MXPA98002067A - Derivatives of the 2-quinolone inhibitors of the farnesil transfer - Google Patents
Derivatives of the 2-quinolone inhibitors of the farnesil transferInfo
- Publication number
- MXPA98002067A MXPA98002067A MXPA/A/1998/002067A MX9802067A MXPA98002067A MX PA98002067 A MXPA98002067 A MX PA98002067A MX 9802067 A MX9802067 A MX 9802067A MX PA98002067 A MXPA98002067 A MX PA98002067A
- Authority
- MX
- Mexico
- Prior art keywords
- βalkyl
- formula
- alkyl
- hydrogen
- compound
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title description 12
- 229950008696 Farnesil Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 137
- 239000000203 mixture Substances 0.000 claims abstract description 115
- -1 hydroxycarbonyl Chemical group 0.000 claims abstract description 83
- 239000001257 hydrogen Substances 0.000 claims abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 58
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 39
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- 239000002253 acid Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000007792 addition Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052717 sulfur Chemical group 0.000 claims abstract description 8
- 239000011593 sulfur Chemical group 0.000 claims abstract description 8
- 125000004951 trihalomethoxy group Chemical group 0.000 claims abstract description 5
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 5
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 25
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
- 230000001131 transforming Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- BZRZRRCJYPDRFJ-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-6-[(4-chlorophenyl)-imidazol-1-ylmethyl]-1-methylquinolin-2-one Chemical compound C1=C2C(C=3C=C4OCOC4=CC=3)=CC(=O)N(C)C2=CC=C1C(N1C=NC=C1)C1=CC=C(Cl)C=C1 BZRZRRCJYPDRFJ-UHFFFAOYSA-N 0.000 claims description 5
- 102000007317 Farnesyltranstransferase Human genes 0.000 claims description 5
- 108010007508 Farnesyltranstransferase Proteins 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003248 quinolines Chemical class 0.000 claims description 4
- 229940093918 Quinoline gynecological antiinfectives Drugs 0.000 claims description 3
- 229940027991 antiseptics and disinfectants Quinoline derivatives Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000005755 formation reaction Methods 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
- LNMVKTAEIBQKGC-UHFFFAOYSA-N 4-(3-chlorophenyl)-6-[(4-chlorophenyl)-imidazol-1-ylmethyl]-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(C=3C=CC(Cl)=CC=3)N3C=NC=C3)C=C2C=1C1=CC=CC(Cl)=C1 LNMVKTAEIBQKGC-UHFFFAOYSA-N 0.000 claims description 2
- AWPASKYXIYDLEO-UHFFFAOYSA-N 4-(3-chlorophenyl)-6-[1-(4-chlorophenyl)-1-(5-methylimidazol-1-yl)ethyl]-1-methylquinolin-2-one Chemical compound CC1=CN=CN1C(C)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 AWPASKYXIYDLEO-UHFFFAOYSA-N 0.000 claims description 2
- VEJDPXJJTIEDBT-UHFFFAOYSA-N 4-(3-chlorophenyl)-6-[1-(4-chlorophenyl)-1-imidazol-1-ylethyl]-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(C)(C=3C=CC(Cl)=CC=3)N3C=NC=C3)C=C2C=1C1=CC=CC(Cl)=C1 VEJDPXJJTIEDBT-UHFFFAOYSA-N 0.000 claims description 2
- NMHLBRAQOAZCOS-UHFFFAOYSA-N 4-(3-chlorophenyl)-6-[1-(4-chlorophenyl)-2-hydroxy-1-imidazol-1-ylethyl]-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(CO)(C=3C=CC(Cl)=CC=3)N3C=NC=C3)C=C2C=1C1=CC=CC(Cl)=C1 NMHLBRAQOAZCOS-UHFFFAOYSA-N 0.000 claims description 2
- SGJOGMWFOAJBCD-UHFFFAOYSA-N 6-[1-(4-chlorophenyl)-2-hydroxy-1-imidazol-1-ylethyl]-1-methyl-4-phenylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(CO)(C=3C=CC(Cl)=CC=3)N3C=NC=C3)C=C2C=1C1=CC=CC=C1 SGJOGMWFOAJBCD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing Effects 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 239000011260 aqueous acid Substances 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 abstract 1
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 37
- 229910001868 water Inorganic materials 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 210000004027 cells Anatomy 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000003480 eluent Substances 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 16
- 235000015320 potassium carbonate Nutrition 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 108020004532 RAS Proteins 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 108020001180 rasD Proteins 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 208000005623 Carcinogenesis Diseases 0.000 description 10
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 125000001309 chloro group Chemical group Cl* 0.000 description 9
- 230000000875 corresponding Effects 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 102000004357 Transferases Human genes 0.000 description 7
- 108090000992 Transferases Proteins 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 238000007126 N-alkylation reaction Methods 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 230000002246 oncogenic Effects 0.000 description 5
- 231100000590 oncogenic Toxicity 0.000 description 5
- 239000001184 potassium carbonate Substances 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000030944 contact inhibition Effects 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000002255 enzymatic Effects 0.000 description 4
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000004881 tumor cells Anatomy 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000000068 chlorophenyl group Chemical group 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 239000002609 media Substances 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002062 proliferating Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- CWGBFIRHYJNILV-UHFFFAOYSA-N (1,4-diphenyl-1,2,4-triazol-4-ium-3-yl)-phenylazanide Chemical compound C=1C=CC=CC=1[N-]C1=NN(C=2C=CC=CC=2)C=[N+]1C1=CC=CC=C1 CWGBFIRHYJNILV-UHFFFAOYSA-N 0.000 description 2
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 2
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 2
- VPZBUAJQMMZMIY-UHFFFAOYSA-N 6-(4-chlorobenzoyl)-1-methyl-4-phenylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(=O)C=3C=CC(Cl)=CC=3)C=C2C=1C1=CC=CC=C1 VPZBUAJQMMZMIY-UHFFFAOYSA-N 0.000 description 2
- FTDBHFOCZAEWDI-UHFFFAOYSA-N 6-[amino-(4-chlorophenyl)methyl]-4-phenyl-1H-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=C(C=3C=CC=CC=3)C2=CC=1C(N)C1=CC=C(Cl)C=C1 FTDBHFOCZAEWDI-UHFFFAOYSA-N 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N Ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010048653 Enzyme inhibition Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 102100011754 LMNA Human genes 0.000 description 2
- 101700066012 LMNA Proteins 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N Phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 230000001594 aberrant Effects 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
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Abstract
The present invention relates to compounds of the formula (I) (See Formula), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts thereof, wherein the dotted line represents an optional bond; x is oxygen or sulfur, R1 is hydrogen, C1-6alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6aqluyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di (C1-6alkyl) aminoC1 -6alkyl, ammoniumC1-6alkyl, or a radical of the formula -A1k1-C (= 0) -R9 or A1k1-S (O) 2 -R9; R9 and R1 and R3, independently, are hydrogen, hydroxy, halo, cyano , halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di (C1-6alkyl) aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1- 6-alkyloxy, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl, or when in adjacent positions, R 2 and R 3 together can form a radical. to the bivalent, each of R4 and R5, independently, is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkitio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS (O) C1-6alkyl or C1-6alkyls (O) (2 (C1-alkyl, each of R6 and R7, independently, is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar2ox1; R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonylC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyloxycarbonyl C 1-6 alkyl, hydroxycarbonyl C 1-6 alkyl, hydroxyC 1-6 alkyl, amino C 1-6 alkyl, mono- or di (C 1-6 alkyl) -amino C 1-6 alkyl, halo C 1 -6alkyl, C1-6aqylaxyC1-6alkyl, C1-6alkylaminocarbonyl, Ar1C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, R10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo, R11 is hydrogen or C1-6alkyl; inhibitor of farnesiltransfereasa, its preparation the compositions that contain them and their use as medicamen
Description
DERIVATIVES OF THE 2-QUIN0L0NA INHIBITORS OF THE FARNESIL TRANSFERASA
MEMORIA DESCRIPCITVA
The present invention relates to novel 2-quinolone derivatives, with the preparation thereof, with pharmaceutical compositions comprising said novel compounds and with the use of these compounds as a medicament, as well as with treatment methods consisting of the administration of these compounds. Oncogenes often encode protein components of signal transduction pathways that lead to the estimation of cell development and itogenesis. The expression of oncogenes in cultured cells gives rise to cell transformation, which is characterized by the ability of cells to develop on soft agar and by the development of cells as dense foci lacking the contact inhibition exhibited by non-cellular cells. transformed. The mutation and / or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras, which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian oncogenes consists of three main components ("isofor as"): H-ras, K-ras, and N-ras. These ras oncogenes encode highly-related proteins known generically as p21raß. Once attached to the plasmid membranes, mutant or oncogenic forms of p21raß produce a signal for the uncontrolled transformation and growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21raß oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl terminal tetrapeptide. Therefore, the inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, prevent the adhesion of p21raß to the membrane and block the aberrant growth of ras-transformed tumors. Accordingly, it is a generally accepted fact in the art that farnesyltransferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to the transformation. Since mutated, oncogenic, ras forms are frequently found in many human cancers, most prominently in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, volume 260, 1834-1837, 1993) It has been suggested that farnesyl-raniferase inhibitors can be very useful against these cancers. EP-0,371,564 describes quinoline (1H-azol-1-ylmethyl) substituted and quinolinone derivatives that suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens of progestins and / or inhibit the action of the aromatase enzyme complex. Unexpectedly, it has been noticed that the novel compounds of the present invention, all of which possess a phenyl substituent in the 4-position of the 2-quinolone portion, exhibit farnesi-11-aransferase inhibitory activity. The present invention encompasses the compounds of the formula (I)
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, in which the dotted line represents an optional bond; X is oxygen or sulfur; RI is hydrogen, C1-2alkyl, Ar ,, Ar2Ci-βalkyl, quinolinylC1-βalkyl, pi-RidylCí-alkyl, hydroxyCi-βalkyl,
Ci-ealkyloxyCi-ealkyl, mono- or di (C? -alkyl) aminoC? -ealkyl, aN-chloroalkyl, or a radical of the formula -Alk1-C (= 0) -R9 or Alki-S (0) 2 -R9, where Alki is alkanediylCy-alkyl, R9 is hydroxy, Ci-βalkyl, Ci -ealkylalkyl, amino, Ci-βalkylamino or Ci-βalkylamino substituted with Ci-6alkyloxycarbonyl; R2 and R3, independently, are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, Ci -alkyloxy, hydroxyCi-βalkyloxy, Ci-βalkyloxyCi-βalkyloxy, aminoCí-βalkyloxy, mono- or di (C?-ΒalkyminoCi-βalkyloxy, Ar 1 , Ar2C? -ealkyl, Ar2oxi, Ar2C? -β-alkyloxy, hydroxycarbonyl, Ci-βalkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-β-alkenyl; or when they are in adjacent positions, R2 and R3 together can form a bivalent radical of the formula -O-CH2-O- (a-1) -O-CH2-CH2O- (a-2) -0-CH = CH- (a-3) -O-CH2-CH2- (a-4) -O-CH2-CH2-CH2- (a-5), or -CJ = CH-CH = CH- (a-6); each of R * and R5, independently, is hydrogen, Ci-βalkyl, Ci-βalkyloxyCi-βalkyl, Ci-βalkyloxy, Ci-ßalkylthio, aminohydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-βalkylS (O) Ci-βalkyl or Ci- 6alkyl S (0) 2C? -βalkyl; each of R6 and R? , independently, it is hydrogen, halo, cyano, Ci-βalkyl, Ci-βalkyloxy or Ar 2 oxy; Rβ is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Ci -alkyloxycarbonyl, Ci-βalkylcarbonylCí -alkyl, cyanoCí-alkyl, Ci -6alkyloxycarbonylC? -ealkyl, hydroxycarbonylC? -6alkyl, hydroxyCi-ealkyl, aminoCy-6alkyl, mono- or di (C? -6alkyl) -aminoC? -ealkyl, haloCi-ealkyl, Ci-ealkyloxyC-ealkyl, aminocarbonylCi-βalkyl, Ar1, Ar2C? -6alkyloxyC? -6alkyl, Ci -alkylthioCi-βalkyl; RIO is hydrogen, Ci -ealkyl, Ci-βalkyloxy or halo; R11 is hydrogen or Ci-βalkyl; Ar1 is phenyl or phenyl substituted with Ci -alkyl, hydroxy, amino, Ci-ealkyloxy or halo; Ar2 is phenyl or phenyl substituted with Ci -alkyl, hydroxy, amino, Ci-βalkyloxy or halo. According to the use assigned to it in the above definitions and thereafter, halo defines fluoro, chloro, bromo, and iodo; Ci-βalkyl defines saturated straight or branched chain hydrocarbon radicals with 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; Ci -alkyl embraces straight or branched chain saturated hydrocarbon radicals as defined in Ci -ealkyl as well as higher homologs thereof containing 7 or 8 carbon atoms such as, for example, heptyl or octyl; once more, Ci -i2alkyl embraces Ci -ealkyl and higher homologs thereof containing from 9 to 12 carbon atoms such as, for example, nonyl, decyl, undecyl, dodecyl, C2-6 alkenyl define straight-chain hydrocarbon radicals or branched which contain a double bond and have 2 a and carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, and the like; Cl-6alkanediyl defines straight or branched chain saturated hydrocarbon radicals with 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propandiyl, 1,4-butanediyl, 1,5-pentandiyl , 1,6-hexanediyl and the branched isomers thereof. The term "C (= 0)" refers to a carbonyl group. The term "S (0)" refers to a sulfoxide of the term "(0) 2" to a sulfone. The aforementioned pharmaceutically acceptable acid or base addition salts should comprise the therapeutically active non-toxic non-toxic acid addition and base addition salt forms which the compounds of formula (I) can form. The compounds of the formula (I) having basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example hydrochloric acid or hydrochloric acid; sulfuric, nitric, phosphoric and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, ethanesulfonic, ethanesulfonic, benzenesulfonic, p -Toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and the like.
The compounds of the formula (I) having acidic properties can be converted to their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Suitable basic salt forms include, for example, the ammonium salts, the alkali metal and the alkaline earth metal salts, for example the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example the salts of benzathine, N-methyl-D-glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine and the like. The terms "acid addition salt" or "base" also include the hydrates and the solvent addition forms that the compounds of the formula (I) can form. Examples of such forms are hydrates, alcoholates and the like. The term "stereochemically isomeric forms" of the compounds of the formula (I), used above, defines all possible compounds constituted by the same atoms linked by the same sequence of bonds, but with different three-dimensional structures that are not interchangeable, than the compounds of the formula (I) can possess. Unless mentioned or indicated to the contrary, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compounds may possess. Said mixture may contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. It is intended that all stereochemically isomeric forms of the compounds of the formula (I), both in pure form and in colloidal aggregate among them, are within the scope of the present invention. Some of the compounds of the formula (I) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the formula set forth, should be included within the scope of the present invention. Whenever used in the following, the term "compounds of the formula (I)" should also include the pharmaceutically acceptable acid or base addition signals and all the forms are re-sporesome. X is preferably oxygen. R1 is, appropriately, hydrogen; Ci -ealkyl, preferably methyl, ethyl, propyl; Ar is preferably phenyl; Ar2C? -6alkyl, preferably benzyl, ethoxyphenylethyl; a radical of the formula -Alk-C (= 0) -R, in which Alk is preferably methylene and R9 is preferably hydroxy; Ci -alkyloxy, for example ethoxy; Ci-β-alkylamino substituted with Ci-ealkyloxycarbonyl. Each of R2 and R3, independently, is conveniently hydrogen, halo, preferably fluoro, chloro, bromo; Ci -alkyl, preferably methyl, trihalomethyl, preferably trifluoromethyl; Ci-βalkyloxy, preferably methoxy or ethoxy;
Ar2oxy, preferably phenoxy; Ar2C? -6alkyloxy, preferably benzyloxy; trihalomethoxy, preferably trifluo rometo i. Each R4 and R5 independently is conveniently hydrogen; Ar1, preferably phenyl; Ci-βalkyl, preferably methyl, Ci-βalkylthio, preferably methylthio; C 1 -alkyloxycarbonyl amino, preferably methoxycarbonyl. Each R6 and R7, independently, is conveniently hydrogen, halo, preferably chloro, fluoro; Ci -alkyl, preferably methyl; O-βalkyloxy, preferably methoxy. R8 is suitably hydrogen, Ci -ealkyl, preferably methyl, ethyl or propyl; Ar1, preferably chlorophenyl; Ci ^ alkyl substituted with hydroxy (preferably hydroxymethylene), Ci -alkyloxy (preferably methoxymethylene), amino, mono- or di-Ci-ealkylamino (preferably N, N-dimethylaminomethylene), Ar2C? -βalkyloxy (preferably chlorobenzyloxymethyl) or Ci-βalkylthio (methylthiomethylene). R10 and R11 are hydrogen. Preferably, the substituent R10 is located at the 5 or 7 position of the quinolinone portion and the substituent Rii is located at the 8 position when R10 is at the 7 position. An interesting group of compounds are those compounds of the formula (I) in which R1 is hydrogen, Ci-i2alkyl or Ci -alkyloxyCi-ealkyl. Another group of interesting compounds are those compounds in which R3 is hydrogen and R2 is halo, preferably chlorine, especially 3-chloro. Yet another group of interesting compounds are those compounds in which R2 and R3 are in adjacent positions and form a bivalent radical of the formula (a-1). Another additional group of interesting compounds are those compounds in which R5 is hydrogen and R * is hydrogen. Ci -ealkyl, or Ar1, preferably phenyl. A further group of interesting compounds are those compounds of the formula (I) in which R7 is hydrogen and R6 is halo, preferably chlorine, especially 4-chloro. Special compounds are those compounds of the formula (I) in which R8 is hydrogen, Ci-βalkyl or hydroxyC ?6alkyl. The most interesting compounds are those compounds of the formula (I) in which R1 is methyl, R2 is 3-chloro, R * is hydrogen or 5-methyl, R5 is hydrogen, R6 is 4-chloro, and R8 is hydrogen, Ci-βalkyl or hydroxyCi-βalkyl. Preferred compounds are: 4- (3-chlorophenyl) -6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -l-methyl-2 (lH) -quinolinone; 4- (3-chloro-enyl) -6- [(4-chloro-enyl) -lH-imidazol-1-ylmethyl] -2- (lH) -quinolinone; 6- [1- (4-chlorophenyl) -2-hydroxy-1- (1H-imidazol-1-yl) ethyl] -1-methyl-4-phenyl-2 (1H) -quinolinone; 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -l- (1H-imidazol-1-yl) ethyl] -1-methyl-2- (1H) -quinolinone; 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -l- (5-methyl-1H-imidazol-1-yl) ethyl] -l-methyl-2 (1H) -quinolinone. 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -2-hydroxy-1- (1H-imidazol-1-yl) ethyl] -l-methyl-2 (1H) -quinolinone; Etandioate of 4- (3-chlorophenyl) -6 - [(4-chlorophenyl) - (1H-1-y1zol-1-yl) -methyl] -l- (2-methoxyethyl) -2 (1H) -quinolinone (2: 3) monohydrate; Etandioate of 6- [(4-chlorophenyl) - (1H-imidazol-1-yl) methyl] -4- (1, 3-benzodioxol-5-yl) -1-methyl-2 (1H) -quinolinone; (1); the steroisomeric forms and the pharmaceutically acceptable acid or base addition salts thereof. The compounds of the formula (I) can be prepared
N-alkylating an imidazole of the formula (II) or an alkali metal salt thereof with a derivative of the formula (II)
(II) (III)
In formula (II) W represents a reactive exit group ap roped as, for example, halo, for example, fluoro, chloro, bromo, iodo or a sulfonyloxy group, for example 4-methylbenzenesulfonyloxy, benzenesulfonyloxy, -naphthalenesulfonyloxy, methanesulfonyloxy, trifuloro-ethanesulfonyloxy and similar reactive groups. The N-alkylation described above is conveniently carried out by stirring the reactants in the presence of a suitable solvent such as, for example, a polar aprotic solvent, for example N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile. , preferably in the presence of an appropriate base such as potassium carbonate, or an organic base such as, for example, N, N-dimethyl-4-pi ridinamine, pyridine, N, N-diethylethanamine. In some cases it may be advantageous to use an excess of imidazole (II) or to first convert the imidazole to a suitable salt form thereof such as, for example, an alkali metal or alkaline earth metal salt, by reacting (II) with an appropriate base according to the foregoing, and then using appropriate base according to the aforementioned, and then using said salt form in the reaction with the alkylation reagent of the formula (III). The compounds of the formula (I) can also be prepared by reacting an intermediate of the formula (IV) with a reagent of the formula (V), in which Y is carbon or sulfur, such as, for example, a 1,1 '. -cabonyl-bis [lH-imidazole].
Said reaction may be conveniently carried out in a suitable solvent such as, for example, in ether, for example tetrahydrofuran, optionally in the presence of a base, such as sodium hydride. In all of the above and in the following preparations, the products of the reaction can be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction. , distillation, crystallization, trituration and chromatography. The compounds of the formula (I) in which the dotted line represents a bond, said compounds being defined as compounds of the formula (Ia) can also be obtained by cyclizing an intermediate of the formula (VI) The cyclization reaction of (VI) it can be carried out according to cyclization procedures known in the art as described in, for example. Synthesis, 739 (1975). Preferably, the reaction is carried out in the presence of a suitable Lewis acid, for example aluminum chloride either pure or in a suitable solvent such as, for example, an aromatic hydrocarbon, for example chlorobenzene. The somewhat elevated temperatures can increase the speed of the reaction. In addition, depending on the nature of the substituents R2 / R3, these substituents of a phenyl portion may be different from the substituents R2 / R3 of another phenyl portion, as described in Natarajan M., et al., Indian Bulletin of Chemistry, 23B 720 -727 (1984). The compounds of the formula (1-a-1), in which
Ri is hydrogen, X is oxygen and the dotted line represents a bond, they can be prepared by hydrolyzing the intermediates of the formula (XXVI), in which R is Ci-ißalkyl, according to methods known in the art, such as stirring the intermediate (XXVI) in an aqueous solution. A suitable acid is, for example, hydrochloric acid. Next, the compounds of the formula (1-a-1) can be converted to the compounds of the formula (1-a) by N-alkylation methods known in the art.
A compound of the formula (1-b), defined as a compound of the formula (I) in which R 6 is hydroxymethylene, can be prepared by opening an epoxide of the formula (VII) with an imidazole of the formula (II).
(il)
The compounds of the formula (I) in which R1 is hydrogen and X is oxygen, said compounds being defined as compounds of the formula (If-1), can be prepared by reacting a nitron of the formula (XB) with an anhydride of a carboxylic acid such as, for example, acetic anhydride, thus forming the corresponding ester in the 2-position of the quinoline moiety. Said quinoline ester can be hydrolyzed in situ to the corresponding quinolinone using a base such as, for example, potassium carbonate.
On the other hand, compounds of the formula (If-1) can be prepared by reacting a nitron of the formula (XV) with a sulfonyl containing an electrophilic reagent such as, for example, p-toluenesulfonyl chloride in the presence of a base such as, for example, aqueous potassium carbonate. The reaction initially consists of the formation of a 2-hydroxyquinoline derivative which is then tautomerized to the desired quinolinone derivative. The application of known conditions in the phase transfer catalysis technique can increase the speed of the reaction. The compounds of the formula (I-f-1) can be prepared by an intramolecular photochemical transposition of the compounds of the formula (XV). Said rearrangement can be carried out by dissolving the reactants in a solvent inert to the reaction and irradiating at a wavelength of 366 mm. It is advantageous to use degassed solutions and to carry out the reaction in an inert atmosphere such as, for example, oxygen-free argon or nitrogen gas, in order to minimize the side reactions or the reduction of the quantum yield.
The compounds of the formula (I), in which R is hydrogen, said compounds being defined as compounds of the formula (Ic-1) can be converted to the compounds of the formula (Ic-2), in which R b is define as Rl except hydrogen. For example, the compounds of the formula (Ic-1) can be N-alkylated with Rib_-Wi, where Wi is an exit reactive group such as, for example, halo or a sulfonyloxy group, in the presence of a base such as , for example, sodium hydride.
Said reaction can be carried out, conveniently, by mixing the reactants in a reaction-inert solvent such as, for example, N, N-dimethylformamide. It may be advisable to carry out the reaction at slightly reduced temperatures. In addition, it may be advantageous to carry out said N-alkylation under an inert atmosphere such as, for example, argon gas, or nitrogen. Said reaction can also be carried out using basic Transfer Catalysis (PTC) conditions, such as stirring the reactants in a mixture of a concentrated sodium hydroxide solution, and an organic solvent, such as tetrahydrofuran, in the presence of a catalyst. phase transfer, such as benzyltriethylammonium chloride, (BTEAC). In the case where Rit > is aryl N-alkylation can be performed by reacting a compound of the formula (Ic-1) with a reactant such as diphenyliodonium chloride in the presence of cuprous chloride (CuCl) in an appropriate solvent, for example methanol, in the presence of a base such like sodium methoxide.
The compounds of the formula (I), in which R is Rib and Rβ is hydrogen, said compounds being defined as compounds of the formula (Id-1) can also be converted into compounds of the formula (Id-2), in which R8a is hydroCalkyl, C6-6alkyl, C6-6alkyloxyC6alkyl, aminoCi-ealkyl, mono- or di-C6alkylaminoC6alkyl. For example, the compounds of the formula (Id-1) can be alkylated with a reagent of the formula R8a-Wi, where W1 is an exit reactive group such as, for example, a halo or sulphonyloxy group, and in the presence of a base such as, for example, sodium hydride.
(l-á-2)
Said alkylation can conveniently be carried out by mixing the reactants of an inert solvent to the reaction such as, for example, tetrahydrofuran or N, N-dimethylformamide, in the presence of a base such as potassium tert-butoxide. In addition, it may be advantageous to perform said alkylation under an inert atmosphere such as, for example, argon or nitrogen gas. A compound of the formula (1-e), defined as a compound of the formula (I) in which X is sulfur, can be repaired by reacting the corresponding compound of the formula (1-f), defined as a compound of formula (I) in which X is oxygen, with a reagent such as phosphate pentasulfur or Lawesson's reagent (C14 G14 O2 P2 SA).
Said reaction may be carried out by stirring and optionally heating a compound of the formula (I-f) in the presence of phosphorus pentasulfide (P4S10) or Lawsson's reagent in a suitable solvent such as, for example, pyridine. The compounds of the formula (I) can also be prepared by constituting the imidazole ring as the final step. These cyclization reactions are exemplified in example Nos. 19 and 21. The compounds of the formula (I) can be converted into one another by means of reactions known in the art or transformations of functional groups. Other examples are the hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; the hydrolysis of amides to the corresponding carboxylic acids or amines; the amino groups in imidazole or phenyl can be replaced by a hydrogen by diazotization reactions known in the art and then by replacing the diazo groups by hydrogen; the alcohols can be converted to esters and ethers; the primary amines can be converted to secondary or tertiary amines; the double bonds can be hydrogenated to the corresponding single bond. The intermediates described above can be prepared according to methods known in the art. Some of these methods are discussed below. The intermediates of the formula (IV) can be prepared by reacting a substituted 4-phenyl-2-quinolone derivative of the formula (VIII) with a carboxylic acid of the formula (IX) or a functional derivative thereof, for example a chloride acid, where a ketone of the formula (X). Said reaction is carried out by stirring the reactants in an appropriate solvent in the presence of an acid, such as polyphosphoric acid. The ketone can then be reduced by giving intermediates in which R8 is hydrogen or reacted with an appropriate addition reagent. Intermediates of formula (III) can be prepared from intermediates of formula (IV) by reacting an intermediate of formula (IV) with an appropriate reagent to convert the hydroxy group to a reactive leaving group. Suitable conversion reagents are, for example, thionyl chloride to obtain intermediates of the formula (III) in which W is chlorine or chlorosulfite; or p-toluenesulfonyl chloride to obtain intermediates of the formula (III) in which W is a p-toluenesulfonyl group. The intermediates of the formula (VII) can be prepared by reacting a ketone of the formula (X) with a sulfur ylide, for example dimethyloxosulfonium methylide, under appropriate conditions.
SCHEME
The intermediates of the formula (VI) can be prepared in the manner described later in Scheme II. A nitrophenyl derivative of the formula (XI) is reacted with an imidazole of the formula (II), said nitrophenyl derivative is then reduced to give an aniline derivative of the formula
(XIII), which then reacts with an acid derivative of formula (XIV) to give an intermediate of formula (VI).
SCHEME II
(XI) (II) (XII)
The intermediate nitrones of the formula (XV) can be prepared by n-oxidizing quinoline derivatives of the formula (XVI) with an appropriate oxidizing agent such as, for example, m-chloro-peroxybenzoic acid in an appropriate solvent such as, for example , dichloromethane. The quinolines of the formula (XVI) can be prepared analogously to the conversion of the intermediates of the formula (X) to the intermediates of the formula (III) and the subsequent N-alkylation with intermediates of the formula (II), but from quinoline derivatives prepared according to procedures known in the art, for example that described in B. Soc. Quim. 299 (1935) by J. Kenner et al. Said N-oxidation can also be carried out in a precursor of a quinoline of the formula (XVI).
(xvn 0 (XV)
The intermediates of the formula (XVI) must be metabolized into compounds of the formula (I). Accordingly, the intermediates of the formula (XVI) can act as prodrugs of the compounds of the formula (I). The intermediates of the formula (X-a), which are intermediates of the formula (X) in which the dotted line represents a bond, can be prepared in accordance with the scheme III SCHEME III
,? - a- X-a)
In scheme III, the intermediates of the formula (XVII) are reacted with intermediates of the formula (XVIII) in which Z is a suitably protected oxo group such as, for example, 1,3-dioxolane, giving intermediates of the formula (XIX), which are subsequently converted to intermediates of formula (XX) using conditions of catalytic hydrogenation, for example using hydrogen gas and palladium on activated carbon in a reaction-inert solvent such as, for example, tetrahydrofuran. The intermediates of the formula (XX) are converted to intermediates of the formula (XXI) by subjecting the intermediates of the formula (XX) to an acetylation reaction, for example by treatment with the anhydride of a carboxylic acid, for example acetic anhydride in a solvent inert to the reaction, for example toluene, optionally in the presence of a base to capture the acid released during the reaction, and then treatment with a base such as, for example, potassium tert-butoxide in an inert solvent the reaction, for example 1,2-dimethoxyethane. The intermediates of the formula (Xa-1), which are intermediates of the formula (Xa) in which Ri is hydrogen, can be obtained by eliminating the protecting group Z from the intermediates of the formula (XXI) using known reaction conditions in the technique, for example acidic conditions. The intermediates of the formula (X-a-1) can be converted to intermediates of the formula (X-a) using N-alkylation reactions known in the art. In addition, the intermediates of the formula (Xa-1) can be obtained by treating intermediates of the formula (XIX) with TÍCI3 in the presence of water, in a solvent inert to the reaction such as, for example, tetrahydrofuran, or by catalytic hydrogenation, giving intermediates of the formula
(XXII) which are then converted to intermediates (X-1) using the same reactions described above to convert intermediates (XX) to intermediates (XXI).
Scheme IV indicates the synthesis of the intermediates of formula (XXVI-a), in which R8b is a substituent suitably selected from R8 to be suitable in the addition reaction of the organolithium derivative of the intermediate (XXIIII) to the oxo group of the intermediate (XXIV). R8b is, for example, hydrogen, Ci-ealkyl, C? -6alkyloxycarbonyl and the like. SCHEME IV
In Scheme IV, an intermediate of the formula (XX? II), in which W * 2 * is halo, is treated with an organolithium reagent such as, for example, n-butyl lithium in a reaction-inert solvent, for example, rahydrofuran, and then reacting with an intermediate of formula (XXIV), or an intermediate of formula (XXV), which is then converted to an intermediate of formula (XXVI) by treatment with an intermediate of formula (V) . The compounds of the formula (I) and some of the intermediates have at least one stereogenic center in their structure. This stereogenic center can be present in the R or S configuration. The compounds of the formula (I) prepared by the processes described above are generally racemic mixtures of enantiomers which can be separated from each other following art-known procedures. The racemic compounds of the formula (I) can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. These forms of diastereomeric salts are then separated, for example by selective or fractional crystallization and the enantiomers are liberated therefrom by alkalis. An alternative way of separating the enantiomeric forms of the compounds of the formula (I) consists of liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be obtained from the pure stereochemically isomeric forms of appropriate starting materials, provided that the reaction occurs this reospecifically. Preferably, if a specific stereoisomer is desired, said compound is synthesized by stereospecific methods of preparation. These methods advantageously use enantiomerically pure initial materials. This invention presents a method for inhibiting the abnormal development of cells, including transformed cells, by administering an effective amount of a compound according to the invention. Abnormal cell development refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that express an activated rs oncogene; (2) tumor cells in which the ras protein is activated as a result of an oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. In addition, it has been suggested in the literature that ras oncogenes not only contribute to the development of tumors in vivo by the direct effect on the development of tumor cells but also indirectly, that is, by facilitating tumor-induced angiogenesis (Rak J. et al. others, Cancer Research, 55, 4575-4580, 1995). Thus, by targeting mutant ras oncogenes pharmacologically, the development of solid tumors in vivo would be suppressed, in part, by inhibiting tumor-induced angiogenesis. This invention also provides a method for inhibiting tumor development by administering an effective amount of a compound according to the present invention to a subject, (e.g., a mammal and more specifically a human) in need of such treatment. Especially, this invention presents a method for inhibiting the development of tumors expressing an activated ras oncogene by administering an effective amount of the compounds according to the present invention. Examples of tumors that can be inhibited, without being limited thereto, are lung cancer (eg, adenocarcinoma), pancreatic cancers (eg, pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (eg, carcinomas). colorectal, such as, for example, colon adenocarcinoma or colon adenoma), hematopoietic tumors of lymphoid origin (e.g. acute lymphocytic leukemia, B-cell lymphoma, Brikitt's lymphoma), myeloid leukemias (e.g., acute myelogenous leukemia (AL ), thioroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (for example fibrosarcomas and rhabdomyosarcomas), melanomas, tet rocarcinomas, neuroblastomas, gliomas, benign skin tumors (for example keratoacanthus), mammary carcinoma, renal carcinoma, ovarian carcinoma, bladder carcinoma, and epidermal carcinoma This invention may also present a method to inhibit proliferative diseases, both benign and malignant, in which the ras proteins are aberrantly activated as a result of the oncogenic mutation in genes, that is to say that the ras gene itself is not activated by mutation to an oncogenic form, said inhibition being effected by the administration of an effective amount of the compounds described herein, to a subject in need of such treatment. For example, neurofibromatosis by proliferative disorder, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes can be inhibited by the compounds according to the present invention. The present invention also relates to compounds of the formula (I) described above, for use as a medicament. By virtue of their useful pharmacological properties, the compounds of concern can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions according to the present invention, an effective amount of a particular compound, in the form of an acid or base addition salt as the active ingredient, is intimately mixed with a pharmaceutically acceptable carrier, a vehicle which assumes a broad range of variety of forms according to the form of preparation proposed for administration. These pharmaceutical compositions are conveniently presented in a unit dose form suitable, preferably, for administration orally, rectally, percutaneously or by parenteral injection. For example, when preparing the compositions in oral dosage form, any of the pharmaceutical media, for example water, glycols, oils, alcohols and the like can be used in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions.; or solid carriers such as starches, sugars, kaolin, lubricating agents, binders, disintegrants and the like in the case of powders, dragees, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually comprises sterilized water, at least in large part, although other ingredients may be included to contribute to solubility, for example, injectable solutions may be prepared in which the vehicle comprises saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, where liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any kind in minor proportions, additives that do not cause a deleterious effect in the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, for example as a transdermal patch, as an oral topical or as an ointment. It is especially advantageous to formulate the said pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form used in the specification and claims herein refers to physically discrete units suitable as unit doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in conjunction with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, seals, injectable solutions or suspensions, teaspoons of tea, soup spoons and the like, and segregated multiples thereof. Those skilled in the art could easily determine the effective amount from the results of the tests presented below. In general, it is contemplated that an effective amount would be from 0.01 mg / kg to 100 mg / kg of body weight, and especially from 0.05 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose in the form of two, three, four or more sub-doses at appropriate intervals during the day. Said sub-doses can be formulated as unit dosage forms, for example containing from 0.5 to 500 mg, and especially from 1 mg to 200 mg of active ingredient per unit dosage form.
Experimental Part Hereinafter, "THF" means tetrahydrofuran,
"DIPE" means diisopropyl ether, "DCM" means dichloromethane, "DMF" means N, N-dimethylformamide and "ACN" means acetonitrile. The absolute stereochemical configuration of some compounds of the formula (I) was not determined experimentally. In those cases, the stereochemically isomeric form isolated in the first place is designated as "A" and the second "B", without further reference to the true stereochemical configuration.
A. Preparation of Intermediates
EXAMPLE 1.
a) Imidazole (121.8 g) was added to a mixture of 1- (chlorophenylmethyl) -4-nitrobenzene (88.7 g) in ACN (1000 ml) and the reaction mixture was stirred and refluxed for 24 hours . The solvent was evaporated. The residue was dissolved in toluene, washed with a 10% K2CO3 solution, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 53 g (53%) of 1 [(4-nitrophenyl) phenylmethyl] -lH-imidazole (int.1-a). b) A mixture of intermediate (1-a) in ethanol (300 ml) (3.9 105 Pa H2) was hydrogenated with Raney nickel (20 g) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was removed by filtration and the filtrate was evaporated, yielding 34.6 g of (±) -4 - [(1H-imidazol-1-yl) phenylmethyl] benzenamine (int. -b). c) A mixture of intermediate (1-b) (8.92 g) and l-chloro-3,3-diphenyl-2-propen-l-one (10.42 g) in DCM was stirred at room temperature overnight. 100 ml). The mixture was poured into a 10% NaHCO 3 solution. This mixture was extracted with DCM and separated. The organic layer was dried (MgSO.sub.1), filtered and evaporated, giving 22.85 g (100%) of (±) -N-4 - [(1H-imidazol-1-yl) phenylmethyl) phenyl] -3,3-diphenyl -2-propenamine (int 1-c). The product was used without further purification.
EXAMPLE 2
a) 4-Chlorobenzoic acid (21.23 g) was heated and
2,4-dihydro-4-phenyl-2 (lH) -quinolinone (15 g) in polyphosphoric acid (150 g) at 140 ° C for 24 hours. The mixture was poured into ice water and filtered. The precipitate was taken up in DCM. The organic layer was washed with NaHCO3 (10%) and water, dried (MgSO *), and evaporated. The residue was crystallized with 2-propanone, yielding 12.34 g (50%) of (±) -6- (4-chlorobenzoyl) -3,4-dihydro-4-phenyl-2 (lH) -quinolinone; p.f. 204 ° C (int 2-a). b) Sodium borohydride (12.5 g) was added portionwise to O'C to a solution of intermediate (2-a) (20 g) in methanol (200 ml) and THF (5 ml) and the mixture was stirred at room temperature. environment for 2 hours. The mixture was quenched with water and evaporated. The residue was taken up in DCM with K2CO3 (10%). The organic layer was dried (MgSO ^), filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 2.8 g (14%) of 6 - [(4-chlorophenyl) -hydroxymethyl-3,4-dihydro-4-phenyl-2 (lH) -quinolinone; (int 2-b).
EXAMPLE 3
A mixture of (±) -6- [hydroxy (3-fluorophenyl) methyl] -4-phenyl-2 (lH) quinolinone was stirred at room temperature for 12 hours; (11 g) in thionyl chloride (11 ml) and DCM (120 ml). The solvent was evaporated to dryness and used without further purification, yielding 11.6 g of (±) -6- [chloro (3-fluorophenyl) methyl] -4-phenyl-2- (lH) -quinolinone (100%) (int . 3).
EXAMPLE 4
A mixture of sodium hydride (1.75 g) in THF (830 ml) was stirred for 5 minutes. The tetrahydride was removed by evaporation. Dimethyl sulfoxide (120), then trimethylsulfoxonium iodide (12.1 g) was added and the resulting mixture was stirred for 30 minutes at room temperature under N2 flow. 6- (4-Chlorobenzoyl) -l-methyl-4-phenyl-2- (1H) -quinolinone (17 g) was added portionwise and the reaction mixture was stirred for 2 hours at room temperature. Ethyl acetate and water were added. The organic layer was separated, washed twice with water, dried (MgSO / v), filtered and the solvent evaporated. The crude product was used without further purification in the next reaction step, giving 17.6 g (100%) of (±) -6- [2- (4-chlorophenyl) -2-oxiranyl] -l-methyl-4-phenyl -2- (1H) -quinolinone (int 4).
EXAMPLE 5
a) A mixture of 6- (4-chlorobenzoyl) -l-methyl-4-phenyl-2- (lH) -quinolinone (24 g) in formamide (130 ml) was stirred and heated at 160 ° C for 12 hours and formic acid (100 ml). The mixture was poured into ice water and extracted with DCM. The organic layer was dried (MgSO.sub.0), filtered and evaporated to dryness. The product was used without further purification, yielding 24.2 g (93%) of (±) -N - [(4-chlorophenyl) - (1,2-dihydro-l-methyl-2-oxo-4-phenyl-6-) quinolinyl) methyl] formamide 8int. 5-a) b) A mixture of intermediate (5-a) (21.2 g) in hydrochloric acid (3N) (150 ml) and 2-propanol (150 ml) was stirred and heated at reflux overnight. The mixture was poured on ice, basified with NH OH and extracted with DCM. The organic layer was dried (MgSO;), filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (eluent; CH 2 Cl 2 / CH 3 OH 98/2 / 0.1). The pure fractions were collected and evaporated, yielding (±) -6- [amino- (4-chlorophenyl) methyl-4-phenyl-2- (lH) -quinolinone (int.5-b). c) N-cyano-ethyl methanimidate (3.6 g) was added dropwise at room temperature to a solution of intermediate (5-b) (10.6 g) in ethanol (90 ml) and the mixture was stirred at room temperature for 48 hours. hours. Water and ethyl acetate were added, the organic layer was decanted, washed with water, dried (MgSO), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1). The pure fractions were collected and evaporated, yielding 10.5 g (88%) of (±) -Nt [[4-chlorophenyl] (1,2-dihydro-l-methyl-2-oxo-4-phenyl-6-quinolinyl) methyl] amino] -methylene] cyanamide (int. 5-c) d) Ethyl 2-brornoacetate (2.45 ml) was added dropwise at 5 ° C to a solution of intermediate (5-c) (9 mg) and salt of potassium of 2-methyl-2-propanol (2.37 g) in dimethyl sulfoxide (100 ml) and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the organic layer was decanted, washed with water, dried (MgSO 3), filtered and evaporated to dryness. The product was used without further purification, yielding (±) -ethyl - [(4-chlorophenyl) (2,3-dihydro-l-methyl-2-oxo-4-phenyl-6-quinolinyl) methyl] -N- [ (cyanoimino)] methyl] glycine (int 5-d).
EXAMPLE 6
a) 2-isothiocyanate-1, 1-dimethoxyethane (85.3 g) was added slowly to a solution of (±) -6- [amino (4-chlorophenyl) methyl] -4-phenyl-2- (lH) -quinolinone (11). g) in methane (100 ml) and the mixture was stirred and heated at 80 ° C for 5 hours. The mixture was evaporated to dryness and the product was used without further purification, giving 15.4 g (100%) of (±) -N - [(4-cyclodexhenyl) (1,2-dihydro-2-oxo-4-). f-enyl-6-quinolinyl) methyl] -N '- (2,2-dimethoxyethyl) thiourea (int. 6-a). b) A mixture of intermediate (6-a) (15.3 g), iodomethane (2.27 ml) and potassium carbonate (5 g) in 2-propanone (50 ml) was stirred at room temperature overnight. The mixture was evaporated, the residue was absorbed in DCM and washed with
K3CO3 at 10%. The organic layer was dried (MgSO, filtered and evaporated, giving 17.8 g (100%) of (±) -methyl-NC (4-chlorophenyl) (1,2-dihydro-2-oxo-4-phenyl-6-quinolinyl) methyl] -N '- (2,2-dimethoxyethyl) carbaminodothioate (int.6-b), which was used without further purification.
EXAMPLE 7
a) Toluene was stirred in a rounded bottom flask (5 1) using a water separator. (4-chlorophenyl) (4-nitrophenyl) methanone (250 g) was added in portions. P-Toluenesulfonic acid was added in portions (54.5 g). Ethylene glycol (237.5 g) was poured into the mixture. The mixture was stirred and heated to reflux for 48 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (51) and washed twice with a 10% K2CO3 solution. The organic layer was separated, dried (MgSO), filtered and evaporated The residue was mixed with DIPE, separated by filtration and dried (vacuum, 40 ° C, 24 hours), giving 265 g (92%) of 2- (4- chlorophenyl) -2- (4-nitrophenyl) -1,3-dioxolane (int.7-a) b) Sodium hydroxide (16.4 g) and (3-methoxyphenyl) acetonitrile (20.6 ml) were added at room temperature. an intern solution. (7-a) (25 g) in methanol (100 ml) and the mixture was stirred at room temperature overnight. Water was added, the precipitate was separated by filtration, washed with cold methanol and dried. The product was used without further purification, giving 30 g (90%) of 5- [2- (4-chlorophenyl) -l, 3-dioxolan-2-yl] -3 (3-methoxyphenyl) -2, 1-benzisoxazole (int 7-b). c) Hydrogenated int. (7-b) (30 g) in THF 8250 ml) with palladium on activated carbon (3 g) as a catalyst at room temperature for 12 hours under a pressure of 2.6-105 in an apparatus Pa rr. After uptake of H 2 (1 equivalent) the catalyst was filtered through celite and the filtrate was evaporated to dryness. The product was used for further purification, giving 31.2 g (100%) of (3-methoxyphenyl) [2-amino-5- [2- (4-chlorophenyl) -l, 3-dioxolan-2-yl] phenyl] methanone (int 7-c). d) Acetic anhydride (13.9 ml) was added to a solution of int. (7-c) (31.2 g) in toluene (300 ml) and the mixture was stirred and heated at reflux for 2 hours. The mixture was evaporated and the product was used without further purification, giving 36.4 g (100%) of N- [2- (3-methoxyphenyl) - (4-chlorophenyl) -l, 3-dioxylan-2-yl] phenyl] acetamide (int 7-d). e) Potassium tert-butoxide (33 g) was added portionwise at room temperature to a solution of int. (7-d) (36.4 g) in 1,2-dimethoxyethane 8350 ml) and the mixture was stirred at room temperature overnight. The mixture was hydrolyzed and extracted with DCM. The organic layer was dried (MgSO.;), filtered and evaporated to dryness. The product was used without further purification, yielding 43 g (100%) of 6- [2- (4-chlorophenyl) -l, 3-dioxolan-2-yl] -4- (3-methoxyphenyl) -2 (lH) -quinolinone (int.7-d). f) A mixture of int was stirred and heated at reflux overnight. (7-e) (43 g) in HVl (3N, 400 ml) and methanol (150 ml). The mixture was cooled and filtered. The precipitate was washed with water and diethyl ether and dried. The product was used without further purification, yielding 27 g (94%) of 6- [2- (4-chlorobenzoyl) -4- (3-methoxyphenyl) -2 (lH) -quinolinone (int.7-f).
g) Methyl iodide (1.58 ml) was added to a solution d int. (7-f) (7.6 g) and benzyltriethylammonium chloride (BTEAC) (2.23 g) in THF (80 ml) and sodium hydroxide (40%, 80 ml). The mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSOu), filtered and the solvent evaporated. The residue was purified by flash column chromatography on silica gel (eluent: DCM 100%). The desired fractions were collected and the solvent was evaporated giving 7.1 g (90%) of 6- (4-clo robenzoi 1) -4- (3-methoxy phenyl) -1-methyl 1-2 (1H) -quinolinone (int. 7-g). h) Int. (7-g) (6.8 g) to DCM (210 ml), was stirred at 0 °. T ri romobo rato (67.3 ml) was added dropwise and the reaction mixture was stirred at 0 ° C for 15 minutes. The mixture was brought to room temperature, stirred at room temperature for 30 minutes and 10% K2CO3 was added. The organic layer was separated, dried (MgSO 4), filtered and the solvent evaporated, giving 6.6 g of 6- (4-chlorobenzoyl) -4- (3-hydroxyphenyl) -l-methyl-2 (lH) -quinolinone (int. 7-h) (quantitative yield, using in the next reaction step, without further purification). i) A mixture of int was stirred and heated to reflux. (7-h), propyl iodide (5.9 ml) and K2CO3 (10.1 g) for 4 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO-filtered and the solvent evaporated to give 10.4 g of 6- (4-chlorobenzoyl) -l-methyl-4- (3-propoxyphenyl) -2 (lH) -quinolinone (int. 7-i) j) A solution of int. (7-i) (3.55 g) in methanol (20 ml and THF (20 ml) Sodium borohydride (0.37 g) was added in portions The mixture was stirred at room temperature for 30 minutes, hydrolyzed and extracted with DCM. The organic layer was separated, dried (MgSO-i), filtered and the solvent evaporated to dryness, giving 3.5 g (100%) of (±) -6- [(4-chlorofluoryl) hydroxymethyl] -4- ( 3-propoxyphenyl) -2 (1H) -quinolinone (int.7-j) k) A solution of int was stirred and heated to reflux. (8-a) (3.5 g) in teloyl chloride (30 ml) overnight. The solvent was evaporated to dryness and the product was used without further purification, giving 3.7 g (100%) of (±) -6- [chloro (4-chlorophenyl) methyl] -4- (3-propoxyphenyl) -2 (lH ) -quinolinone (int 7-k).
EXAMPLE 8
a) HCl / diethyl ether 830.8 ml) was added to a solution of 4-amino-4'-chlorobenzophenone (35 g) in ethanol 8250 ml) at room temperature and the mixture was stirred for 15 minutes. FeCl36H2 was added? (69.4 g) and then ZnCl 2 (2.05 g) per portion and the mixture was stirred for 30 minutes at 65 ° C. 3-Chloro-1-phenyl- was added; propanone (25.46 g) and the mixture was stirred and heated to reflux overnight. The mixture was poured into ice and extracted with DCM. The organic layer was washed with 10% K2CO3, dried (MgSO4), filtered and evaporated. The residue was crystallized with ACN. The mother layers were purified by column chromatography on silica gel (eluent; CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were collected and evaporated, yielding 19.4 g (37%) of (4-chlorophenyl) (4-phenyl-6-quinolinyl) methanone (int.8-a). b) Using the same procedure as the reaction described in example 7j, it became int. (8-a) to (±) -a- (4-chlorophenyl) -4-phenyl-6-quinolinone (int.8-b). c) Using the same reaction procedure described in example 7k, it became int. (8-b) to (±) -6- [chloro (4-chlorophenyl) methyl] -4-phenylquinolinone hydrochloride (int 8-c). d) A mixture of int was stirred and heated to reflux.
(8-c) (12.6 g) and lH-i idazole (11.8 g) in ACN 8300 ml) for 16 hours. The mixture was evaporated to dryness and the residue was absorbed in DCM. The organic layer was washed with 10% K2CO3, dried (MgSO), filtered and evaporated The residue was purified by column chromatography on silica gel (eluent;
CH 2 Cl 2 / CH 3 OH / NH 4 OH 97.5 / 2.5 / 0.1). The pure fractions were collected and evaporated. The residue was converted to the nitric acid salt (1: 2) and crystallized with CH3? H / 2-propanol / diethyl ether, giving 4.28 g (28%) of (±) -6 - [(4-chlorophenyl) - lH-imidazol-l-methyl] -4-quinolinone (int.-8-d pf 152 ° C).
EXAMPLE 9"Int (7-a) (50 g) and then (3-chlorophenyl) acetonitrile (34.8 ml) were added to a mixture of sodium hydroxide 832.8 g) in methanol (100 ml). The reaction was carried out twice with the same amounts, the mixtures were combined, ice was added, then ethanol, the mixture was allowed to crystallize, the precipitate was filtered, washed with ethanol and dried to give 58 g (86%) of 3- (3-chlorophenyl-5- [2- (4-chlorophenyl) -l, 3-dioxolan-2-yl] -2, l-benzisoxazole (int.9-a). TiCl3 / 15% H2 (308 ml) was added at room temperature to a mixture of int (9-a) (51 G) in THF (308 ml) The mixture was stirred at room temperature for two days. water was added and the mixture was extracted with DCM The organic layer was separated, washed with 10% K2CO3, dried (MgSO-4), filtered and the solvent evaporated, part of this fraction (5.9 g) was crystallized with 2-propanone / CH30H / diethyl ether The precipitate was filtered, d 1.92 g (41%) of l-amino-2,4-finylene- (3-chlorophenyl) (4-chlorophenyl) dimethanone 8int. 9-b). c) Using the same reaction procedure described in example 7d, the int was converted. (9-b) to N- [2- (3-chlorobenzoyl) -4- (4-chlorobenzoyl) -phenyl] acetamide (int.9-c). d) Using the same reaction procedure described in example 7a, it became int. (9-c) to 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -2- (lH) -quinilinone (int.9-d).
d) Sodium hydride (601 g) was added in portions under reflux from 2 to a solution of int. (9-d) (15 g) in dimethylsulfoxide (200 ml). The mixture was stirred at room temperature for 30 minutes. 2-Chloromethyl ether (25.2 ml) was added. The mixture was stirred at 50 ° C for 72 hours, poured on ice and extracted with ethyl acetate. The organic layer was separated, washed with dried 10% K2CO3 (MgSO4), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 70/30). The pure fractions were collected and the solvent was evaporated, yielding 602 g (36%) of 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -l- (2-methoxyethyl) -2 (lH) -quinoline. (int 9-e) f) Using the same reaction procedure described in Example 7j, it became int. (9-e) a (±) -4- (3-chloro-enyl) -6- [(4-chloro-enyl) -hydroxymethyl-1- (2-methoxyethyl) -2 (lH) -quinolinone (int. F). g) Using the same procedure as the reaction described in example 7k, the int was converted. (9-f) a (±) -6-Cchloro (4-chlorofenyl) methyl] -4- (3-chlorofenyl) -l- (2-methoxyethyl) -2 (lH) -quinolinone 8int. 9-g).
EXAMPLE 10
a) n-Butyl lithium (37.7 ml) was added slowly at -20 ° C under flow of 2 to a mixture of 6-bromo-4- (3-chlorophenyl) -2-methoxyquinoline 820 g) in THF 8150 ml). The mixture was stirred at -20 ° C for 30 minutes and then slowly added -20 ° C under a flow of 2 to a mixture of ethyl 4-chloro-a-oxobenzeneacetate (12.2 g) in THF (80 ml). The mixture was allowed to warm to room temperature and was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (MgSO), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / cyclohexane 90/10). The desired fractions were collected and the solvent was evaporated, yielding 9.3 g (33.5%) of (±) -ethyl 4- (3-chlorophenyl) -a-hydroxy-2-methoxy-6-quinolinoacetate (int. b) Intermediate (10-a) (9.3 g) and 1.1-carbonylbis-lH-imidazole 822 g) were heated at 120 ° C for 1 hour. The mixture was cooled. Ice was added slowly and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2 / Cl / 2-propane / NH..0H 95/5 / 0.5), giving 7.15 g of (4- (3-chlorophenyl) -a - ((chlorophenyl) -a- (lH-imidazol-1-yl) -2-methoxy-6-quinolinoacetate of (±) -ethyl (int.10-b).
B. PREPARATION OF FINAL COMPOUNDS EXAMPLE 11
A mixture of int. (1-c) (22.8 g) and aluminum chloride (48 g) in chlorobenzene (200 ml) at 95 ° C overnight. The mixture was cooled, poured into ice water, basified with NH 4 OH and evaporated to dryness. The residue was taken up in DCM and ethanol. The residue was filtered and evaporated. The residue was taken up in DCM and stirred with 3N HCl overnight. The mixture was extracted, the aqueous layer was washed with ethyl acetate, basified then extracted with ethyl acetate and the organic layer was dried (MgSO ^) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl / 2 CH 3 OH / NH 4 OH 95/5/0, 5) (35-7 μm). The pure fractions were collected and the solvent was evaporated, yielding 2.13 g (16%) of (±) -6 - [(1H-imidazol-1-yl) phenylmethyl] -4-phenyl-2- (1H) -quinolinone, pf 243.0 ° C (comp.1)
EXAMPLE 12
Sodium hydride (0.002 g) and then 1,1'-carbonylbis-lH-imidazole (2.5 g) were added per portion at room temperature to intermediate (2-b) (2.8 g) dissolved in THF 830 ml) and the mixture was stirred and heated at 60 ° C for 1 hour. The mixture was hydrolyzed with water and evaporated. The residue was taken up in DCM and washed with water. The organic layer was dried (MgSOu), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: toluene / 2-propanol / NH /; 0H 90/10 / 0.5). The pure fractions were collected and evaporated. The residue (2.1 g) was crystallized with 2-pro-anonane, giving 1.55 g (48%) of (±) -6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -3,4-dihydro -4-pheny1-2 (1H) -quinoli ona, mp225.0 ° C (Compound 57).
EXAMPLE 13
A mixture of intermediate 3 (11.6 g), imidazole (6.5 g) and potassium carbonate (13.8 g) in ACN (150 ml) was heated at reflux for 12 hours. The mixture was evaporated to dryness, the residue was taken up in water and extracted with dichloromethane. The organic layer was dried (MgSO *), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95/5) (70-200 μm). The pure fractions were collected and evaporated, yielding 9 g (71%) of (±) -6 - [(3-fluorophenyl) (lH-imidazol-1-yl) methyl] -4-phenyl-2 (lH) - quinolinone, pf 225, 0 ° C (comp 5).
EXAMPLE 14
Sodium hydride (1.15 g) was added in portions
° C under N 2 to a mixture of compound (2) (10 g) in DMF (100 ml) and the mixture was stirred at room temperature for 30 minutes. Ethanol iodine 81.5 ml) was added dropwise at 15 ° C and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water and filtered. The precipitate was taken up in a mixture of DCM and methanol. The organic layer was dried (MgSO *), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluting: ethyl acetate / CH30H95 / 5). The pure fractions were collected and evaporated. The residue (3.3 g) was recrystallized with CH3CN / DIPE, giving 1.9 g 819%) of (±) -6-C (4-chlorophenyl) -lH-imidazol-1-yl-methyl] -1-methyl-1 4-f-enyl .2 (1H) -quinolinone, mp. 154.7 ° C (comp.8).
EXAMPLE 15
A solution of sodium methoxide in methane (82.8 ml) was added dropwise to a mixture of compound (82) (6 g) and diphenyliodonium chloride (6.9 g) in methanol (400 ml). Copper (I) chloride (1.72 g) was added and the mixture was stirred and heated at 60 ° C for 12 hours. The mixture was filtered over celite and the filtrate evaporated. The residue was taken up in DCM and 10% NH 4 OH. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried (MgSO 4), filtered and evaporated in vacuo to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.1). The pure fractions were collected and evaporated. The residue (1.1 g) was dissolved in CH 3 OH and converted to the nitric acid salt (1: 1) in / CH 3 OH, giving 0.9 g (11.2%) of mononitrate of (±) -6 - [(4-clo rof enyl) -lH-imidazol-1-i 1-meti 1] -1,4-dif eni 1-2- (1H) -quinolinone, mp 212 ° C (comp.19).
EXAMPLE 16
Potassium salt of 2-methyl-2-propanol (135 g) was added in portions at 0 ° C under N 2 to a mixture of compound (15) (2.8 g) and iodomethane (1.9 ml) in tetrahydrofuran (85 ml) and The mixture was stirred at room temperature for 5 minutes. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO,), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97.5 / 2.5 / 0.1). The pure fractions were collected and evaporated. The residue (2.3 g) was recrystallized with CH3OH and diethyl ether, yielding 1.7 g (60%) of (±) -4- (3-cyclo-phenyl) -6- [1- (4-chlorophenyl) -l- (lH- imidazol-l-yl) ethyl] -methyl-2 (lH) -quinolinone, mp 120.2 ° C (comp 62).
EXAMPLE 17
A mixture of int was stirred and heated to reflux. 4
(17.6 g) and imidazole (9.3 g) in ACN (250 ml), then cooled to room temperature. The precipitate was filtered, washed with an aqueous solution of 10% K2CO3 and diethyl ether, then air-dried, yielding 11.2 g (55%) of product. A sample (3g) was recrystallized from THF, methanol, diethyl ether. The precipitate was filtered and dried, yielding 2 g (37%) of (±) -6- [1- (4-chlorofluoryl) -2-hydroxy-1- (1H-imidazol-1-yl) ethyl] - 1-methyl 1-4-phenyl-2 (lH) -quinolinone, mp 180 ° C (comp 59).
EXAMPLE 18
1-Chloromethylbenzene (83.2 g) was added to a solution of compound 59 (7 g) and benzyltriethylammonium chloride (1.75 g) in sodium hydroxide (40%) (100 ml) and THF (100 ml) and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added. The organic layer was decanted, washed with water, dried (MgSO?), Filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH2CI2 / CH30H / NH.0.0 98.5 / 1.5 / 0.1). The pure fractions were collected and evaporated. The residue (3.7 g) was recrystallized with 2-propanone / C2Hs) 2 ?, giving 2.1 g (24%) of (±) -6- [1- (4-chlorophenyl) -2 - [(4-chlorophenyl) - 2 - [(4-Clo rofyl) methoxy] - (1H-imidazol-1-yl) ethyl] -1-methyl-1-4-phenyl -2 (lH) -quinolinone, mp 176.8 ° C (compare 61).
EXAMPLE 19
Sodium methoxide (0.8 ml) was added at room temperature to a solution of intermediate 5-d in methanol (100 ml), the mixture was stirred at room temperature overnight and then stirred and heated at reflux for 2 hours. Water was added and the mixture was extracted with DCM. The organic layer was dried (MgSO). filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.1). The pure fractions were collected and evaporated, yielding 8.3 g (79%) of product. A sample (2.3 g) was converted to the ethanoic acid salt (82.3) and recrystallized from 2-propanone, giving 2.35 g (63%) of (±) -methyl-4-amino-1 - [(4)) ethanedioate. chlorophenyl) (1,2-dihydro-l-methyl-2-oxo-4-phenyl-6-quinolini) -methyl] -lH-imidazole-5-carboxylate (2: 3); p.f. 168.7 ° C (comp.70).
EXAMPLE 20
Nitric acid (30 ml) was added followed by sodium nitrite (0.64 g) at 0 ° C to a solution of compound 70 (4.6 g) in phosphoric acid (45 ml) and the mixture was stirred at 0 ° C for 45 minutes. Hypophosphorous acid (30 ml) was carefully added in portions and the mixture was stirred at room temperature for 1 hour. The mixture was poured onto ice, basified with NH 4 OH and extracted with ethyl acetate. The organic layer was dried (MgSO¿), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98.5 / 1.5 / 0.1). The pure fractions were collected and the residue evaporated (1.5 g) was converted to the ethanoic acid salt (2: 3) and recrystallized with 2-propanone and DIPE, giving 1.14 g (20%) of (±) ethanedioate. -methyl-l - [(4-chlorophenyl) (1,2-dihydro ro-1-methyl-2-oxo-4-f-enyl-6-qui-nol-ini-1) -methyl] -lH-imidazole-5- carboxylate (2: 3), p. f. 140.8 ° C (comp.54).
EXAMPLE 21
Int was added (6-b) (15.66 g) to sulfuric acid (120 ml) which was cooled to 0 ° C and the mixture was stirred at room temperature overnight. The mixture was carefully added to a solution cooled to 0 ° C of ice and concentrated NH40H. The basic aqueous layer was extracted with DCM, the organic layer was dried (MgSOí), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent:
CH2Cl2 / CH3OH / NH4OH 97.5 / 2.5 / 0.2). The pure fractions were collected and evaporated, yielding 7.4 g (52%) of product. A sample was crystallized with 2-propanone, giving 2 g of (±) -6- [4-chlorofenyl] - [2- (methyl thio) -lH-imidazol-1-yl] methyl] -4-phenyl - 2 (lH) -quinolinone monohydrate, p. f. 205.6 ° C (comp.51) EXAMPLE 22
A solution of compound 17 (12.7 g) in sodium hydroxide (3N) (130 ml) was stirred at 120 ° C overnight. The mixture was cooled to room temperature and NH4OH was added until obtaining pH = 5.2. The precipitate was filtered, washed with water and air dried, yielding 12 g of (±) -6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -2-oxo-4-phenyl-1 ( 2H) -quinoline-1-acetic acid (Compound 38).
EXAMPLE 23
At room temperature, N, N-metatraylyl-biscyclohexanamine (5.3 g) in DCM was added dropwise to a mixture of compound 38 (12.4 g) in methyl 2-amino-4-methyl-pentoate (6 g) in THF (120 ml) and 1-hydroxybenzothiazole hydrate and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO-v), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1). The pure fractions were collected and evaporated, yielding 6.8 g (43%) of product. A sample was crystallized with DIPE, yielding 1 g of 2 [[2-6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -l, 2-dihydro-2-oxo-4-phenyl-1- quinolyl] -2-oxoethyl-lamino] -4-methylpentanoate of (±) -methyl, mp 117.9 ° C (comp. 39).
EXAMPLE 24
Compound 2 (1 g) was dissolved in n-hexane (81 ml) and ethanol (54 ml). This solution was separated and purified by column chromatography on a Chiralcel AD column (250 g, 20 μm, Daicel, eluent: n-hexane / ethanol 60/40% vol). Two fractional groups were collected. The fractions, corresponding to the first chromatographic peak, were evaporated. The residue was dissolved in small amounts of DCM. Diethyl ether was added until precipitation occurs. The precipitate was filtered by a Millipore filter 810 μm), then dried (vacuum, 40 ° C, 2 hours), giving 0.430 g (43%). This fraction was dissolved in 2-propanone and precipitated with DIPE. The precipitate was filtered and dried, yielding 0.25 g (25%) of (±) - (A) -6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -4-phenyl-2 (lH) - quinolinone; p.f. 190, 0 ° C; a [a] D20 = 13.10 ° C (c = 0.1% in methanol) (Comp.6). The fractions corresponding to the second chromatographic peak were evaporated. The residue was dissolved in small amounts of DCM. Diethyl ether was added until precipitation occurs. The precipitate was filtered on a Millipore filter 10 μm, then dried (vacuum, 40 ° C, 2 hours), giving 0.410 g (41%). This fraction was dissolved in 2-propanone and precipitated with DIPE. The precipitate was filtered and dried, giving 0.20 g (20%) of (-) - (B) -6 - [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] -4-phenyl-2 (lH) - quinolinone; p.f. 155, 8 ° C;
[OÜD20 = 6.32 ° C (c = 0.1% in methanol) (comp.7).
EXAMPLE 25
Phosphorus pentasulfide (4.45 g) was added per portion at room temperature to a solution of (±) -4- (3-cyclo rofyl) -6-C (4-chlorofluoryl) -lH-imidazol-1-ylmethyl. ] -4-f-enyl-2 (lH) -quinolinone (4.5 g) in pyridine (54 ml) and the mixture was stirred and heated to reflux for 4 hours. The mixture was evaporated to dryness and the residue taken up in ethyl acetate. The organic layer was washed with HCl and water, dried (MgSO,), filtered and evaporated to dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 97/3). The pure fractions were collected and evaporated. The residue (2.7 g) was crystallized with DMF, yielding 1.6 g (33%) of (±) -4- (3-chlorophenyl) -6- [(4-chlorophenyl) -lH-imidazol-1-yl-methyl] -2 (lH) -quinolinothione monohydrate; p.f.
263, 5 ° C (comp.72).
EXAMPLE 26
Imidazole (83.34 g) was added to a solution of int.
(8-b) (3.7 g) in ACN (50 ml). The mixture was stirred and heated to reflux for 4 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO-4), filtered and evaporated to dryness. The residue (3.8 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue (2.7 g) was crystallized with 2-propanone / DIPE and dried, giving 1.8 g (45%) of (±) -6- [(4-chlorophenyl) -lH-imidazol-1-ylmethyl] ethanedioate] -methyl-4- (3-propoxyphenyl) -2- (lH-quinolinone (2: 3) sesquihydrate (Compound 74).
EXAMPLE 27
A mixture of int was stirred at 120 ° C for 2 hours. (10-b) (7.1g) in THF (825 ml) and 3N HCl (190 ml). The mixture was veined in ice, basified with K2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO *), filtered and evaporated, yielding 6.2 g (90%) of (±) -ethyl-4- (3-chlorophenyl) -alpha- (4-chlorofenyl) -1. , 2-dihyd ro-alpha- (1H-imidazol-1-yl) -2-0x0-6-quinolinacetate (Compound 87).
TABLE I
TABLE 2
or. Ex. Rj R- D3 R ~ o. No. i = physical atos
0 i- 1 H H H 2 -CH 3 p.f. > 260'C
47 • 13! H H H 4- phenyl "p.f. 40-C 1 48 13; K H u 4-CK3 p.f. 260'C 1 49 13 | K H 5 -CH 3 p.f. > 260'C
fifty _; > H H H 2- fer.ilo p.f. 160 * C
51 -. 51 -i H H H. H20 1 ^ 'I 1' T-7 _ i. C] H 4-CH 3 - * "• il HC n 5 -CH - 20 CH 3 HH 5 -CO-OCK 3, p.f. 140'C / .3 / 2C2H2? - 5 14 CH;, Ci H ^ -Ct ^ ~ p. F .145 ° C / .3 / 2C2H20
5o 20 CH3 Ci H 5 -CO- CH3! P- * ~ .170oC / .3 / 2C2H2?
26 CK3 Ci 2-fer. lo - Só 26 CH Cl u? i 2-femlo .C2H2O4
S3 26 CH-, -0 -CH2- C- * H C2H20 ^
*: R2 and R3 together to form a bivalent radical TABLE 3
TABLE 4
i. Rl R2 R Rd RS Physical data or 12 H H H j -Cl CH3! 255'C r CK3 H K r- 'CH2-OK p.f.160-170"C / .H2O! 12 H H H L 4. chlorophenyla 1> 260'C / i / ZH O
18 CH3 H K 4-c: 4-chlorobenzyl. 180'C 1 1 oxunetil 16 CH3 3-C1 H ^ v_? CH3 _, r T ^ 'C 1 16 CH3 3-C1 H 1 -c: CH2CK3 p. £ .158 * C /' CH? C .H? 0 1 l 1 CH3 3-C1 5-CK3] ~ - C! CH3 íj.f.po'C 16 'CH3 3-C1 u ¿-C. (CK2J2CK iD. ± 16D'C, HCl H20
I CH3 3-C1 H 4-C. - CH2-OH p.f. ISO'C
18 CH3 3-C1 H -C-CK2-OCH3 p.f. : 7S'C C H2O.
* CH3 3-C1 K 4-C CH: -N (CH3J2 pf6-1! O'C 1 'CH3 3-C1 H 4-C CH2-S-CK3? .I.120-150'C C2H O- H; 0 3-C1 K 4-C. -COOCH 2 CH 3 CH-3-C! 4.r -COOCHoCH- TABLE 5
Co. lEj. R 'R4 R5 R6 Physical data No.! Do not. 70 I 19 I H 4- ^ 2 I 5 -COOCH3; 4-Cl ¡p.f.168.7'C / .3 / 2C2H,? 4? i 19 3-C1 '4-NH? í 5-COQCH. 4-Cl!
TABLE 6
V_0 3- X, R:, R2 R6 RIO Rn 1 Physical data
No. 1 No. 1 '1 1 72 1 25' s K! 3-C1 4-Cl H H p.f.263.5'C / .K20
73 i 25 s CH3 i 3-C1. 4-Cl H H | p.f.161.rC / .l / 2K20
89 '26 0 CH3 3-C1 4-Cl S-Cm | ! '0 K' 3-C1 1 -C 1 --CH-- 8-CH- p.f. lOL'C C. Pharmacological example Example 28: In vitro assay for the inhibition of farnesyl protein transferase
Human farnesylprotein transferase was prepared essentially as described by Y.Reiss et al., Methods: A Complement of Methods in Enzymology vol 1, 241-245, (1990). Human osteosarcoma cells transformed with Kirsten virus (KHOS) (American Type Culture Collection, Rockville, MD, USA) cultured as solid tumors in peeled mice or as monostratified cell cultures as human enzyme source were used. Briefly, cells or tumors were homogenized in buffer containing 50 M Tris, 1 M EDTA, 1 M EGTA and 0.2 mM phenyl ethylsulfonyl fluoride (pH 7.5). The homogenates were centrifuged at 28,000 x g for 60 min, and the supernatants were collected. A fraction of 30-50% ammonium sulfate was prepared, and the resulting precipitate was resuspended in a small volume (10 to 20 m) of dialysis buffer containing 20 mM Tris, 1 mM dithiothreitol and 20 μM ZnCl2. The ammonium sulfate fraction was dialyzed overnight against two changes of the same buffer. The dialyzed material was applied to a 10 x 1 cm Q Fast Flow Sepharose column (Pharmacia LKB Biotechnology Inc., Piscataway, NJ, USA) which had previously been equilibrated with an additional 50 ml of dialysis buffer plus 0.05 M NaCl followed by a gradient of between 0.05 M and 0.25 M NaCl prepared in the dialysis buffer: The enzymatic activity was eluted with a linear gradient of 0.25 to 1.0 M NaCl prepared in the dialysis buffer. Fractions containing 4 to 5 ml of the eluate from the column were collected and analyzed to determine farnesyl protein transferase activity. Fractions with enzymatic activity were pooled and supplemented with 100 μM ZnCl2. The enzymatic samples were stored frozen at 70 ° C. The farnesyl protein transferase activity was measured using the [3 H] Farnesyl Transferase Centello Proximity Assay (Amersham International Foot, England) under the conditions specified by the manufacturer. To analyze the inhibitors of the enzyme, 0.20 μCi of the substrate of [3 H] -farnesylpyrophosphate and the peptide substrate the in. Biotinylated B (biotin-YRASNRSCAIM) with the test compounds in a reaction buffer consisting of 50 M HEPES, 30 mM MgCl-2, 20 M KCl, 5 mM dithiothreitol, 0.01% Triton X-100 . The test compounds were deposited in a volume of 10 μl of di-ethylsulfoxide (DMSO) to obtain concentrations of 1 and 10 μg / ml in a final volume of 100 Ml. The reaction mixture was heated to 37 ° C. The enzymatic reaction was initiated by adding 20 μl of diluted human farnesylprotein transferase. Sufficient enzyme preparation was added to produce between 4000 and 15000 cpm of the reaction product during the 60 min incubation of the reaction at 37 ° C. The reactions were suspended by the addition of proximity flask reagent / STOP (Amersham). The reaction product, lamin peptide. B [3 H] -pharnesyl (Cys) -biotin was captured in the proximity bead of scintillation bound in streptavidin. The amount of lamin peptide. B C3H] -farnesyl (Cys) -biotin synthesized in the presence or absence of the test compounds was quantified in cpm by counting in an Eallac Liquid Centello Conductor, Model 1480 Microbeta. The cpm of the product was considered farnesylprotein transferase activity. The protein activity of the farnesyltransferase observed in the presence of the test compound was normalized to farnesyltransferase activity in the presence of 10% DMSO and expressed as percent inhibition. In separate studies, some test compounds exhibiting 50% or more inhibition of the farnesyltransferase protein were evaluated for the concentration-dependent inhibition of enzyme activity. The effects of the test compounds in these studies were calculated as Clso (concentration of the test compound that produces 50% inhibition of enzyme activity) using the computer program LGIC50 written by the Science Information Division of R.W. Johnson Pharmaceutical Research Institute (Spring House, PA, U.S.) on a VAX computer.
TABLE 7
15
EXAMPLE 29 REVERSION TEST OF CELL PHENOTYPES TRANSFORMED BY Ras
The insertion of activated oncogenes such as the mutant ras gene into mouse NIH 3T3 cells converts the cells to a transformed phenotype. The cells become rogeneous, exhibit independent development of the anchor in semi-solid medium and lose contact inhibition. The loss of contact inhibition produces cell cultures that no longer form uniform monolayers. On the contrary, the cells are stacked in multicellular nodules and grow at very high saturation densities in plastic tissue culture disks. Agents, such as farnesyltransferase inhibitors that reverse the transformed phenotype by ras restores the uniform monolayer development pattern to the cells of the culture. This reversal is easily monitored by counting the number of cells that have reverted to an untransformed phenotype. Compounds that reverse the transformed phenotype must produce antitumor effects in tumors that contain ras gene mutations.
Method
The compounds are classified in tissue culture in NIH 3T3 cells transformed by the human H-ras gene activated with T24. The cells are seeded at an initial density of 200,000 cells per receptacle 89.6 cm2 surface area) in clustered tissue culture plates of six receptacles. The test compounds are immediately added to 3.0 ml of 0.1% cell culture medium. The test compounds are analyzed in concentrations of 5, 10, 50, 100 and 500 nM together with the control vehicle treated with DMSO. (If a high activity is observed at 5 nM, the test compound is analyzed at even lower concentrations, the cells are allowed to proliferate for 72 hours, then the cells are separated in a dissociation medium of 1.0 ml trypsin-EDTA and They are counted in a Coulter particle counter.
Measurements
The cell numbers expressed in cells per cell are measured using a Coulter particle counter. All cell counts are corrected for the initial cell income density minus 200,000. Control cell counts = [cell counts of cells incubated with vehicle DMSO-200,000]. Cell counts of the test compound = [-200,000]% inhibition of the test compound = Cl- cell counts with the test compound] x 100% IC50 control cell counts (ie, the concentration of the test compound needed to inhibit the activity enzymatic in 50%) is calculated if sufficient data are available, summarized in Table 8. TABLE 8
D. Examples of Compositions
The following formulations exemplify typical pharmaceutical compositions in unit dosage form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention. "Active ingredient" (l.A) is used in these examples to refer to a compound of the formula (1), a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof.
EXAMPLE 30 ORAL SOLUTIONS
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 liters of boiling purified water. In 3 liters of this solution, 10 g of 2,3-dihydroxybutadiene acid are first dissolved and then 20 g of l.A. This last solution is combined with the remaining part of the previous solution and 12 liters of 1,2,3-propanetriol and 3 liters of 70% sorbitol are added thereto. Dissolve 40 g of sodium saccharin in 0.5 liters of water and 2 ml of raspberry essence and 2 ml of gooseberry. The latter is combined with the previous one, water is added, amount necessary until obtaining a volume of 20 liters producing an oral solution comprising 5 mg of l.A. per teaspoon (5 ml). The resulting solution is packaged in suitable containers.
EXAMPLE 31 CAPSULES
g of the lA, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate are vigorously mixed. The resulting mixture is then filled into 1000 suitable hardened gelatin capsules, each of which comprises 20 mg of i. to.
EXAMPLE 32 TABLETS WITH FILM CLADDING
Preparation of the core of the tablet.
A mixture of 100 g of the i is mixed well. to. 570 g of lactose and 200 g of starch and then moistened with a solution of 5 g of sodium dodecylsulfate and 10 g of polyvinyl pyrrolidone in approximately 200 ml of water. The wet powder mixture is screened, dried and re-sifted. > Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are added. Everything is mixed well and compressed into tablets, giving 10,000 tablets, each of which contains 10 mg of i.a.
COATING
To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. This last solution is added to the previous one and then 2.5 g of magnesium octadecanoate, 5 g of polyvinyl pyrrolidone and 30 ml of concentrated color suspension are added and everything is homogenized. The cores of the boards are coated with the mixture thus obtained in a coating apparatus.
EXAMPLE 33: INJECTABLE SOLUTION
1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiled water for injection. After cooling to about 50 ° C, 4 g of lactic acid were added while stirring, 0.05 g of propylene glycol and 4 g of i. to. The solution was cooled to room temperature and supplemented with water for injection, amount necessary to obtain 1 1 volume, giving a solution of 4 mg / ml of i. to. The solution was sterilized by filtration and packaged in sterile containers.
EXAMPLE 34: SUPPOSITORIES
3 g of i.a. were dissolved in a solution of 3 g of 2,3-dihydroxybutadiene acid in 24 ml of polyethylene glycol 400. 12 grams of surfactant and 300 g of triglycerides were melted. This last mixture was mixed with the previous solution. The mixture thus obtained was poured into molds at a temperature of 37-38 ° C to form 100 suppositories, each of which contained 30 mg / ml of i.a.
Claims (12)
1. - A compound of the formula (I) a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt and the stereochemically isomeric forms thereof, in which the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, C1-2alkyl, Ari, Ar2C? β-alkyl, quinolinylCí-alkyl, pyridylCí-alkyl, hydroxyCi-βalkyl, Ci-βalkyloxyCi-βalkyl, mono- or di (C?-βalkyl) aminoC? -βalkyl, aminoCí-alkyl, or a radical of the formula -Alk1-C (= 0) -R9 or Alki-S (0) 2 -R9, where Alk is alkanediylCi-βalkyl, R * is hydroxy, Ci-βalkyl, Ci-βalkyloalkyloxy, amino, Ci-βalkylamino or Ci-βalkylamino substituted with Ci-βalkyloxycarbonyl; R2 and R3 - independently, are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, Ci-βalkyloxy, hydroxyCi-βalkyloxy, Ci-βalkyloxyCi-βalkyloxy, aminoCí-βalkyloxy, mono- or di (C?-Βalkyl) aminoC? -alkyloxy, Ar1, Ar2C? -alkyl, Ar2oxi, Ci-βalkyloxy, nidroxycarbonyl, Ci-βalkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-βalkenyl; or when they are in adjacent positions, R2 and R3 together can form a bivalent radical of the formula -0-CH2-0- (a-1) -O-CH2-CH2O- (a-2) -0-CH = CH- (a-3) -O-CH2-CH2- (a-4) -O-CH2-CH2-CH2- (a-5), or -CJ = CH-CH = CH- (a-6); each of * and R *, independently, is hydrogen, Ci-βalkyl, Ci-βalkyloxyCi-βalkyl, Ci-βalkyloxy, O-βalkylthio, aminohydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-βalkylS (O) Ci-βalkyl or Ci- ßalkyl (0) 2C? -alkyl; each of R6 and R? , independently, is hydrogen, halo, cyano, Ci-βalkyl, Ci-βalkyloxy or Ar 2 oxy; R8 is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-βalkylcarbonylCí-βalkyl, cyanoCCalßalkyl, Ci-βalkyloxycarbonylCí-βalkyl, hydroxycarbonylCí-alkyl, hydroxyCi-βalkyl, to inoCy-βalkyl, mono- or di ( C? -alkyl) -aminoC? -alkyl, haloCy-alkyl, Ci-βalkyloxyCi-βalkyl, aminocarbonylCí-βalkyl,
Ari, Ar2C? -ßalkyloxyC? β-alkyl, Ci-βalkylthio-Cal-alkyl; Rio is hydrogen, Ci-βalkyl, Ci-βalkyloxy or halo; RH is hydrogen or Ci-βalkyl; Ari is phenyl or phenyl substituted with Ci-βalkyl, hydroxy, amino, Ci-βalkyloxy or halo; Ar2 is phenyl or phenyl substituted with Ci-βalkyl, hydroxy, amino, Ci-βalkyloxy or halo. 2. A compound as claimed in claim 1, wherein X is oxygen.
3. A compound as claimed in claim 1, wherein R1 is hydrogen, Ci-β alkyl or Ci-βalkyloxy alkyloxy.
4. A compound as claimed in claim 1, wherein R6 is hydrogen, and R7 is halo.
5. A compound as claimed in claim 1, wherein R8 is hydrogen, Ci-β alkyl or hydroxyalkylCi -2.
6. A compound as claimed in claim 1, wherein the compound is: 4- (3-chlorophenyl) -6- [(4-chlorophenyl) -1H-imidazol-1-ylmethyl] -1-methyl- 2 (1H) -quinolinone; 4- (3-chlorophenyl) -6- [(4-chlorophenyl) -lH-1-idazol-1-ylme i1] -2- (1H) -quinolinone; 6- [1- (4-chlorophenyl) -2-hydroxy-1- (1H-imidazol-1-yl) ethyl] -l-methyl-4-phenyl-2 (1H) -quinolinone; 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -l- (1H-imidazol-1-yl) ethyl] -1-methyl-2 (1H) -quinolinone; 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -l- (5-methyl-lH-imidazol-1-yl) ethyl] -1-methyl-2- (1H) -quinolinone; 4- (3-chlorophenyl) -6- [1- (4-chlorophenyl) -2-hydroxy-1- (1H-imidazol-1-yl) ethyl] -l-methyl-2 (1H) -quinolinone; Etandioate of 4- (3-cyclo-phenyl) -6 - [(4-chlorophenyl) - (1H-imidazol-1-yl) -methyl] -l- (2-methoxyethyl) -2 (1H) -quinolinone (2: 3) ) monohydrate; Etandioate of 6 - [(4-chlorophenyl) - (1H-imidazol-1-yl) methyl] -4- (1, 3-benzodioxol-5-yl) -l-methyl-2 (1H) -quinolinone; (1: 1); a rheoisome form or a pharmaceutically acceptable acid or base addition salt thereof.
7. A pharmaceutically composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claims 1 to 6.
8. A process for preparing a pharmaceutical composition as claimed in claim 7 wherein the pharmaceutically acceptable carriers and the compound claimed in claims 1 to 6 are thoroughly mixed.
9. A compound of the formula (XVI) in which the radicals R, R3, R *, S, R6, 7, RS t RIO and RII are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
10. - A compound of the formula (XV) in which the radicals R2, R3, R *, R5, R6. 7 t Rβ t RIO and RII are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof. (XV)
11. - A compound as claimed in any of claims 1 to 6 for use as a medicament.
12. A process for preparing a compound as claimed in claim 1, characterized by a) N-alkylating an imidazole of the formula (II) or an alkali metal salt thereof with a solvent of the formula (III) ); (II) (III) b) reacting an intermediate of the formula (IV) with a reagent of the formula (V), in which Y is carbon or sulfur, such as, for example, an l, 1-carbonyl-bis [lH-imidazole); c) they can also be obtained by cyclizing an intermediate of the formula (VI), thus obtaining compounds of the formula (I-a), defined as compounds of the formula (I) in which the dotted line is a bond; d) hydrolyzing an intermediate of the formula (XXVI), in which R is Ci-β alkyl, in an aqueous acid solution, giving a compound of the formula (Ia) defined as a compound of the formula (Ia) in which R 1 it is hydrogen; e) opening an epoxide of the formula (VII) with an imidazole of the formula (II) thereby obtaining a compound of the formula (I-b), defined as a compound of the formula (I) in which R8 is hydroxymethylene; (VII) f) transforming intermediate nitrones of the formula (XV), prepared N-oxidizing quinoline derivatives of the formula (XVI), either by formation of esters and subsequent hydrolysis or by means of an intramolecular photochemical transformation, thus giving the compounds of the Formula (IfI) or, if desired, converting a compound of the formula (I) to a pharmaceutically acceptable acid addition salt, or, conversely, converting the acid addition salt to the free base form with an alkali; and / or preparing the stereochemically isomeric forms thereof. SUMMARY OF THE INVENTION The present invention relates to compounds of the formula (I) the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, C1-β alkyl, Ar1, Ar2C? β-alkyl, quinolinylCí-alkyl, pyridylCí-alkyl, hydroxyCi-βalkyl, Ci-βalkyloxyCi-βalkyl, mono- or di (C?-βalkyl) aminoC? -β-alkyl, aminoCi-β-alkyl, or a radical of the formula -Alk! -C (= 0) -R9 or Alk1-S (0) 2 -R9; R9 and R2 and R3, independently, are hydrogen, hydroxy, halo, cyano, halo, cyano, Ci-βalkyl, Ci-βalkyloxy, hydroxyCi-βalkyloxy, Ci-βalkyloxyCi-βalkyloxy, aminoC-βalkyloxy, mono- or di (C?); -alkyl) aminoC? -β-alkyloxy, Ar1, ArC? -alkyl, Ar2oxi, Ar2C? β-alkyloxy, hydroxycarbonyl, Ci-βalkyloxycarbonyl, trihalomethyl, trihalomethoxy, C 2 βalkenyl; or when they are in adjacent positions, R2 and R3 together can form a bivalent radical; each of R < and R5, independently, is hydrogen, Ci-βalkyl, Ci-βalkyloxyCi-βalkyl, Ci-βalkyloxy, Ci-βalkitium, amino, hydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-βalkylS (0) C? -β-alkyl or Ci-βalkylS (0) 2C? -alkyl; each of R6 and R? , independently, is hydrogen, halo, cyano, Ci-βalkyl, Ci-βalkyloxy or Ar 2 oxy; R8 is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-βalkylcarbonylCí-βalkyl, cyanoCCal -alkyl, Ci-βalkyloxycarbonyl Ci-βalkyl, hydroxycarbonylCí-βalkyl, hydroxyCi-βalkyl, aminoCí-βalkyl, mono- or di ( C? -alkyl) -aminoC? -alkyl, haloC? -alkyl, Ci-βalkyloxyCi-βalkyl, aminocarbonylCí-βalkyl, Ari, Ar C?-ΒalkyloxyC? β-alkyl, Ci-βalkylthio-Cal-alkyl; R o is hydrogen, Ci-βalkyl; Ci-βalkyloxy or halo; 11 is hydrogen or Ci-βalkyl; having farnesyltransferase inhibitory activity; its preparation the compositions that contain them and their use as medicine. P98 / 253F JP / amm * fac * elt * apm * mmm * blm *
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95202945.2 | 1995-10-31 | ||
EP95202945 | 1995-10-31 |
Publications (2)
Publication Number | Publication Date |
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MX9802067A MX9802067A (en) | 1998-08-30 |
MXPA98002067A true MXPA98002067A (en) | 1998-11-12 |
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