IL86157A - Derivatives of 1,2,5,6-tetrahydropyridine, process for preparing them and pharmaceutical compositions containing them - Google Patents
Derivatives of 1,2,5,6-tetrahydropyridine, process for preparing them and pharmaceutical compositions containing themInfo
- Publication number
- IL86157A IL86157A IL8615788A IL8615788A IL86157A IL 86157 A IL86157 A IL 86157A IL 8615788 A IL8615788 A IL 8615788A IL 8615788 A IL8615788 A IL 8615788A IL 86157 A IL86157 A IL 86157A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- compound
- carbon atoms
- radical
- compounds
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 3
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical class C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000007513 acids Chemical class 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 4
- 239000001257 hydrogen Substances 0.000 claims abstract 4
- -1 cyclic alkyl radical Chemical class 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 11
- 238000003776 cleavage reaction Methods 0.000 claims description 6
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 6
- 230000007017 scission Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 238000006884 silylation reaction Methods 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical group [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 2
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 3
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 239000000047 product Substances 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 238000010992 reflux Methods 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 229910010277 boron hydride Inorganic materials 0.000 description 6
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical group CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 210000003608 fece Anatomy 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 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
- 229920002472 Starch Polymers 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- YKWNUSJLICDQEO-UHFFFAOYSA-N ethoxyethane;propan-2-ol Chemical compound CC(C)O.CCOCC YKWNUSJLICDQEO-UHFFFAOYSA-N 0.000 description 4
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000003405 ileum Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229940100486 rice starch Drugs 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 230000000718 cholinopositive effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- MSRXORUOQNNOKN-RMKNXTFCSA-N (ne)-n-(1-pyridin-3-ylethylidene)hydroxylamine Chemical compound O\N=C(/C)C1=CC=CN=C1 MSRXORUOQNNOKN-RMKNXTFCSA-N 0.000 description 1
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- KTOQRRDVVIDEAA-UHFFFAOYSA-N 2-methylpropane Chemical compound [CH2]C(C)C KTOQRRDVVIDEAA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ICPOKTZORRQGLK-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound C[C](C)C=C ICPOKTZORRQGLK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- MWECDLUSOJZZOI-UHFFFAOYSA-N CCON=C(C)C1=CC=CN=C1 Chemical compound CCON=C(C)C1=CC=CN=C1 MWECDLUSOJZZOI-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical compound [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 238000010494 dissociation reaction Methods 0.000 description 1
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- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229950002932 hexamethonium Drugs 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- AXOJRQLKMVSHHZ-UHFFFAOYSA-N methyl 1-methyl-1,2,3,6-tetrahydropyridin-1-ium-5-carboxylate;bromide Chemical compound Br.COC(=O)C1=CCCN(C)C1 AXOJRQLKMVSHHZ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DNGJUSFTUAPBFE-UHFFFAOYSA-N n-(1-pyridin-3-ylpropylidene)hydroxylamine Chemical compound CCC(=NO)C1=CC=CN=C1 DNGJUSFTUAPBFE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- YEMKVBRHRNHHGE-UHFFFAOYSA-N n-methyl-1-(1-methylpyrrol-2-yl)methanamine Chemical compound CNCC1=CC=CN1C YEMKVBRHRNHHGE-UHFFFAOYSA-N 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
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/94—Oxygen atom, e.g. piperidine N-oxide
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
New compounds (I): <IMAGE> in which R denotes a hydrogen, a hydroxyl or an alkyl containing up to 8 C, optionally substituted by a carboxy or R denotes an aralkyl containing up to 10 C or -COOZ, Z being an alkyl containing up to 8 C or an aralkyl containing from 7 to 10 C, R1 denotes an alkyl containing up to 8 C, R2 denotes a hydrogen or an alkyl containing up to 8 C, -COalk1 or (CH2)2N(alk2)2, alk1 and alk2 denoting an alkyl containing up to 8 C, it being understood that if R denotes an alkyl, R2 does not denote a hydrogen, and their addition salts with acids.
[EP0288394A2]
Description
LM 25/IL NEW DERIVATIVES Og 1,2, » 6-TETRA HYDROPYR ID INE , PBOGESS FOR PHARMACEUTICAL PREPARING THEM, AND COMPOSITIONS CONTAINING THEM ninpn n»»Din dnaa ^ no e> ,in>i am>niDO-6,5,3,i main ηπΐ η OATH o>i»3an The invention is concerned with new derivatives of 1,2,5,6-tetra-hydropyridine and their salts, the process for preparing them, their use as medicaments and the compositions containing them.
The subject of the invention is the compounds with the formula (I) : in which R represents a hydrogen atom, a hydroxyl radical, a saturated or unsaturated, linear, branched or cyclic alkyl radical containing up to 8 carbon atoms, or R represents an aralkyl radical containing up to 10 carbon atoms, Ri represents a saturated or unsaturated, linear, branched or cyclic alkyl radical containing up to 8 carbon atoms and R2 represents a hydrogen atom or a saturated or unsaturated, linear or branched alkyl radical containing up to 8 carbon atoms, a COalki radical or a (CH2)2N(alk2)2 radical, alki and alk2 representing an alkyl radical containing up to 8 carbon atoms, as well as their addition salts with acids on condition that if R represents an alkyl radical, R2 does not represent a hydrogen atom.
Among the addition salts with acids, there can be cited those formed with mineral acids, such as hydrochloric, hydrobromic, sulphur! or phosphoric acids, or with organic acids, such as formic, acetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspar ic, alkanesulphonic , such as methane- or ethanesulphonic , aryIsulphonic , such as benzene- or paratoluene-sulphonic acids.
When R, R^ , R2 or Z represents a saturated, linear or branched alkyl radical, it is preferred to be a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl or n-hexyl radical.
When R, R^ , R2 or Z represents an unsaturated alkyl radical, it is preferred to be an ethylene radical such, for example, as an allyl or 1 , 1-dimethylallyl radical, or an acetylene radical such, for example, as an ethynyl or propynyl radical.
When R, R^ or Z represents a cyclic alkyl radical, it is preferred to be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical .
When R or Z represents an aralkyl radical, it is preferred to be benzyl radical. alkj^ and alk preferably represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl radical.
The products with the formula (T) in which R represents an alkyl radical and R2 a hydrogen atom, notably l-methyl-4-acetyl-l , 2 , 5 ,6--tetrahydropyridin-oxime , are products known for their parasympathomimetic properties (see on this subject the American Patent N°. 3,004,979 .
The invention products present quite unexpected pharmacological properties in view of the American Patent, which are very interesting as are shown by the results of biological tests summarized further on in the experimental part.
The invention has particularly as its subject the compounds with the formula (1) in which R^ represents a linear alkyl radical containing from 1 - 4 carbon atoms, for example, the methyl radical.
Among the preferred compounds of the invention, there can be cited the compounds with the formula (I) in which R represents a hydrogen atom, as well as those in which R represents a hydroxyl radical and those in which R represents a linear or branched, saturated or unsaturated alkyl radical, containing from 1 to 4 carbon atoms , such, for example, as a methyl, ethyl, propyl or allyl radical, as well as their addition salts with acids.
There can also be cited the compounds with the formula (I) in which R2 represents a hydrogen atom, those in which R9 represents an alkyl radical containing from 1 to 4 carbon atoms and notably a methyl radical.
Naturally, the invention has more particularly as subject the compounds of which the preparation is given further on in the experimental part and quite specially the products of examples 2, 3 and 12.
The invention products notably present an important cholinomimetic activity of long duration of activity, by oral route.
The products further present a strong dissociation between the central activity and the peripheral activity, as is shown by the results of the tests set out further on.
Therefore, a subject of the invention is the invention products as medicaments, useful in particular in the treatment of Alzheimer's disease or of senile dementia and equally in the treatment of memory disorders .
It is well known that disorders of learning and of memory in aged persons are connected above all with a deficiency in the central cholinergic system, particularly in senile dementia and Alzheimer's disease.
It is therefore evident that products having a central cholinergic action could be employed in the therapeutic treatment of these diseases (Bartus, R. I., Science 217, 408, 1982).
It has been demonstrated that arecoline injected by intravenous route has a positive effect on patients having a memory defect (Sitaram N. et al., Science 201, 274, 1978), (Christie J.E. et al . Brit. J. Psychiatry, 138, 46, 1981).
A limitation to the therapeutic use of arecoline is bound up with the fact that this product has a very weak activity by oral route and a short duration of action.
The products which are the subject of the invention, after administration by oral route, have shown a central cholinomimetic activity much superior to that of arecoline and with a longer duration of action.
The usual posology is variable according to the affection concerned, the subject treated and the administration route; it can be between 50 mg and 300 mg per day, for example, between 15 and 150 mg per day in one or more doses for the product of example 3, administered by oral route.
The present invention also has as its subject the pharmaceutical compositions containing as active principle at least one product with the formula (I). The pharmaceutical compositions of the invention can be solid or liquid and can be presented in the pharmaceutical forms currently used in human medecine, such, for example, as plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations : they are prepared according to the usual methods. The active principle or principles can be incorporated in them with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, the various wetting, dispersing or emulsifying agents, and preservatives.
The invention also has as its subject a process for the prepar-ation of the products with the formula (I) in which and R2 have the significance previously indicated and R has the significance previously indicated with the exception of the hydroxyl value, characterized in that a compound with the formula (II) : in which R^ retains the same significance as previously, is submitted to the action of a compound with the formula (III) : NH OR' (III) or one of its salts, in which R'2 represents a hydrogen atom or a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms, in order to obtain the compound with the formula which is submitted to the action of an alkyl halide with the formula (V) : R'-Hal (V) in which Hal represents a halogen atom and R' represents a linear, branched or cyclic alkyl radical, saturated or unsaturated, containing up to 8 carbon atoms, possibly substituted by a free or esterified carboxy radical or R' represents an aralkyl radical containing up to 10 carbon atoms, in order to obtain the compound with the formula (VI) : which is submitted to the action of a hydrogenation agent, in order to obtain the compound with the formula (I^) : in which R', and R'2 are defined as previously which, if required, is either salified, or, if R^ represents a hydrogen atom, is submitted to the action of a compound with the formula R"2-Hal in which Hal represents a halogen atom and R"2 represents a radical COalk^ or a radical -(CH2)2N(Alk2)2> alk^ and alk2 being defined as previously, in order to obtain the corresponding compound with the formula (Ι in which R^ , R' and R"2 are defined as previously which, if required, either is salified, or if R' represents an aralkyl radical, is submitted to the action of a cleavage agent, in order to obtain the compound with the formula (Ις.) : in which R^ and R'2 are defined as previously, which, if required, is salified, and products with the formulae (I^) or (Ig) in which R' represents an aralkyl radical or (IQ) which, if desired, are submitted to the action of an alkyl or aralkyl halogeno formate in order to obtain a compound with the formula (IQ): cooz in which R^ , R2 and Z are defined as previously, which, if required, is* salified .
In a preferred mode of realizing the process of the invention : - the compound with the formula (III) is used in the form of the hydrochloride , - Hal (in the compound with the formulae R*-Hal or R"2-Hal) represents a bromine or iodine atom, - the hydrogenation agent is sodium borohydride, - the cleavage agent is alpha-chloroethoxycarbonyl chloride, the halogenoformate which is used is a chloroformate , for example, of ethyl or of benzyl.
The invention also has as its subject a variant of the preceding process characterized in that a compound with the formula ' in which R" represents an aralkyl radical containing up to 10 carbon atoms and R^ retains its previous significance is submitted to the action of a silylation agent, in order to obtain the compound with the formula (VII) : in which alk^ represents an alkyl radical containing from 1 to 8 carbon atoms, which is submitted to the action of a cleavage agent, in order to obtain the compound with the formula (Ig) : in which R-^ is defined as previously, which, if required, is salified.
In a preferred way of realizing this process : - -R" represents a benzyl radical, - the silylation agent is trimethylsilyl chloride, - the cleavage agent is alpha-chloroethoxycarbonyl chloride.
The invention also has as subject a process for preparing the products with the formula (I) in which and R2 have the previously Indicated significance and R represents a hydroxyl radical, characterized in that a compound with the formula (VIII) : Is submitted to the action of a reducing agent in order to obtain a compound with the formula (Ip) : in which and R2 are defined as previously, which, if required, is salified.
In a preferred way of realizing the invention process : - the reducing agent is sodium borohydride.
The eventual salification of the products with the formula (I) is carried out according to the usual methods, by making a mineral or organic acid react in sensibly stoechiometric proportions on the said products with the formula (I).
The compounds with the formula (II) are products known in a general way, which can be prepared according to the process described in the American patent 3 , 004 , 979 .
The compounds with the formula (VIII) are products described or obtained according to the process described in J.Het.Chem., JL6 , 1459 , 1979 .
The following examples illustrate the invention without, however, Stage A : l-benzyl-3-acetyl-l , 2 , 5 ,6-tetrahydropyridine-oxirae bromide . 7 .4 g of 3-acetylpyridine oxime is dissolved in 80 craJ of ethanol, 8 cm of benzyl bromide is added to it, with heating at reflux for 6. hours. The solvent is eliminated followed by crystal-lization from an ether/methanol mixture. 14 . 21 g of the expected product is obtained, m.p. = 200-201°C.
Analysis : Calculated : C % 54 .74 H % 4 .92 N % 9 . 12 Found : 54 . 56 4 .98 9 .07 Stage B : l-benzyl-3-acetyl-l , 2 , 5 , 6-tetrahydropyridine-oxirae . 13 .7 6 g of the product obtained at stage A in solution in is added, the whole is allowed to return to ambient temperature and agitated for 45 minutes. After concentrating under reduced pressure, water is added and extraction is done with chloroform. The organic phase is dried, the solvent is eliminated, and the residue is chromatographed on silica (eluent : ethyl acetate - toluene 8-2).
After crystallization of the residue from ethyl acetate, 7.8 g of the expected product is obtained, ra.p. 103-105°C.
Analysis : Calculated : C % 73.01 H Z 7.88 N % 12.16 Found : 72.74 7.81 12.04 Stage C : l-benzyl-3-acetyl-l ,2 ,5 ,6-tetrahydropyridine-triraethyl-silyl oxime. 3.6 g of the product obtained at stage B is dissolved in 60 cm of benzene and 1.86 g of 1 ,4-diazabicyclo [2.2.2.] octane, and over 5 minutes, under an inert atmosphere, 2.07 cm of trimethylchlorosilane is added. The suspension is heated to reflux for 3 hours, then cooled, filtered and concentrated to dryness. The residue is taken up in ethyl ether, filtered, the solvent is eliminated under reduced pressure, and 4.5 g of the expected product is obtained. (b.p. 150° c, under 0.05 mbar) Analysis : Calculated : C % 67.50 H Z 8.66 N % 9.26 Found Stage D : 3-acetyl-l ,2,5 ,6-tetrahydropyridine-oxime hydrochloride .
Under an inert atmosphere, 20 g of the product obtained as at stage C in solution in 20 cmJ of methylene chloride is cooled to 0°C, 21.6 g of alpha-chloroethyl chloroformate is added, followed by heating to reflux for two-and-a-half hours. After cooling, filtering and eliminating the solvent, the residue is taken up in ethyl ether, triturated and filtered. The solvent is evaporated off, the residue is taken up in methanol, heated to reflux for 30 minutes, then concentrated to dryness. The residue is taken up in methanol and ethyl ether, filtered, crystallized from ethanol, and 2.1 g of the expected product is collected, m.p. 237eC (with decomposition).
Analysis : C7H12N2°» HC1 Calculated : C % 47.59 H Z 7.42 N % 15.86 Found : 47.74 7.38 15.78 Example 2 : l-methyl-3-acet l-l ,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride.
Stage A : 3-acetyl-pyridine-O-methyl-oxirae . 6.85 g of methoxylamine hydrochloride is added to 10 g of 3-acetyl pyridine in 50 cm of methanol and the whole is heated to reflux for 3 hours. The solvent is eliminated under reduced pressure, the residue is taken up in water, alkalized with potassium carbonate and extracted with ethyl acetate. After evaporating, 11 g of the expected product is recovered, (b.p. : 115-118°C under 18 mm Hg).
Stage B : 1-methyl 3-acetyl~pyridiije-0-methyl oxime chloride. 20.5 g of methyl iodide is added to 11 g of the product obtained at stage A in 110 cm of ethyl acetate, and the whole is heated to reflux for 3 hours. After cooling, filtering and crystallizing the product from ethanol, 19.3 g of the expected product is obtained. m.p. 155-157°C.
Stage C : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride. 1.7 g of sodium hydroboride is added to a solution of 10 g of the product obtained at stage B in 100 cm of methanol and the whole is cooled to +5/+10eC. After agitating for 1 hour at ambient temperature, the solvent is eliminated under reduced pressure, and the residue is taken up in water, extracted with ethyl ether, and evaporated to dryness. The residue is taken up with ethyl ether, filtered on activated charcoal and salified with gaseous hydrochloric acid. The salt is recrys tallized from a mixture of isopropanol and ethyl ether, and 2.8 g of the expected product is obtained, m.p. 169-171°C.
Analysis : CQH16 20, HC1 Calculated : C % 52.80 H % 8.37 N % 13.68 Found : 53.06 8.44 13.57 Example 3 : 3-acet l-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride Stage A : l-benzyl-3-acetyl-pyridine-0-methyl-oxime bromide. 27.8 cm of benzyl bromide is added to 23.4 g of the product prepared at stage A of example 2 in solution in 200 era of ethyl acetate. This is heated to reflux for 8 hours, then cooled and filtered, and the solid obtained is crystallized from ethanol. 46 g of the expected product is obtained, m.p. 191-192°C.
Analysis : Calculated : C % 56.09 H % 5.34 N % 8.72 Found : 56.24 5.37 8.67 Stage B : l-benzyl-3-acetyl-l , 2 ,5 ,6-tetrahydropyridine-0-methyl-oxime . 20 g of the product prepared at stage A in solution in 150 era of methanol is cooled to 0°C. At this temperature 3.6 g of sodium borohydride is added, with agitation for 1 hour at ambient temperature. The methanol is eliminated under reduced pressure, the residue is taken up with water, sodium carbonate is added until saturated, and extraction is done with ethyl ether. The organic phase is dried and the solvent is evaporated. 10.66 g of the expected product is obtained, (b.p. 128-130°C. under 0.4 mbar).
Analysis : Calculated : C % 73.74 H % 8.25 N % 11.47 Found : " 73.56 8.21 11.52 Stage C : l-alpha-chloroethoxycarbonyl-3-acetyl-l,2,5,6-tetrahydro-pyridine-O-raeth l-oxirae . 7.2 g of the product obtained at stage B in solution in 100 cm of dichloroethane is cooled to 0°C and, over 20 minutes, 6.05 g of alpha-chloroethyl chloroformate is added, dissolved in dichloroethane.
After heating to reflux for one-and-a-half hours, cooling and filtering, the solvent is eliminated under reduced pressure. The residue is taken up in ethyl ether and filtered again. The solvent is evaporated off, and 8.44 g of product is obtained which is utilized as it is for the following stage, (b.p. 210°C under 0.06 mbar).
Analysis Calculated : C % 50.68 H % 6.57 N % 10.75 Found : 50.86 6.46 10.59 /hydroxhloride/ Stage D : 3-acetyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its ^ The product obtained at stage C in 70 cm of methanol is heated to reflux for 2 hours, then cooled, evaporated to dryness, and the residue is crystallized from ethanol. 3.9 g of the expected product is obtained, m.p. 199-200°C. Using the process of example 2 the expected/\ Analysis /hydrochloride is obtained/ Calculated : C % 50.39 H % 7.93 N % 14.69 Found : 50.31 7.84 14.55 Example 4 : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl-oxlme and its hydrochloride.
Stage A : 3-acetyl-pyridine-O-ethyl-oxime. 4.8 cm of 3-acetyl pyridine is dissolved in 50 cm of methanol, to this 4.27 g of orthoethyl hydrox lamine hydrochloride is added and the whole is taken to reflux for 3 hours, then cooled and evaporated to dryness under reduced pressure. The residue is taken up with water, neutralized with sodium bicarbonate and extracted with ethyl acetate.
The extracts are dried and concentrated to dryness under reduced pressure. 6.9 g of the expected product is obtained, utilisable for the following stage. m.p. 160-162°C, crystallized from an ether-isopropanol mixture in the form of the hydrochloride.
Stage B : l-methyl-3-acetyl-pyridine-0-ethyl-oxime iodide.
A mixture of 5.3 g of the product obtained at stage A and 4.1 cm of methyl iodide is agitated for 8 hours at reflux in 80 cm of ethanol, then distilled to dryness. 9.3 g of the expected product is obtained, m.p. 95°C, crystallized from an ether-isopropanol mixture.. /and its hydrochloride/ Stage C : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl-oxiraeV 1.7 g of boron and sodium hydride is added to a solution of 9.1 g of the product obtained at stage B in 90 cm of methanol, maintained at 5°C. After 4 hours at ambient temperature, this is evaporated to dryness under reduced pressure. The residue is taken up with water, extracted with ethyl acetate, and concentrated to dryness under reduced pressure. The residue is taken up with water, extracted with ethyl acetate, and the extracts are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluent : chloroform-raethanol 5-1). The 3.5 g of oil obtained is dissolved in ether and salified with gaseous hydrochloric acid. After evaporating to dryness, 3.7 g of the expected product is obtained, m.p. 186-188°C, recrys tallized from an isopropanol-ether mixture.
Analysis Calculated : C % 54.91 H % 8.76 N % 12.81 Found : 54.88 8.94 12.76 /and its/ ί Example 5 : 3-acetyl-l ,2,5,6-tetrahydropyridine-0-ethyl-oxime hydro-chloride Stage A : l-N-benzyl-3-acetyl-pyridine-0-ethyl-oxime bromide. 6.9 g of the product obtained at stage A of example 4 is dissolved in 70 cm of ethanol, 6 cm of benzyl bromide is added, and the whole is heated to reflux for 6 hours, then cooled, evaporated under reduced pressure, and 13.9 g of the expected product is isolated from the ether.
Stage B : l-N-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl oxime. a) To a solution of 0.8 g of sodium in 50 cm of ethanol, 3.8 g of 3 the product obtained at stage B of example 1 and 1.25 cm of bromo-ethane are added and the whole is taken to reflux for 3 hours, then cooled and concentrate to dryness. 2.84 g of the expected product is obtained, after elution on a column (eluent : ethyl acetate - toluene, 3-2). (b.p. 180-190°C under 0.05 mbar). b) The product can also be obtained with a yield of 71 % by reduction with boron and sodium hydride, operating as at stage B of example 1, starting with the product obtained at stage A of example 5. ^ drochi0ride/ Stage C : 3-acetyl-l,2,5 ,6-tetrahydropyridine-0-ethyl-oxime and itsV 2.7 g of the product obtained at stage B is dissolved in 50 cm of dichloroethane , then, at 0°C, 1.8 g of alpha-chloroethyl-chloro-formate is added; the whole is taken to reflux for 1 hour 30 minutes, then evaporated to dryness and taken up with ether. The insoluble matter is filtered off and evaporated to dryness under reduced pressure. The residual oil is taken up with 40 cm of methanol, taken to reflux for 1 hour 30 minutes, then evaporated to dryness. The residue is taken up with ether, filtered, and 4.2 g of the expected base is isolated and crystallized from an ether-methanol mixture. m.p. 198-19.9°C .(decomposition) . Using the process of example 2 the expected hydrochloride is obtained.
Analysis Calculated : C % 52.81 H % 8.37 N % 13.69 Found : 52.59 8.25 13.48 Example 6 : 3-acetyl-l,2>5,6-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride.
Stage A : l-N-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-2-propynyl. 5 g of the product obtained at stage B of example 1 is added to a solution of 1.1 g of sodium in 50 cnr of ethanol, then, at 0°C, 3.95 g of propargyl bromide is added. After heating for 3 hours to 40eC, the insoluble matter is filtered off, the solvent is evaporated, and the residue is chroma tographed on silica (eluent : ethyl acetate). 4.5 g of the expected product is obtained.
Stage B : 3-acetyl-l,2,5,6-tetrahydropyridine-0-2-propynyl-oxirae and its hydrochloride. 7.5 g of the product obtained at stage A is dissolved in 100 cm of dichloroethane. After 1 hour at reflux, the solvent is evaporated, the residue is taken up with ether, the insoluble matter is filtered off and the remainder is evaporated to dryness. The residue is taken up with methanol, taken to reflux for 30 minutes, then evaporated to dryness, and the residue is taken up with a solution of sodium bicarbonate. This is extracted with ethyl acetate and the extracts are evaporated to dryness. The residue is taken up with ether and salified with gaseous hydrochloric acid. 1.25 g of the expected product is obtained, m.p. 178°C, isolated from an ether-ethanol mixture.
Analysis Calculated : C % 55.94 H % 7.04 N % 13.05 Found : 55.72 7.01 12.99 Example 7 : l-methyl-3-acetyl-tetrahydropyridine-0-2-propynyl-oxime an its hydrochloride .
Stage A : 3-acetyl-pyridine-0-2-propynyl oxime. 5 g of 3-acetyl-pyridine is dissolved in 20 cnr of water, 3.45 g of sodium bicarbonate and 4.45 g of ortho-2-propynyl-hydroxylamine hydrochloride in 30 cm of water are added, and the mixture is left for 16 hours, then heated for 3 hours at 40°C. After concentrating, it is extracted with ethyl acetate, the extracts are evaporated to dryness and purified on silica gel (eluent ethyl acetate). 5.7 g of the expected product is obtained, m.p. 156-157°C, recrys tallized from isopropanol.
Stage B : l-N-methyl-3-acetyl-pyridine-0-2-propynyl-oxime iodide. 3 5.6 g of product obtained at stage A is dissolved in 60 cm of methanol and 8.6 g of methyl iodide is added. After 3 hours of reflux, and evaporating to dryness, the residue is taken up with a mixture of acetone and ether and filtered. 9.7 g is obtained, m.p. 150-151°C recrys tallized from isopropanol.
Stage C : l-methyl-3-acetyl-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride. 9.7 g of product obtained at stage B is dissolved in 100 cnr of methanol, and 2.35 g of boron and sodium hydride is added at 0°C.
After 1 hour at 0° C, then evaporating, the residue is taken up with water and extracted with ethyl acetate. The extracts are dried and evaporated to dryness. The residue is salified in ether with gaseous hydrochloric acid, and 2.7 g of the expected product is obtained, ra.p. 195-196°C, recrystallized from an isopropanol-ether mixture.
Analysis : Ο^Η^Ν,Ο, HC1.
Calculated : C % 57.76 H % 7.49 N % 12.25 Found : Example 8 : Stage A : l- -benzyl-3-propionyl-pyridine-oxime bromide.
A mixture of 17.8 g of 3-propionyl pyridine oxime [US Patent 3,004,979 (1961) and 18 cm3 of benzyl bromide is maintained at reflux 3 for 7 hours 30 minutes in 250 cm of ethyl acetate. After cooling and separating, 36.5 g of the expected product is obtained, m.p. 178-180°C, recrystallized from an ethanol-ether mixture.
Stage B : l-N-benzyl-3-propionyl-l,2,5 ,6-tetrahydropyridine-oxirae . 36.2 g of product obtained at stage A is dissolved in 250 cm of methanol, and the temperature is maintained at 10°C while 6.4 g of boron and sodium hydride is added in portions, with agitation for 3 hours. After evaporating under reduced pressure, the residue is taken up with water, and extracted with ethyl acetate. The extracts are dried and the solvent is evaporated. The residue is purified by chromatography on a column (eluent : ethyl acetate) and 21 g of the expected product is obtained, m.p. 111-112°C, recrystallized from ethyl acetate.
Stage C : l-N-benzyl-3-propionyl-l , 2 ,5 ,6-tetrahydropyridine-0-tri-raethyl-silyl-oxime . 3 6 g of the product obtained at stage B, 70 cm of benzene and 2.95 g of l,4-diazabicyclo[2.2.2.]octane are mixed together. 3.23 cmJ of trimethylsilyl chloride is added, and the whole is taken to reflux for 3 hours, then cooled. The insoluble matter is filtered off, the solvent is evaporated, and the residue is taken up with ether. The insoluble matter is filtered off and the remainder is evaporated to dryness. 7.5 g of the expected product is obtained, b.p. : 250°C under 0.06 mbar) .
Stage D : 3-propionyl-l , 2 ,5 ,6-tetrahydropyridine oxime and its hydrochloride. 16 g of the product obtained at stage C is dissolved in 150 cmJ of dichloroethane, and after cooling to 0°C, 16.2 g of alpha-chloro-ethyl chloroformate is added and the whole is maintained at reflux for 3 hours, then the solvent is evaporated off. The residue is taken up with ether, filtered, and concentrated to dryness. The residue Is taken up with 100 cm of methanol, and taken to reflux for 6 hours. The methanol is evaporated off, and the remainder is purified by passage through alumina (eluent : chloroform-methanol 7-3, then methanol alone). After evaporating to dryness, the residue is taken up with ethanol, filtered on charcoal and precipitated by adding he ane . The precipitate is filtered and, after purification in an ethanol-hexane mixture, 1.3 g of the expected product is obtained, m.p. 205-206°C. Using the process of example 2, the expected hydrochloride is obtained. Analysis : CgHj^ jO, HC1.
Calculated : C % 50.39 H % 7.93 N % 14.69 Found : 50.08 7.87 14.48 Example 9 : 3-propionyl-l ,2,5,6-tetrahydropyridine-O-methyl-oxime and its hydrochloride .
Stage A : l-N-benzyl-3-propionyl-l , 2 ,5 ,6-tetrahydropyridine-0-methyl-oxime . 6.11 g of the product obtained at stage B of example 8 is added 3 to a solution of 1.2 g of sodium in 80 cm of ethanol. 1.58 cm of methyl iodide is added, the whole is taken to reflux for 6 hours, then cooled and concentrated to dryness under reduced pressure. The residue is taken up with water and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and the residue is chromatographed (eluent : ethyl acetate - toluene 6-4), so obtaining 2.5 g of the expected product, (m.p. 170°C at 0.05 rabar).
Stage B : 3-propionyl-l , 2 ,5 ,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride. 3.5 g of product from stage A is dissolved in 50 cm of chloroethane , and at 0°C, 2.04 g of alpha-chloroethyl chloroforraate is added. After 3 hours at reflux, the solvent is evaporated off, the residue is taken up with ether, filtered and evaporated to dryness.
The residue is taken up with 30 cm of methanol and taken to reflux for 30 minutes, then evaporated to dryness. The residue is re-crystallized from a mixture of ethanol and ether, and 1.17 g of the expected product is obtained, m.p. 210-212°C.
Using the process of example 2, the expected hydrochloride is obtained. Analysis : CgH^NjO, HC1.
Calculated : C I 52.53 H % 8.26 N % 13.56 Found : 52.80 8.37 13.68 Example 10 : l-N-carboxyethyl 3-acetyl-l ,2,5,6-tetrahydropyridine- O-methyl-oxime . 1.8 g of the product obtained at example 3 is dissolved in 30 cm^ of benzene at 5°C, then 1.63 cm^ of triethylamine and 1.12 cm^ of ethyl chloro formate are added. After agitating for 30 minutes at ambient temperature, washing with water, evaporating to dryness and rectifying, 2.56 g of the expected product is obtained, (b.p. 155°C under 0.07 mbar).
Analysis Calculated : C % 58.39 H % 8.02 N 7, 12.38 Found : 58.41 7.88 12.29 Example 11 : l-N-benzyl-3-acetyl-l ,2,5,6-tetrahydropyridine-0-methy1-oxime . 2.5 g of product obtained at stage B of example 3 is dissolved in 40 cm 3 of anhydrous benzene, 2.7 cm3 of benzyl chloroformate is added; the mixture is taken to reflux for 1 hour, then cooled, washed with 10 cm of 5 % hydrochloric acid and dried, and the solvent is evaporated. The benzyl chloride formed is eliminated, and 2.3 g of the expected product is obtained, re-crystallized from cyclohexane. m.p. 90°C.
Analysis Calculated : C % 65.68 H % 6.61 N % 10.21 Found : 65.81 6,58 10.17 Example 12 : l-N-hydroxyl-3-acetyl-l ,2,5,6-tetrahydropyridine-O-methyl-oxime . 3.5 g of 3-acetyl-pyridine-0-methyl-oxime-N-oxide [J. Heterocyclic ■j Chera. 16_ 1459, (1979)] is dissolved in 50 cm of methanol and cooled to -10°C. 2.4 g of boron and sodium hydride is added, with agitation for 2 hours at ambient temperature followed by evaporation to dryness. The residue is taken up with water and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and purified by chromatography on silica gel, ( eluent : ethyl acetate). 2.85 g of the expected product is obtained, m.p. 94-96°C, after crystallizing from hexane .
Analysis Calculated : C % 56.45 H % 8.29 N % 16.46 Found : 56.28 8.32 16.31 Example 13 : l-methyl-3-cyclopropylcarbonyl-l ,2.5,6-tetrahydropyridine- -O-methyl-oxlme and its benzene sulphonate .
Stage A : 3-pyridyl-cyclopropylcetone-0-methyl-oxirae . 2.03 g of raethoxylamine hydrochloride is added to a solution of 3.5 g of 3-pyridyl-cyclopropylcetone in 50 cm of methanol. After heating to reflux for 4 hours, the solvent is evaporated off and the remainder is taken up with an aqueous solution of sodium bicarbonate. This is extracted with methylene chloride, the extracts are dried then evaporated, and 4.1 g of the expected product is obtained.
Stage B : l-methyl-3-cyclopropylcarbonyl-pyridine-0-methyl oxime iodide . 4 g of the product obtained at stage A is added to a solution of 5.3 g of methyl iodide in 50 cm of methanol, and taken to reflux for 3 hours. After evaporating to dryness, the residue is triturated in a mixture of ethanol and ether, then filtered, and 6.6 g of the expected product is obtained, recrystallized from isopropanol. m.p. 133°C, (decomposes) .
Analysis : C11H15IN20 Calculated : C % 41.52 H % 4.75 N % 8.80 Found : 41.17 4.66 8.76 Stage C : l-methyl-3-cyclopropylcarbonyl-l ,2 ,5 ,6-tetrahydropyridine- -O-methyl-oxime and its benzene sulphonate.
To a solution of 6.4 g of product obtained at stage B in 70 cm of methanol, 1.52 g of boron and sodium hydride is introduced at 0°C, and the mixture is allowed to react for 1 hour 30 minutes at ambient temperature, then evaporated. The residue is taken up with water, and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and purified by elution on alumina (eluent : toluene-ethyl acetate 6-4). After distilling at 160°C under 0.2 mm of mercury, 2.45 g of the base obtained is taken up in 100 cm of benzene with 1.994 g of benzene sulphonic acid, evaporated to dryness, triturated in a little ethyl acetate, filtered, and 1.7 g of the expected product is obtained, m.p. 76°C (decomposes).
Analysis : C11H1gN20, C6H5S03H Calculated : C % 57.93 H % 6.86 N % 7.95 Found : 58.04 6.94 7.87 Examples of pharmaceutical compositions a) Tablets have been prepared answering to the following formula ; - Product of example 3 200 mg - Excipient q.s. for a tablet finished at 300 mg (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc). b) Capsules have been prepared answering to the following formula : - Product of example 1 100 mg - Excipient q.s. for a capsule terminated at 300 mg (Detail of excipient : talc, magnesium stearate, aerosil). c) Tablets have been prepared answering to the following formula ; - Product of example 2 50 mg - Excipient q.s. for a tablet finished at 300 mg (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc). b) Tablets have been prepared answering to the following formula : - Product of example 12 50 mg - Excipient q.s. for a capsule terminated at 300 mg (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc).
Biological activity The products have been utilized in the hydrochloride form.
Acute toxicity The test was carried out on male mice (CD^ Charles Rivers) of 22 to 24 g, fasting for 16 hours. The products are administered by oral route at doses of 1000, 500, 250, 125, 62 and 31 mg/kg. The mortality is noted during the 7 days following the treatment. 1 Product of example LD5Q in mg/kg I 1 1 350 1 1 2 ! 350 1 1 3 125 1 1 12 1 175 1 1 Arecoline HBr 600 1 Test on ileum isolated from guinea-pig Pieces of the ileum are removed from guinea-pigs killed by de-capitation. The isolated ileum is placed in 10 cmJ of Tyrode's solution at 37°C and aerated with a mixture of oxygen (95 %) and carbon dioxide gas (5 %). The contractions due to the products are recorded by means of a detector connected to a polygraph. The products to be tested are added at concentrations between 1.10~½/1 and 1.10~½/1.
The products presenting a contraction effect are tested relative to atropine and hexamethonium to establish whether the activity is of the "muscarine" or "nicotine" type.
The agonist activity is expressed in pD2 (negative logarithm of the dose which produces 50 % of the maximum effect. 1 Example | pD2 1 1 1 1 5.25 1 1 2 1 4.85 1 1 3 1 7.50 1 1 12 1 5.39 1 1 Arecoline I 6.48 1 Diarrhoeic activity.
The test is carried out on male mice (CD^, Charles Rivers) weighing 25 to 30 g, fasting for 6 hours. The product dissolved at 5 % in methocel is administered by oral route, by means of an oesophagic probe .
The control animals receive only the excipient.
After treatment, the animals are put separately in cages the base of which is covered with blotting paper and are put under observation for 30, 60, 120 and 180 minutes.
The sheets of absorbent paper are changed after each observation. The consistency of the feces is evaluated according to the method of Randall and Baruth (Arch. Int. Pharmacodyn. 220, 94, 1976) and according to the following scale of values : 0 : firm consistency 1 : feces slightly soft with or without humid aureola. 2 : feces slightly soft with presence of a well defined humid circle. 3 : feces soft with presence of a large humid circle. 4 : feces without consistency with presence of a very large humid circle .
For each product, the dose was noted which caused a diarrhoea in 50 % of the animals according to the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. _5_7, 261, 1944).
Hypothermic activity The test is carried out on male mice (CD^ Charles Rivers), weighing 25 - 30 g, fasting for 6 hours.
The temperature of the body is noted by means of a thermocouple placed in the rectum to about 1.5 cm and connected to an electric temperature recorder.
The products are administered by oral route or sub-cutaneously and the temperatures are noted at the instant 0 and 30 minutes, 1 hour, 2 hours and 2-and-a-half hours after treatment.
The degree of hypothermia is evaluated as the difference between the treated animals and the controls, and the dose necessary to reduce the body temperature by 1°C. is determined. 1 Example Effective dose (-1°C) in mg/kg 1 per os 1 s .c . 1 1 1 9 1 11 1 1 2 12 1 25 1 1 3 0.87 1 0.91 1 1 12 0.77 1 0.72 1 1Arecollne 194 1 3 1 The duration of action of the products has been evaluated by using the dose which reduces the body temperature by 1° to 1.5°C.
VARIATION OF THE BODY TEMPERATURE 1 Product of 1 Dose 1 Admin. 1 Times in minutes after treatment I 1 example mg/kg route 1 o 30 60 120 180 1 1 1 10 p.o . 1 0 -0.7 -1.0 -0.2 +0.1 1 1 10 s .c 1 0 -0.6 -0.8 -0.2 1 o 1 1 2 1 20 p.o . 1 +0.1 -1.31 -1.31 -0.9 1 o 1 1 40 s .c 1 +0.1 -1.0 -1.4 -1.1 -0.8 1 1 3 1 p.o. 1 +0.1 -1.1 -1.0 -0.1 -o.i 1 1 s .c . 1 +0.1 -1.0 -0.8 +0.1 +0.1 1 1 12 p.o . 1 o -1.3 1 -1.1 0 o 1 1 s .c . 1 -o.i 1.4 -1.3 +0.1 o 1 1 1 Arecoline 200 p.o . 1 +0.1 -1.1 -1.0 -0.2 1 -o.i 1 1 HBr 1 3.5 s .c . 1 -o.i -1.5 -0.1 +0.2 +0.21
Claims (14)
1. The compounds of formula (I): R in which R represents a hydrogen atom, a hydroxyl radical, a saturated or unsaturated, linear, branched or cyclic alkyl radical containing up to 8 carbon atoms, or R represents an aralkyl radical containing up to 10 carbon atoms, Ri represents a saturated or unsaturated, linear, branched or cyclic alkyl radical containing up to 8 carbon atoms and R2 represents a hydrogen atom or a saturated or unsaturated, linear or branched alkyl radical containing up to 8 carbon atoms, a COalki radical or a (CH2)2N(alk2 >2 radical, alki and alk2 representing an alkyl radical containing up to 8 carbon atoms, as well as their addition salts with acids on condition that if R represents an alkyl radical, R2 does not represent a hydrogen atom.
2. The compounds of formula (I) as defined in claim 1 , in which Ri represents a linear alkyl radical ^ containing 1 to 4 carbon atoms as well as their addition salts with acids.
3. The compounds of formula (I) as defined in claim 2, in which Ri represents a methyl radical, as well as \S their addition salts with acids.
4. The compounds of formula (I) as defined in any one of claims 1 to 3 in which R represents a hydrogen ^ atom or a hydroxyl radical, as well as their addition salts with acids.
5. The compounds of formula (I) as defined in any one of claims 1 to 3 in which R represents a saturated^ or unsaturated, linear or branched alkyl radical containing 1 to 4 carbon atoms, as well as their addition salts with acids.
6. The compounds of formula (I) as defined in claim 5, in which R represents a methyl, ethyl, propyl or allyl radical, as well as their addition salts with acids.
7. The compounds of formula (I) as defined in any one of claims 1 to 6, in which R2 represents a w' hydrogen atom, as well as their addition salts with acids.
8. The compounds of formula (I) as defined in any one of claims 1 to 6, in which R2 represents an alkyl radical containing 1 to 4 carbon atoms and in particular a methyl radical.
9. The compounds of formula (I) as defined in claim 1 of which the names follow: - 1 -methyl-3-acetyl-1 ,2,5,6-tetrahydropyridine-0-methyl oxime and its hydrochloride. - 3-acetyl-1 ,2.5,6-tetrahydropyridine-0-methyl oxime and its hydrochloride, - 1 -N-hydroxyl-3-acetyl-1 ,2,5,6-tetrahydropyridine-O-methyl oxime. - 24 - 86157/2
10. Preparation process for compounds of formula (I) in which Ri and R2 have the meaning indicated previously and R has the meaning indicated previously with the exception of the hydroxyl value, characterized in that a compound of formula (II): in which Ri keeps the same meaning as previously, is subjected to the action of a compound of formula (III): NH2OR'2 (III) or of one of its salts, in which R'2 represents a hydrogen atom or a saturated or unsaturated, linear or branched alkyl radical containing up to 8 carbon atoms, in order to obtain the compound of formula (IV): which is subjected to the action of an alkyl halide of formula (V): R'-Haf (V) in which Hal represents a halogen atom and R' represents a saturated or unsaturated, linear, branched or cyclic alkyl radical containing up to 8 carbon atoms, optionally substituted by a free or esterified carboxy radical or R' represents an aralkyi radical containing up to 10 carbon atoms, in order to obtain the compound of formula (VI): which is subjected to the action of a hydrogenation agent, in order to obtain the compound of formula ( ): 86157/2 in which R", Ri and R'2 are defined as previously, which, if appropriate, either is salified, or is subjected, in the case where R'2 represents a hydrogen atom, to the action of a compound of formula: RVHa! in which Hal represents a halogen atom and RM2 represents a COalki radical or a -(CH2 )2 N(alk2)2 radical, alki and alk2 being defined as previously, in order to obtain the corresponding compound of formula (lB): in which Ri , R' and RH2 are defined as previously, which, if appropriate, is salified, or in the case where R' represents an aralkyi radical, the compound of formula (lA) or (lB) is subjected to the action of a cleavage agent, in order to obtain the compound of formula (lc): in which Ri and R2 are defined as previously, which if appropriate is salified.
11. Variant of the process according to claim 10, characterized in that a compound of formula (l'A): in which R" represents an aralkyi radical containing up to 10 carbon atoms and Ri keeps its previous meaning, is subjected to the action of a silylation agent, in order to obtain the compound of formula (VII): I R" in whicli alk:? represents an alkyl radical containing I to 0 carbon atoms,, which is subjected to the action ol a cleavage agent, in order to obtain the compound o( formula (lE): in which Ri is defined as previously, which if appropriate is salified.
12. Preparation process for compounds of formula (I) in which R( and R2 have the meaning indicated previously and R represents a hydroxyl radical, characlerized in that a compound of formula (VIII): is subjected to the action of a reducing agent in order to obtain a compound of formula (IF): OH in which Ri and R? are defined as previously, which if appropriate is salified,
13. Pharmaceutical compositions comprising an effective amount of the compounds of formula (1) as defined in any of one of claims 1 to 9, as well as their addition salts with pharmaceutically acceptable acids.
14. The pharmaceutical compositions containing as active ingredient at least one medicament defined in Cla,m 1 3 COHEN ZEDE * ΚΛΡΛΙΌΚΊ P. O. Box 33116 , Tel-Λνΐν A ttort js lor Applicant
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20260/87A IT1203971B (en) | 1987-04-24 | 1987-04-24 | 1,2,5,6-TETRAHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION PROCEDURE AND THEIR APPLICATION AS MEDICATIONS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL86157A0 IL86157A0 (en) | 1988-11-15 |
| IL86157A true IL86157A (en) | 1994-04-12 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL8615788A IL86157A (en) | 1987-04-24 | 1988-04-22 | Derivatives of 1,2,5,6-tetrahydropyridine, process for preparing them and pharmaceutical compositions containing them |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0288394B1 (en) |
| JP (1) | JP2727192B2 (en) |
| KR (1) | KR960012365B1 (en) |
| AT (1) | ATE80387T1 (en) |
| AU (1) | AU614283B2 (en) |
| CA (1) | CA1340986C (en) |
| DE (1) | DE3874396T2 (en) |
| DK (1) | DK167758B1 (en) |
| ES (1) | ES2043863T3 (en) |
| FI (1) | FI93211C (en) |
| GR (1) | GR3005647T3 (en) |
| HU (1) | HU199795B (en) |
| IE (1) | IE63172B1 (en) |
| IL (1) | IL86157A (en) |
| IT (1) | IT1203971B (en) |
| MX (1) | MX11201A (en) |
| NZ (1) | NZ224357A (en) |
| OA (1) | OA08835A (en) |
| PH (1) | PH25574A (en) |
| PT (1) | PT87290B (en) |
| SU (1) | SU1678203A3 (en) |
| ZA (1) | ZA882595B (en) |
Families Citing this family (14)
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|---|---|---|---|---|
| IL81610A (en) * | 1986-02-27 | 1990-12-23 | Roussel Uclaf | Derivatives of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime,their preparation and pharmaceutical compositions containing them |
| US4786648A (en) * | 1986-12-08 | 1988-11-22 | Warner-Lambert Company | O-substituted tetrahydropyridine oxime cholinergic agents |
| IT1222526B (en) * | 1987-08-21 | 1990-09-05 | Roussel Maestretti Spa | OXYME DERIVATIVES OF 1,2,5,6-TETRAIDROPIRIDIN-3-CARBOXALDEHYDE, THEIR PREPARATION PROCEDURE AND THEIR USE AS MEDICINAL SUBSTANCES |
| US5110828A (en) * | 1988-04-15 | 1992-05-05 | Beecham Group P.L.C. | Azabicyclo oxime derivatives |
| US5278170A (en) * | 1989-04-13 | 1994-01-11 | Beecham Group P.L.C. | Azabicylo oxime compounds |
| DK0392803T3 (en) * | 1989-04-13 | 2004-10-18 | Beecham Group Plc | Hitherto unknown compounds |
| MX9100779A (en) * | 1990-08-24 | 1992-04-01 | Beecham Group Plc | AZABICICLIC COMPOUNDS AND PROCEDURE FOR THE PREPARATION |
| GB9019095D0 (en) * | 1990-09-01 | 1990-10-17 | Beecham Group Plc | Novel compounds |
| EP0552213A1 (en) * | 1990-10-12 | 1993-07-28 | Beecham Group Plc | 1,2,5,6-tetrahydropyridine oxime derivatives |
| CA2080536A1 (en) * | 1991-10-17 | 1993-04-18 | John S. Ward | Nicotinic activity of a series of arecolones and isoarecolones |
| WO1993011767A1 (en) * | 1991-12-18 | 1993-06-24 | Warner-Lambert Company | Transdermal delivery of (e)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxaldehyde-o-methyloxine hcl and related compounds in the treatment of cognitive disorders and for analgesia |
| US5362860A (en) * | 1993-02-01 | 1994-11-08 | Warner-Lambert Company | Neutral stabilization complex for CI-979 HCl, a cognition activator |
| US5424301A (en) * | 1993-02-01 | 1995-06-13 | Warner-Lambert Company | Starch stabilized o-substituted tetrahydropyridine oxime cholinergic agents |
| US6250886B1 (en) | 1999-09-03 | 2001-06-26 | Chittom International, Inc. | Axial flow fan and fan blade |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1258847A (en) * | 1960-02-12 | 1961-04-21 | Ciba Geigy | Process for the preparation of novel pyridine derivatives, including 1-methyl-3 or 4-acetyl-1, 2, 5, 6-tetrahydropyridine oxime |
| IL81610A (en) * | 1986-02-27 | 1990-12-23 | Roussel Uclaf | Derivatives of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime,their preparation and pharmaceutical compositions containing them |
| JPH0641332B2 (en) * | 1986-09-17 | 1994-06-01 | 株式会社共同精機工作所 | Sheet feeding device for cutting machine |
| US4786648A (en) * | 1986-12-08 | 1988-11-22 | Warner-Lambert Company | O-substituted tetrahydropyridine oxime cholinergic agents |
| US4710508A (en) * | 1986-12-08 | 1987-12-01 | Warner-Lambert Company | O-substituted tetrahydropyridine oxime cholinergic agents |
| US4798841A (en) * | 1987-03-31 | 1989-01-17 | Warner-Lambert Company | Tetrahydropyridine oxime cholinergic agents and method of treatment |
-
1987
- 1987-04-24 IT IT20260/87A patent/IT1203971B/en active
-
1988
- 1988-04-13 ZA ZA882595A patent/ZA882595B/en unknown
- 1988-04-21 PT PT87290A patent/PT87290B/en not_active IP Right Cessation
- 1988-04-21 DK DK216388A patent/DK167758B1/en not_active IP Right Cessation
- 1988-04-21 MX MX1120188A patent/MX11201A/en unknown
- 1988-04-22 FI FI881892A patent/FI93211C/en not_active IP Right Cessation
- 1988-04-22 JP JP63098476A patent/JP2727192B2/en not_active Expired - Fee Related
- 1988-04-22 PH PH36830A patent/PH25574A/en unknown
- 1988-04-22 HU HU882057A patent/HU199795B/en not_active IP Right Cessation
- 1988-04-22 OA OA59335A patent/OA08835A/en unknown
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- 1988-04-22 IL IL8615788A patent/IL86157A/en not_active IP Right Cessation
- 1988-04-22 AT AT88400996T patent/ATE80387T1/en not_active IP Right Cessation
- 1988-04-22 EP EP88400996A patent/EP0288394B1/en not_active Expired - Lifetime
- 1988-04-22 AU AU15111/88A patent/AU614283B2/en not_active Ceased
- 1988-04-22 DE DE8888400996T patent/DE3874396T2/en not_active Expired - Fee Related
- 1988-04-22 SU SU884355793A patent/SU1678203A3/en active
- 1988-04-22 CA CA000564817A patent/CA1340986C/en not_active Expired - Fee Related
- 1988-04-22 NZ NZ224357A patent/NZ224357A/en unknown
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1992
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