WO2009106586A1 - Quinolines as inhibitors of farnesyl pyrophosphate synthase - Google Patents
Quinolines as inhibitors of farnesyl pyrophosphate synthase Download PDFInfo
- Publication number
- WO2009106586A1 WO2009106586A1 PCT/EP2009/052314 EP2009052314W WO2009106586A1 WO 2009106586 A1 WO2009106586 A1 WO 2009106586A1 EP 2009052314 W EP2009052314 W EP 2009052314W WO 2009106586 A1 WO2009106586 A1 WO 2009106586A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- naphthalen
- quinolin
- amino
- compound
- quinoline
- Prior art date
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- 102100035111 Farnesyl pyrophosphate synthase Human genes 0.000 title abstract description 53
- 101710125754 Farnesyl pyrophosphate synthase Proteins 0.000 title abstract description 53
- 239000003112 inhibitor Substances 0.000 title description 28
- 150000003248 quinolines Chemical class 0.000 title description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 428
- 238000011282 treatment Methods 0.000 claims abstract description 69
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 62
- 201000010099 disease Diseases 0.000 claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- -1 hydroxy, amino, N-substituted amino Chemical group 0.000 claims description 138
- 150000003839 salts Chemical class 0.000 claims description 76
- 125000001424 substituent group Chemical group 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 51
- 150000002431 hydrogen Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 230000001419 dependent effect Effects 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 17
- 229920002554 vinyl polymer Polymers 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 13
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- 229910003002 lithium salt Inorganic materials 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical group C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical group C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 4
- KCKZIWSINLBROE-UHFFFAOYSA-N 3,4-dihydro-1h-naphthalen-2-one Chemical group C1=CC=C2CC(=O)CCC2=C1 KCKZIWSINLBROE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- XQSFNIQCLKPWQI-UHFFFAOYSA-N 6-amino-8-naphthalen-1-ylquinoline-2-carboxylic acid Chemical compound N1=C(C(O)=O)C=CC2=CC(N)=CC(C=3C4=CC=CC=C4C=CC=3)=C21 XQSFNIQCLKPWQI-UHFFFAOYSA-N 0.000 claims description 3
- JVXSIISWWVEGMB-UHFFFAOYSA-N 8-naphthalen-1-yl-2-(2h-tetrazol-5-yl)-6-thiophen-2-ylquinoline Chemical compound C1=CSC(C=2C=C3C=CC(=NC3=C(C=3C4=CC=CC=C4C=CC=3)C=2)C2=NNN=N2)=C1 JVXSIISWWVEGMB-UHFFFAOYSA-N 0.000 claims description 3
- QMAYJELNBDAEMC-UHFFFAOYSA-N 8-naphthalen-1-ylquinoline-2-carboxylic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)C(=O)O)=CC=CC2=C1 QMAYJELNBDAEMC-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- FLUITQDECLFMSB-UHFFFAOYSA-N [8-naphthalen-1-yl-6-(1h-pyrrol-2-yl)quinolin-2-yl]phosphonic acid Chemical compound C1=C(C=2C3=CC=CC=C3C=CC=2)C2=NC(P(O)(=O)O)=CC=C2C=C1C1=CC=CN1 FLUITQDECLFMSB-UHFFFAOYSA-N 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- CIZJXTCJOYALTD-UHFFFAOYSA-N (8-naphthalen-1-ylquinolin-2-yl)methylphosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)CP(O)(=O)O)=CC=CC2=C1 CIZJXTCJOYALTD-UHFFFAOYSA-N 0.000 claims description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 2
- AJOJYBPWVCYZEO-UHFFFAOYSA-N 2-(1-methyltetrazol-5-yl)-8-naphthalen-1-yl-6-thiophen-2-ylquinoline Chemical compound CN1N=NN=C1C1=CC=C(C=C(C=C2C=3C4=CC=CC=C4C=CC=3)C=3SC=CC=3)C2=N1 AJOJYBPWVCYZEO-UHFFFAOYSA-N 0.000 claims description 2
- DJFCUWXVSXDRNS-UHFFFAOYSA-N 2-(2-methyltetrazol-5-yl)-8-naphthalen-1-yl-6-thiophen-2-ylquinoline Chemical compound CN1N=NC(C=2N=C3C(C=4C5=CC=CC=C5C=CC=4)=CC(=CC3=CC=2)C=2SC=CC=2)=N1 DJFCUWXVSXDRNS-UHFFFAOYSA-N 0.000 claims description 2
- WJSHUENBZMQQTM-UHFFFAOYSA-N 2-(8-naphthalen-1-yl-2-phosphonoquinolin-6-yl)pyrrole-1-carboxylic acid Chemical compound OC(=O)N1C=CC=C1C1=CC(C=2C3=CC=CC=C3C=CC=2)=C(N=C(C=C2)P(O)(O)=O)C2=C1 WJSHUENBZMQQTM-UHFFFAOYSA-N 0.000 claims description 2
- HKXZGIHPMHLNHK-UHFFFAOYSA-N 2-methyl-8-(2-methylquinolin-8-yl)quinoline Chemical group C1=C(C)N=C2C(C3=CC=CC4=CC=C(N=C43)C)=CC=CC2=C1 HKXZGIHPMHLNHK-UHFFFAOYSA-N 0.000 claims description 2
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Chemical group C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 2
- RWXMAPWKGJNKFO-BUHFOSPRSA-N [(e)-2-(8-naphthalen-1-ylquinolin-2-yl)ethenyl]phosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)/C=C/P(O)(=O)O)=CC=CC2=C1 RWXMAPWKGJNKFO-BUHFOSPRSA-N 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical group C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 2
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
- 101100503323 Artemisia annua FPS1 gene Proteins 0.000 claims 4
- 101100503326 Gibberella fujikuroi FPPS gene Proteins 0.000 claims 4
- AEEMWRLWXPTKQF-UHFFFAOYSA-N (6-amino-8-naphthalen-1-ylquinolin-2-yl)phosphonic acid Chemical compound N1=C(P(O)(O)=O)C=CC2=CC(N)=CC(C=3C4=CC=CC=C4C=CC=3)=C21 AEEMWRLWXPTKQF-UHFFFAOYSA-N 0.000 claims 1
- PIHNCPKKZDMBQU-UHFFFAOYSA-N (8-naphthalen-1-ylquinolin-2-yl)phosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)P(O)(=O)O)=CC=CC2=C1 PIHNCPKKZDMBQU-UHFFFAOYSA-N 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- PJVKVUKOHHEMBQ-UHFFFAOYSA-N 6-(ethoxycarbonylamino)-8-naphthalen-1-ylquinoline-2-carboxylic acid Chemical compound N1=C(C(O)=O)C=CC2=CC(NC(=O)OCC)=CC(C=3C4=CC=CC=C4C=CC=3)=C21 PJVKVUKOHHEMBQ-UHFFFAOYSA-N 0.000 claims 1
- LASMXCXZNGKTJK-UHFFFAOYSA-N 6-chloro-8-naphthalen-1-ylquinoline-2-carboxylic acid Chemical compound C1=CC=C2C(C3=CC(Cl)=CC4=CC=C(N=C43)C(=O)O)=CC=CC2=C1 LASMXCXZNGKTJK-UHFFFAOYSA-N 0.000 claims 1
- VJGUWLBDNRYANG-UHFFFAOYSA-N [(8-naphthalen-1-ylquinolin-2-yl)amino]methylphosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)NCP(O)(=O)O)=CC=CC2=C1 VJGUWLBDNRYANG-UHFFFAOYSA-N 0.000 claims 1
- DFJHEAAUBDRUFT-UHFFFAOYSA-N [(8-naphthalen-1-ylquinolin-2-yl)methylamino]methylphosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)CNCP(O)(=O)O)=CC=CC2=C1 DFJHEAAUBDRUFT-UHFFFAOYSA-N 0.000 claims 1
- LJNGARCVBHPRBS-UHFFFAOYSA-N [(8-naphthalen-1-ylquinoline-2-carbonyl)amino]methylphosphonic acid Chemical compound C1=CC=C2C(C3=CC=CC4=CC=C(N=C43)C(=O)NCP(O)(=O)O)=CC=CC2=C1 LJNGARCVBHPRBS-UHFFFAOYSA-N 0.000 claims 1
- QPJKPQZMYOIBTG-UHFFFAOYSA-N [6-(3-hydroxyphenyl)-8-naphthalen-1-ylquinolin-2-yl]phosphonic acid Chemical compound OC1=CC=CC(C=2C=C3C=CC(=NC3=C(C=3C4=CC=CC=C4C=CC=3)C=2)P(O)(O)=O)=C1 QPJKPQZMYOIBTG-UHFFFAOYSA-N 0.000 claims 1
- KOPQIYWIJIZHKP-UHFFFAOYSA-N [6-(3-methoxyphenyl)-8-naphthalen-1-ylquinolin-2-yl]phosphonic acid Chemical compound COC1=CC=CC(C=2C=C3C=CC(=NC3=C(C=3C4=CC=CC=C4C=CC=3)C=2)P(O)(O)=O)=C1 KOPQIYWIJIZHKP-UHFFFAOYSA-N 0.000 claims 1
- TVZSJHZLCGEPMV-UHFFFAOYSA-N [8-naphthalen-1-yl-6-(1h-pyrrol-3-yl)quinolin-2-yl]phosphonic acid Chemical compound C1=C(C=2C3=CC=CC=C3C=CC=2)C2=NC(P(O)(=O)O)=CC=C2C=C1C=1C=CNC=1 TVZSJHZLCGEPMV-UHFFFAOYSA-N 0.000 claims 1
- TWKSFBHDPHIEOI-UHFFFAOYSA-N [[8-naphthalen-1-yl-6-(1h-pyrrol-3-yl)quinolin-2-yl]amino]methylphosphonic acid Chemical compound C1=C(C=2C3=CC=CC=C3C=CC=2)C2=NC(NCP(O)(=O)O)=CC=C2C=C1C=1C=CNC=1 TWKSFBHDPHIEOI-UHFFFAOYSA-N 0.000 claims 1
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- 229940053867 xeloda Drugs 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- 239000011722 γ-tocotrienol Substances 0.000 description 1
- 235000019150 γ-tocotrienol Nutrition 0.000 description 1
- 239000002446 δ-tocopherol Substances 0.000 description 1
- 239000011729 δ-tocotrienol Substances 0.000 description 1
- ODADKLYLWWCHNB-LDYBVBFYSA-N δ-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 ODADKLYLWWCHNB-LDYBVBFYSA-N 0.000 description 1
- 235000019144 δ-tocotrienol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Definitions
- the invention relates to novel Bi-Aryl derivatives of formula (I) given below; to Bi-Aryl derivatives of the formula (I " ) given below as medicament; to the use of compounds of formula (I) and (P) for use in the treatment of a disorder that depends on the activity of farnesyl pyrophosphate synthase (FPPS), especially a proliferative disease and/or a cholesterol biosynthesis related disorder; to pharmaceutical preparations, optionally in the presence of a combination partner; to the use of such preparations in the treatment of a disease or disorder, in particular a disorder as disclosed herein; to the manufacture of a compound of formula (I) and (P); to the manufacture of a pharmaceutical preparation containing a compound of formula (I) and/or (P) .
- FPPS farnesyl pyrophosphate synthase
- FPPS is a key branchpoint enzyme in the mevalonate pathway. Hence, FPPS is recognized as an important drug target. It is anticipated that new FPPS inhibitors would have therapeutic potential for the treatment of bone diseases, in oncology, for the treatment of elevated cholesterol levels and as anti- infectives.
- Bi-Aryl derivatives of the present invention show FPPS inhibition although they are not bisphosphonates, and that they are appropriate for the treatment of diseases that depend on FPPS activity, especially against tumor and cancer diseases of soft and hard tissues, especially metastasis, e.g. bone metastasis, or as cholesterol-lowering agents.
- FPPS inhibitors e.g. a large number of novel compounds of this class have been found that are FPPS inhibitors.
- any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
- compounds of any formula given herein may have one or more asymmetric centers or other elements of asymmetry, and therefore exist in different enantiomeric forms. If at least one asymmetrical carbon atom is present in a compound of the formula (I), such a compound may exist in optically active form or in the form of a mixture of optical isomers, e. g. in the form of a racemic mixture. All optical isomers and their mixtures, including the racemic mixtures, are part of the present invention.
- any given formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
- certain structures may exist as geometric isomers (i.e. cis and trans isomers), as tautomers, or as atropisomers.
- any formula given herein is intended to represent hydrates, solvates, polymorphs of such compounds, and mixtures thereof.
- any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 I respectively.
- isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated.
- Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- an 18 F or labeled compound may be particularly preferred for PET or SPECT studies.
- isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a. readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere.
- the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula (where one or more up to all more general expressions in embodiments characterized as preferred above or below can be replaced with a more specific definition, thus leading to a more preferred embodiment of the invention, respectively).
- a compound, “a” salt, “a” disorder, “a” disease or the like preferably means “one or more” compounds, salt, disorders, diseases or the like. Where the plural form (e.g. compounds, salts) is used, this includes the singular (e.g. a single compound, a single salt). “A compound” does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the formula (I) (or a salt thereof) is present.
- Treatment refers to the prophylactic or preferably therapeutic (including but not limited to palliative, curing, symptom-alleviating, symptom-reducing, FPPS-activity- regulating and/or FPPS-inhibiting) treatment of said diseases/disorder, especially of the diseases/disorders mentioned herein.
- Salts are preferably pharmaceutically acceptable salts.
- Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula (I) with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
- Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
- Suitable organic acids are, e.g., carboxylic acids or sulfonic acids, such as fumaric acid or methansulfonic acid.
- any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
- Esters (which, what is meant by “or ester thereof or “or a ester thereof), can be present alone or in mixture with free compound of the formula (I)) are preferably pharmaceutically acceptable esters. Such esters are formed, for example, with alcohols from compounds of formula (I) with an acid group, such as -CO 2 H, -P(O)(OH) 2 and the like. Suitable alcohols are, for example, ethanol, methanol, benzylalcohol. For therapeutic use, only pharmaceutically acceptable esters or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
- any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding esters, as appropriate and expedient.
- Halo (or halogen) is preferably fluoro, chloro, bromo or iodo, most preferably F, Cl or Br.
- alkyl In unsubstituted or substituted "alkyl”, alkyl (also in alkoxy or the like) preferably has up to 20, more preferably up to 12 carbon atoms, is linear or branched, and is more preferably lower alkyl, such as Ci-C 6 -alkyl, especially Ci-C 4 -alkyl.
- Substituted alkyl is preferably C 1 - to C 20 -alkyl, more preferably lower alkyl, that can be linear or branched one or more times (provided the number of carbon atoms allows this), e.g.
- pyrrolidinyl such as pyrrolidine, oxopyrrolidinyl, such as oxopyrrolidino, C 1 -C 7 - alkyl-pyrrolidinyl, 2,5-di-(C 1 -C 7 alkyl)pyrrolidinyl, such as 2,5-di-(C 1 -C 7 alkyl)-pyrrolidino, tetrahydrofuranyl, thiophenyl, CrC T -alkylpyrazolidinyl,
- halo especially fluoro, chloro, bromo or iodo, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy, azido, amino, N-mono- or N,N-di-(lower alkyl, phenyl, naphthyl, C 1 -C 7 - alkanoyl, phenyl-lower alkyl and/or naphthyl-lower alkyl)-amino, nitro, formyl (CHO), carboxy, lower-alkoxycarbonyl carbamoyl, cyano and/or sulfamoyl.
- substituents independently selected from halo, especially fluoro, chloro, bromo or iodo, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy, azido, amino, N-mono- or N,N-di-(lower alkyl, pheny
- unsubstituted or substituted alkyl is preferably CrC 7 -alkyl, such as methyl or ethyl, halo-C r C 7 -alkyl, such as halomethyl, hydroxyl-C- ⁇ -C 7 -alkyl, such as hydroxymethyl, amino-CrC 6 - alkyl, such as aminomethyl, or carboxy-Ci-C 7 -alkyl, such as carboxymethyl.
- Unsubstituted or substituted "alkenyl” is preferably C 2 -C 2 o-alkenyl, more preferably C 2 -C 12 - alkenyl, yet more preferably C 2 -C 7 -alkenyl, which is linear or branched and includes one or more double bonds.
- the substituents are preferably one or more, especially up to three, substituents independently selected from those mentioned for substituted alkyl, preferably with the proviso that substituents with active hydrogen (such as amino or hydroxyl) can also be present in tautomeric form (as keto or imino compounds) or are excluded from the substituents where the stability is too low.
- alkynyl is preferably C 2 -C 20 -alkynyl, more preferably C 3 -C 12 - alkynyl, yet more preferably C 3 -C 7 -alkynyl, which is linear or branched and includes one or more triple bonds.
- the substituents are preferably one or more, especially up to three, substituents independently selected from those mentioned for substituted alkyl, preferably with the proviso that substituents with active hydrogen (such as amino or hydroxyl) can also be present in tautomeric form (as keto or imino compounds) or are excluded from the substituents where the stability is too low.
- alkandiyl is preferably a straight-chain or branched-chain alkandiyl group bound by two different Carbon atoms to the moiety, it preferably represents a straight-chain or branched-chain C 1-I2 alkandiyl, particularly preferably represents a straight- chain or branched-chain C-,.
- methandiyl for example, methandiyl (-CH 2 -), 1 ,2-ethanediyl (- CH 2 -CH 2 -), 1 ,1-ethanediyl ((-CH(CH 3 )-), 1 ,1-, 1 ,2-, 1 ,3-propanediyl and 1 ,1-, 1 ,2-, 1 ,3-, 1 ,4- butanediyl, with particular preference given to methandiyl, 1 ,1-ethanediyl, 1 ,2-ethanediyl, 1 ,3-propanediyl, 1 ,4-butanediyl.
- alkandiyl is interrupted by one or more groups, e.g. - 0-, -C(O)-, -N(H)-, this includes groups such as -CH 2 -C(O)-; -CH 2 -C(O)-N(H)-; -CH 2 -N(H)- C(O)-; -C(O)-CH 2 -N(H)- and the like.
- aryl is preferably an unsaturated carbocyclic system of not more than 20 carbon atoms, especially not more than 16 carbon atoms, is preferably mono-, bi- or tri-cyclic, e.g. phenyl, naphthyl, phenanthrenyl or fluorenyl, which is unsubstituted or, as substituted aryl, substituted preferably by one or more, preferably up to three, e.g. one or two substituents independently selected from those mentioned above for substituted alkyl, and from alkenyl.
- the substituents are independently selected from the group consisting of d-C 7 -alkyl, such as methyl, hydroxyl-C 1 -C 7 -alkyl, such as hydroxymethyl, halo, such as fluoro, chloro, bromo or iodo, hydroxyl, C r C 7 -alkoxy, such as methoxy, halo-CrC 7 -alkoxy, such as trifluoromethoxy, amino, Ci-C 7 -alkanoylamino, such as acetylamino, amino-alkyl, such as aminomethyl, N-mono- or N,N-disubstituted amino-alkyl, preferably N-mono- or N,N-disubstituted amino-CrC T -alkyl, such as N-mono- or N, N- disubstituted aminomethyl, and azidoalkyl, preferably azido-C- ⁇ -C 7 -alky
- cycloalkyl is preferably a saturated mono- or bi- cyclic hydrocarbon group with 3 to 16, more preferably 3 to 9 ring carbon atoms, especially C 3 -C 8 -cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo- octyl, and is substituted by one or more, preferably one to three, substitutents independently selected from those described for substituted alkyl, especially from C 1 -C 7 -alkyl and hydroxy, or is (preferably) unsubstituted.
- alkanoyl In unsubstituted or substituted "alkanoyl" (or alkylcarbonyl), alkanoyl is preferably formyl or more preferably C 2 -C 20 - yet more preferably C 2 -C 7 -alkanoyl, such as acetyl, propanoyl or butyroyl, is linear or branched and is substituted with one or more, especially up to three, substitutents independently selected from those mentioned above for substituted alkyl or is preferably unsubstituted as mentioned above, or is formyl (-CHO).
- alkanoyl is preferably formyl or more preferably C 2 -C 20 - yet more preferably C 2 -C 7 -alkanoyl, such as acetyl, propanoyl or butyroyl, is linear or branched and is substituted with one or more, especially up to three, substitutents independently selected from those mentioned above for substituted alkyl or is preferably unsub
- alkyl is preferably as defined above and is unbranched or branched.
- the amino moiety is preferably bound to a terminal carbon atom.
- Preferred is amino-C 1 -C 7 -alkyl, especially aminomethyl.
- N-mono- or N,N-disubstituted amino-alkyl alkyl is preferably as defined above and is unbranched or branched.
- the mono- or disubstituted amino moiety is preferably bound to a terminal carbon atom.
- the substituents are preferably selected from unsubstituted or substituted alkyl, especially C r C 7 -alkyl or phenyl-d-Cy-alkyl, such as methyl, ethyl or benzyl, acyl, especially CrC 7 -alkanoyl, such as acetyl, unsubstituted or substituted aryl, preferably as defined above, especially phenyl, unsubstituted or substituted aroyl, preferably as defined above, e.g. benzoyl, and unsubstituted or substituted cycloalkyl, preferably as defined above, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- alkyl is preferably as defined above and is unbranched or branched.
- the azido moiety is preferably bound to a terminal carbon atom.
- Preferred is azido-C ⁇ C T -alkyl, especially azidomethyl.
- "Etherified hydroxyl” is preferably unsubstituted or substituted (preferably C 1 -C 7 -) alkyloxy, wherein the substituents are preferably independently selected from those mentioned for substituted alkyl, preferably methoxy or 3-(2-trimethylsilyl-ethoxy-methoxy; or is unsubstituted or substituted aryloxy wherein unsubstituted or substituted aryl is as defined above; e.g. substituted or prefreably unsubstituted phenyloxy or naphthyloxy, respectively.
- Esterified hydroxyl is preferably acyloxy with acyl as defined below, more preferably Ci-C 7 - alkanoyloxy, such as acetoxy, benzoyloxy, naphthoyloxy, C- ⁇ -C 7 -alkansulfonyloxy (alkyl- S(O) 2 -O-), or phenyl- or naphthylsulfonyloxy (phenyl-S(O) 2 -O- or naphthyl-S(O) 2 -O-) wherein phenyl is unsubstituted or substituted, e.g. by one or more, e.g. up to 3, Ci-C 7 -alkyl moieties.
- Ci-C 7 - alkanoyloxy such as acetoxy, benzoyloxy, naphthoyloxy, C- ⁇ -C 7 -alkansulfonyloxy (alkyl- S(O) 2 -O-
- the invention relates to a compound of the formula (I),
- A represents an aryl, cycloalkyl, heterocyclyl condensed to the phenyl ring;
- R 1 represents a substituent different from hydrogen;
- R 2 represents hydrogen, halogen, nitro, optionally substituted amino, optionally substituted aryl, optionally substituted heterocyclyl;
- R 4 represents hydrogen, alkoxy X 1 represents a direct bond or an alkanediyl which is optionally interrupted by one or more groups selected from -O-, -C(O)-, -N(H)-, -N(lower alkyl)-, alkenediyl, provided that when more than one of said groups is present, two or more oxygen or nitrogen atoms are not bonded together (adjacent to each other);
- n represent an integer from 0 - 3; except the compounds 2-methyl-8-naphthalen-quinoline and 2,2'-dimethyl-
- the invention relates to a compound of the formula (I), in free base form or in acid addition salt form, wherein the substituents are as defined herein.
- A preferably represents - together with the phenyl ring to which it is attached - a moiety selected from the group consisting of naphthalene, 1 ,2,3,4-tetrahydronaphthalene, indole, isoindole, quinoline, isoquinoline, aryl, cycloalkyl, heterocyclyl condensed to the phenyl ring; said moiety optionally substituted by one or more substituents selected from the group consisting of lower alkyl, hydroxyl, oxo.
- R 1 advantageously represents a substituent different from hydrogen and different from unsubstituted alkyl.
- R 1 preferably represents one of the following groups:
- R 5 represents hydrogen, unsubstituted alkyl, alkyl substituted by aryl
- R 6 represents hydrogen, unsubstituted alkyl
- R 6 * represents hydrogen, unsubstituted alkyl
- R 7 represents hydrogen, halogen, hydroxy, amino, N-substituted amino, N,N-disubstituted amino and
- R 7* represents hydrogen, carboxy, alkoxycarbonyl or R 7* and R 7 represent together with the carbon to which they are attached an optionally substituted heterocycle. Preferably, R 7 and R 7* are not at the same time both hydrogen.
- R 1 particular preferably represents the group (R 1 -1 ).
- R 1 further preferably represents the group (R 1 -2).
- R preferably represents hydrogen, chloro, bromo, iodo, nitro or amino, N-substituted amino, N,N-disubstituted amino, the substituents being selected from the group consisting of (C 1 -C 4 )-alkylcarbonyl, (d-C 4 )-alkoxycarbonyl, aryl, heteroarylcarbonyl, benzoxycarbonyl, (CrC 4 )-alkylsulfonyl or (C ⁇ -CeJ-alkylcarbonyl wherein the alkyl of the (C r C 6 )-alkylcarbonyl is substituted by NH 2 , (C r C 4 )-alkyl or (C r C 4 )-alkoxycarbonyl or unsubstituted or substituted aryl the substituents being selected from the group consisting of halo, cyano, hydroxy, lower alkyl, lower haloalkyl, lower alkyl substitute
- R 2 particular preferably represents hydrogen, iodo, chloro, nitro, or amino, N-substituted amino, N,N-disubstittuted amino, the substituents being selected from the group consisting of ethoxycarbonyl, methylsulfonyl or unsubstituted or substituted phenyl the substituents being selected from the group consisting of hydroxy, methyl, ethyl, iso-propyl, tert.-butyl, trifluoromethyl, benzyl, methoxy, ethoxy, iso-propoxy, tert.-butoxy, benzoxy, acyl, m ethoxycarbonyl, ethoxycarbonyl, iso-propoxycarbonyl, tert.-butoxycarbonyl, trimethylsilyl or unsubstituted heterocyclyl or heterocyclyl substituted by one or two substitutents, said heterocyclyl being selected from the group consisting of
- R 3 particularly preferably represents oxo, amino, methyl, ethyl, propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-propyl, substituted methyl, ethyl, propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, 1 ,2,2- trimethylpropyl, 1-ethyl-propyl, the substituents being selected from the group consisting of hydroxy, lower acetyl, propanoyl, butyroyl, acetyloxy, propanoyloxy, butyroyloxy.
- R 4 preferably represents hydrogen, lower alkoxy (such as methoxy, ethoxy).
- R 4 particularly preferably represents hydrogen.
- R 5 preferably represents hydrogen, lower alkyl, lower alkyl substituted by phenyl (in particular R 5 is: benzyl, methyl, ethyl, propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2- dimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-propyl).
- R 5 particularly preferably represents hydrogen, benzyl, methyl, ethyl.
- R 6 preferably represents hydrogen, lower alkyl (in particular: methyl, ethyl, propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-propyl).
- R 6 * particularly preferably represents hydrogen, methyl, ethyl.
- R 7 preferably represents hydrogen, halogen, hydroxy, amino, N-substituted amino, N 1 N- disubstituted amino, the substituents being selected from the group consisting of (C 1 - C 4 )-alkoxycarbonyl, benzoxycarbonyl, aminosulfonyl, (C 1 -C 4 )-alkoxycarbonyl- aminosulfonyl, benzoxycarbonyl-aminosulfonyl, and R 7* preferably represents hydrogen, carboxy, (Ci-C 4 )-alkoxycarbonyl or
- R 7 * and R 7 preferably represent together with the carbon to which they are attached a heterocycle optionally substituted by one or two oxo groups.
- R 7 particular preferably represents hydrogen, halogen, hydroxy, amino, N-substituted amino, N,N-disubstituted amino the substituents being selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoxycarbonyl, aminosulfonyl, methoxycarbonyl-aminosulfonyl, ethoxycarbonyl-aminosulfonyl, benzoxycarbonyl-aminosulfonyl and R 7* particular preferably represents carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoxycarbonyl or
- R 7* and R 7 particular preferably represent together with the carbon to which they are attached a five-membered heterocycle optionally substituted by one or two oxo groups, for example, R 7* and R 7 preferably represent together with the carbon to which they are attached 2H-tetrazol-5-yl, 2H-tetrazol-3-yl, 2-methyl-2H-tetrazol-5-yl, 2-methyl-2H- tetrazol-3-yl.
- X 1 preferably represents a direct bond or a straight-chain or branched-chain Ci -12 alkandiyl which is optionally interrupted by one or more groups selected from -O-, -C(O)-, -N(H)- , -N(lower alkyl)-, or a straight-chain or branched-chain C 2 - 6 alkendiyl.
- X 1 very particular preferably represents a direct bond, vinyl, methandiyl, 1 ,2-ethanediyl.
- n preferably represents 0 or 1 , most preferably 0.
- the invention relates to a compound of formula (I-A)
- the invention relates to a compound of formula (I-B)
- the invention relates to a compound of formula (I-C)
- the invention relates to a compound of formula (I-D
- the invention relates to a compound of formula (I-E)
- the invention further relates to pharmaceutically acceptable prodrugs of a compound of formula (I).
- the invention thus relates also to pharmaceutically acceptable esters of a compound of formula (I); in particular to lower alkyl esters of a compound of formula (I).
- the invention further relates to pharmaceutically acceptable metabolites of a compound of formula (I).
- the invention relates especially to the compounds of the formula (I) given in the Examples, as well as the methods of manufacture described therein.
- the compounds of formula (I) have valuable pharmacological properties, as described hereinbefore and hereinafter. Other preferred embodiments are mentioned above and below or in the claims which are incorporated by reference herein.
- the invention relates to a compound of formula (T)
- A represents an aryl, cycloalkyl, heterocyclyl condensed to the phenyl ring;
- R 1 represents a substituent different from hydrogen
- R 2 represents hydrogen, halogen, nitro, optionally substituted amino, optionally substituted aryl, optionally substituted heterocyclyl;
- R 4 represents hydrogen, alkoxy X 1 represents a direct bond or an alkanediyl which is optionally interrupted by one or more groups selected from -O-, -C(O)-, -N(H)-, -N(lower alkyl)-, alkenediyl;
- n represent an integer from 0 - 3; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, as medicament.
- the invention relates to a compound of forula (T) wherein the substituents are as defined for a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, as medicament.
- the invention relates to methods of manufacturing a compound of formula (I) and intermediates thereof.
- a compound of the formula (I) may be prepared by processes that, though not applied hitherto for the new compounds of the present invention where they thus form new processes, are known per se.
- Schemes 1 and 2 illustrate methods for preparations according to this invention.
- the invention relates to a method of manufacturing (a manufacturing process) for a compound of formula (I) comprising the step of
- Hal represents halogen, in particular bromo, in the presence of an activating agent, such as a catalyst, in particular a homogeneous Pd catalyst; and, if desired, converting a compound of the formula (I) obtained according to method A, method B or method C into a different compound of the formula (I), and/or converting an obtainable salt of a compound of the formula (I) into a different salt thereof, and/or converting an obtainable free compound of the formula (I) into a salt thereof, and/or converting an obtainable ester of a compound of the formula (I) into the free acid thereof, and/or separating an obtainable isomer of a compound of the formula (I) from one or more different obtainable isomers of the formula (I).
- an activating agent such as a catalyst, in particular a homogeneous Pd catalyst
- the invention relates further to a method of manufacturing (a manufacturing process) a compound of formula (I-B) comprising
- step e1 reacting a compound of formula (H-A)
- Hal represents halogen, in particular chloro.with an alcohol R 5 OH, wherein R 5 represents unsubstituted alkyl, in the presence of CO and a homogeneous catalyst, such as a Pd catalyst, to obtain a compound of formula (II- B) wherein the substituents are as defined herein and
- step a.1 converting a compound of formula (H-B), optionally after purification, into a compound of formula (I-B)
- Step e.1 may take place at elevated CO pressure, e.g. 1-100 bar, preferably 5-50 bar.
- one or more other functional groups for example carboxy, hydroxy, amino or the like are or need to be protected in a starting material of the formula Il or any precursor, because they should not take part in the reaction or disturb the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
- Protecting groups are such groups that are no longer present in the final compounds once they are removed, while groups that remain as substitutents are not protecting groups in the sense used here which is groups that are added at a starting material or intermediate stage and removed to obtain a final compound. For example, tert-butoxy if remaining in a compound of the formula (I) is a substituent, while if it is removed to obtain the final compound of the formula (I) it is a protecting group.
- the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etheri- fications, esterifications, oxidations, soivolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by acetolysis, protonolysis, soivolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
- the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and below.
- a compound of the formula (I) may be converted into a different compound of the formula (I), e.g. by the methods as described herein, in particular below.
- Carbonyl, hydoxy group reduction reactions are generally known. Typical condition suitable for the process as described herein are: carbonyl group reduction with sodium borohydride, e.g. as described in "Sodium Borohydride” in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York. Reduction of benzyl alcohols using triethylsilane in presence of TFA, eg as described in Tetrahedron Letters, 1993, 34, 1605-1608; or using a combination of hypophosphorous acid and iodine, e.g. as described in Tetrahedron Letters, 2001 , 42, 831 -833, the content of these documents is incorporated by reference.
- a substituent is present which is carboxy
- said carboxy can be reduced to hydroxymethyl, e.g. by treatment first with ethylchloroformate in the presence of a tertiary nitrogen base, such as triethylamine or diiso- propylethylamine, in an appropriate solvent, e.g. a cyclic ether, such as tetrahydrofuran, preferably at temperatures in the range from -50 0 C to 30 0 C, followed by treatment with a reducing agent, e.g. sodium borohydride, in an appropriate solvent or solvent mixture, such as an alcohol, e.g. methanol, preferably at a temperature in the range from -50 to 20 0 C, e.g. from -20 to 10 0 C.
- a tertiary nitrogen base such as triethylamine or diiso- propylethylamine
- an appropriate solvent e.g. a cyclic ether, such as te
- This reaction also known as Buchwald amination or Buchwald-Hartwig reaction is generally known in the field.
- This reaction is catalyzed by transition metals, in particular Cu or Pd complexes or salts; takes place in the presence of one or more basic compounds (such as an amine or an alkalialkoxide) and one or more diluents (such as polar aprotic diluents). Further details may be found in the examples.
- Carbonyl groups may be converted in the corresponding alkylated hydroxyl group using a Grignard reaction. Typical conditions suitable for the process are described, e.g. in Synthesis, 1981 , 585-604. Further, carbonyl groups may be converted in the corresponding dialkylated compounds using a multi-step protocol, e.g. as described in Chem. Ber., 1985, 1 18, 1050-1057. Furthermore, carbonyl groups may be converted in the corresponding ispiro cyclopropane compound in two steps by Wittig olefination, e.g. as described in Chem. Rev., 1989, 89, 863-927, and subsequent cyclopronation reaction, e.g. Simmons-Smith as described in Org. React., 2001 , 58, 1-415; the content of the above documents is incorporated by reference.
- a Grignard reaction Typical conditions suitable for the process are described, e.g. in Synthesis, 1981 , 585-604. Further, carbonyl groups may
- the invention further relates to a process for manufacturing a compound of formula (III) which comprises
- substituents are as defined above and -B(OR 10 ) 2 represents boronic acid or an ester thereof; in the presence of an activating agent, such as a catalyst, in particular a homogeneous Pd catalyst; and optionally converting a substituent R 2 or R 3 into an other substituent R 2 or R 3 .
- an activating agent such as a catalyst, in particular a homogeneous Pd catalyst
- Suzuki coupling may be useful to convert a compound of formula (I), (II), (III), (V), (VII) wherein R 2 represents halo, in particular iodo, into another compound of formula (I), (II), (III), (V), (VII) wherein R 2 represents optionally substituted aryl.
- Suzuki coupling may be useful to convert a compound of formula (X) into a compound of formula (I).
- Reaction conditions starting materials and catalysts for converting lactames to halogen compounds are generally known in the field. This reaction typically takes place in the presence of a halogenating agent, in particular P(O)HaI 3 ., such as POCI3.
- a halogenating agent in particular P(O)HaI 3 ., such as POCI3.
- the invention further relates to a process for manufacturing a compound of formula (II) which comprises reacting a compound of formula (III)
- functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned herein- above under “protecting groups”.
- the protecting groups are then wholly or partly removed according to one of the methods described there.
- Salts of a compound of formula (I) with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula (I) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
- a salt with two acid molecules for example a dihalogenide of a compound of formula I
- Salts can usually be converted to free compounds, e.g. by treating with suitable basic compounds, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
- Stereoisomeric mixtures e.g. mixtures of diastereomers
- Dia- stereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula (I) itself.
- Enantiomers may be separated through the formation of dia- stereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
- the starting materials of the formulae (II), (III), (IV), (V), (Vl), (VII), (MX), (IX), (X) as well as other starting materials (including intermediates) mentioned herein, e.g. below, can be prepared according to or in analogy to methods that are known in the art, are known in the art and/or are commercially available.
- Novel starting materials, in particular compound of theformula (II), (III) and (HX), as well as processes for the preparation thereof, are likewise an embodiment of the present invention. In the preferred embodiments, such starting materials are used and the reactions chosen are selected so as to enable the preferred compounds to be obtained.
- a compound of formula (X) may be obtained by converting the corresponding hydroxy compound (Xl)
- the invention relates to the use of compounds of formula (I) as defined herein.
- compounds of formula (I) and (I " ) are FPPS inhibitors and are thus useful as medicaments.
- the invention relates also to a compound of formula (! or (I ' ) for use in the treatment of a warm-blooded animal, especially a human, preferably for the treatment of an FPPS dependent disorder; to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the treatment of an FPPS dependent disease; to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation useful in the treatment of an FPPS dependent disease; to a method of treatment comprising administering a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to a warmblooded animal, especially a human, especially where in need of such treatment; to a pharmaceutical preparation for the treatment of an
- the activity of the compounds of the present invention as FPPS inhibitors can be tested using the scintillation proximity principal similar to a previously reported fatty acid synthase assay using a phospholipid-coated flashplate (see Weiss DR, Glickman JF (2003) Characterization of Fatty Acid Synthase Activity Using Scintillation Proximity. Assay and Drug Development Technologies; 1 (1-2):161-6).
- Prior FPPS assay methods have used organic:aqueous extraction to separate substrate from product. These methods are extremely time consuming and not compatible with testing large numbers (greater than 20,000) compounds.
- the FlashPlate method described below has the advantages of enabling the rapid testing of large numbers of compounds, easily, and directly.
- the product formation can be detected by using a phospholipid-coated "Flashplate” (trademark, Perkin- Elmer Lifesciences) which comprises surface-embedded scintillation materials.
- Flashplate (trademark, Perkin- Elmer Lifesciences) which comprises surface-embedded scintillation materials.
- the lipophilic tritiated FPP which is formed binds to the plate while the tritiated IPP does not.
- the radiolabeled lipophilic product of the reaction is thus captured on the "Image FlashPlate” which emits photons when tritium is in close proximity.
- the use of the LEADseeker imager General Electric, Amersham Lifesciences Division, Cambridge, GB is incorporated which has distinct advantages in plate reading time and in reduced compound interference from yellow compounds over the previously cited Fatty Acid synthase assay.(Weiss Glickman 2003).
- the compounds of the formula (I) are, inter alia, useful in the treatment or in the manufacture of pharmaceutical preparations for the treatment of cholesterol biosynthesis related disorders, e.g. for the lowering of the cholesterol level in blood, on the one hand, and/or protein farnesylation related disorders on the other hand, especially proliferative diseases such as cancer or tumor diseases. Metastasis, especially also bone metastasis, of any cancer or tumor disease is to be included especially.
- a compound of the formula (I) may also be used to diminish the susceptibility to cholera toxin by diminishing the number of membrane bound G 5 protein molecules and for the treatment of pertussis toxin induced coughing by diminishing the number of G proteins. All these disorders are referred to as FPPS-dependent diseases hereinafter (the plural also including the singular, i.e. only one disease).
- an instruction insert e.g. package leaflet or the like
- formulation appropriate preparation
- use of a compound of the formula (I) for such preparation and/or all other prophylactic or therapeutic uses mentioned hereinbefore or below
- a method of treatment comprising administering a compound of the formula (I) for the treatment of an FPPS-dependent disease and one or more compounds of the formula (I) for use in the treatment of a protein kinase dependent disease, as appropriate and expedient and if not stated otherwise.
- diseases to be treated and are thus preferred for "use” of a compound of formula (I) are selected from FPPS-dependent disease ("dependent” meaning dependent “on the activity of”, but also “supported”, not only “solely dependent”, e.g. in case where the FPPS activity is inadequate absolutely or in a given physiological context, either directly or indirectly due to other (e.g. preceding) regulatory mechanisms) diseases mentioned herein, especially proliferative diseases mentioned herein.
- the compounds of formula (I) are especially suitable for the treatment of neoplastic diseases such as cancers and tumors (especially solid tumours but also leukemias, benign or especially ma- lignnant tumors), e.g.
- AML acute myeloid leukemia
- AMM angiogenic myeloid metaplasia
- mesothelioma mesothelioma, gliom
- compounds of the formula (I) are especially appropriate for treating cholesterol biosynthesis related disorders, e.g. for the lowering of the cholesterol level in blood, for example for the treatment (including prophylaxis) of atherosclerosis, bilestones, especially cholelithiasis, lipocalcinogranulomatosis, hypercholesterolaemia, hyperlipoproteinaemia, cholesterol crystal embolism, myocardial infection, cerebral infarction, angina pectoris, and/or the like, also as auxiliary treatment together with other treatment (Including prophylactic) measures.
- the compounds of the formula (I) are especially appropriate for treating in general or inflammation related types of bone loss, including osteoporose, arthritis including rheumatoid arthritis, osteoarthritis and Paget's disease.
- the invention relates also to pharmaceutical compositions comprising a compound of formula (I), to their use in the therapeutic (in a broader aspect of the invention also prophylactic) treatment or a method of treatment of an FPPS-dependent disease, especially the preferred diseases mentioned above, to the compounds for said use and to pharmaceutical preparations and their manufacture, especially for said uses, and to methods of use of a compound of the formula (I) in the treatment of such a disease.
- the present invention also relates to pro-drugs of a compound of formula (I), in particular an ester that converts in vivo to the compound of formula (I) as such.
- Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula (I), as appropriate and expedient.
- pharmacologically acceptable compounds of the present invention may be present in or employed, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as active ingredient together or in admixture with one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers (carrier materials).
- the invention relates also to a method of treatment for a disease that responds to inhibition of an FPPS-dependent disease and/or a proliferative disease, which comprises administering a prophylactically or especially therapeutically (against the mentioned diseases) effective amount of a compound of formula (I) according to the invention, or a tautomer thereof or a pharmaceutically acceptable salt thereof, especially to a warm-blooded animal, for example a human, that, on account of one of the mentioned diseases, requires such treatment.
- the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of an FPPS-dependent disease, especially a proliferative disease or a cholesterol biosynthesis related disorder.
- the invention expecially relates to the use of a compound of the formula (I) (or a pharmaceutical formulation comprising a compound of the formula I) in the treatment of one or more of the diseases mentioned above and below where the disease(s) respond or responds (in a beneficial way, e.g. by partial or complete removal of one or more of its symptoms up to complete cure or remission) to an inhibition of FPPS, especially where FPPS shows (in the context of other regulatory mechanisms) inadequately high or more preferably higher than normal (e.g. constitutive) activity.
- the invention relates to a combination of a compound of formula (I) with one or more other therapeutically active agents.
- a compound of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
- a compound of formula (I) can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these.
- Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
- Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
- a compound of the formula (I) may also be used in combination with other antiproliferative compounds.
- antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase Il inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibit- tors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; N- bisphosphonic acid derivatives; cathepsin K inhibitors; biological response modifiers; antiproliferative antibodies; heparanase inhibitor
- aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
- the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
- Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.
- Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON.
- Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA.
- Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX.
- Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.
- Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORIMETEN.
- a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors.
- antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
- the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
- Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX.
- Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
- Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
- a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
- anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505.
- bicalutamide CASODEX
- gonadorelin agonist as used herein includes, but is not limited to abarelix, go- serelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX.
- Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
- topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macro- molecular camptothecin conjugate PNU-166148 (compound A1 in WO99/ 17804).
- Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTO- SAR.
- Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
- topoisomerase Il inhibitor includes, but is not limited to the anthra- cyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
- Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
- Teniposide can be administered, e.g. in the form as it is marketed, e.g.
- Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
- Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN.
- Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
- Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
- microtubule active compound relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, colchicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
- Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
- Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
- Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P..
- Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN.
- Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
- Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247.
- Epothilone A and/or B are Especially preferred.
- alkylating compound includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN.
- Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXAN.
- histone deacetylase inhibitors or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity.
- SAHA Suberoylanilide hydroxamic acid
- antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
- Capecitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
- Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
- platinum compound as used herein includes, but is not limited to, carboplatin, cis- platin, cisplatinum and oxaliplatin.
- Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
- Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
- compounds targeting/decreasing a protein or lipid kinase activity includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g., a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g.
- PDGFR platelet-derived growth factor-receptors
- a N-phenyl-2- pyrimidine-amine derivative e.g. imatinib, SU101 , SU6668 and GFB-111 ; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF- IR, especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor
- imatinib compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases - (part of the PDGFR family), such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g. imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-AbI kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g.
- N-phenyl-2-pyrimidine-amine derivative e.g. imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825) j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1 , PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin- dependent kinase family (CDK) and are especially those staurosporine derivatives disclosed in US 5,093,330, e.g.
- PKC protein kinase C
- Raf family of serine/threonine kinases members of the MEK, SRC, JAK, FAK, PDK1 , PKB/Akt
- examples of further compounds include e.g. UCN-01 , safingol, BAY 43-9006, Bryostatin 1 , Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521 ; LY333531/ LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein- tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
- GLEEVEC imatinib mesylate
- tyrphostin include imatinib mesylate (GLEEVEC) or
- a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S- arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin);
- compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex.
- trastuzumab HerceptinTM
- cetuximab ErbituxTM
- Iressa Tarceva
- OSI- 774 Tarceva
- OSI- 774 Tarceva
- EKB-569 E1.1 , E2.4, E2.5, E6.2, E6.4, E2.11 , E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541 ; and m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF.
- compounds targeting, decreasing or inhibiting the activity of the c-Met receptor such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of
- anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
- TAALOMID thalidomide
- TNP-470 TNP-470.
- Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1 , phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
- Compounds which induce cell differentiation processes are e.g. retinoic acid, oc- ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
- cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as cele- coxib (CELEBREX) 7 rofecoxib (VlOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophe- nylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
- Cox-2 inhibitors 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as cele- coxib (CELEBREX) 7 rofecoxib (VlOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophe- nylacetic acid, e.g. 5-methyl
- N-bisphosphonic acid derivatives includes, but is not limited to, 3- amino-1-hydroxypropane-1 ,1-diphosphonic acid (pamidronic acid), e.g. pamidronate (APD); 3-(N,N-dimethylamino)-1-hydroxypropane-1 ,1-diphosphonic acid, e.g. dimethyl-APD; 4- amino-1-hydroxybutane-1 ,1-diphosphonic acid (alendronic acid), e.g. alendronate; 1- hydroxy-3-(methylpentylamino)-propylidene-bisphosphonic acid, ibandronic acid, e.g.
- risedronate including N-methyl pyridinium salts thereof, for example N-methyl pyridinium iodides such as NE-10244 or NE-10446; 3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1 ,1-di- phosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1 ,1 -diphosphonic acid, e.g. EB 1053 (Leo); 1-(N-phenylaminothiocarbonyl)methane-1 ,1 -diphosphonic acid, e.g.
- FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, e.g. U- 81581 (Upjohn); and 1-hydroxy-2-(imidazo[1 ,2-a]pyridin-3-yl)ethane-1 ,1-diphosphonic acid, e.g. YM 529. especially etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
- "Etridonic acid” can be administered, e.g., in the form as it is marketed, e.g.
- DIDRONEL can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
- Tidronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID.
- Pamidronic acid can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIATM.
- Alendronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX.
- Ibandronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
- Risedronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
- Zoledronic acid can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
- AIi the N-bisphosphonic acid derivatives mentioned above are well known from the literature. This includes their manufacture (see e.g. EP-A-513760, pp. 13- 48).
- 3-amino-1-hydroxypropane-1 ,1-diphosphonic acid is prepared as described e.g. in US patent 3,962,432 as well as the disodium salt as in US patents 4,639,338 and 4,711 ,880, and 1-hydroxy-2-(imidazol-1-yl)ethane-1 ,1-diphosphonic acid is prepared as described e.g. in US patent 4,939,130. See also US patents 4,777,163 and 4,687,767.
- cathepsin K inhibitors includes, but is not limited to, the compounds exemplified in US 6,353,017B1 and WO 03/020278A1.
- mTOR inhibitors relates to compounds which inhibit the mammalian target of ra- pamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamu- ne®), everolimus (CerticanTM), CCI-779 and ABT578.
- heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
- the term includes, but is not limited to, PI-88.
- biological response modifier refers to a lymphokine or interferons, e.g. interferon ⁇ .
- inhibitor of Ras oncogenic isoforms e.g. H-Ras, K-Ras, or N-Ras
- H-Ras, K-Ras, or N-Ras refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).
- telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
- Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomes- tatin.
- methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
- Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
- proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
- Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (VelcadeTM)and MLN 341.
- matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551 ) BMS- 279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.
- MMP matrix metalloproteinase inhibitor
- FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
- FMS-like tyrosine kinase recap- tors are especially compounds, proteins or antibodies which inhibit members of the Fit-3R receptor kinase family, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
- HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
- Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
- antiproliferative antibodies includes, but is not limited to, trastuzu- mab (HerceptinTM), Trastuzumab-DM1 ,erbitux, bevacizumab (AvastinTM), rituximab (Ritu- xan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
- antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
- compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
- compounds of formula (I) can be administered in combination with, e.g., famesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
- antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2 ' -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
- HDAC histone deacetylase
- SAHA suberoylanilide hydroxamic acid
- HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, in particular, N-hydroxy-3-[4-[[[2-(2-methyl-1 H-indol-3-yl)-ethyl]-amino]me- thyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydro- xy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1 H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
- Somatostatin receptor antagonists refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
- Tumor cell damaging approaches refer to approaches such as ionizing radiation.
- ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1 , pp. 248-275 (1993).
- EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
- ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thiogua- nine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
- Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1 H-isoindole-1 ,3-dione derivatives, such as PL-1 , PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
- S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in US 5,461 ,076.
- VEGF vascular endothelial growth factor
- WO 98/35958 e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol. 93, pp.
- Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
- Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
- Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-ct-epihydrocotisol, cortexolone, 17oc-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
- Implants containing corticosteroids refers to compounds, such as e.g. fluocinolone, dexamethasone.
- “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
- ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic effect.
- the invention also provides a pharmaceutical preparation, comprising a compound of formula (I) as defined herein, or an N-oxide or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
- a compound of formula (I) can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic (including prophylactic) compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
- a compound of formula (I) can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
- the dosage of the active ingredient depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
- a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of drug within the range that yields efficacy requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
- the dose of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals is preferably from approximately 3 mg to approximately 1 O g, more preferably from approximately 10 mg to approximately 2.5 g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
- the compounds of the invention may be administered by any conventional route, in particular parenterally, for example in the form of injectable solutions or suspensions, enterally, e.g. orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
- Topical administration is e.g. to the skin.
- a further form of topical administration is to the eye.
- Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
- the invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of a compound of formula (I) or an N-oxide or a tautomer thereof together with one or more pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
- tablets or gelatin capsules that comprise the active ingredient together with pharmaceutically acceptable carrier materials, e.g. diluents, for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
- pharmaceutically acceptable carrier materials e.g. diluents, for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
- Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or in the form of infusion solutions.
- binders for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
- disintegrators for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or
- the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilisers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
- excipients for example preservatives, stabilisers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
- the present pharmaceutical compositions which may, if desired, comprise other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectionning, dissolving or lyophilising processes, and comprise approximately from 1 % to 99%, especially from approximately 1% to approximately 20%, active ingredient(s).
- the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt of such a compound, for use in a method for the treatment of the human or animal body, especially for the treatment of a disease mentioned herein, most especially in a patient requiring such treatment.
- the present invention also relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt of such a compound, for the preparation of a medicament for the treatment of a proliferative disease.
- the invention relates to a method for the treatment of a proliferative disease which responds to an inhibition of FPPS, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above, especially in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
- the invention relates to a pharmaceutical composition for treatment of solid or liquid tumours in warm-blooded animals, including humans, comprising an antitumor effective dose of a compound of the formula (I) as described above or a pharmaceutically acceptable salt of such a compound together with a pharmaceutical carrier.
- HPLC high pressure liquid chromatography System: UPLC-system Acquity, Waters;
- Hyflo Hyflo Super Cel ® filtering aid based on diatomaceous earth; obtainable from
- Ph phenyl propylphosphonic anhydride 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphophorinane-2,4,6-trioxide [68957-94-8]; 50 % in DMF
- TLC thin layer chromatography The R f values which indicate the ratio of the distance moved by each substance to the distance moved by the eluent front are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany) by thin-layer chromatography using the respective named solvent systems.
- Example 1 ⁇ -Naphthalen-i-yl-quinoline ⁇ -carboxylic acid To 210 mg Pd/C 10 % in 20 ml MeOH, 8-naphthalen-1-yl- quinoline-2-carboxylic acid benzyl ester (210 mg, 0.54 mMol) is added, followed by ammonium formiate (170 mg, 2.7 mMol). This mixture is stirred for 40 min at 65 0 C. Then the catalyst is filtered off and extensively washed with MeOH. The filtrate is concentrated and triturated in hexane.
- the starting material is prepared as follows: Step 1.1 : ⁇ -Hvdroxy-quinoline ⁇ -carboxylic acid benzyl ester
- Step 1.2 8-Trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid benzyl ester ⁇ -Hydroxy-quinoline ⁇ -carboxylic acid benzyl ester (1.396 g, 5.0 mMol) and pyridine (1.61 ml, 20 mMol) are dissolved in 75 ml CH 2 CI 2 /dioxane 2:1 and cooled to -75 0 C. Then a solution of (F 3 CSO 2 ) 2 O (1.65 ml, 10 mMol) in 1 ml CH 2 CI 2 is added and the mixture is allowed to warm up slowly to 5 0 C during 260 min.
- (F 3 CSO 2 ) 2 O (1.65 ml, 10 mMol) in 1 ml CH 2 CI 2 is added and the mixture is allowed to warm up slowly to 5 0 C during 260 min.
- reaction mixture is stirred for VA h at 80 °C, diluted with brine and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na 2 SO 4 ) and concentrated, yielding the title compound, which is used in the next step without further purification.
- Step 1.4 8-Naphthalen-1-yl-quinoline-2-carboxylic acid benzyl ester 1.0 mMol 8-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-quinoline-2-carboxylic acid benzyl ester is dissolved in 5 ml toluene. Then 1-bromo-naphthaline (140 ⁇ l, 1.00 mMol) and K 2 CO 3 (207 mg, 1.5 mMol) are added. After degassing the mixture, (Ph 3 P) 4 Pd (50 mg, 0.043 mMol) is added.
- Example 2 the following derivatives are obtained analogously to Ex. 1 :
- Example 3 fr(8-Naphthalen-1-yl-quinoline-2-carbonyl)-aminol-methyl)-phosphonic acid
- a solution of ⁇ [(8-naphthalen-1-yl-quinoline-2-carbonyl)- amino]-methyl ⁇ -phosphonic acid diethyl ester (104 mg, 0.23 mMol) in 5 ml CH 2 CI 2 is cooled in an icebath.
- bromo- trimethyl-silane (268 ⁇ l, 2.07 mMol) is added and the mixture is stirred for 18.5 h at rt.
- the mixture is concentrated in vacuo, the residue re-dissolved in MeOH and again concentrated.
- the starting material is prepared as follows:
- Step 3.1 ([( ⁇ -Naphthalen-i-yl-quinoline ⁇ -carbonvD-aminoi-methyD-phosphonic acid diethyl ester
- the starting material is prepared as follows: Step 4.1 : 8-Naphthalen-1-yl-1 H-quinolin-2-one
- Step 4.3 (8-Naphthalen-1-yl-quinolin-2-yl)-phosphonic acid diethyl ester
- a mixture of 2-chloro-8-naphthalen-1-yl-quinoline (200 mg, 0.69 mMol), (EtO) 3 P (460 mg, 2.76 mMol) and dry NiCI 2 (30 mg, 0.23 mMol) is stirred for 5 h at 170 0 C. After cooling to rt dilution with CH 2 CI 2 and addition of 4 g SiO 2 , the mixture is concentrated.
- Step 5.2 8-Naphthalen-1-yl-6-nitro-1 H-quinolin-2-one
- Step 5.4 r(6-Nitro-8-naphthalen-1-yl-quinolin-2-ylamino)-meth ⁇ l1-phosphonic acid diethyl ester
- Step 5.5 [(e-Amino- ⁇ -naphthalen-i-yl-quinolin ⁇ -ylaminoVmethyli-phosphonic acid diethyl ester
- Step 5.6 [(e-lodo- ⁇ -naphthalen-i-yl-quinolin ⁇ -ylaminoVmethyli-phosphonic acid diethyl ester
- Step 5.7 [( ⁇ -Naphthalen-i-yl-quinolin ⁇ -ylaminoVmethyll-phosphonic acid diethyl ester
- the catalyst is filtered off, washed with MeOH and the filtrate concentrated.
- the residue is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc.
- Example 7 r(6-Amino-8-naphthalen-1-yl-quinolin-2-ylamino)-methyl1-phosphonic acid
- the starting material is prepared as follows:
- Step 9.1 (r8-Naphthalen-1-yl-6-(1-triisopropylsilanyl-1 H-pyrrol-3-vO-quinolin-2-ylamino1- methvD-phosphonic acid diethyl ester
- the starting material is prepared as follows:
- Step 10.1 [(8-Naphthalen-1-yl-6-pyridin-3-yl-quinolin-2-ylamino)-methyll-phosphonic acid diethyl ester
- Example 1 (8-Naphthalen-1-yl-quinolin-2-ylmethyl)-phosphonic acid
- the starting material is prepared as follows:
- Step 1 8-Hvdroxy-quinoline-2-carboxylic acid methyl ester
- Me 3 SiCI (3.8 ml, 30 mMol) is added to a suspension of 8-hydroxy-quinoline-2-carboxylic acid
- Step 11.2 ⁇ -Trifluoromethanesulfonyloxy-quinoline ⁇ -carboxylic acid methyl ester
- a solution of ⁇ -hydroxy-quinoline ⁇ -carboxylic acid methyl ester (2.03 g, 10 mMol) in 100 ml CH 2 CI 2 is cooled to -78 0 C.
- Et 3 N 4.3 ml, 31 mMol
- a solution of trifluoromethanesulfonic anhydride 2.3 ml, 14 mMol
- the mixture is poured into EtOAc and water/sat. NaHCO 3 10:1.
- Step 11.3 8-Naphthalen-1-yl-quinoline-2-carboxylic acid methyl ester A solution of 8-trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid methyl ester (1 .05 g, 3.13 mMol) in 50 ml terf-butanol is degassed by repeated evacuation to HV and flushing with N 2 .
- 1-naphthalene-boronic acid (0.59 g, 3.44 mMol)
- Pd(OAc) 2 56 mg, 0.25 mMol
- K 3 PO 4 1.592 g, 7.5 mMol
- 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl 179 mg, 0.375 mMol
- Step 1 2-Hvdroxymethyl-8-naphthalen-1-yl-quinoline
- Step 11.6 ( ⁇ -Naphthalen-i-yl-quinolin ⁇ -ylmethvO-phosphonic acid diethyl ester A mixture of 2-chloromethyl-8-naphthalen-1-yl-quinoline hydrochloride (187 mg, 0.55 mMol) and (EtO) 3 P (0.41 g, 2.4 mMol) is stirred for 2 h at 170 0 C. The cooled mixture is dissolved in EtOAc and H 2 O/sat. NaHCO 3 9:1 , the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na 2 SO 4 ) and concentrated.
- the starting material is prepared as follows:
- Step 12.1 ⁇ r(8-Naphthalen-1-yl-quinolin-2-ylmethyl)-amino1-methyl)-phosphonic acid ethyl ester
- the starting material is prepared as follows:
- Step 13.1 rac. 2-(Benzyloxycarbonyl-amino)-3-r(8-trifluoromethanesulfonyloxy-quinoline-2- carbonylVaminol-propionic acid methyl ester
- Step 13.2 rac. 2-(Benzyloxycarbonyl-aminoV3-r(8-naphthalen-1-yl-quinoline-2-carbonvO- aminoi-propionic acid methyl ester rac. 2-(Benzyloxycarbonyl-amino)-3-[(8-trifluoromethanesulfonyloxy-quinoline-2-carbonyl)- amino]-propionic acid methyl ester (1.49 g, 2.68 mMol) in 150 ml te/t-butanol is degassed by repeated evacuation to HV and flushing with N 2 .
- 1-naphthalene-boronic acid (507 mg, 2.95 mMol), K 3 PO 4 (1.37 g, 6.45 mMol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '- biphenyl (179 mg, 0.375 mMol) and Pd(OAc) 2 (54 mg, 0.24 mMol) are added successively.
- This mixture is stirred for 70 min at 80 0 C, cooled to rt and concentrated in vacuo. The residue is re-dissolved in EtOAc and water, the aq. phase separated off and extracted twice with EtOAc.
- Step 13.3 rac. 2-Amino-3-[(8-naphthalen-1-yl-quinoline-2-carbonyl)-amino1-propionic acid methyl ester hydrochloride
- Example 14 rac. 2-r(Amino-sulfonyl)-aminol-3-[(8-naphthalen-1-yl-quinoline-2-carbonyl)- aminoi-propionic acid methyl ester
- 2-[(terf-butoxycarbonylamino- sulfonyl)-amino]-3-[(8-naphthalen-1-yl-quinoline-2- carbonyl)-amino]-propionic acid methyl ester (265 mg, 0.458 mMol) in 5 ml dioxane, 5 ml HCI (4 M in dioxane) is added. After 1 10 min, the reaction mixture is concentrated in vacuo, giving the hyrochloride of the title compound.
- Example 15 rac. 8-Naphthalen-1 -yl-quinoline-2-carboxylic acid (1.1.4-trioxo-1 lambda * 6*- f1 ,2.5lthiadiazolidin-3-ylmethyl)-amide A and rac. 2-r(amino-sulfonvO-aminol-3-r(8- naphthalen-1-yl-quinoline-2-carbonyl)-amino1-propionic acid B
- Example 16 r6-(3-Methoxy-phenyO-8-naphthalen-1-yl-quinolin-2-yll-phosphonic acid obtained analogously to Ex. 4 starting enyl)-8-naphthalen-1-yl-quinolin-2-yl]- yl ester (84 mg, 0.169 mMol): MS:
- the starting material is prepared as follows: Step 16.1 : 6-Amino-8-naphthalen-1-yl-1 H-quinolin-2-one
- Step 16.3 6-(3-Metho ⁇ y-phenyl)-8-naphthalen-1-yl-1 H-quinolin-2-one
- a suspension of 6-iodo-8-naphthalen-1-yl-1 H-quinolin-2-one (460 mg, 1.16 mMol), 3- methyoxy-phenyl boronic acid (211 mg, 1.39 mMol) and 2.5 ml 1 M aq. K 2 CO 3 in 5 ml DMF is degassed by repeated evacuation by HV and flushing with N 2 . Then (Ph 3 P) 2 PdCI 2 (49 mg, 0.069 mMol) is added and heated up to 110 0 C for 1 h.
- Step 16.4 2-Chloro-6-(3-methoxy-phenv ⁇ -8-naphthalen-1-yl-Quinoline
- 6-(3-methoxy-phenyl)-8-naphthalen-1-yl-1 H-quinolin-2-one 480 mg, 1.27 mMol
- Et 4 NCI 463 mg, 2.8 mMol
- N,N-dimethylaniline 355 ⁇ l, 2.8 mMol
- POCI 3 (1.51 ml, 16.5 mMol
- Step 16.5 e-O-Methoxy-phenvD- ⁇ -naphthalen-i -yl-quinolin ⁇ -yll-phosphonic acid diethyl ester
- 2-Chloro-6-(3-methoxy-phenyl)-8-naphthalen-1-yl-quinoline (223 mg, 0.56 mMol) is dissolved in 3 ml degassed toluene. Then diethylphosphite (80 ⁇ l, 0.62 mMol), Et 3 N (86 ⁇ l, 0.62 mMol) and (Ph 3 P) 4 Pd (65 mg, 0.056 mMol) are added. This solution is stirred for 21 h at 100 0 C in a sealed vessel. The cold reaction mixture is diluted in water and EtOAc, the aq. layer separated off and extracted twice with EtOAc.
- (+0.72 HBr +3.5 H 2 O +0.2 hexane): C 1 H 1 N 1 S 1 Br; MS: [M+1] + 418; 1 H-NMR (DMSO-d 6 ): ⁇ ppm 8.58 (dd, 1 H) 1 8.40 (s, 1 H), 8.96 (S, 1 H), 8.02 (d, 1 H), 8.00 (d, 1 H), 7.90 (dd, 1 H), 7.78 (d, 1 H), 7.67 (d, 1 H), 7.63 (t, 1 H), 7.55 (d, 1 H), 7.49 (t, 1 H), 7.35 (m, 2 H), 7.18 (dd, 1 H).
- the starting material is prepared as follows:
- Step 17.1 (8-Naphthalen-1 -yl-6-nitro-quinolin-2-yl)-phosphonic acid diethyl ester
- Step 17.2 (e-Amino- ⁇ -naphthalen-i-yl-quinolin ⁇ -vO-phosphonic acid diethyl ester (8-Naphthalen-1 -yl-6-nitro-quinolin-2-yl)-phosphonic acid diethyl ester (5.9 g, 13.5 mMol) in 300 ml THF is hydrogenated in presence of 4 g Raney-Nickel (in EtOH; B113 W Degussa). The catalyst is filtered off through Hyflo and washed with THF.
- Step 17.3 (e-lodo- ⁇ -naphthalen-i-yl-quinolin ⁇ -vO-phosphonic acid diethyl ester
- (6-amino-8-naphthalen-1-yl-quinolin-2-yl)-phosphonic acid diethyl ester (4.8 g, 1 1.8 mMol) in 73 ml cone. HCI, pieces of ice are added and the mixture is cooled to -15 0 C. Then a solution of NaNO 2 (1.63 g, 23.6 mMol) in 96 ml H 2 O is added during 20 min.
- Step 17.4 (8-Naphthalen-1-yl-6-thiophen-2-yl- ⁇ uinolin-2-yl)-phosphonic acid diethyl ester
- a solution of (6-iodo-8-naphthalen-1-yl-quinolin-2-yl)-phosphonic acid diethyl ester (250 mg, 0.483 mMol), 2-thiophene boronic acid (74.2 mg, 0.58 mMol) and 1.1 ml 1 M aq. K 2 CO 3 in 2.5 ml DMF is degassed by repeated evacuation by HV and flushing with N 2 .
- Example 20 (e-Amino- ⁇ -naphthalen-i-yl-quinolin ⁇ -vD-phosphonic acid A solution of (6-amino-8-naphthalen-1-yl-quinolin-2-yl)-phosphonic acid diethyl ester (134 mg, 0.33 mMol) in 10 ml CH 2 CI 2 is cooled in an icebath. Then bromo-trimethyl-silane (427 ⁇ l, 3.3 mMol) is added and the orange solution is stirred for 5 h at rt in a sealed vessel. The mixture is concentrated in vacuo and the residue triturated from hot EtOAc, yielding the title compound as the hydrobromide salt: Anal.
- the starting material is prepared as follows:
- Step 22.1 2-r2-(Diethoxy-phosphorvn-8-naphthalen-1-yl-quinolin-6-yn-pyrrole-1-carboxylic acid tert-butyl ester A and [8-naphthalen-1-yl-6-(1 H-pyrrol-2-yl)-quinolin-2-yll-phosphonic acid diethyl ester B
- the starting material is prepared as follows:
- Step 24.1 2-r2-(Diethoxy-phosphoryl)-8-naphthalen-1 -yl- ⁇ uinolin-6-yll-indole-1 -carboxylic acid terf-butyl ester A and r ⁇ -d H-indol ⁇ -vD- ⁇ -naphthalen-i-yl-quinolin ⁇ -vn-phosphonic acid diethyl ester B
- Example 25 r6-(6-Methoxy-pyridin-3-yl)-8-naphthalen-1-yl-quinolin-2-yl1-phosphonic acid A and r6-(6-hvdroxy-pyridin-3-yl)-8-naphthalen-1 -yl-quinolin-2-yl1-phosphonic acid B
- the starting material is prepared as follows:
- Step 25.1 r6-(6-Methoxy-pyridin-3-v ⁇ -8-naphthalen-1-yl-quinolin-2-vn-phosphonic acid diethyl ester
- the starting material is prepared as follows:
- Step 26.1 F8-Naphthalen-1 -yl-6-H -(triisopropylsilvD-1 H-pyrrol-S-vn- ⁇ uinolin ⁇ -yll-phosphonic acid diethyl ester A and r ⁇ -naphthalen-i-yl-e-d H-pyrrol-S-vD-quinolin ⁇ -yll-phosphonic acid diethyl ester B
- Step 28.1 f6-(3-Hvdroxy-phenyl)-8-naphthalen-1-yl-quinolin-2-yn-phosphonic acid diethyl ester
- the starting material is prepared as follows:
- Step 29.1 e-Ethoxycarbonylamino- ⁇ -naphthalen-i-yl-quinoline ⁇ -carboxylic acid ethyl ester A; ⁇ -amino- ⁇ -ethoxy- ⁇ -naphthalen-i-yl-quinoline ⁇ -carboxylic acid ethyl ester B and 6- amino- ⁇ -naphthalen-1-yl-quinoline-2-carboxylic acid ethyl ester C
- Example 31 6-Amino-8-naphthalen-1-yl-quinoline-2-carboxylic acid Prepared as described in Ex. 29 from 6-amino-8-naphthalen-1-yl- quinoline-2-carboxylic acid ethyl ester (100 mg, 0.292 mMol) and isolated as its TFA-salt via reversed phase chromatography: Anal.
- Step 32.1 6-lodo-8-naprithalen-1-yl-quinoline-2-carboxylic acid ethyl ester 6-Amino-8-naphthalen-1-yl-quinoline-2-carboxylic acid ethyl ester (364 mg, 1.06 mMol) and pieces of ice in 6.6 ml cone. HCI are cooled to -15 0 C. Then a solution of NaNO 2 (146 mg, 2.1 mMol) in 8.7 ml H 2 O is added dropwise and the mixture is stirred for 20 min. The suspension is added portion wise to an ice cooled solution of Kl (9.6 g, 58 mMol) in 40 ml H 2 O.
- Step 33.1 ⁇ -Ethoxy-e-iodo- ⁇ -naphthalen-i-yl-quinoline ⁇ -carboxylic acid ethyl ester
- the starting material is prepared as follows:
- Step 34.1 8-Naphthalen-1-yl-6-thiophen-3-yl- ⁇ uinoline-2-carboxylic acid ethyl ester
- the starting material is prepared as follows:
- Step 35.1 ⁇ -Naphthalen-i-yl-e-thiophen ⁇ -yl-quinoline ⁇ -carboxylic acid ethyl ester Prepared as described in Step 34.1 from 6-iodo-8-naphthalen-1-yl-quinoline-2-carboxylic acid ethyl ester (125 mg, 0.276 mMol) and thiophen-2-boronic acid (70.6 mg, 0.552 mMol) in
- the starting material is prepared as follows:
- Step 36.1 6-(1-te/t-Butoxycarbonyl-1 H-pyrrale ⁇ -vQ- ⁇ -naphthalen-i-yl-quinoline ⁇ -carboxylic acid ethyl ester
- the starting material is prepared as follows:
- Step 37.1 ⁇ -Trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid methyl ester 8-Hydroxy-quinoline-2-carboxylic acid methyl ester (2.03 g, 10.0 mMol) is dissolved in 100 ml CH 2 CI 2 and cooled to -78 0 C. Then Et 3 N (4.3 ml, 31 mMol) is added, followed by a solution of (F 3 CSO 2 ) 2 O (2.4 ml, 14 mMol) in 10 ml CH 2 CI 2 . After 3 h at -78 0 C, the mixture is poured into a mixture of EtOAc and water/sat.
- Step 37.2 ⁇ -f ⁇ -Hydroxymethyl-naphthalen-i-vO-quinoline ⁇ -carboxylic acid methyl ester ⁇ -Trifluoromethanesulfonyloxy-quinoline ⁇ -carboxylic acid methyl ester (1.0 g, 2.9 ⁇ mMol) is dissolved in 14 ml dry DMF. Then bis-(pinacolato)-diboron (909 mg, 3.58 mMol), potassium acetate (878 mg, 8.95 mMol) and 4 g molecular sieves 4 A are added.
- the starting material is prepared as follows:
- Step 38.1 ⁇ -fS-Acetoxymethyl-naphthalen-i -vO-quinoline ⁇ -carboxylic acid methyl ester
- a solution of 8-(5-hydroxymethyl-naphthalen-1 -yl)-quinoline-2-carboxylic acid methyl ester (99 mg, 0.288 mMol), 0.1 ml acetic acid anhydride and a trace of DMAP in 2 ml CH 2 CI 2 and 0.2 ml pyridine is stirred for 16 h at rt and then diluted with EtOAc and water. The aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na 2 SO 4 ), concentrated to the crude title compound: MS: [M+1] + 386.
- Step 38.2 8-(5-Methyl-naphthalen-1-yl)-quinoline-2-carboxylic acid methyl ester
- the crude ⁇ - ⁇ -acetoxymethyl-naphthalen-i-yty-quinoline ⁇ -carboxylic acid methyl ester from Step 38.1 is dissolved in 10 ml MeOH and hydrogenated in presence of 60 mg Pd/C (5 %, E101 N/D Degussa). The catalyst is then filtered off, washed with MeOH and the filtrate is concentrated.
- the starting material is prepared as follows:
- Example 40 r(EV2-(8-Naphthalen-1-yl-quinolin-2-v ⁇ -vinvn-phosphonic acid
- (+0.9 HBr +2 H 2 O): C 1 H 1 N 1 Br; MS: [M+1] + 362; 1 H-NMR (DMSO- d ⁇ ): ⁇ ppm 8.50 (d, 1 H), 8.10 (d, 1 H), 7.99 (d, 2 H), 7.91 (d, 1 H), 7.75 (m, 2 H), 7.61 (t, 1 H), 7.48 (m, 2 H), 7.28 (m, 2 H), 7.00 (dd, 1 H), 6.59 (dd, 1 H); 31 P-NMR (DMSO-d 6 ): ⁇ 13.0 ppm.
- the starting material is prepared as follows:
- Step 40.1 f(E)-2-(8-Hvdroxy-quinolin-2-yl)-vinv ⁇ -phosphonic acid diethyl ester
- Step 40.3 r(E)-2-(8-Naphthalen-1-yl-quinolin-2-yl)-vinvn-phosphonic acid diethyl ester [(E)-2-(8-Trifluoromethanesulfonyloxy-quinolin-2-yl)-vinyl]-phosphonic acid diethyl ester (1.2 g, 2.73 mMol) dissolved in 84 ml tert.-butanol is degassed by repeated evacuation to HV and flushing with N 2 .
- 1-naphthalene boronic acid (477 mg, 2.77 mMol), Pd(OAc) 2 (128 mg, 0.57 mMol), K 3 PO 4 (1.452 g, 6.8 mMol) and 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos; 323 mg, 0.68 mMol) are added.
- the reaction mixture is stirred for 2 1 /2 h at 82 0 C, diluted with water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na 2 SO 4 ) and concentrated.
- the starting material is prepared as follows:
- (E)-2-(8-Naphthalen-1-yl-quinolin-2-yl)-vinyl]-phosphonic acid diethyl ester (0.48 g, 1.15 mMol) in 15 ml EtOH is hydrogenated in presence of 0.1 g Pd/C (10 %; Engelhard 4505).
- the starting material is prepared as follows:
- Step 42.1 r(E)-2-(6-Nitro-8-naphthalen-1-yl-quinolin-2-v ⁇ -vinyl1-phosphonic acid diethyl ester
- 2-chloro-8-naphthalen-1-yl-6-nitro-quinoline 3.0 g, 8.96 mMol; Step 5.3
- diethyl vinylphosphonate (1.66 ml, 10.8 mMol)
- Et 3 N 3.74 ml, 26.9 mMol
- Pd(OAc) 2 (40.2 mg, 0.179 mMol)
- Tri(o-tolyl)phosphine 109 mg, 0.358 mMol
- Step 42.2 r(E)-2-(6-Amino-8-naphthalen-1-yl-quinolin-2-yl)-vinyl1-phosphonic acid diethyl ester
- the starting material is prepared as follows:
- Step 44.1 r(E)-2-(6-Methoxycarbonylamino-8-naphthalen-1 -yl-quinolin-2-yl)-vinvH- phosphonic acid diethyl ester
- Example 45 [(E ⁇ -fe-Acetylamino- ⁇ -naphthalen-i-yl-quinolin ⁇ -ylVvinyll-phosphonic acid [(E)-2-(6-Acetylamino-8-naphthalen-1 -yl-quinolin-2-yl)- vinyl]-phosphonic acid diethyl ester (33 mg, 0.070 mMol) is
- the starting material is prepared as follows:
- Step 45.1 rfE ⁇ -fe-Acetylamino- ⁇ -naphthalen-i-yl-quinolin ⁇ -vO-vinyli-phosphonic acid diethyl ester
- Example 46 r(EV2-(6-Methanesulfonylamino-8-naphthalen-1 -yl-quinolin-2-yl)-vinyl1- phosphonic acid
- the starting material is prepared as follows:
- Step 46.1 r(E)-2-(6-Methanesulfonylamino-8-naphthalen-1-yl-quinolin-2-yl)-vinyn-phosphonic acid diethyl ester
- Example 47 ⁇ (E)-2-r6-(di-methanesulfonyl)amino-8-naphthalen-1 -yl-quinolin-2-yll-vinyl)- phosphonic acid
- Example 48 ((E)-2- ⁇ 8-Naphthalen-1 -yl-6-r(pyridine-3-carbonyl)-aminol-quinolin-2-yl)-vinyl)- phosphonic acid n-1-yl-6-[(pyridine-3-carbonyl)- ⁇ -vinyl)-phosphonic acid diethyl mMol) is deprotected as yielding the title compound as the 1 TFA +1.3 H 2 O): C 1 H 1 N 1 F 1 P; MS:
- the starting material is prepared as follows:
- Step 48.1 ((E ⁇ -l ⁇ -Naphthalen-i-yl-e-rfPyridine-S-carbonylVaminoi-quinolin ⁇ -ylVvinv ⁇ - phosphonic acid diethyl ester
- the starting material is prepared as follows:
- Step 49.1 rac. ⁇ f(E)-2-f6-(2-feAt-Butoxycarbonylamino-3,3-dimethyl-butyrylamino)-8- naphthalen-1-yl-quinolin-2-yll-vinyl>-phosphonic acid diethyl ester
- a mixture of sodium azide (228 mg, 3.5 mMol) and 0.2 ml toluene in a dried vessel is cooled in an ice-bath. Then 1.95 ml Et 2 AICI (1.8 M in toluene, 3.5 mMol) are added and the mixture is stirred for 5.5 h at rt. After cooling in an ice-bath, N-(2-cyano-8-naphthalen-1 -yl-quinolin-6-yl)- carbamic acid ethyl ester (100 mg, 0.27 mMol) is added during 20 min divided in 3 portions. After 40 h at rt, the mixture is poured into a mixture of EtOAc and 10 % aq.
- the starting material is prepared as follows:
- Step 50.1 8-Naphthalen-1-yl-6-nitro-quinoline-2-carbonitrile
- Step 50.3 N-(2-Cvano-8-naphthalen-1-yl-quinolin-6-v ⁇ -carbamic acid ethyl ester 6-Amino-8-naphthalen-1-yl-quinoline-2-carbonitrile (470 mg, 1.59 mMol) in 1 1 ml CH 2 CI 2 and 7 ml pyridine is cooled in an ice bath. Then ethyl chloroformate (190 ⁇ l, 2.0 mMol) is added, warmed up to rt and stirred for 1 h. The solution is diluted with 5 % aq. citric acid and EtOAc, the aq. layer separated off and extracted twice with EtOAc.
- Step 51.1 N-(2-Cvano-8-naphthalen-1 -yl-quinolin-6-vD-acetamide 6-Amino-8-naphthalen-1-yl-quinoline-2-carbonitrile (200 mg, 0.68 mMol) in 4.6 ml CH 2 CI 2 and 3 ml pyridine is cooled in an ice bath. Then acetic acid anhydride (77 ⁇ l, 0.82 mMol) is added, warmed up to rt and stirred for 9 h.
- the starting material is prepared as follows: Step 52.1 : 6-lodo-8-naphthalen-1-yl-quinoline-2-carbonitrile ⁇ -Amino- ⁇ -naphthalen-i-yl-quinoline ⁇ -carbonitrile (400 mg, 1.35 mMol) and pieces of ice in 8.4 ml cone. HCI are cooled to -15 0 C. Then a solution of NaNO 2 (186 mg, 2.7 mMol) in 1 1 ml H 2 O is added dropwise and the mixture is stirred for 20 min. The suspension is added portion wise to an ice cooled solution of Kl (12.1 g, 73 mMol) in 51 ml H 2 O.
- Step 52.2 e-Thiophen ⁇ -yl- ⁇ -naphthalen-i-yl-quinoline ⁇ -carbonitrile
- Example 53 6-Thiophen-2-yl-2-(2-methyl-2H-tetrazol-5-yl)-8-naphthalen-1-yl-quinoline A and 6-thiophen-2-yl-2-(1 -methyl-1 H-tetrazol-5-yl)-8-naphthalen-1-yl-quinoline B
- 6-Thiophen-2-yl-8-naphthalen-1-yl-2-(2H-tetrazol-5-yl)-quinoline (65 mg, 0.16 mMol) is dissolved in 1 ml dioxane. Then Cs 2 CO 3 (156 mg, 0.48 mMol) is added, followed by methyl-iodide (11.2 ⁇ l, 0.18 mMol). After 5 d at rt, another portion of 11.2 ⁇ l methyl- iodide is added. The mixture is stirred for 3 h and then diluted with EtOAc and water. The aq. layer is separted off and extracted twice with EtOAc.
- the starting material is prepared as follows:
- Step 54.2 e-Chloro- ⁇ -naphthalen-i-yl-quinoline ⁇ -carbonitrile
- V V max [S]/[S] + K m
- V max equals the maximal rate of product formation over time
- [S] the concentration of IPP or GPP
- K m the Henri-Michaelis-Menten constant which is includes factors for affinity and catalytic rate.
- K cat is determined by V max / [FPPS]; IC 50 curves are fit to a variable slope, sigmoidal curve using non-linear regression algorithm in GraphPad Prism software as (log IC50-X) x Hill Slope
- FPPS Farnesyl Pyrophosphate synthase
- the FPPS assay is performed in a final detection volume of 12 ⁇ l under steady-state conditions as follows:
- LEADseeker (trademark) should be spelled consistently.
- FlashPiates (trademark) should be spelled consistently throughout.
- test compound solution in 18% DMSO/water or 18% DMSO/assay buffer (carrier control) (end concentration of DMSO in the assay 4.5 %)
- the inhibition of the FPPS enzymatic reaction by compounds is measured, in a LEADseeker IV (Amersham Biotech), reader, reading time 2 min, method SPA, using for flat field correction the Amersham 384-well standard and quasi-coincident radiation correction, is used.
- Test compounds are arrayed in an 8 or 16 point, 2 or 3-fold serial dilution series in 90% DMSO such that the highest concentration is 2 mM in 90% DMSO.
- these compound source plates are diluted and replicated into 384 well image FlashPiates (using a CyBiWeII HTS pipetter) to contain 3 ⁇ L of compound solution each, to which the assay reagents are added and read. This procedure results in a dose response curve performed in triplicate with 100 ⁇ M being the highest concentration tested.
- Zometa can be used, which inhibits the reaction with an IC50 of between 50 and 200 nM. Selected compounds were assayed in an antibody based assay as described above; results are summarized in the following table.
- LC/MS/MS analyses are performed on a Micromass Quattro Micro interfaced to an Agilent 1 100 binary LC pump. Injection is performed by a Gilson 215/889 autosampler using an injection loop size of 2.5 ⁇ l_. Chromatography is performed on a Waters 2.1 x 20 mm Xterra MS C18 5 ⁇ m guard column (P/N 186000652) contained in a guard column holder (P/N 186000262) using 0.1 % DMIPA/methanol as solvent A and 0.1% DMIPA/water as solvent B. The gradient is 5% A from 0.00 to 0.30 min, 50% A at 0.31 min, 80% A at 1.00 min, and 5% A from 1.01 to 2.00 min. The flow rate is 0.3 mL/min and the flow is diverted to waste from 0.00 to 0.50 min and again from 1.20 to 2.00 min.
- the MRM transitions monitored are 381 " >79 " for FPP and 397 “ >159 " for FSPP at a collision energy of 22 eV and a collision cell pressure of 2.1 x 10 ⁇ 3 mbar of Ar.
- the dwell time per transition is 400 msec with a span of 0.4 Da.
- the interchannel delay and interscan delay are both 0.02 sec.
- Other mass spectrometric operating parameters are: capillary, 2.0 kV; cone, 35 V; extractor, 2.0 V, source temp., 100 0 C; desolvation gas temp., 250 0 C; desolvation gas flow, 650 L/hr; cone gas flow, 25 L/hr; multiplier, 650 V.
- the total cycle time per sample is 2.5 minutes. Since the analysis is formatted for 384-well plates, a plate is analyzed in 16 hours. The chromatograms are processed using Quanlynx software, which divides the area of individual FPP peaks by the area of the FSPP peaks (internal standard). The resulting values are reported as the relative response for the corresponding sample well.
- the results of LC-MS the assay are summarized in the following table.
- the compounds of the present invention show FPPS inhibition in the range of 1 nM to >100 ⁇ M, preferably from 1 nM to 50 ⁇ M, more preferably from 1 nM to 10 ⁇ M, more preferably from 1 nM to 1 ⁇ M, more preferably from 1 nM to 900 nM, more preferably from 1 nM to 800 nM, more preferably from 1 nM to 700 nM, more preferably from 1 nM to 600 nM, more preferably from 1 nM to 500 nM, more preferably from 1 nM to 400 nM, more preferably from 1 nM to 300 nM, more preferably from 1 nM to 200 nM, more preferably from 1 nM to 100 nM, more preferably from 1 nM to 90 nM, more preferably from 1 nM to 80 nM, more preferably from 1 nM to 70 nM, more preferably from 1 nM to 60 nM, more preferably from
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Abstract
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JP2010548111A JP2011514893A (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase |
CA2717011A CA2717011A1 (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase |
EA201001362A EA201001362A1 (en) | 2008-02-28 | 2009-02-26 | QUINOLINES AS PHARNESILPYROPHOSPHATSINTAZES INHIBITORS |
AU2009218468A AU2009218468A1 (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase |
MX2010009518A MX2010009518A (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase. |
BRPI0908396-0A BRPI0908396A2 (en) | 2008-02-28 | 2009-02-26 | quinolines as farnesyl pyrophosphate synthase inhibitors |
CN2009801064544A CN101959865A (en) | 2008-02-28 | 2009-02-26 | Quinolines as farnesyl pyrophosphate synthase inhibitor |
EP09715302A EP2250152A1 (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase |
US12/918,880 US20120094958A1 (en) | 2008-02-28 | 2009-02-26 | Quinolines as inhibitors of farnesyl pyrophosphate synthase |
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BR (1) | BRPI0908396A2 (en) |
CA (1) | CA2717011A1 (en) |
EA (1) | EA201001362A1 (en) |
MX (1) | MX2010009518A (en) |
WO (1) | WO2009106586A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010101949A1 (en) * | 2009-03-02 | 2010-09-10 | Sirtris Pharmaceuticals, Inc. | 8-substituted quinolines and related analogs as sirtuin modulators |
WO2013090929A1 (en) * | 2011-12-15 | 2013-06-20 | Gilead Sciences, Inc. | Amino quinoline derivatives inhibitors of hcv |
WO2019076269A1 (en) | 2017-10-16 | 2019-04-25 | 清华大学 | Mevalonic acid pathway inhibitor and pharmaceutical composition thereof |
CN111440161A (en) * | 2020-05-15 | 2020-07-24 | 中国药科大学 | Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof |
CN112980809A (en) * | 2021-03-17 | 2021-06-18 | 云南中烟工业有限责任公司 | Tobacco farnesyl pyrophosphate synthase gene and application thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104142378B (en) * | 2014-07-29 | 2015-12-30 | 华南理工大学 | The method of thin-layered chromatography semiquantitative determination urethanes |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5254544A (en) * | 1992-09-25 | 1993-10-19 | E. R. Squibb & Sons, Inc. | Hydroxyphosphinyl phosphonate squalene synthetase inhibitors and method |
US20040235797A1 (en) * | 2000-02-25 | 2004-11-25 | Bergstrom James D. | Methods for identifying compounds useful for inhibiting farnesyl diphosphate synthase |
-
2009
- 2009-02-26 EP EP09715302A patent/EP2250152A1/en not_active Withdrawn
- 2009-02-26 KR KR1020107019046A patent/KR20100124732A/en not_active Application Discontinuation
- 2009-02-26 JP JP2010548111A patent/JP2011514893A/en active Pending
- 2009-02-26 WO PCT/EP2009/052314 patent/WO2009106586A1/en active Application Filing
- 2009-02-26 MX MX2010009518A patent/MX2010009518A/en not_active Application Discontinuation
- 2009-02-26 BR BRPI0908396-0A patent/BRPI0908396A2/en not_active IP Right Cessation
- 2009-02-26 EA EA201001362A patent/EA201001362A1/en unknown
- 2009-02-26 CA CA2717011A patent/CA2717011A1/en not_active Abandoned
- 2009-02-26 AU AU2009218468A patent/AU2009218468A1/en not_active Abandoned
- 2009-02-26 US US12/918,880 patent/US20120094958A1/en not_active Abandoned
- 2009-02-26 CN CN2009801064544A patent/CN101959865A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5254544A (en) * | 1992-09-25 | 1993-10-19 | E. R. Squibb & Sons, Inc. | Hydroxyphosphinyl phosphonate squalene synthetase inhibitors and method |
US20040235797A1 (en) * | 2000-02-25 | 2004-11-25 | Bergstrom James D. | Methods for identifying compounds useful for inhibiting farnesyl diphosphate synthase |
Non-Patent Citations (4)
Title |
---|
DATABASE BEILSTEIN [online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002490408, Database accession no. 8496039 (BRN) * |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002490409, Database accession no. 909076-67-1 (RN) * |
J. CHEM. RES., vol. 1, 2000, pages 46 - 47 * |
SANDERS ET AL.: "3-D QSAR INVESTIGATIONS OF THE INHIBITION OF LEISHMANIA MAJOR FARNESYL PYROPHOSPHATE SYNTHASE BY BISPHOSPHONATES", J. MED. CHEM., vol. 46, no. 24, 20 November 2003 (2003-11-20), pages 5171 - 5183, XP009064956, ISSN: 0022-2623 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010101949A1 (en) * | 2009-03-02 | 2010-09-10 | Sirtris Pharmaceuticals, Inc. | 8-substituted quinolines and related analogs as sirtuin modulators |
WO2013090929A1 (en) * | 2011-12-15 | 2013-06-20 | Gilead Sciences, Inc. | Amino quinoline derivatives inhibitors of hcv |
WO2019076269A1 (en) | 2017-10-16 | 2019-04-25 | 清华大学 | Mevalonic acid pathway inhibitor and pharmaceutical composition thereof |
CN111440161A (en) * | 2020-05-15 | 2020-07-24 | 中国药科大学 | Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof |
CN111440161B (en) * | 2020-05-15 | 2023-04-14 | 中国药科大学 | Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof |
CN112980809A (en) * | 2021-03-17 | 2021-06-18 | 云南中烟工业有限责任公司 | Tobacco farnesyl pyrophosphate synthase gene and application thereof |
Also Published As
Publication number | Publication date |
---|---|
KR20100124732A (en) | 2010-11-29 |
EP2250152A1 (en) | 2010-11-17 |
CN101959865A (en) | 2011-01-26 |
AU2009218468A1 (en) | 2009-09-03 |
MX2010009518A (en) | 2010-09-14 |
BRPI0908396A2 (en) | 2019-03-06 |
EA201001362A1 (en) | 2011-04-29 |
JP2011514893A (en) | 2011-05-12 |
CA2717011A1 (en) | 2009-09-03 |
US20120094958A1 (en) | 2012-04-19 |
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