EP0906282A1 - Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators - Google Patents
Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulatorsInfo
- Publication number
- EP0906282A1 EP0906282A1 EP97928856A EP97928856A EP0906282A1 EP 0906282 A1 EP0906282 A1 EP 0906282A1 EP 97928856 A EP97928856 A EP 97928856A EP 97928856 A EP97928856 A EP 97928856A EP 0906282 A1 EP0906282 A1 EP 0906282A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- pharmaceutically acceptable
- acceptable salt
- compound
- cyclobut
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 102000004257 Potassium Channel Human genes 0.000 title description 3
- 108020001213 potassium channel Proteins 0.000 title description 3
- RGBVWCQARBEPPW-UHFFFAOYSA-N cyclobut-3-ene-1,2-dione Chemical class O=C1C=CC1=O RGBVWCQARBEPPW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- -1 alkenoyl Chemical group 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 6
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229920001774 Perfluoroether Polymers 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 125000005596 alkyl carboxamido group Chemical group 0.000 claims abstract description 3
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims abstract description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims abstract description 3
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 3
- 125000005533 aryl carboxamido group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000005421 aryl sulfonamido group Chemical group 0.000 claims abstract description 3
- 150000001602 bicycloalkyls Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 206010046543 Urinary incontinence Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000016160 smooth muscle contraction Effects 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
- FAIMPPDFGLVQFY-UHFFFAOYSA-N 3-(tert-butylamino)-4-(pyridin-3-ylmethylamino)cyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(NC(C)(C)C)=C1NCC1=CC=CN=C1 FAIMPPDFGLVQFY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 2
- TUGZYHDPJQKDGK-UHFFFAOYSA-N 2-[[[2-(2-methylbutan-2-ylamino)-3,4-dioxocyclobuten-1-yl]amino]methyl]-1-benzofuran-5-carbonitrile Chemical compound O=C1C(=O)C(NC(C)(C)CC)=C1NCC1=CC2=CC(C#N)=CC=C2O1 TUGZYHDPJQKDGK-UHFFFAOYSA-N 0.000 claims description 2
- VFFYDAZRLQZYJY-UHFFFAOYSA-N 2-[[[2-(3,3-dimethylbutan-2-ylamino)-3,4-dioxocyclobuten-1-yl]amino]methyl]-1-benzofuran-5-carbonitrile Chemical compound O=C1C(=O)C(NC(C)C(C)(C)C)=C1NCC1=CC2=CC(C#N)=CC=C2O1 VFFYDAZRLQZYJY-UHFFFAOYSA-N 0.000 claims description 2
- BHBULKCJZSEHNQ-UHFFFAOYSA-N 2-[[[2-(tert-butylamino)-3,4-dioxocyclobuten-1-yl]amino]methyl]-1-benzofuran-5-carbonitrile Chemical compound O=C1C(=O)C(NC(C)(C)C)=C1NCC1=CC2=CC(C#N)=CC=C2O1 BHBULKCJZSEHNQ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 230000002411 adverse Effects 0.000 claims 6
- UYORNJPTYBZQQO-UHFFFAOYSA-N 3-(2-methylbutan-2-ylamino)-4-(pyridin-4-ylmethylamino)cyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(NC(C)(C)CC)=C1NCC1=CC=NC=C1 UYORNJPTYBZQQO-UHFFFAOYSA-N 0.000 claims 1
- AZTHBZLZTLHOQI-UHFFFAOYSA-N 3-(3,3-dimethylbutan-2-ylamino)-4-(pyridin-4-ylmethylamino)cyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(NC(C)C(C)(C)C)=C1NCC1=CC=NC=C1 AZTHBZLZTLHOQI-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000007787 solid Substances 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 229960004132 diethyl ether Drugs 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- 230000008602 contraction Effects 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
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- 239000002904 solvent Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
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- 239000007858 starting material Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000037020 contractile activity Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- GELMWIVBBPAMIO-UHFFFAOYSA-N 2-methylbutan-2-amine Chemical compound CCC(C)(C)N GELMWIVBBPAMIO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
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- JVUDRPCXOMXYBI-UHFFFAOYSA-N 3-(tert-butylamino)-4-(pyridin-4-ylmethylamino)cyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(NC(C)(C)C)=C1NCC1=CC=NC=C1 JVUDRPCXOMXYBI-UHFFFAOYSA-N 0.000 description 2
- SVZSHSCFQKJOEI-UHFFFAOYSA-N 3-butoxy-4-[(5-nitro-1-benzofuran-2-yl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(OCCCC)=C1NCC1=CC2=CC([N+]([O-])=O)=CC=C2O1 SVZSHSCFQKJOEI-UHFFFAOYSA-N 0.000 description 2
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- NXSHODVXBOPCHO-UHFFFAOYSA-N benzene-1,2-dicarboxamide;potassium Chemical compound [K].NC(=O)C1=CC=CC=C1C(N)=O NXSHODVXBOPCHO-UHFFFAOYSA-N 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- RVSGRNKUJJUAPV-UHFFFAOYSA-N benzo[d][1,2]benzoxazepine Chemical group O1N=CC2=CC=CC=C2C2=CC=CC=C12 RVSGRNKUJJUAPV-UHFFFAOYSA-N 0.000 description 1
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- 229910052791 calcium Inorganic materials 0.000 description 1
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- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 125000001047 cyclobutenyl group Chemical class C1(=CCC1)* 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
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- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
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- 239000000050 smooth muscle relaxant Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Definitions
- the present invention relates to novel heterocyclylmethylamino derivatives of cyclobutene 3-4-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of disorders associated with smooth muscle contraction via potassium channel modulation.
- disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, cerebral vascular disease and hypertension.
- Stemp et al. disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity. Takeno et al. report a series of diaminocyclobuten-3,4-diones in Public Patent Disclosure Bulletin No. 6-92915. Our own efforts in this area have been disclosed in the following US Patents: 5,464,867;
- a 4-pyridinylmethylamino derivative of cyclobutendione was disclosed by Chandrakumar et al. in US Patent 5,354,746 to possess analgesic activity.
- the compounds of the Chandrakumar series require the presence of a tricyclic dibenzoxazepine moiety.
- a 3-pyridinylmethylamino derivative of cyclobutendione was disclosed by Ife in EP- 112704 and was reported to be an H-2 antagonist.
- the compounds of the Ife series require the presence of an N'-pyridyl-diamino moiety.
- Ri and R.2 are, independently, hydrogen, straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, bicycloalkyl of 4 to 10 carbon atoms or aralkyl of 7 to 20 carbon atoms, wherein the aromatic moiety of the aralkyl group may be optionally substituted with one to three straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 1 to 10 carbon atoms, halogen, nitro, cyano, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, trifluoromethyl or trifluoromethoxy groups;
- R3 is hydrogen, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkyl- sulfonyl of 7 to 12 carbon atoms;
- A is selected from the group consisting of:
- n is 0 or 1 ;
- R ⁇ R5 and R6 are, independently, cyano, nitro, amino, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy, of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, sulfamyl, alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 12 carbon atoms, alkyl- carboxamido of 2 to 7 carbon atoms, arylcarboxamido of 7 to 13 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl- sulfonyl of 1 to 6 carbon atoms, perfluoroalkylsulfonyl of 1 to
- a preferred aspect of this invention includes compounds of formula (I) wherein:
- Rl and R2 are as stated above; R3 is hydrogen; A is selected from the following:
- R ⁇ R5 and R6 are as defined above; or a pharmaceutically acceptable salt thereof.
- Ri and R2 are, independently, hydrogen, methyl, ethyl, n- or iso-propyl, n-, iso, sec- or tert-butyl, straight or branched chain pentyl, or phenylalkyl in which the alkyl is methylene or ethylene and in which the phenyl moiety may be optionally substituted with one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxyoxycarbonyl, ethoxyoxycarbonyl, trifluoromethyl and trifluoromethoxy.
- R3 is preferably hydrogen. Preferably n is 0.
- R4, R5 and R6 are, independently, hydrogen, cyano, nitro, amino, methyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethoxy or carboxyl.
- R2, R3, R4, R5 or R6 contain asymmetric chiral centers, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of formula (I). The compounds of this invention, throughout this specification, are equivalently named as 3,4-diones or 1,2-diones.
- the pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
- R4, R5 or R6 contains a carboxyl group
- salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).
- the present invention also provides a process for the preparation of a compound of formula (I). More particularly, the compounds of formula (I) may be prepared by reacting a compound of formula (II):
- X is a suitable leaving group, for example, methoxy, ethoxy, isopropoxy, butoxy, halogen or a similar leaving group with a compound of formula (III):
- a j is A as defined hereinbefore or a group of atoms convertible thereto.
- the reactions mentioned above may be carried out in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or dioxane at elevated or ambient temperatures.
- a compound of formula (II) may be allowed to react initially with a compound of formula (IV), The subsequent intermediate may then be allowed to react with a compound of formula (III) as described hereinbefore, to give the compounds of formula (I).
- the compounds of formula (I) and their pharmaceutically acceptable salts are smooth muscle relaxants functioning via potassium channel activation. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma and hair loss. Furthermore, the compounds of formula (I) are, as potassium channel activators, useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
- the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
- the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
- compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
- a composition of the invention is in the form of a unit dose.
- Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
- Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg.
- Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
- the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
- Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
- compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and ⁇ - blocking agents.
- the present invention further provides a compound of the invention for use as an active pharmaceutical or therapeutic substance.
- Compounds of formula (I) are of particular use in the induction of smooth muscle relaxation.
- the present invention further provides a method of treating smooth muscle disorders in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
- Acetone oxime (6.34 g, 86.64 mmol) was added to a suspension of sodium hydride (as a 80% dispersion in mineral oil; 2.72 g, 90.82 mmol) in N, N- dimethylformamide (400 mL) at 0°C. The frothy suspension was stirred for 1 hour as the mixture was warmed to 25°C. p-Fluorobenzonitrile (10.00 g, 82.51 mmol) was added and the reaction mixture was stirred at 0°C for 15 minutes and then allowed to warm to room temperature. After stirring overnight, the reaction mixture was poured into brine (300 mL).
- Example 11 To a solution of the product of paragraph 6 in Example 11 (0.250 g, 0.79 mmol ) in ethanol (17 mL) was added tert-butyl amine (0.17g, 2.37 mmol). The reaction mixture was heated at 70°C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane.
- Sprague-Dawley rats (150-200 g) are rendered unconscious by CO2 asphyxiation and then euthanized by cervical dislocation.
- the bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition (mM): NaCl, 1 18.4; KC1, 4.7; CaCl 2 , 2.5; MgSO 4) 4.7; H 2 O, 1.2; NaHCO 3 , 24.9; KH 2 PO 4 , 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% O2; 2/5% CO 2 ; pH 7.4.
- PES physiological salt solution
- the bladder is opened and then cut into strips 1-2 mm in width and 7-10 mm in length.
- the strips are subsequently suspended in a 10 mL tissue bath under an initial resting tension of 1.5 g.
- the strips are held in place by two surgical clips one of which is attached to a fixed hook while the other is attached to an isometric force transducer.
- the preparations which usually exhibit small spontaneous contractions, are allowed to recover for a period of 1 hour prior to a challenge with 0.1 uM carbachol.
- the carbachol is then washed out and the tissue allowed to relax to its resting level of activity. Following a further 30 min period of recovery an additional 15 mM KC1 are introduced into the tissue bath.
- the isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity (IC50 concentration) and is calculated from this concentration-response curve.
- IC50 concentration concentration required to elicit 50% inhibition of pre-drug contractile activity
- the maximum percentage inhibition of contractile activity evoked by a test compound is also recorded for concentrations of test compound less than or equal to 30 ⁇ M.
- mice Female Sprague-Dawley rats, ranging in weight from 190-210g are used. Up to 25 animals are prepared each time. After development of bladder hypertrophy 4-8 animals are used per test.
- Compounds are dissolved in PEG-200 and administered by gastric gavage or intraveneously in a volume of 5 ml/kg.
- All drugs are administered at the arbitrary dose of 10 mg/kg p.o. to groups of 4 rats.
- the animals are anesthetized with halothane.
- halothane Through a midline incision the bladder and urethra are exposed and a ligature of 4-0 silk is tied around the proximal urethra in the presence of a stainless steel rod (1 mm diameter) to produce a partial occlusion. The rod is then removed. The abdominal region is closed using surgical staples and each rat receives 150,000 units of bicillin C-R. The animals are allowed six weeks to develop sufficient bladder hypertrophy. After six weeks, the ligature is removed under halothane anesthesia and a catheter (PE 60) with a cuff is placed in the dome of the bladder and secured with a purse string suture.
- PE 60 catheter
- the catheter is tunneled under the skin and exteriorized through an opening in the back of the neck.
- the abdominal incision is sutured and the free end of the catheter sealed.
- the rats receive an injection of bicillin C-R (150000 units/rat).
- Two days later the animals are used in cystometrical evaluations.
- the animals are placed in the metabolic cages and the catheter is attached (using a "T" connector) to a Statham pressure transducer (Model P23Db) and to a Harvard infusion pump.
- a plastic beaker attached to a force displacement transducer (Grass FTO3) is placed under the rat's cage to collect and record urine volume.
- Basal bladder pressure the lowest bladder pressure during cystometry
- Threshold pressure bladder pressure immediately prior to micturition
- Spontaneous activity mean amplitude of bladder pressure fluctuations during filling
- the mean value of each variable is calculated before and after compound administration. For each compound the changes in the variables measured are compared to the values obtained before treatment and expressed as percent inhibition. The data are also subjected to 2-way analysis of variance to determine significant (p ⁇ 0.05) changes in the variable measured.
- the compounds of this invention have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating compounds by administration, orally, parenterally, or by aspiration to a patient in need thereof.
Abstract
Description
Claims
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US66458396A | 1996-06-17 | 1996-06-17 | |
US664583 | 1996-06-17 | ||
PCT/US1997/009744 WO1997048682A1 (en) | 1996-06-17 | 1997-06-10 | Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators |
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EP0906282A1 true EP0906282A1 (en) | 1999-04-07 |
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EP97928856A Withdrawn EP0906282A1 (en) | 1996-06-17 | 1997-06-10 | Heterocyclylmethylamino derivatives of cyclobutene-3,4-diones as potassium channel modulators |
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EP (1) | EP0906282A1 (en) |
JP (1) | JP2000512655A (en) |
KR (1) | KR20000016815A (en) |
CN (1) | CN1227543A (en) |
AR (1) | AR008238A1 (en) |
AU (1) | AU727217B2 (en) |
BR (1) | BR9709905A (en) |
CA (1) | CA2258536A1 (en) |
IL (1) | IL127261A0 (en) |
NZ (1) | NZ332859A (en) |
TW (1) | TW442473B (en) |
WO (1) | WO1997048682A1 (en) |
ZA (1) | ZA975287B (en) |
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CA2415899A1 (en) * | 2000-07-18 | 2003-01-13 | Chikashi Saitoh | Medicine comprising dicyanopyridine derivative |
US6495576B2 (en) | 2001-02-07 | 2002-12-17 | Abbott Laboratories | Aminal diones as potassium channel openers |
US9173887B2 (en) | 2010-12-22 | 2015-11-03 | Abbvie Inc. | Hepatitis C inhibitors and uses thereof |
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AU2222083A (en) * | 1982-12-14 | 1984-06-21 | Smith Kline & French Laboratories Limited | Pyridine derivatives |
JPS60255756A (en) * | 1984-06-01 | 1985-12-17 | Ikeda Mohandou:Kk | Aminoalkylphenoxy derivative |
JPH0692915A (en) * | 1992-07-28 | 1994-04-05 | Sumitomo Metal Ind Ltd | 1,2-diaminocyclobutene-3,4-dione derivative and its use |
US5354763A (en) * | 1993-11-17 | 1994-10-11 | American Home Products Corporation | Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones |
US5466712A (en) * | 1994-11-04 | 1995-11-14 | American Home Products Corporation | Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones |
US5464867A (en) * | 1994-11-16 | 1995-11-07 | American Home Products Corporation | Diaminocyclobutene-3,4-diones |
-
1997
- 1997-06-10 WO PCT/US1997/009744 patent/WO1997048682A1/en not_active Application Discontinuation
- 1997-06-10 IL IL12726197A patent/IL127261A0/en unknown
- 1997-06-10 CA CA002258536A patent/CA2258536A1/en not_active Abandoned
- 1997-06-10 CN CN97197139A patent/CN1227543A/en active Pending
- 1997-06-10 KR KR1019980710500A patent/KR20000016815A/en not_active Application Discontinuation
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- 1997-06-10 AU AU33017/97A patent/AU727217B2/en not_active Ceased
- 1997-06-10 EP EP97928856A patent/EP0906282A1/en not_active Withdrawn
- 1997-06-10 BR BR9709905A patent/BR9709905A/en unknown
- 1997-06-10 JP JP10503051A patent/JP2000512655A/en active Pending
- 1997-06-11 TW TW086108282A patent/TW442473B/en active
- 1997-06-13 AR ARP970102616A patent/AR008238A1/en unknown
- 1997-06-13 ZA ZA975287A patent/ZA975287B/en unknown
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AU3301797A (en) | 1998-01-07 |
ZA975287B (en) | 1998-12-14 |
IL127261A0 (en) | 1999-09-22 |
BR9709905A (en) | 1999-08-10 |
TW442473B (en) | 2001-06-23 |
CN1227543A (en) | 1999-09-01 |
NZ332859A (en) | 2000-06-23 |
AR008238A1 (en) | 1999-12-29 |
WO1997048682A1 (en) | 1997-12-24 |
JP2000512655A (en) | 2000-09-26 |
CA2258536A1 (en) | 1997-12-24 |
AU727217B2 (en) | 2000-12-07 |
KR20000016815A (en) | 2000-03-25 |
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