CA2275943A1 - Inhibiteurs de farnesyle transferase - Google Patents
Inhibiteurs de farnesyle transferase Download PDFInfo
- Publication number
- CA2275943A1 CA2275943A1 CA002275943A CA2275943A CA2275943A1 CA 2275943 A1 CA2275943 A1 CA 2275943A1 CA 002275943 A CA002275943 A CA 002275943A CA 2275943 A CA2275943 A CA 2275943A CA 2275943 A1 CA2275943 A1 CA 2275943A1
- Authority
- CA
- Canada
- Prior art keywords
- 3ars
- methoxyphenyl
- 9ars
- hexahydro
- ethano
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 108
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 76
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 49
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 45
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 42
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 29
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 28
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 27
- 230000003287 optical effect Effects 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 102000007317 Farnesyltranstransferase Human genes 0.000 claims abstract description 10
- 108010007508 Farnesyltranstransferase Proteins 0.000 claims abstract description 10
- 229910052736 halogen Chemical group 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 6
- -1 alkyl radicals Chemical class 0.000 claims description 398
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 283
- 239000002253 acid Substances 0.000 claims description 231
- 150000003254 radicals Chemical class 0.000 claims description 146
- 125000004432 carbon atom Chemical group C* 0.000 claims description 107
- 125000003118 aryl group Chemical group 0.000 claims description 90
- 150000001875 compounds Chemical class 0.000 claims description 85
- 238000010992 reflux Methods 0.000 claims description 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 71
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 55
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 54
- 230000009471 action Effects 0.000 claims description 51
- 125000004429 atom Chemical group 0.000 claims description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 239000001301 oxygen Substances 0.000 claims description 45
- 239000011541 reaction mixture Substances 0.000 claims description 43
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 35
- 239000003960 organic solvent Substances 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 238000011282 treatment Methods 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
- 125000004434 sulfur atom Chemical group 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 22
- 239000011593 sulfur Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 150000001412 amines Chemical group 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 16
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
- 150000008064 anhydrides Chemical class 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 15
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 13
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 11
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 10
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 9
- 238000007127 saponification reaction Methods 0.000 claims description 9
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 210000004027 cell Anatomy 0.000 claims description 8
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 8
- 230000009466 transformation Effects 0.000 claims description 8
- 210000001072 colon Anatomy 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 230000004663 cell proliferation Effects 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 210000004185 liver Anatomy 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 150000002513 isocyanates Chemical class 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- 210000004072 lung Anatomy 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 210000000496 pancreas Anatomy 0.000 claims description 5
- 125000006665 (C2 to C4) alkoxycarbonyl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 238000006619 Stille reaction Methods 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 150000001543 aryl boronic acids Chemical class 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 150000002540 isothiocyanates Chemical class 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 210000003205 muscle Anatomy 0.000 claims description 3
- 210000001672 ovary Anatomy 0.000 claims description 3
- 230000007170 pathology Effects 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 210000003491 skin Anatomy 0.000 claims description 3
- 210000002784 stomach Anatomy 0.000 claims description 3
- 210000001550 testis Anatomy 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- 210000003932 urinary bladder Anatomy 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
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 210000002808 connective tissue Anatomy 0.000 claims description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims description 2
- 230000001926 lymphatic effect Effects 0.000 claims description 2
- 230000003211 malignant effect Effects 0.000 claims description 2
- 210000004216 mammary stem cell Anatomy 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000008026 nephroblastoma Diseases 0.000 claims description 2
- 125000002734 organomagnesium group Chemical group 0.000 claims description 2
- 230000002195 synergetic effect Effects 0.000 claims description 2
- 208000001608 teratocarcinoma Diseases 0.000 claims description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 2
- 210000001685 thyroid gland Anatomy 0.000 claims description 2
- 210000001519 tissue Anatomy 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims 6
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 6
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- NIZLCDXSMPCBME-UHFFFAOYSA-N 1,2,3,4,9,9a-hexahydrobenzo[f]isoindole-3a-carboxylic acid Chemical compound C1C2=CC=CC=C2CC2(C(=O)O)C1CNC2 NIZLCDXSMPCBME-UHFFFAOYSA-N 0.000 claims 1
- VORXAFJKNDAIRT-UHFFFAOYSA-N 1,2,3,6,7,8,8a,9-octahydrobenzo[f]isoindole-9a-carboxylic acid Chemical compound C1CCC2CC(CNC3)(C(=O)O)C3=CC2=C1 VORXAFJKNDAIRT-UHFFFAOYSA-N 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- LLNZWRSVTDNLHJ-UHFFFAOYSA-N benzo[f]isoindole-3a-carboxylic acid Chemical compound C1=C2C=CC=CC2=CC2(C(=O)O)C1=CN=C2 LLNZWRSVTDNLHJ-UHFFFAOYSA-N 0.000 claims 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- XQTIWNLDFPPCIU-UHFFFAOYSA-N cerium(3+) Chemical compound [Ce+3] XQTIWNLDFPPCIU-UHFFFAOYSA-N 0.000 claims 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 claims 1
- 210000004324 lymphatic system Anatomy 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 125000001979 organolithium group Chemical group 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims 1
- 210000005227 renal system Anatomy 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 230000000719 anti-leukaemic effect Effects 0.000 abstract description 2
- 125000003367 polycyclic group Chemical group 0.000 abstract description 2
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- 230000002476 tumorcidal effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 466
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 194
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 191
- 239000000203 mixture Substances 0.000 description 155
- 239000000047 product Substances 0.000 description 147
- 238000002844 melting Methods 0.000 description 129
- 230000008018 melting Effects 0.000 description 127
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 117
- 239000000243 solution Substances 0.000 description 116
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 89
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 86
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 82
- 238000001819 mass spectrum Methods 0.000 description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 77
- 238000003818 flash chromatography Methods 0.000 description 76
- 238000000746 purification Methods 0.000 description 72
- 239000000741 silica gel Substances 0.000 description 69
- 229910002027 silica gel Inorganic materials 0.000 description 69
- 239000000377 silicon dioxide Substances 0.000 description 65
- 239000007787 solid Substances 0.000 description 62
- 239000007864 aqueous solution Substances 0.000 description 57
- 230000002829 reductive effect Effects 0.000 description 57
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 55
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 50
- 239000000843 powder Substances 0.000 description 49
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 238000001953 recrystallisation Methods 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- 239000012153 distilled water Substances 0.000 description 39
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 36
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 238000002425 crystallisation Methods 0.000 description 32
- 230000008025 crystallization Effects 0.000 description 32
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 26
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 23
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 20
- 238000010908 decantation Methods 0.000 description 19
- 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 18
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 18
- 239000000499 gel Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 17
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 17
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 17
- 239000011777 magnesium Substances 0.000 description 17
- 229910052749 magnesium Inorganic materials 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 16
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9616206A FR2757855B1 (fr) | 1996-12-30 | 1996-12-30 | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
| FR9616206 | 1996-12-30 | ||
| PCT/FR1997/002407 WO1998029390A1 (fr) | 1996-12-30 | 1997-12-23 | Inhibiteurs de farnesyle transferase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2275943A1 true CA2275943A1 (fr) | 1998-07-09 |
Family
ID=9499293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002275943A Abandoned CA2275943A1 (fr) | 1996-12-30 | 1997-12-23 | Inhibiteurs de farnesyle transferase |
Country Status (32)
| Country | Link |
|---|---|
| EP (1) | EP0948483B1 (en, 2012) |
| JP (1) | JP2001509147A (en, 2012) |
| KR (1) | KR20000062391A (en, 2012) |
| AR (1) | AR008950A1 (en, 2012) |
| AT (1) | ATE214367T1 (en, 2012) |
| AU (1) | AU741921B2 (en, 2012) |
| BR (1) | BR9714498A (en, 2012) |
| CA (1) | CA2275943A1 (en, 2012) |
| CO (1) | CO4920252A1 (en, 2012) |
| CZ (1) | CZ233599A3 (en, 2012) |
| DE (1) | DE69711081T2 (en, 2012) |
| DK (1) | DK0948483T3 (en, 2012) |
| DZ (1) | DZ2389A1 (en, 2012) |
| EA (1) | EA002114B1 (en, 2012) |
| ES (1) | ES2172033T3 (en, 2012) |
| FR (1) | FR2757855B1 (en, 2012) |
| HU (1) | HUP0001747A3 (en, 2012) |
| ID (1) | ID22922A (en, 2012) |
| IL (1) | IL130453A0 (en, 2012) |
| MA (1) | MA26460A1 (en, 2012) |
| NO (1) | NO993225L (en, 2012) |
| NZ (1) | NZ336042A (en, 2012) |
| PE (1) | PE28199A1 (en, 2012) |
| PL (1) | PL334345A1 (en, 2012) |
| PT (1) | PT948483E (en, 2012) |
| SK (1) | SK88399A3 (en, 2012) |
| TN (1) | TNSN97214A1 (en, 2012) |
| TR (1) | TR199901502T2 (en, 2012) |
| UY (1) | UY24832A1 (en, 2012) |
| WO (1) | WO1998029390A1 (en, 2012) |
| YU (1) | YU30299A (en, 2012) |
| ZA (1) | ZA9711734B (en, 2012) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2787327B1 (fr) * | 1998-12-21 | 2003-01-17 | Aventis Pharma Sa | Compositions contenant des inhibiteurs de farnesyle transferase |
| FR2796641B1 (fr) * | 1999-07-22 | 2001-09-21 | Aventis Pharma Sa | Nouveau procede de preparation de composes benzoperhydroisoindole |
| FR2796640A1 (fr) * | 1999-07-22 | 2001-01-26 | Aventis Pharma Sa | Nouveaux inhibiteurs de farnesyle transferase, leur preparation, les compositions pharmaceutiques qui les contiennent et leur utilisation pour la preparation de medicaments |
| FR2845994B1 (fr) * | 2002-10-18 | 2006-05-19 | Servier Lab | Nouveaux derives de benzo[e][1,4]oxazino[3,2-g]isoindole substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO2005089504A2 (en) * | 2004-03-18 | 2005-09-29 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US20250154171A1 (en) | 2023-10-12 | 2025-05-15 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU681454B2 (en) * | 1993-11-05 | 1997-08-28 | Warner-Lambert Company | Substituted DI- and tripeptide inhibitors of protein:farnesyl transferase |
| FR2736641B1 (fr) * | 1995-07-10 | 1997-08-22 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
-
1996
- 1996-12-30 FR FR9616206A patent/FR2757855B1/fr not_active Expired - Fee Related
-
1997
- 1997-12-03 PE PE1997001089A patent/PE28199A1/es not_active Application Discontinuation
- 1997-12-23 DK DK97953000T patent/DK0948483T3/da active
- 1997-12-23 KR KR1019997005966A patent/KR20000062391A/ko not_active Ceased
- 1997-12-23 CA CA002275943A patent/CA2275943A1/fr not_active Abandoned
- 1997-12-23 JP JP52968698A patent/JP2001509147A/ja not_active Ceased
- 1997-12-23 AT AT97953000T patent/ATE214367T1/de not_active IP Right Cessation
- 1997-12-23 EP EP97953000A patent/EP0948483B1/fr not_active Expired - Lifetime
- 1997-12-23 SK SK883-99A patent/SK88399A3/sk unknown
- 1997-12-23 EA EA199900608A patent/EA002114B1/ru not_active IP Right Cessation
- 1997-12-23 WO PCT/FR1997/002407 patent/WO1998029390A1/fr not_active Application Discontinuation
- 1997-12-23 ES ES97953000T patent/ES2172033T3/es not_active Expired - Lifetime
- 1997-12-23 HU HU0001747A patent/HUP0001747A3/hu unknown
- 1997-12-23 IL IL13045397A patent/IL130453A0/xx unknown
- 1997-12-23 BR BR9714498A patent/BR9714498A/pt not_active IP Right Cessation
- 1997-12-23 ID IDW990618A patent/ID22922A/id unknown
- 1997-12-23 TR TR1999/01502T patent/TR199901502T2/xx unknown
- 1997-12-23 PL PL97334345A patent/PL334345A1/xx unknown
- 1997-12-23 NZ NZ336042A patent/NZ336042A/xx unknown
- 1997-12-23 AU AU56694/98A patent/AU741921B2/en not_active Ceased
- 1997-12-23 YU YU30299A patent/YU30299A/sh unknown
- 1997-12-23 DE DE69711081T patent/DE69711081T2/de not_active Expired - Fee Related
- 1997-12-23 CZ CZ992335A patent/CZ233599A3/cs unknown
- 1997-12-23 PT PT97953000T patent/PT948483E/pt unknown
- 1997-12-26 MA MA24915A patent/MA26460A1/fr unknown
- 1997-12-26 TN TNTNSN97214A patent/TNSN97214A1/fr unknown
- 1997-12-27 DZ DZ970239A patent/DZ2389A1/xx active
- 1997-12-29 CO CO97075391A patent/CO4920252A1/es unknown
- 1997-12-30 UY UY24832A patent/UY24832A1/es not_active Application Discontinuation
- 1997-12-30 ZA ZA9711734A patent/ZA9711734B/xx unknown
- 1997-12-30 AR ARP970106263A patent/AR008950A1/es unknown
-
1999
- 1999-06-29 NO NO993225A patent/NO993225L/no not_active Application Discontinuation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |