NO309565B1 - Nye farnesyl-transferase-inhibitorer, deres fremstilling og farmasöytiske preparater inneholdende disse - Google Patents

Nye farnesyl-transferase-inhibitorer, deres fremstilling og farmasöytiske preparater inneholdende disse Download PDF

Info

Publication number: NO309565B1
Authority: NO; Norway
Prior art keywords: phenyl; residue; mmol; acid; benzo
Prior art date: 1995-07-10

Application number

NO980094A

Other languages

English (en)

Norwegian (no)

Other versions

NO980094L (no

NO980094D0 (no

Inventor

Auguste Commeyras

Alain Lebrun

Patrick Mailliet

Jean-Francois Peyronel

Fabienne Sounigo

Alain Truchon

Martine Zucco

Original Assignee

Rhone Poulenc Rorer Sa

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-07-10

Filing date

1998-01-09

Publication date

2001-02-19

1998-01-09 Application filed by Rhone Poulenc Rorer Sa filed Critical Rhone Poulenc Rorer Sa

1998-01-09 Publication of NO980094D0 publication Critical patent/NO980094D0/no

1998-02-17 Publication of NO980094L publication Critical patent/NO980094L/no

2001-02-19 Publication of NO309565B1 publication Critical patent/NO309565B1/no

Links

238000002360 preparation method Methods 0.000 title claims description 17
239000000825 pharmaceutical preparation Substances 0.000 title claims description 4
239000003528 protein farnesyltransferase inhibitor Substances 0.000 title 1
239000002253 acid Substances 0.000 claims description 266
150000004702 methyl esters Chemical class 0.000 claims description 141
150000001875 compounds Chemical class 0.000 claims description 139
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 96
-1 hydroxy, amino Chemical group 0.000 claims description 67
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 40
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
229910052760 oxygen Inorganic materials 0.000 claims description 33
239000001301 oxygen Substances 0.000 claims description 33
229910052717 sulfur Inorganic materials 0.000 claims description 33
125000004434 sulfur atom Chemical group 0.000 claims description 33
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 31
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
125000000217 alkyl group Chemical group 0.000 claims description 26
125000004432 carbon atom Chemical group C* 0.000 claims description 24
229910052739 hydrogen Inorganic materials 0.000 claims description 23
238000006243 chemical reaction Methods 0.000 claims description 22
150000001412 amines Chemical group 0.000 claims description 19
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
239000001257 hydrogen Substances 0.000 claims description 18
239000003795 chemical substances by application Substances 0.000 claims description 16
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
230000003287 optical effect Effects 0.000 claims description 14
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
229910052757 nitrogen Inorganic materials 0.000 claims description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
238000000034 method Methods 0.000 claims description 11
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
150000008064 anhydrides Chemical class 0.000 claims description 10
150000004820 halides Chemical class 0.000 claims description 10
238000007127 saponification reaction Methods 0.000 claims description 10
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
125000001118 alkylidene group Chemical group 0.000 claims description 9
125000004414 alkyl thio group Chemical group 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 7
IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 7
150000002148 esters Chemical class 0.000 claims description 7
125000005843 halogen group Chemical group 0.000 claims description 7
230000000269 nucleophilic effect Effects 0.000 claims description 7
125000004076 pyridyl group Chemical group 0.000 claims description 6
229920006395 saturated elastomer Polymers 0.000 claims description 6
150000003512 tertiary amines Chemical class 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 5
125000004430 oxygen atom Chemical group O* 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 4
125000000623 heterocyclic group Chemical group 0.000 claims description 4
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
125000003342 alkenyl group Chemical group 0.000 claims description 3
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
239000012948 isocyanate Substances 0.000 claims description 3
150000002513 isocyanates Chemical class 0.000 claims description 3
239000000126 substance Substances 0.000 claims description 3
PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical group [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
238000007280 thionation reaction Methods 0.000 claims description 3
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
125000005842 heteroatom Chemical group 0.000 claims description 2
150000002540 isothiocyanates Chemical class 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 2
239000005977 Ethylene Substances 0.000 claims 2
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 1
125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims 1
125000004663 dialkyl amino group Chemical group 0.000 claims 1
ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims 1
125000001984 thiazolidinyl group Chemical group 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 453
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 213
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 169
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 158
238000002844 melting Methods 0.000 description 157
230000008018 melting Effects 0.000 description 157
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 149
239000000243 solution Substances 0.000 description 143
238000001819 mass spectrum Methods 0.000 description 140
125000003118 aryl group Chemical group 0.000 description 111
239000000843 powder Substances 0.000 description 106
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 95
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 94
238000003756 stirring Methods 0.000 description 86
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 76
239000000741 silica gel Substances 0.000 description 74
229910002027 silica gel Inorganic materials 0.000 description 74
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 72
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 71
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
238000010828 elution Methods 0.000 description 59
238000003818 flash chromatography Methods 0.000 description 59
238000000746 purification Methods 0.000 description 58
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
239000013078 crystal Substances 0.000 description 52
239000012074 organic phase Substances 0.000 description 49
238000010992 reflux Methods 0.000 description 48
229910052943 magnesium sulfate Inorganic materials 0.000 description 47
235000019341 magnesium sulphate Nutrition 0.000 description 47
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 40
239000000377 silicon dioxide Substances 0.000 description 38
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 36
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 34
238000001914 filtration Methods 0.000 description 34
239000011541 reaction mixture Substances 0.000 description 31
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
239000012043 crude product Substances 0.000 description 28
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 28
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 26
239000003960 organic solvent Substances 0.000 description 26
238000001953 recrystallisation Methods 0.000 description 26
238000005406 washing Methods 0.000 description 24
239000000203 mixture Substances 0.000 description 23
235000012239 silicon dioxide Nutrition 0.000 description 23
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 22
125000006239 protecting group Chemical group 0.000 description 21
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
239000003921 oil Substances 0.000 description 19
235000019198 oils Nutrition 0.000 description 19
239000002904 solvent Substances 0.000 description 19
239000000725 suspension Substances 0.000 description 19
239000003054 catalyst Substances 0.000 description 17
238000004587 chromatography analysis Methods 0.000 description 17
239000007787 solid Substances 0.000 description 17
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
125000004494 ethyl ester group Chemical group 0.000 description 15
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
238000010908 decantation Methods 0.000 description 14
IVEWTCACRDEAOB-UHFFFAOYSA-N 2-(2-methoxyphenyl)acetic acid Chemical compound COC1=CC=CC=C1CC(O)=O IVEWTCACRDEAOB-UHFFFAOYSA-N 0.000 description 13
238000001035 drying Methods 0.000 description 13
238000001816 cooling Methods 0.000 description 12
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
102000016914 ras Proteins Human genes 0.000 description 11
108010014186 ras Proteins Proteins 0.000 description 11
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 9
238000002425 crystallisation Methods 0.000 description 9
230000008025 crystallization Effects 0.000 description 9
238000010438 heat treatment Methods 0.000 description 9
239000002244 precipitate Substances 0.000 description 9
239000000047 product Substances 0.000 description 9
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 8
239000012153 distilled water Substances 0.000 description 8
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
229910052740 iodine Inorganic materials 0.000 description 8
239000002609 medium Substances 0.000 description 8
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 8
229910052938 sodium sulfate Inorganic materials 0.000 description 8
235000011152 sodium sulphate Nutrition 0.000 description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
239000002585 base Substances 0.000 description 7
239000012230 colorless oil Substances 0.000 description 7
230000032050 esterification Effects 0.000 description 7
238000005886 esterification reaction Methods 0.000 description 7
238000001704 evaporation Methods 0.000 description 7
230000008020 evaporation Effects 0.000 description 7
238000007327 hydrogenolysis reaction Methods 0.000 description 7
IQOSVINVIDSMQE-UHFFFAOYSA-N 2-(2-methoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=CC=C1C(=C)C(O)=O IQOSVINVIDSMQE-UHFFFAOYSA-N 0.000 description 6
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
230000009435 amidation Effects 0.000 description 6
238000007112 amidation reaction Methods 0.000 description 6
239000008346 aqueous phase Substances 0.000 description 6
230000007062 hydrolysis Effects 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
238000002329 infrared spectrum Methods 0.000 description 6
239000003208 petroleum Substances 0.000 description 6
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
HPTPZJBSQUULAV-UHFFFAOYSA-N 11-[(2-methylpropan-2-yl)oxycarbonylamino]undecanoic acid Chemical compound CC(C)(C)OC(=O)NCCCCCCCCCCC(O)=O HPTPZJBSQUULAV-UHFFFAOYSA-N 0.000 description 5
RGOJMRLSECAMJM-UHFFFAOYSA-N 2-(2-methoxyphenyl)-2-oxoacetic acid Chemical compound COC1=CC=CC=C1C(=O)C(O)=O RGOJMRLSECAMJM-UHFFFAOYSA-N 0.000 description 5
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 5
229910052783 alkali metal Inorganic materials 0.000 description 5
238000010790 dilution Methods 0.000 description 5
239000012895 dilution Substances 0.000 description 5
238000000921 elemental analysis Methods 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
238000000605 extraction Methods 0.000 description 5
239000000499 gel Substances 0.000 description 5
239000005457 ice water Substances 0.000 description 5
229910052500 inorganic mineral Inorganic materials 0.000 description 5
239000007788 liquid Substances 0.000 description 5
235000010755 mineral Nutrition 0.000 description 5
239000011707 mineral Substances 0.000 description 5
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 5
125000005372 silanol group Chemical group 0.000 description 5
239000012312 sodium hydride Substances 0.000 description 5
229910000104 sodium hydride Inorganic materials 0.000 description 5
CCVYRRGZDBSHFU-UHFFFAOYSA-N (2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1O CCVYRRGZDBSHFU-UHFFFAOYSA-N 0.000 description 4
BPUXSWXILWMDDD-HNNXBMFYSA-N (2s)-2-[(3,5-dinitrophenyl)methylamino]-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NCC=1C=C(C=C(C=1)[N+]([O-])=O)[N+]([O-])=O)C1=CC=CC=C1 BPUXSWXILWMDDD-HNNXBMFYSA-N 0.000 description 4
MSFLKDPXWDHGHU-UHFFFAOYSA-N 2-(2-propan-2-yloxyphenyl)acetic acid Chemical compound CC(C)OC1=CC=CC=C1CC(O)=O MSFLKDPXWDHGHU-UHFFFAOYSA-N 0.000 description 4
ZPZDIFSPRVHGIF-UHFFFAOYSA-N 3-aminopropylsilicon Chemical compound NCCC[Si] ZPZDIFSPRVHGIF-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
102000007317 Farnesyltranstransferase Human genes 0.000 description 4
108010007508 Farnesyltranstransferase Proteins 0.000 description 4
QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 4
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
230000000903 blocking effect Effects 0.000 description 4
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
238000009833 condensation Methods 0.000 description 4
230000005494 condensation Effects 0.000 description 4
230000000694 effects Effects 0.000 description 4
LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 4
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210000002966 serum Anatomy 0.000 description 1
KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 description 1
JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
229960001922 sodium perborate Drugs 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
239000012265 solid product Substances 0.000 description 1
KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
229910000080 stannane Inorganic materials 0.000 description 1
239000001119 stannous chloride Substances 0.000 description 1
235000011150 stannous chloride Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
230000001954 sterilising effect Effects 0.000 description 1
238000004659 sterilization and disinfection Methods 0.000 description 1
239000003206 sterilizing agent Substances 0.000 description 1
229940014800 succinic anhydride Drugs 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000003826 tablet Substances 0.000 description 1
SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
239000005051 trimethylchlorosilane Substances 0.000 description 1
ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 description 1
AALUTIYNYXEFNT-UHFFFAOYSA-N trimethylsilane hydroiodide Chemical compound C[SiH](C)C.I AALUTIYNYXEFNT-UHFFFAOYSA-N 0.000 description 1
LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
239000002966 varnish Substances 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
238000001262 western blot Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/72—4,7-Endo-alkylene-iso-indoles
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Molecular Biology (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Indole Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

NO980094A 1995-07-10 1998-01-09 Nye farnesyl-transferase-inhibitorer, deres fremstilling og farmasöytiske preparater inneholdende disse NO309565B1 (no)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
FR9508296A FR2736641B1 (fr)	1995-07-10	1995-07-10	Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR1996/001062 WO1997003050A1 (fr)	1995-07-10	1996-07-08	DERIVES DE 4,9-ETHANO-BANZO(f)ISOINDOLE COMME INHIBITEURS DE FARNESYL TRANSFERASE

Publications (3)

Publication Number	Publication Date
NO980094D0 NO980094D0 (no)	1998-01-09
NO980094L NO980094L (no)	1998-02-17
NO309565B1 true NO309565B1 (no)	2001-02-19

Family

ID=9480830

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO980094A NO309565B1 (no)	1995-07-10	1998-01-09	Nye farnesyl-transferase-inhibitorer, deres fremstilling og farmasöytiske preparater inneholdende disse

Country Status (32)

Country	Link
US (1)	US5936097A (cs)
EP (1)	EP0839133B1 (cs)
JP (1)	JPH11511123A (cs)
KR (1)	KR19990028856A (cs)
CN (1)	CN1096448C (cs)
AR (1)	AR003143A1 (cs)
AT (1)	ATE185341T1 (cs)
AU (1)	AU712194B2 (cs)
BR (1)	BR9609440A (cs)
CA (1)	CA2224414A1 (cs)
CO (1)	CO4700457A1 (cs)
CZ (1)	CZ291620B6 (cs)
DE (1)	DE69604588T2 (cs)
DK (1)	DK0839133T3 (cs)
EA (1)	EA000797B1 (cs)
ES (1)	ES2139373T3 (cs)
FR (1)	FR2736641B1 (cs)
GR (1)	GR3031409T3 (cs)
IL (1)	IL122812A (cs)
MA (1)	MA23929A1 (cs)
MX (1)	MX9800262A (cs)
MY (1)	MY114792A (cs)
NO (1)	NO309565B1 (cs)
NZ (1)	NZ313211A (cs)
PE (1)	PE11898A1 (cs)
PL (1)	PL324430A1 (cs)
SK (1)	SK282250B6 (cs)
TN (1)	TNSN96098A1 (cs)
TW (1)	TW438792B (cs)
UY (1)	UY24276A1 (cs)
WO (1)	WO1997003050A1 (cs)
ZA (1)	ZA965868B (cs)

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US6124465A (en) *	1997-11-25	2000-09-26	Rhone-Poulenc S.A.	Farnesyl transferase inhibitors, their preparation, the pharmaceutical compositions which contain them and their use in the preparation of medicaments
AU1767599A (en) *	1997-12-23	1999-07-19	Aventis Pharma S.A.	Novel farnesyl transferase inhibitors, preparation, pharmaceutical compositions containing them and use for preparing medicines
FR2772764B1 (fr) *	1997-12-23	2000-01-14	Rhone Poulenc Rorer Sa	Nouveaux inhibiteurs de farnesyle transferase, leur preparation, les compositions pharmaceutiques qui les contiennent et leur utilisation pour la preparation de medicaments
FR2787327B1 (fr) *	1998-12-21	2003-01-17	Aventis Pharma Sa	Compositions contenant des inhibiteurs de farnesyle transferase
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1995
- 1995-07-10 FR FR9508296A patent/FR2736641B1/fr not_active Expired - Fee Related
1996
- 1996-07-03 MA MA24302A patent/MA23929A1/fr unknown
- 1996-07-04 PE PE1996000510A patent/PE11898A1/es not_active Application Discontinuation
- 1996-07-05 TW TW085108158A patent/TW438792B/zh not_active IP Right Cessation
- 1996-07-08 NZ NZ313211A patent/NZ313211A/xx unknown
- 1996-07-08 DK DK96924952T patent/DK0839133T3/da active
- 1996-07-08 AT AT96924952T patent/ATE185341T1/de not_active IP Right Cessation
- 1996-07-08 PL PL96324430A patent/PL324430A1/xx unknown
- 1996-07-08 UY UY24276A patent/UY24276A1/es not_active IP Right Cessation
- 1996-07-08 CZ CZ199854A patent/CZ291620B6/cs not_active IP Right Cessation
- 1996-07-08 CN CN96195415A patent/CN1096448C/zh not_active Expired - Fee Related
- 1996-07-08 AU AU65224/96A patent/AU712194B2/en not_active Ceased
- 1996-07-08 US US08/981,840 patent/US5936097A/en not_active Expired - Fee Related
- 1996-07-08 IL IL12281296A patent/IL122812A/en not_active IP Right Cessation
- 1996-07-08 WO PCT/FR1996/001062 patent/WO1997003050A1/fr not_active Ceased
- 1996-07-08 EP EP96924952A patent/EP0839133B1/fr not_active Expired - Lifetime
- 1996-07-08 KR KR1019980700157A patent/KR19990028856A/ko not_active Ceased
- 1996-07-08 DE DE69604588T patent/DE69604588T2/de not_active Expired - Fee Related
- 1996-07-08 MX MX9800262A patent/MX9800262A/es not_active IP Right Cessation
- 1996-07-08 JP JP9505557A patent/JPH11511123A/ja active Pending
- 1996-07-08 SK SK26-98A patent/SK282250B6/sk unknown
- 1996-07-08 EA EA199800118A patent/EA000797B1/ru not_active IP Right Cessation
- 1996-07-08 ES ES96924952T patent/ES2139373T3/es not_active Expired - Lifetime
- 1996-07-08 BR BR9609440A patent/BR9609440A/pt not_active Application Discontinuation
- 1996-07-08 CA CA002224414A patent/CA2224414A1/fr not_active Abandoned
- 1996-07-09 TN TNTNSN96098A patent/TNSN96098A1/fr unknown
- 1996-07-10 MY MYPI96002848A patent/MY114792A/en unknown
- 1996-07-10 CO CO96036152A patent/CO4700457A1/es unknown
- 1996-07-10 AR ARP960103511A patent/AR003143A1/es unknown
- 1996-07-10 ZA ZA965868A patent/ZA965868B/xx unknown
1998
- 1998-01-09 NO NO980094A patent/NO309565B1/no unknown
1999
- 1999-10-07 GR GR990402001T patent/GR3031409T3/el unknown

Also Published As

Publication number	Publication date
DE69604588T2 (de)	2000-05-18
SK282250B6 (sk)	2001-12-03
ZA965868B (en)	1997-01-29
CN1190389A (zh)	1998-08-12
PE11898A1 (es)	1998-03-15
NZ313211A (en)	1999-11-29
WO1997003050A1 (fr)	1997-01-30
MX9800262A (es)	1998-04-30
PL324430A1 (en)	1998-05-25
TW438792B (en)	2001-06-07
BR9609440A (pt)	1999-06-29
ES2139373T3 (es)	2000-02-01
SK2698A3 (en)	1998-07-08
EA199800118A1 (ru)	1998-08-27
AU6522496A (en)	1997-02-10
IL122812A0 (en)	1998-08-16
DK0839133T3 (da)	2000-04-17
DE69604588D1 (en)	1999-11-11
MY114792A (en)	2003-01-31
EA000797B1 (ru)	2000-04-24
JPH11511123A (ja)	1999-09-28
NO980094L (no)	1998-02-17
FR2736641A1 (fr)	1997-01-17
EP0839133A1 (fr)	1998-05-06
UY24276A1 (es)	2001-10-25
FR2736641B1 (fr)	1997-08-22
GR3031409T3 (en)	2000-01-31
NO980094D0 (no)	1998-01-09
IL122812A (en)	2001-04-30
CA2224414A1 (fr)	1997-01-30
CN1096448C (zh)	2002-12-18
CZ291620B6 (cs)	2003-04-16
AR003143A1 (es)	1998-07-08
AU712194B2 (en)	1999-10-28
KR19990028856A (ko)	1999-04-15
TNSN96098A1 (fr)	2005-03-15
US5936097A (en)	1999-08-10
CO4700457A1 (es)	1998-12-29
EP0839133B1 (fr)	1999-10-06
ATE185341T1 (de)	1999-10-15
CZ5498A3 (cs)	1998-04-15
MA23929A1 (fr)	1997-04-01

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GB2061934A (en)	1981-05-20	Mercaptoacyldihydropyrazole carboxylic acid derivatives