CA2128536A1 - Composes azabicyclo comme antagonistes des canaux a calcium - Google Patents

Composes azabicyclo comme antagonistes des canaux a calcium

Info

Publication number: CA2128536A1
Authority: CA; Canada
Prior art keywords: formula; compound; azabicyclo; heptane; compounds
Prior art date: 1992-01-28
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA002128536A

Other languages

English (en)

Inventor

Barry S. Orlek

Thomas H. Brown

David G. Cooper

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

SmithKline Beecham Ltd

Original Assignee

Individual

Priority date (The priority date 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 date listed.)

1992-01-28

Filing date

1993-01-27

Publication date

1993-08-05

1993-01-27 Application filed by Individual filed Critical Individual

1993-08-05 Publication of CA2128536A1 publication Critical patent/CA2128536A1/fr

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 165
229940127291 Calcium channel antagonist Drugs 0.000 title abstract description 4
238000000034 method Methods 0.000 claims abstract description 27
150000003839 salts Chemical class 0.000 claims abstract description 25
229910052760 oxygen Inorganic materials 0.000 claims abstract description 17
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 12
239000001301 oxygen Substances 0.000 claims abstract description 12
230000008569 process Effects 0.000 claims abstract description 11
MJYFVDNMTKLGTH-UHFFFAOYSA-N 4-bromo-6-(3,4-dichlorophenyl)sulfanyl-1-[[4-(dimethylcarbamoyl)phenyl]methyl]indole-2-carboxylic acid Chemical compound BrC1=C2C=C(N(C2=CC(=C1)SC1=CC(=C(C=C1)Cl)Cl)CC1=CC=C(C=C1)C(N(C)C)=O)C(=O)O MJYFVDNMTKLGTH-UHFFFAOYSA-N 0.000 claims abstract description 8
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
125000003118 aryl group Chemical group 0.000 claims abstract description 7
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
239000001257 hydrogen Substances 0.000 claims abstract description 7
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
239000005864 Sulphur Substances 0.000 claims abstract description 5
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
238000006243 chemical reaction Methods 0.000 claims description 41
-1 4-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[2.2.1]heptane Chemical compound 0.000 claims description 28
238000002360 preparation method Methods 0.000 claims description 22
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
125000000217 alkyl group Chemical group 0.000 claims description 12
230000009467 reduction Effects 0.000 claims description 9
125000004429 atom Chemical group 0.000 claims description 5
201000010099 disease Diseases 0.000 claims description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
210000004958 brain cell Anatomy 0.000 claims description 4
239000011575 calcium Substances 0.000 claims description 4
229910052791 calcium Inorganic materials 0.000 claims description 4
239000003153 chemical reaction reagent Substances 0.000 claims description 4
238000002560 therapeutic procedure Methods 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
238000009825 accumulation Methods 0.000 claims description 2
229910052783 alkali metal Inorganic materials 0.000 claims description 2
150000001340 alkali metals Chemical group 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000012038 nucleophile Substances 0.000 claims description 2
FFZDXNYYKHLGHB-UHFFFAOYSA-N 4-[2-(3,4-dichlorophenoxy)ethyl]-1-azabicyclo[2.2.1]heptane Chemical compound C1=C(Cl)C(Cl)=CC=C1OCCC1(C2)CCN2CC1 FFZDXNYYKHLGHB-UHFFFAOYSA-N 0.000 claims 1
RAQJERMBICMKOW-UHFFFAOYSA-N 4-[3-(4-phenylmethoxyphenyl)propoxy]-1-azabicyclo[2.2.1]heptane Chemical compound C1CN(C2)CCC12OCCCC(C=C1)=CC=C1OCC1=CC=CC=C1 RAQJERMBICMKOW-UHFFFAOYSA-N 0.000 claims 1
OABNZHLOMJYDKI-UHFFFAOYSA-N 5-(2-dibenzofuran-2-yloxyethyl)-1-azabicyclo[3.2.1]octane Chemical compound C1=CC=C2C3=CC(OCCC45CN(CC4)CCC5)=CC=C3OC2=C1 OABNZHLOMJYDKI-UHFFFAOYSA-N 0.000 claims 1
239000003814 drug Substances 0.000 abstract description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 37
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 33
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
239000000243 solution Substances 0.000 description 28
239000000203 mixture Substances 0.000 description 25
239000007787 solid Substances 0.000 description 24
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
KGZLFTWMCMEEJR-UHFFFAOYSA-N heptane;hydrochloride Chemical compound Cl.CCCCCCC KGZLFTWMCMEEJR-UHFFFAOYSA-N 0.000 description 17
239000003921 oil Substances 0.000 description 16
235000019198 oils Nutrition 0.000 description 16
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
229910052938 sodium sulfate Inorganic materials 0.000 description 15
235000011152 sodium sulphate Nutrition 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 9
150000002148 esters Chemical class 0.000 description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 9
239000000284 extract Substances 0.000 description 9
150000002500 ions Chemical class 0.000 description 9
239000012280 lithium aluminium hydride Substances 0.000 description 9
229910052757 nitrogen Inorganic materials 0.000 description 9
229910000027 potassium carbonate Inorganic materials 0.000 description 9
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
239000006185 dispersion Substances 0.000 description 8
235000011181 potassium carbonates Nutrition 0.000 description 8
229910000104 sodium hydride Inorganic materials 0.000 description 8
239000012312 sodium hydride Substances 0.000 description 8
239000000725 suspension Substances 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
150000001299 aldehydes Chemical class 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
210000004027 cell Anatomy 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
239000002253 acid Substances 0.000 description 5
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
229910000041 hydrogen chloride Inorganic materials 0.000 description 5
239000002480 mineral oil Substances 0.000 description 5
235000010446 mineral oil Nutrition 0.000 description 5
238000000746 purification Methods 0.000 description 5
239000000377 silicon dioxide Substances 0.000 description 5
239000002904 solvent Substances 0.000 description 5
239000003826 tablet Substances 0.000 description 5
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
239000002202 Polyethylene glycol Substances 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
229910052799 carbon Inorganic materials 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
239000012043 crude product Substances 0.000 description 4
125000004122 cyclic group Chemical group 0.000 description 4
USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
229940079593 drug Drugs 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
230000007935 neutral effect Effects 0.000 description 4
229920001223 polyethylene glycol Polymers 0.000 description 4
238000011176 pooling Methods 0.000 description 4
239000000047 product Substances 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
239000011734 sodium Substances 0.000 description 4
SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 3
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
229960000583 acetic acid Drugs 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
239000002585 base Substances 0.000 description 3
125000002619 bicyclic group Chemical group 0.000 description 3
239000002775 capsule Substances 0.000 description 3
VVBOMPMTWAYUQB-UHFFFAOYSA-N ethoxyethane;methanol;propan-2-one Chemical compound OC.CC(C)=O.CCOCC VVBOMPMTWAYUQB-UHFFFAOYSA-N 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
238000009472 formulation Methods 0.000 description 3
239000012362 glacial acetic acid Substances 0.000 description 3
229910052736 halogen Inorganic materials 0.000 description 3
125000005843 halogen group Chemical group 0.000 description 3
150000002367 halogens Chemical class 0.000 description 3
238000002955 isolation Methods 0.000 description 3
239000007788 liquid Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
238000010561 standard procedure Methods 0.000 description 3
239000007858 starting material Substances 0.000 description 3
125000001424 substituent group Chemical group 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
HGIDRHWWNZRUEP-UHFFFAOYSA-N 2-hydroxydibenzofuran Chemical compound C1=CC=C2C3=CC(O)=CC=C3OC2=C1 HGIDRHWWNZRUEP-UHFFFAOYSA-N 0.000 description 2
NJCVPQRHRKYSAZ-UHFFFAOYSA-N 3-(4-Hydroxyphenyl)-1-propanol Chemical compound OCCCC1=CC=C(O)C=C1 NJCVPQRHRKYSAZ-UHFFFAOYSA-N 0.000 description 2
FZALPKMIIYFLAP-UHFFFAOYSA-N 3-(4-phenylmethoxyphenyl)propan-1-ol Chemical compound C1=CC(CCCO)=CC=C1OCC1=CC=CC=C1 FZALPKMIIYFLAP-UHFFFAOYSA-N 0.000 description 2
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 2
ZVTWZSXLLMNMQC-UHFFFAOYSA-N 4-phenylmethoxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OCC1=CC=CC=C1 ZVTWZSXLLMNMQC-UHFFFAOYSA-N 0.000 description 2
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
PBQVPVJEIXHPPZ-UHFFFAOYSA-N 5-(4-phenylmethoxyphenyl)pentan-1-ol Chemical compound C1=CC(CCCCCO)=CC=C1OCC1=CC=CC=C1 PBQVPVJEIXHPPZ-UHFFFAOYSA-N 0.000 description 2
UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
206010065040 AIDS dementia complex Diseases 0.000 description 2
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241000976983 Anoxia Species 0.000 description 2
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
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206010012335 Dependence Diseases 0.000 description 2
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DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
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AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
235000010980 cellulose Nutrition 0.000 description 2
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239000002800 charge carrier Substances 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
229960001760 dimethyl sulfoxide Drugs 0.000 description 2
238000004821 distillation Methods 0.000 description 2
206010013663 drug dependence Diseases 0.000 description 2
230000000694 effects Effects 0.000 description 2
206010015037 epilepsy Diseases 0.000 description 2
MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 2
238000001914 filtration Methods 0.000 description 2
NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
239000012458 free base Substances 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
150000004820 halides Chemical class 0.000 description 2
238000011905 homologation Methods 0.000 description 2
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238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
238000001990 intravenous administration Methods 0.000 description 2
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230000001225 therapeutic effect Effects 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Engineering & Computer Science (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Immunology (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Obesity (AREA)
Hematology (AREA)
Diabetes (AREA)
Psychiatry (AREA)
Endocrinology (AREA)
Rheumatology (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Hospice & Palliative Care (AREA)
Pain & Pain Management (AREA)
Virology (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

CA002128536A 1992-01-28 1993-01-27 Composes azabicyclo comme antagonistes des canaux a calcium Abandoned CA2128536A1 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GB9201751.6		1992-01-28
GB929201751A GB9201751D0 (en)	1992-01-28	1992-01-28	Compounds
PCT/GB1993/000174 WO1993015080A1 (fr)	1992-01-28	1993-01-27	Composes azabicyclo servant d'antagonistes des canaux calciques

Publications (1)

Publication Number	Publication Date
CA2128536A1 true CA2128536A1 (fr)	1993-08-05

Family

ID=10709351

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002128536A Abandoned CA2128536A1 (fr)	1992-01-28	1993-01-27	Composes azabicyclo comme antagonistes des canaux a calcium

Country Status (9)

Country	Link
EP (1)	EP0625981A1 (fr)
JP (1)	JPH07503462A (fr)
KR (1)	KR950700305A (fr)
AU (1)	AU3364593A (fr)
CA (1)	CA2128536A1 (fr)
GB (1)	GB9201751D0 (fr)
MX (1)	MX9300406A (fr)
WO (1)	WO1993015080A1 (fr)
ZA (1)	ZA93549B (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9314973D0 (en) *	1993-07-20	1993-09-01	Smithkline Beecham Plc	Medicaments
UY25225A1 (es)	1997-10-29	2000-12-29	Smithkline Beecham Plc	Derivados de pleuromutilina utiles como agentes antimicrobianos
US6251919B1 (en)	1998-02-27	2001-06-26	Warner-Lambert	Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) *	1998-03-11	2000-12-26	Warner-Lambert Company	Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
HUP0303529A3 (en)	2000-12-22	2008-03-28	Almirall Ag	New quinuclidine carbamate derivatives, process for their preparation and pharmaceutical compositions containing them and their use
ES2203327B1 (es)	2002-06-21	2005-06-16	Almirall Prodesfarma, S.A.	Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen.
ES2204295B1 (es)	2002-07-02	2005-08-01	Almirall Prodesfarma, S.A.	Nuevos derivados de quinuclidina-amida.
KR101565469B1 (ko)	2007-10-01	2015-11-03	코멘티스, 인코포레이티드	알츠하이머병의 치료를 위한 알파 7 니코틴 아세틸콜린 수용체 리간드로서 퀴누클리딘-4-일메틸 1ｈ-인돌-3-카르복실레이트 유도체
US20170166561A1 (en)	2014-07-11	2017-06-15	Alpharmagen, Llc	Quinuclidine compounds for modulating alpha7-nicotinic acetylcholine receptor activity

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1250534A (fr) *	1969-03-03	1971-10-20
GB9005737D0 (en) *	1990-03-14	1990-05-09	Beecham Group Plc	Novel compounds

1992
- 1992-01-28 GB GB929201751A patent/GB9201751D0/en active Pending
1993
- 1993-01-26 ZA ZA93549A patent/ZA93549B/xx unknown
- 1993-01-26 MX MX9300406A patent/MX9300406A/es unknown
- 1993-01-27 AU AU33645/93A patent/AU3364593A/en not_active Abandoned
- 1993-01-27 CA CA002128536A patent/CA2128536A1/fr not_active Abandoned
- 1993-01-27 WO PCT/GB1993/000174 patent/WO1993015080A1/fr not_active Ceased
- 1993-01-27 EP EP93902470A patent/EP0625981A1/fr not_active Withdrawn
- 1993-01-27 JP JP5513048A patent/JPH07503462A/ja active Pending
1994
- 1994-07-27 KR KR1019940702589A patent/KR950700305A/ko not_active Withdrawn

Also Published As

Publication number	Publication date
GB9201751D0 (en)	1992-03-11
JPH07503462A (ja)	1995-04-13
MX9300406A (es)	1994-07-29
AU3364593A (en)	1993-09-01
ZA93549B (en)	1994-09-22
KR950700305A (ko)	1995-01-16
WO1993015080A1 (fr)	1993-08-05
EP0625981A1 (fr)	1994-11-30

Legal Events

Date	Code	Title	Description
1996-07-27	FZDE	Dead

Publication	Publication Date	Title
CA2226292C (fr)	2001-12-11	Composes de benzolactam substitues utilises comme antagonistes de la substance p
FI114637B (fi)	2004-11-30	Menetelmä terapeuttisesti käytettävien substituoitujen kinuklidiinien valmistamiseksi
JP2500279B2 (ja)	1996-05-29	アザ二環式化合物、これを含有する医薬組成物及び治療のための使用方法
EP0625979A1 (fr)	1994-11-30	Composes azabicycliques servant d'antagonistes des canaux calciques
NZ192175A (en)	1984-05-31	Preparation of dextrorotatory trans 4a,9b-2-substituted-5--aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido-(4,3-b)indoles
JP2674199B2 (ja)	1997-11-12	二環式アミン化合物およびその製造法
NL193541C (nl)	2000-01-04	8 Alfa-acylaminoergolinen, werkwijzen voor de bereiding daarvan en preparaten die ze bevatten.
US3976660A (en)	1976-08-24	Pyrrolidine derivatives
WO1993015080A1 (fr)	1993-08-05	Composes azabicyclo servant d'antagonistes des canaux calciques
FI71936B (fi)	1986-11-28	Foerfarande foer framstaellning av neuroleptiskt aktiva 2-substituerade-8-fluor-5-(4-fluorfenyl)-2,3,4,4a 5,9b-hexahydro-4a 9b-trans-1h-pyrido/4,3-b/indolderivat
US4033969A (en)	1977-07-05	Vincamine derivatives
WO1995003302A1 (fr)	1995-02-02	Quinolizidines a activite antagoniste des canaux a calcium
AU610492B2 (en)	1991-05-23	5-substituted octahydroindolizine analgesics compounds and 7-keto intermediates
PL141501B1 (en)	1987-07-31	Method of obtaining novel derivatives of quinoline and indene
IE49800B1 (en)	1985-12-25	Benzimidazolone derivatives,process for their preparation and pharmaceutical compositions containing them
EP0175452B1 (fr)	1988-09-21	Composés de pipéridine 1,3-disubstitués comme agents neuroleptiques
US4665076A (en)	1987-05-12	Pharmacologically active piperidine derivatives and their use
US5618822A (en)	1997-04-08	N-substituted trifluoromethylphenyltetrahydropyridines, process for the preparation thereof, intermediates in said process and pharmaceutical compositions containing them
HU196388B (en)	1988-11-28	Process for preparing derivatives of dibenzo/be/oxepinylaeacetic acid derivatives and pharmaceutical compositions containing such compounds
US3583997A (en)	1971-06-08	Benzothiopyrano(2,3-c)pyridines
US4123545A (en)	1978-10-31	N-Propyl-3(β-hydroxyethyl)-3-(meta-hydroxyphenyl)-pyrrolidine
US4784996A (en)	1988-11-15	Pyrimidoindoles useful as hypoglycaemics
US3385846A (en)	1968-05-28	Nu-cycloalkyl-azabicyclooctanes and-nonanes and nu-(2-cycloalken-1-yl)-azabicyclooctane and -nonane intermediates
US4800207A (en)	1989-01-24	Hexahydropyrrolizine compounds useful as analgesics
US4751238A (en)	1988-06-14	Substituted alkyl amine derivatives of 6,11-dihydro-11-oxodibenz[b,e]oxepins