JP5118788B2 - スピロ複素環式誘導体およびその使用方法 - Google Patents
スピロ複素環式誘導体およびその使用方法 Download PDFInfo
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- JP5118788B2 JP5118788B2 JP2008504447A JP2008504447A JP5118788B2 JP 5118788 B2 JP5118788 B2 JP 5118788B2 JP 2008504447 A JP2008504447 A JP 2008504447A JP 2008504447 A JP2008504447 A JP 2008504447A JP 5118788 B2 JP5118788 B2 JP 5118788B2
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- compound
- alkyl
- derivative
- compounds
- acid
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- 238000000034 method Methods 0.000 title description 127
- 150000001875 compounds Chemical class 0.000 claims description 625
- 125000000217 alkyl group Chemical group 0.000 claims description 284
- 150000003839 salts Chemical class 0.000 claims description 66
- 239000003814 drug Substances 0.000 claims description 41
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 claims description 23
- 108700023159 delta Opioid Receptors Proteins 0.000 claims description 23
- 102000048124 delta Opioid Receptors Human genes 0.000 claims description 23
- 210000003169 central nervous system Anatomy 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000027455 binding Effects 0.000 claims description 7
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- -1 (3-hydroxyphenyl) methyl Chemical group 0.000 description 309
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
- 238000011282 treatment Methods 0.000 description 136
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 121
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 114
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 111
- 230000002378 acidificating effect Effects 0.000 description 82
- 239000003153 chemical reaction reagent Substances 0.000 description 80
- 125000003118 aryl group Chemical group 0.000 description 75
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 73
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 71
- 238000006243 chemical reaction Methods 0.000 description 69
- 238000006069 Suzuki reaction reaction Methods 0.000 description 67
- 239000000203 mixture Substances 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 230000015572 biosynthetic process Effects 0.000 description 63
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 229910000029 sodium carbonate Inorganic materials 0.000 description 56
- 239000002253 acid Substances 0.000 description 55
- 125000005843 halogen group Chemical group 0.000 description 55
- 125000001072 heteroaryl group Chemical group 0.000 description 55
- 229910052757 nitrogen Inorganic materials 0.000 description 54
- 229910052799 carbon Inorganic materials 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 50
- 230000008878 coupling Effects 0.000 description 49
- 238000010168 coupling process Methods 0.000 description 49
- 238000005859 coupling reaction Methods 0.000 description 49
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- 125000003545 alkoxy group Chemical group 0.000 description 41
- 150000002576 ketones Chemical class 0.000 description 40
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 37
- 208000035475 disorder Diseases 0.000 description 37
- 229940002612 prodrug Drugs 0.000 description 37
- 239000000651 prodrug Substances 0.000 description 37
- 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 34
- 239000000243 solution Substances 0.000 description 34
- 239000012453 solvate Substances 0.000 description 34
- 201000010099 disease Diseases 0.000 description 33
- 230000002265 prevention Effects 0.000 description 33
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 30
- 230000000694 effects Effects 0.000 description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 30
- 150000001204 N-oxides Chemical class 0.000 description 29
- 229940079593 drug Drugs 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 229910001868 water Inorganic materials 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 208000002193 Pain Diseases 0.000 description 28
- 125000006239 protecting group Chemical group 0.000 description 26
- ZCGVBHIMRVYWOH-UHFFFAOYSA-N [4-(diethylcarbamoyl)phenyl]boronic acid Chemical compound CCN(CC)C(=O)C1=CC=C(B(O)O)C=C1 ZCGVBHIMRVYWOH-UHFFFAOYSA-N 0.000 description 25
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- 125000001424 substituent group Chemical group 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 230000036407 pain Effects 0.000 description 23
- 150000001721 carbon Chemical group 0.000 description 22
- 239000000126 substance Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 238000009833 condensation Methods 0.000 description 21
- 230000005494 condensation Effects 0.000 description 21
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 21
- 229910052763 palladium Inorganic materials 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 150000001638 boron Chemical class 0.000 description 20
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 20
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 20
- 238000000926 separation method Methods 0.000 description 19
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical class CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 18
- 208000024891 symptom Diseases 0.000 description 18
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 17
- 239000000758 substrate Substances 0.000 description 17
- 239000012467 final product Substances 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- 238000005804 alkylation reaction Methods 0.000 description 15
- 125000004438 haloalkoxy group Chemical group 0.000 description 15
- 238000005984 hydrogenation reaction Methods 0.000 description 15
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 15
- 210000000056 organ Anatomy 0.000 description 15
- 229960003742 phenol Drugs 0.000 description 15
- 230000029936 alkylation Effects 0.000 description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 14
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 14
- 150000007513 acids Chemical class 0.000 description 13
- 150000001263 acyl chlorides Chemical class 0.000 description 13
- 150000008064 anhydrides Chemical class 0.000 description 13
- 125000001153 fluoro group Chemical group F* 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 206010002091 Anaesthesia Diseases 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000037005 anaesthesia Effects 0.000 description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 12
- 150000004677 hydrates Chemical class 0.000 description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 12
- 150000002989 phenols Chemical class 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 11
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 11
- 230000004064 dysfunction Effects 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 11
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical class NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 10
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- 125000000753 cycloalkyl group Chemical group 0.000 description 9
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 9
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
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- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 8
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- 125000000623 heterocyclic group Chemical group 0.000 description 8
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- 238000001356 surgical procedure Methods 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 7
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- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 7
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- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 description 6
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 208000006011 Stroke Diseases 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 206010046543 Urinary incontinence Diseases 0.000 description 6
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- 230000036506 anxiety Effects 0.000 description 6
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- 229940124587 cephalosporin Drugs 0.000 description 6
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- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 6
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
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Classifications
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- 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
- C07D491/10—Spiro-condensed systems
-
- 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
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-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
- C07D495/10—Spiro-condensed systems
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- Medicinal Chemistry (AREA)
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- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
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| US11/393,133 US7598261B2 (en) | 2005-03-31 | 2006-03-30 | Spirocyclic heterocyclic derivatives and methods of their use |
| US11/393,133 | 2006-03-30 | ||
| PCT/US2006/012081 WO2006105442A2 (en) | 2005-03-31 | 2006-03-31 | Spirocyclic heterocyclic derivatives and methods of their use |
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| US7576207B2 (en) * | 2006-04-06 | 2009-08-18 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| CA2662115A1 (en) * | 2006-09-12 | 2008-03-20 | Adolor Corporation | Methods for enhancing cognitive function |
| US8258131B2 (en) * | 2007-08-01 | 2012-09-04 | Mitsubishi Tanabe Pharma Corporation | Fused bicyclic compound |
| WO2009143299A1 (en) | 2008-05-20 | 2009-11-26 | Neurogesx, Inc. | Hepatoprotectant acetaminophen mutual prodrugs |
| WO2011140425A1 (en) | 2010-05-06 | 2011-11-10 | Vertex Pharmaceuticals Incorporated | Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels |
| TW201604196A (zh) | 2011-02-02 | 2016-02-01 | 維泰克斯製藥公司 | 作為離子通道調節劑之吡咯并吡-螺環哌啶醯胺 |
| MX2013009393A (es) * | 2011-02-18 | 2013-08-29 | Vertex Pharma | Piperidinamidas cromano-espirociclicas como moduladores de canales de iones. |
| EP2686325B1 (en) | 2011-03-14 | 2016-12-14 | Vertex Pharmaceuticals Incorporated | Morpholine-spirocyclic piperidine amides as modulators of ion channels |
| GB201113538D0 (en) | 2011-08-04 | 2011-09-21 | Karobio Ab | Novel estrogen receptor ligands |
| SG11201501130PA (en) | 2012-08-16 | 2015-04-29 | Janssen Pharmaceutica Nv | Substituted pyrazoles as n-type calcium channel blockers |
| MX2016002043A (es) * | 2013-08-16 | 2016-05-26 | Janssen Pharmaceutica Nv | Imidazoles sustituidos como bloqueadores de canales de calcio tipo n. |
| US9453002B2 (en) | 2013-08-16 | 2016-09-27 | Janssen Pharmaceutica Nv | Substituted imidazoles as N-type calcium channel blockers |
| CN107602515A (zh) * | 2017-10-13 | 2018-01-19 | 南开大学 | 一类5a5b6c三环螺环内酯衍生物及其制备方法和用途 |
| US20240166596A1 (en) * | 2021-07-16 | 2024-05-23 | Aphiotx Inc. | Sulfamoyl benzene derivatives and uses thereof |
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| SE0300103D0 (sv) | 2003-01-16 | 2003-01-16 | Astrazeneca Ab | Diarylmethylidene piperidine derivatives, preparations thereof and uses thereof |
| SE0300104D0 (sv) | 2003-01-16 | 2003-01-16 | Astrazeneca Ab | Diarylmethylidene piperidine derivatives, preparations thereof and uses thereof |
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| AU2004278414B2 (en) * | 2003-10-01 | 2012-05-24 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| US7598261B2 (en) * | 2005-03-31 | 2009-10-06 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
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- 2006-03-31 EP EP06749077A patent/EP1871761A4/en not_active Withdrawn
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2009
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2011
- 2011-04-29 US US13/097,940 patent/US20110218186A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
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| CA2603126A1 (en) | 2006-10-05 |
| WO2006105442A2 (en) | 2006-10-05 |
| US7598261B2 (en) | 2009-10-06 |
| US8022060B2 (en) | 2011-09-20 |
| EP1871761A4 (en) | 2011-10-19 |
| EP1871761A2 (en) | 2008-01-02 |
| WO2006105442A3 (en) | 2007-08-02 |
| BRPI0612189A2 (pt) | 2009-01-20 |
| MX2007011962A (es) | 2007-12-13 |
| US20060270695A1 (en) | 2006-11-30 |
| AU2006230517A1 (en) | 2006-10-05 |
| AU2006230517B2 (en) | 2012-09-13 |
| JP2008534613A (ja) | 2008-08-28 |
| KR20080005245A (ko) | 2008-01-10 |
| IL186342A0 (en) | 2008-01-20 |
| US20110218186A1 (en) | 2011-09-08 |
| NZ562144A (en) | 2011-04-29 |
| US20100029614A1 (en) | 2010-02-04 |
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