NZ627149B2 - Piperazinyl derivatives for the treatment of cancer - Google Patents
Piperazinyl derivatives for the treatment of cancer Download PDFInfo
- Publication number
- NZ627149B2 NZ627149B2 NZ627149A NZ62714912A NZ627149B2 NZ 627149 B2 NZ627149 B2 NZ 627149B2 NZ 627149 A NZ627149 A NZ 627149A NZ 62714912 A NZ62714912 A NZ 62714912A NZ 627149 B2 NZ627149 B2 NZ 627149B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- inhibitors
- alkyl
- formula
- compound
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- 201000011510 cancer Diseases 0.000 title claims abstract description 29
- 125000004193 piperazinyl group Chemical group 0.000 title abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drugs Drugs 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 60
- -1 antinomycin D Chemical compound 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 108090001123 antibodies Proteins 0.000 claims description 12
- 102000004965 antibodies Human genes 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- VWUXBMIQPBEWFH-WCCTWKNTSA-N (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 8
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 8
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- 229960002258 Fulvestrant Drugs 0.000 claims description 8
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 8
- 229960001592 Paclitaxel Drugs 0.000 claims description 8
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 claims description 8
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- 230000000259 anti-tumor Effects 0.000 claims description 8
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- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 229930002330 retinoic acid Natural products 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 229930003347 taxol Natural products 0.000 claims description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 8
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- 150000001412 amines Chemical class 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 150000002829 nitrogen Chemical group 0.000 claims description 7
- 229940009456 Adriamycin Drugs 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- 230000036740 Metabolism Effects 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 230000004060 metabolic process Effects 0.000 claims description 5
- 230000035786 metabolism Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 claims description 4
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 4
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5S,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 claims description 4
- OMJKFYKNWZZKTK-POHAHGRESA-N (5Z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1/N=CN=C1C(N)=O OMJKFYKNWZZKTK-POHAHGRESA-N 0.000 claims description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 4
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-N-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 claims description 4
- HPLNQCPCUACXLM-PGUFJCEWSA-N 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 claims description 4
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- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
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- PLHJCIYEEKOWNM-HHHXNRCGSA-N 6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 claims description 4
- 229940100198 ALKYLATING AGENTS Drugs 0.000 claims description 4
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- 229940045714 Alkyl sulfonate alkylating agents Drugs 0.000 claims description 4
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 4
- BIIVYFLTOXDAOV-YVEFUNNKSA-N Alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 claims description 4
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- GHOVLEQTRNXASK-UHFFFAOYSA-N ethyl 2-oxo-2-thiophen-2-ylacetate Chemical compound CCOC(=O)C(=O)C1=CC=CS1 GHOVLEQTRNXASK-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 229940021222 peritoneal dialysis Isotonic solutions Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- 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
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
The present disclosure relates to piperazinyl derivatives of formula (I) and the use thereof as a drug, particularly for the treatment of cancer, the pharmaceutical compositions containing said derivatives, and the method for synthesising same. An example of the piperazinyl derivatives is 2–chloro–N–[1–(4–fluoro–phenyl)–2–((R)–3–isopropyl–piperazin–1–yl)–2–oxo–ethyl]–N–(4–phenoxy–phenyl)–acetamide. –[1–(4–fluoro–phenyl)–2–((R)–3–isopropyl–piperazin–1–yl)–2–oxo–ethyl]–N–(4–phenoxy–phenyl)–acetamide.
Description
Piperazinyl derivatives for the treatment of cancer
The present invention concerns piperazinyl compounds particularly useful in the
treatment of cancer, compositions containing the same and their method of preparation.
With lengthening lifetimes cancer, one of the leading causes of mortality in the
world, affects an increasingly greater number of persons and remains difficult to treat.
The developing resistance to anticancer agents is a serious problem which
considerably curbs the treatment of numerous types of cancer. Lowered tolerance to an
agent is often accompanied by cross–resistance to a variety of other agents. This
multiple resistance to anticancer agents known as Multidrug Resistance, MDR, is
caused by numerous mechanisms of which only a very small number have been well
characterized. These mechanisms include an increase in drug efflux, an increase in cell
detoxifying capability, alteration of molecular targets affected by these anticancer
agents, modification of the DNA repair system and modification of apoptotic routes
(Baguley, Mol. Biotechnol., 2010, 46, 308–316; Gatti et al., Methods Mol. Med. 2005,
111, 127–148; Longley et al., J. Pathol. 2005, 205, 275–292; Kohno et al., Eur. J.
Cancer 2005, 41, 2577–2586).
The development of anticancer treatments able to avoid these resistance
mechanisms is a major challenge and up until the present time the initiated trials have
given few results.
Anticancer agents more particularly intended for the treatment of chemotherapy–
resistant cancer are described in . They meet the following general
formula:
where R1 and R2, together with the nitrogen atom which carries them, may form a
heterocycle such as a piperazinyl group optionally substituted, the only exemplified
compounds being optionally substituted on the nitrogen atom of the piperazine.
Reference to any prior art in the specification is not, and should not be taken as,
an acknowledgment, or any form of suggestion, that this prior art forms part of the
common general knowledge in Australia or any other jurisdiction or that this prior art
could reasonably be expected to be ascertained, understood and regarded as relevant by
a person skilled in the art.
As used herein, except where the context requires otherwise, the term
"comprise" and variations of the term, such as "comprising", "comprises" and
"comprised", are not intended to exclude other additives, components, integers or steps.
The inventors of this patent application have surprisingly discovered that the
insertion of a substituent X at alpha position of the second nitrogen atom of piperazine
(see formula (I) below) allows an improvement in the physicochemical properties of the
compounds, in particular their solubility, their pharmacokinetic properties and
biological activities.
The subject of the present patent application is therefore more particularly a
substituted piperazinyl compound of following general formula (I):
and the pharmaceutically acceptable salts thereof, its stereoisomers or mixtures of
stereoisomers in any proportion, in particular an enantiomer mixture and notably a
racemic mixture,
where:
– X is a (C –C ) alkyl, phenyl, benzyl, C(O)OR5 or C(O)NHR5 group;
– R1 is a hydrogen atom or a C(O)H, C(O)R6 or C(O)OR6 group;
– R2 is a hydrogen atom or a (C C )alkyl group;
1– 6
or R2 together with R1 or X forms a saturated hydrocarbon chain to form a 5 or
6–membered ring, in particular a 5–membered ring;
– R3 is a hydrogen or halogen atom or a (C –C )alkyl or (C –C )alkoxy
1 6 1 6
group;
– R4 is a hydrogen or halogen atom, CN, NO , or a (C –C )alkyl, (C –
2 1 6 1
C )alkoxy, aryloxy, benzyloxy or heteroaryloxy group, the said group optionally
being substituted by one or more halogen atoms;
– Ar is a thiophenyl group or a phenyl group optionally substituted by one
or more halogen atoms; and
- R5 and R6 independently of one another are a (C –C )alkyl, aryl–(C –
1 6 1
C )alkyl or aryl group, the said group optionally being substituted by one or
more halogen atoms.
By « halogen » in the meaning of the present invention is meant a fluorine,
bromine, chlorine or iodine atom. Advantageously it is a fluorine, bromine or chlorine
atom.
By « alkyl » group in the meaning of the present invention is meant any
saturated, straight–chain or branched hydrocarbon group, advantageously having 1 to 6,
preferably 1 to 4 carbon atoms. These may particularly be methyl, ethyl, n–propyl, iso–
propyl, n–butyl, iso–butyl, sec–butyl, tert–butyl, n–pentyl, neopentyl or n–hexyl groups.
Advantageously it is a methyl, ethyl, isopropyl, tert–butyl or isobutyl group.
In some cases, the alkyl group may optionally be substituted by one or more
halogen atoms, in particular bromine, chlorine and fluorine and advantageously
fluorine. In this case the group will particularly be the –CF group.
By « alkoxy » group in the meaning of the present invention is meant an alkyl
group such as defined above linked to the remainder of the molecule via an oxygen
atom. Examples of alkoxy group are the methoxy, ethoxy, isopropoxy or tert–butoxy
groups. Advantageously it is the methoxy or tert–butoxy group, and further
advantageously the methoxy group.
In some cases, the alkoxy group can be substituted by one or more fluorine
atoms. In this case, it is advantageously the –OCHF or –OCF group, in particular –
OCF .
By « aryl » group in the meaning of the present invention is meant an aromatic
group preferably having 5 to 10 carbon atoms and comprising one or more fused rings.
Advantageously it is the phenyl group.
By « heteroaryl » group in the meaning of the present invention is meant any
aryl group such as defined above in which one or more carbon atoms have been
replaced by one or more heteroatoms, advantageously 1 to 4 and more advantageously 1
to 2, such as sulfur, nitrogen or oxygen atoms for example. Advantageously it is a furyl,
thiophenyl, pyridinyl, pyrimidyl, quinolinyl, 1,2,3–thiadiazolyl benzoimidazolyl,
indazolyl or 1,2,3–benzotriazolyl group.
By « aryloxy » group in the meaning of the present invention is meant an aryl
group such as defined above linked to the remainder of the molecule via an oxygen
atom. It is advantageously a phenyloxy group.
By « heteroaryloxy » group in the meaning of the present invention is meant a
heteroaryl group such as defined above linked to the remainder of the molecule via an
oxygen atom. It is advantageously a pyridinyloxy group.
By « aryl–(C –C )alkyl » group in the meaning of the present invention is meant
an aryl group such as defined above linked to the remainder of the molecule via an
alkyl group such as defined above comprising 1 to 6 carbon atoms. Advantageously it is
a benzyl or 1–phenethyl group, and more advantageously benzyl.
In the present invention by « pharmaceutically acceptable » is meant that which
is useful for the preparation of a pharmaceutical composition that is generally safe, non–
toxic and neither biologically nor otherwise undesirable and is acceptable for veterinary
use and human pharmacopeia use.
By « pharmaceutically acceptable salts » of a compound in the present invention
is meant salts which are pharmaceutically acceptable as defined herein and which have
the desired pharmacological activity of the parent compound. Such salts comprise:
(1) hydrates and solvates;
(2) acid addition salts formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar; or formed with
organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic
acid, citric acid, ethane–sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,
glutamic acid, glycolic acid, hydroxynaphthoic acid, 2–hydroxyethanesulfonic acid,
lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid,
2–naphtalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl–L–
tartaric acid, tartaric acid, p–toluenesulfonic acid, trimethylacetic acid, trifluoroacetic
acid and similar, advantageously it is hydrochloric acid; and
(3) the salts formed when an acid proton present in the parent compound is either
+ + +
replaced by a metal ion e.g. an alkaline metal ion (Na , K or Li for example), an
2+ 2+
alkaline–earth metal ion (such as Ca or Mg ) or an aluminium ion; or it is
coordinated with an organic or inorganic base. Acceptable organic bases comprise
diethanolamine, ethanolamine, N–methylglucamine, triethanolamine, tromethamine and
similar. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide,
potassium hydroxide, sodium carbonate and sodium hydroxide.
In the present invention by « stereoisomers » it is meant to designate
diastereoisomers or enantiomers. They are therefore optical isomers. The stereoisomers
which are not images of one another in a mirror are therefore designated as
« diastereoisomers », and the stereoisomers which are non–superimposable images in a
mirror are designated as « enantiomers ».
A carbon atom linked to four non–identical substituents is called a chiral centre.
An equimolar mixture of two enantiomers is called a racemic mixture.
The compounds of the present invention can in particular meet the following
formula (I–bis):
(I –bis),
the nitrogen atom carrying the X group then being of (S) configuration.
Advantageously X is a (C –C )alkyl, in particular (C –C )alkyl, phenyl or
1 6 1 4
benzyl group.
Advantageously R1 is a hydrogen atom or a C(O)R6 or C(O)OR6 group, in
particular a hydrogen atom.
Advantageously R2 is a hydrogen atom or a (C –C )alkyl group e.g. methyl.
Advantageously R3 is a hydrogen atom or a (C –C )alkyl group e.g. methyl.
Advantageously R4 is a hydrogen or halogen atom, or a (C –C )alkyl, (C –
1 6 1
C )alkoxy or aryloxy group, the said group optionally being substituted by one or more
halogen atoms, fluorine in particular.
Advantageously Ar is a thiophenyl group or a phenyl group substituted by one or
more fluorine atoms such as 4–fluoro–phenyl.
According to one particular embodiment of the invention, X is a (C –C )alkyl,
phenyl, benzyl, C(O)OR5, C(O)NHR5 group; R1 is a hydrogen atom; R2 is a hydrogen
atom or a (C –C )alkyl group, advantageously (C –C )alkyl or together with R1 or X
1 6 1 4
forms a saturated hydrocarbon chain to form a 5–membered ring; R3 is a hydrogen or
halogen atom or a (C –C )alkyl group, in particular (C –C )alkyl, or a (C –C )alkoxy
1 6 1 3 1 6
e.g. methoxy; R4 is a halogen atom, CN, NO or a (C –C )alkyl, (C –C )alkoxy,
2 1 6 1 6
aryloxy, benzyloxy or heteroaryloxy group, the said group optionally being substituted
by one or more halogen atoms; Ar is a thiophenyl group or a phenyl group optionally
substituted by a halogen; and R5 and R6 independently of one another are a (C –
C )alkyl, aryl–(C –C )alkyl or aryl group, the said group optionally being substituted by
6 1 6
one or more halogen atoms.
More advantageously, X is a (C –C )alkyl, phenyl, benzyl, C(O)OR5,
C(O)NHR5 group; R1 is a hydrogen atom; R2 is a hydrogen atom or a C –C )alkyl
group, advantageously (C –C )alkyl; R3 is a hydrogen or halogen atom or a (C –
1 4 1
C )alkyl group, in particular (C –C )alkyl, or a (C –C )alkoxy, e.g. methoxy; R4 is a
6 1 3 1 6
halogen atom or a (C –C )alkyl, (C –C )alkoxy, aryloxy, benzyloxy or heteroaryloxy
1 6 1 6
group, the said group optionally being substituted by one or more halogen atoms; Ar is
a thiophenyl group or phenyl group optionally substituted by a halogen; and R5 and R6
independently of one another are a (C –C )alkyl, aryl–(C –C )alkyl or aryl group, the
1 6 1 6
said group optionally being substituted by one or more halogen atoms.
Further advantageously, X is a (C –C )alkyl, phenyl or benzyl group; R1 and R2
are a hydrogen atom; R3 is a hydrogen or halogen atom or a (C –C )alkyl group, in
particular (C –C )alkyl; R4 is a halogen atom or a (C –C )alkyl, (C –C )alkoxy, aryloxy
1 3 1 6 1 6
or benzyloxy group, the said group optionally being substituted by one or more halogen
atoms; Ar is a thiophenyl group or a phenyl group optionally substituted by a halogen;
and R5 and R6 independently of one another are a (C –C )alkyl, aryl–(C –C )alkyl or
1 6 1 6
aryl group, the said group optionally being substituted by one or halogen atoms.
Preferably X is a (C –C )alkyl, phenyl or benzyl group; R1 and R2 are a
hydrogen atom; R3 is a hydrogen atom or a (C –C )alkyl group, in particular (C –
1 6 1
C )alkyl; R4 is a halogen atom or a (C –C )alkyl, (C –C )alkoxy, aryloxy or benzyloxy
3 1 6 1 6
group, the said group optionally being substituted by one or more halogen atoms; Ar
represents a thiophenyl group or a phenyl group optionally substituted by a fluorine
atom such as 4–fluoro–phenyl; and R5 and R6 independently of one another are a (C –
C )alkyl, aryl–(C –C )alkyl or aryl group, the said group optionally being substituted by
6 1 6
one or more fluorine atoms.
In particular it is one of the compounds in Examples I–1a to I–63 described in
the experimental part below, or one of the pharmaceutically acceptable salts thereof,
their stereoisomers or mixtures of stereoisomers in any proportion, in particular an
enantiomer mixture and especially a racemic mixture.
The present invention also concerns a compound of formula (I) such as defined
above for use thereof as drug intended in particular for the treatment or prevention of
cancer, and particularly to treat chemotherapy–resistant cancer.
The present invention also concerns the use of a compound of formula (I) such
as defined above to produce a drug particularly intended to treat or prevent cancer, in
particular to treat chemotherapy–resistant cancer.
The present invention also concerns a method for treating or preventing cancer,
in particular chemotherapy–resistant cancer, comprising the administration of a
sufficient amount of formula (I) compound such as defined above to a patient in need
thereof.
A further subject of the invention is a pharmaceutical composition comprising at
least one formula (I) compound such as defined above in association with one or more
pharmaceutically acceptable excipients.
In one particular embodiment, this composition may comprise at least one other
active ingredient.
In particular this or these active ingredient(s) may be anticancer agents
conventionally used to treat cancer. These anticancer agents can be selected in particular
from among cisplatin and the derivatives thereof such as carboplatin and oxalyplatin;
taxanes such as taxol, taxotere, paclitaxel and docetaxel; vinca alkaloids such as
vinblastine, vincristine and vinorelbine; purine analogues such as mercaptopurine,
thioguanine, pentostatin and 2–chlorodeoxyadenosine; topoisomerase I inhibitors such
as camptothecin compounds e.g. irinotecan and topotecan; topoisomerase II inhibitors
such as epipodophyllotoxin, podophyllotoxin and the derivatives thereof e.g. etoposide
and teniposide; anti–tumour nucleoside derivatives such as 5–fluorouracil, leucovorin,
gemcitabine or capecitabine; alkylating agents such as nitrogen mustards e.g.
cyclophosphamide, mechlorethamine, chlorambucil and melphalan, nitroso–ureas such
as carmustin, lomustin and streptozocin, alkylsulfonates such as busulfan, ethylenimines
and methylmelamines such as thiotepa and hexamethylmelamine, and tetrazines such as
dacarbazine; derivatives of anti–tumour anthracyclines such as daunorubicin,
adriamycin, doxil, idarubicin and mitoxantrone; molecules targeting the IGF–I receptor
such as picropodophyllin; derivatives of tetracarcin such as tetrocarcin A;
corticosteroids such as prednisone; antibodies such as trastuzumab (anti–HER2
antibody), rituximab (anti–CD20 antibody), gemtuzamab, cetuximab, pertuzumab and
bevacizumab; antagonists or selective modulators of oestrogen receptors such as
tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; aromatase
inhibitors such as exemestane, anastrozole, letrozole and vorozole; differentiating
agents such as retinoids e.g. retinoic acid and vitamin D and agents blocking the
metabolism of retinoic acid such as accutane; DNA methyl–transferase inhibitors such
as azacytidine and decitabine; antifolates such as permetrexed disodium; antibiotics
such as antinomycin D, bleomycin, mitomycin C, actinomycin D, carminomycin,
daunomycin and plicamycin; antimetabolites such as chlofarabine, aminopterin,
cytosine arabinoside, floxuridine and methotrexate; apoptosis–inducing agents and anti–
angiogenic Bcl–2 inhibitors such as YC 137, BH 312, ABT 737, gossypol, HA 14–1,
TW 37 and decanoic acid; agents binding to tubulin such as combrestatin, derivatives of
colchicine and nocodazole; kinase inhibitors such as flavoperidol, imatinib mesylate,
erlotinib and gefitinib; farnesyl transferase inhibitors such as tipifarnib; inhibitors of
histone–deacetylases such as sodium butyrate, suberoylanilide hydroxamic acid,
depsipeptide, NVP- LAQ824, R306465, JNJ–26481585 and trichostatin A; inhibitors of
the ubiquitin–proteasome system such as MLN .41, bortezomib and yondelis; and
telomerase inhibitors such as telomestatin.
The compounds of the invention can be given via oral, sublingual, parenteral,
sub–cutaneous, intramuscular, intravenous, transdermal, local or rectal route.
In the pharmaceutical compositions of the present invention for oral, sublingual,
parenteral, sub–cutaneous, intramuscular, intravenous, transdermal, local or rectal route,
the active ingredient can be administered in unit administration forms, in a mixture with
conventional pharmaceutical carriers, to animals or to human beings. Suitable unit
administration forms include forms via oral route such as tablets, capsules, powders,
granules and oral solutions or suspensions, sublingual and buccal administration forms,
parenteral, sub–cutaneous, intramuscular, intravenous, intranasal or intraocular
administration forms, and rectal administration forms.
When a solid composition is prepared in tablet form, the main active ingredient
is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium
stearate, talc, gum arabic or analogues. It is possible to coat the tablets with sucrose or
other suitable materials, or they can be treated so that they have sustained or delayed
release and continuously release a predetermined amount of active ingredient.
A capsule preparation is obtained by mixing the active ingredient with a diluent
and pouring the mixture obtained into soft or hard capsules.
A preparation in syrup or elixir form can contain the active ingredient together
with a sweetener, an antiseptic and taste enhancer and suitable colouring agent.
Water–dispersible powders or granules can contain the active ingredient in a
mixture with dispersing agents or wetting agents, or suspending agents, and also with
taste enhancers or sweeteners.
For rectal administration, recourse is made to suppositories prepared with
binders which melt at rectal temperature e.g. cocoa butter or polyethylene glycols.
For parenteral, intranasal or intraocular administration use is made of aqueous
suspensions, of saline isotonic solutions or sterile, injectable solutions which contain
pharmacologically compatible dispersing agents and/or wetting agents.
The active ingredient can also be formulated in microcapsule form optionally
with one or more additive carriers.
The compounds of the invention can be used at doses of between 0.01 mg and
1000 mg per day, given in a single daily dose or in several doses throughout the day e.g.
twice daily in equal doses. The daily administered dose is advantageously between 5 mg
and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to
use doses outside these ranges which persons skilled in the art will know how to
determine.
A further subject of the invention is a pharmaceutical composition comprising:
(i) at least one formula (I) compound such as defined above; and
(ii) at least one other active ingredient
as combination products for simultaneous, separate or time–staggered use.
It is effectively frequent for cancer to be treated with bi- or tri–therapy. It may
be useful in particular to associate the molecules of the invention with one or more
anticancer compounds first allowing treatment of the cancer and secondly preventing
the onset of resistant cancer cells.
In particular, this or these active ingredient(s) may be anticancer agents usually
used to treat cancer. These anticancer agents can be selected in particular from among
cisplatin and its derivatives such as carboplatin and oxalyplatin; taxanes such as taxol,
taxotere, paclitaxel and docetaxel; vinca alkaloids such as vinblastine, vincristine and
vinorelbine; purine analogues such as mercaptopurine, thioguanine, pentostatin and 2–
chlorodeoxyadenosine; topoisomerase I inhibitors such as camptothecin compounds
e.g. irinotecan and topotecan; topoisomerase II inhibitors such as epipodophyllotoxin,
podophyllotoxin and the derivatives thereof such as etoposide and teniposide; anti–
tumour nucleoside derivatives such as 5–fluorouracil, leucovorin, gemcitabine or
capecitabine; alkylating agents such as nitrogen mustards e.g. cyclophosphamide,
mechlorethamine, chlorambucil and melphalan, nitroso–ureas such as carmustin,
lomustin and streptozocin, alkylsulfonates such as busulfan, ethylenimines and
methylmelamines such as thiotepa and hexamethylmelamine, and tetrazines such as
dacarbazine; anti–tumour anthracycline derivatives such as daunorubicin, adriamycin,
doxil, idarubicin and mitoxantrone; molecules targeting the IGF–I receptor such as
picropodophyllin; tetracarcin derivatives such as tetrocarcin A; corticosteroids such as
prednisone; antibodies such as trastuzumab (anti–HER2 antibody), rituximab (anti–
CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; antagonists or
selective modulators of oestrogen receptors such as tamoxifen, fulvestrant, toremifene,
droloxifene, faslodex and raloxifene; aromatase inhibitors such as exemestane,
anastrozole, letrozole and vorozole; differentiating agents such as retinoids e.g. retinoic
acid and vitamin D and agents blocking the metabolism of retinoic acid such as
accutane; DNA methyl–transferase inhibitors such as azacytidine and decitabine;
antifolates such as permetrexed disodium; antibiotics such as antinomycin D,
bleomycin, mitomycin C, actinomycin D, carminomycin, daunomycin and plicamycin;
antimetabolites such as chlofarabine, aminopterin, cytosine arabinoside, floxuridine and
methotrexate; apoptosis–inducing agents and anti–angiogenic agents of Bcl–2
inhibitors such as YC 137, BH 312, ABT 737, gossypol, HA 14–1, TW 37 and decanoic
acid; agents binding to tubulin such as combrestatin, derivatives of colchicine an
nocodazole; kinase inhibitors such as flavoperidol, imatinib mesylate, erlotinib an
gefitinib; farnesyl transferase inhibitors such as tipifarnib; inhibitors of histone–
deacetylases such as sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide,
NVP- LAQ824, R306465, JNJ–26481585 and trichostatin A; inhibitors of the
ubiquitin–proteasome system such as MLN .41, bortezomib and yondelis; and
telomerase inhibitors such as telomestatin.
A further subject of the invention is a pharmaceutical composition such as
defined above, for use thereof as drug to treat or prevent cancer in particular, and
particularly chemotherapy–resistant cancer.
The present invention also concerns a method for preparing a formula (I)
compound such as defined above comprising the following successive steps:
a) reacting an amine of following formula (II):
(II)
where X, R1, R2, R3, R4 and Ar are such as previously defined, R1 not
representing a hydrogen atom;
with chloroacetyl chloride in the presence of a base to give a formula (I)
compound where R1 ≠ H; and
b) optionally deprotecting the nitrogen atom carrying the R1 ≠ H group to give a
formula (I) compound where R1 = H.
Step a) :
The base used for this step is preferably a weak base such as NaHCO .
The amine of formula (II) can be obtained by reaction of a piperazine of
following formula (III):
(III)
where X, R1 and R2 are as previously defined, R1 not representing a hydrogen atom,
with an acid of following formula (IV):
(IV)
where R3, R4 and Ar are as previously defined.
This reaction can be conducted under peptide coupling conditions well known to
skilled persons.
Coupling is therefore preferably performed in the presence of a coupling agent
such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1–(3–
dimethylaminopropyl)–3–ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole
(CDI), 2–(1H–benzotriazole–1–yl)–1,1,3,3–tetramethyluronium hexafluorophosphate
(HBTU), 2–(1H–benzotriazole–1–yl)–1,1,3,3–tetramethyluronium tetrafluoroborate
(TBTU) or O–(7–azobenzotriazol–1–yl)–1,1,3,3–tetramethyluronium
hexafluorophosphate (HATU), optionally associated with a coupling auxiliary such as
N–hydroxy succinimide (NHS), N–hydroxy benzotriazole (HOBt), 3,4–dihydro–3–
hydroxy–4–oxo–1,2,3–benzotriazole (HOOBt), l–hydroxy–7–azabenzotriazole (HAt) or
N–hydroxysulfosuccinimide (sulfo NHS). Preferably it is HBTU.
A base such as diisopropyl–ethylamine (DIPEA) may also be present.
The piperazine of formula (III) is either obtained commercially or prepared
following methods well known to persons skilled in the art.
The acid of formula (IV) can be prepared using the following successive steps:
i) reacting a ketoester of following formula (V):
where Ar is as previously defined and R represents a (C –C )alkyl group e.g.
ethyl,
with an aniline of following formula (VI):
(VI)
where R3 and R4 are as previously defined,
to give an imine of following formula (VII):
(VII)
where R, R3, R4 and Ar are as previously defined;
ii) reducing the imine of formula (VII) obtained at the preceding step to give an
amine of following formula (VIII) :
(VII)
where R, R3, R4 and Ar are as previously defined; and
iii) saponifying the ester function of the formula (VIII) compound obtained at the
preceding step to give the acid of formula (IV).
Step i) can be conducted in the presence of an acid such as paratoluene sulfonic
acid (PTSA). The reaction can be performed in a polar solvent such as toluene.
Preferably the reaction medium is heated under reflux using Dean–Stark apparatus to
remove the water as and when it is formed during the reaction.
The ketoester (V) used for this reaction is either obtained commercially or
prepared via Friedel–Crafts reaction using ethyl oxalyl chloride and the corresponding
aromatic in the presence of a Lewis acid such as aluminium chloride AlCl .
The aniline (VI) used for this reaction is either obtained commercially or
prepared using methods well known to skilled persons.
Reducing step ii) can be performed in the presence of a reducing agent well
known to skilled persons such as sodium cyanoborohydride.
Saponification step iii) can be performed under conditions well known to skilled
persons, in particular in the presence of a base such as NaOH, KOH or LiOH.
Step b):
This step is preferably conducted with a formula (I) compound in which R1 =
CO R6, such as CO tBu, via treatment with an acid such as HCl.
The compound thus obtained can be separated from the reaction medium using
methods well known to skilled persons, e.g. by extraction, evaporation of the solvent or
by precipitation and filtration.
The compound may also be purified if necessary using techniques well known to
skilled persons, e.g. by recrystallization if the compound is crystalline, by distillation,
by silica gel chromatography or high performance liquid chromatography (HPLC).
The method of the present invention to prepare compounds of the present
invention where R1 ≠ H is shown in the following reaction scheme:
The following examples illustrate the invention but are not limiting thereof.
FIGURE:
Figure 1 gives the time–plasma concentration curves for a mouse given
compound I–43 dia2 administered via intravenous route (IV) at a dose of 10 mg/kg or
via oral route (PO) at a dose of 30 mg/kg.
EXAMPLES:
I - Synthesis of compounds of the invention
In the following section two different nomenclatures were adopted when the two
diastereoisomers of a compound of the invention were separated:
a / b each designating the particular structure of a single diastereoisomer;
dia1 / dia2 respectively designating the least polar and most polar
diastereoisomer in the chromatographic system used.
The particular stereochemistry of each of the diastereoisomers was not determined.
Therefore, it was impossible to allocate the particular structure a and b to each isolated
diastereoisomer dia1 and dia2. This is why a double nomenclature is used.
The following abbreviations are used in this section:
TLC Thin Layer Chromatography
DCM Dichloromethane
DIEA Diisopropylethylamine
HBTU 2–(1H–Benzotriazole–1–yl)–1,1,3,3–tetramethyluronium hexafluorophosphate
LCMS Liquid Chromatography coupled with Mass Spectrometer
NMR Nuclear Magnetic Resonance
RT Room temperature
Examples I –1a and I –1b : Diastereoisomers of the tert –butyl ester of 4–[2–[(2 –
chloro –acetyl) –(4 –phenoxy –phenyl) –amino] –2–(4 –fluoro –phenyl) –acetyl] –(S) –2–
isopropyl –piperazine –1–carboxylic acid.
I –1a I –1b
Stage 1: Ethyl ester of (4–fluoro–phenyl)–oxo–acetic acid (1):
To a solution of aluminium chloride (21.13 g; 160 mmol) in DCM (200 mL) at 0°C
under argon, ethyl oxalyl chloride (17.9 mL; 160 mmol) was added dropwise for 10
min. The medium was left under agitation for 10 minutes. Fluorobenzene (14.7 mL; 160
mmol) diluted in 30 mL of DCM, was added dropwise at 0°C. The medium was left
under agitation at room temperature for 12 hours. The medium was washed with water
and the organic phase dried over MgSO . After evaporation, the recovered oil was
purified by flash chromatography on silica gel eluting with cyclohexane–ethyl acetate
90:10.
A yellow oil was recovered (17.08 g; 54 %).
H NMR (300 MHz, CDCl ): 8.04–8.14 (m; 1.8 H); 7.15–7.24 (m; 1.9 H); 4.46 (q; J =
7.2 Hz; 2.0 H); 1.44 (t; J = 7.2 Hz; 3.0 H).
Stage 2: Ethyl ester of (4–fluoro–phenyl)–[(Z)–4–phenoxy–phenylimino]–acetic acid
(2):
To a solution of 1 (3.92 g; 20 mmol) in toluene (25 mL) were successively added para–
toluene sulfonic acid (200 mg; 1 mmol) and 4–phenoxyphenyl–aniline (3.70 g; 20
mmol) in the presence of a molecular sieve. The medium was placed under reflux in
DeanStark apparatus for 20 hours. The medium was washed in water and the organic
phase dried over MgSO . After evaporation, the recovered oil was purified by flash
silica gel chromatography eluting with cyclohexane–ethyl acetate 90:10.
Recovery of a yellow oil (6.27 g; 86 %).
LCMS [M+H] = 364 (C H FNO )
22 18 3
Stage 3: Ethyl ester of (4–fluoro–phenyl)–(4–phenoxy–phenylamino)–acetic acid (3):
To a solution of 2 (6.27 g; 17.26 mmol) in methanol (75 mL) and acetic acid (7.5 mL),
sodium cyanoborohydride (1.63 g; 26 mmol) was added. The medium was left under
agitation for 1 hour at RT. The methanol was partly evaporated, the solution neutralized
with Na CO with the addition of water if necessary. The medium was extracted with
DCM and the organic phase dried over MgSO . After evaporation, the recovered oil was
purified by flash chromatography on silica gel eluting with cyclohexane–ethyl acetate
95:5.
Recovery of a yellow oil (5.91 g; 93 %).
LCMS [M+H] = 366 (C H FNO )
22 20 3
H NMR (300 MHz, CDCl ): 7.45–7.54 (m; 1.9 H); 7.23–7.31 (m; 1.9 H); 6.97–7.11
(m; 2.9 H); 6.81–6.94 (m; 3.9 H); 6.54 (d; J = 9.0 Hz; 2.0 H); 5.01 (br; 1.0 H); 4.90 (br;
0.9 H); 4.10–4.32 (m; 2.0 H); 1.23 (t; J = 7.0 Hz; 3.0 H).
Stage 4: (4–fluoro–phenyl)–(4–phenoxy–phenylamino)–acetic acid (4) :
To a solution of 3 (8.04 g; 22 mmol) in 130 mL of acetonitrile was added 66 mL of a 1
M solution of LiOH (3 eq). The reaction medium was left under agitation for 2 to 3
hours, completion of the reaction being controlled by TLC (cyclohexane–ethyl acetate
60:40). The acetonitrile was partly evaporated, the medium acidified with a 1 M
solution of HCl with the addition of 200 mL of water. The medium was filtered and the
recovered solid washed three times in water and dried in vacuo in a drying oven in the
presence of P O .
Recovery of a white powder (7.17 g; 97 %).
LCMS [M+H] = 338 (C H FNO )
16 3
H NMR (300 MHz, DMSO): 7.55 (dd; J = 8.5 Hz; J = 5.6 Hz; 2.1 H); 7.28 (t; J = 7.9
Hz; 2.1 H); 7.20 (t; J = 8.5 Hz; 2.1 H); 6.99 (t; J = 7.0 Hz; 1.1 H); 6.74–6.90 (m; 4.0 H;
6.62–6.70 (m; 2.0 H); 5.10 (s 1.0 H).
Stage 5: Tert–butyl ester of 4–[2–(4–fluoro–phenyl)–2–(4–phenoxy–phenylamino)–
acetyl]–(S)–2–isopropyl–piperazine–1–carboxylic acid (5):
To a solution of 4 (7.17 g; 21.2 mmol) in DCM (150 mL) in the presence of one
equivalent of DIEA (3.7 mL) was added a solution of Boc–alpha–(S)–isopropyl–
piperazine hydrochloride (5.63 g; 21.26 mmol) in the presence of 1 eq of DIEA (3.7
mL) in 50 mL of DCM, followed by HBTU (8.06 g; 21.2 mmol). The medium was left
under agitation for 12 hours. The medium was washed with water and the organic phase
dried over MgSO . After evaporation the recovered oil was purified by flash
chromatography on silica gel eluting with cyclohexane–ethyl acetate 80:20.
Recovery of a white foam (11.90 g; 100 %).
LCMS [M+H] = 548 (C H FN O )
32 38 3 4
Stage 6 Tert–butyl ester of 4–[2–[(2–chloro–acetyl)–(4–phenoxy–phenyl)–amino]–2–
(4–fluoro–phenyl)–acetyl]–(S)–2–isopropyl–piperazine–1–carboxylic acid
To a solution of 5 (11.86 g; 22.66 mmol) in 250 mL of DCM in the presence of
NaHCO (7.30 g; 87.0 mmol) the chloroacetyl chloride (3.45 mL; 43.3 mmol) was
added. The medium was left under agitation for 12 hours. The medium was washed
with water and the organic phase dried over MgSO . After evaporation the recovered oil
was purified by flash chromatography on silica gel with cyclohexane–ethyl acetate
gradient of 95–5’ to 50–50 to obtain two diastereoisomers separately in the form of
colourless foam:
Least polar diastereoisomer (I –1 dia1)
(3.80 g; 28 %)
LCMS [M+H] = 625 (C H ClFN O )
34 39 3 5
H NMR (300 MHz, CDCl ): 7.92–8.01 (m; 1.0 H); 7.30–7.40 (m; 2.0 H); 7.10–7.18
(m; 1.1 H); 7.01–7.09 (m; 1.1 H); 6.84–7.00 (m; 6.1 H); 6.55–6.65 (m; 1.1 H); 6.32–
6.48 (m; 2.1 H); 4.72 (d; J = 13.5 Hz; 0.5 H) 4.63 (d; J = 13.5 Hz; 0.4 H); 3.52–3.96 (m;
4.0 H); 3.10–3.27 (m; 0.5 H); 2.85–3.07 (m; 0.4 H); 2.23–2.85 (m; 0.5 H + 0.7 H + 0.4
H); 1.87–2.14 (m; 0.6 H); 1.42 (s; 8.7 H); 1.17 (d; J = 6.6 Hz; 1.0 H); 1.03 (d; J = 6.6
Hz; 1.3 H); 0.88 (d; J = 6.6 Hz; 1.1 H); 0.69 (d; J = 6.6 Hz; 1.3 H).
Most polar diastereoisomer (I –1 dia2)
(3.29 g; 24 %)
LCMS [M+H] = 625 (C H ClFN O )
34 39 3 5
H NMR (300 MHz, CD Cl ): 7.85–8.00 (m; 1.0 H); 7.36 (t; J = 7.6 Hz; 2.1 H); 6.99–
7.21 (m; 3.2 H); 6.81–6.98 (m; 5.2 H); 6.63 (br; 1.1 H); 6.35–65.5 (m; 2.1 H); 4.65 (d; J
= 13.1 Hz; 0.6 H) 4.42 (d; J = 13.1 Hz; 0.3 H); 3.50–4.16 (m; 4.9 H); 3.00–3.43 (m; 0.9
H); 2.57–2.90 (m; 1.9 H); 1.98–2.18 (m; 0.7 H); 1.36–1.49 (m; 10.0 H); 1.73 (d; J = 6.5
Hz; 2.1 H); 0.90 (d; J = 6.5 Hz; 2.1 H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.20 (d; J = 6.5 Hz;
0.9 H).
Examples I –2a and I –2b: Diastereoisomers of the tert –butyl ester of 4–[ –2–[(2 –
chloro –acetyl) –(4 –phenoxy –phenyl) –amino] –2–(4 –fluoro –phenyl) –acetyl] –(R) –2–
isopropyl –piperazine –1–carboxylic acid.
I –2a I –2b
Stage 1: Tert–butyl ester of 4–[2–(4–fluoro–phenyl)–2–(4–phenoxy–phenylamino)–
acetyl]–(R)–2–isopropyl–piperazine–1–carboxylic acid (6):
To a solution of (4–fluoro–phenyl)–(4–phenoxy–phenylamino)–acetic acid 4
(253 mg; 0.75 mmol) in DCM (10 mL) in the presence of one equivalent of DIEA
(131 µL) was added a solution of Boc–alpha–(R)–isopropyl–piperazine (171 mg; 0.75
mmol) in the presence of 1 eq of DIEA (131 µL) in 5 mL of DCM, followed by HBTU
(285 mg; 0.75 mmol). The medium was left under agitation for 12 hours. The medium
was washed with water and the organic phase dried over MgSO . After evaporation the
recovered oil was purified by flash chromatography on silica gel eluting with
cyclohexane–ethyl acetate 80:20.
Recovery of a white foam (369 mg; 90 %).
LCMS [M+H] = 548 (C H FN O )
32 38 3 4
Stage 2: Ter–butyl ester of 4–[–2–[(2–chloro–acetyl)–(4–phenoxy–phenyl)–amino]–2–
(4–fluoro–phenyl)–acetyl]–(R)–2–isopropyl–piperazine–1–carboxylic acid:
Both diastereoisomers were prepared from 6 following the same operating mode as for
the preparation in Example 1 (stage 6).
Separate recovery of the two diastereoisomers in the form of a colourless foam.
Least polar diastereoisomer (I –2 dia1) (195 mg; 42 %)
LCMS [M+H] = 625 (C H ClFN O )
34 39 3 5
H NMR (300 MHz, CD Cl ): 7.85–8.00 (m; 1.0 H); 7.36 (t; J = 7.6 Hz; 2.0 H); 6.99–
7.21 (m; 3.1 H); 6.81–6.98 (m; 4.9 H); 6.63 (br; 1.0 H); 6.35–6.55 (m; 2.1 H); 4.65 (d; J
= 13.0 Hz; 0.7 H) 4.42 (d; J = 13.0 Hz; 0.2 H); 3.50–4.16 (m; 4.9 H); 3.00–3.43 (m.; 0.8
H); 2.57–3.90 (m; 2.0 H); 1.98–2.18 (m; 0.8 H); 1.36–1.49 (m; 10.5 H); 1.73 (d; J = 6.5
Hz; 2.0 H); 0.90 (d; J = 6.5 Hz; 2.0 H); 0.63 (d; J = 6.5 Hz; 0.8 H);0.20 (d; J = 6.5 Hz;
0.8 H).
Most polar diastereoisomer (I –2 dia2) (122 mg; 26 %)
LCMS [M+H] = 625 (C H ClFN O )
34 39 3 5
H NMR (300 MHz, CDCl ): 7.92–8.01 (m; 1.0 H); 7.30–7.40 (m; 2.0 H); 7.10–7.18
(m; 1.0 H); 7.01–7.09 (m; 1.1 H); 6.84–7.00 (m; 6.0 H); 6.55–6.65 (m; 1.1 H); 6.32–
6.48 (m; 2.1 H); 4.72 (d; J = 13.5 Hz; 0.4 H) 4.63 (d; J = 13.5 Hz; 0.3 H); 3.52–3.96 (m;
4.7 H); 3.10–3.27 (m; 0.7 H); 2.85–3.07 (m; 0.5 H); 2.23–2.85 (m; 0.5 H + 0.6 H + 0.8
H); 1.87–2.14 (m; 0.9 H); 1.42 (s; 8.6 H); 1.17 (d; J = 6.6 Hz; 1.4 H); 1.03 (d; J = 6.6
Hz; 2.1 H); 0.88 (d; J = 6.6 Hz; 2.1 H); 0.69 (d; J = 6.6 Hz; 1.6 H).
Examples I –3a and I –3b : Hydrochloride of the diastereoisomers of 2–chloro –N –
[1–(4 –fluoro –phenyl) –2 –((S) –3–isopropyl –piperazin –1–yl) –2–oxo –ethyl]–N –(4–
phenoxy –phenyl) –acetamide.
I –3a I –3b
To a solution of the I–1dia2 diastereoisomer (3.24 g; 5.2 mmol) in 50 mL of DCM the
HCl gas was added by bubbling. The reaction medium was left under agitation for 12
hours at RT. The DCM was evaporated and the residual oil precipitated in ether.
The example I –3 dia2 was obtained in the form of a white power after filtration: (2.53
g; 87 %).
LCMS [M+H] = 524 (C H Cl FN O )
29 32 2 3 3
H NMR (300 MHz, DMSO): 8.60–9.35 (m; 1.6 H); 7.77 (br; 0.8 H); 7.30–7.40 (m;
2.0 H); 7.00–7.23 (m; 5.1 H); 6.80–7.00 (m; 3.1 H); 6.54–6.76 (m; 3.0 H); 4.56 (d; J =
13.3 Hz; 1.0 H); 3.88–4.16 (m; 3.0 H); 3.00–3.30 (m; 3.1 H); 2.65–2.96 (m; 1.7 H);
1.52–2.00 (m; 1.6 H); 1.00 (t; J = 7.4 Hz; 2.4 H); 0.59 (dd; J = 15.6 Hz; J = 6.7 Hz; 3.5
Applying the same procedure starting from example I –1dia1, example I –3 dia1 was
obtained in the form of a white powder after filtration: (63 mg).
LCMS [M+H] = 524 (C H Cl FN O )
29 32 2 3 3
H NMR (300 MHz, DMSO): 8.65–9.6 (br; 1.2 H); 7.77 (br.; 0.8 H); 7.30–7.40 (m;
2.0 H); 6.36–7.25 (m; 11.7 H); 4.40–4.60 (m; 0.8 H); 4.00–4.12 (m; 2.0 H); 3.76–3.98
(m; 0.9 H); 3.37–3.63 (m; 0.9 H); 2.65–3.30 (m; 4.0 H); 1.77–2.06 (m; 1.6 H); 0.89–
1.06 (m; 6.1 H).
Examples I –4a and I –4b : Hydrochloride of the diastereoismers of 2–Chloro –N –
[1–(4 –fluoro –phenyl) –2 –((R) –3–isopropyl –piperazin –1–yl) –2–oxo –ethyl]–N –(4–
phenoxy –phenyl) –acetamide.
I –4a I –4b
The same protocol was followed as for Examples I–3a and I–3b starting from each of
the diastereoisomers I–2a and I–2b.
Starting from the first diastereoisomer of Example I –2 (I –4 dia1):
Recovery of a white powder after filtration: (95 mg)
LCMS [M+H] = 524 (C H Cl FN O )
29 32 2 3 3
H NMR (300 MHz, DMSO): 8.65–9.6 (br; 1.3 H).; 7.77 (br; 0.4 H); 7.30–7.40 (m;
2.0 H); 6.36–7.25 (m; 11.8 H); 4.40–4.60 (m; 0.9 H); 4.00–4.12 (m; 2.0 H); 3.76–3.98
(m; 1.0 H); 3.37–3.63 (m; 1.0 H); 2.65–3.30 (m; 3.8 H); 1.77–2.06 (m; 1.8 H); 0.89–
1.06 (m; 6.1 H).
Starting from the second diastereoisomer of Example I –2 (I –4 dia2):
Recovery of a white powder after filtration: (95 mg)
LCMS [M+H] = 524 (C H Cl FN O )
29 32 2 3 3
H NMR (300 MHz, DMSO): 8.60–9.35 (m; 1.7 H); 7.77 (br; 0.9 H); 7.30–7.40 (m;
2.0 H); 7.00–7.23 (m; 5.0 H); 6.80–7.00 (m; 3.0 H); 6.54–6.76 (m; 2.9 H); 4.56 (d; J =
13.3 Hz; 1.0 H); 3.88–4.16 (m; 3.0 H); 3.00–3.30 (m; 3.1 H); 2.65–2.96 (m; 1.7 H);
1.52–2.06 (m; 1.9 H); 1.00 (t; J = 7.2 Hz; 2.4 H); 0.59 (dd; J = 15.4 Hz; J = 6.7 Hz; 3.3
Examples I –5a and I –5b: Diastereoisomers of the tert –butyl ester of 4–[ –2–[(2 –
chloro –acetyl) –(2 –methyl –4–phenoxy –phenyl)–amino] –2–(4 –fluoro –phenyl) –
acetyl] –(S) –2–isopropyl –piperazine –1–carboxylic acid.
I –5a I –5b
Stage 1: Tert–butyl ester of 4–[2–(4–fluoro–phenyl)–2–(2–methyl–4–phenoxy–
phenylamino)–acetyl]–(S)–2–isopropyl–piperazine–1–carboxylic acid (8):
To a solution of (4–fluoro–phenyl)–(2–methyl–4–phenoxy–phenylamino)–acetic acid
(9.29 g; 26.4 mmol) in DCM (150 mL) in the presence of one equivalent of DIEA
(4.6 mL) was added a solution of Boc–alpha–(S)–isopropyl–piperazine hydrochloride
(7.00 g; 26.4 mmol) in the presence of 1 eq of DIEA (4.6 mL) in 50 mL of DCM,
followed by HBTU (10.00 g; 26.4 mmol). The medium was left under agitation for 12
hours. The medium was washed with water and the organic phase dried over MgSO .
After evaporation the recovered oil was purified by flash chromatography on silica gel
eluting with cyclohexane–ethyl acetate 80:20.
Recovery of a white foam (14.13 g; 95 %).
LCMS [M+H] = 562 (C H FN O )
33 40 3 4
Stage 2: Tert–butyl ester of 4–[–2–[(2–chloro–acetyl)–(2–methyl–4–phenoxy–phenyl)–
amino]–2–(4–fluoro–phenyl)–acetyl]–(S)–2–isopropyl–piperazine–1–carboxylic acid
To a solution of 8 (14.13 g; 25.1 mmol) in 250 mL of DCM in the presence of NaHCO
(8.40 g; 100.0 mmol) was added chloroacetyl chloride (4.00 mL; 50.0 mmol). The
medium was left under agitation for 12 hours. The medium was washed with water and
the organic phase dried over MgSO . After evaporation the recovered oil was purified
by flash chromatography on silica gel eluting with cyclohexane–ethyl acetate 90:10
gradually up to 50:50.
Recovery of both diastereoisomers in the form of a colourless foam:
Least polar diastereoisomer (I –5 dia1) (3.83 g; 24 %)
LCMS [M+H] = 639 (C H ClFN O )
41 3 5
H NMR (300 MHz, CD Cl ): 7.94–8.57 (m; 1.0 H); 7.35 (t; J = 7.9 Hz; 2.0 H); 7.07–
7.27 (m; 3.0 H); 6.74–6.95 (m; 5.0 H); 6.58 (br d; J = 2.6 Hz; 1.1 H); 6.51 (br s; 0.2 H);
6.41 (s; 0.8 H); 6.31 (br s; 0.3 H); 4.62 (d; J = 13.5 Hz; 0.7 H) 4.39 (d; J = 13.5 Hz; 0.3
H); 3.53–4.05 (m; 4.8 H); 3.04–3.46 (m; 0.8 H); 2.41–2.96 (m; 2.1 H); 2.04–2.23 (m;
0.8 H); 1.82–1.95 (m; 2.2 H); 1.43 (br s; 10.1 H); 1.07 (d; J = 6.5 Hz; 2.1 H); 0.90 (d; J
= 6.5 Hz; 2.3 H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.29 (d; J = 6.5 Hz; 0.8 H).
Most polar diastereoisomer (I –5 dia2) (4.40 g; 27 %)
LCMS [M+H] = 639 (C H ClFN O )
41 3 5
H NMR (300 MHz, CDCl ): 8.00–8.10 (m; 1.0 H); 7.30–7.40 (m; 2.1 H); 6.98–7.18
(m; 3.2 H); 6.73–6.90 (m; 5.3 H); 6.52–6.58 (m; 1.0 H); 6.34–6.39 (m; 1.0 H); 4.71 (d;
J = 13.5 Hz; 0.7 H); 4.49 (d; J = 13.5 Hz; 0.4 H); 3.50–4.00 (m; 4.7 H); 3.10–3.30 (m;
0.7 H); 2.86–3.07 (m; 0.4 H); 2.54–2.85 (m; 1.5 H); 2.30–2.47 (m; 0.4 H); 1.80–1.87
(m; 2.8 H); 1.54–1.60 (m; 2.5 H); 1.42 (br s; 8.8 H); 1.19 (d; J = 6.6 Hz; 1.1 H); 1.00 (d;
J = 6.6 Hz; 1.5 H); 0.88 (d; J = 6.6 Hz; 1.2 H); 0.64 (d; J = 6.6 Hz; 1.5 H).
Examples I –6a and I –6b : Diastereosiomers of the tert –butyl ester of 4–[ –2–[(2–
chloro –acetyl) –(4 –phenoxy –phenyl) –amino] –2–(4 –fluoro –phenyl) –acetyl] –(R) –2–
isopropyl –piperazine –1–carboxylic acid
I –6a I –6b
These two diastereoisomers were prepared in the same manner as in the preceding
example in the form of colourless foam:
Least polar diastereoisomer (I –6 dia1) (97 m; 30 %)
LCMS [M+H] = 639 (C H ClFN O )
41 3 5
H NMR (300 MHz, CD Cl ): 7.94–8.57 (m; 0.9 H); 7.35 (t; J = 7.9 Hz; 1.9 H); 7.05–
7.25 (m; 3.1 H); 6.72–6.93 (m; 5.0 H); 6.58 (br d; J = 2.6 Hz; 1.1 H); 6.41 (s; 0.8 H);
6.31 (br s; 0.3 H); 4.63 (d; J = 13.5 Hz; 0.8 H) 4.40 (d; J = 13.5 Hz; 0.3 H); 3.51–4.06
(m; 4.8 H); 3.03–3.45 (m; 1.0 H); 2.41–2.96 (m; 1.6 H); 2.02–2.21 (m; 0.8 H); 1.82–
1.95 (m; 2.1 H); 1.43 (br s; 10.1 H); 1.07 (d; J = 6.5 Hz; 2.1 H); 0.90 (d; J = 6.5 Hz; 2.3
H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.29 (d; J = 6.5 Hz; 0.8 H).
Most polar diastereoisomer (I –6 dia2) (90 mg; 28 %)
LCMS [M+H] = 639 (C H ClFN O )
41 3 5
H NMR (300 MHz, CDCl ): 8.00–8.10 (m; 1.0 H); 7.30–7.40 (m; 2.1 H); 6.98–7.18
(m; 3.1 H); 6.73–6.90 (m; 5.1 H); 6.52–6.58 (m; 1.0 H); 6.34–6.39 (m; 1.0 H); 4.70 (d;
J = 13.5 Hz; 0.7 H); 4.49 (d; J = 13.5 Hz; 0.4 H); 3.50–4.00 (m; 4.8 H); 3.10–3.30 (m;
0.7 H); 2.86–3.07 (m; 0.4 H); 2.54–2.85 (m; 1.5 H); 2.30–2.47 (m; 0.4 H); 1.80–1.87
(m; 2.8 H); 1.54–1.60 (m; 2.6 H); 1.42 (br s; 8.6 H); 1.20 (d; J = 6.6 Hz; 1.1 H); 1.01 (d;
J = 6.6 Hz; 1.5 H); 0.89 (d; J = 6.6 Hz; 1.2 H); 0.64 (d; J = 6.6 Hz; 1.5 H).
Examples I –7a and I –7b: Hydrochloride of the diastereoisomers of 2–chloro –N –[ –
1–(4–fluoro –phenyl)–2–((S) –3–isopropyl –piperazin –1–yl) –2–oxo–ethyl] –N –(2–
methyl –4–phenoxy –phenyl)–acetamide
I –7a I –7b
To a solution of one of the diastereoisomers I–5a and I–5b in 50 mL of DCM the HCl
gas was added by bubbling. The reaction medium was left under agitation for 12 hours
at RT. The DCM was evaporated and the residual oil precipitated in ethyl ether.
Starting from the first diastereoisomer of Example I –5 (I –7 dia1):
Recovery of a white powder after filtration: (26 mg)
LCMS [M+H] = 538 (C H Cl FN O )
34 2 3 3
H NMR (300 MHz, DMSO): 8.79–9.33 (m; 1.3 H); 7.83 (t; J = 9.0 Hz; 1.0 H); 7.24–
7.40 (m; 4.0 H); 6.97–7.15 (m; 3.1 H); 6.73–6.89 (m; 3.2 H); 6.64 (d; J = 2.7 Hz; 0.9
H); 6.51–6.59 (m; 1.0 H); 4.40–4.55 (br m; 1.1 H); 3.86–4.09 (m; 3.6 H); 3.45–3.60 (m;
0.7 H); 2.78–3.05 (m; 2.8 H); 1.79–2.00 (m; 4.5 H); 1.61–1.77 (m; 0.7 H); 0.97 (d; J =
6.7 Hz; 6.0 H).
Starting from the second diastereoisomer of Example I –5 (I –7 dia2):
Recovery of a white powder after filtration: (2.62 g)
LCMS [M+H] = 538 (C H Cl FN O )
34 2 3 3
H NMR (300 MHz, DMSO) : 8.78–9.51 (m; 1.9 H); 7.82 (t; J = 8.9 Hz; 0.9 H); 7.20–
7.41 (m; 4.0 H); 6.97–7.16 (m; 3.1 H); 6.71–6.90 (m; 3.1 H); 6.61–6.70 (m; 1.9 H);
4.46–4.60 (br m; 1.0 H); 3.85–4.15 (m; 3.1 H); 3.00–3.30 (m; 3.0 H); 2.57–2.96 (m; 1.8
H); 1.43–1.98 (m; 4.3 H); 1.00 (dd; J = 8.8 Hz; J = 7.0 Hz; 2.7 H); 0.71 (d; J = 6.8 Hz;
1.6 H); 0.65 (d; J = 6.8 Hz; 1.5 H).
Example I –8: Hydrochloride of 2–chloro –N –[ –1–(4–fluoro –phenyl) –2–((R) –3–
isopropyl –piperazin –1–yl) –2–oxo–ethyl] –N –(2 –methyl –4–phenoxy –phenyl)–
acetamide
I –8a I –8b
The same protocol as in the preceding example was followed starting from each of the
diastereoisomers of Example I–6.
Starting from the first diastereoisomer of Example I –6 (I –8 dia1) :
Recovery of a white powder after filtration: (34 mg; 56 %)
LCMS [M+H] = 538 (C H Cl FN O )
34 2 3 3
H NMR (300 MHz, DMSO): 8.79–9.33 (m; 1.3 H); 7.83 (t; J = 9.0 Hz; 0.9 H); 7.24–
7.40 (m; 4.0 H); 6.97–7.15 (m; 3.1 H); 6.73–6.89 (m; 3.1 H); 6.64 (d; J = 2.7 Hz; 1.0
H); 6.51–6.59 (m; 1.0 H); 4.41–4.56 (br m; 1.1 H); 3.86–4.09 (m; 3.4 H); 3.45–3.60 (m;
0.7 H); 2.78–3.05 (m; 2.8 H); 1.79–2.00 (m; 4.4 H); 1.61–1.77 (m; 0.8 H); 0.97 (d; J =
6.7 Hz; 6.0 H).
Starting from the second diastereoisomer of Example I –6 (I –8 dia2):
Recovery of a white powder after filtration: (30 mg; 54 %)
LCMS [M+H] = 538 (C H Cl FN O )
34 2 3 3
H NMR (300 MHz, DMSO): 8.78–9.51 (m; 1.5 H); 7.82 (t; J = 8.9 Hz; 1.0 H); 7.20–
7.41 (m; 4.0 H); 6.97–7.16 (m; 3.1 H); 6.71–6.90 (m; 3.2 H); 6.61–6.70 (m; 1.9 H);
4.46–4.60 (br m; 1.0 H); 3.85–4.15 (m; 3.1 H); 3.00–3.30 (m; 2.9 H); 2.57–2.96 (m; 1.8
H); 1.43–1.98 (m; 4.3 H); 1.00 (dd; J = 8.8 Hz; J = 7.0 Hz; 2.7 H); 0.71 (d; J = 6.8 Hz;
1.6 H); 0.65 (d; J = 6.8 Hz; 1.5 H).
Using the same operating modes and the same separation modes by silica
chromatography as above, the following examples were prepared from diversely
substituted anilines and piperazines. They were isolated either in the form of a mixture
of two or four diastereoisomers (one example number for the same chemical structure)
or in the form of separate diastereoisomers. In this latter case the nomenclature a / b was
used to designate each of the diastereoisomers.
I–10
I–11 I–12
I–13 I–14
I–15a I–15b
I–16a I–16b
I–17a I–17b
I–18a I–18b
I–19a I–19b
I–20a I–20b
I–21a I–21b
I–22a I–22b
I–24
I–23
I–25a I–25b
I–26a I–26b
I–27a I–27b
The following examples were obtained by replacing the ethyl ester of (4–fluoro–
phenyl)–oxo–acetic acid by ethyl thiophene–2–glyoxylate and following the same
operating modes as previously.
I–29
I–28
I–31
I–30
I–32
I–33
I–34
I–35
I–36
I–37
I–38
I–39
I–40a I–40b
I–41a I–41b
I–42a I–42b
I–43a I–43b
I–44
I–45
I–46a I–46b
I–47a I–47b
I–49
I–48
I–50a I–50b
I–51a I–51b
I–52a I–52b
I–53a I–53b
I–54a I–54b
I–55a I–55b
I–56b
I–56a
HN O
N Cl
N Cl
I–58
I–57
Cl N Cl
I–60
I–59
N Cl
I–61
I–62
I–63
II - Pharmacological study of the compounds of the present invention
1) Cytotoxicity tests
The effects of the compounds of the invention on the proliferation of cancer cells were
studied on different human cancer cell lines of different tissue origin (MCF–7: breast
cancer, MCF–7/adr adriamycin–resistant breast cancer, HL–60: acute promyelocytic
leukaemia, HL–60/R10: doxorubicin–resistant acute promyelocytic leukaemia, HT29 :
colon adenocarcinoma, Mia Paca2: pancreatic tumour, Panc–1: pancreatic exocrine
tumour, SK–OV–3: cisplatin- and adriamycin resistant ovarian cancer). The cancer cells
used for this study were incubated at 37°C in the presence of one of the compounds of
the invention added to the culture medium at different concentrations.
The cancer cell lines were obtained from ATCC (American Type Culture Collection)
for MCF–7, from Hôpital de la Pitié Salpetrière for MCF–7/adr and from Oncodesign
(Dijon, France) for HL–60, HL–60/R10, HT29, MiaPaCa2, Panc–1 and SK–OV–3.
They were cultured in RPMI 1640 medium containing 2 mM L–Glutamine
supplemented with 10 % foetal calf serum (Lonza; Verviers, Belgium). All the cell lines
were held in culture at 37°C in a humid atmosphere containing 5 % CO . Cell
proliferation was assessed using the ViaLight® Plus Assay Kit (Lonza; Verviers,
Belgium) following the manufacturer’s instructions. The cells were seeded in 96–well
culture plates compatible with luminescence read–off (white plates with transparent
bottom) in a proportion of 5 000 to 10 000 cells per well in 100 µl of culture medium.
After a pre–incubation time of 24 hours at 37°C, the compounds of the invention
dissolved in dimethylsulfoxide (DMSO) were individually added to each well in a
proportion of 0.5 µl per well. After 72 hours’ incubation at 37°C in a humid atmosphere
containing 5 % CO , 50 µl of lysis buffer were added to each well and 15 minutes later
100 µl of ATP measuring agent were added. The plates were read under a luminometer
to evaluate cell viability. The data obtained was processed by computer to obtain the
EC value i.e. the concentration value of each of the compounds which induces 50 %
cell viability compared with a control value (0.5 % DMSO alone).
The results obtained are given in following Tables 1 and 2.
Table 1: Results obtained with cell lines HL–60, HL60/R10, MCF–7 and MCF–7/adr
(EC expressed in nM)
EC (nM)
Example N° HL –60 HL60/R10 MCF –7 MCF –7 /adr
I–1 dia1 1799 –219 –2500 338
I–1 dia2 824 23 1304 39
I–2 dia1 728 40 2091 49
I–2 dia2 2061 472 2500 645
I–3 dia1 1311 15 927 55
I–3 dia2 504 2 301 9
I–4 dia1 648 4 315 13
I–4 dia2 1321 62 863 166
I–7 dia1 2500 604 2500 618
I–7 dia2 1938 26 1954 98
I–8 dia1 2029 54 1740 148
I–8 dia2 1737 312 2410 477
I–9 771 99 2500 108
I–10 641 131 2500 151
EC (nM)
Example N° HL –60 HL60/R10 MCF –7 MCF –7 /adr
I–11 939 68 2500 102
I–12 2321 82 1787 421
I–13 1989 88 2500 532
I–14 1848 95 2500 232
I–16 dia1 1478 450 2500 527
I–16 dia2 1913 317 2500 443
I–17 dia1 2313 353 2500 898
I–17 dia2 1604 49 1994 152
I–18 dia1 1596 140 2500 485
I–18 dia2 352 44 591 152
I–19 dia1 516 97 2500 128
I–19 dia2 453 24 2500 35
I–20 dia1 196 80 1571 73
I–20 dia2 1478 139 2500 165
I–21 dia1 2447 13 1950 93
I–21 dia2 630 8 869 10
I–22 dia1 1995 17 569 131
I–22 dia2 1149 18 430 34
I–23 559 12 nd nd
I–24 626 15 nd nd
I–25 dia1 1122 43 nd nd
I–25 dia2 819 103 nd nd
I–26 dia1 2447 13 1950 93
I–26 dia2 630 8 869 10
I–27 dia1 1995 17 569 131
I–27 dia2 1149 18 430 34
I–28 623 206 nd nd
I–29 939 38 1032 54
I–30 202 10 1006 44
I–31 766 64 2500 89
I–32 175 78 2500 58
I–33 2500 157 2500 394
I–34 1123 30 1775 100
I–35 300 249 632 863
I–36 372 28 2500 24
I–37 967 154 2500 156
I–38 2500 189 2500 851
I–39 1814 9 776 52
EC (nM)
Example N° HL –60 HL60/R10 MCF –7 MCF –7 /adr
I–40 dia1 2129 248 2500 371
I–40 dia2 2500 487 2500 827
I–43 dia2 1886 20 1424 126
I–44 215 7 nd nd
I–45 2136 17 nd nd
I–46 dia1 2500 318 2500 544
I–46 dia2 449 10 1184 58
I–47 dia1 936 54 nd nd
I–47 dia2 849 8 nd nd
I–48 1991 10 nd nd
I–49 1166 321 nd nd
I–50 dia1 2102 259 nd Nd
I–50 dia2 841 8 nd nd
I–51 dia1 145 96 nd nd
I–51 dia2 3 1 nd nd
I–52 dia1 2500 194 nd nd
I–52 dia2 223 24 nd nd
I–53 dia1 1981 645 2064 462
I–53 dia2 547 305 nd nd
I–58 1058 11 870 88
I–59 956 16 745 106
nd = non–determined
Table 2: Results obtained with other cell lines (EC expressed in nM)
Example N°
EC (nM)
HT29 Mia PaCa2 Panc –1 SK –OV –3
I–3 dia2
1 2 1 1
I–7 dia2
8 13 5 7
I–43 dia2
18 7 9
I–46 dia2
6 10 4 6
I–50 dia2
9 2200 9 11
Following Tables 3 and 4 illustrate the gain in cytotoxic activity on the resistant
HL60/R10 line, obtained with the compounds having a piperazine substituted at alpha
position of nitrogen 4 of the piperazine compared with a non–substituted piperazine
and/or substituted at another position of the piperazine. The best cytotoxic activity is
obtained with the absolute configuration (S) of this substitution.
Table 3: Results obtained with different substitutions of piperazine
EC (nM)
Example
HL –60 HL –60/R10
1627 226
Comparative example
2321 82
I–12
EC (nM)
Example
HL –60 HL –60/R10
1989 88
I–14
1848 95
I–13
Table 4: Results obtained with different substitutions of piperazine
EC (nM)
Example
HL –60 HL –60/R10
579 21
Comparative example
1058 11
I–58
662 65
Comparative example
EC (nM)
Example
HL –60 HL –60/R10
966 16
I–59
311 38
Comparative example
2) Determination of aqueous solubility
Aqueous solubility is a major physicochemical parameter for improving the ADME
properties (Absorption, Distribution, Metabolism and Excretion) in a molecule (Drug–
like properties: concepts, structure design and methods, Edward Harvel Kerns, Li Di;
Academic Press, 2008).
The aqueous solubility of each compound was measured at pH 7.4. It was measured
using HPLC on the supernatants obtained by centrifugation after saturation of the media
with excess compound after an agitation time of 24 h and at a temperature of 20°C. The
preparation and treatment of the samples was robotized.
Table 5 shows the gain in aqueous solubility obtained for a compound of the invention
I–58 compared with a non–substituted piperazine or substituted at another position.
Table 5: Aqueous solubility obtained with different piperazine substitutions.
Solubility
Example
(µg/mL)
Comparative example
I–58
Comparative example
Solubility
Example
(µg/mL)
I–59
I–62
3) Pharmacokinetic parameters in mice
The pharmacokinetic behaviour of compounds is a pre–requisite for reasonable use
thereof in in vivo experimentation. The compounds were given in DMSO solution via
intravenous route (IV) or oral route (PO) to balb/c mice. Blood samples were taken at
times ranging from 5 minutes to 6 hours, the plasmas were collected and the
concentration of the compounds in each sample was assayed by LC/MS/MS. The data
obtained allowed the plotting of time–concentration curves and determination of
fundamental parameters such as plasma half–life of the compound (T½), area under
curve at a given time (AUCt) and the maximum concentration obtained (Cmax). Table 6
shows the gain contributed by piperazine substitution on the pharmacokinetic
parameters of the compounds administered via intravenous route at a dose of 10 mg/kg.
Figure 1 gives the time - plasma concentration curves in a mouse after administration of
I–43 dia2 via IV and PO route. Compound I–43 dia2 therefore shows good
bioavailability in a mouse, in particular via oral route.
Table 6: Pharmacokinetic parameters obtained with various piperazine substitutions.
Cmax AUCt AUCinf
Example t (h)
(ng/mL) (ng/mL*h) (ng/mL*h)
1469.50 1278.25 1321.68 1.38
Comparative example
3797.6 3287.08 3837.61 2.64
I–63
1424.37 1677.94 2057.38 2.47
I–43 dia 2
Claims (17)
1. A compound of following general formula (I): and the pharmaceutically acceptable salts thereof, its stereoisomers or mixtures of stereoisomers in any proportion, in particular an enantiomer mixture, and particularly a racemic mixture, where: – X is a (C –C )alkyl, phenyl, benzyl, C(O)OR5 or C(O)NHR5 group; – R1 is a hydrogen atom or a C(O)H, C(O)R6 or C(O)OR6 group; – R2 is a hydrogen atom or a (C –C )alkyl group; or R2 together with R1 or X forms a saturated hydrocarbon chain to form a 5- or 6–membered ring, in particular a 5–membered ring; – R3 is a hydrogen or halogen atom or a (C –C )alkyl or (C –C )alkoxy group; 1 6 1 6 – R4 is a hydrogen or halogen atom, CN, NO , or a (C –C )alkyl, (C –C )alkoxy, 2 1 6 1 6 aryloxy, benzyloxy or heteroaryloxy group, the said group optionally being substituted by one or more halogen atoms; – Ar is a thiophenyl group or a phenyl group optionally substituted by one or more halogen atoms; and - R5 and R6 independently of one another are a (C –C )alkyl, aryl–(C –C )alkyl 1 6 1 6 or aryl group, the said group optionally being substituted by one or more halogen atoms.
2. The compound according to claim 1, characterized in that it meets the following formula (I–bis): (I –bis).
3. The compound according to any one of claims 1 and 2, characterized in that Ar is a thiophenyl group or a phenyl group substituted by one or more fluorine atoms such as 4–fluoro–phenyl.
4. The compound according to any one of claims 1 to 3, characterized in that R4 is a hydrogen or halogen atom or a (C –C )alkyl, (C –C )alkoxy or aryloxy group, 1 6 1 6 the said group optionally being substituted by one or more halogen atoms, fluorine in particular.
5. The compound according to any one of claims 1 to 4, characterized in that R3 is a hydrogen atom or a (C –C )alkyl group e.g. methyl.
6. The compound according to any one of claims 1 to 5, characterized in that X is a (C –C )alkyl, phenyl or benzyl group; R1 and R2 are a hydrogen atom; R3 is a hydrogen atom or a (C –C )alkyl group, in particular (C –C )alkyl; R4 is a halogen 1 6 1 3 atom or a (C –C )alkyl, (C –C )alkoxy, aryloxy or benzyloxy group, the said group 1 6 1 6 optionally being substituted by one or more halogen atoms; Ar is a thiophenyl group or a phenyl group optionally substituted by a fluorine atom such as 4–fluoro–phenyl; and R5 and R6 independently of one another are a (C –C )alkyl, aryl–(C –C )alkyl or aryl 1 6 1 6 group, the said group optionally being substituted by one or more fluorine atoms.
7. The compound according to claim 1, characterized in that the compound is selected from among: I–1a I–1b I–2a I–2b I–3a I–3b I–4a I–4b I–5a I–5b I–6a I–6b I–7a I–7b I–8a I–8b I–9 I–10 I–11 I–12 I–13 I–14 I–15a I–15b I–16a I–16b I–17a I–17b I–18a I–18b I–19a I–19b I–20a I–20b I–21a I–21b I–22a I–22b I–23 I–24 I–25a I–25b I–26a I–26b I–27a I–27b I–28 I–29 I–30 I–31 I–32 I–33 N Cl I–34 I–35 N Cl I–36 I–37 I–39 I–38 I–40a I–40b I–41a I–41b I–42a I–42b I–43a I–43b I–45 I–44 I–46a I–46b I–47a I–47b I–48 I–49 I–50a I–50b I–51a I–51b I–52a I–52b I–53a I–53b I–54a I–54b I–55a I–55b I–56a I–56b HN O N Cl I–57 I–58 N Cl I–59 I–60 I–61 I–62 I–63
8. A compound of general formula (I) according to any one of claims 1 to 7 for use as a drug.
9. A compound of general formula (I) according to any one of claims 1 to 7 for use in the treatment or prevention of cancer and chemotherapy–resistant cancer.
10. A pharmaceutical composition comprising at least one compound of general formula (I) according to any one of claims 1 to 7, in association with one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition according to claim 10, characterized in that it comprises at least one other active ingredient such as an anticancer agent.
12. The pharmaceutical composition according to claim 11, characterized in that the active ingredient(s) are chosen from among cisplatin and its derivatives such as carboplatin and oxalyplatin; taxanes such as taxol, taxotere, paclitaxel and docetaxel; vinca alkaloids such as vinblastine, vincristine and vinorelbine; purine analogues such as mercaptopurine, thioguanine, pentostatin and 2–chlorodeoxyadenosine; topoisomerase I inhibitors such as camptothecin compounds e.g. irinotecan and topotecan; topoisomerase II inhibitors such as epipodophyllotoxin, podophyllotoxin and the derivatives thereof such as etoposide and teniposide; anti–tumour nucleoside derivatives such as 5–fluorouracil, leucovorin, gemcitabine or capecitabine; alkylating agents such as nitrogen mustards e.g. cyclophosphamide, mechlorethamine, chlorambucil and melphalan, nitroso–ureas such as carmustin, lomustin and streptozocin, alkylsulfonates such as busulfan, ethylenimines and methylmelamines such as thiotepa and hexamethylmelamine, and tetrazines such as dacarbazine; derivatives of anti–tumour anthracyclines such as daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; molecules targeting the IGF–I receptor such as picropodophyllin; tetracarcin derivatives such as tetrocarcin A; corticosteroids such as prednisone; antibodies such as trastuzumab (anti–HER2 antibody), rituximab (anti– CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; antagonists or selective modulators of oestrogen receptors such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene, aromatase inhibitors such as exemestane, anastrozole, letrozole and vorozole; differentiating agents such as retinoids e.g. retinoic acid and vitamin D and agents blocking the metabolism of retinoic acid such as accutane; DNA methyl–transferase inhibitors such as azacytidine and decitabine; antifolates such as permetrexed disodium; antibiotics such as antinomycin D, bleomycin, mitomycin C, actinomycin D, carminomycin, daunomycin and plicamycin; antimetabolites such as chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; apoptosis–inducing agents and anti–angiogenic agents of Bcl–2 inhibitors such as YC 137, BH 312, ABT 737, gossypol, HA 14–1, TW 37 and decanoic acid; agents binding to tubulin such as combrestatin, colchicine derivatives and nocodazole; kinase inhibitors such as flavoperidol, imatinib mesylate, erlotinib and gefitinib; farnesyl transferase inhibitors such as tipifarnib; histone–deacetylase inhibitors such as sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP- LAQ824, R306465, JNJ–26481585 and trichostatin A; inhibitors of the ubiquitin–proteasome system such as MLN .41, bortezomib and yondelis; and telomerase inhibitors such as telomestatin.
13. A pharmaceutical composition comprising: (i) at least one formula (I) compound according to any one of claims 1 to 7; and (ii) at least one other active ingredient such as an anticancer agent, as combination products for simultaneous, separate or time–staggered use thereof.
14. The pharmaceutical composition according to claim 13, characterized in that the active ingredient(s) are selected from among cisplatin and the derivatives thereof such as carboplatin and oxalyplatin; taxanes such as taxol, taxotere, paclitaxel and docetaxel; vinca alkaloids such as vinblastine, vincristine and vinorelbine; purine analogues such as mercaptopurine, thioguanine, pentostatin and 2– chlorodeoxyadenosine; topoisomerase I inhibitors such as camptothecin compounds e.g. irinotecan and topotecan; topoisomerase II inhibitors such as epipodophyllotoxin, podophyllotoxin and the derivatives thereof such as etoposide and teniposide; anti– tumour nucleoside derivatives such as 5–fluorouracil, leucovorin, gemcitabine or capecitabine; alkylating agents such as nitrogen mustards e.g. cyclophosphamide, mechlorethamine, chlorambucil and melphalan, nitroso–ureas such as carmustin, lomustin and streptozocin, alkylsulfonates such as busulfan, ethylenimines and methylmelamines such as thiotepa and hexamethylmelamine, and tetrazines such as dacarbazine; derivatives of anti–tumour anthracyclines such as daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; molecules targeting the IGF–I receptor such as picropodophyllin; tetracarcin derivatives such as tetrocarcin A; corticosteroids such as prednisone; antibodies such as trastuzumab (anti–HER2 antibody), rituximab (anti–CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; antagonists or selective modulators of oestrogen receptors such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; aromatase inhibitors such as exemestane, anastrozole, letrozole and vorozole; differentiating agents such as retinoids e.g. retinoic acid and vitamin D and agents blocking the metabolism of retinoic acid such as accutane; DNA methyl–transferase inhibitors such as azacytidine and decitabine; antifolates such as permetrexed disodium; antibiotics such as antinomycin D, bleomycin, mitomycin C, actinomycin D, carminomycin, daunomycin and plicamycin; antimetabolites such as chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; apoptosis–inducing agents and anti–angiogenic agents of Bcl–2 inhibitors such as YC 137, BH 312, ABT 737, gossypol, HA 14–1, TW 37 and decanoic acid; agents binding to tubulin such as combrestatin, colchicine derivatives and nocodazole; kinase inhibitors such as flavoperidol, imatinib mesylate, erlotinib and gefitinib; farnesyl transferase inhibitors such as tipifarnib; histone–deacetylase inhibitors such as sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP- LAQ824, R306465, JNJ–26481585 and trichostatin A; inhibitors of the ubiquitin–proteasome system such as MLN .41, bortezomib and yondelis; and telomerase inhibitors such as telomestatin.
15. The pharmaceutical composition according to any one of claims 10 to 14 for use as a drug intended to treat or prevent cancer, in particular to treat a chemotherapy– resistant cancer.
16. A method for preparing a formula (I) compound according to any one of claims 1 to 7 comprising the following successive steps: a) reacting an amine of following formula (II): (II) where X, R1, R2, R3, R4 and Ar are as defined in claim 1, R1 not representing a hydrogen atom, with chloroacetyl chloride in the presence of a base to give a formula (I) compound where R1 ≠ H; and b) optionally deprotecting the nitrogen atom carrying the R1 ≠ H group to give a formula (I) compound where R1 = H.
17. The method according to claim 16 comprising the following successive steps: i) reacting a ketoester of following formula (V): where Ar is as defined in claim 1 and R represents a (C –C )alkyl group, such as ethyl; with an aniline of following formula (VI): (VI) where R3 and R4 are as defined in claim 1, to give an imine of following formula (VII): (VII) where R3, R4 and Ar are as defined in claim 1 and R is as defined above in claim 17; ii) reducing the imine of formula (VII) obtained at the preceding step to give an amine of following formula (VIII): (VII) where R3, R4 and Ar are as defined in claim 1 and R is as defined above in claim 17; iii) saponifying the ester function of the formula (VIII) compound obtained at the preceding step to give an acid of following formula (IV): (IV) where R3, R4 and Ar are as defined in claim 1; iv) reacting the acid of formula (IV) obtained at the preceding step with a piperazine of following formula (III): (III) where X, R1 and R2 are as defined in claim 1, R1 not representing a hydrogen atom, to give an amine of formula (II) according to claim 16; v) reacting the amine of formula (II) obtained at the preceding step with chloroacetyl chloride in the presence of a base to give a formula (I) compound where R1 ≠ H; and vi) optionally deprotecting the nitrogen atom carrying the R1 ≠ H group to give a formula (I) compound where R1 = H.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1162586 | 2011-12-30 | ||
FR1162586A FR2985256B1 (en) | 2011-12-30 | 2011-12-30 | PIPERAZINYL DERIVATIVES FOR THE TREATMENT OF CANCERS |
PCT/EP2012/077059 WO2013098393A1 (en) | 2011-12-30 | 2012-12-28 | Piperazinyl derivatives for the treatment of cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ627149A NZ627149A (en) | 2015-08-28 |
NZ627149B2 true NZ627149B2 (en) | 2015-12-01 |
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