EP0563036A1 - 4-azatricyclo 2.2.1.0?2,6 ]heptanes et compositions pharmaceutiques - Google Patents
4-azatricyclo 2.2.1.0?2,6 ]heptanes et compositions pharmaceutiquesInfo
- Publication number
- EP0563036A1 EP0563036A1 EP91901866A EP91901866A EP0563036A1 EP 0563036 A1 EP0563036 A1 EP 0563036A1 EP 91901866 A EP91901866 A EP 91901866A EP 91901866 A EP91901866 A EP 91901866A EP 0563036 A1 EP0563036 A1 EP 0563036A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- alkyl
- azatricyclo
- hydrogen
- 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.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 8
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 82
- -1 (C1-3 alkyl) amide Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 9
- 229940002612 prodrug Drugs 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- LMLFWALLPVKQBH-UHFFFAOYSA-N 127745-59-9 Chemical compound C1C2C3(C(=O)OC)C2CN1C3 LMLFWALLPVKQBH-UHFFFAOYSA-N 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 238000011200 topical administration Methods 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical group C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims description 3
- PIQVDOLPTUNSAV-UHFFFAOYSA-N 5-(4-azatricyclo[2.2.1.02,6]heptan-1-yl)-1,3-oxazole Chemical compound C1C2C3CN1CC23C1=CN=CO1 PIQVDOLPTUNSAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000005336 allyloxy group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 2
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical group C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000010561 standard procedure Methods 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 11
- 150000001408 amides Chemical class 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 3
- GQFQOQFGFADCCY-UHFFFAOYSA-N 4-azatricyclo[2.2.1.02,6]heptane Chemical class C12CN3CC1C2C3 GQFQOQFGFADCCY-UHFFFAOYSA-N 0.000 abstract description 2
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000003826 tablet Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 208000024827 Alzheimer disease Diseases 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 150000001733 carboxylic acid esters Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000812 cholinergic antagonist Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 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
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 206010020651 Hyperkinesia Diseases 0.000 description 2
- 208000000269 Hyperkinesis Diseases 0.000 description 2
- 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 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 2
- 208000000323 Tourette Syndrome Diseases 0.000 description 2
- 208000016620 Tourette disease Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000004406 elevated intraocular pressure Effects 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000000472 muscarinic agonist Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- VZPRMKOCTSUHCR-UHFFFAOYSA-N 1-azabicyclo[2.2.1]heptan-3-one Chemical compound C1CC2C(=O)CN1C2 VZPRMKOCTSUHCR-UHFFFAOYSA-N 0.000 description 1
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- WMIKGIIJWWWYPK-UHFFFAOYSA-N 3-hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile Chemical compound C1CC2C(O)(C#N)CN1C2 WMIKGIIJWWWYPK-UHFFFAOYSA-N 0.000 description 1
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- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000016776 visual perception Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- 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
-
- 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
Definitions
- the present invention relates to a class of substituted azatricyclic compounds which stimulate central muscarinic acetylcholine receptors and therefore are useful in the treatment of neurological and mental illnesses whose clinical manifestations are due to cholinergic deficiency.
- diseases include presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette Syndrome.
- Alzheimer's disease the most common dementing illness, is a slowly progressive neurological disorder characterised by marked deficirs in cognitive functions including memory, attention, language and visual perception capabilities .
- the compounds may also lower intraocular pressure and may therefore be used against glaucoma.
- EPA- 239309 discloses a class of oxadiaozle compounds having a first substituent of low lipophilicity, and an azacyclic or azabicyclic second substituent, which are useful in the treatment of neurodegenerative disorders.
- Published European Patent Application No. EPA-323,864 discloses a class of oxadiazoles having a first substituent selected from certain hydrocarbon groups and an azacyclic or azabicyclic substituent which also stimulate cholinergic transmission. There is no disclosure of azatricyclic structures in these specifications.
- the compounds of the present invention are 4-azatricyclo[2.2.1.0 2,6 ]heptanes, or salts or prodrugs thereof, substituted on one of the ring carbon atoms thereof with an amide, ester, oxime ether, or an oxa- or thia-diazole or an oxa- or thia-zole ring system which may itself be substituted on its other ring carbon atoms with a substituent of low lipophilicity or a hydrocarbon substituent.
- R 1 is -COOR 3 , -CONR 3 R 4 , -C(NR 5 )R 6 ;
- R 3 and R 4 are each independently C 1-6 alkyl or taken together with the nitrogen to which they are attached may form a ring having up to 6 carbon atoms or
- R 4 may also be hydrogen
- R 5 is OA where A is C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, OCOAi where A 1 is hydrogen or A, or NHA 2 or
- NA 3 A 4 where A 2 , A 3 and A 4 are each independently C 1-2 alkyl;
- R 6 is hydrogen or C 1-4 alkyl provided that when R 5 is
- R 6 is C 1-4 alkyl
- R 1 is a heterocyclic ring system selected from
- one of X,Y and Z represents an oxygen or sulphur atom and the remainder represent nitrogen atoms, or one of X and Y represents a nitrogen atom, the other of X and Y represents a carbon atom and Z represents an oxygen or sulphur atom, or one of X and Y represents an oxygen or sulphur atom, the other of X and Y represents a nitrogen atom and Z represents a carbon atom; and
- R 2 represents hydrogen, halo, -CF 3 , -OR 7 ,
- R 7 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and R 8 is hydrogen or C 1-6 alkyl.
- alkyl groups may be straight, branched or cyclic.
- R 1 examples include (C 1-6 alkoxy)- carbonyl such as methoxycarbonyl, -CONR 3 R 4 such as when R 3 and R 4 taken together with the nitrogen atom form a ring such as a pyrrolidine ring or a (C ⁇ _ 3 alkyl) amide or di(C 1-3 alkyl) amide such as n- or i-propylamide or N,N-diethylamide and -C(NR 5 )R 6 wherein, in R 5 , A and A 1 are selected from methyl, ethyl, allyl and propargyl, and A 2 , A 3 and A 4 are methyl.
- R 5 examples include methoxy, ethoxy, allyloxy, propargyloxy, acetoxy and dimethylamino.
- R 6 is preferably hydrogen or methyl, and when R 5 is -OCOA 1 or -NHA 2 , then R 6 is preferably methyl.
- Suitable ring systems for the group R 1 include the following: 1,2,4-oxadiazole, 1,2,4- thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3- oxazole, 1,3-thiazole, isoxazole and isothiazole,
- the group R 2 is a hydrocarbon substituent, it may be C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl or aralkyl.
- the alkyl, alkenyl or alkynyl groups may be straight, branched or cyclic groups.
- the alkyl group comprises from 1 to 6 carbon atoms.
- hydrocarbon group(s) may carry one or more substituents.
- Suitable substituent groups include halo, -OR 7 , -CF 3 and
- Particular values of the group R 2 are hydrogen, hydroxy, chloro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, amino, dimethylamino, methoxy, ethoxy, isopropoxy, n-butoxy, allyloxy and propargyloxy.
- Preferred values are n- or iso-propyl.
- a suitable subgroup of compounds of formula (I) are those wherein R 1 is (C 1-6 alkoxy) carbonyl such as methoxycarbonyl, -CONR 3 R 4 such as pyrrolidine carboxamide or a heterocyclic ring such as 1,2,4-oxadiazole, 1,3-oxazole or isoxazole (and their corresponding thiaanalogues); and, when R 1 is a heterocyclic ring, R 2 is hydrogen, C 1-6 alkyl such as methyl or -NR 7 R 8 such as -NH 2 .
- One group of prodrugs of compounds of this invention have a substituent on the heterocyclic ring R 1 which is hydrolysable in vivo to an amino group.
- Groups which are hydrolysable in vivo to an amino group on the compounds of this invention may be readily ascertained by administering the compound to a human or animal and detecting, by conventional analytical
- the presence of the corresponding compound having an amino substituent in the urine of a human or animal examples include, for example, amido and urethane substituents, in particular a group of formula -NH.Q, wherein Q represents CHO, COR or CO 2 R, and R represents an optionally substituted hydrocarbon group.
- the hydrocarbon group R includes groups having up to 20 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms.
- Suitable groups R include C 1-9 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl (C 1-6 ) alkyl, aryl, and aryl (C 1-6 ) alkyl.
- the alkyl group R may be straight or branched chain and may contain, for example, up to 12 carbon atoms, suitably from 1 to 6 carbon atoms. In particular the group may be substituted methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, n- or iso- heptyl, or n- or iso-octyl.
- Suitable cycloalkyl groups include cyclopentyl and cyclohexyl.
- the aryl group R includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, substitu
- salts of the novel compounds are also included within the scope of the present invention. It will be appreciated that salts of the compounds for use in medicine will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful for the preparation of the compounds of the invention or their non-toxic salts.
- Acid addition salts may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- salts thereof preferably non- toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
- Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Such quaternary ammonium derivatives penetrate poorly into the central nervous system and are therefore useful as
- peripherally selective muscarinic agents useful for example as antispasmodic agents, agents to reduce gastric acid secretion, agents to block the muscarinic actions of acetylcholinesterase inhibitors in the treatment of
- the method of treatment of this invention includes a method of treating Alzheimer's disease, senile dementia of the Alzheimer type, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania or Tourette syndrome by the administration to a patient in need of such treatment of an effective amount of one or more of the novel compounds.
- This invention therefore also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier
- a peripherally acting cholinergic antagonist or anti-muscarinic agent.
- the compounds of the invention may advantageously be administered together with a peripheral cholinergic
- N-methylscopolamine such as N-methylatropine, propantheline, methantheline or glycopyrrolate.
- the compounds of the invention can be administered orally, parenterally or rectally at a daily dose of about 0.01 to 10 mg/kg of body weight, preferably about 0.1 to 1 mg/kg, and may be administered on a regimen of 1-4 times a day.
- a cholinergic antagonist When a cholinergic antagonist is administered, it is incorporated at its conventional dose.
- the pharmaceutical formulations of this invention preferably are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or suppositories for oral, parenteral or rectal administration.
- a pharmaceutical carrier e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose,
- sorbitol talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills or capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups and flavoured
- Suitable dispersing or suspending agents for aqueous suspension include
- methylcellulose methylcellulose, polyvinyl-pyrrolidone and gelatin.
- the active compound When administered for the treatment of elevated intraocular pressure or glaucoma, the active compound is preferably administered topically to the eye, although systemic treatment is, as indicated, also possible.
- the dose administered can be from as little as 0.1 to 25 mg or more per day, singly, or preferably on a 2 to 4 dose per day regimen althougn a single dose per day is
- the active compound or an ophthalmologically acceptable salt thereof such as the hydrochloride salt is formulated into an ophthalmic preparation.
- an ophthalmic preparation from 0.0005% to 15% by weight can be employed.
- the objective is to administer a dose of from 0.1 to 1.0 mg per eye per day to the patient, with treatment continuing so long as the condition persists.
- an ophthalmic solution insert, ointment or suspension for topical delivery, or a tablet, intramuscular or intravenous composition for systemic delivery, the active medicament or an equivalent amount of a salt thereof is employed, the remainder being carrier, excipients, preservatives and the like as are customarily used in such compositions.
- the active drugs of this invention for use in treating glaucoma are suitably administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye such as a suspension, ointment, or as a solid insert.
- a preferred composition is eye drops.
- Formulations of these compounds may contain from 0.0005 to 15% and especially 0.05% to 2% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing or controlling elevated intraocular pressure.
- As a unit dosage from between 0.001 to 10.0 mg, preferably 0.005 to 2.0 mg, and especially 0.1 to 1.0 mg of the compound is generically applied to the human eye, generally on a daily basis in single or divided doses so long as the condition being treated exists.
- This invention therefore further provides a pharmaceutical formulation adapted for topical
- composition comprising a compound of formula (I) and a carrier suitable for topical administration.
- dosage values are believed accurate for human patients and are based on the known and presently understood pharmacology of the compounds, and the action of other similar entities in the human eye. As with all medications, dosage
- pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic
- the pharmaceutical preparation may also contain non-toxic auxiliary substances such as
- emulsifying, preserving, wetting agents, bodying agents and the like as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercurie salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates,
- gluconate buffers and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol,
- suitable ophthalmic vehicles can be used as carrier media for the present purpose including
- the pharmaceutical formulation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact, or a bio- erodible insert that is soluble in lacrimal fluids or otherwise disintegrates.
- R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined
- R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined in formula (I).
- R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined in formula (I).
- cyclisation may be undertaken with diethylaminosulphur trifluoride by the method of A.M. MacLeod, R. Herbert and K. Hoogsteen, J. Chem. Soc. Chem. Commun.. (1990), 100.
- the cyclisation may also be achieved using other reagents which generate a carbonium ion in the compound of formula (III) such as SOCI 2 or a strong acid eg trifluoroacetic acid.
- the compounds of formula (I) wherein R 1 is -C(NR 5 )R 6 may be prepared by reacting a compound of formula (IV)
- R 6 is as defined in formula (I) with a compound of formula R 5' -NH 2 (V) wherein R 5' is R 5 as defined in formula (I) or hydroxy and thereafter, if necessary, converting R 5' (when OH) to R 5 .
- the reaction between the compounds (IV) and (V) is preferably carried out in a hydroxylic solvent such as an alcohol such as methanol or ethanol either at ambient or elevated temperature.
- a hydroxylic solvent such as an alcohol such as methanol or ethanol either at ambient or elevated temperature.
- R in formula (I) is OA, NHA 1 , or NA 1 A 2
- R 5' is preferably R 5 .
- R 5 in formula (I) is OCOA 1
- R 5' is preferably hydroxy.
- R 5' (when OH) to R 5 may take place by conventional acylation methods, for example by treatment with a suitable acylating agent such as an acyl halide eg. acetyl chloride.
- a suitable acylating agent such as an acyl halide eg. acetyl chloride.
- the compounds of formula (IV) may be prepared from the tricyclic nitrile of formula (VI):
- the compounds of formula (IV) may be prepared from the corresponding tricyclic chlorocarbonyl compound by reaction with N,0-dimethylhydroxylamine and an alkyl lithium.
- the nitrile (VI) may be used as an intermediate and may be converted to an ester -CO 2 R 3 or amide -CONR 3 R 4 by conventional techniques.
- a compound of formula (VII) may be prepared by the method of C.J. Swain, CO. Kneen and R. Baker,
- a compound of formula (III) wherein R 1 is an oxazole or thiazole may be prepared by reaction of 1-azabicyclo-[2.2.1]heptan-3-one with a metal derivative of an oxazole or thiazole of formula (VIII) wherein L represents oxygen or sulphur, R 2 is as defined in relation to formula (I) and M represents a metal atom, for example and alkali metal such as lithium.
- the lithium derivative may be prepared, for instance, by reacting the corresponding halo-substituted such as chloro-substituted oxazole or thiazole with n-butyl lithium.
- R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
- R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
- R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
- an oxazole may be prepared from a carboxylic ester by reaction with the anion of an
- Suitable reagents for generating the anion include lithium hexamethyldisilazide or lithium diisopropylamide in a solvent such as tetrahydrofuran or dimethoxyethane.
- An isoxazole may be prepared by reacting a carboxylic ester with the anion of an oxime CH 3 C(NOH)R 2 followed by heating in an acid such as sulphuric acid.
- the oxime anion may be formed using a strong base such as butyl lithium in a solvent such as tetrahydrofuran.
- An oxadiazole may be prepared by reacting a carboxylic ester with an amide oxime R 2 (NOH)NH2 or a salt thereof in a solvent such as tetrahydrofuran, dimethyl formamide or a lower alkanol such as methanol, ethanol or propanol.
- a solvent such as tetrahydrofuran, dimethyl formamide or a lower alkanol such as methanol, ethanol or propanol.
- one substituent R 2 can be converted to another.
- an amino group may be converted to chloro via the intermediacy of diazonium, -N 2 -
- a chloro substituent may be converted to methoxy by reaction with a nucleophile such as methoxide
- alkoxycarbonyl groups may be converted, via carboxy, to an amino substituent, -NH 2
- methoxy may be converted to hydroxy by treatment with concentrated hydrobromic acid.
- any sensitive groups in the compounds it may be necessary and/or desirable to protect any sensitive groups in the compounds.
- the reactants employed include amino, carboxy, keto, hydroxy or thiol groups, these may be protected in conventional manner.
- protecting groups for hydroxy groups include silyl groups such as trimethylsilyl or t-butyldimethylsilyl, and
- etherifying groups such as tetrahydropyranyl; and for amino groups include benzyloxycarbonyl and t-butoxycarbonyl.
- Keto groups may be protected in the form of a ketal.
- Carboxy groups are preferably protected in a reduced form such as in the form of their corresponding protected alcohols, which may be subsequently oxidised to give the desired carboxy group.
- Thiol groups may be protected by disulphide formation, either with the thiol itself or with another thiol to form a mixed disulphide.
- the protecting groups may be removed at any convenient stage in the synthesis of the desired compound according to conventional techniques.
- Each of the compounds of the Examples demonstrates an affinity for the muscarinic receptor, having an IC 50 (concentration required to displace 50% of specific [ 3 H]-N-methylscopolamine binding from rat cortical membrane preparations)
- Acetamide oxime (140mg) was stirred in tetrahydrofuran (10ml) with NaH (55% in oil, 80mg) and type 4A molecular sieves (0.5g) for 30 minutes.
- l-Methoxycarbonyl-4- azatricyclo[2.2.1.0 2,6 ]heptane (183mg) in tetrahydrofuran (10ml) was added and the mixture heated under reflux for 1.5 hours. The reaction was allowed to cool and filtered then evaporated under reduced pressure. The residue was partitioned between aqueous K 2 CO 3 and CH 2 Cl 2 and the organic phase separated and dried with Na 2 SO 4 . The solution was concentrated and the residue crystallised from Et 2 O/hexane to give the title compound (105mg) as white crystals, mp 75°C.
- Acetoneoxime (210mg) was dissolved in tetrahydrofuran (5ml) and cooled to 0°C under N 2 n-Butyllithium (3.6ml) was added and the solution stirred at 0°C for 1h.
- 1-Methoxycarbonyl-4-azatricyclo[2.2.1.0 2,6 ]heptane (350mg) in tetrahydrofuran (4ml) was then added dropwise and the reaction mixture stirred at 0°C for lh. The solution was then warmed to room temperature and stirred for a further 16h. The reaction mixture was then poured into a rapidly stirred solution of 1.2g cone. H 2 SO 4 diluted to 10ml with 4:1 tetrahydrofuran-water.
- Compound (I) 1.0 2.0 25.0 Microcrystalline cellulose 49.25 48.75 37.25
- Compound (I) lactose, and a portion of the corn starch are mixed together and granulated to a 10% corn starch paste.
- the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
- the resulting granulation is then compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of compound (I) per tablet.
- the formulation is sterilised by autoclaving.
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- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
On décrit des 4-azatricyclo(2.2.1.02,6)heptanes, (I) ou sels ou précurseurs de médicaments de ceux-ci, où R' est un amide, un ester, un éther d'oxime ou un hétérocycle à 5 chaînons et avec un substituant faiblement lipophile utilisables pour le traitement de troubles neurologiques et du glaucome. On peut préparer lesdits heptanes en faisant appel à des procédés de synthèses publiées ou analogues ou bien, en vue de leur administration, on peut les formuler dans des compositions pharmaceutiques traditionnelles.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/GB1990/002016 WO1992011261A1 (fr) | 1990-12-21 | 1990-12-21 | 4-azatricyclo[2.2.1.02,6]heptanes et compositions pharmaceutiques |
Publications (1)
Publication Number | Publication Date |
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EP0563036A1 true EP0563036A1 (fr) | 1993-10-06 |
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EP91901866A Withdrawn EP0563036A1 (fr) | 1990-12-21 | 1990-12-21 | 4-azatricyclo 2.2.1.0?2,6 ]heptanes et compositions pharmaceutiques |
Country Status (3)
Country | Link |
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EP (1) | EP0563036A1 (fr) |
JP (1) | JPH06502616A (fr) |
WO (1) | WO1992011261A1 (fr) |
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US5914338A (en) * | 1996-04-02 | 1999-06-22 | Novo Nordisk | Heterocyclic compounds and their preparation and use |
CA2340946A1 (fr) | 1998-08-18 | 2000-03-02 | Anna Toy-Palmer | Agonistes et antagonistes muscariniques |
WO2012033956A1 (fr) * | 2010-09-08 | 2012-03-15 | Mithridion, Inc. | Composés et compositions améliorant la cognition, méthodes de préparation et méthodes de traitement |
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CA2000041A1 (fr) * | 1988-10-13 | 1990-04-13 | Barry S. Orlek | Composes |
DK0392803T3 (da) * | 1989-04-13 | 2004-10-18 | Beecham Group Plc | Hidtil ukendte forbindelser |
-
1990
- 1990-12-21 EP EP91901866A patent/EP0563036A1/fr not_active Withdrawn
- 1990-12-21 JP JP3500080A patent/JPH06502616A/ja active Pending
- 1990-12-21 WO PCT/GB1990/002016 patent/WO1992011261A1/fr not_active Application Discontinuation
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