DE68916699T2 - Benzopyridopiperidin, -piperidyliden und -piperazin-Verbindungen, Zusammensetzungen, Methoden zur Herstellung und Verwendung. - Google Patents
Benzopyridopiperidin, -piperidyliden und -piperazin-Verbindungen, Zusammensetzungen, Methoden zur Herstellung und Verwendung.Info
- Publication number
- DE68916699T2 DE68916699T2 DE68916699T DE68916699T DE68916699T2 DE 68916699 T2 DE68916699 T2 DE 68916699T2 DE 68916699 T DE68916699 T DE 68916699T DE 68916699 T DE68916699 T DE 68916699T DE 68916699 T2 DE68916699 T2 DE 68916699T2
- Authority
- DE
- Germany
- Prior art keywords
- compound
- formula
- alkyl
- acetyl
- piperidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 18
- -1 piperidylidene Chemical group 0.000 title abstract description 31
- 238000000034 method Methods 0.000 title abstract description 26
- 150000004885 piperazines Chemical class 0.000 title abstract description 5
- RIOPPPCBVKCDAC-UHFFFAOYSA-N 1,2,3,4-tetrahydrobenzo[b][1,5]naphthyridine Chemical compound C1=CC=C2N=C(CCCN3)C3=CC2=C1 RIOPPPCBVKCDAC-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 title description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 245
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 208000026935 allergic disease Diseases 0.000 claims abstract description 7
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 6
- 206010061218 Inflammation Diseases 0.000 claims abstract description 6
- 230000007815 allergy Effects 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 230000004054 inflammatory process Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 24
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 6
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 6
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 101150020251 NR13 gene Proteins 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
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- RNWRZTHVFADULG-UHFFFAOYSA-N 1-[4-(11,12-dihydro-10h-benzo[1,2]cycloocta[3,4-b]pyridin-5-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2CCCC2=CC=CC=C21 RNWRZTHVFADULG-UHFFFAOYSA-N 0.000 claims description 3
- XSORBBIFYSNFCG-UHFFFAOYSA-N 1-[4-(8-chloro-5h-[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2CSC2=CC(Cl)=CC=C21 XSORBBIFYSNFCG-UHFFFAOYSA-N 0.000 claims description 3
- AZSBZFLEBKZIBO-UHFFFAOYSA-N 1-[4-(8-chloro-5h-[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2COC2=CC(Cl)=CC=C21 AZSBZFLEBKZIBO-UHFFFAOYSA-N 0.000 claims description 3
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- HUOOXDPPQPUUPL-UHFFFAOYSA-N 1-(4-chromeno[2,3-b]pyridin-5-ylidenepiperidin-1-yl)ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=CC=CN=C2OC2=CC=CC=C21 HUOOXDPPQPUUPL-UHFFFAOYSA-N 0.000 claims description 2
- YRRBONKGMNMPBW-UHFFFAOYSA-N 1-(4-thiochromeno[3,2-b]pyridin-10-ylidenepiperidin-1-yl)ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2SC2=CC=CC=C21 YRRBONKGMNMPBW-UHFFFAOYSA-N 0.000 claims description 2
- LVWULLFAHCCKHY-UHFFFAOYSA-N 1-[4-(8-chloro-1-oxido-6,6-dioxo-5h-[1]benzothiepino[4,3-b]pyridin-1-ium-11-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=[N+]([O-])C=CC=C2CS(=O)(=O)C2=CC(Cl)=CC=C21 LVWULLFAHCCKHY-UHFFFAOYSA-N 0.000 claims description 2
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- ZVLDBRPGHOBYLH-UHFFFAOYSA-N 1-[4-(8-chloro-6,6-dioxo-5h-[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2CS(=O)(=O)C2=CC(Cl)=CC=C21 ZVLDBRPGHOBYLH-UHFFFAOYSA-N 0.000 claims description 2
- IDZMYHFCFPVBDZ-UHFFFAOYSA-N 1-[4-(8-chloro-6-oxo-5h-[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1=C1C2=NC=CC=C2CS(=O)C2=CC(Cl)=CC=C21 IDZMYHFCFPVBDZ-UHFFFAOYSA-N 0.000 claims description 2
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 119
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- 239000000243 solution Substances 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
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- 238000006243 chemical reaction Methods 0.000 description 38
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000002585 base Substances 0.000 description 19
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QCWTWMJMLSKQCJ-UHFFFAOYSA-N Isonicotinic acid N-oxide Chemical compound OC(=O)C1=CC=[N+]([O-])C=C1 QCWTWMJMLSKQCJ-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101000663001 Mus musculus TNFAIP3-interacting protein 1 Proteins 0.000 description 1
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- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
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- 150000004753 Schiff bases Chemical class 0.000 description 1
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- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- LKWPYXAYOBEGSS-UHFFFAOYSA-N [C]=C1CCCCN1 Chemical group [C]=C1CCCCN1 LKWPYXAYOBEGSS-UHFFFAOYSA-N 0.000 description 1
- HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229960000880 allobarbital Drugs 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
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- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- GHQPBDDZGPAVJP-UHFFFAOYSA-N azanium;methanol;hydroxide Chemical compound N.O.OC GHQPBDDZGPAVJP-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
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- 230000007885 bronchoconstriction Effects 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- FUFYHFFDYUIPAL-UHFFFAOYSA-N ethyl 4-(8-chloro-5h-[1]benzothiepino[4,3-b]pyridin-11-ylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CSC2=CC(Cl)=CC=C21 FUFYHFFDYUIPAL-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- ZCQVEMXIVISDLV-UHFFFAOYSA-M magnesium;1-methylpiperidin-4-ide;chloride Chemical compound [Mg+2].[Cl-].CN1CC[CH-]CC1 ZCQVEMXIVISDLV-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- YNPGMSBBWAMPFP-UHFFFAOYSA-N n-tert-butyl-3-[3-(4-fluorophenyl)propyl]-5-methylpyridine-2-carboxamide Chemical compound CC1=CN=C(C(=O)NC(C)(C)C)C(CCCC=2C=CC(F)=CC=2)=C1 YNPGMSBBWAMPFP-UHFFFAOYSA-N 0.000 description 1
- XYBOIZQGIVYRFV-UHFFFAOYSA-N n-tert-butyl-3-methylpyridine-2-carboxamide Chemical compound CC1=CC=CN=C1C(=O)NC(C)(C)C XYBOIZQGIVYRFV-UHFFFAOYSA-N 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- HZOTZTANVBDFOF-PBCQUBLHSA-N physostigmine salicylate Chemical compound OC(=O)C1=CC=CC=C1O.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C HZOTZTANVBDFOF-PBCQUBLHSA-N 0.000 description 1
- 229960002516 physostigmine salicylate Drugs 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (15)
1. Verbindung, welche durch die Strukturformel
dargestellt wird, oder ein pharmazeutisch annehmbares Salz oder
Solvat derselben, worin
eines von a, b, c und d Stickstoff oder -NR¹¹ bedeutet, worin R¹¹
-O-, -CH&sub3; oder -(CH&sub2;)pCO&sub2;H ist, worin p 1 bis 3 ist, und die
verbleibenden Gruppen a, b, c und d CH sind, das gegebenenfalls mit
R¹ oder R² substituiert sein kann;
R¹ und R² gleich oder verschieden sein können und jeweils
unabhängig Halogen, -CF&sub3;, -OR¹&sup0;, -C(O)R¹&sup0;, -S(O)eR¹², worin e 0, 1
oder 2 ist, -N(R¹&sup0;)&sub2;, -NO&sub2;, SH, CN, -OC(O)R¹&sup0;, -CO&sub2;¹&sup0;, -OCO&sub2;R¹²,
-NR¹&sup0;C(O)R¹&sup0;, C&sub1;-C&sub2;&sub0;-Alkyl, C&sub2;-C&sub1;&sub2;-Alkenyl oder C&sub2;-C&sub1;&sub2;-Alkinyl
bedeutet, wobei die Alkyl- oder Alkenylgruppen mit Halogen, -OR¹&sup0; oder
-CO&sub2;R¹&sup0; substituiert sein können, oder R¹ und R² zusammen einen an
den Pyridinring kondensierten Benzolring bilden können;
R¹&sup0; H, C&sub1;-C&sub2;&sub0;-Alkyl oder C&sub6;-C&sub1;&sub5;-Aryl bedeutet;
R¹² C&sub1;-C&sub2;&sub0;-Alkyl oder C&sub6;-C&sub1;&sub5;-Aryl bedeutet;
R³ und R&sup4; gleich oder verschieden sein können und jeweils
unabhängig H oder irgendeinen der Substituenten R¹ und R² bedeuten
oder R³ und R&sup4; zusammengenommen werden können, um einen
gesättigten oder ungesättigten, an den Benzolring kondensierten C&sub5;-C&sub7;-
Ring darzustellen;
R&sup5;, R&sup6;, R&sup7; und R&sup8; jeweils unabhängig H, -CF&sub3;, -CO&sub2;R¹&sup0;, -C(O)R¹&sup0;,
C&sub1;-C&sub2;&sub0;-Alkyl oder C&sub6;-C&sub1;&sub5;-Aryl bedeuten, wobei das Alkyl oder Aryl
durch -OR¹&sup0;, -SR¹&sup0;, -N(R¹&sup0;)&sub2;, -NO&sub2;, -C(O)R¹², -OC(O)R¹², -OCO&sub2;R¹²,
-CO²R¹&sup0; und -OPO&sub3;(R¹&sup0;)&sub2; substituiert sein kann, oder eines von R&sup5;,
R&sup6;, R&sup7; und R&sup8; mit dem nachstehend definierten R zusammengenommen
werden kann, um -(CH&sub2;)r- zu bedeuten, worin r 1 bis 4 ist, wobei
die Kombination gegebenenfalls mit C&sub1;-C&sub6;-Niederalkyl,
C&sub1;-C&sub6;-Niederalkoxy, -CF&sub3; oder C&sub6;-C&sub1;&sub5;-Aryl substituiert ist, oder R&sup5; mit R&sup6;
zusammengenommen werden kann, um =O oder =S zu bedeuten und/oder
R&sup7; mit R&sup8; zusammengenommen werden kann, um =O oder =S zu
bedeuten;
T Kohlenstoff oder Stickstoff bedeutet, wobei, wenn T
Kohlenstoff ist, die mit T verbundene punktierte Linie eine wahlfreie
Doppelbindung darstellt;
m und n ganze Zahlen 0, 1, 2 oder 3 sind, so daß die Summe in
plus n 0 bis 3 entspricht;
wenn m plus n 1 entspricht, X -O-, -S(O)e-, worin e 0, 1 oder 2
ist, -NR¹&sup0;-, -C(O)NR¹&sup0;-, -NR¹&sup0;C(O)-, -C(S)NR¹&sup0;-, -NR¹&sup0;C(S)-, -CO&sub2;-
oder -O&sub2;C- bedeutet, worin R¹&sup0; wie vorstehend definiert ist;
wenn m plus n 2 entspricht, X -O-, -S(O)e-, worin e 0, 1 oder 2
ist, oder -NR¹&sup0; bedeutet;
wenn m plus n 0 darstellt, X irgendein Substituent für m plus n
beträgt 1 sein kann und X auch Cyclopropylen oder Propenylen
sein kann;
wenn m plus n 3 entspricht, X
dann einer direkten Bindung
entspricht;
Ra jeweils gleich oder verschieden sein kann und jeweils
unabhängig H, C&sub1;-C&sub6;-Niederalkyl oder Phenyl bedeutet;
Z =O, =S oder =NR¹³ bedeutet, wobei R¹³ R¹&sup0; oder -CN entspricht,
worin R¹&sup0; wie vorstehend definiert ist, so daß
wenn Z O oder S ist, R mit den vorstehend definierten R&sup5;,
R&sup6;, R&sup7; oder R&sup8; zusammengenommen werden kann, oder R C&sub1;-C&sub2;&sub0;-
Alkyl, C&sub6;-C&sub1;&sub5;-Aryl, -SR¹², -N(R¹&sup0;)&sub2;, C&sub3;-C&sub2;&sub0;-Cycloalkyl, C&sub2;-C&sub1;&sub2;-
Alkenyl, C&sub2;-C&sub1;&sub2;-Alkinyl oder -D bedeutet, worin -D C&sub3;-C&sub1;&sub5;-
Heterocycloalkyl,
bedeutet, worin R³ und R&sup4; wie vorstehend definiert sind und
W O, S oder NR¹&sup0; ist und worin Y N oder NR¹¹ ist,
wobei das Cycloalkyl, Alkyl, Alkenyl und Alkinyl gegebenenfalls
mit 1-3 Gruppen substituiert ist, die aus Halogen, -CON(R¹&sup0;)&sub2;,
C&sub6;-C&sub1;&sub5;-Aryl, -CO&sub2;R¹&sup0;, -OR¹&sup4;, -SR¹&sup4;, -N(R¹&sup0;)&sub2;, -N(R¹&sup0;)CO&sub2;R¹&sup0;, -COR¹&sup4;, -NO&sub2;
oder -D ausgewählt sind, worin -D und R¹&sup0; wie vorstehend
definiert sind und R¹&sup4; R¹&sup0;, -(CH&sub2;)rOR¹&sup0; oder -(CH&sub2;)qCO&sub2;R¹&sup0; bedeutet,
worin r 1 bis 4 ist, q 0 bis 4 ist;
wobei die Alkenyl- und Alkinyl-R-Gruppen an einem Kohlenstoff in
einer Doppel- beziehungsweise Dreifachbindung kein -OH, -SH oder
-N(R¹&sup0;)&sub2; enthalten und
(b) wenn Z =NR¹³ bedeutet, R H, C&sub1;-C&sub2;&sub0;-Alkyl, C&sub6;-C&sub1;&sub5;-Aryl, N(R¹&sup0;)&sub2;,
C&sub3;-C&sub2;&sub0;-Cycloalkyl, C&sub2;-C&sub1;&sub2;-Alkenyl oder C&sub2;-C&sub1;&sub2;-Alkinyl bedeutet.
2. Verbindung wie in Anspruch 1 definiert, bei welcher d
Stickstoff oder NO bedeutet und die Gruppen a, b und c CH sind,
das mit R¹ oder R² substituiert sein kann.
3. Verbindung wie in Anspruch 1 oder 2 definiert, die weiter
dadurch gekennzeichnet ist, daß eines von R³ und R&sup4; Halogen,
Alkyl, -CF&sub3; oder -OR¹&sup0; ist.
4. Verbindung wie in Anspruch 1-3 definiert, die weiter
dadurch gekennzeichnet ist, daß R&sup5;, R&sup6;, R&sup7; und R&sup8; H oder Alkyl ist.
5. Verbindung wie in den Ansprüchen 1-4 definiert, die weiter
dadurch gekennzeichnet ist, daß m plus n 1 entspricht und X -O-,
oder -S(O)e- bedeutet, worin e 0, 1 oder 2 ist.
6. Verbindung wie vorstehend in den Ansprüchen 1-4 definiert,
die weiter dadurch gekennzeichnet ist, daß m plus n 0 ist und X
Cyclopropylen, Propenylen, -O- oder -S(O)e bedeutet, worin e 0,
1 oder 2 ist.
7. Verbindung wie vorstehend in den Ansprüchen 1-4 definiert,
die weiter dadurch gekennzeichnet ist, daß m plus n 3 ist und X
eine direkte Bindung ist.
8. Verbindung wie in den Ansprüchen 1-7 definiert, die weiter
dadurch gekennzeichnet ist, daß T Kohlenstoff ist und die mit T
verbundene, punktierte Linie eine Doppelbindung bedeutet.
9. Verbindung wie in den Ansprüchen 1-7 definiert, die weiter
dadurch gekennzeichnet ist, daß T Stickstoff ist.
10. Verbindung wie in Anspruch 1 definiert, die weiter dadurch
gekennzeichnet ist, daß Z O ist und R Alkyl oder D bedeutet.
11. Verbindung wie in Anspruch 1 definiert mit der Bezeichnung
1-Acetyl-4-(10H-[1]benzothiopyrano[3,2-b]pyridin-10-yliden)piperidin,
1-Acetyl-4-(8-chlor-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-
yliden)piperidin,
1-Acetyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-yliden)piperidin,
1-Acetyl-4-(5H-[1]benzopyrano[2,3-b]pyridin-5-yliden)piperidin,
1-Acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-yliden)piperidin,
1-Methoxyacety1-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-
b]pyridin-12-yliden)piperidin,
11-(1-Acetyl-4-piperidinyliden)-8-chlor-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridin,
11-(1-Acetyl-4-piperidinyliden)-8-chlor-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridin-1,6-dioxid,
11-(1-Acetyl-4-piperidinyliden)-8-chlor-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridin-6,6-dioxid,
11-(1-Acetyl-4-piperidinyliden)-8-chlor-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridin-6-oxid,
11-(1-Acetyl-4-piperidinyliden)-8-chlor-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridin-1,6,6-trioxid, und
1-(4-Pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta-
[1,2-b]pyridin-12-yliden)-piperidin-N'-oxid.
12. Pharmazeutische Zusammensetzung umfassend eine wie in einem
der vorangehenden Ansprüche definierte Verbindung der Formel I
oder ein pharmazeutisch annehmbares Salz oder Solvat derselben
in Verbindung mit einem pharmazeutisch annehmbaren Träger.
13. Verwendung einer wie in irgendeinem der Ansprüche 1 bis 11
definierten Verbindung der Formel I oder eines pharmazeutisch
annehmbaren Salzes oder Solvats derselben zur Herstellung eines
Arzneimittels zur Behandlung von Asthma, einer Allergie und/oder
Entzündung.
14. Verfahren zum Herstellen einer pharmazeutischen
Zusammensetzung umfassend das Vermischen einer in irgendeinem der
Ansprüche 1 bis 11 definierten Verbindung der Formel I oder eines
pharmazeutisch annehmbaren Salzes oder Solvats derselben mit
einem pharmazeutisch annehmbaren Träger.
15. Verfahren zum Herstellen einer Verbindung der Formel I oder
eines pharmazeutisch annehmbaren Salzes oder Solvats derselben,
umfassend das
A. Umsetzen einer Verbindung der Formel II mit einer
Verbindung der Formel III
worin L eine geeignete Abgangsgruppe ist,
B. Umsetzen einer Verbindung der Formel V mit einer geeigneten
Verbindung der Formel III
Base
Wärme
C. Cyclisieren einer Verbindung der Formel XLV zu einer
Verbindung der Formel I
D. Umsetzen einer Verbindung der Formel XXX mit einer
Verbindung der Formel XXXII und XXIX unter Erzeugen einer
Verbindung der Formel I, falls Rc Z(C)R ist.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18760488A | 1988-04-28 | 1988-04-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE68916699D1 DE68916699D1 (de) | 1994-08-18 |
| DE68916699T2 true DE68916699T2 (de) | 1994-12-01 |
Family
ID=22689668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE68916699T Expired - Fee Related DE68916699T2 (de) | 1988-04-28 | 1989-04-26 | Benzopyridopiperidin, -piperidyliden und -piperazin-Verbindungen, Zusammensetzungen, Methoden zur Herstellung und Verwendung. |
Country Status (17)
| Country | Link |
|---|---|
| EP (2) | EP0341860B1 (de) |
| JP (1) | JPH0678315B2 (de) |
| KR (1) | KR950004004B1 (de) |
| AT (1) | ATE108453T1 (de) |
| AU (1) | AU629835B2 (de) |
| CA (1) | CA1341044C (de) |
| DE (1) | DE68916699T2 (de) |
| DK (1) | DK256890A (de) |
| ES (1) | ES2056214T3 (de) |
| FI (1) | FI96690C (de) |
| IE (1) | IE64522B1 (de) |
| IL (1) | IL90101A (de) |
| MY (1) | MY106280A (de) |
| NZ (1) | NZ228888A (de) |
| OA (1) | OA09629A (de) |
| WO (1) | WO1989010369A1 (de) |
| ZA (1) | ZA893104B (de) |
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|---|---|---|---|---|
| US5089496A (en) * | 1986-10-31 | 1992-02-18 | Schering Corporation | Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies |
| US5665726A (en) * | 1986-10-31 | 1997-09-09 | Schering Corporation | Benzo[5,6]cycloheptapyridines, compositions and methods of use |
| CA2004211A1 (en) * | 1988-11-30 | 1990-05-31 | Masataka Syoji | Piperidine derivatives and hyportensives containing the same |
| IE68935B1 (en) * | 1990-06-22 | 1996-07-24 | Schering Corp | Bis-benzo or benzopyrido cyclohepta piperidene piperidylidene and piperazine compounds compositions and methods of use |
| US5393753A (en) * | 1990-10-10 | 1995-02-28 | Schering Corporation | Substituted imidazobenzazepines |
| GB9109557D0 (en) * | 1991-05-02 | 1991-06-26 | Wellcome Found | Chemical compounds |
| WO1992020681A1 (en) * | 1991-05-23 | 1992-11-26 | Schering Corporation | Novel benzopyrido piperidylidene compounds, compositions, methods of manufacture and methods of use |
| EP0595989A1 (de) * | 1991-07-23 | 1994-05-11 | Schering Corporation | Benzopyrido piperidyliden-verbindungen als paf antagonisten |
| JP2974529B2 (ja) * | 1992-02-20 | 1999-11-10 | 北陸製薬株式会社 | 両性型三環系化合物 |
| ES2089815T3 (es) * | 1992-03-27 | 1996-10-01 | Schering Corp | Derivados de bis-aril-carbinol sin enlaces de puente, composiciones y metodos de uso. |
| JPH07505394A (ja) * | 1992-03-27 | 1995-06-15 | シェリング・コーポレーション | 橋渡しビスアリールカルビノール誘導体，組成物および使用法 |
| US5538986A (en) * | 1993-12-06 | 1996-07-23 | Schering Corporation | Tricyclic derivatives, compositions and methods of use |
| US5464840A (en) * | 1993-12-06 | 1995-11-07 | Schering Corporation | Tricyclic derivatives, compositions and methods of use |
| US5574173A (en) * | 1993-12-06 | 1996-11-12 | Schering Corporation | Tricyclic derivatives, compositions and methods of use |
| US6524832B1 (en) | 1994-02-04 | 2003-02-25 | Arch Development Corporation | DNA damaging agents in combination with tyrosine kinase inhibitors |
| IL117798A (en) * | 1995-04-07 | 2001-11-25 | Schering Plough Corp | Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them |
| US5801175A (en) | 1995-04-07 | 1998-09-01 | Schering Corporation | Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
| US6323206B1 (en) | 1996-07-12 | 2001-11-27 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| PE92098A1 (es) * | 1996-07-31 | 1998-12-31 | Schering Corp | N-cianoiminas triciclicas utiles como inhibidores de transferasa de proteina farnesilo |
| CH688412A5 (de) * | 1997-03-11 | 1997-09-15 | Cilag Ag | Verfahren zur Herstellung von 1,4-disubstituierten Piperidinverbindungen. |
| US6051582A (en) * | 1997-06-17 | 2000-04-18 | Schering Corporation | Compounds useful for inhibition of farnesyl protein transferase |
| HUP0004806A3 (en) * | 1997-06-17 | 2002-11-28 | Schering Corp | Benzo[5,6]cyclohepta[1,2-b]pyridine derivatives useful for inhibition of farnesyl protein transferase and medicaments containing the compounds |
| US5925648A (en) * | 1997-07-29 | 1999-07-20 | Schering Corporation | Tricyclic N-cyanoimines useful as inhibitors of a farnesyl-protein transferase |
| US6632455B2 (en) | 1997-12-22 | 2003-10-14 | Schering Corporation | Molecular dispersion composition with enhanced bioavailability |
| AU2335699A (en) | 1998-01-21 | 1999-08-09 | Kyowa Hakko Kogyo Co. Ltd. | Chemokine receptor antagonists and methods of use therefor |
| CA2319077A1 (en) | 1998-01-21 | 1999-07-29 | Yoshisuke Nakasato | Chemokine receptor antagonists and methods of use therefor |
| US6613905B1 (en) | 1998-01-21 | 2003-09-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US6509346B2 (en) | 1998-01-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US7271176B2 (en) | 1998-09-04 | 2007-09-18 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use thereof |
| WO2000023023A1 (en) * | 1998-10-20 | 2000-04-27 | The University Of North Carolina At Chapel Hill | Methods of hydrating mucosal surfaces |
| US6316462B1 (en) | 1999-04-09 | 2001-11-13 | Schering Corporation | Methods of inducing cancer cell death and tumor regression |
| US6455554B1 (en) | 1999-06-07 | 2002-09-24 | Targacept, Inc. | Oxopyridinyl pharmaceutical compositions and methods for use |
| EP1204664A1 (de) * | 1999-07-28 | 2002-05-15 | Millennium Pharmaceuticals, Inc. | Chemokin-rezeptor-antagonisten und methoden ihrer anwendung |
| AR030946A1 (es) | 2000-09-20 | 2003-09-03 | Schering Corp | Derivados de imidazoles sustituidos un metodo para su preparacion, composiciones farmaceuticas y el uso de dichos derivados para la manufactura de medicamentos como agonistas o antagonistas duales de h1 y h3 de histamina |
| NZ532827A (en) | 2001-11-21 | 2007-09-28 | Millennium Pharm Inc | Chemokine receptor antagonists and methods of use thereof |
| US7541365B2 (en) | 2001-11-21 | 2009-06-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| ES2211315B1 (es) * | 2002-11-12 | 2005-10-16 | Almirall Prodesfarma, S.A. | Nuevos compuestos triciclicos. |
| TWI291467B (en) | 2002-11-13 | 2007-12-21 | Millennium Pharm Inc | CCR1 antagonists and methods of use therefor |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4282233B1 (en) * | 1980-06-19 | 2000-09-05 | Schering Corp | Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines |
| AU570306B2 (en) * | 1984-02-15 | 1988-03-10 | Schering Corporation | 8-chloro-6, 11-dihydro-11-(4-piperidylidene)-5h-benzo (5,6) cyclohepta (1,2-b) pyridine and its salts. |
| DE3677842D1 (de) * | 1985-05-13 | 1991-04-11 | Schering Corp | Verfahren zur herstellung von piperidyliden-dihydrodibenzo(a,d)zykloheptenen und deren azoderivate, so hergestellte verbindungen und ihre anwendung zur vorbereitung von heilmitteln. |
| US4804666A (en) * | 1985-08-14 | 1989-02-14 | Schering Corporation | Antiallergic 6,11-dihydro-11-(4-piperidylidene)-5H-benzo(5,6)cyclohepta(1,2-B)pyridines |
| US4826853A (en) * | 1986-10-31 | 1989-05-02 | Schering Corporation | 6,11-Dihydro-11-(N-substituted-4-piperidylidene)-5H-benzo(5,6)cyclohepta(1,2-B)pyridines and compositions and methods of use |
-
1989
- 1989-04-26 ES ES89304169T patent/ES2056214T3/es not_active Expired - Lifetime
- 1989-04-26 EP EP89304169A patent/EP0341860B1/de not_active Expired - Lifetime
- 1989-04-26 CA CA000597849A patent/CA1341044C/en not_active Expired - Fee Related
- 1989-04-26 DE DE68916699T patent/DE68916699T2/de not_active Expired - Fee Related
- 1989-04-26 NZ NZ228888A patent/NZ228888A/en unknown
- 1989-04-26 WO PCT/US1989/001688 patent/WO1989010369A1/en active IP Right Grant
- 1989-04-26 EP EP89905928A patent/EP0411048A1/de active Pending
- 1989-04-26 MY MYPI89000537A patent/MY106280A/en unknown
- 1989-04-26 AU AU37344/89A patent/AU629835B2/en not_active Ceased
- 1989-04-26 ZA ZA893104A patent/ZA893104B/xx unknown
- 1989-04-26 KR KR1019890702471A patent/KR950004004B1/ko not_active IP Right Cessation
- 1989-04-26 AT AT89304169T patent/ATE108453T1/de not_active IP Right Cessation
- 1989-04-26 JP JP1505871A patent/JPH0678315B2/ja not_active Expired - Lifetime
- 1989-04-27 IL IL9010189A patent/IL90101A/en not_active IP Right Cessation
- 1989-04-27 IE IE137989A patent/IE64522B1/en not_active IP Right Cessation
-
1990
- 1990-10-25 DK DK256890A patent/DK256890A/da not_active Application Discontinuation
- 1990-10-26 OA OA59879A patent/OA09629A/en unknown
- 1990-10-26 FI FI905280A patent/FI96690C/fi not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR900700486A (ko) | 1990-08-13 |
| DK256890A (da) | 1990-12-21 |
| FI905280A0 (fi) | 1990-10-26 |
| KR950004004B1 (ko) | 1995-04-22 |
| FI96690B (fi) | 1996-04-30 |
| DK256890D0 (da) | 1990-10-25 |
| IL90101A (en) | 1996-11-14 |
| IL90101A0 (en) | 1989-12-15 |
| JPH03504012A (ja) | 1991-09-05 |
| EP0341860A1 (de) | 1989-11-15 |
| MY106280A (en) | 1995-04-29 |
| OA09629A (en) | 1993-04-30 |
| NZ228888A (en) | 1991-12-23 |
| FI96690C (fi) | 1996-08-12 |
| EP0341860B1 (de) | 1994-07-13 |
| JPH0678315B2 (ja) | 1994-10-05 |
| DE68916699D1 (de) | 1994-08-18 |
| IE891379L (en) | 1989-10-28 |
| AU629835B2 (en) | 1992-10-15 |
| WO1989010369A1 (en) | 1989-11-02 |
| ZA893104B (en) | 1989-12-27 |
| ES2056214T3 (es) | 1994-10-01 |
| ATE108453T1 (de) | 1994-07-15 |
| CA1341044C (en) | 2000-07-04 |
| EP0411048A1 (de) | 1991-02-06 |
| IE64522B1 (en) | 1995-08-09 |
| AU3734489A (en) | 1989-11-24 |
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