together in xylene (15 mL) to reflux for 6 hours. The reaction mixture was allowed to cool and the product was then filtered and dried. Recrystallization from diethyl ether / isohexane gave the title compound as pale brown needles (0.69 g). T. t. 112 [deg.] C.
MS (APCI) 278 ((M + H)+) 1H NMR (ds-DMSO) δ 2.36 (3H, s), 2.73 (2H, t), 2.95 (2H, t), 7.29 (3H, m), 7.68 (1H, dd), 7.92 (1H, d), 7.94 (1H, m), 8.07 (1H, s), 12.73 (1H, s, br).MS (APCI) 278 ((M + H) +) 1 H NMR (d s -DMSO) δ 2:36 (3H, s), 2.73 (2H, t), 2.95 (2H, t), 7.29 (3H, m) 7.68 (1 H, dd), 7.92 (1 H, d), 7.94 (1 H, m), 8.07 (1 H, s), 12.73 (1 H, s, br).
Príklad 117Example 117
2-[4-(Trifluórmetyl)fenyl]-2H-benz[g]indazol-3-ol2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazole-3-ol
4.5- Dihydro-2-[4-(trifluórmetyl)fenyl]-2H-benz[g]indazol-3-ol (0,30 g) a 10% paládia na uhlíku (0,10 g) sa zahrievali v dimetylacetamide (5 ml) a cyklohexéne (5 ml) na reflux počas 1 hodiny. Titulná zlúčenina (0,26 g), 1.1. > 235 °C (rozkl.).4,5-Dihydro-2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol (0.30 g) and 10% palladium on carbon (0.10 g) were heated in dimethylacetamide (5). ml) and cyclohexene (5 ml) to reflux for 1 hour. The title compound (0.26 g), m.p. > 235 ° C (dec.).
MS (APCI) 329 ((M + H)+) 1H NMR (d6-DMSO) δ 7.70 (4H, m), 7.85 (2H, d), 8.07 (1H, m), 8.27 (2H, d), 8.30(1 H'm), 11.70(1 H, s, br)?MS (APCI) 329 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 7.70 (4H, m), 7.85 (2H, d), 8.07 (1H, m), 8.27 (2H, d) , 8.30 (1H, m), 11.70 (1H, s, br)?
Príklad118EXAMPLE 118
2-(5-Metyl-2-pyridinyl)-2H-benz[g]indazol-3-ol2- (5-methyl-2-pyridinyl) -2H-benz [g] indazole-3-ol
4.5- Dihydro-2-(5-metyl-2-pyridinyl)-2H-benz[g]indazol-3-ol (0,40 g) a 10% paládia na uhlíku (0,20 g) sa zahrievali v dimetylacetamide (15 ml) a cyklohexéne (15 ml) na reflux počas 8 hodín. Zmes sa potom nechala vychladnúť na laboratórnu teplotu a potom sa prefiltrovala. Filtrát sa odparil (100 °C/1 mm Hg) a zvyšok sa rekryštalizoval z etylacetátu, čím sa získala titulná zlúčenina ako svetlooranžové kryštály (0,12 g). T. t. 214 °C.4,5-Dihydro-2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol (0.40 g) and 10% palladium on carbon (0.20 g) were heated in dimethylacetamide ( 15 ml) and cyclohexene (15 ml) to reflux for 8 hours. The mixture was then allowed to cool to room temperature and then filtered. The filtrate was evaporated (100 ° C / 1 mm Hg) and the residue was recrystallized from ethyl acetate to give the title compound as pale orange crystals (0.12 g). T. t. Mp 214 ° C.
MS (APCI) 276 ((M + H)+) 1H NMR (d6-DMSO) δ 2.36 (3H, s), 7.52 (1H, d), 7.66 (3H, m), 7.82 (1H, dd), 8.02 (1H, d), 8.41 (1H, s, br), 8.53 (2H, m).MS (APCI) 276 ((M + H) + ) 1 H NMR (d 6 -DMSO) δ 2.36 (3H, s), 7.52 (1H, d), 7.66 (3H, m), 7.82 (1H, dd) 8.02 (1 H, d), 8.41 (1 H, s, br), 8.53 (2 H, m).
Farmakologické údajePharmacological data
Test A - chronická choroba štep verzus hostiteľTest A - Chronic Graft versus Host Disease
Farmakologickú aktivitu zlúčenín podľa vynálezu možno demonštrovať pomocou spôsobu J. M. Doutrelepnota a kol. [Clin. Exp. Immunol., 1991, , 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. Testovaná zlúčenina sa podávala myšiam subkutánne ako suspenzia vo fyziologickom roztoku s TWEEN-80 každý deň počas 21 dní.The pharmacological activity of the compounds of the invention can be demonstrated by the method of J. M. Doutrelepnota et al. [Clin. Exp. Immunol., 1991, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. The test compound was administered to the mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.
Test B - inhibícia eozinofílieTest B - Inhibition of eosinophilia
Účinky zlúčenín podľa vynálezu na zápalové bunky v pľúcach myši sa vyhodnotili nasledujúcou metódou adaptovanou podľa Brusselle a kol. Clin. Exp. Allergy, 1994, , 73 - 80. Meranie eozinofil peroxidázy ako markera pre počty eozinofilu bola adaptovaná podľa Cheng a kol., J. Pharmacol. Exp. Ther. 1993, , 922 - 929. Samce myši Balb/c boli senzibilizované na zmes ovalbumín/AI(OH)3.The effects of the compounds of the invention on inflammatory cells in the lungs of mice were evaluated by the following method adapted from Brussell et al. Clin. Exp. Allergy, 1994, 73-80. Measurement of eosinophil peroxidase as a marker for eosinophil counts was adapted according to Cheng et al., J. Pharmacol. Exp. Ther. 1993, 922-929. Male Balb / c mice were sensitized to ovalbumin / Al (OH) 3 .
II
Podávanie zlúčeniny začalo 14 dní po senzibilizácii. Zlúčenina sa podávala denne buď orálne alebo subkutánne ako suspenzia alebo roztok (v závislosti na dávke a rozpustnosti zlúčeniny) v 5 % TWEEN 80.Compound administration began 14 days after sensitization. The compound was administered daily either orally or subcutaneously as a suspension or solution (depending on the dose and solubility of the compound) in 5% TWEEN 80.
dní po senzibilizácii a jednu hodinu po štvrtej dávke zlúčeniny sa myši umiestnili do komôr Prespex, do ktorých bol rozprášený roztok ovalbumínu (2 % hmotnosť/objem). Myši sa nechali inhalovať ovalbumín 30 - 40 minút. Toto pôsobenie sa opakovalo denne v tom istom čase počas ďalších 3 alebo 7 dní.days after sensitization and one hour after the fourth dose of compound, mice were placed in Prespex chambers into which an ovalbumin solution (2% w / v) was sprayed. Mice were allowed to inhale ovalbumin for 30-40 minutes. This treatment was repeated daily at the same time for a further 3 or 7 days.
-64V prípade štvordňového pôsobenia sa na posledný deň podávania vykonalo ďalšie pôsobenie ovalbumínom 4 hodiny po prvom.-64 For a four-day treatment, an additional ovalbumin treatment was performed on the last day of administration 4 hours after the first.
Nasledujúci deň boli zvieratá usmrtené a merala sa inhibícia nasledujúcich parametrov porovnaním s kontrolnými zvieratami:The following day the animals were sacrificed and inhibition of the following parameters was measured by comparison with control animals:
I ;I;
1. Nárast počtu zápalových buniek v bronchoalveolárnej laváži, najmä eozinofilov (po štvordňovom podávaní);An increase in the number of inflammatory cells in bronchoalveolar lavage, especially eosinophils (after four days of administration);
2. Akumulácia eozinofilov v pľúcnom tkanive (po 8 dňoch podávania);2. Accumulation of eosinophils in lung tissue (after 8 days of administration);
3.. Nárast titrov protilátok (IgE, IgGI a lgG2a) prítomných v sére získanom z celej krvi (po 8 dňoch podávania).3. Increase in antibody titers (IgE, IgG1 and IgG2a) present in whole blood serum (after 8 days of administration).
Niektoré zlúčeniny podľa vynálezu vykazujú aktivity v teste chronickej choroby štepu proti hostiteľovi a teste inhibície eozinofilov s ED50 v rozmedzí 0,1 10 mg/kg.Certain compounds of the invention show activity in the assay of chronic disease, graft vs. host assay and inhibition of eosinophils with ED 50 in the range of 0.1 10 mg / kg.
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---|---|---|---|---|
US4524146A (en) * | 1982-12-08 | 1985-06-18 | Ciba-Geigy Corporation | Certain -2-heterocycle substituted pyrazoloquinolines |
JPS61112075A (en) * | 1984-11-05 | 1986-05-30 | Shionogi & Co Ltd | Thienylpyrazoloquinoline derivative |
SE8903564D0 (en) * | 1989-10-26 | 1989-10-26 | Pharmacia Ab | NEW USE CONDENSED QUINOLINE COMPOUND |
JPH05194515A (en) * | 1991-07-31 | 1993-08-03 | Kyowa Hakko Kogyo Co Ltd | Condensed naphthyridine derivative |
-
1997
- 1997-03-19 AR ARP970101094A patent/AR006520A1/en unknown
- 1997-03-19 ID IDP970892A patent/ID16283A/en unknown
- 1997-03-20 NZ NZ331614A patent/NZ331614A/en unknown
- 1997-03-20 IL IL12627197A patent/IL126271A0/en unknown
- 1997-03-20 WO PCT/SE1997/000471 patent/WO1997034893A1/en not_active Application Discontinuation
- 1997-03-20 PL PL97328921A patent/PL328921A1/en unknown
- 1997-03-20 CA CA002247814A patent/CA2247814A1/en not_active Abandoned
- 1997-03-20 JP JP9533412A patent/JP2000506884A/en active Pending
- 1997-03-20 EP EP97914729A patent/EP0888347A1/en not_active Withdrawn
- 1997-03-20 CN CN97194665A patent/CN1218472A/en active Pending
- 1997-03-20 TR TR1998/01861T patent/TR199801861T2/en unknown
- 1997-03-20 BR BR9708103A patent/BR9708103A/en unknown
- 1997-03-20 CZ CZ982977A patent/CZ297798A3/en unknown
- 1997-03-20 SK SK1187-98A patent/SK118798A3/en unknown
- 1997-03-20 AU AU21867/97A patent/AU712141B2/en not_active Ceased
- 1997-03-20 EE EE9800298A patent/EE9800298A/en unknown
- 1997-03-20 KR KR1019980707441A patent/KR20000064716A/en not_active Application Discontinuation
-
1998
- 1998-09-16 NO NO984290A patent/NO984290L/en unknown
- 1998-09-16 IS IS4848A patent/IS4848A/en unknown
Also Published As
Publication number | Publication date |
---|---|
IS4848A (en) | 1998-09-16 |
KR20000064716A (en) | 2000-11-06 |
CN1218472A (en) | 1999-06-02 |
BR9708103A (en) | 1999-07-27 |
CA2247814A1 (en) | 1997-09-25 |
AR006520A1 (en) | 1999-09-08 |
PL328921A1 (en) | 1999-03-01 |
AU712141B2 (en) | 1999-10-28 |
JP2000506884A (en) | 2000-06-06 |
AU2186797A (en) | 1997-10-10 |
NO984290D0 (en) | 1998-09-16 |
NZ331614A (en) | 2000-07-28 |
CZ297798A3 (en) | 1999-03-17 |
ID16283A (en) | 1997-09-18 |
IL126271A0 (en) | 1999-05-09 |
NO984290L (en) | 1998-10-27 |
TR199801861T2 (en) | 1998-12-21 |
EP0888347A1 (en) | 1999-01-07 |
EE9800298A (en) | 1999-02-15 |
WO1997034893A1 (en) | 1997-09-25 |
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