CA2517281A1 - Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) - Google Patents
Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) Download PDFInfo
- Publication number
- CA2517281A1 CA2517281A1 CA002517281A CA2517281A CA2517281A1 CA 2517281 A1 CA2517281 A1 CA 2517281A1 CA 002517281 A CA002517281 A CA 002517281A CA 2517281 A CA2517281 A CA 2517281A CA 2517281 A1 CA2517281 A1 CA 2517281A1
- Authority
- CA
- Canada
- Prior art keywords
- mmol
- alkyl
- aryl
- crdre
- membered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- -1 sulfate ester compounds Chemical class 0.000 title claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 15
- 239000010452 phosphate Substances 0.000 title abstract description 14
- 108090000623 proteins and genes Proteins 0.000 title abstract description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title abstract description 12
- 102000004169 proteins and genes Human genes 0.000 title abstract description 10
- 230000002401 inhibitory effect Effects 0.000 title description 9
- 101150037009 pin1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 13
- 230000004663 cell proliferation Effects 0.000 claims abstract description 12
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 8
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 208000014644 Brain disease Diseases 0.000 claims abstract description 7
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 239000002207 metabolite Substances 0.000 claims description 17
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 2
- 102000005591 NIMA-Interacting Peptidylprolyl Isomerase Human genes 0.000 claims description 2
- 108010059419 NIMA-Interacting Peptidylprolyl Isomerase Proteins 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 36
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 23
- 125000001475 halogen functional group Chemical group 0.000 claims 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 74
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000000069 prophylactic effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 293
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 215
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 211
- 229910052739 hydrogen Inorganic materials 0.000 description 210
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 151
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 147
- 238000005481 NMR spectroscopy Methods 0.000 description 146
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 118
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- 235000019439 ethyl acetate Nutrition 0.000 description 106
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 96
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 88
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 85
- 238000000746 purification Methods 0.000 description 85
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 82
- 230000015572 biosynthetic process Effects 0.000 description 76
- 238000004440 column chromatography Methods 0.000 description 76
- 238000003786 synthesis reaction Methods 0.000 description 76
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 71
- 238000002953 preparative HPLC Methods 0.000 description 51
- 239000000725 suspension Substances 0.000 description 51
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
- 229910000029 sodium carbonate Inorganic materials 0.000 description 50
- 150000002148 esters Chemical class 0.000 description 49
- 235000017550 sodium carbonate Nutrition 0.000 description 48
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 45
- 239000011734 sodium Substances 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 40
- 239000007787 solid Substances 0.000 description 36
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 34
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 31
- YTFJQDNGSQJFNA-UHFFFAOYSA-N benzyl dihydrogen phosphate Chemical compound OP(O)(=O)OCC1=CC=CC=C1 YTFJQDNGSQJFNA-UHFFFAOYSA-N 0.000 description 31
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000004949 mass spectrometry Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 28
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 28
- 239000012267 brine Substances 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- ANPWLBTUUNFQIO-UHFFFAOYSA-N n-bis(phenylmethoxy)phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound C=1C=CC=CC=1COP(N(C(C)C)C(C)C)OCC1=CC=CC=C1 ANPWLBTUUNFQIO-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 239000000454 talc Substances 0.000 description 18
- 229910052623 talc Inorganic materials 0.000 description 18
- 235000012222 talc Nutrition 0.000 description 18
- 239000012298 atmosphere Substances 0.000 description 17
- 229910000085 borane Inorganic materials 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- STVVMTBJNDTZBF-SECBINFHSA-N (2r)-2-amino-3-phenylpropan-1-ol Chemical compound OC[C@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-SECBINFHSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 13
- 235000021317 phosphate Nutrition 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 12
- XNLBCXGRQWUJLU-UHFFFAOYSA-N naphthalene-2-carbonyl chloride Chemical compound C1=CC=CC2=CC(C(=O)Cl)=CC=C21 XNLBCXGRQWUJLU-UHFFFAOYSA-N 0.000 description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- DNGLRCHMGDDHNC-UHFFFAOYSA-N 1-benzothiophene-2-carbonyl chloride Chemical compound C1=CC=C2SC(C(=O)Cl)=CC2=C1 DNGLRCHMGDDHNC-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 10
- 239000006184 cosolvent Substances 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- JYSLFQTWNRYWJT-UHFFFAOYSA-N 8-(3,5-dichlorophenyl)sulfanyl-9-[3-(propan-2-ylamino)propyl]purin-6-amine Chemical compound N=1C2=C(N)N=CN=C2N(CCCNC(C)C)C=1SC1=CC(Cl)=CC(Cl)=C1 JYSLFQTWNRYWJT-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 description 7
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000011278 mitosis Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
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- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 6
- VWHRYODZTDMVSS-MRVPVSSYSA-N (2r)-2-amino-3-(3-fluorophenyl)propanoic acid Chemical compound OC(=O)[C@H](N)CC1=CC=CC(F)=C1 VWHRYODZTDMVSS-MRVPVSSYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 125000005605 benzo group Chemical group 0.000 description 4
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- KQPYUDDGWXQXHS-UHFFFAOYSA-N juglone Chemical compound O=C1C=CC(=O)C2=C1C=CC=C2O KQPYUDDGWXQXHS-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- ZHFMVVUVCALAMY-UHFFFAOYSA-N pipecolate Natural products OC1CNC(C(O)=O)C(O)C1O ZHFMVVUVCALAMY-UHFFFAOYSA-N 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- 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
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- C07C305/18—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings containing six-membered aromatic rings
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- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- 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
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- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
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- Cardiology (AREA)
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- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
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US45316303P | 2003-03-10 | 2003-03-10 | |
US60/453,163 | 2003-03-10 | ||
PCT/IB2004/000574 WO2004087720A1 (fr) | 2003-03-10 | 2004-02-23 | Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) |
Publications (1)
Publication Number | Publication Date |
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CA2517281A1 true CA2517281A1 (fr) | 2004-10-14 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002517281A Abandoned CA2517281A1 (fr) | 2003-03-10 | 2004-02-23 | Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) |
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Country | Link |
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EP (1) | EP1603926A1 (fr) |
JP (1) | JP2006523669A (fr) |
BR (1) | BRPI0408477A (fr) |
CA (1) | CA2517281A1 (fr) |
MX (1) | MXPA05009241A (fr) |
WO (1) | WO2004087720A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US11203565B2 (en) | 2016-11-29 | 2021-12-21 | Hiroshima University | Ester compound and PIN1 inhibitor, inflammatory disease therapeutic, and colon cancer therapeutic in which said ester compound is used |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005080406A2 (fr) * | 2003-12-19 | 2005-09-01 | Jerini Ag | Composes chimiques pour l'inhibition de proliferation cellulaire indesirable et leurs utilisation |
US7618981B2 (en) | 2004-05-06 | 2009-11-17 | Cytokinetics, Inc. | Imidazopyridinyl-benzamide anti-cancer agents |
US7504413B2 (en) | 2004-05-06 | 2009-03-17 | Cytokinetics, Inc. | N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases |
US7795448B2 (en) | 2004-05-06 | 2010-09-14 | Cytokinetics, Incorporated | Imidazoyl-benzamide anti-cancer agents |
WO2006040646A1 (fr) * | 2004-10-14 | 2006-04-20 | Pfizer, Inc. | Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1 |
EP2845588A1 (fr) * | 2013-09-09 | 2015-03-11 | Centre National de la Recherche Scientifique (C.N.R.S.) | Inhibiteurs PIN1 destiné à être utilisé dans la prévention et/ou le traitement de theileriosis et applications associées |
AP2017009809A0 (en) | 2014-10-03 | 2017-03-31 | Ucb Biopharma Sprl | Fused pentacyclic imidazole derivatives |
WO2017063757A1 (fr) | 2015-10-12 | 2017-04-20 | Polyphor Ag | Composés macrocycliques à conformation limitée |
WO2017063755A1 (fr) | 2015-10-12 | 2017-04-20 | Polyphor Ag | Composés macrocycliques à conformation limitée |
WO2017063756A1 (fr) * | 2015-10-12 | 2017-04-20 | Polyphor Ag | Utilisation de composés macrocycliques à conformation limitée comme modulateurs de pin1 |
WO2017063754A1 (fr) | 2015-10-12 | 2017-04-20 | Polyphor Ag | Utilisation de composés macrocycliques à conformation limitée comme modulateurs de pin1 |
CN109219608B (zh) | 2016-04-01 | 2021-12-21 | Ucb生物制药私人有限公司 | 作为tnf活性调节剂的稠合五环咪唑衍生物 |
BR112018069941A2 (pt) | 2016-04-01 | 2019-02-05 | Sanofi Sa | derivados de imidazol pentacíclicos fundidos como moduladores de atividade do tnf |
CN109195969B (zh) | 2016-04-01 | 2021-12-21 | Ucb生物制药私人有限公司 | 作为tnf活性调节剂的稠合五环咪唑衍生物 |
CN109219609B (zh) | 2016-04-01 | 2022-02-01 | Ucb生物制药私人有限公司 | 作为tnf活性调节剂的稠合六环咪唑衍生物 |
TWI714820B (zh) * | 2017-01-31 | 2021-01-01 | 美商基利科學股份有限公司 | 替諾福韋艾拉酚胺(tenofovir alafenamide)之晶型 |
WO2018167176A1 (fr) | 2017-03-15 | 2018-09-20 | Ucb Biopharma Sprl | Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf |
JP7205830B2 (ja) | 2017-08-07 | 2023-01-17 | 国立大学法人広島大学 | 新規アントラニル酸系化合物、並びにそれを用いたPin1阻害剤、炎症性疾患の治療剤及び癌の治療剤 |
EP3679930A4 (fr) | 2017-08-07 | 2021-11-17 | Hiroshima University | Agent thérapeutique contre la stéatose hépatique, et agent thérapeutique contre l'obésité |
WO2019031470A1 (fr) | 2017-08-07 | 2019-02-14 | 国立大学法人広島大学 | Nouveau composé à base d'amide, et inhibiteur de pin1, agent thérapeutique contre les maladies inflammatoires ainsi qu'agent thérapeutique contre le cancer mettant en œuvre celui-ci |
US20230133581A1 (en) | 2020-03-12 | 2023-05-04 | Hiroshima University | Novel 3,5-Diaminobenzoic Acid Compound, and PIN1 Inhibitor and Therapeutic Agent for Inflammatory Diseases Using Same |
WO2022032179A1 (fr) * | 2020-08-07 | 2022-02-10 | The Regents Of The University Of California | Inhibiteurs de pin1 et utilisations associées |
JP2022080079A (ja) | 2020-11-17 | 2022-05-27 | 国立大学法人広島大学 | Covid-19の治療剤又は予防剤 |
JPWO2022270628A1 (fr) * | 2021-06-25 | 2022-12-29 |
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US5508387A (en) * | 1993-08-04 | 1996-04-16 | Glycomed Incorporated | Selectin binding glycopeptides |
BR0312555A (pt) * | 2002-07-09 | 2007-06-19 | Pfizer | polipeptìdeos pin1 peptidil-prolil isomerase, suas estruturas cristalinas e a utilização destes para projeto de remédios |
-
2004
- 2004-02-23 EP EP04713610A patent/EP1603926A1/fr not_active Withdrawn
- 2004-02-23 WO PCT/IB2004/000574 patent/WO2004087720A1/fr not_active Application Discontinuation
- 2004-02-23 CA CA002517281A patent/CA2517281A1/fr not_active Abandoned
- 2004-02-23 BR BRPI0408477-2A patent/BRPI0408477A/pt not_active IP Right Cessation
- 2004-02-23 MX MXPA05009241A patent/MXPA05009241A/es unknown
- 2004-02-23 JP JP2006506287A patent/JP2006523669A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11203565B2 (en) | 2016-11-29 | 2021-12-21 | Hiroshima University | Ester compound and PIN1 inhibitor, inflammatory disease therapeutic, and colon cancer therapeutic in which said ester compound is used |
Also Published As
Publication number | Publication date |
---|---|
EP1603926A1 (fr) | 2005-12-14 |
JP2006523669A (ja) | 2006-10-19 |
WO2004087720A1 (fr) | 2004-10-14 |
MXPA05009241A (es) | 2005-10-19 |
BRPI0408477A (pt) | 2006-04-04 |
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