EP0929550A1 - DERIVES DE $i(N)-(BENZOTHIAZOL-2-YL)PIPERIDINE-1-ETHANAMINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE - Google Patents
DERIVES DE $i(N)-(BENZOTHIAZOL-2-YL)PIPERIDINE-1-ETHANAMINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUEInfo
- Publication number
- EP0929550A1 EP0929550A1 EP97943001A EP97943001A EP0929550A1 EP 0929550 A1 EP0929550 A1 EP 0929550A1 EP 97943001 A EP97943001 A EP 97943001A EP 97943001 A EP97943001 A EP 97943001A EP 0929550 A1 EP0929550 A1 EP 0929550A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- general formula
- compound
- mixture
- reacted
- piperidine
- 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.)
- Ceased
Links
- 239000003814 drug Substances 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims description 5
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical class NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- -1 lithium aluminum hydride Chemical compound 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000010496 Heart Arrest Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 206010038669 Respiratory arrest Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 210000004004 carotid artery internal Anatomy 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- CRZAGGWQDVXLCY-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)ethyl]piperidine Chemical compound C1=CC(F)=CC=C1CCN1CCCCC1 CRZAGGWQDVXLCY-UHFFFAOYSA-N 0.000 description 1
- MUJKUOUAMJJKFL-UHFFFAOYSA-N 2-[4-[2-(4-fluorophenyl)ethyl]piperidin-1-yl]-1,3-benzothiazole Chemical compound S1C(=NC2=C1C=CC=C2)N1CCC(CC1)CCC1=CC=C(C=C1)F MUJKUOUAMJJKFL-UHFFFAOYSA-N 0.000 description 1
- KXKCRYHRRIFFKX-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)ethyl]piperidine Chemical compound C1=CC(F)=CC=C1CCC1CCNCC1 KXKCRYHRRIFFKX-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 208000027776 Extrapyramidal disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010028923 Neonatal asphyxia Diseases 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- RMHDLBZYPISZOI-UHFFFAOYSA-N borane;methylsulfanylmethane Chemical compound B.CSC RMHDLBZYPISZOI-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- KDXZREBVGAGZHS-UHFFFAOYSA-M methohexital sodium Chemical compound [Na+].CCC#CC(C)C1(CC=C)C(=O)N=C([O-])N(C)C1=O KDXZREBVGAGZHS-UHFFFAOYSA-M 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CXLNKIFVGQZLQR-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-2-chloroacetamide;hydrochloride Chemical compound Cl.C1=CC=C2SC(NC(=O)CCl)=NC2=C1 CXLNKIFVGQZLQR-UHFFFAOYSA-N 0.000 description 1
- BYYLVIMOFHNUDJ-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)formamide Chemical compound C1=CC=C2SC(NC=O)=NC2=C1 BYYLVIMOFHNUDJ-UHFFFAOYSA-N 0.000 description 1
- SLDOBMOFHWAPFE-UHFFFAOYSA-N n-(2-piperidin-1-ylethyl)-1,3-benzothiazol-2-amine Chemical class N=1C2=CC=CC=C2SC=1NCCN1CCCCC1 SLDOBMOFHWAPFE-UHFFFAOYSA-N 0.000 description 1
- PACAIXLGJUCBHX-UHFFFAOYSA-N n-[2-(4-benzylpiperidin-1-yl)ethyl]-n-methyl-1,3-benzothiazol-2-amine Chemical compound N=1C2=CC=CC=C2SC=1N(C)CCN(CC1)CCC1CC1=CC=CC=C1 PACAIXLGJUCBHX-UHFFFAOYSA-N 0.000 description 1
- HOPVACMFVYCYHG-UHFFFAOYSA-N n-[2-[4-[2-(4-fluorophenyl)ethyl]piperidin-1-yl]ethyl]-1,3-benzothiazol-2-amine Chemical compound C1=CC(F)=CC=C1CCC1CCN(CCNC=2SC3=CC=CC=C3N=2)CC1 HOPVACMFVYCYHG-UHFFFAOYSA-N 0.000 description 1
- QVKPPRYUGJFISN-UHFFFAOYSA-N n-methyl-1,3-benzothiazol-2-amine Chemical compound C1=CC=C2SC(NC)=NC2=C1 QVKPPRYUGJFISN-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- ILXAOQAXSHVHTM-UHFFFAOYSA-M sodium;2-amino-2-(hydroxymethyl)propane-1,3-diol;chloride Chemical compound [Na+].[Cl-].OCC(N)(CO)CO ILXAOQAXSHVHTM-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- n represents the number 0, 1, 2 or 3
- R represents a hydrogen or halogen atom or a methyl or methoxy group
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents a hydrogen atom or one or two halogen atoms.
- the compounds of the invention may exist in the form of free bases or of addition salts with acids.
- amide at a temperature of 50 to 80 ° C. , and in the presence of a mineral base, for example potassium carbonate.
- a simple or complex reducing agent such as an alkali metal hydride, for example, lithium aluminum hydride, boron hydride, boron hydride-tetrahydro
- a piperidine of general formula (V), in which n and R 3 are as defined above, is reacted with l-bromo-2-chloroethane, under the conventional conditions for such a reaction, it that is to say in a polar solvent, for example N, iV-dimethylformamide, in the presence of a mineral base, for example potassium carbonate, at a temperature of 50 to 80 ° C.
- a polar solvent for example N, iV-dimethylformamide
- a mineral base for example potassium carbonate
- N- (Benzothiazolyl-2-yl) -4- [(4-fluorophenyl) methyl] piperidine-1 -ethanamine, ethanedioate 1.3 g (0.00349 mole) of N- (benzothiazolyl-) are introduced into a 250 ml three-necked flask 2-yl) -4- [(4-fluorophenyl) methyl] piperidme-1-acetamide in solution in 25 ml of dry tetrahydrofuran, 1.09 ml, or 3 equivalents, of borane-methyl sulfide complex is added, and heats the mixture at reflux for 4 hours.
- a suspension of 0.854 g (0.0224 mole) of lithium aluminum hydride in 50 ml of tetrahydrofuran is prepared, it is heated to reflux, a solution of 2 g (0.0112 mole) of intermediate is added. formylated in 100 ml of tetrahydrofuran and heating is continued for 30 mm. The mixture is cooled, 100 ml of ethyl acetate are added and, dropwise, 38 ml of water, the organic phase is separated by decantation, it is evaporated under reduced pressure, the crystallized residue is triturated in petroleum ether, it is filtered and dried in the presence of phosphorus pentoxide. 1.5 g of compound are obtained.
- N- (Benzothiazol-2 -yl) -4- [2- (4-fluorophenyl) ethyl] piperidine-1-ethanamine 0.96 g (0.025 mole) of lithium aluminum hydride and 140 ml of dry tetrahydrofuran are introduced into a 500 ml three-necked flask, under nitrogen atmosphere, the suspension is heated to reflux, drip, 5.0 g (0.01 mole) of N- (benzothiazol -2 -yl) -4- [2- (4-fluorophenyl) - ethyl] piperidine-1-acetamide dissolved in 60 ml of tetrahydrofuran dry and heating continues 30 min.
- the compounds of the invention have been subjected to tests which have demonstrated their interest as therapeutic active substances.
- test compounds are administered after intravenous occlusion. 24 hours after occlusion of the middle cerebral artery, the animals are sacrificed and the brain is removed.
- the volume of the cerebral infarction is evaluated from the measurement of the surface of the necrosis on 6 coronal sections stained with 2, 3, 5-t ⁇ phenyltetrazol ⁇ um chloride.
- compound No. ll of the above table significantly reduces the volume of the infarction by approximately
- the compounds of the invention were also subjected to the test of global cerebral ischemia in mice.
- the ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride.
- the "survival time” is measured, that is to say the interval between the moment of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.
- Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention.
- the results are given in the form of the difference between the survival time measured in a group of 10 mice having received the compound and the survival time measured in a group of 10 mice having received the carrier liquid.
- the relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.
- a 3 second increase in survival time is both statistically significant and reproducible.
- the ED 3 ride of the most active compounds of the invention are less than 5 mg / kg intraperitoneally.
- the compounds according to the invention have also been the subject of an in vitro study as to their affinity for the dopaminergic receptors D 4 obtained by transfection of human receptors D 4 ⁇ 4 into CHO cells, essentially as described by Van Toi . et al., Nature (1991) 350 610-614 and Van Toi. et al., Nature (1992) 358 149-152.
- the membrane suspension (100 ⁇ l, 78 ⁇ g of membrane) is incubated at 25 ° C for 60 min in the presence of 0.5 nM of [ 3 H] spiperone (specific activity 17 to 20 Ci / mmol, New England Nuclear / Du Pont de Nemours, Boston, MA, USA) in a final volume of 1 ml of incubation buffer in the presence or absence of the test compound.
- the filters are dried in an oven at 120 ° C for 5 min.
- the radioactivity retained on the filters is determined by liquid scintigraphy.
- the non-specific binding is determined in the presence of 1 ⁇ M of haloperidol.
- the percentage inhibition of the specific binding of [ 3 H] spiperone is calculated, then the IC 50 , concentration which inhibits 50% of the binding, is determined.
- the IC 50 values of the compounds of the invention are of the order of 3 to 30 nM.
- results of the tests show that, in vivo, the compounds according to the invention have neuroprotective properties and that, in vi tro, they displace the specific binding of [ 3 H] spiperone to human D 4 4 dopaminergic receptors.
- ischemic or hypoxic origin Cerebral infarction, cranial or spinal trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia
- glaucoma progressive neurodegenerative diseases
- senile dementia such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.
- senile dementia such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.
- psychoses in particular schizophrenia (deficit and productive forms) and acute and chronic extrapyramidal symptoms, induced by neuroleptics or consecutive to Parkinson's disease, for the treatment various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder, for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and disorders of the hypothalamic-pituitary function, and for the treatment cognitive impairment related to age or Alzheimer's disease.
- psychoses in particular schizophrenia (deficit and productive forms) and acute and chronic extrapyramidal symptoms, induced by neuroleptics or consecutive to Parkinson's disease
- various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and disorders of the hypothalamic-pituitary function, and for the treatment cognitive impairment related to age or Alzheimer's disease.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9611925 | 1996-10-01 | ||
| FR9611925A FR2753970B1 (fr) | 1996-10-01 | 1996-10-01 | Derives de n-(benzothiazol-2-yl) piperidine-1-ethanamine, leur preparation et leur application en therapeutique |
| PCT/FR1997/001692 WO1998014444A1 (fr) | 1996-10-01 | 1997-09-26 | Derives de n-(benzothiazol-2-yl)piperidine-1-ethanamine, leur preparation et leur application en therapeutique |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0929550A1 true EP0929550A1 (fr) | 1999-07-21 |
Family
ID=9496217
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97943001A Ceased EP0929550A1 (fr) | 1996-10-01 | 1997-09-26 | DERIVES DE $i(N)-(BENZOTHIAZOL-2-YL)PIPERIDINE-1-ETHANAMINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0929550A1 (cs) |
| JP (1) | JP2001501217A (cs) |
| KR (1) | KR20000048767A (cs) |
| CN (1) | CN1230959A (cs) |
| AR (1) | AR009105A1 (cs) |
| AU (1) | AU722147B2 (cs) |
| BG (1) | BG103271A (cs) |
| BR (1) | BR9711842A (cs) |
| CA (1) | CA2266510A1 (cs) |
| CO (1) | CO4650030A1 (cs) |
| CZ (1) | CZ112699A3 (cs) |
| EE (1) | EE9900135A (cs) |
| FR (1) | FR2753970B1 (cs) |
| HU (1) | HUP9904091A3 (cs) |
| IL (1) | IL128902A (cs) |
| NO (1) | NO991581L (cs) |
| NZ (1) | NZ334553A (cs) |
| PL (1) | PL332648A1 (cs) |
| SK (1) | SK42299A3 (cs) |
| TR (1) | TR199900634T2 (cs) |
| TW (1) | TW438800B (cs) |
| WO (1) | WO1998014444A1 (cs) |
| ZA (1) | ZA978772B (cs) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9725541D0 (en) * | 1997-12-02 | 1998-02-04 | Pharmacia & Upjohn Spa | Amino-benzothiazole derivatives |
| US6107313A (en) * | 1998-10-02 | 2000-08-22 | Combichem, Inc. | Dopamine receptor antagonists |
| HRP20020962A2 (en) | 2000-06-21 | 2005-02-28 | F. Hoffmann - La Roche Ag | Benzothiazole derivatives |
| US7087761B2 (en) | 2003-01-07 | 2006-08-08 | Hoffmann-La Roche Inc. | Cyclization process for substituted benzothiazole derivatives |
| KR20060061393A (ko) * | 2003-10-24 | 2006-06-07 | 에프. 호프만-라 로슈 아게 | Ｃｃｒ3 수용체 길항제 |
| PT1753760E (pt) | 2004-05-24 | 2008-02-12 | Hoffmann La Roche | '' - metoxi - 7 - morfolin - 4 - il - benzotiazol - 2 - il) - amida do ácido 4 - hidroxi - 4 - metil - piperidina - 1 - carboxílico'' |
| DE602005008095D1 (de) | 2004-11-05 | 2008-08-21 | Hoffmann La Roche | Verfahren zur herstellung von isonikotinsäurederivaten |
| ES2339477T3 (es) | 2005-03-23 | 2010-05-20 | F.Hoffmann-La Roche Ag | Derivados de acetilenil-pirazolo-pirimidina como antagonistas de mglur2. |
| DE602006013493D1 (de) | 2005-09-27 | 2010-05-20 | Hoffmann La Roche | Oxadiazolylpyrazolopyrimidine als mglur2-antagonisten |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1260474A (en) * | 1984-12-03 | 1989-09-26 | Raymond A. Stokbroekx | Benzoxazol- and benzothiazolamine derivatives |
| KR930005004B1 (ko) * | 1985-04-15 | 1993-06-11 | 쟈안센 파아마슈우티카 엔. 부이. | 치환된 n-[(4-피페리디닐)알킬]이환 축합 옥사졸아민 및 티아졸아민의 제조방법 |
-
1996
- 1996-10-01 FR FR9611925A patent/FR2753970B1/fr not_active Expired - Fee Related
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1997
- 1997-09-26 EE EEP199900135A patent/EE9900135A/xx unknown
- 1997-09-26 TR TR1999/00634T patent/TR199900634T2/xx unknown
- 1997-09-26 CZ CZ991126A patent/CZ112699A3/cs unknown
- 1997-09-26 AU AU44638/97A patent/AU722147B2/en not_active Ceased
- 1997-09-26 KR KR1019990702753A patent/KR20000048767A/ko not_active Withdrawn
- 1997-09-26 WO PCT/FR1997/001692 patent/WO1998014444A1/fr not_active Application Discontinuation
- 1997-09-26 CA CA002266510A patent/CA2266510A1/en not_active Abandoned
- 1997-09-26 SK SK422-99A patent/SK42299A3/sk unknown
- 1997-09-26 HU HU9904091A patent/HUP9904091A3/hu unknown
- 1997-09-26 CN CN97198112A patent/CN1230959A/zh active Pending
- 1997-09-26 IL IL12890297A patent/IL128902A/en not_active IP Right Cessation
- 1997-09-26 BR BR9711842A patent/BR9711842A/pt not_active Application Discontinuation
- 1997-09-26 EP EP97943001A patent/EP0929550A1/fr not_active Ceased
- 1997-09-26 CO CO97056315A patent/CO4650030A1/es unknown
- 1997-09-26 NZ NZ334553A patent/NZ334553A/xx unknown
- 1997-09-26 PL PL97332648A patent/PL332648A1/xx unknown
- 1997-09-26 JP JP10516272A patent/JP2001501217A/ja active Pending
- 1997-09-30 ZA ZA9708772A patent/ZA978772B/xx unknown
- 1997-09-30 TW TW086114229A patent/TW438800B/zh active
- 1997-09-30 AR ARP970104493A patent/AR009105A1/es not_active Application Discontinuation
-
1999
- 1999-03-22 BG BG103271A patent/BG103271A/xx unknown
- 1999-03-30 NO NO991581A patent/NO991581L/no not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9814444A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998014444A1 (fr) | 1998-04-09 |
| EE9900135A (et) | 1999-12-15 |
| CO4650030A1 (es) | 1998-09-03 |
| PL332648A1 (en) | 1999-09-27 |
| KR20000048767A (ko) | 2000-07-25 |
| CA2266510A1 (en) | 1998-04-09 |
| HUP9904091A2 (hu) | 2000-05-28 |
| FR2753970A1 (fr) | 1998-04-03 |
| CN1230959A (zh) | 1999-10-06 |
| CZ112699A3 (cs) | 1999-06-16 |
| BR9711842A (pt) | 1999-08-24 |
| IL128902A0 (en) | 2000-02-17 |
| HUP9904091A3 (en) | 2000-07-28 |
| AU722147B2 (en) | 2000-07-20 |
| TR199900634T2 (xx) | 1999-06-21 |
| SK42299A3 (en) | 1999-12-10 |
| TW438800B (en) | 2001-06-07 |
| NO991581L (no) | 1999-06-01 |
| NZ334553A (en) | 2000-11-24 |
| BG103271A (en) | 2000-05-31 |
| AR009105A1 (es) | 2000-03-08 |
| ZA978772B (en) | 1998-03-27 |
| FR2753970B1 (fr) | 1998-10-30 |
| AU4463897A (en) | 1998-04-24 |
| NO991581D0 (no) | 1999-03-30 |
| JP2001501217A (ja) | 2001-01-30 |
| IL128902A (en) | 2001-07-24 |
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