MXPA01005429A - Substituted benzofuranoindoles and indenoindoles as novel potassium channel openers - Google Patents
Substituted benzofuranoindoles and indenoindoles as novel potassium channel openersInfo
- Publication number
- MXPA01005429A MXPA01005429A MXPA/A/2001/005429A MXPA01005429A MXPA01005429A MX PA01005429 A MXPA01005429 A MX PA01005429A MX PA01005429 A MXPA01005429 A MX PA01005429A MX PA01005429 A MXPA01005429 A MX PA01005429A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- halogen
- furo
- carboxylic acid
- Prior art date
Links
- 102000004257 potassium channel family Human genes 0.000 title claims abstract description 16
- 108020001213 potassium channel family Proteins 0.000 title claims abstract description 16
- RXXXUIOZOITBII-UHFFFAOYSA-N indeno[1,2-g]indole Chemical class C1=C2C=CC=CC2=C2C1=C1N=CC=C1C=C2 RXXXUIOZOITBII-UHFFFAOYSA-N 0.000 title description 5
- TYBGSZGTQQIASN-UHFFFAOYSA-N 1H-[1]benzofuro[2,3-g]indole Chemical class C1=CC=C2C3=C(NC=C4)C4=CC=C3OC2=C1 TYBGSZGTQQIASN-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 230000000051 modifying Effects 0.000 claims abstract description 9
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 239
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- UTWGRMYWDUMKNY-UHFFFAOYSA-N indole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)C=CC2=C1 UTWGRMYWDUMKNY-UHFFFAOYSA-N 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 43
- -1 alkali metal cation Chemical class 0.000 claims description 35
- 239000011780 sodium chloride Substances 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 17
- 125000003435 aroyl group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- XFGPVJJBSADMOF-UHFFFAOYSA-N 8-bromo-10H-[1]benzofuro[3,2-b]indole-1-carboxylic acid Chemical compound C12=CC(Br)=CC=C2OC2=C1NC1=C2C=CC=C1C(=O)O XFGPVJJBSADMOF-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- RCPGQGOKKBCOJD-UHFFFAOYSA-N CC([NH-])C(C)(C)C Chemical compound CC([NH-])C(C)(C)C RCPGQGOKKBCOJD-UHFFFAOYSA-N 0.000 claims description 4
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- MEFLHDMSBIBIEW-UHFFFAOYSA-N CCC(C)(C)[NH-] Chemical compound CCC(C)(C)[NH-] MEFLHDMSBIBIEW-UHFFFAOYSA-N 0.000 claims description 3
- XOLBGRWLNZPGJA-UHFFFAOYSA-N C[N-]O Chemical compound C[N-]O XOLBGRWLNZPGJA-UHFFFAOYSA-N 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- PAUPUUZSICTYGB-UHFFFAOYSA-N indole-1-carbonitrile Chemical compound C1=CC=C2N(C#N)C=CC2=C1 PAUPUUZSICTYGB-UHFFFAOYSA-N 0.000 claims description 3
- MTSGEHKSKUVBCN-UHFFFAOYSA-N N-methylindole-1-carboxamide Chemical compound C1=CC=C2N(C(=O)NC)C=CC2=C1 MTSGEHKSKUVBCN-UHFFFAOYSA-N 0.000 claims description 2
- QIOKAJYDPLUEOK-UHFFFAOYSA-N O.O.N1(C=CC2=CC=CC=C12)C(=O)O Chemical compound O.O.N1(C=CC2=CC=CC=C12)C(=O)O QIOKAJYDPLUEOK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 230000002411 adverse Effects 0.000 claims 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 1
- FHOPBCYBMWVMGJ-UHFFFAOYSA-N methyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)C=CC2=C1 FHOPBCYBMWVMGJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutic aid Substances 0.000 claims 1
- 230000016160 smooth muscle contraction Effects 0.000 abstract description 6
- 239000007787 solid Substances 0.000 description 46
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 37
- 238000000921 elemental analysis Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 19
- 210000001519 tissues Anatomy 0.000 description 19
- 238000000354 decomposition reaction Methods 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 210000003932 Urinary Bladder Anatomy 0.000 description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 229960004132 diethyl ether Drugs 0.000 description 11
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 11
- KFGVDCBVGNMCJC-UHFFFAOYSA-N 2-hydrazinylbenzoic acid Chemical compound NNC1=CC=CC=C1C(O)=O KFGVDCBVGNMCJC-UHFFFAOYSA-N 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000004809 Teflon Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000000875 corresponding Effects 0.000 description 8
- 239000008079 hexane Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000037020 contractile activity Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 150000007857 hydrazones Chemical class 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 208000006673 Asthma Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 230000000763 evoked Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrugs Drugs 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- GHTDODSYDCPOCW-UHFFFAOYSA-N 1H-indole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C=CNC2=C1 GHTDODSYDCPOCW-UHFFFAOYSA-N 0.000 description 3
- 210000000709 Aorta Anatomy 0.000 description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- 208000006111 Contracture Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 229960001031 Glucose Drugs 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010062575 Muscle contracture Diseases 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 3
- JZWXUCFEVWHNKB-UHFFFAOYSA-N indole-1-carbaldehyde Chemical compound C1=CC=C2N(C=O)C=CC2=C1 JZWXUCFEVWHNKB-UHFFFAOYSA-N 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- ZYZIFFMSPJVFOX-UHFFFAOYSA-N 10H-[1]benzofuro[3,2-b]indole Chemical compound C12=CC=CC=C2OC2=C1NC1=CC=CC=C21 ZYZIFFMSPJVFOX-UHFFFAOYSA-N 0.000 description 2
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3H-1-benzofuran-2-one Chemical class C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- BYSZBZYZDMXHEI-UHFFFAOYSA-N 8-bromo-N-methyl-10H-[1]benzofuro[3,2-b]indole-1-carboxamide Chemical compound C12=CC(Br)=CC=C2OC2=C1NC1=C2C=CC=C1C(=O)NC BYSZBZYZDMXHEI-UHFFFAOYSA-N 0.000 description 2
- LHFHMANUCGWIQD-UHFFFAOYSA-N 8-chloro-10H-[1]benzofuro[3,2-b]indole-1-carboxylic acid Chemical compound C12=CC(Cl)=CC=C2OC2=C1NC1=C2C=CC=C1C(=O)O LHFHMANUCGWIQD-UHFFFAOYSA-N 0.000 description 2
- FWRKQNYOLURUPO-UHFFFAOYSA-N 8-iodo-10H-[1]benzofuro[3,2-b]indole-1-carboxylic acid Chemical compound C12=CC(I)=CC=C2OC2=C1NC1=C2C=CC=C1C(=O)O FWRKQNYOLURUPO-UHFFFAOYSA-N 0.000 description 2
- LTGSTLZXMGFGHJ-UHFFFAOYSA-N 8-nitro-10H-[1]benzofuro[3,2-b]indole-1-carboxylic acid;dihydrate Chemical compound O.O.C12=CC([N+]([O-])=O)=CC=C2OC2=C1NC1=C2C=CC=C1C(=O)O LTGSTLZXMGFGHJ-UHFFFAOYSA-N 0.000 description 2
- 206010003497 Asphyxia Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 206010005052 Bladder irritation Diseases 0.000 description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N Carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 2
- 210000000170 Cell Membrane Anatomy 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N Diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N Indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- 206010024855 Loss of consciousness Diseases 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000003708 Urethra Anatomy 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 210000004027 cells Anatomy 0.000 description 2
- 230000002490 cerebral Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 201000006233 congestive heart failure Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 2
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 2
- OEXNQFWEJRSZBW-UHFFFAOYSA-N ethyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC)C=CC2=C1 OEXNQFWEJRSZBW-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000008241 heterogeneous mixture Substances 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000050 smooth muscle relaxant Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000002269 spontaneous Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
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Abstract
Compounds of Formulae (I) and (II):wherein R1, R2, R3, X, Y and Z are as defined in the specification which compounds are useful in the treatment of disorders associated with smooth muscle contraction via potassium channel modulation.
Description
BENZOFURANOINDOLES AND INDENOINDOLES SUBSTITUTED AS NOVEDOUS OPENERS OF THE POTASSIUM CHANNEL
BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a series of substituted benzofuranoindoles and indenoindoles, tetracyclic heteroaromatics 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 a modulation of the potassium channel. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
Description of the Prior Art The modulation of potassium channels remains at the forefront of current approaches to control the potential of the latent cell membrane and to affect cell excitability. There is a wide variety of discrete potassium channels and these have been meticulously classified
REF: 129609 according to the structure, function, pharmacological properties, and activation mechanisms in several recent journals [Rudy, B. Neuroscience 1988, 25, 729-749; At al, K., Medicinal Research Reviews 1992, 12, 569-591; Gopala rishnan, M. et al., Drug
Development Research 1993, 28, 95-127; Primeau, J. et al., Current Pharmaceutical Design 1995 1, 391-406; Ed ards, G. et al., Exp. Opin. Invest. Drugs 1996 5 (11), 1453-1464]. The activation of these channels increases the flow of the K + transmembrane, thus affecting the hyperpolarization of the cell membrane towards the equilibrium potential of Nernst K + (-90 mV), and subsequent closure of the voltage-activated Ca2 + channels. As a result, the overactive cell becomes less excitable and therefore less prone to additional stimulation; leading in this way to relaxation in the case of smooth muscle. As a result of this pharmacological action, the therapeutic potential for activators of the potassium channel in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is widely explored. A series of heterotopicyl methylamino benzofuranoindole compounds are reported by Bair, K.W., in WO 91/14688 and EP-447703-A1 and are useful as antimodal agents and biocides.
One example described is 2-methyl-2- (((10-met il-10H-benzofuro (3, 2-b) indol-6-yl) methyl) amino) -1,3-propanediol. A series of indenoindoles claimed as useful medicinal antioxidants and free radical scavengers are described by Sainsbury et al. In EP-404536-A1.
A series of indenoindoles useful as a component in an organic electroluminescent element are described in JP-06-228554.
X is -O-, -S, -, SO2-, or -NR9 A related series of tetrahydro indene-indole analogues is described by Sainsbury, M. in WO 90/15799 and in EP-409410-B1.
These compounds are also claimed as useful antioxidants for the treatment of atherosclerosis, thrombosis, embolism and Parkinson's disease. The synthesis and antioxidant properties of a series of indeno-indoles and indolines are reported in several journals [Brown, D. W. et al., Te trahedron 1991, 47 (25), 4383-4408; Brown, D. W. et al., Te trahedron 1993, 49 (39), 8919-8932; Graupner, P. R. et al., Te trahedron Le t t. 1995, 36 (32) 5827-5830; Shertzer, H. G. et al., Fd. Chem. Tox. 1991, 29 (6) 391-400]. Also reported by Brown, F. C. et al., Te trahedron Le t t. 1991, 32 (6) 801-802 are methods of instantaneous vacuum pyrolysis for the synthesis of indeno [1,2-b] substituted. The present invention differs from the prior art by requiring the substituent Z, defined below as a carboxylic acid moiety, a bioisostomeric equivalent of a carboxylic acid, or a derivative thereof to be substituted at the a position of the benzofuranoindoles and tetracycline indenoindoles heteroaromatics of the formulas (I) and (II). The compounds of this invention have reported activation of the potassium channel and the resulting smooth muscle relaxant properties are originally tissue-selective for the bladder tissue.
BRIEF DESCRIPTION OF THE INVENTION Accordingly, the present invention describes compounds represented by Formula (I):
wherein Ri, R2 and R3 are independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen) , amino, alkylamino of 1 to 10 carbon atoms, -S03H, -S02NH2, -NHS02R14,
Ri5S02- carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkysulfonyl of 7 to 12 carbon atoms; And it is -O- and -NR4; X is -O-, when Y is -NR4; X is -NR4, when Y is -0-; R is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms carbon and arylalkylsulfonyl of 7 to 12 carbon atoms; R5 and R6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; Z substituted at position a is selected from the group consisting of
M is an alkali metal cation or an alkaline earth metal cation; R is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of
6 to 12 carbon atoms; R8 and R9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to
carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
Rio, Rn. R12 and R13 are independently alkyl of 1 to 10 carbon atoms; Ri4 is a straight chain alkyl of 1 to 10 carbon atoms; Ris is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen); arolTLo is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl; aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; with the proviso that Ri, R2 and R3 are not hydrogen when Z is -CHO, Y is -O- and X is -N-CH3; or a pharmaceutically acceptable salt thereof. A preferred aspect of this invention includes: compounds of Formula (I), which include pharmaceutically acceptable salts thereof are those in the subgroup below, wherein the other variables of Formula (I) in the subgroups are as defined in the above, where: a) Y is -NR4 when X is -O-; More preferred aspects of this invention include compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined in the above wherein: Z is -C02H; Ri is halogen or nitro; a) X is -O-, when Y is -NR4; and b) X is -NR4, when Y is -O-; Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or a pharmaceutically acceptable salt thereof; 8-Bromo-10H-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid; 8-Iodo-10H-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid; 8-Chloro-10H-benzo [4.5] furo [3,2-b] indole-1-carboxylic acid; 8-Nitro-10H-benzo [4, 5] -furo [3,2-b] indol-1-carboyl acid dihydrate; Amide of 8-bromo-10H-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid; Methyl ester of 8-bromo-1 OH-benzo [4, 5] -furo [3,2-b] indole-l-carboxylic acid; (8-Bromo-1 OH-benzo [4, 5] furo [3, 2-b] indol-1-yl) -methanol; Hydroxy-methylamide of 8-bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8 -Bromo-1 OH-benzo [4, 5] furo [3, 2-b] indole-1-carbaldehyde; Hydrate of 8-bromo-l OH-benzo [4, 5] furo [3, 2-b] indole-1-carbonitrile; 8 -Bromo- 1- (lH-tetrazol-5-yl) -1 OH-benzo [4,5] -furo [3,2- b] indole;
(1, 2, 2-Trimethyl-propyl) -amide of 8-bromo-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; (1, 1-Dimethyl-propyl) -amide of 8-bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Bromo-1 OH-benzo [4, 5] -furc [3, 2-b] indol-1-carboxylic acid methylamide; Methyl ester of 8-bromo-10-met il-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; and 1OH-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid. In particular, this invention also provides a method for the treatment or inhibition of disorders associated with the contraction of smooth muscle, via a modulation of the potassium channel in warm-blooded animals in need thereof, which comprises administering to warm-blooded animals. preferably mammals, more preferably human, an effective amount of a compound of the general Formula (II) or a pharmaceutically acceptable salt thereof:
wherein Ri / R2 and 3 are independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen) , amino, alkylamino of 1 to 10 carbon atoms, -S03H, -S02NH2, -NHS02R? 4,
R? 5S02-carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkysulfonyl of 7 to 12 carbon atoms; And it is -NR4 and -CR5Re; X is -O-, when Y is ~ NR4; X is -NR, when Y is -CR5R6; X is -CR5R6, when Y is -NR4; R 4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms carbon and arylalkylsulfonyl of 7 to 12 carbon atoms; R5 and R6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; Z substituted at position a is selected from the group consisting of
"12 M is an alkali metal cation or an alkaline earth metal cation, R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of
6 to 12 carbon atoms; R8 and Rg are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to
carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
Rio, Rii, R12 and R13 are independently, alkyl of 1 to 10 carbon atoms; Ri4 is a straight chain alkyl of 1 to 10 carbon atoms; Ris is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen); Aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl; aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; or a pharmaceutically acceptable salt thereof. A preferred aspect of this invention includes compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method for the treatment or inhibition of disorders associated with smooth muscle contraction, via modulation of the potassium channel in warm-blooded animals, preferably mammals, more preferably human, which need it, are those in the subgroups below, where the other variables of Formula (II) in the subgroups are as defined above where: a ) X is -0-, when Y is -NR4; b) X is -NR4, when Y is -CRsR'β; and c) X is -CR5R6, when Y is -NR4. More preferred aspects of this invention include compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method of treatment or inhibition of disorders associated with smooth muscle contraction, via modulation of the potassium channel in animals of warm blood preferably mammals, most preferably human needing it are those in the subgroups below, where the other variables of Formula (II) in the subgroups are as defined in the above where: Z is -C02H; Ri is halogen or nitro; a) X is -0-, when Y is -NR4; b) X is -NR, when Y is -CR5R6; and c) X is -CR5R6 when Y is -NR4. Specifically preferred compounds of this invention according to General Formula (II) for use as a method of treatment or inhibition of disorders associated with smooth muscle contraction, via modulation of the potassium channel in warm-blooded animals, preferably mammals , most preferably human requiring it, are the following compounds or a pharmaceutically acceptable salt thereof; 8-Bromo-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Iodo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Chloro-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Nitro-10H-benzo [4, 5] -furo [3,2-b] indol-1-carboxylic acid dihydrate;
Amide of 8-bromo-l OH-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid; Methyl ester of 8-bromo-l-OH-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid; (8-Bromo-1 OH-benzo [4, 5] furo [3, 2-b] indol-1-yl) -methanol; Hydroxy-methylamide of 8-bromo-10H-benzo [4,5] furo [3,2-b] indol-1-carboxylic acid; 8-Bromo-1 OH-benzo [4,5] furo [3,2-b] indole-1-carbaldehyde; Hydrate of 8-bromo-l OH-benzo [4, 5] furo [3, 2-b] indole-1-carbonitrile; 8 -Bromo- 1- (lH-tetrazol-5-yl) -1 OH-benzo [4,5] -furo [3,2- b] indole; (1, 2, 2-trimethyl-propyl) -amide of 8-brono-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; (1, 1-Dimethyl-propyl) -amide of 8-bromo-lOH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Bromo-10H-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid methylamide; Methyl ester of 8-bromo-10-met il-lOH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; LOH-Benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; Hydrate 0.6 of 8-iodo-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid;
8-Sulfamoyl-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid semi-hydrochloride; 8-Fluoro-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid; 8-Chloro-5,10-dihydro-indene [1,2-b] indol-1-carboxylic acid; 8-Trifluoromethoxy-5,1-O-dihydro-indene- [1,2-b] indole-1-carboxylic acid; Ethyl ester of 8-chloro-5,10-dihydro-indene [1,2-b] indol-1-carboxylic acid; Ethyl ester of 8-bromo-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid; 10,10-Dimethyl-3-nitro-5,10-dihydro-indene- [1,2-b] indole-6-carboxylic acid; 8-Bromo-5,10-dihydro-indene [1,2-b] indol-1-carboxylic acid; and 3-bromo-5,10-dihydro-indene [1,2-b] indole-6-carboxylic acid. It is understood that the definition of the compounds of Formulas (I) and (II), when Ri, R2, 3 / R / R5, Re, R7, R8, g / Rio, R11, R12, R13 or R15 contain asymmetric carbons , all encompass the possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, the definition covers racemic modifications and any optical isomers that possess the indicated activity. The optical isomers can be obtained in pure form by standard separation techniques or specific synthesis of the enantiomer. It is understood that this invention encompasses all crystalline forms of compounds of Formulas (I) and (II). 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, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where Ri, R2, R3, R4, R5, R6, R7, e, or Rg contain a carboxyl group, or in the cases where Z is a carboxylic acid, the salts of the compounds in this invention can be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg). For the compounds of Formulas (I) and (II) defined in the foregoing and referenced herein, unless otherwise noted, the following terms are defined: Halogen, or halo as used herein means chlorine , fluorine, bromine and iodine.
"Alkyl" as used herein means a straight or branched chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. Cycloalkyl as used herein means a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Aryl" as used herein means an aromatic homocyclic radical, whether or not fused, having 6 to 12 carbon atoms. Preferred aryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms. Aroyl as used herein refers to -C (O) aryl where aryl is as previously defined. Examples include benzoyl and naphthoyl which may be optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3 and phenyl. Aralkyl as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined. Exemplary aralkyl groups include benzyl and phenethyl. "Alkenyl" as used herein means a straight or branched chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon double bond. Alkenyl can be used with the same meaning with the term olefin and includes alkylidenes. Exemplary alkenyl groups include ethylene, propylene and isobutylene. Alkanoyl as used herein refers to -C (O) alkyl wherein alkyl is as previously defined. Alkenoyl as used herein refers to -C (O) alkenyl where alkenyl is as previously defined. "Alkoxy" as used herein means an O-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Arylalkanoyl as used herein refers to a carbonyl group or radical directly attached to an alkyl group of 1 to 10 carbon atoms which is terminally substituted by an aryl group as previously defined, for example phenylacetic acid. The aryl group can optionally be substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, CF3, and phenyl and substituted phenyl where the substituents they are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF3. Arylalkenoyl as used herein refers to a carbonyl group or radical directly attached to an alkenyl group of 2 to 12 carbon atoms that is terminally substituted by an aryl group as previously defined. The aryl group can optionally be substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and -CF3.
Alkulsulphonyl as used herein refers to the radical -S02alkyl wherein alkyl is as previously defined. Arsulfonyl as used herein refers to the radical -S02aryl wherein aryl is as previously defined. Arylalkylsulfonyl as used herein refers to the arylalkyl-02S- radical wherein arylalkyl is as previously defined. Phenyl as used herein refers to a 6-membered aromatic ring. When the terms are used in combination, the definition for each individual part of the combination applies unless it is defined otherwise. For example, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above. The range of carbon atoms defines the number of carbons in the carbon structure and does not include carbon atoms that occur in substituent groups. The present invention also provides a process for the preparation of compounds of the
Formulas (I) and (II). The compounds of Formulas (I) and (II) wherein X is -O- and Y is -NR, where R 4 is as defined above, can be prepared as shown in Reaction Scheme 1. The treatment of an appropriately substituted benzofuranone 1_ where Ri / 2 and R3 are defined in the foregoing with 2-hydrazinobenzoic acid 2_ in aqueous media produces the corresponding 3-phenylhydrazone. This intermediate is either isolated or purified and then converted, or subjected to crude cyclization of indole in a Fischer apparatus facilitated with microwaves in an acidic medium such as, but not limited to, formic acid to produce benzo [4, 5] furo [3, 2-b] indole 4_ substituted. Standard procedures may be used to introduce R when R is not a hydrogen atom to prepare carboxylic acid 5.
Alternatively, for examples represented by Formulas (I) and (II) wherein X is -NR, and Y is -CR5R6, where R4, R5 and R6 are as defined above, they may be prepared as shown in Reaction Scheme II. An appropriately substituted phenylhydrazine (6_) where Ri, R2 and R3 are defined in the above can be treated with an indanon-1-carboxylic acid (7_) where R5 and Re are defined in the above to produce phenylhydrazone (8_) which is made reacting further in the presence of an acid, such as, but not limited to, formic acid in an indole cyclization in a Fischer apparatus provided with microwaves to produce indeno [1,2-b] indole 9_. Reaction Scheme 11
Standard procedures can then be used to introduce R when R is not a hydrogen atom to give carboxylic acid 10.
The compounds of Formulas (I) and (II) wherein X is -CR5R6, and Y is -NR4, where R4, R5 and Re are as defined above, may be prepared as shown in the Reaction Scheme. III. An indanone (JJ appropriately substituted where Ri, R2, R3, R5 and R6 are defined in the above can be treated with a 2-hydrazinobenzoic acid (2) in an intermediate medium to produce intermediate phenylhydrazone (12) .The intermediate phenylhydrazone can be subjected to microwave radiation to facilitate an indole cyclization in a Fischer apparatus in an acidic medium such as, but not limited to, formic acid to produce the substituted [1, 2-b] indole (13). then they are used to introduce R4 when R4 is not a hydrogen atom to give carboxylic acid 14.
The carboxylic acid portion of benzo [4, 5] furo [3,2-b] indole 4_ substituted, carboxylic acid 5_, indene [1,2-b] indole 9_, carboxylic acid 10, indene [1,2-b] ] substituted _13_ indole and carboxylic acid 1_4_ can be prepared in other groups represented by Z in Formulas (I) and (II). For example, treatment with an alkaline or alkaline earth base will result in the formation of the corresponding carboxylate salts. Treatment with an alcohol (R70H, where R is as described above) in the presence of acid will result in the formation of an ester. The esters can also be formed by other methods known to those skilled in the art. Reduction of the ester with an appropriate reducing agent such as diisobutyl aluminum hydride, sodium borohydride, lithium aluminum hydride will yield the corresponding alcohol or aldehyde. If only the alcohol is formed, it can be oxidized to the aldehyde with a suitable mild oxidant such as pyridinium chlorochromate or 1,1, 1-triacetoxy-1, 1-dihydro-1,2-benzoindoxol-3 (1H) -one , or per-ruthenate tetrapropylammonium in acetonitrile in the presence of a 4 Á sieve.
The carboxylic acid moiety can also be converted to the corresponding amide by treatment with an amine '- (NHR8R, where R8 and Rg are as described above) in the presence of an activating agent such as 2-chlorohydrate. dimethylaminoisopropyl / 4-dimethylamino-pyridine, or diethyl azodicarboxylate / triphenyl-phosphine. Alternatively, the carboxylic acid can be converted to the corresponding acid chloride derivative using an appropriate agent such as thionyl chloride or oxalyl chloride. Treatment with the appropriate amine - (NHR8Rg, where R8 and Rg are as described above) in the presence of an external base could then produce the desired amide. In a similar manner, the corresponding hydroxamic acid can be prepared by treatment of the acid chloride derivative with an appropriately substituted hydroxylamine (NHR80H, where R8 is as described above). The treatment of the carboxylic acid with urea in the presence of a strong acid will provide the corresponding nitrile (Z is CN). The nitrile can be converted to a tetrazole via a cyclization reaction with sodium azide.
Alkylation of the carboxylic acid with Cl (Rio) COC (0) Rn using the conditions as described by Kim, K. S. et al., J. Med. Ch em. 1993, 36, 2335 in the presence of an appropriate base or Ag20 in a solvent such as tetrahydrofuran or dichloromethane; or with C1CH2C (0) N (R? 2R? 3) using the conditions as reported by Bundgaard, H. In t. J. Pha rm. 1989, 55, 91 in the presence of sodium iodide / N, N-dimethylformamide and an appropriate base will produce the analogs of bioequivalent prodrugs. The compounds of Formulas (I) and (II) and their pharmaceutically acceptable salts relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders that involve contraction of excessive smooth muscle of the urinary tract (such as incontinence), or of the gastrointestinal tract (such as irritable bowel syndrome), asthma , and hair loss. In addition, the compounds of Formulas (I) and (II) are active as potassium channel activators which are provided for the treatment of peripheral vascular disease, congestive heart failure, fulminating attack or crisis, anxiety, cerebral anoxia and others. neurodegenerative disorders.
Compounds of the present invention potently relax smooth muscle in standard pharmacological tests. The compounds of this invention exert their smooth muscle relaxant activity via the activation of potassium channels. In addition, the compounds of the present invention are unique in that they possess intrinsic selectivity for bladder tissue over vascular tissue as demonstrated by the bladder / aorta IC50 ratios (Table 1). The present invention also provides a pharmaceutical composition comprising a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of this invention and a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral administration. However, they can also be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure. To obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. Suitable unit dosage forms include tablets, capsules and powders in sachets or ampoules. Such dosage unit forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still other preferred dosage unit forms contain from 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 can be administered from 1 to 6 times per day, more usually from 1 to 4 times per day. The compositions of the invention can 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 a conventional manner, for example, in a manner similar to that used for antihypertensive agents, diuretics and known β-blockers. The present invention further provides a compound of the invention for use as an active therapeutic substance. The compounds of Formula (I) and (II) are of particular use in the induction of smooth muscle relaxation.
The present invention further provides a method for the treatment of 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. The following examples are represented to illustrate rather than to limit the methods for the production of representative compounds of the invention.
EXAMPLE 1 8-Brorno-1 OH-benzo [4, 5] furo [3,2-b] indo-1-carboxylic acid Step 1) Preparation of o- [(2,3-dihydro-5-bromo- benzofuran-3-ylidene) hydrazino] -benzoic acid To a solution of 5-bromo-3 (2H) -benzofuranone
(3.10 g, 14.6 mmol) [Ellingboe, J. et al., J. Med.
Chem. 1992, 35 (7), 1176-1183] in ethanol (100 ml) was added a solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 ml). The mixture was stirred for one hour at room temperature and then allowed to stir while cooling (0 ° C). Vacuum filtration and in-va drying gave 3.65 g (72%) of the title compound as a brown solid: m.p. 195 ° C (decomposition) which was used without further purification.
Step 2) Preparation of 8-bromo-10H-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid hydrazone (from Step 1, Example 1 above) (0.500 g, 1.51 mmoles) in formic acid (2 ml, 96%) were. irradiated for two minutes in a Teflon container with a closed stopper in a microwave oven (700 W). The mixture was vacuum filtered hot and the solid was dried in vacuo to yield 0.271 g (57%) of the title compound as a yellow solid: m.p. 312-313 ° C; 1 H NMR (DMSO-d 6): d 13.36 (s, 1 H), 11.64 (s, 1 H), 8.27 (s, 1 H), 8.07 (d, 1 H), 7.92 (d, 1 H), 7.70 (d, 1 H) 7.50 (d, 1H), 7.27 (t, 1H); IR (KBr): 3420, 1685 cm "1; MS (m / z) 329 (M +). Elemental Analysis for Ci5H8BrN03 Calculated: C, 54.57; H, 2.44; N, 4.24 Found: C, 54.22; H, 2.32; N, 4.30.
Example 2 8-Iodo-1-OH-benzo [4,5] furo [3,2-b] indol-1-carboxylic acid Step 1) Preparation of o- [(2,3-dihydro-5-iodine - benzofuran-3-ylidene) hydrazino] -benzoic acid To a solution of 5-iodo-3 (2H) -benzofuranone (0.551 g, 2.12 mmol) [Cagniant, P. et al., Hebd. Sean ces Aca d. Sci. , Be . C, 1976, 282 (21), 993-6] in ethanol (100 ml) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 ml). The mixture was stirred for one hour at room temperature and then allowed to stir while cooling (0 ° C). Vacuum filtration and in-va drying gave 0.480 g (58%) of the title compound as a brown solid: m.p. 169 ° C (decomposition) which was used without further purification.
Step 2) Preparation of 8-iodo-lOH-benzo [5] -furo [3, 2-b] indole-1-carboxylic acid The hydrazone (from Step 1, Example 2 above) (0.480 g, 1.22 mmol) in formic acid (2 ml,
96%) was irradiated for two minutes in a container of
Teflon with closed plug of a microwave oven
(700 W). The mixture was vacuum filtered hot and the solid was dried in vacuo to yield 0.240 g (52%) of the title compound as a yellow solid: m.p.
297 ° C (decomposition); NMR 1 (DMS0-d6): d 13.33 (s,
1H), 11.63 (s, 1H), 8.47 (s, 1H), 8.07 (d, 1H), 7.91
(d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.28 (t, 1H); GO
(KBr): 3420, 1670 cm "1; MS (m / z) 377 (M +).
Elemental Analysis for C? 5H8IN03 Calculated: C, 47.77; H, 2.14; N, 3.71 Found: C, 47.61; H, 1.92; N, 3.68
EXAMPLE 3 8-Chloro-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid Step 1) Preparation of o- [(2,3-dihydro-5-chlorobenzofuran -3-ylidene) hydrazino] -benzoic acid To a solution of 5-chloro-3 (2H) -benzofuranone
(0.357 g, 2.12 mmol) [Ellingboe, J. et al., J. Med. Chem. 1992, 35 (7), 1176-1183] in ethanol (100 ml) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 ml). The mixture was stirred for one hour at room temperature and then allowed to stir while cooling (0 ° C). Vacuum filtration and in-va drying gave 0.400 g (62%) of the title compound as a light yellow solid: m.p. 190 ° C (decomposition) which was used without further purification.
Step 2) Preparation of the acid 8-chloro-10H-benzo [4,5] -furo [3,2-b] indol-1-carboxylic acid The hydrazone (from Step 1, Example 3 above) (0.400 g, 1.32 mmol ) in formic acid (2 ml, 96%) was irradiated for two minutes in a Teflon container with a closed plug of a microwave oven
(700 W). The mixture was vacuum filtered hot and the solid was dried in vacuo to yield 0.220 g (58%) of the title compound as a yellow solid: m.p. 303 ° C (decomposition); XH NMR (DMS0-d6): d 13.24 (s, 1H), 11.64 (s, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 7.92
(d, 1H), 7.75 (d, 1H), 7.39 (d, 1H), 7.28 (t, 1H); GO
(KBr): 3430, 1685 cm "1; MS (m / z) 285 (M +). Elemental Analysis for C? 5HsClN03 Calculated: C, 63.06; H, 2.82; N, 4.90 Found: C, 63.00; H, 2.57; N, 4.98.
Example 4 8-nit ro-1 OH-benzo [4, 5] furo [3, 2-b] indole-1-carboxylic acid dihydrate Step 1) Preparation of o- [(2,3-dihydro-5) acid nitrobenzofuran-3-ylidene) hydrazino] -benzoic acid 5-Nitro-3 (2H) -benzofuranone (0.500 g, 2.79 mmole) [Tobias, P. et al., J. Amer. Chem. Soc. 1969
91 (18), 5171-5173] and 2-hydrazinobenzoic acid hydrochloride (0.526 g, 2.79 mmol) were combined in pyridine (10 ml) and stirred overnight at room temperature. The mixture was filtered under vacuum and dried in vacuo to yield 0.800 g (86%) of the title compound as a yellow solid: m.p. 210 ° C (decomposition) which was used without further purification.
Step 2) Preparation of 8-nitro-10H-benzo [4,5] -furo [3,2-b] indole-l-carboxylic acid dihydrate The hydrazone (from Step 1, Example 4 above) (0.500 g, 1.51 mmole) in formic acid (2 ml, 96%) was irradiated for two minutes in a Teflon container with a closed plug of a microwave oven (700 W). The mixture was filtered under vacuum and the solid was dissolved in dimethyl sulfoxide and re-precipitated with water to yield 0.296 g (66%) of the title compound as a yellow solid: m.p. 325 (decomposition); XH NMR (DMS0-d6): d 13.42 (s, 1H), 11.82 (s, 1H), 9.07 (d, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.97 (d, 1H- ), 7.95 (s, 1H), 7.32 (t, 1H); IR (KBr): 3380, 1675 cm "1; MS (m / z) 296 (M +). Elemental Analysis for Ci5H8N205.2H20 Calculated: C, 54.22; H, 3.64; N, 8.43 Found: C, 54.25; 3.48; N, 7.68.
Example 5 Amide of 8-bromo-1 OH-benzo [4,5] furo [3,2-b] indol-1-carboxylic acid The product of Example 1, Step 2 (0.100 g, 0.303 mmol) was dissolved in diethyl ether (20 ml). Phosphorus pentachloride (72.0 mg, 0.345 mmol) was added to this solution under argon. After stirring at room temperature for 30 minutes, a yellow precipitate formed. Diethyl ether saturated with ammonia (75 ml) was added and the reaction was allowed to stir overnight. The mixture was concentrated and subjected to chromatography (hexane / ethyl acetate, 1: 1) collecting the upper eluent amide (60 mg). The isolated product was triturated with diethyl ether to yield 0.024 g (24%) of the title compound as a light yellow solid: m.p. 300-301 ° C; 1R-NMR (DMSO-d6): d 11.72 (s, 1H), 8.31 (s, 1H), 8.24 (broad s, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 7.68 (d, 1H) ), 7.58 (broad s, 1H), 7.47 (d, 1H), 7.22 (t, 1H); IR (KBr): 1650 cm "1; MS (m / z) 328 (M +). Elemental Analysis for C? 5HgBrN202 Calculated: C, 54.74; H, 2.75; N, 8.51 Found: C, 54.53; H, 2.72; N, 8.34.
Example 6 8-Bromo-10H-benzo [4, 5] furo [3, 2-b] indol-1-carboxylic acid methyl ester The product of Example 1, Step 2 (5.75 g, 17.4 mmol) was combined with sulfuric acid concentrated (3 ml) and methanol (500 ml) and heated in an oil bath (100 ° C) for three days. The mixture was cooled and concentrated to a residue. The residue was triturated with diethylether to yield 2.40 g (40%) of the title compound as a brown solid: m.p. 204-205 ° C; X H NMR (DMSO-d 6): d 11.66 (s, 1 H), 8.23 (s, 1 H), 8.10 (d, 1 H), 7.93 (d, 1 H), 7.71 (d, 1 H), 7.52 (d, 1 H) 7.30 (t, 1H), 4.01 (s, 3H); IR (KBr): 3420, 1710 cm "1; MS (m / z) 343 (M +). Elemental Analysis for C? 6H? 0BrNO3 Calculated: C, 55.84; H, 2.93; N, 4.07 Found: C, 55.49; H, 2.82; N, 4.01.
Example 7 (8-Bromo-1 OH-benzo [4, 5] furo [3,2-b] indol-1-yl) methanol To a solution of the product of Example 6 (0.196 g, 0.570 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride powder (0.025 g, 0.659 mmoles). After stirring at room temperature for 18 hours, deionized water (0.20 ml) was carefully added, followed by 2.5 N sodium hydroxide (0.20 ml), and then water (2 ml). The mixture was filtered through a diatomaceous earth bearing and the filtrate was dried with magnesium sulfate. The crude product was chromatographed (hexane / ethyl acetate, 3: 1) to yield 0.060 g (33%) of the title compound as a white solid: m.p. 218-219 ° C; XH NMR (DMS0-d6): d 11.25 (s, 1H), 8.01 (s, 1H), 7.68 (d, 2H), 7.49 (d, 1H), 7.25 (d, 1H),
7. 14 (t, 1H), 5.38-5.41 (broad s, 1H), 4.88 (s, 2H);
IR (KBr): 3600-3100 (broad) cm "1; MS (m / z) 315 (M +).
Elemental Analysis for C? 5H? OBrN02 Calculated: C, 56.99; H, 3.19; N, 4.43. Found: C, 57.23; H, 2.45; N, 4.45.
Example 8 8-Bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid hydroxymethylamide To a solution of the product of Example 1,
Step 2 (1.00 g, 3.03 mmol) in diethyl ether (100 ml) and
N, N-dimethylformamide (0.40 ml) was added oxalyl chloride (1.00 ml, 11.5 mmol). After one hour, the yellow mixture was concentrated in va cuo. The residue was dissolved in dichloromethane (80 ml) and added to a stirring mixture of N-methylhydroxylamine hydrochloride (1.26 g, 15.1 mmol) in tetrahydrofuran / water.
(16 ml, 15: 1) and triethylamine (4.20 ml, 30.3 mmol). After stirring overnight the mixture was partitioned between ethyl acetate and water. The organic phase was dried with magnesium sulfate. The crude product was chromatographed (hexane / ethyl acetate, 1: 1) to yield 0.100 g (9%) of the title compound as a white solid: m.p. 174-175 ° C; 1H NMR (DMS0-d6): d 10.22-11.18 (broad s, 2H), 8.12 (s, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.50 (d , 1H), 7.20 (t, 1H), 3.38 (s, 3H), IR (KBr): 1640 cm "1; MS (m / z) 358 (M +). Elemental Analysis for Ci6HnBrN203 Calculated: C, 53.50; H 3.09; N, 7.80, Found: C, 53.33; H, 2.98; N, 7.71.
Example 9 8 -Brino- 1 OH-benzo [4, 5] furo [3, 2-b] indole-1-carbaldehyde
To a solution of the product of Example 7,
(0.390 g, 1.23 mmq) in acetonitrile (50 ml) is added a solution of 1,1-triacetoxy-1,1-dihydro-1,2-benzyodoxol-3 (1H) -one (0.522 g, 1.23 mmoles) ) in acetonitrile (20 ml). The reaction was monitored by CCF
(hexane / ethyl acetate, 1: 1). The yellow mixture was poured into a saturated solution of sodium thiosulfate containing sodium bicarbonate (0.187 g, 1.18 mmol). The mixture was partitioned and the organic phase was washed with aqueous sodium bicarbonate and brine, dried (MgSO 4), then concentrated to a residue. Trituration yielded a solid that was dried in va cuo to yield 0.117 g (30%) of the title compound as a yellow solid: m.p. 280-281 ° C; XH NMR (DMSO-de): d 12.10 (s, 1H), 10.23 (s, 1H), 8.24 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.73 (d, 1H) 7.54 (d, 1H), 7.43 (t, 1H); IR (KBr): 1660 cm "1; MS (m / z) 313 (M +). Elemental Analysis for Ci5H8BrN02 Calculated: C, 57.35; H, 2.57; N, 4.46 Found: C, 57.05; H, 2.37; N , 4.86.
Example 10 8-Bromo-10H-benzo [4,5] furo [3, 2-b] indol-1-carbonitrile hydrate The product of Example 1, Step 2 (0.500 g,
1. 51 mmole) was mixed thoroughly with ground urea powder (8.67 g, 144 mmol). Phosphoric acid (2.5 g, 21.7 mmol) was added, followed by N, N-dimethylformamide (DMF) (7 ml). The reaction mixture was irradiated in a microwave oven for a total of 35 minutes (15-30% powder, 700W), then cooled. The crude product was milled and divided between water and diethyl ether. The organic phase was concentrated in vacuo and the residue was dissolved in acetone / diethylether (1: 1) and filtered through a silica gel plug and eluted with diethyl ether and hexane (1: 1) to yield 0.088 g. (19%) of the title compound as a light yellow solid: mp 277-280 ° C (decomposition); 1 H NMR (DMSO-d 6): d 11.44 (s, 1H), 8.18 (d, 1H), 7.97 (s, 1H), 7.79 (d, 1H), 7.76 (d, 1H), 7.58 (d, 1H) 7.34 (t, 1H); IR (KBr): 2230 cm "1. Elemental Analysis for C? 5H7BrN20.H20 Calculated: C, 54.74; H, 2.76; N, 8.51, Found: C, 55.29; H, 2.36; N, 8.22.
Example 11 8 -Bromo-1- (1H-tetrazol-5-yl) -10H-benzo [4,5] furo [3,2- b] indole The product of Example 10 (0.350 g, 1.13 mmol), NaN3 ( 0.102 g, 1.58 mmole), and n-Bu3SnCl
(0.43 ml, 1.58 mmol) were stirred together in xylenes
(5 ml) at 120 ° C for 18 h. The reaction was monitored by
TLC and DMF (2 ml) was added. The reaction was stirred
18 additional hours at 130 ° C. The reaction mixture was cooled and diluted with 6N HCl (10 mL) and stirred for 1 hour while purging with N2 gas. A solid formed and was filtered and washed under vacuum with H20. The solid was recrystallized from hot methanol and then triturated with hot ethyl acetate. The title compound (0.15 g, 38%) was collected by filtration as an off white solid: m.p. 275-277 ° C (decomposition); XH NMR (DMS0-d6): d 11.87 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.97 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H) 7.41 (dd, 1H); IR (KBr): 3360, 1440 cm "1; MS (m / z) 353 (M +). Elemental Analysis for CisHsBrNsO Calculated: C, 50.87; H, 2.27; N, 19.77 Found: C, 50.93; H, 2.52; N, 18.06.
Example 12 (1, 2, 2-Trimethyl-propyl) -amide of 8-bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid To the product of Example 1, Step 2 (0.15 g, 0.455 mmoles) in dichloromethane (4 ml) were added 5 drops of DMF followed by oxalyl chloride (0.12 ml, 1.53 mmoles). The mixture was stirred 1 hour at room temperature and concentrated in vacuo. The residue was redissolved in dichloromethane (5 ml) and 3,3-dimethyl-2-aminobutane (0.134 ml, 1.00 mmol) was added to the solution. The reaction mixture was stirred for 4 hours and concentrated to a residue. The residue was partitioned between aqueous Na 2 CO 3 and ethyl acetate. The organic phase was dried and decolorized. The concentration produced a residue which was triturated with hexanes to give 0.07 g (37%) of the title amide as an off-white solid: m.p. 173-175 ° C; X H NMR (DMSO-d 6): d 11.69 (s, 1 H), 8.26 (s, 1 H), 8.19 (d, 1 H), 7.97 (d, 1 H), 7.87 (d, 1 H), 7.67 (d, 1 H) , 7.50 (d, 1H), 7.24 (m, 1H), 4.14 (m, 1H), 1.17 (d, 3H), 0.96 (s, 9H); IR (KBr): 3390, 3300, 2960, 1640 cm "1; MS (m / z) 412 (M +). Elemental Analysis for C2? H2? BrN202 Calculated: C, 61.03; H, 5.12; N, 6.78. : C, 59.97; H, 5.32; N, 7.10.
Example 13: 8-Bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid 1 (1-dimethyl-propyl) -amide A heterogeneous mixture of the product of Example 1, Step 2 (300 mg, 909 mmol) in anhydrous N, N-dimethylformamide (281 μL) and CH2C12 (9.0 mL) at 0 ° C was added oxalyl chloride (317 μL, 3.63 mmol). With stopping the evolution of gas, the mixture was warmed to room temperature and stirred for 1 hour, then cooled to 0 ° C whereby ter-amylamine (425 μl, 3.63 mmol) was added. The reaction mixture was stirred for 12 hours, whereby all the volatiles were removed by rotary evaporation. The solid residue was dissolved in hot acetone-ethanol (8: 1, 50 ml), filtered to give a clear solution to which water (50 ml) was added to induce precipitation. Filtration followed by drying under high vacuum at 50 ° C afforded 111 mg (30%) of the title compound as an off-white solid: m.p. 242-244 ° C
(decomposition); 1 H NMR (DMS0-d 6): d 11.66 (s, 1H), 8.28 (d, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.77 (s, 1H), 7.68 (d, 1H) , 7.48 (dd, 1H), 7.21 (dd, 1H), 1.90
(q, 2H), 1.42 (s, 6H), 0.87 (t, 3H); IR (KBr): 3420, 3340, 2990, 1650, 1590, 1520, 1430, 1380, 1280, 1190, 1160, 980, 800, 750 cm "1; MS (m / z) 398/400 (M +). Elemental for C20H? GBrN2O2 Calculated: C, 60.16; H, 4.79; N, 7.02. Found: C, 59.53; H, 4.35; N, 6.88.
Example 14 8-Bromo-10H-benzo [4,5] furo [3, 2-b] indole-1-carboxylic acid methylamide To a heterogeneous mixture of the product of the
Example 1, Step 2 (300 mg, 909 mmol) in anhydrous N, N-dimethylformamide (281 μL) and CH2C12 (9.0 mL) at 0 ° C was added oxalyl chloride (317 μL, 3.63 mmol). With stoppage of gas evolution, the mixture was warmed to room temperature and stirred for 1 hour, then cooled to 0 ° C whereupon methylamine (4-5 ml) was added. The reaction mixture was stirred for 12 hours, at which point all the volatiles were removed by rotary evaporation. The solid residue was sonicated in acetonitrile (10 ml), filtered, then washed little with acetonitrile. The solid was then dissolved in hot acetone-ethanol (8: 1, 50 ml), filtered, and precipitation was induced by the addition of water (50 ml) while sonification. Filtration followed by drying under high vacuum at 50 ° C afforded 55 mg (18%) of the title compound as a white solid: m.p. 264-265 ° C (decomposition); XH NMR (DMSO-d6): d 11.74 (s, 1H), 8.66 (q, 1H), 8.27 (d, 1H), 7.95 (d, 1H), 7.76 (d, 1H), 7.68 (d, 1H) 7.49 (dd, 1H), 7.23 (dd, 1H), 2.90 (d, 3H); IR (KBr): 3460, 3310, 3060, 1680, 1630, 1590, 1560, 1450, 1440, 1410, 1380, 1330, 1290, 1200, 1160, 1150, 1050, 860, 810, 750 cm "1; m / z) 344/342 (M +) Elemental Analysis for C? 6H1? BrN202 Calculated: C, 56.00; H, 3.23; N, 8.16 Found: _ C, 55.73; H, 3.08; N, 7.99.
Example 15 Methyl ester of 8-bromo-10H-benzo [4,5] furo [3, 2-b] indole-1-carboxylic acid To a homogeneous solution of the product of the
Example 1, Step 2 (1.78 g, 5.40 mmol) in N, N-dimethylformamide (20 ml) at -5 ° C was added in portions 80% sodium hydride (324 mg, 10.8 mmol). The resulting red mixture was stirred for 1 hour while heating slowly to room temperature, whereupon it was treated with methyl trifluoromethanesulfonate (1.83 ml, 16.2 mmol), yielding an abundant precipitate. Additional N, N-dimethylformamide (5 ml) was added to facilitate stirring. The reaction mixture was stirred for an additional 1 hour, then diluted with water, filtered and washed consecutively with water and methanol. The solid material was recrystallized from acetone-water, filtered, then dried under high vacuum at 50 ° C yielding 357 mg (19%) of a white solid: m.p. 195-196 ° C; XH NMR (DMSO-d6): d 8.31 (d, 1H9, 8.04 (dd, 1H), 7.74 (d, 1H), 7.68 (dd, 1H), 7.56 (dd, 1H), 7.29 (dd, 1H), 7.04 (s, 3H9, 3.97 (s, 3H); IR (KBr): 3430, 2980, 1720, 1465, 1435, 1270, 1165, 1105, 1080, 940, 790, 755, 730 cm "1; / z) 357/359 (M +) Elemental Analysis for C? H12BrN03 Calculated: C, 57.00; H, 3.38; N, 3.91, Found: C, 56.83; H, 3.17; N, 3.83.
Example 16 lOH-Benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid To a homogeneous solution of 3-coumaranone (2.63 g, 20 mmol) in ethanol (50 ml) was added dropwise a phenyl-hirazine-2-carboxylic acid hydrochloride solution (6.79 g, 36 mmol) in water (75 ml). The resulting mixture was stirred for 12 hours at room temperature, filtered, then dried in vacuo, yielding 2.17 g (40%) of the corresponding hydrazone as a white solid. A suspension of the previous phenylhydrazone
(268 mg, 1.0 mmol) in formic acid (5.0 ml) was heated to 110 ° C at which point the mixture became homogeneous, followed by the formation of an abundant precipitate. Heating of the reaction mixture was continued for a further 5 minutes, cooled in an ice bath and the solid collected. The solid was washed with water, recrystallized from acetone-water, and then dried in vacuo yielding
156 mg (62%) of a yellow solid: m.p. 279-280 ° C
(decomposition); 1R NMR (DMSO-d6): d 13.28 (m, 1H),
11. 65 (s, 1H), 8.09 (ddd, 2H), 7.89 (dd, 1H), 7.71 (m,
1H), 7.36 (m, 2H), 7.26 (d, 1H); IR (KBr): 3420, 3000,
(broad), 1670, 1600, 1435, 1290, 750, 720 cm "1; EM
(m / z) 251 (M +). Elemental Analysis for C? 5HgN03 Calculated: C, 71.71; H, 3.61; N, 5.57. Found: C, 71.83; H, 3.39; N, 5.47.
EXAMPLE 17 Hydrate 0.6 of 8-iodo-5,10-dihydro-indene [1, 2-b l indole-1-carboxylic acid l-Oxo-indan-4-carboxylic acid (0.528 g, 2.99 mmol) was mixed together and 4-iodophenylhydrazine hydrochloride (0.698 g, 2.58 mmol) in a PFA Teflon container to form a paste in formic acid (2 ml, 96%) containing 3 drops of concentrated HCl. The vessel was irradiated in complete powder (760W) in a CEM Microwave (MDS2000) for one minute (T = 140C, P <50PSI), allowed to cool for 2 minutes, then irradiated again for one minute (T = 140C , P <50PSI). The mixture was vacuum filtered by heat. The solid was washed with formic acid, and dried in a sintering or calcined apparatus. Chromatography (acetone / hexane) and trituration with diethyl ether gave the title compound (0.059 g, 5%) as a brown solid: m.p. 251 ° C; 1H-NMR (DMSO-de): d 3.98 (s, 2H), 7.30-7.37 (m, 2H), 749 (t, 1H), 777-780 (m, 2H), 798 (d, 1H), 11.82 ( s, 1H), 13.53 (s, 1H); MS [El, m / z]: 375 [M] +. Elemental Analysis for C? 6H? 0INO2'0.6 (H20) Calculated: C, 49.87; H, 2.72; N, 3.63. Found: C, 49.59; H, 2.81; N, 3.66.
Example 18 8-Sulfaloyl-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid semi-hydrate In a manner similar to Example 17, l-oxo-indan-4- acid was converted carboxylic acid (0.528 g, 2.99 mmol) and 4-sulfamoylhydrylhydrazine hydrochloride (0.671 g, 3.0 mmol) to the title compound (0.240 g, 5%) as a brown solid: mp 270-272 ° C (decomposition); H NMR (DMS0-d6): d 4.07 (s, 2H), 7.15 (broad s, 2H), 7.52 (t, 1H), 7.59-763 (m, 2H), 7.80-7.85 (m, 2H), 8.11 (d, 1H), 12.10 (s, 1H), 13.13 (s, 1H); MS [El, m / z]: 328 [M] +. Elemental Analysis for C? 6H? 2N204S • 0.5 (H20) Calculated: C, 56.97; H, 3.88; N, 8.30. Found: C, 56.71; H, 3.49; N, 8.19.
Example 19 8-Fluoro-5,10-dihydro-indene [1,2-b] indol-1-carboxylic acid In a manner similar to Example 17, l-oxo-indan-4-carboxylic acid (1.00) was converted g, 5.68 mmol) and 4-fluorophenylhydrazine hydrochloride (0.923 g, 5.68 mmol) to the title compound (0.140 g, 10%) as an off-white solid: mp. > 300 ° C;
NMR? R (DMS0-d6) d 3.91 2H) 6.93 (d of t, 1H) 7.38 (d of d, 1H), 7.44 (d of d.1H), 7.50 (d, 1H), 7.77-7.80 (m , 2H), 11.72 (s, 1H), 13.43 (s, 1H); MS [El, m / z]: 267 [M] +. Elemental Analysis for C? 6H? OF 02 Calculated: C, 71.91; H, 3.77; N, 5.24. Found: C, 71.33; H, 3.78; N, 5.22.
Example 20 8-Chloro-5,10-dihydro-indene [1,2-b] indol-1-carboxylic acid In a manner similar to Example 17, l-oxo-indan-4-carboxylic acid (1.00 g) was converted , 5.68 mmol) and 4-chlorophenylhydrazine hydrochloride (1.03 g, 5.75 mmol) to the title compound (0.230 g, 14%) as a light brown solid: mp > 300 ° C; 1N-NMR (DMSO-d6): d 4.00 (s, 2H), 7.10 (d of d, 1H), 7.46 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.78-7.81 ( m, 2H), 11.83 (s, 1H), 13.57 (s, 1H); MS [El, m / z]: 283 [M] +. Elemental Analysis for Ci6H? 0ClNO2 Calculated: C, 67.74; H, 3.55; N, 4.94. Found: C, 67.08; H, 3.69; N, 4.78.
Example 21 8-Trifluoromethoxy-5,10-dihydro-indene [1, 2-b] indol-1-carboxylic acid In a manner similar to Example 17, l-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-trifluoromethoxyphenyl-hydrazine hydrochloride (1.03 g, 5.68 mmol) to the title compound (0.160 g, 8%) as a light brown solid: mp 256-265 ° C (decomposition); 1H-NMR (DMS0-d6): d 4.03 (s, 2H), 7.05-7.08 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.61 (d, 1H), 7.79-7.83 ( m, 2H), 11.92 (s, 1H), 13.08 (s, 1H); MS [El, m / z]: 333 [M] +. Elemental Analysis for C? H? OF3N03 Calculated: C, 61.27; H, 3.02; N, 4.20. Found: C, 60.82; H, 3.15; N, 4.32.
Example 22 8-Chloro-5,10-dihydro-indene [1, 2-b] indol-1-carboxylic acid ethyl ester The product of Example 20 was converted to its ethyl ester by treatment with sulfuric acid in ethanol to give the compound of title as a whitish solid: mp 202-204 ° C; H NMR (DMSO-d6): d 1.39 (t, 3H), 4.00 (s, 2H), 4.38 (q, 2H), 7.11 (d, 1H), 748 (d, 1H), 7.52 (t, 1H) 7.67 (s, 1H), 7.79-7.84 (m, 2H), 11.86 (s, 1H); MS [El, m / z]: 311 [M] +. Elemental Analysis for C? 8H? 4ClN? 2 Calculated: C, 60.69; H, 3.96; N, 3.93. Found: C, 60.47; H, 3.76; N, 3.78.
Example 23 8-Bromo-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid ethyl ester In a manner similar to Example 17, l-oxo-indan-4-carboxylic acid is reacted and 4-Bromophenylhydrazine hydrochloride to form the 8-bromo-5,10-dihydro-indene [1,2-b] indole-1-carboxylic acid which is converted to the ethyl ester in a manner similar to that described in Example 22 for produce the title compound as a brown solid: mp 198-200 ° C; XH NMR (DMSO-d6): d 1.39 (t, 3H), 4.00 (s, 2H), 4.37 (q, 2H), 7.22 (d, 1H), 7.42 (d, 1H), 7.52 (t, 1H) 7.79-7.84 (m, 3H), 11.86 (s, 1H); MS [El, m / z]: 355 [M] +. Elemental Analysis for C? 8H? 4BrN02 Calculated: C, 69.35; H, 4.53; N, 4.49. Found: C, 69.17; H, 4.39; N, 4.37.
EXAMPLE 24 10,10-Dimethyl-3-ni t -ro-5,10-dihydro-indene [1, 2-b] indole-6-carboxylic acid 6-Nitro-3, 3-dimethyl-l-indanone (0.612) g, 2.98 mmol) [Smith, JG et al., Org. prep. . and Proc.
In t. 1978, 10 (3), 123-131] and 2-hydrazinobenzoic acid hydrochloride (0.562 g, 2.98 mmol) in formic acid (2 ml, 96%), were irradiated for two minutes in a Teflon container with a closed lid. a microwave oven (700W). The mixture was filtered under vacuum, and the crude product was subjected to chromatography
(hexane / ethyl acetate 1: 1) and triturated with petroleum ether / diethylether. Drying in va cuo yielded 0.178 g (19%) of the title compound as a yellow solid: m.p. 310 ° C (decomposition); 1 H-NMR (DMSO-d 6): d 13.43 (s, 1 H), 11.85 (s, 1 H), 8.95 (s, 1 H), 8.12
(d, 1H), 7.98 (d, 1H), 7.81 (m, 2H), 7.19 (t, 1H), 1.59 (s, 6H); IR (KBr): 3460, 1670 cm "1; MS (m / z) 322 (M +). Elemental Analysis for C? 8H? FN204 Calculated: C, 67.08; H, 4.38; N, 8.69 Found: C, 66.29; H, 4.45; N, 8.37.
Example 25 Acid 8-bromo-5, 10-dihydro-indene [1,2-b] indol-1-carboxylic acid l-Oxo-4-indanecarboxylic acid (0.528 g, 2.98 mmole) [Aono, T. et al., Chem. Pha rm. Bul l. 1978, 26 { A), 1153-1161] and 2-hydrazinobenzoic acid hydrochloride (0.566 g, 2.98 mmol) in formic acid (2 ml, 96%), were irradiated for two minutes in a Teflon container with a closed lid of a microwave oven (700W). The mixture was filtered under vacuum. The crude product was dissolved in acetone / diethyl ether (1: 1) and treated with decolorizing charcoal, filtered, concentrated and dried in va cuo to yield 0.530 g.
(54%) of the title compound as a white solid: m.p. 328-330 ° C (decomposition); 1 H NMR (DMSO-d 6): d 13.43 (s, 1H), 11.85 (s, 1H), 7.78-7.83 (m, 3H), 7.50
(t, 1H), 7.43 (d, 1H), 7.21 (d, 1H), 4.00 (s, 2H); GO
(KBr): 3440, 1690 cm "1; MS (m / z) 327 (M +). Elemental Analysis for CißHioBrNO Calculated: C, 58.56; H, 3.07; N, 4.27 Found: C, 58.57; H, 2.88; N, 4.30.
Example 26 3-Bromo-5,10-dihydro-indene [1,2-b] indole-6-carboxylic acid Step 1) Preparation of o- [(2,3-dihydro-6-bromoinden-3-ylide ) hydrazino] benzoic To a solution of 6-bromoindanone (0.447 g,
2. 12 mmoles) [Adamczyk, M. et al., J. Org. Ch em. 1984,
49, 4226-4237] in ethanol (100 ml) was added a solution of 2-hydrazinobenzoic acid hydrochloride
(0.800 g, 4.24 mmol) in deionized water (50 ml). The mixture was stirred for 1 hour then cooled to 0 ° C. The precipitated hydrazone was filtered under vacuum and dried in vacuo to yield 0.628 g (86%) of the title compound as a yellow solid: m.p. 186 ° C (decomposition).
Step 2) Preparation of 3-bromo-5, 10-dihydro-indene [1, 2-b] indo-1-6-carboyl acid The hydrazone (from Step 1, Example 26 above) (0.620 g, 1.80 mmol) in Formic acid (2 ml, 96%) was irradiated for two minutes in a microwave oven (700W) in a Teflon container with a closed lid. The reaction mixture was vacuum filtered by heat and the solid was dried in vacuo to yield 0.360 g (61%) of the title compound as a yellow solid: m.p. 245-247 ° C (decomposition); X H NMR (DMSO-d 6): d 13.43 (s, 1 H), 11.73 (s, 1 H), 8.32 (s, 1 H), 7.86 (d, 1 H), 7.78 (d, 1 H), 7.49 (d, 1 H) , 7.36 (d, 1H), 7.16 (t, 1H), 3.71 (s, 2H); IR (KBr): 3460, 1650 cm "1; MS (m / z) 327 (M +). Elemental Analysis for Ci6H? OBrN02 Calculated: C, 58.56; H, 3.07; N, 4.27 Found: C, 58.62; , 2.83; N, '4.22.
Examples 27-32 are prepared in a manner similar to that described for Example 17 using the appropriate phenylhydrazine and l-oxo-indan-4-carboxylic acid
Example 27 8-Bromo-7-methoxy-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid Example 28 8-Bromo-6-methoxy-5,10-dihydro-indene acid [1 , 2 - b] indole-1-carboxylic acid
EXAMPLE 29 8-Chloro-7-methoxy-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid
EXAMPLE 30 8-Chloro-6-methoxy-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid
Example 31 8-Chloro-6-methoxy-5,10-dihydro-indene [l, 2-b] indole-1-carboxylic acid
EXAMPLE 31 8-Bromo-9-methoxy-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid
EXAMPLE 32 8-Bromo-6-methoxy-5,10-dihydro-indene [1, 2-b] indole-1-carboxylic acid Examples 33-36 are repaired in a manner similar to that described for Example 1 Utilizes all appropriate benzofuranone and 2- (hydrazinobenzoic acid).
EXAMPLE 33 8-Bromo-7-methoxy-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid
EXAMPLE 34 8-Chloro-7-methoxy-10H-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid
Example 35 8-Chloro-9-methoxy-1-OH-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid
Example 36 8-Chloro-6-methoxy-1-OH-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid
The smooth muscle (bladder) relaxant activity of the compounds of this invention was stabilized according to the pharmaceutically accepted, standard test procedures with representative compounds as follows.
Sprague-Dawley rats (150-200 g) were rendered unconscious by suffocation with C02 and then killed by cervical dislocation. The bladder was removed in warm physiological salt solution (37 ° C) (PSS) of the following composition (mM): NaCl, 118.4; KCl, 4.7; CaCl2, 2.5; MgSO4, 4.7; H20, 1.2; NaHCO 3, 24.9; KH2P04, 1.2; glucose, 11.1; EDTA, 0.023; gassed with 02 to 95%; C02 at 2/5%; pH of 7.4. The bladder was opened and then cut into strips 1-2 mm wide and 7-10 long. The strips were subsequently suspended in a 10 ml tissue bath under an initial latent tension of 1.5 g. The strips were held in place by two surgical fasteners, one of which was attached to a fixed hook while the other was 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 stimulation with 0.1 μM carbachol. The carbacol was then washed and the tissue was allowed to relax to its latent level of activity. Following a period of 30 additional minutes of recovery, additional 15 mM KCl was introduced into the tissue bath. This increase in KCl concentration results in a large increase in the amplitude of spontaneous contractions (and initiation of contractions in previously quiescent strips or at rest) superimposed with a small increase in basic or fundamental tone. Following the stabilization of this improved level of contractile activity, incremental increases in the concentration of the test compound or vehicle were introduced into the tissue bath. The contractile activity was measured for each compound or vehicle concentration during the last minute of a 30-minute stimulus. The development of isometric forces by the bladder strips was measured using a concentration required for 50% inhibition deduced from the prodrug contractile activity (concentration ICso) and calculated from this concentration response curve. The inhibition of maximum percentage of contractile activity evoked by a test compound was also recorded for test compound concentrations less than or equal to 30 μM. The smooth muscle (aorta) relaxant activity of the compounds of this invention are established according to the pharmaceutically accepted, standard test procedures with representative compounds as follows. Sprague-Dawley rats (150-200 g) were rendered unconscious by suffocation with C02 and then killed by cervical dislocation. The thoracic aorta was eliminated in warm physiological salt solution
(37 ° C) (PSS) of the following composition (M): NaCl,
118. 4; KCl, 4.7; CaCl2, 2.5; MgSO4, 4.7; H20, 1.2;
NaHCO 3, 24.9; KH2P04, 1.2; glucose, 11.1; EDTA, 0.023; gassed with 02 to 95%; C02 at 2/5%; pH of 7.4. The aorta was cleaned of loose fat and adventitia and cut into rings 3-4 mm wide. The rings were subsequently suspended between two stainless steel wire tissue supports in a 10 ml tissue bath. A wire weave support is attached to a fixed hook while the other is attached to an isometric force transducer. The latent voltage is set at 1 g. The tissues are recovered for a period of 60 min before the start of the experiment. The tissues were stimulated with PSS containing 25 Mm KCl to reduce a contracture. The tissues were then washed repeatedly with fresh PSS for a period of 30 minutes and allowed to recover at a baseline tension. The PSS containing 30-35 mM KCl was then introduced into the tissue bath to evoke a contracture that was allowed to stabilize for not less than 45 minutes. (Another stimulus such as ñorepinefri a, PGF2a, histamine, angiotensin II, endothelin or PSS containing 80 M KCl can also be used to evoke a contracture as needed). By increasing the concentrations of the test compound or vehicle, they are then added to the tissue bath in a cumulative manner. The development of isometric forces by the aortic rings was measured using a force transducer and recovered in a polygraph. The percent inhibition of the contractile forces evoked by each concentration of a given test compound was used to generate a concentration response curve. The concentration of the test compound required to deduce the 50% inhibition of contractile forces of the prodrug (concentration of IC50) was calculated from this dose response curve. [The Log concentration against the response curves are approximately linear between 20% and 80% of the maximum response. As such, the concentration of IC5o of the drug was determined by linear regression analysis (giving x = concentration log yy =% inhibition) of the data points in the region from 20% to 80% of the curve.] percentage of maximum inhibition of contractile forces evoked by a test compound was also recorded for concentrations of the test compound < o = at 30 uM. The data collected from 2 animals were averaged by primary screens. The results of these studies are shown in Table I. Relationship Example Bladder tissue Aorta tissue Aorta! Cs "np ICso number (μ) IC50.μM) Bladder ICS0 1 8 15.1 = 4.7 4 118.8 + 21.8 7.9 2 8 6.1 ± 3.0 3 128 ± 16.9 21 3 6 5.8 + 1.5 4 268.0 + 82.3 46.2 4 8 6.3 ± 2.6 3 125 + 13.8 19.8 5 2 1 = 13.5% '... 6 4 I = 31%' ... 8 3 19.8 = 4.02 3 8.1 ± 3.6 0.41 9 2 1 = 19% '- 10 4 ¡= 10.1% * ._ 11 2 I = 30.9%' ._ 12 2 13.9 + 0.95 3 25 ± 3.9 1.8 13 2 1 = 28.5% '- 14 3 1 = 4.8%' __ 15 2 1 * 4.5% '- 16 4 31.0 ± 6.5 - ... 17 8 10.1 ± 3.2 18 2 I = 5.2%' - 19 6 12.5 + 5 3 46.6 + 18.7 3.74 20 5 22.6 + 1.8 ._ 21 4 15.4 + 4.8 _. 22 2 i = 8% '- 23 2 I = 20%' - 24"4 5.2 ± 1.8 4 17.2 ± 2.3 3.3 25 8 4.4 ± 0.95 6 109.6 + 12.4 25 26 7 8.6 + 3.0 4 210.4 ± 45 24.5
Percent inhibition at 30 μM Several compounds in this invention were tested for their ability to relax a whole rat rat bladder. The protocol for this trial is as follows. Female Sprague-Dawley rats were anesthetized weighing between 200-300 g with Ne butol® (50 mg / kg, i.p.). After performing adequate anesthesia, the bladder and urethra were exposed through a midline incision. A 4-0 silk ligature was tied around the proximal end of the urethra in the presence of a 1 mm diameter stainless steel rod. The rod was then removed resulting in a partial exit obstruction. The wound was closed with surgical staples and the animals received 15,000 units of Bicillin® antibiotic. After a period of 6 weeks, the animals were asphyxiated with C02 gas. The vejijas were placed by contractile analysis in a physiological salt solution (PSS) at 37 ° C of the following composition (in mM): NaCl (118.4), KCl
(4.7), CaCl2 (2.5), MgSO4 (1.2), KH2P04 (1.2), NaHCO3
(24.9) and D-glucose (11.1) gassed with C02-02 (95% -5%) to achieve a pH of 7.4.
The isolated bladders were secured through the urethral opening with a silk ligature for a length of a polyethylene tube (PE-200). The opposite end of the tube was connected to a pressure transducer to monitor the development of pressure in the bladder. The bladders were placed in a tissue bath containing PSS at 37 ° C and inflated with PSS to achieve optimal contractions. The bladder contractions were exposed and monitored in a 7D Grass polygraph. The following stabilization, incremental increases in the concentration of the compound or test vehicle were introduced into the tissue bath. Contractile activity was measured by each compound or vehicle concentration during the last minute of a 30-minute stimulus. The concentration required to deduce the inhibition
50% of the contractile activity of the prodrug
(concentration of IC5o) was calculated from this concentration response curve. The percentage of maximum inhibition of contractile activity evoked by a test compound is also recorded by concentrations of the test compound of less than or equal to 30 μM. Example 24 presents an IC50 value of 5 μM in this assay.
Based on the results of standard pharmacological test procedures, the compounds of this invention are selective for bladder tissue and have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, disease of the irritable bladder and bowel, asthma, attack or fulminating crisis, and similar diseases as mentioned above, which are sensitive to treatment with compounds that activate the potassium channel by administration, orally, parenterally or by aspiration to a patient who you need it It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (21)
1. A compound of the general Formula (I): Characterized by: i 2 and 3 are independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen) , amino, alkylamino of 1 to 10 carbon atoms, -S03H, R15SO2-carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulphonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulphonyl of 7 to 12 carbon atoms; Y is -0- and -NR4; X is -0-, when Y is -NR4; X is -NR4, when Y is -O-; R is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms carbon and arylalkylsul fonyl of 7 to 12 carbon atoms; • Rs and Rβ are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; Z substituted at position a is selected from the group consisting of M is an alkali metal cation or an alkaline earth metal cation; R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; R8 and g are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; io / ii 12 and R13 are independently, alkyl of 1 to 10 carbon atoms; R 4 is a straight chain alkyl of 1 to 10 carbon atoms; Ri5 is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen); Aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl; aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; with the proviso that Rl R2 and R3 are not hydrogen when Z is -CHO, Y is -O- and X is -N-CH3; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, characterized in that X is -O- when And it is -NR or a pharmaceutically acceptable salt of mine.
3. A compound according to claim 1, characterized in that X is -O- when Y is -NR4 and Rx is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1, characterized in that X is -NR4 when Y is -O- and Ri is halogen or nitro and Z is -CO? H or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1, characterized in that it is selected from the group consisting of: 8-bromo-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8-Iodo-10H-benzo [4, 5] furo [3,2-b] indo 1-1-carboxylic acid; 8-Chloro-10H-enzo [4, 5] furo [3,2-b] indole-1-carboxylic acid; 8-Nitro-1-OH-benzo [, 5] -furo [3,2-b] indole-1-carboxylic acid dihydrate; Amide of 8-bromo-1 OH-benzo [, 5] -furo [3,2-b] indole-1-carboxylic acid; 8-Bromo-10H-benzo [, 5] -furo [3,2-b] indole-1-carboxylic acid methylester; (8-Bromo-1 OH-benzo [4,5] furo [3,2- b] indol-1-yl) -methanol; Hydroxy-methylamide of 8-bromo-10H-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; 8 -Bromo-1 OH-benzo [, 5] furo [3, 2-b] indo 1-1-carbaldehyde; Hydrate of 8-bromo-l OH-benzo [4, 5] furo [3, 2-b] indole-1-carbonitrile; 8 -Bromo- 1- (lH-tetrazol-5-yl) -1 OH-benzo [4,5] -furo [3,2- b] indole; (1, 2, 2-Trimethyl-propyl) -amide of 8-bromo-1 OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; (1, 1-Dimethyl-propyl) -amide of 8-bromo-lOH-benzo [4, 5] furo [3,2-b] indole-1-carboxylic acid; 8-Bromo-1 OH-benzo [4, 5] -furo [3,2-b] indole-1-carboxylic acid methylamide; Methyl ester of 8-bromo-10-methyl-1-OH-benzo [4,5] furo [3,2-b] indole-1-carboxylic acid; and lOH-benzo [4.5] furo [3,2-b] indole-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition for the treatment or inhibition of disorders associated with the contraction of smooth muscle, via a modulation of the potassium channel in warm-blooded animals in need thereof, which comprises administering to the warm-blooded animals, an effective amount of a composed of the general formula (II) characterized in that: Ri / R2 and 3 are independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen ), amino, alkylamino of 1 to 10 carbon atoms, -S03H, -S02NH2, -NHS02R? 4, R? 5S02-carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkysulfonyl of 7 to 12 carbon atoms; And it is -NR4 and -CR5R6; X is -O-, when Y is -NR4; X is -NR4, when Y is -CR5R6, "X is -CR5R6, when Y is -NR; R4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkyl Isul fonilo of 7 to 12 carbon atoms; Rs and R6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; Z substituted at position a is selected from the group consisting of M is an alkali metal cation or an alkaline earth metal cation; R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; R8 and Rg are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; Rio, Rn, R12 and R13 are independently, alkyl of 1 to 10 carbon atoms; Ri4 is a straight chain alkyl of 1 to 10 carbon atoms; Ris is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen); Aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl; aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
7. A pharmaceutical composition according to claim 6, characterized in that X is -O- when Y is -NR4 or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition according to claim 6, characterized in that X is -NR4 when Y is -CR5Re or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition according to claim 6, characterized in that X is -CR ^ Re when Y is -NR4 or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition according to claim 6, characterized in that X is -0- when Y is -NR and Rx is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition according to claim 6, characterized in that X is -NR4 when Y is -CR5R6 and Rx is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition according to claim 6, characterized in that X is -CR5Rβ when Y is -NR and Rx is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
13. A method for the treatment or inhibition of disorders associated with the contraction of smooth muscle, via a modulation of the potassium channel in warm-blooded animals in need thereof, which comprises administering to the warm-blooded animals, an effective amount of a compound of the general formula (II) characterized in that: i / 2 and 3 are independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen ), amino, alkylamino of 1 to 10 carbon atoms, -S03H, -S02NH2, -NHSO2R14, R? .S02- carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkyl sui fonyl of 7 to 12 carbon atoms; And it is -NR4 and -CR5R6; X is -O-, when Y is -NR4; X is -NR4, when Y is -CR5R6; X is -CR5R6, when Y is -NR; R 4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from 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, aryisulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms carbon and arylalkylsulfonyl of 7 to 12 carbon atoms; Rs and Re are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; Z substituted at position a is selected from group ^ consisting of M is an alkali metal cation or an alkaline earth metal cation; R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; Rs and R9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms; io / ii / R12 and R13 are independently, alkyl of 1 to 10 carbon atoms; R14 is a straight chain alkyl of 1 to 10 carbon atoms; Ris is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen); Aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the halogen group, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, -CF3, and phenyl; aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; or a pharmaceutically acceptable salt thereof.
14. A method according to claim 13, characterized in that X is -0- C-Y-YN-NR4 or a pharmaceutically acceptable salt thereof.
15. A method according to claim 13, characterized in that X is -NR4 when Y is -CR5R6 or a pharmaceutically acceptable salt thereof.
16. A method according to claim 13, characterized in that X is -CR5R6 when Y is -NR4 or a pharmaceutically acceptable salt thereof.
17. A method according to claim 13, characterized in that X is -O- when Y is -NR4 and R1 is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
18. A method according to claim 13, characterized in that X is -NR4 when Y- is -CR5R6 and Ri is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
19. A method according to claim 13, characterized in that X is -CR5R6 when Y is -NR4 and Ri is halogen or nitro and Z is -C02H or a pharmaceutically acceptable salt thereof.
20. A method according to claim 13, characterized in that the adverse contraction of the smooth muscle causes urinary incontinence.
21. A method according to claim 13, characterized in that the adverse contraction of the smooth muscle causes irritable bowel syndrome.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/205,770 | 1998-12-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01005429A true MXPA01005429A (en) | 2002-03-26 |
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