MXPA99005024A - Benzodioxole, benzofuran, dihydrobenzofuran, and benzodioxane melatonergic agents - Google Patents
Benzodioxole, benzofuran, dihydrobenzofuran, and benzodioxane melatonergic agentsInfo
- Publication number
- MXPA99005024A MXPA99005024A MXPA/A/1999/005024A MX9905024A MXPA99005024A MX PA99005024 A MXPA99005024 A MX PA99005024A MX 9905024 A MX9905024 A MX 9905024A MX PA99005024 A MXPA99005024 A MX PA99005024A
- Authority
- MX
- Mexico
- Prior art keywords
- trans
- methyl
- cycloprop
- dihydrobenzofuran
- dihydro
- Prior art date
Links
- BNBQRQQYDMDJAH-UHFFFAOYSA-N Benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 title abstract description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title abstract description 4
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 title abstract description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-Benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims description 89
- 150000001875 compounds Chemical class 0.000 claims description 82
- -1 (-) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] -ethyl] trifluoroacetamide Chemical compound 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 13
- 125000004565 2,3-dihydrobenzofuran-4-yl group Chemical group O1CCC2=C1C=CC=C2* 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 10
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 10
- 206010040984 Sleep disease Diseases 0.000 claims description 8
- 230000001225 therapeutic Effects 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
- MTCPVWSSXTWJNQ-GXSJLCMTSA-N N-[[(1R,2R)-2-(1,3-benzodioxol-4-yl)cyclopropyl]methyl]propanamide Chemical compound CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1OCO2 MTCPVWSSXTWJNQ-GXSJLCMTSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- UGJKIZHUQIQHEA-BNPZDMCGSA-N N-[[(1R,2R)-2-(2-methyl-2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]cyclopropanecarboxamide Chemical compound C([C@@H]1C[C@H]1C1=CC=CC2=C1CC(O2)C)NC(=O)C1CC1 UGJKIZHUQIQHEA-BNPZDMCGSA-N 0.000 claims description 3
- NNZZWCYHHZWCGS-SMDDNHRTSA-N N-[[(1R,2R)-2-(3,4-dihydro-2H-chromen-5-yl)cyclopropyl]methyl]propanamide Chemical compound CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCCO2 NNZZWCYHHZWCGS-SMDDNHRTSA-N 0.000 claims description 3
- 230000035591 circadian rhythms Effects 0.000 claims description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims description 2
- VXIVSQZSERGHQP-UHFFFAOYSA-N Chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 claims description 2
- 241000065675 Cyclops Species 0.000 claims description 2
- QGZFNJQLTUGLGU-GXTWGEPZSA-N N-[[(1R,2R)-2-(2,2-dimethyl-3H-1-benzofuran-4-yl)cyclopropyl]methyl]butanamide Chemical compound CCCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CC(C)(C)O2 QGZFNJQLTUGLGU-GXTWGEPZSA-N 0.000 claims description 2
- XLIBIVRRQMKGCN-SWLSCSKDSA-N N-[[(1R,2R)-2-(3,4-dihydro-2H-chromen-5-yl)cyclopropyl]methyl]butanamide Chemical compound CCCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCCO2 XLIBIVRRQMKGCN-SWLSCSKDSA-N 0.000 claims description 2
- ZWTTUSKMTRPACS-CMPLNLGQSA-N N-[[(1R,2R)-2-(1,3-benzodioxol-4-yl)cyclopropyl]methyl]cyclopropanecarboxamide Chemical compound C([C@H]1[C@@H](C1)C=1C=2OCOC=2C=CC=1)NC(=O)C1CC1 ZWTTUSKMTRPACS-CMPLNLGQSA-N 0.000 claims 2
- XOCFJFOLZXONSO-GXFFZTMASA-N N-[[(1R,2R)-2-(1-benzofuran-4-yl)cyclopropyl]methyl]propanamide Chemical compound CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1C=CO2 XOCFJFOLZXONSO-GXFFZTMASA-N 0.000 claims 2
- DUVGGVDKVKDKOI-WCQYABFASA-N N-[[(1R,2R)-2-(2-methyl-1-benzofuran-4-yl)cyclopropyl]methyl]acetamide Chemical compound CC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1C=C(C)O2 DUVGGVDKVKDKOI-WCQYABFASA-N 0.000 claims 2
- ZGELHOWKZDKQCO-GXTWGEPZSA-N N-[[(1R,2R)-2-(2-methyl-1-benzofuran-4-yl)cyclopropyl]methyl]butanamide Chemical compound CCCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1C=C(C)O2 ZGELHOWKZDKQCO-GXTWGEPZSA-N 0.000 claims 2
- VCRCOHQUQRDIGR-WCQYABFASA-N N-[[(1R,2R)-2-(2-methyl-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide Chemical compound CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1C=C(C)O2 VCRCOHQUQRDIGR-WCQYABFASA-N 0.000 claims 2
- 230000027288 circadian rhythm Effects 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 1
- HNHRUMBSKWPEPI-OJBNZGHXSA-N 2-chloro-N-[[(1R,2R)-2-(2-methyl-2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]acetamide Chemical compound O1C(C)CC2=C1C=CC=C2[C@@H]1C[C@H]1CNC(=O)CCl HNHRUMBSKWPEPI-OJBNZGHXSA-N 0.000 claims 1
- 229920001076 Cutan Polymers 0.000 claims 1
- 101710033382 GINS1 Proteins 0.000 claims 1
- 101800000268 Leader protease Proteins 0.000 claims 1
- FWKOJMWDEFTOBO-SMDDNHRTSA-N N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]butanamide Chemical compound CCCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 FWKOJMWDEFTOBO-SMDDNHRTSA-N 0.000 claims 1
- NDYSAPOPLJAPBY-DALSCRRLSA-N N-[[(1R,2R)-2-(2-methyl-2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]acetamide Chemical compound O1C(C)CC2=C1C=CC=C2[C@@H]1C[C@H]1CNC(C)=O NDYSAPOPLJAPBY-DALSCRRLSA-N 0.000 claims 1
- 101710041402 PABG_02447 Proteins 0.000 claims 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N Ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims 1
- 150000005528 benzodioxoles Chemical class 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 239000000243 solution Substances 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 238000000034 method Methods 0.000 description 67
- 239000003921 oil Substances 0.000 description 61
- 235000019198 oils Nutrition 0.000 description 61
- 229910001868 water Inorganic materials 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000000047 product Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 45
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 239000012267 brine Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 229960003987 Melatonin Drugs 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 21
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HRPVXLWXLXDGHG-UHFFFAOYSA-N acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 12
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 239000000969 carrier Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000002024 ethyl acetate extract Substances 0.000 description 11
- 229940086542 triethylamine Drugs 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 101700067048 CDC13 Proteins 0.000 description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 239000008079 hexane Substances 0.000 description 8
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-Hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- 230000002829 reduced Effects 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 5
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- 108050009605 Melatonin receptor family Proteins 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
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- 238000000746 purification Methods 0.000 description 5
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- HJNKGZJKCPGURN-GZMMTYOYSA-N (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carbaldehyde Chemical compound O=C[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 HJNKGZJKCPGURN-GZMMTYOYSA-N 0.000 description 4
- UATDSCPOQLULBO-CAWIPBJDSA-N (1R,2R)-2-(2-methyl-2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carbaldehyde Chemical compound O1C(C)CC2=C1C=CC=C2[C@@H]1C[C@H]1C=O UATDSCPOQLULBO-CAWIPBJDSA-N 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N Diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
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- 238000007792 addition Methods 0.000 description 4
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- 125000004122 cyclic group Chemical group 0.000 description 4
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- 239000003085 diluting agent Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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- 229910052763 palladium Inorganic materials 0.000 description 4
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- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
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- RLBNWXQWPDJHAT-UHFFFAOYSA-N 1-benzofuran-4-carbaldehyde Chemical compound O=CC1=CC=CC2=C1C=CO2 RLBNWXQWPDJHAT-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- CHDSHBWEGSCEDX-UHFFFAOYSA-N 2,3-dihydro-1-benzofuran-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1CCO2 CHDSHBWEGSCEDX-UHFFFAOYSA-N 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- IOLCXVTUBQKXJR-UHFFFAOYSA-M Potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 3
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- 150000001298 alcohols Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
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- 238000007796 conventional method Methods 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- DPRHUPBFIBSLKQ-UHFFFAOYSA-N methane;sulfuryl dichloride Chemical compound C.ClS(Cl)(=O)=O DPRHUPBFIBSLKQ-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- COJXFXOWPFGTPH-UHFFFAOYSA-N naphthalene;urea Chemical class NC(N)=O.C1=CC=CC2=CC=CC=C21 COJXFXOWPFGTPH-UHFFFAOYSA-N 0.000 description 1
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- YIKSCQDJHCMVMK-UHFFFAOYSA-N oxalic acid diamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
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Abstract
Novel derivatives of benzodioxole, benzofuran, 2,3-dihydrobenzofuran, and benzodioxane are useful as melatonergic agents.
Description
BENZODIOXO, BENZOFURAN, DIHYDROBENZOFURAN, AND BENZODIOXAN MELATONERGIC AGENTS
Field of Invention
The invention relates to novel substi tuted benzodioxoles, benzofurans, dihydrobenzofurans, benzodi oxanes and related derivatives having medical and bio-fec tive properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns benzodioxoles, benzofurans, dihydrobenzofurans and related derivatives in the presence of amino substituted cyclopropyl methyl groups. These groups possess the strongest properties that r can. make them useful in the treatment of certain medical disorders.
Background of the Invention
Eiatonin d -'-ace l-S-methoxy-tryptamine) is a normone that is first synthesized and secreted by the pineal gland. The mulato ina levels are a cycle, a circadia pattern, or high levels that occur during
Re .: 30248 the dark period of a circadian light-dark cycle. Melatonin is involved in the translation of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in mammals foperperiodics, the control of cardiac rhythms and the modulation of the retinal physiology.
NHCOCH3
Melatonin
Recent evidence shows that melatonin exerts these biological effects through specific receptors. The use of the agonist radi oe ti that is biologically active ['s |] -2-sodomela to 1 na is the main one for the identification of high affinity melatonin receptors in the CNS of a variety of species The areas of two cloned melatonin receptors are reported in [Reppert, et al., Proc. Nati, Acad. Sci. 92, pages 8734-8738, (1995) and Reppert, et al., Neuron 13 , pages 1177-1185, (1994).] In mammalian brains, autoradiography studies have localized the distribution of melatonin receptors for some specific structures, however these have significant differences in the distribution of the melatonin receptor between related species. In general, the site with the highest density of binding occurs in the discrete nucleus of the hypothalamus.In humans, the specific [125 |] -2-iodomela onine that binds to the hypothalamus is completely localized to the suppressive nuclei, receptors are located from melatonin strongly suggested with the human bioioaic clock.
Exogenous administration of melatonin was found to synchronize circadian rhythms in rats (Cassor, e, e t al., J. Biol. Rhythms, 1: 219-229, 1986). In hands, the administration of the melamine was used to treat the disturbances at. dream related to flight delay, which is considered for the desynchronization of circadian kidneys Arenat, e t al. , Br. Med. J.
292: 1170, 1986). In addition, the use of a single dose of melatonin to induce sleep in humans is claimed by Wurtman in International Patent Application WO 94/07487, published on April 14, 1994.
Thus, melatonin agonists may be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists may also be useful for further studies of melatonin receptor interactions or as in treatment of conditions affected "by the activity of meiatonir, a, such as depression, flight delay, change syndrome, work, sleep disorders, glaucoma, reproduction, cancer, syndromic and premenstrual, disorders of immunity, disorder is of joint inflammation and neurological disorders.
In addition to simple mdol derivatives of the same metal, several bicyclic structures can be used. prepare and describe its use as a melatonin link. In general, these bicyclic amide structures can be represented as:
wherein Z is an aryl or heteroaryl system linked by two carbon atoms attached to the amide group. The following are some specific examples.
Yous, e t al., In the European Patent Application EP-527,687A, published on February 17, 1993, describes r i ie t i laminae i_ as linkages of the ina melato,
Ar '' VR '
in aonoe es ír.te alia, a radical t e. zoo thiophen -3-? l benzimidazol-1-yl, ben: cib? f: ar.-3-? l, l, 2-benzisoxazol-3-yl, 1,2-ben zi so 11 ao 1 - 3 - 1, or substituted or unsubstituted indazol-3-yl; Ri is, inter alia, an alkyl or cycloalkyl group; and R2 is hydrogen or lower alkyl.
Yous, e t al. , - in the European Patent Application EP-506,539A, published on September 30, 1992, claims links ii,
eleven
where A is oxygen or sulfur; X is a methylene group or a bond; and R is H or lower alkyl wherein p is 1 and B is defined by the radical iii,
R, H2CH2C '' 4y R, 0 iii
wherein Rj is hydrogen or lower alkyl and R2 e s, er alia, hydrogen, lower alkyl or c 1 to i or 1. Alternatively, R is defined by the r a d: cal i i do of p is 0 or 1 and B is lower alkoxy.
Several naphthalene derivatives are also described as melatonin bonds.
Andrieux, et al. , in the European Patent Application EP-447,285A, published on September 18, 1991, claims amidoalqui Ina ft alenos iv,
IV
wherein R is lower alkyl; Ri is hydrogen or lower alkyl; and R is, inter al a, hydrogen, lower alkyl, or cycloalkyl.
You s, e t al., In the Patent Application
EP-562.95cA, published on September 29, 1993, describes derivatives of amide and urea naphthalene v,
wherein R is hydrogen or 0R4 wherein R4 is inter alia hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; Ri is hydrogen or COOR5 wherein R5 is hydrogen or alkyl; R2 is hydrogen or alkyl; X is NH or a bond; and R3 is, inter alia, alkyl, alkenyl, or cycloalkyl.
Lesieur, et al. , in the European Patent Application EP-530,087A, published on March 3, 1993, describes naftileti lureas and na f t i le t t tioureas vi,
yj
wherein R is hydrogen or OR where R3 is, inter alia, hydrogen, lower alkyl, or cycloalkyl; R: is hydrogen or lower alkyl; X is oxygen or sulfur; and R 2 is, inter alia, lower alkyl or c 1 c 1 or 1 q i 1 o.
Langlo s, et al., In Australian Patent Application U-A-48729/93 describes arylalkyl (thio) amides il as melatonergic bonds,
VII
wherein Ri is hydrogen or lower alkyl; R2 is hydrogen, halogen, or lower alkyl; R3 and R4 are identical or different groups including, inter alia, hydrogen, halogen, or lower alkyl or R3 and R4, together with the benzene ring bearing the same, forms an E3 ring system chosen from, inter alia, naphthalene , understanding that the portion of the ring system E3 formed by R3 and R < and the two carbon atoms of the benzene ring carried thereon are unhydrogenated or partially hydrogenated; R5 is hydrogen or lower alkyl; and R¿ is,
X rX
wherein X is sulfur or oxygen and R7 is, inter alia, lower alkyl or alkenyl. Compound vii i is included as a specific example,
Horn and Dobocovich, et al. , in European Patent Application EP-420,064A, published on April 3, 1991, discloses 2-aminotetrains Vx as melatonin bonds,
IX
where R; is, er, hydrogen, lower alkyl, or lower alkoxy; R 2 is, inter alia, hydrogen, halogen, or lower alkoxy; R3 is, go. ter alia, hydrogene, or lower alkyl; R 4 is, n er al a, lower alkyl, haloalkyl or cycloalkyo; and R5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Copinga et al. , in J Med. Chem. , 36, pages 2891-2898 (1993), describes ami dometo-xi tetralinos of structure x_ and its mela tonergic properties.
H
In structure _x, Ri is H or OCH3 and R2 is alkyl, haloalkyl, phenylalkyl or phenyl.
Lesieur, et al. , in EP-708,099A, published on April 24, 1996, describes compound structure x_i, which are useful for the treatment of disorders caused by an imbalance of elatonin.
XI where = J * - = is a single double c link; Ri = Me or MeNH; and X-Y = -CH (Me) -CH2-, CH2CH (OH) - or (CH2) 3-.
North e t., In International Application WO 95/29173, published November 2, 1995, describes naphthalene derivatives of structure xii:
m
wherein R 1 is a group of the formula CR, R 4 (CH 2) FNRs CORE; R2 is hydrogen, halogen, C-alkyl, OR? or CO; R7; and it can be the same or different subtituent when q is 2; R3, R4 and R5, which may be the same or different, are hydrogen or C-alkyl. _ó; R < = is C 1 -O-alkyl or C 3 -R-cycloalkyl is hydrogen or C 1-6 alkyl; n is zero, 1 or 2; p is an integer of 1, 2, 3 or 4; q is 1 or 2; and the puff lines indicate the absence or presedence of an additional eniace. The crtn et al. Compounds are taught to treat corkobs or 1 óg 1 eos.
In International Application WO 95/17405, published June 29, 1995, North et al. , describes compounds of structure xiii and teaches their use in the treatment of conditions related to the melatonin system.
???? Wherein R x is hydrogen, halogen or Ci-β alkyl; R2 is a group of formula -CR3R4 (CH2) pNR5COR6; R3 R and R5, which may be the same or different, are hydrogen or C alquilo alkyl.; Re is C 1_6 alkyl or
cycloalkyl C 3 _-; n is an integer of 2, 3 or 4; and p is a in ero oe i, 2, 3 c 4.
The descriptions aforementioned do not teach or suggest the new benzodioxol,
- > n benzofurans or dih drcoer. melatonergic zcfurancs of the present invention. The novel compounds of the present invention exhibit antagonist activity me 1 to t one r g 1 ca.
Brief description of the invention.
The invention provides a series of novel compounds of Formula I
wherein R, R1, R2, Q1, Q2, X, Y, Z and m are as defined above, including hydrates and solvates thereof which bind to the human receptor and therefore are useful as The agents treat me in the treatment of sleep disorders, temporary depression, changes in cardiac cycles, melancholy, tension, regulation of appetite, benign prostatic hyperplasia and related conditions.
Detailed description of the invention
The invention provides a series of novel compounds of Formula I and solvates thereof having the formula:
wherein Q1 and Q "are each independently hydrogen or halogen, X is CH2, CH or oxygen, Y is CR3, CR3R4 or (CH2) n, with n = 1-4, z is CH2, CH or oxygen; hydrogen, halogen or C alquilo4 alkyl in both cases, month 1 or 2, R: is Cj-6 alkyl, C3_6 cycloalkyl, C halo-3 haloalkyl, C?-6 alkylamino, C2 al ally =,, C: 4-alkoxy (C? _ Alkyl, C i _ a 1 qu i 1 t io { C •.) To 1 qu i 1 oo trifluoromethylalkyl C i -4; R "is hydrogen or C 1-4 alkyl; and R3 and R 'are each independently hydrogen or C: -4 alkyl.
The invention also provides a method for treating sleep disorders and related conditions, which comprises administering a therapeutically effective amount of a compound of Formula I or a solvate or hydrate thereof.
Q1 and Q2 are selected from H and halogen (ie, bromine, chlorine, iodine or fluorine). It is more preferred that Q1 and Q2 are H.
X can be CH2, CH (when a double bond is present) or oxygen.
Y is CR (when a double bond is present), CR R4 or - (CH2) n- * and n is from 1 to 4, but preferably 1 or 2.
Z may be CH2, CH (when a double bond is present) or oxygenates, with the oxygen bond being more preferred.
When X and Y are CH; and Z is oxygen or Z and Y are CH; and X is oxygen, the compound is a dinidrcber. zcfura o. When X and Y are CH and Z is ex gene or or Z and Y so CH and X is oxygen, the compound is benzofuran. When X and Z are oxygen and Y is CH2, the compound is a benzodioxole. When X and Z are oxygen and Y is (CH2) 2 / the compound is benzodioxane. Preferred are compounds in which X and Y are CH2 and Z is oxygen.
Both groups R are the same portion. Useful R groups include hydrogen, halogen and C alquilo _ alkyl, R is preferably hydrogen.
m is 2, preferring that m = 1
R1 is one of several types of groups. R1 is selected from Ci_6 alkyl, C3_ecycloalkyl, haloalkyl C * groups. - 3, alkylamino C? _6, alkenyl C2_ c, C- ai cox ii C; -4 to 1 quio, C: -4 a lqui 11 io (C? - a 1 qui 1 oorif 1 uor ome i lalqui 1 or C. R 1 is preferably C 1 -alkyl or C 3 -cycloalkyl.
R ~ is idroge o or alkyl C i_. R 'is preferably hydrogen.
R and P "are hydrogen or C 1 alkyl It is preferred that R 3 and R 4 are both hydrogen It is also preferred that R 'is hydrogen and R 4 is methyl.
When R3 is hydrogen and R4 is methyl, both enantiomers and racemates are preferred.
"Alkyl" means a straight or branched monovalent chain group of the formula C? H2x + ?, with x being the number of carbon atoms.
"Y - X" and "Y - Z" refer to a single bond or fixed double bond when defined by 'the substituent X, Y, and Z.
"Cycloalkyl" groups are monovalent cyclic portions containing at least 3 carbon atoms and conforming to the formula C? H (2? -?), With x being the number of carbon atoms present. The cyclopropyl group is a preferred cycloalkyl moiety.
"Haloalkyl" includes hydrocarbon radicals of each straight or rationed having from 1 to 3 portions of halogen. "Halogen" means F, Ci, Br or I. The preferred allogens in the? :: r :: or, is loalqic of P, include F and Cl.
"Alkylamino" refers to substituents -NHalkyl -containing 1 to 6 carbon atoms, preferably -NHCH3 or -NHCH2CH3 groups.
Preferred compounds have IC 50 values of 250 nM or less in melatonergic binding tests described herein.
A group of preferred compounds include the benzofurans of Formula I wherein the group, -X-Y-Z-, consists of -CH = CH-O- and -CH = CCH3-O-.
Some preferred compounds of this group include: (-) - (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-ylmethyl-cyclopropanecarbo amide; (-) - (trans) -N- [[2 - (benzcyuran-4-yl) cycloprop-1-yl] r.ethyl} -propa to ida; (trans) - N - [[2- (2-met? l-bep zcfuran-4-yl) cycloprop-1-yl] ethyl] -acetamide; (trans) -N- [[2- (2-methyl-be.n zcfuran-4-yl) cycloprop-i-ii] ethyl] -propanarr. Going; .transí - N - [[2- (I-rr.et? l- Denzofuran-4-yl) cycloprop-1-ymethyl] -measure;
(trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-yl] methyl] -acetamide; (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-yl] -yl] -propanamide; (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-ylmethyl] -butanamide; (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-y1] me t yl] -2-methylpropanamide; (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-y1] me t i 1] cyclopropane carboxamide; and (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-ylmethyl] -N-methylurea.
A second group of preferred compounds includes the dihy droben zofu ranos of Formula I wherein the group, -XYZ-, consists of -CH2-CH2-0-, -CH2-C (CH3); -0- and -CH; -CH CH3) -O-.
Some preferred compounds of this second group include: (+) - N - [[2- (2, 3-d? H? Drober, zofuran-4-yl) cycloprop-1-yl] methyl j prcpanamioa; .'-) - (trans) - N - [[2- (2,3-dihydrobenzofuran-4? i) cyclcprop-1-? i > , et? i] -acetamide;
(-) -. { trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloproprop-1-yl] methyl] -butanamide; (-) - (trans) -N - [[2- (2,3-dihydrobehzofuran-4-yl) cycloprop-1-yl] methyl] -N-me t i 1 urea; (-) - (trans) -N- [[2- (2,3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] -methoxyacetamide; (-) - (rans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] cyclopropanecarboxamide;
(-) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] trifluoroacetamide; (trans) -N- [[2- (2, 3-dihydro-2,2-dimeti-1-benzofuran-4-ii) cycloprop-1-yl] me t i 1] propanamide; (trans) -N- [[2- (2,3-dihydro-2,2-dimethyl-benzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (+) - (trans) -N- [[2 - (2-methyl-2, 3-dihydrobenzofuran-4? i; cycloprop-1-yl] methy1] acetamide; { - > -) - ( trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl] c? cloprop-1-yl] met? l) propanamide; (+) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (+) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-ii! cicioprop-l-? l] methyl] -2-methylpropanamide; • * - (trar.s ! - N - [[2- (2-met? L-2, 3-dihydrobenzofuran-4-? Lc? Cloprop-l-? L] methyl] chloroacetamide;
(-) - (trans) -N - [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] propanamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] -2-methylpropanamide; (-) - (trans) -N- f [2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] acetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] methoxyacetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] cyclopropane carboxamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) c? cloprop-l-? l] metii] -acetamide; • - - (trans) - N - [[2 - (2,3-d? Hydrobenzofuran-4-yl 1 c? Cloprop-1? L] methyl] -propanamide; ítrans) - - [[2- (2 , 3-oih? Drobenzofuran-4-yi) cyclic? Rop-1-? Ljmet? Lj -propanamide; (trans) -N- [[2- (2, 3-d?? drobenzofuran-4-11) cycloprop-1-yl] met? l] -butanamide; (tra s) -N- [[2- (2, 3-dihydro-5,7-diiodobenzofuran-4-yl c? cloprop-l-? ij et? i] propanam? da; and lUansí - - [ 2- i 2, 3-d?? Dro-5-diiodobenzofuran-4-yl) c? Clo? Rop-l-? L] methyl] propanamide.
A third group of preferred compounds includes the benzodioxoles of Formula I wherein the group, -X-Y-Z-, consists of -0-CH2-0-.
Some preferred compounds in the third group include: (trans) -N- [[2- (1,3-benzodioxol-4-yl) cycloprop-1-yl] methyl] -acetamide; (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1 -i 1] me t il] -ace tamide; (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-y1] me t i 1] -propanamide; (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methyl] -propanamide; (trans) -N- [[2- (1,3-benzodioxol-VII) cycloprop-1- 11] m e t i 1] -butanamide; (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-y1] methyl] -b-tanamide; (trans) -N- [[2- (1, 3-benzod? oxol-4-yl) cycloprop-1? l] methyl] cyclopropane carboxamide; (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methy] cyclopropane carboxamide; . { trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] -2] -methypropane amide;
(-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] eti] -2-methylpropanamide; (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methyl] -N'-ethylurea; and (-) - (trans) -N- [[2- (1,3-benzodioxol-4-yl) cycloprop-1-yl] methyl] -N'-ethylurea.
Another group of preferred compounds include the ben zodioxanes of Formula I wherein the group, -X-Y-Z-, consists of -O- (CH) 2-0-.
Some preferred benzodioxanes include: (-) - (trans) -N- [[2- (2,3-dihydro-l, 4-benzodioxin-5-yl) cyclopro? -1-yl] ethyl] propanamide; (-) - (trans) -N- [[2- (2, 3-dihydro-l, 4-benzodioxin-5 -. - »- •. c? cloprop-l-? l.} et. i] acetamide; (+) - trans) -N - [[2- (2,3-dihydro-1,4-benzodioxin-5-yl) cycloprop-1-ii Jrnetii] -N-met-lurea; : +) - (transí -N- [[2- (2, 3-d? h? dro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] met? l] -2-methoxyacetamide; (-) - (trans - N - [[2-1, 2-d? -hydro-l, 4-benzodioxin-5-c? clo? rop-1-? lj etii] cyclopropanecarboxamide;
- (trans) -N - [[2- (2, 3-d?? dro-1,4-benzodioxin-5-c? elcprop-1? ljmet? ljbutanamide;
(+) - (trans) -N- [[2- (2, 3-dihydro-l, -benzodioxin-5-yl) cyclop "rop-1-yl] methyl] propenamide; (-) - (trans) - N- [[2- (2, 3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] trifluoroacetamide; (-) - (trans) -N- [[2- (2, 3-dihydro-l, -benzodioxin-5-yl) cycloprop-l-yl] methyl] -3,3,3-trifluoropropanamide; (+) - (trans) -N- [[2 - (2,3-dihydro -l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] propanamide; (trans) -N- [[2- (2,3-dihydro-l, 4-benzodioxin-5-yl) cycloprop- l-yl] methyl] acetamide; (trans) -N- [[2- (2,3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-l-yl] methyl] propanamide; (trans) -N - [[2 - (2,3-dihydro-l, 4-benzodioxin-5-yl) cicioprop-l-yl] met? L] bunamide; (trans) - N - [[2- (2, 3- d? n? dro-l, 4-benzodioxin-5-yl) c? cloprop-l-yl] met? i] -2-met? lpropanamide; (trans) -N- [[2- (2, 3- d? h? arc-l, -benzod? oxin-5-ii) c? cloprop-1-? li etii) cyclopropane carboxamide; (trans) -N- [[2- (2, 3-d? -l, 4-benzodioxin-5-yl) c? cloprop-l-yl] met? l] -N-methylurea; and ( trans; -rJ - [[2-. { 2,3-d? N? Arc-l, 4-benzodioxin-5-yl) c? Cloprop-1? I] methyl] -N-ethylurea.
Yet another group of preferred compounds includes the benzofurans of Formula I wherein the group, X-Y-Z-, consists of -O-CH = CH- and -0-CCH3 =
CH-.
Some preferred compounds of this group include: (trans) -N- [[2- (benzofuran-7-yl) cycloprop-1-y1] methyl] acetamide; (trans) -N- [[2- (benzofuran-7-yl) cycloprop-1-yl] methyl] propanamide; (trans) -N- [[2- (benzofuran-7-yl) cycloprop-1-yl] methyl] butanamide; and (trans) -N- [[2- (benzofuran-7-yl) cycloprop-1-yl] methyl] -cyclopropanecarboxamide.
In still another group of preferred compounds includes the benzopyrans of Formula I wherein the group, -X-Y-Z, 'consists of -CH 2 - (CH 2) 2 -O-.
Some preferred compounds of this group include: (trans) -N- [[2 - (3,4-d? H? Oro-2H-l-benzopyran-5-yl.) Cycloprcp-1-ii-methyl. ] propanamide;
(trans) -N- [[2- (3, 4-dihydro-2H-l-benzopyran-5-yl) cycloprop-1-yl] methyl] cyclopropanecar oxamide;
(-) - (trans) -N- [[2- (3, 4-dihydro-2 H -l-benzopyran-5-yl) cycloprop-1-yl] methyl] propanamide; (-) - (trans) -N- [[2 - (3, 4-dihydro-2H-1-benzopyran-5-yl) cycloprop-1-yl] methyl] acetamide; (trans) -N- [[2- (3, 4-dihydro-2H-l-benzopyran-5-yl) cycloprop-1-yl] methyl] butanamide; and (+) - (trans) -N - [[2- (3,4-dihydro-2H-1-benzopyran-5-yl) cycloprop-1-yl] methyl] propanamide.
Additionally, the compounds of Formula I encompass all pharmaceutically acceptable solvents, particularly hydrates, thereof. The present invention also encompasses diastereomers as optical isomers, for example, mixtures of enantiomers including racemic mixtures, or as individual enantiomers and dihedral esters, which result as a consequence of structural asymmetry in certain compounds of Formula I. The separation of the individual isomers or selective synthesis of the individual isomers is accomplished by 1 application to various methods that are well-known to practitioners in the art.
The compounds of Formula I can be prepared using all the processes shown in the following Reaction Schemes:
Reaction Scheme 1
The synthesis of the 4-aryl-propenoic acid derivatives, 2_ and _3, are shown in Reaction Scheme 1. The starting aldehydes, 1, can be prepared by methods well known to those skilled in the art. The condensation of malonic acid with the aldehydes 1_, in solvents such as pyriaine with catalysts such as piperi r.a c pyrrolidine, yields 4-aryl-propenoic acid, 2_. Subsequent conversion of the acid to the acid chloride using reagents such as thionyl chloride, phosphoryl chloride, or the like, followed by reaction with hydroxylamine of N, 0-dimethyl gives the intermediate amide 3_ in good yield. Alternatively, the aldehyde 1 can be converted directly to the 3-amide by using reagents such as a diethyl (-methoxy-N-me-t-yl-carboxymethyl) phosphonone with a strong base such as sodium hydride.
Reaction System 2
The conversion of the intermediate amide 3_ to the racemic carbcxaidehide trans-cyclopropane intermediate, 4_, is shown in Reaction Scheme 2. The 3 rd ediary is allowed to react with cyclpropanded reagents such as sodium trirheratide iodide and sodium hydride. in solvents such as DMF, THF, or the like. Subsequent reduction using reagents such as LAH in solvent such as THF, ethyl ether, or the like, yields the trans-cyclopropane carboxaldehyde intermediate, racemic, 4_.
Reaction scheme 3.
The racemate of racemic cyclopropane 5_ (R = halogen) can be prepared from intermediate 2_ as shown in Reaction Scheme 3. The average medium 2 is converted to the corresponding alcor, allylic by treatment with reducing agents such as such as borohydride of soi .: rr.js-do in solvents such as THF. The acylation is carried out using reagents such as acetic anhydride or acetyl chloride gives the acetate which is allowed to react with cyclopropanating reagents such as sodium chloro-di-fluoroacetate in diglyme to provide the racemic, trans-cyclopropane acetate intermediate.
Reaction Scheme 4
The conversion of the acid 2_ to the intermediate ca rboxa ldeh i do cyclopropano chiral,. { -) - (t ra ns) - 4_, is shown in the Reaction scheme 4. Intermediary 2_, is condensed with (-) - 2,10-canforsultam ba or standard conditions, and then it is pressed ted in the presence of a catalyst such as palladium acetate using diazomethane generated from reagents such as 1-methyl-3-ni tro-l-ni t rosoguanidino. Subsequent reduction using reagents such as LAH in solvent such as THF, followed by oxidation of the intermediate alcohols using reagents such as DMSO / oxalyl chloride, or PCC, gives the intermediate cyclopropane carboxy ldehyde, (-) - (trans) -4_ , in good performance. The enantiomer, (+) - (trans) -4_, can also be obtained by employing a similar procedure using (+) - 2,10-camphorsultam instead of (-) -2, 10-campforsul tam.
When this is desired to prepare compounds of Formula I where m = 2, the intermediate alcohol can be activated in conventional manner such as with mesyl chloride and treated with sodium cyanide followed by reduction of the nitrile group with a reducing agent such as or LAH to produce the intermediate amine 6.
Reaction Scheme 5
Reaction Scheme 5 shows the conversion of the intermediates 4_ and 5 to the intermediate amine, 7_, and the subsequent conversion of 6_ or 1_ to compounds of Formula I. The liquid acetate 5_ is hydrolyzed with potassium hydroxide for the alcohol, converting the mesylate with sulfonyl chloride methane and triethyl amino to CH; C1; and then with pouring the azido by treating with sodium azide in solvents such as DMF. The subsequent reduction of the azido group with a reducing agent such as LAH produces the amine in the intermediate. Further reaction of 6_ or 1_ with acylating reagents gives compounds of Formula I. Suitable acylating agents include carboxylic acid halides, anhydrides, acyl imidazoles, alkyl isocyanates, alkyl isothiocyanates, and carboxylic acids in the presence of condensing agents. , such as carbonyl imidazole, carbodiimides, and the like.
Reaction Scheme 6.
The Reaction Scheme shows the addition of secondary compounds of Formula I (R '= H?) To give tertiary amides of Formula I (R.sub.2 = alkyl) .The secondary amide is reacted with a base ta.sub.i cone sodium hydride, tert - potassium oxide, or else illates, and then reacted with an acidic reagent such as alkyl halides, alkyl sulfonate esters, or the like to produce tertiary amines of Formula I.
Reaction Scheme 7
Reaction Scheme 7 shows the halogenation of the compound of Formula I. The carboxamides, (Q1 = Q2 = H), are reacted with excessive amounts of halogenating agents such as iodide, N-bromosuccinimide, or the like to give the dihalo compounds. of Formula I (Q1 = Q2 = halogen). In addition, an amount is optional of these halogenating agents can be used to give the monohalo compounds of Formula
I (CV = H, Q2 = halogen, or Q1 = halogen, Q2 = H).
In both cases, additives such as the first tetraacetate VI can be used to facilitate the reaction.
Biological Activity of the Compounds
The compounds of the invention are melatonergic agents. These are found to bind the human mela tonergic receptors expressed in a stable cell line with good affinity. In addition, the compounds are agonists determined by their ability, such as melatonin, to block the forskolin-stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the invention may be useful as sedatives, chronobiotics, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents find use in the treatment of tension, sleep disorders, temporal depression, appetite regu- lation, changes in cardiac cycles, elastin, prostatic hyperplasia b ig and ccndicic are related.
Linker Activity of the Melatonergic Receptor
Reagents
(a) TME = 50 mM Tris buffer solution containing 12.5 mM MgCl2, and 2 mM EDTA, pH 7.4 at 37 ° C with concentrated HCl. (b) Washable buffer: 20 mM Tris base containing 2 mM MgCl2, pH 7.4 at room temperature. (c) Melatonin 10 ~ 4M (10 ~ 5M final concentration). (d) 2 - [1 * 5 | ] -Yodóme la t oni na, final concentration 0.1 M.
Homogenates of Membra a
The ML melatonin cDNA receptor is subcloned into peDNA 3 and is introduced into NIH-3T3 cells using Lipofectarr. go. to. The transformed NIH-3T3 cells resistant to geneticin (G-418) were isolated, and single colonies expressing the elastones of linked elastin Odo were isolated. LJS cells were maintained in DMEM supplemented with 10% calf serum and G-418 (0.5 g / liter). Cells grew to confluence in a T-175 flask, cure using a Hank balanced salt solution, and freezing at -80 ° C. To prepare homogeneous membranes, melting pellets on ice, and resuspending in a TME buffer solution in the presence of 10 μg / ml of aprotinin and leupeptin, and 100 μM of phenylethylsulfonyl fluoride. The cells were then homogenized using a dounce homogenizer, and centrifuged. The resulting pellets were resuspended with the homogenizer dounce in TME (supplemented with the above protease inhibitors) and frozen. On the day of analysis, the small aliquot was thawed on ice and resuspended in cold TME ice (1: 50-1: 100 v / v) and frozen and frozen until analyzed.
Incubation: C for 1 hour. The reaction was terminated by filtration. The filters were washed times
References: Reppert, e t al., Neuron, 13 pages 11 85 (1994). The binding data for some compounds of Formula I are shown in Table 1. -
Table 1: Link of Melatonin for some Compound of Formula I
a = IC50 values for the human melatonin binding receptor ML? a + = 250 nM > IC50 > 100 nM ++ = 100 nM > IC50 > 10 nM +++ = 10 nM > IC50.
The compounds of the present invention have affinity for the receptors of the endogenous pineal hormone, melatonin, as determined in a receptor binding assay, as described above in Table 1 for the (human) ML? A receptors. Melatonin is diffuse in the regulation of a variety of biological rhythms and exerts these biological effects through interaction with specific receptors. This evidences that the administration of melatonia agonists are of clinical utility in the treatment of several conditions regulated by the activity of melatonin. Such conditions include depression, flight delays, work shift syndrome, sleep disorders, glaucoma, some disorders associated with reproduction, cancer, benign prostatic hyperplasia, immune disorders and neuroendocrine disorders.
For therapeutic use, the pharmacologically active compounds of Formula I can normally be administered as a pharmaceutical composition comprising as the active ingredient (s) essential (s) at least one of such compound in association with a pharmaceutically carrier. acceptable solid or liquid and, optionally, with pharmaceutically acceptable adjuvants and excipients employed in standard and conventional techniques.
The pharmaceutical compositions include dosage forms suitable for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), transdermal, bronchial or nasal administration. Thus, if a solid carrier is used, the preparation can be tableted, placed in hard gelatin capsules in the form of powders or pellets, or in the form of a trocho or pellet. The solid carrier may contain conventional excipients such as binding agents, fillers, lubricating tablets, disintegrators, wetting agents and the like. The tablet can, if desired, be covered with a film by conventional techniques. If a liquid carrier is employed, the preparation can be in the form of a slurry, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or it can be a dry product for reconstitution with water or other Appropriate vehicle before use. The liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agent, non-aqueous vehicle (including edible oils), preservatives, or flavoring or coloring agents. For parenteral administration, a vehicle can normally comprise sterile water, at least in large part, however saline solutions, glucose solutions and the like can be used. Injectable suspensions may also be used, in which case conventional suspending agents may be employed. Conventional preservatives and similar regulatory agents can also be added for parenteral dosage forms.
Particularly useful is the administration of a compound of Formula I in oral dose formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate for the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.
To make the pharmaceutical compositions containing the compounds of the present invention, the active ingredient (s) can usually be mixed with a carrier, a diluent for a carrier, or enclosed within a carrier which can be in the form of a carrier. capsule, pad, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pads, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example more than 10% by weight of the active compound, hard and soft gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
Some examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methyl cellulose , methyl- and propylhydroxybenzoa os, talc, magnesium stearate and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preservatives, softening agents or flavoring agents. The compositions of the invention can be formulated to be rapidly, sustained release or delayed release of the active ingredient after administration to the patient.
The dose of the compounds of Formula I to perform a therapeutic effect will depend not only on such factors as the age, weight, and sex of the patient and mode of administration, but also on the degree of desired neurological activity and the potential of the patient. compound in particular to be used for the particular disorder or condition concerned. It is also contemplated that the treatment and dose of the particular compound may be administered in unit dose forms and that the unit dosage form may be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision of the particular dose to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may vary by titration of the dose for the particular circumstances of this invention to produce the desired therapeutic effect. .
The compositions are preferably formulated in unit dosage form, each dose containing from about 0.1 to 100 mg, more usually 1 to 10 mg, of the active ingredient. The term "unit dose form" refers to units given physically appropriate as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with the pharmaceutically required carrier. .
These active compounds are effective in a wide dose range. For example, normal daily doses fall within the range of about 0.1 to 500 mg. In the treatment of adult humans, the range of about 0.1 to 10 mg / day, in single or divided doses, is preferred. Generally, the compounds of the invention can be used in the treatment of sleep and related disorders in a manner similar to that used for melatonin.
However, it will be understood that the amount of the compound currently administered will be determined by a physician, in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the choice of route of administration, age, weight , and individual patient response, and the severity of patient symptoms.
The compounds constituting this invention, their methods of preparation and their biological actions will appear more fully for consideration by the following examples, which are given only for the purpose of illustration and will not be construed as limiting the invention in sphere or scope.
Description of the Preferred Modalities.
In the following examples, used to illustrate the aforementioned processes, all temperatures are expressed in degrees centigrade and the melting points are incorrect. The proton magnetic resonance spectrum (1H NMR) is determined in the indicated solvents, and the chemical changes are reported in units d of the low field for the internal standard tetramethyl (TMS) and the constant coupling of the interproton are reported in Hertz (Hz ). The disintegration of the patterns is designated by the following: s, singlet; d, doublet; t, triplet; q, quartet; m, multipleto; double peak; dd, doublet of doublet; bd, double doublet; dt, triplet double; bs, double singlet; dq, doublet - quartet. The descriptions of the infrared (IR) spectrum includes only wave absorption of numbers (cm-1) having functional group identification values. The IR determinations are used using the pure compounds as a film or using potassium bromide (KBr) as a diluent. Optical rotations [cx] 25D were determined in the indicated solvents and concentration. Elemental analysis is reported as percent by weight.
Preparation of Formula 1 Intermediaries.
Preparation 1
Benzofuran-4-carboxaldehyde.
Step 1: N -metox i -N-me t i 1 -benzofuran-4-carboxamide.
A mixture of benzofuran-4-carboxylic acid [Eissenstat, et al., J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (2.8 g, 17.4 mmol) and thionyl chloride (25 mL) were added. they were heated to reflux for 2 hours and then concentrated in vacuo. The solid residue was dissolved in ethyl acetate (50 mL) and a solution of N, O-dimethyl-tilhydroxylamine dihydrochloride (2.8 g) in saturated NaHCO 3 (60 mL) was added with stirring. After stirring for 1.5 hours, the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated NaHCO 3 and concentrated in vacuo to give an oil (3.2 g, 95.4%).
Step 2: Benzofuran-4-carboxaldehyde.
A solution of N-met oxy-N-met i 1 -benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45 ° C and then LAH (0.7 g, 18.7 mmol) was added. ). The mixture was stirred for 15 minutes, allowed to warm to -5 ° C, and then cooled again to -45 ° C. Saturated KHS04 (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%).
Preparation 2.
2, 3-dihydrobenzofuran-4-carboxaldehyde.
Step 1: Acid 2, 3-dihydrobenzofuran-4-carboxylic acid.
Hydrogenated (60 psi) benzofuran-4-carboxylic acid (10.0 g, 61.7 mmol) in acetic acid (100 mL) over 10% Pd / C (2 g) for 12 hours. The mixture was filtered and the filtrate was diluted in water (500 mL) to give the acid 2, 3 -dihi droben zofuran-4-caboxylate as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5 ° C).
Step 2: (2,3-dihydrobenzofuran-4-yl) methanol.
A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred and LAH (4.64 g) was slowly added., 122 mmol). The mixture was heated to reflux for 30 minutes. The mixture was cooled and quenched cautiously with ethyl acetate and then with IN HCl (150 mL). The mixture was then made acidic with 12 N HCl until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was distilled in Kügelrohr to a clear oil which crystallized on cooling (8.53 g, 87.6%).
Step 3: 2,3-dihydrobenzo furan-4-carboxaldehyde.
DMSO (8.10 mL, 114 mmol) was added at -78 ° C to a stirred solution of oxalyl chloride in CH2C12 (40 mL of a 2M solution). A solution of (2,3-dihydrobenzofuran-4-yl) me tanol (8.53 g, 56.9 mmol) in CH C12 (35 mL) was added dropwise, and the solution was stirred at -78 ° C for 30 minutes . Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 minutes and diluted with CH2C12 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) which was used without purification.
Preparation 3.
2,3,4,5-tetrahydrobenzoxepin-6-carboxaldehyde.
Step 1: 2 -al i 1 -3 -benz loxibenzoa t o ethyl.
A mixture of ethyl 2-allyl-3-hydroxybenzoate (20.6 g, 100 mmol), benzyl bromide (18 g, 105 mmol), and potassium carbonate (17 g, 123 mmol), was heated in DMF to 100 ° C. C for 18 hours. The mixture was cooled and diluted with water (500 mL), and extracted with ethyl acetate three times. The ethyl acetate extracts were dried over brine and concentrated in vacuo as an oil (29.6 g, 100%).
Step 2: Ethyl 2- (3-hydroxypropyl) -3-benzyloxybenzoate.
A solution of 2 to 1 i 1 -3-benzyl-1-oxenzoa t or ethyl (29.6 g, 100 mmol) in THF (300 mL) was cooled to -10 ° C under nitrogen. A THF complex solution of borane (110 mL of IM, 110 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. A solution of hydrogen peroxide (12 mL) in saturated NaHCO 3 (200 mL) was then added slowly, and the mixture was stirred for 30 minutes, the mixture was extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water, dried over brine, and then concentrated in vacuo to give a clear oil (27.6 g, 88%).
Step 3: ethyl 2- (3-methanolsulfonyloxypropyl) -3-benzyloxybenzoate.
A solution of ethyl 2- (3-hydroxypropyl 1) -3-benzyloxybenzoate (10.19 g, 32.5 mmol), and triethyl amine (4.05 g, 40 mmol) in methylene chloride (100 mL) was cooled in a bath of ice and sulfonyl methane chloride was added slowly
(2.79 mL, 36 mmol). The ice bath was removed and the reaction was allowed to warm to room temperature for a period of 1 hour. The mixture was diluted with water, and the methylene chloride layer was separated. The methylene chloride layer was washed with water twice, twice with 1N HCl, and then filtered through a pad of silica gel to give a clear solution. The solution was concentrated in vacuo to give a clear oil (12.4 g, 98%).
Step 4: 2 - ethyl (3-cyanopropyl) -3-benzyloxybenzoate.
A mixture of ethyl 2 - (3-me tanosulfoni loxipropi 1) -3-benzyloxybenzoate (19.42 g, 31.7 mmol) and potassium cyanide (2.28 g, 35 mmol) in DMF (50 mL) was heated to 100 ° C. 8 hours. The mixture was cooled, diluted with water (250 mL), and extracted three times with ethyl acetate. The ethyl acetate extracts were dried with brine, and concentrated in vacuo. The crude product was chromatographed on silica gel using methylene chloride as the eluent to give the product as an oil (5.25 g, 53%).
Step 5: 4- [2-Benzyloxy-6-carboxyphenyl] butanoic acid.
A mixture of ethyl 2- (3-cyanopropyl) -3-benzyloxybenzoate (5.25 g, 16.9 mmol) in 5 N sodium hydroxide (75 mL) was heated to reflux for 18 hours. The solution was cooled and made acidic with 12 N HCl. The white precipitate was collected and dried with air (5 g, 94%).
Step 6: 4- [2-Hydroxy-6-carboxy-phenyl] butanoic acid.
A solution of 4 - [2-benzyloxy-6-carboxy-phenyl-butanoic acid (5 g, 15.9 mmol) in ethanol was hydrogenated at 60 psi for 4 hours over 10% Pd / C (1 g). The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid (3.95 g, 99%).
Step Ethyl 4- [2-ethoxycarbonyl-6-hydroxy phenyl] butanoic acid.
A solution of - [2-hydroxy-6-carboxy phenyl] butanoic acid (7.84 g, 35 mmol) in ethanol and sulfuric acid (10 drops) was heated to reflux for 18 hours. The solution was neutralized with sodium bicarbonate and cooled. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting oil was dissolved in ethyl acetate, washed with water, dried with brine, and concentrated in vacuo to give the product as an oil (9.06 g, 92.4%).
Acid Step 4- [2-ethoxycarbonyl-6-hydroxyphenyl] butanoic acid.
Ethyl 4 - [2 -etoxycarbonyl-6-hydroxy phenyl] butonic acid (9.06 g, 32.4 mmol) was dissolved in a room temperature solution of potassium hydroxide (3.62 g, 64.6 mmol) in water (68 mL) . The solution was stirred at room temperature for 2 hours, and then made acidic with 12 N HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined and extracted with 10% aqueous potassium carbonate three times. These aqueous extracts were made acidic with 12 N HCl and extracted twice with ethyl acetate. The ethyl acetate extracts were concentrated as a white solid (6.4 g, 79%).
Step 9: 4- [2-ethoxycarbonyl-6-hydroxyphenyl] butan-1-ol.
A complex of borane THF (56 mL of 1 M in THF, 56 mmol) was added slowly to a solution of 4- [2-e toxic rboni 1-6-hydroxy phenyl] butanoic acid in THF at 0 ° C. The solution was stirred for 2 hours and allowed to warm to room temperature. The reaction was quenched slowly with aqueous acetic acid (5 ml 50%). And it stirred until the bubbling subsided. The mixture was concentrated in vacuo to a syrup, which was dissolved in 10% cold potassium carbonate. The solution was extracted with ethyl acetate twice. The organic extracts were dried with brine and concentrated until an oil solidified leaving it (5.14 g, 84.9%).
Step 10: 2, 3, 4, 5-tetrahydrobenzoxepin-6-carboxylic acid ethyl ester.
A solution of 4 - [2-ethoxy-carbonyl-1-6-hydroxyphenyl] butan-1-ol (5.14 g, 21.6 mmol) in
THF (20 mL) was added dropwise to a cooled solution in a triphenyl phosphine ice bath.
(7.37 g, 28.1 mmol ") and diethyl azodicarboxylate
(4.89 g, 28.1 mmol) in THF (60 mL). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was purified by chromatography on silica gel using methylene chloride as the eluent to give the product as an oil (2.85 g, 60%).
Step 11: 2, 3, 4, 5- tet rahi droben zoxepin-6-methanol.
A solution of 2, 3, 4, 5, 1, 4-hydroxybenzoxepin-4-carboxylic acid (2.85 g, 13 mmol) in THF (30 ml) was stirred and LAH (1 g, 26 mmol) was slowly added. The mixture was stirred for 18 hours, and then quenched by sequential addition of water (1 mL), 15% sodium hydroxide (1 mL), and water (3 L). The mixture was filtered and the filtered cake was washed with ethanol. The filtrate was concentrated in an oil to be an oil (2.3 g, 100%).
Step 12 2, 3, 4, 5-tetrahydrobenzoxepin-6-carboxaldehyde
DMSO (1.85 mL, 26 mmol) was added slowly to a solution at -78 ° C of oxalyl chloride in methylene chloride (10 mL of 2 M, 20 mmol). To this solution was slowly added a solution of 2, 3, 5-tet therein, zoxepi-4-methylol (2.3 g, 13 mmol) in methylene chloride, and the mixture was stirred 30 minutes at -78 °. C. Triethyl amine (7.53 ml, 52 mmol) was slowly added to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with methylene chloride (50 ml) and washed with water and then brine. The organic layer was concentrated in vacuo as an oil (2.28 g, 100%).
Preparation 4
Benzofuran-7-carboxaldehyde
Step 1: 2 to 1 i 1 oxybenzene or methyl.
A mixture of allyl bromide (152.4 g, 1.27 mol), methyl salicylate (162.44 g, 1.06 mol), and potassium carbonate (219.75 g, 1.59 mol) in THF (600 ml) and DMF (600 ml) was heated at reflux for 6 hours. The mixture was poured into water (3 L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil which was distilled under vacuum for a clear oil (163.45 g, 80%).
Step 2: 3-al il-salicilat or methyl
Methyl 2-allyloxybenzoate (163.5 g, 848 mmol) was heated to 220 ° C for 1 hour, and then distilled in vacuo to give the product (163.5 g, 100%).
Step 3: Benzofuran-7-methyl carboxylate
Ozone was bubbled through a solution of 3-methyl-methyl salt (30 g, 156 mmol) at -78 ° C for 2 hours until the non-starting material was presented on TLC. The reaction was quenched with dimethyl sulfide and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was dissolved in ether. The ether solution was washed with brine three times, and concentrated in a green oil. This oil was dissolved in toluene and heated to reflux with sulfuric acid (0.5 mL) for 4 hours. Sodium carbonate (5 g) was added, and the mixture was cooled and then filtered. The filtrate was concentrated in vacuo to a dark oil which was purified by chromatography on silica gel using methylene chloride as the eluent to give the product as a green oil (12 g, 44%).
Step 4: benz ofuran-7-methanol.
A solution of methyl benzofuran-7-carboxylate (5.34 g, 30 mmol) was added to a suspension of LAH (2.31 g, 61 mmol) in THF and then heated to reflux for 30 minutes.
The reaction was quenched with ethyl acetate and water.
The mixture was made acidic with 12 N HCl until all the precipitate dissolved, the ethyl acetate layer was separated, washed with water, dried with brine, and concentrated in vacuo to give a yellow oil. (4.03 g, 94%).
Step 5: Benzofuran-7-carboxaldehyde.
DMSO (2.87 ml, 40 mmol) was added slowly to a solution at -78 ° C of oxalyl chloride in methylene chloride (20 ml of 2 M, 40 mmol). To this solution, a solution of benzofuran-7-me tanol (4.03 g, 27 mmol) in methylene chloride was added slowly, and the mixture was stirred 30 minutes at -78 ° C. Triethyl amine (30 ml) was slowly added to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with methylene chloride and washed with water and then with brine. The organic layer was concentrated in vacuo for an oil (3.16 g, 80%).
Preparation 5
2, 3-dihydro-benzo ran-7-carboxaldehyde.
Step 2, ethyl 3-dihydro-benzofuran-7-carboxylate.
Benzo furan-7-carboxymethyl or methyl (12 g, 68 mmol) was hydrogenated at 60 psi on 10% Pd / C (2 g) in acetic acid (60 ml) for 18 hours. The mixture was concentrated in vacuo to give a pale green oil (12 g, 100%).
Step 2: 2, 3-dihydro-benzofu ran-7-me tanol Methyl 2,3-dihydro-benzofuran-7-carboxylate (12 g, 68 mmol) was reduced with LAH (5.14 g, 136 mmol) in THF similarly to the above procedures to give the product as a dark oil (8.13 g, 80%).
Step 3: 2,3-dihydro-benzofuran-7-carboxaldehyde.
A solution of 2,3-dihydro-benzofuran-7-methanol (8.13 g, 54.5 mmol) was oxidized using
DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as an oil (7.7 g, 95%).
Preparation 6
2, 2-dimethyl-2,3-dihydro-benzofuran-4-carboxaldehyde.
Step 1: Ethyl-3- (methylpropenyloxy) benzoate.
A mixture of 2-methyl-3-chloropropane (64.2 g, 710 mmol), ethyl 3-hydroxybenzoate (48.21 g, 590 mmol), and potassium carbonate (122.3 g, 890 mmol) in THF (600 mg). ml) and DMF (600 ml) was heated to reflux for 6 hours. The mixture was poured into water (3 L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and washed with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil which was vacuum distilled to a clear oil (112.9 g, 87%).
Step 2: 2,2-dimethyl-2, 3-dihydro-benzofuran-4-carboxylic acid ethyl ester.
A mixture of ethyl-3- (2-me thiolpropeni loxy) benzoate (23.6 g, 107 mmol) was stirred with SCX resin (2 g) at 220 ° C for 1 hour. The crude product was purified by chromatography on silica gel using methylene chloride with eluent to give a clear oil (8.7 g, 37%).
Step 3: 2, 2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid.
Ethyl 2,2-dimethyl-2, 3-dihydrobenzofluoride (10 g, 45 mmol) was heated at reflux with sodium hydroxide (16.3 ml of 10 N, 163 mmol). ) in ethanol (50 ml) for 2 hours. The mixture was concentrated in vacuo, diluted with water and made acidic with 12 N HCl. The precipitate was filtered and dried with air (8.6 g, 100%).
Step 4: 2, 2 -dimeti 1-2, 3-dihydro-benzofuran-4-methanol
2, 2-Dimethyl-2-yl, 2,3-dihydro-benzofuran-4-carboxylic acid (8.6 g, 45 mmol) was reduced with
LAH (3.41 g, 89 mmol) similarly to the previous procedures to give the product as a clear oil (7.35 g, 93%).
Step 5: 2, 2-dimethyl-2,3-dihydro-benzofuran-4-carboxaldehyde.
2, 2 -dimet i 1-2, 3 -dihydro-benzofuran-4-methanol (7.35 g, 41 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similarly to the above procedures to give the product as an oil clear (8.87 g, 100%).
Preparation 7.
2 - . 2-yl-benzofuran-4-carboxaldehyde.
Step 1: 2 -methyl 1 -benzofuran-4-ethylcarboxylate.
Ozone was bubbled through a solution of ethyl-3- (2-methylpropropyloxy) -benzoate (10 g, 45 mmol) at -78 ° C for 2 hours until the non-starting material was presented on TLC. The reaction was quenched and the product was isolated similarly to the previous procedures to give the product as a white solid (8.05 g, 87%).
Step 2: 2 -me ti 1 -ben zo furan-4-me tanol.
2-Methyl-benzofuran-carboxylic acid (5.11 g, 26.6 mmol) was reduced with LAH (2 g, 53 mmol) similar to the previous procedures to give the product as a clear oil (3.34 g, 78%).
Step 3 2-methyl-benzofuran-4-carboxaldehyde 2-Methyl-benzofuran-4-methanol (3.34 g, 21 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similarly to the above procedures to give the product as a light oil (3.14 g, 93%).
Preparation
2,3-dihydro-1,4-benzodioxan-5-carboxaldehyde.
2,3-dihydroxybenzaldehyde (58 g, 420 mmol) was added to a reflux mixture of dibromoethane
(107.4 g, 570 mmol), sodium hydroxide (35.7 g, 890 mmol) and tetrabutyl ammonium bromide (3 g) in water (50 mL). After heating to reflux for 4 hours, the mixture was cooled and the organic layer was separated, washed with base, dried over sodium sulfate and concentrated in vacuo. The residue was distilled in Kugelrohr at 135 ° to give the product
(48 g, 70%) that solidified solid (p.p. 61-62 ° C). Calculated analysis: C, 65.85; H, 4.91. Found: C, 65.73; H, 4.86.
Preparation 9.
2H-3, 4-dihydro-l, 5-benzodioxapine-6-carboxaldehyde.
2,3-dihydroxybenzaldehyde and 1,3-dibromopropane (107.4 g, 570 mmol), sodium hydroxide (35.7 g, 890 mmol) were reacted as described above to give an oil (43%).
Preparation 10
(2H-3, -dihydrobenzopyran-5-yl) carboxaldehyde
Acid Step 2H-3, -dihydrobenzopyran-5-yl) carboxylic acid
Borane complex THF (55 mL of IM, 55 mmol) was added to a solution of ethyl 2-allyl-3-hydroxybenzoate (10.3 g, 50 mmol) in THF at -10 ° C. The reaction was allowed to Warm to room temperature and stir for 1 hour. Saturated sodium bicarbonate (100 ml) was added slowly and then hydrogen peroxide (6 ml) was added dropwise. The mixture was stirred for 30 minutes, diluted with ethyl acetate (150 ml). The ethyl acetate layer was separated, washed with water, dried with brine, and concentrated in vacuo to a clear oil. This material was dissolved with THF (100 ml) and added slowly to a solution of triphenylphosphine (20.85 g, 79.5 mmol) and diethyl azodicarboxylate (13.84 g, 79.5 mmol) in THF (250 ml). The solution was stirred for 18 hours and then concentrated in vacuo. The residue was distilled in va c u o to give an oil. This oil was purified by chromatography on silica gel using ethyl acetate / methylene chloride (1: 1) as the eluent to give a clear oil (11.3 g). This oil was heated to reflux for 2 hours with sodium hydroxide (25 ml of 10 N, 250 mmol) and water (50 ml). The reaction was cooled and filtered. The filtrate was made acidic with 12N hydrochloric acid to give a white precipitate (7.96 g, 89%).
Step 2: (2H-3, 4-dihydrobenzopyran-5-yl) methanol
Acid (2 H-3, 4 -dihydr-oben- hopyrene-5-yl) carboxylic acid was reduced with LAH by the above procedures to give the product (97%).
Step 3: 2H-3, 4-dihydrobenzopyran-5-yl) carboxaldehyde.
Oxidized (2 H -3,4-dihydrobenzopyran-5-yl) methanol using DMSO, oxalyl chloride, and triethyl amine similarly to the above procedures to give the product as a clear oil (100%).
Preparation 11
2-methyl-2, 3-dihydrobenzofuran-4-carboxaldehyde
Step 1: 2-methyl ethyl 2, 3-dihydrobenzofuran-4 carboxylate.
The 2-me t i lbenzof uran- 4 -carboxi ethyl t
(10 g), obtained as described in Preparation 7, was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd / C (2 g) for 24 hours. The mixture was filtered through celite and the pad filter was washed well with ethyl acetate. The filtrate was concentrated in vacuo to obtain ethyl 2-methyl-2, 3-dihydrobenzofuran-4-carboxylate.
Step 2: 2 -methyl -2, 3-dihydrobenzofuran-4-methanol
A solution of ethyl 2-methyl-2, 3-dihydrobenzofuran-4-carboxylate (10 g) in THF (100 mL) was stirred and LAH (4.64 g, 122 mmol) was added slowly. The mixture was heated to reflux for 30 minutes. The mixture was cooled and quenched carefully with ethyl acetate and then with IN HCl (150 mL). The mixture was then made acidic with 12N HCl until all the inorganic precipitates were dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo to provide the desired alcohol.
Step 2-methyl-2, 3-dihydrobenzofuran-4-carboxaldehyde
To a solution of oxalyl chloride (51.6 mL of a 2M solution, 103.36 mmol) in dichloromethane (200 mL) at -78 ° C under N2 was added dropwise DMSO (9.2 mL, 129.2 mmol) for 10 minutes. After stirring for 20 minutes, a solution of alcohol (10.6 g, 64.6 mmol) in dichloromethane (50 mL) was added dropwise over 10 minutes. The resulting mixture was stirred for 1 hour. Trimethylamine (36 mL, 258.4 mmol) was added and allowed to warm to room temperature, and stirred for 0.5 hour. The reaction was quenched with water (30 mL), washed with brine, dried over MgSO4, concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel, eluting with 6% ethyl acetate in hexane, to give 8.5 g (81%) of the aldehyde as an oil.
Preparation of the Formula 2 intermediaries
Preparation 12
(Trans) -3- (2,3-Dihydrobenzodioxin-5-yl) propenoic acid.
A mixture of 2, 3-dihydrobenzodioxane-5-ca rboxa ldehyde (Morishima, et al., Sol. De Pat.
Eur. 309,766, April 5, 1989) (9.25 g, 56.4 mmol), malonic acid (11.73 g, 112.8 mmol), pyrrolidine (1 mL), and pyridine (25 mL) was heated to reflux for 2 hours, cooled , and then it was emptied into ice water (300 mL). The white precipitate was filtered, washed with IN HCl, and air-dried (9.83 g, 84.6%).
Preparation 13.
The following compounds of Formula 2, (a) - (1), were prepared by the general procedure described for the compound of Preparation 12.
(a) (trans) -3- (2,3-Dihydrobenzofuran-4-yl) propenoic acid. 2,3-Dihydrobenzofuran-4-carboxydehyde was subjected to the above procedure to give a pale yellow powder which was recrystallized from isopropanol to give white flakes (95.3%, m.p., 205-207 ° C).
Anal is is Calculated for CpH? O03: C, 69.46; H, 5.30. Found: C, 69.36; H, 5.17.
(b) (trans) -3- (benzofuran-4-yl) propenoic acid.
The benzofuran-4-carboxaldehyde was subjected to the above procedure to give a white powder (83%).
(c) (trans) -3- (1,3-benzodioxol-4-yl) propenoic acid.
The 1,3-benzodioxol-4-carboxaldehyde was subjected to the above procedure to give a white powder (99%).
(d) (trans) -3- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) propenoic acid.It was subjected to 2, 3, 4, 5-te t rahidroben zoxepin-4-carboxaldehyde to the above procedure to give this product as a white solid (89%).
(e) (trans) -3- (benzofuran-7-yl) propenoic acid.
It was subjected to the benz or fu-7 -ca rboxal dehído to the above procedure to give this product as a white solid (100%).
(f) trans) -3- (2,3-dihydro-benzofuran-7-yl) propenoic acid.
2, 3-Dihydro-benzofuran-7-carboxaldehyde was subjected to the above procedure to give this product as a white solid (100%).
(g) (trans) -3- (2,2-dimethyl-2,3-dihydro-benzofuran-4-yl) propenoic acid
The 2, 2 -dime t i 1-2, 3 -dihydro-ben zofuran-4 -ca rboxaldehyde was subjected to the above procedure to give this product as a white solid (81%).
(h) trans) -3- (2-methyl-benzofuran-4-yl) propenoic acid co.
It was subjected to the 2-me t i 1 -ben zofuran-4-carboxy ideid to the above procedure to give this product as a white solid (97%).
(i) (trans) -3- (2,3-dihydro-l, 4-benzodioxan-5-yl) propenoic acid.
2, 3-Dihydro-l, 4-benzodioxan-5-carboxaldehyde was reacted with malonic acid as described above to give a white solid (90%).
(j) (trans) -3- (2 H -3,4-dihydro-l, 5-benzodioxapin-6-yl) propenoic acid.
2, 3-Dihydro-l, 4-benzodioxan-5-carboxaldehyde was reacted with malonic acid as described above to give a white solid (74%).
() (trans) -3- (2H-2,3-Dihydrobenzopyran-4-yl) propenoic acid.
Reaction (2 H-2, 3-dihydrobenzopy ran-1) carboxaldehyde with malonic acid was carried out by the above procedures to give the white solid (98%).
(1) trans) -3- (2-methyl-2,3-dihydrobenzofuran-4-yl) propenoic acid.
2-Me t i 1 -2, 3-dihydrobenzofuran-4-carboxaldehyde was reacted with malonic acid by the above procedures to give the desired acid (92%).
Preparation of the intermediaries of Formula 3_.
Preparation 14.
(trans) -N-methoxy-N-methyl-3- (2,3-dihydrobenzodioxan-5-yl) propenamide.
A mixture of (trans) -3- (2,3-dihydrobenzodioxan-5-yl) propenoic acid (9.83 g, 47.7 mmol), thionyl chloride (20 mL), and CH 2 Cl 2 (75 mL) was heated to reflux by 1 hour, and then concentrated in va cuo to give a solid green yellow. This material was dissolved in ethyl acetate (75 mL), and a solution of N, 0-d ime t i 1 h idr oxy lamine (9.5 g) in saturated Na 2 CO 3 (100 mL) was added with stirring. The mixture was stirred for 90 minutes and then diluted with water and ethyl acetate. The ethyl acetate layer was separated and washed twice with water and twice with saturated Na 2 CO 3. The ethyl acetate layer was concentrated in vacuo to give a brown oil. This crude product was chromatographed on silica gel using ethyl acetate / methylene chloride 1: 1 as the eluent to give a clear oil which was crystallized by signature (11.1 g, 93.1%).
Preparation 15
The following compounds of Formula 3_, (a) - (k) were prepared by the general procedure described for the compound of Preparation 14.
(a) (trans) -N-methoxy-N-methyl 1-3- (benzofuran-4-yl) propenamide.
The (rans) -3- (benzofuran-4-y1) propenoic acid was subjected to the above procedure to give an oil (97.7%).
(b) (trans) -N-methoxy-N-methyl-3- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) propenamide.
The (trans) -3- (2,3,4,5-tet rahydrobenzoxepin-6-yl) propenoic acid was subjected to the above procedures to give this product (88.6%).
(c) (trans) -N-methoxy-N-methyl-3- (benzofuran-7-yl) propenamide.
The (trans) -3- (benzofuran-7-yl) propenoic acid was subjected to the above procedures to give this product (90%).
() (trans) -N-methoxy-N-methyl -3- (2,3-dihydro-benzofuran-7-yl) propenamide
The (trans) -3- (2,3-dihydro-benzofuran-7-yl) propenoic acid was subjected to the above procedures to give this product (68%).
(e) (trans) -N-methoxy-N-methyl-3- (2,2-dimethyl-2,3-dihydro-benzofuran-4-yl) propenamide.
The (trans) -3- (2, 2-dimethyl-2, 3-dihydride) was reacted to the above procedures to give this product (92%).
(f) (trans) -N-methoxy-N-methyl-3- (2-methyl-benzofuran-yl) propenamide. It was subjected to (trans) -3- (2-methyl-benzofuran-4-yl) propenoic acid to the above procedures to give this product (100%).
(g) (trans) -N-methoxy-N-methyl-3- (2,3-dihydro-1,4'-benzodioxan-5-yl) propenamide.
The propenoic acid (t rans) -3- (2,3-dihydro-1,4-benzodioxan-5-yl) was subjected to the above procedures to give this product (85%).
(h) (trans) -N-methoxy-N-methyl-3- (2 H -3,4-dihydro-1,5-benzodioxapin-6-yl) propenamide.
It was subjected to the acid (t rans) -2 H- 3 - (3, 4-dih-idro-1, 5-ben z odi oxap in- 6-i 1) p ropernoi co to the above procedures to give this product (86 %). (i) (t r ans -N-me toxy-N-met il-3- (2H-2, 3-dihydrobenzopyran-4-yl) propenamide.
The (trans) -3- (2H-2, 3-dihydroben zopi ran-4-i 1) propenoic acid was subjected to the above procedures to give this product (quantitative percentage).
(j) (trans) -N-methoxy-N-methyl-3- (1,3-benzodioxol-4-yl) -propenamide.
The 1,3-benzodi oxol-4-carboxaldehyde was subjected to the above procedure to give a red oil (100%).
(k) (trans) -N-methoxy-N-methyl-3- (2,3-dihydrobenzofuran-4-yl) propenamide.
Diethyl phosphonate (n-met oxy-N-me t il -ca rbamoi lme ti 1) (4.0 g, 16.7 mmol) was added dropwise to a suspension of sodium hydride (671 mg, 60% dispersion in mineral oil , 16.7 mmoles) in THF
(75 mL) at 0 ° C. A solution of 2,3-dihydrobenzofuran-4-carboxy idenate (3.0 g, 15.2 mmol) in THF (25 mL) was added dropwise. The resulting suspension was allowed to warm to room temperature. After 18 hours, water (60 mL) was added and the solution was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over K2CO3, and concentrated to give a pale red oil, 3.5 g (100%).
Preparation of the intermediaries of Formula 4_.
Preparation 16.
(±) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropane-carboxaldehyde.
Step (±) - (trans) -N-methoxy-N-methyl-2- (2,3'-dihydrobenzofuran-4-yl) cyclopropanecarboxamide
Thioxonium t-imide iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1.8 g, 45 mmol) in DMF (120 mL). After decreasing the foam (10 minutes), a solution of (trans) -N-methoxy-N-methyl-3- (2,3-dihydrobenzofuran-4-yl) propenamide (3.5 g, 15 g) was added dropwise. mmoles) in DMF (60 mL), with the temperature maintained between 35-40 ° C. The mixture was stirred for 3 hours at room temperature. NH 4 Cl saturated (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H20 and brine, dried over K2CO3, and concentrated in vacuo to give a white wax (3.7 g, 100%).
Step 2: '±) - (t rans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxaldehyde.
A solution of (±) - (trans) -N-me toxi-N-me t -yl-2- (2, 3-dihydrobenzofuran-4-yl) with the oxycarboxyamine (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45 ° C, keeping the temperature completely at -40 ° C. The cooling bath was removed, the reaction allowed to warm to 5 ° C, and then the reaction was immediately cooled to -45 ° C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H20 (50 mL) was cautiously added dropwise, the temperature was kept completely below -30 ° C. The cooling bath was removed and the suspension was stirred at room temperature for 30 minutes. The mixture was filtered through Celite and the filtered cake was washed with ether. The combined filtrates were then washed with cold 1N HCl, INN NaOH, and brine. The filtrates were dried over MgSO, and concentrated in vacuo to give a clear oil (2.6 g, 99%).
Preparation 17.
The following compounds of Formula 4_ (a) - (k) were prepared by the general procedure described for the compound of Preparation 16.
(a) (±) - (trans) -2- (benzofuran-4-yl) cyclopropanecarboxaldehyde
The (t ra ns) -N-methoxy-N-me ti 1 -3 (benzofuran-4-y1) propenamide was subjected to the above procedure to give an oil (93.3%).
(b) (±) - (trans) -2- (1,3-benzodioxol-4-yl) cyclopropanecarboxaldehyde.
The (trans) -N-methoxy-N-methyl-3- (1,3-benzodioxol-4-yl) propenamide was subjected to the above procedure to give a clear oil (100%).
(c) (±) - (trans) -2- (2,3-dihydrobenzodioxan-5-yl) cyclopropanecarboxaldehyde.
The (trans) -N-raetoxy-N-phenyl-3- (2,3-dihydrobenzodioxan-5-yl) propenamide was subjected to the above procedure to give an orange oil (90%).
(d) (±) - (trans) -2- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) cyclopropanecarboxaldehyde.
The (t rans) -N-me toxi -N-me ti 1 -3- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) propenamide was subjected to the above procedures to give this product (36%).
(e) (±) - (trans benzofuran-7 'il) cyclopropanecarboxaldehyde.
The (t rans) -N-me t.oxi-N-methyl-3- (benzofuran-1) propenamide was subjected to the above procedures to give this product (67%).
(f) (±) - (trans) -2- (2,3-dihydro-benzofuran-7-yl) cyclopropane-carboxaldehyde.
The (trans) -N-me toxi-N-me t -yl-3- (2,3-dihydro-benzofuran-7-yl) propenamide was subjected to the above procedures to give this product (55%).
(g) (±) - (trans) -2- (2,2-dimethyl-2, 3-dihydro-benzofuran-4-yl) -cyclopropanecarboxaldehyde.
It was subjected to (trans) -N-met oxy-N-met il-3- (2,2 -dimeti 1-2, 3-dihydro-benzofuran-4-yl) propenamide to the above procedures to give this product (64 %).
(h)! ±) - (trans) -2- (2-methyl-benzofuran-4-yl) cyclopropane-carboxaldehyde
It was subjected to (t rans) -N-me t-oxy-N-me t -yl-3 - (2-methyl-1-benzofuran-4-yl) propenamide to the above procedures to give this product (100%) .
(i) (trans) -2- (2,3-dihydro-l, 4-benzodioxan-5-yl) cyclopropanecarboxaldehyde.
It was subjected to (t rans) -N-methoxy-N-me t -yl-3- (2,3-dihydro-1,4-benzodioxan-5-yl) propenamide to the above procedures to give this product (79%) .
(j) [(trans) -2- (2 H -3,4-dihydro-l, 5-benzodioxapin-6-yl)] - cyclopropanecarboxaldehyde.
The (t rans) -N-me toxi -M-methyl-3 - (2 H -3,4-dihydro-1,5-benzodioxapin-6-yl) propenamide was subjected to the above procedures to give an oil (55). %).
(k) (±) - (trans) -2- (2H-2,3-dihydrobenzopyran-yl) cyclopropane-carboxaldehyde.
The (trans) -N-me toxi-N-met il-3 - (2H-2,3-dihydrobenzopyran-4-yl) propenamide was subjected to the above procedure to give this product (86%).
Preparation ll
(-) - (trans) -2- (2,3-dihydroxybenzofuran-4-yl) cyclopropanecarboxaldehyde.
Step 1: (-) - (trans) -N- [3- (2, 3-dihydrobenzofuran-yl) -propenoyl] -2, 10-camphorsultam.
To a solution of (-) -2, 10-camphor sultan (8.15 g, 37.9 mmol) in 50 mL of toluene at 0 ° C was added sodium hydride (1.67 g, 41.7 mmol). After stirring for 0.33 hours at 0 ° C and 0.5 hours at 20 ° C and re-cooling to 0 ° C, a solution of 3- (2,3-dihydrobenzofuran-4 -i 1) chloride was added dropwise. -2-propenoyl (37.9 mmol), prepared in situ from the corresponding acid and thionyl chloride (75 mL), in toluene (50 mL). After stirring for 18 hours at 20 ° C, the mixture was diluted with ethyl acetate and washed with water, IN HCl, and INN NaOH. The organic solution was dried and concentrated in vacuo to give 15.8 g of the crude product. Recrystallization from ethanol-methanol (600 mL, 1: 1) gave the product (13.5 g, 92%, m.p., 199.5-200 ° C).
Step 2: (-) - N - [[(trans) -2- (2,3-dihydrobenzofuran-4-yl) -cyclopropyl] -carbonyl] -2,10-camphorsultam.
1-met il-3-ni t-1-nitride oguanidine (23.88 g, 163 mmol) was added in portions to a mixture of 10 N sodium hydroxide (60 mL) and ether (200 mL) at 0 °. C. The mixture was stirred vigorously for 0.25 hours and the ether layer was carefully decanted into a solution of (-) -N- [3 - (2, 3-dihydrobenzofuran-4-yl) -2-propenoyl] -2,10-camphorsultam (9.67g, 25 mmol) and palladium acetate (35 mg) in methylene chloride (200 mL). After stirring for 18 hours, acetic acid (5 mL) was added to the reaction and the mixture was stirred for 0.5 hour. The mixture was washed with IN HCl, IN NaOH and brine. The solution was dried, concentrated in vacuo and the residue was recrystallized twice from ethanol to give the product (6.67 g, 66.5%, m.p., 157-159 ° C).
Step (-) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropane-methanol. A solution of (-) - N - [(t rans) -2 - (2,3-dihydrobenzofuran-4-yl) cyclopropanecarbonyl] -2,10-camphorsultam (4.3 g, 10.7 mmol) in THF (50 mL) was added dropwise to a mixture of LAH (0.81 g, 21.4 mmol) in THF (50 mL) at -45 ° C. The mixture was stirred for 2 hours while warming to 10 ° C. The mixture was again cooled to -40 ° C and hydrolyzed by the addition of saturated KHS04 (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was washed twice with acetone. The combined filtrate and washed acetone were concentrated in vacuo. The gummy residue was dissolved in ether, washed with IN NaOH and IN HCl, and then dried in vacuo to give the product (2.0 g, 98.4%).
Step 4: (-) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxaldehyde.
DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH2C12 (7.4 mL of 2M solution, 14.8 mmol) at -78 ° C. The (-) - (trans) -2- (2,3-dihydrobenzo furan- -i 1) -cyclopropylmethylene (2.0 g,
. 5 mmol) in CH2C12 (15 mL). The mixture was stirred for 20 minutes and then triethylamine was added.
(4.24 g, 42 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was diluted with CH: C12 and washed with water, IN HCl, and then NaOH IN. The organic layer was dried and concentrated in vacuo to give the product aldehyde (1.98 g, 100%).
Preparation 19.
(-) - (trans) -2- (2,3-dihydro-1,4-benzodioxan-5-yl) cyclopropanecarboxaldehyde.
Step 1: (-) - (trans) -N- [3- (2,3-dihydro-1,4-benzodioxan-5-yl) propenoyl] -2,10-camphorsultam.
The propenoic acid (t rans) -3- (2,3-dihydro-1,4-benzodioxan-5-y1) was subjected to the above procedure (88%, m.p., 187-188 ° C).
Step 2: (-) -N- (trans) - [[2- (2, 3-dihydro-l, -benzodioxan-5-yl) cycloprop-1-yl] carbonyl] -2, 10-canf orsul tam.
It was subjected to (-) - (t rans) -N- [3- (2,3-dihydro-1,4-benzodioxan-5-yl) propenoyl] -2, 10-canforsultam to the above procedure to give it (84%) , mp, 214-215 ° C, [a] 25D = -138.9).
Step (-) - (trans) -2- (2,3-Dihydro-1,4-benzodioxan-5-yl) -1-cyclopropanmethanol The (-) - N- (t rans) - [[3- (2,3-dihydro-1,4-benzodioxan-5-yl) cyclopropyl] carbonyl] -2,10-camphorsultam with LAH as described above to give the product as an oil (100%).
Step 4: (-) - (trans) -2- (2,3-dihydro-l, 4-benzodioxan-5-yl) -1-cyclopropanecarboxaldehyde.
The (-) - (t rans) -2 - (2, 3-dihydro-1,4-benzodi oxan-5 i 1) -1-cyclic opropane-methanol was oxidized as described above to give the aldehyde as a oil (100%) that was used immediately in the next reaction.
Preparation 20
(+) -trans-2- (2-methyl-2, 3-dihydrobenzo-ran-4-yl) -cyclopropane-carboxaldehyde and (-) - (trans) -2- (2-methyl-2,3-dihydrobenzofuran-4-yl) ) cyclopropanecarboxaldehyde.
Step (trans) -N- [3- (2-methyl 1-2, 3-d? Hydrobenzofuran-4-yl) propenoyl] -2, 10-can for sul tam.
The (trans) -N- [3- (2-methyl-2, 3-dihydrobenzofuran-4-yl) propenoic acid was subjected to the above procedure to give the desired sultam (95% yield by two steps).
Step 2: N- (trans) - [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] carbonyl] -2,10-camphorsultam.
It was subjected to (t rans) -N- [3- (2-methyl-2, 3-dihydrobenzofuran-4-yl) propenoyl] -2, 10-camphorsultam to the above procedure to give the desired cyclopropane derivative (61). %).
Step 3: (trans) -2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) -1-cyclopropanmethanol.
N- (trans) - [[2- (2-met il-2,3-dihydrobenzofuran-4-yl) cycloprop-1-yl] carbonyl] -2, 10-can f or s ul t am was reduced LAH as described above to give the desired alcohol as a mixture of diastereomers (96%). The mixture of alcohols di as ter eomé ri eos was separated by chiral HPLC (Quiracel OD, i PrOH / hexanes) to give both (+) - (trans) -2- (2-methyl-2,3-dihydrobenzofuran) 4-yl) -1-cyclopropane-methanol such as (-) - (t rans) -2- (2-methi 1-2, 3-dihydrobenzofuran-4-yl) -1-cyclopropanome tannol.
Step 4: (+) - (trans) -2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) -1-cyclopropanecarboxaldehyde? _ (-) - (trans) -2- (2-methyl-2 , 3-dihydrobenzofuran-4-yl) -1-cyclopropanecarboxaldehyde.
The (+) - (trans) -2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) -1-cyclopropanecarboxaldehyde separated and (-) - (trans) -2- (2-methyl-2 , 3-dihydrobenzofuran-4-yl) -1-cyclopropanecarboxaldehyde was separately oxidized as described above to give the desired corresponding aldehydes (98% and 97% yield, respectively).
Preparation of the intermediaries of Formula 5:
Preparation 21
2, 2-difluoro-3- (2-methyl-4-benzo-ranil) cyclopropane-methanol O-acetate.
Step (trans) -3- (2-methyl-4-benzofuranyl) -2 propen-1 -ol
A solution of (t rans) -3 - (2-methyl-4-benzofuranyl) -2-propenoic acid (2.53 g, 10.9 mmol) in 30 mL of anhydrous THF was slowly added to a mixture of sodium borohydride ( 592 mg, 15.6 mmol) in 15 mL of anhydrous THF at room temperature. Once the hydrogen evolution had ceased, the reaction mixture was cooled to 0 ° C and a solution of I2 (1.72 g, 6.76 mmol) in 15 mL of THF was added. The reaction mixture was stirred at 0 ° C for 1 hour, allowing it to warm to room temperature and stirring at room temperature for an additional 3 hours. The reaction was then quenched with 3N HCl and the aqueous layer was extracted with ether. The combined organic layers were washed with 3N NaOH and brine, then dried with MgSO 4 and concentrated in vacuo. Purification on silica gel (ethyl acetate / hexanes) provided a mixture of aulic alcohol and saturated alcohol (10: 1) in a combined yield of 46%. The mixture was passed to the next step.
Step O-aceta to of (trans) -3- (2-methyl-4-benzofuranyl) -2-propen-l-ol.
Acetic anhydride (1.20 mL, 12.6 mmol) was added to a solution of the mixture containing
(trans) -3- (2-methyl-benzofuranyl) -2-propen-l-ol
(as obtained in the previous step) in 10 mL of pyridine at 5 ° C. The reaction mixture was stirred at room temperature for 20 hours and then diluted with ether. The crude mixture was washed with IN HCl, saturated NaHCO3, water, and brine and then dried over MgSO4, filtered and dried in vacuo. Purification on silica gel (ethyl acetate / hexanes) provided a mixture of acetate acetate and saturated acetate in a combined yield of 73%.
Step 3: 2,2-Di-luo-3- (2-me t -yl-4-benzofuranyl) -cyclopropanomethanol Q-acetate.
To a reflux solution of O-acetate from
(trans) -3- (2-methyl-4-benzofuranyl) -2-propen-l-ol
(0.1 g, 4.35 mmol) in 10 ml of diglyme was slowly added a solution of CIF2CCOONa (5.0 g, 32.6 mmoles) in 10 ml of diglyme. The reaction solution was stirred at 165 ° C for 1.5 hours, cooled to room temperature and filtered through celite. The filtrate was diluted with ether and washed with large amounts of water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine solution and dried over MgSO4. The solvent was removed in vacuo. Purification on silica gel (ethyl acetate / hexanes) yielded the 2,2-difluoro-3- (2-methyl-4-benzofuranyl) c-O-acetate opropanome tanol (560 mg, 56%) as a colorless liquid. 3 H NMR (300 MHz, CDC13) d 2.12 (s, 3 H), 2.25-2.36 (m, 1 H), 2.46 (s, 3 H), 2.76-2.88 (m, 1 H), 4.27-4.45 (m, 2 H), 6.47 (s, 1H), 7.00 (d, 1H, J = 7.5 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.33 (d, 1H, J = 7.5 Hz), 13C NMR (75 MHz, CDC13 ) d 14.4, 18.4, 27.8 (t, J = 10.4 Hz), 29.8 (t, J = 10.4 Hz), 61.2, 101.2, 110.4, 113.5 (t, J = 286.7 Hz), 121.7, 123.3, 124.3, 129.7, 154.8, 156.2, 171.1.
Preparation of the intermediaries of Formula 1_
Preparation 22.
(+ _) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropane-methanamine.
A solution of (+) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropane-carboxaldehyde (2.6 g, 15 mmol), hydroxylamine hydrochloride (3.13 g), 45 mmol), ethanol (60 mL), water (40 mL), and NaOH ION (4.5 mL, 45 mmol) was heated to reflux for 4 hours. The solution was cooled to room temperature, then diluted with ethyl acetate.The ethyl acetate layer was separated and washed sequentially with H2O and brine.The ethyl acetate extracts were dried over K2CO3 and concentrated in vacuo. The residue was dissolved in THF (50 mL) and added dropwise to a suspension of LAH at -45 ° C (1.06 g, 28 mmol) in THF (100 mL), maintaining the temperature below -40 ° C. The reaction was warmed to room temperature and stirred for 2 hours.The reaction was again cooled to -45 ° C, and IN HCl (50 mL) was carefully added dropwise.
The cooling bath was removed and the suspension was stirred at room temperature for 30 minutes. The resulting paste was then diluted with ethyl ether and extracted with IN HCl. The acid extracts were combined, washed with ethyl ether, made basic with 50% NaOH, and extracted with dichloromethane. The dichloromethane extracts were combined, washed with brine, dried over K2CO3, and concentrated in vacuo to give a clear oil (900 mg, 40%).
Preparation 23
The following compounds of Formula 1_, (a) - (m) were prepared by the general procedure described for the compound in Preparation 22.
(a) (±) - (rans) -2- (benzofuran-4-yl) -cyclopropanomethanamine.
It was subjected to (±) - (trans) -2 - (benzofuran-4-y1) cyclopr opaneca rboxaldehyde to the above procedure to give an oil (73.5%).
(b) (±) - (trans) -2- (1, 3-benzodioxol-4-yl) cyclopropanomethanamine.
Reacted to (±) - (trans) -2- (1,3-benzodioxol-4-yl) cyclopropanecarboxaldehyde by the above procedure to give a red oil (61%).
(c) (±) - (trans) -2- (2,3-dihydrobenzodioxan-5-yl) cyclopropane-methanamine.
Reaction to (i) - (trans) -2- (2,3-dihydrobenzodioxan-5-yl) cyclopropanecarboxaldehyde was reacted by the above procedure to give an orange oil (91.1%).
(d) (±) - (trans) -2- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) cyclopropane-methanamine.
Reacted to (+) - (trans) -2- (2, 3, 4, 5-tetrahydrobenzoxepin-6-yl) cyclopropanecarboxaldehyde by the above procedures to give this product (50%).
(e) (±) - (trans) -2- (benzofuran-7-yl) cyclopropanomet anamine.
The (±) - (trans) -2 - (benzofuran-7-yl) cyclocarboxaldehyde was reacted by the above procedures to give this product (66%).
(f) (±) - (trans) -2- (2,3-dihydro-benzofuran-7-yl) c i clopr opanome t anamina.
Reacted to (±) - (t rans) -2- (2, 3-dihydro-benz or f-ran-7-i 1) ci-clopropanoca rboxa Idehído by the above procedures to give this product (87%).
(g) (±) - (trans 2, 2-di methyl-2, 3-dihydro-benzofuran-4-yl) cyclopropanometanalamine
Reaction was carried out to (+) - (trans) -2- (2,2-dimethyl-2,3-dihydro-benzofuran-4-yl) cyclopropanecarboxaldehyde by the above procedures to give this product (60%).
(h) (±) - (trans) -2- (2-methyl-beta-zofuran-4-yl) -cyclopropanomethanamine.
Reacted to (+) - (trans) -2- (2-ethyl-benzofuran-4-yl) cyclopropanecarboxaldehyde by the above procedures to give this product (63%).
(i) '(trans) -2- (2,3-dihydro-l, 4-benzodioxan-5-yl) cyclone opropanome tanamine.
Reacted to (t rans) -2 - (2,3-dihydro-1,4-benzoodioxan-5-yl) cyclopropanecarboxaldehyde by the above procedures to give the amine (67%) which was converted to the fumarate (mp 183) -184 ° C).
(j) (trans) -2- (2 H -3,4-dihydro-l, 5-benzodioxan-6-yl) cyclone opropanome tanamine.
The tr ans - (tr ans) -2 - (2 H -3,4-dihydro-1,5-benzod? Oxan-6-yl) cyclopropanecarboxaldehyde was reacted by the above procedures to give the amine which was converted to the fumarate (35%, mp, 152-153 ° C).
Analysis calculated for 0.3 H2O: C, 59.92; H, 6.39; N, 4.11. Found: C, 50.78; H, 6.33; N, 4.01.
(k) (±) - (trans) -2- (2H-2, 3-dihydrobenzopyran-4-yl) cyclopetropanome t anamina.
Reacted to (±) - (trans) -2- (2H-2,3-dihydrobenzopy-ran-4-yl) cyclopropanecarboxaldehyde by the above procedure to give this product (42%).
(1) (-) - (trans) -2- (2-methyl-2,3-dihydrobenzofuran-4-yl) cyclopropane-methanamine.
It was subjected to (-) - (t rans) -2 - (2-methyl-2, 3-dihydrobenzofuran- -i 1) cyclopropanecarboxaldehyde to the above procedure to give the desired amine (71%).
(m) +) - (trans) -2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cyclopropane-methanamine It was subjected to (+) - (t rans) -2- (2-methyl-2 , 3-dihydrobenzofuran-4-yl) cyclopropanecarboxaldehyde to the above procedure to give the desired amine (59%).
Preparation 24
(-) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanomethanamine.
A mixture of (±) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxaldehyde
(1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH
(3.5 mL, 35 mmol), in ethanol / water 5: 1 (50 mL) was heated in a steam bath for 2 hours. The solution was concentrated in vacuo, and the residue was mixed with water. The mixture was extracted with CH2Cl2. The organic extracts were dried and concentrated in vacuo to give a solid which was analyzed by NMR to be a mixture of cis and trans oximes. The material was dissolved in THF (20 mL) and added to a solution of alane in YHF
[prepared from LAH (1.14 g, 30 mmol) and H2SO4 (1.47 g, 15 mmol) at 0 ° C]. The reaction was stirred for 18 hours, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then IN HCl. The washed acid was made basic and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo to give the product amine (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (m.p .: 197-198 ° C). Analysis calculated for Ci2Hi5NO'C4H4? 4: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.87; H, 6.31; N, 4.52.
Preparation 25.
(-) - (trans) -2- (1,3-benzodioxol-4-yl) cyclopropane-methanamine.
The (-) - (t rans) -2- (1, 3-ben zodioxol -4 -i1) cyclopr opaneca rboxa ldehído was subjected to the general procedure described in Preparation 24 to give a beige solid (52.6%).
Preparation 26.
(+) - (trans) -2- [(2,3-dihydro-1,4-benzodioin-5-yl) cycloprop-1-yl] methylamine.
Step 1: oxime of (-) - (t r ans) -2 - (2,3-dihydro-1,4-benzodioxin-5-yl) -1-cyclopropanecarboxaldehyde.
Reacted to (-) - (t rans) -2 - (2,3-dihydro-1,4-benzodioxin-5-yl) -1-cyclopropane carboxydehyde with hydroxyl amine as described above to give the oxime as a mixture of isomers.
Step 2: (+) -trans-2- [(2, 3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methylamine.
The above oxime was reduced with alane as described above to give the amine which was converted to the fumarate (80%, m.p., 173-174 ° C for the fumarate, [a] 25c = 6.15).
Analysis calculated for 0.5 H20 C, 58.36; H, 6.10; N, 4.24. Found C * 58.36; H, 6.09; N, 4.24.
Preparation 27
2, 2-difluoro-3- (2-methyl-4-benzofuranyl) cyclopropane-methanamine
Step 2,2dilufuoro-3- (2-methyl-4-benzofuranyl) cyclopropane-methanol.
To a stirred solution of 2,2-difluoro-3- (2-methyl-4-benzofuranyl) -cyclopropan-methanol O-acetate (560 mg, 2.0 mmol) in MeOH / THF (10 mL, 3/1) was added KOH powder (560 mg, 10.0 mmol). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was diluted with ether and water. The aqueous layer was extracted with ether and the combined organic layers were washed with saturated NaHCO3, water solution and brine. The solvent was removed in vacuo. Purification on silica gel (ethyl acetate / hexanes) yielded 2,2-difluoro-3- (2-methyl-4-benzofuranyl) cyclopropanmethanol (420 mg, 88%) as a white solid. 1 NMR (300 MHz, CDC13) d 1.67 (bs, 1H), 2.19-2.31 (m, 1H), 2.46 (s, 3H), 2.73-2.80 (m, 1H), 3.95-3.98 (m, 2H), 6.51 (s, 1H), 7.02 (d, 1H, J = 7.5 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.32 (d, 1H, J = 7.5 Hz). 13 C NMR (75 Mhz, CDC 13) d 14.4, 29.3 (t, J = 10.4 Hz), 31.3 (t, J = 10.4 Hz), 60.1, 101.3, 110.2, 114.1 (t, J = 286.7 Hz), 121.7, 123.3 , 124.7, 129.8, 154.7, 156.1.
Step 2. 4- [2- (azidomethyl) -3,3 difluorocyclopranyl] -2-methylbenzofuran.
Triethylamine (916 ml, 6.55 mmol) followed by CH3S02C1 (355 ml, 4.59 mmol) was added to a solution of 2, 2di-f luoro-3- (2-methyl-4-yl-benzofu rani 1) cyclopropanome tanol (390 mg , 1.64 mmole) in 15 ml of CH2C1 ^. The reaction was stirred at room temperature for 0.5 hour and diluted with CH2Cl2. The organic layer was washed with water and NaHCO 3 and dried over anhydrous K 2 CO 3. Removal of the solvent in vacuo provided the crude mesylate, which was used immediately in the next step. A solution of the mesylate and NaN3 (213 mg, 3.27 mmol) in 12 ml of CH2C12 was heated to 70 ° C for 2.5 hours. The resulting solution was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. Removal of the solvent in vacuo afforded 4 [2 - (a-zidomethyl) -3,3-di-furocyclopanyl] -2-methylbenzofuran (422 mg, 98%). 1 H NMR (300 MHz, CDC13) d 2.16-2.28 (m, 1H), 2.47 (s, 3H), 2.74-2.81 (m, 1H), 3.52-3.70 (m, 2H), 6.49 (s, 1H), 7.02 (d, 1H, J = 7.5 Hz), 7.16 (t, 1H, J = 7.5 Hz), 7.34 (d, 1H, J = 7.5 Hz).
Step 3. 2,2-difluoro-3- (2-met il-4-benzofuranyl) cyclopropane-methanamine.
A solution of 4 - [2 - (az idomet il) -3,3-di f luoroci cloprani 1] -2-methyl benzofuran (203 mg, 0.78 mmol) in 4 ml of THF was added dropwise to a solution of LAH (1.0 M solution in THF, 1.56 ml, 1.56 mmol) at -30 ° C. The resulting solution was allowed to warm to room temperature and was stirred at room temperature for 3 hours. A solution of KHS04 (130 mg, 0.96 mmol) in 1 ml of water was added to the reaction at -30 ° C. After stirring at room temperature for 20 minutes, the reaction solution was filtered and the filtrate was diluted with CH2Cl2. The solution was adjusted to pH = 10 by the addition of NH 4 OH. The aqueous layer was extracted with CH2C12. The combined organic layers were washed with brine and dried over K2C03. The solvent was removed in vacuo to provide 2,2-difluoro-3- (2-methyl-1-4-benzofuranyl) cyclopropanemethanamine (182 mg, 99%) as a colorless liquid.
Ex empl os
The following examples illustrate the preparation of the compounds of the invention by the following general procedures described above.
E 1
(±) - (trans) -N- [[2- (2, 3-dihydrofuran-4-yl) cycloprop-1-yl] ethyl] acetamide.
Acetic anhydride (0.14 mL, 1.8 mmol) was added dropwise to a stirred solution of (±) - (trans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanome tanamine (300 mg, 1.6 mmol) and triethylamine (0.67 g, 4.8 mmol) in dry dichloromethane (15 mL) at 0 ° C. The resulting suspension was warmed to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, CH2C12 and then 2% EtOAc / CH2Cl2) to give 200 mg (54%) of a clear oil. IR (NaCl Film): 3287, 2923, 1651, 1553, 1459 was "1. Analysis calculated for Cu H17NO2 '0.3 H20: C, 71.0; H, 7.50; N, 5.92 Found: C, 70.79; H, 7.41; N, 5.58.
Example 2
(±) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-yl) cycloprop-1-yl] methyl] propanamide.
This compound was prepared in a manner similar to that of the previous procedure using propionyl chloride and (-) - (t rans) -2- (2,3-dihydrobenzofuran-4-yl) cyclopropanemethanamine to give an oil that solidly solidified for an off white solid (61%, mp: 71-72 ° C). IR (NaCl Film): 3298, 1645, 1548, 1459, 1235
[a] 25D: -17.3 ° Anal isi s calculated for Ci5H? 9N02: C, 73.4; H, 7.87; N, 5.71. Found: C, 73.28; H, 7.68; N, 5.58.
The following compounds of Formula I were prepared by these general methods:
t-J I-J - > (_p or (_n or cp Physical Data Table for the Compounds of Formula I
H -
t! ro («o (Jl (Jl r-> - * -.
ro n o cn t_n
H H tn
r ro r- > or (_p or
M
ro IS o o 01
M
Ui
00
. 1 < SW
r i • (Jl or CJl i '
or
Example 95
N- t [2- (2-methyl-benzofuranyl) -3,3-difluorocyclopropanyl] -methyl] propanamide
95% of a white solid was obtained p.f 55-56 ° C.
Analysis calculated for C 16 H 17 F 2 N 0 2: C, 65.52; H, 5.8; N, 4.78. Found: C, 66.15; H, 5.95; N, 4.73.
Example 96
(+) - (trans) -N- [[2- (3, 4-dihydro-2H-l-benzopyran-5 'yl) cyclopropyl-l] methyl] propanamide.
14 * was obtained from a white solid, m.p., 81-: ° C.; a] 25I? = 16.29. Purity = 95% by HPLC. 1 HOUR
?,; -; :: .300 MF.Z, CD ::. ' d 6.98 (t, j = 7.8 HZ, IH), c. í l, d, J = 7.9 Hz, IH 6.50 (d, J = 7.5 Hz,
: K, 5.57 i s,: H; , 4.12 v, j = 4.5 H z, 2 H), 3.49-3.30 (m, 1H), 3.23-3.16 (m, 1H), 2.84-2.78 (m, 2H), 2.21 (q, J = 7.6 Hz, 2H), 2.07-1.99 (m, 2H), 1.75-1.69 (m, 1H), 1.26-1.09"(m, 4H), 0.92-0.81 (, 2H); 13C NMR (75 MHz, CDC13) d 173.9, 155.2, 141.1, 126.1, 117.6, 115.1, 66.0, 43.9, 30.0, 22.6, 20.9, 19.6, 12.7, 10.1.
Example 97
(+) - (trans) -N- [[2 (3, 4-dihydro-2H-l-benzopyran-5-yl) cycloprop-1-yl) methyl] butanamide.
Was it obtained 10? of a yellow oil. Purity = 8"d by NMR: H NMR (300 MHz, CDCl 3) d 6.95 (d, J = d 3 Hz, 1 H), ß. € C (d, J = 7.4 Hz, 1H), 6.50 (d , J = ". Hz, 1H), 5.58 (s, 1H), 4.07 (t, J = 4.7 Hz, 2 H, 3.44-3.35; m, 1 H d 3.25-3.11 (ra, 1H), 2.78- rr ., H] .. -5 ~ - = 7.3 Hz, 2H), 2.02- 1.9 'rr. , 2 H), -i, - - c .. í rr. , 3H), 1.23-1.09 (m,
1 H d C .91 - 0.75 (rr., 5 H:: C NMR ("75 MHz, CDCl 3) d
55. 1, 141. C, 126.5, 2.1, 117.5, 115.1, 65.9,
8, .3 S .9, - > 1 C - > p p 8, 19.5, 19.3, 13.9, 12.7.
Example 98
(+) - (trans) -N - [[2- (2, 3-dihydro-1, -benzodioxin-5 'yl) ciclsprop-1-yl] methyl] acetamide.
18% of an oil was obtained. [a] 25D = 5.89. Purity = 99% by HPLC. H NMR (300 MHz, CDC13) d 6.77-6.71 (m, 2H), 6.50-6.44 (m, 1H), 6.04 8s, 1K), 4.36-4.33 (m, 2H), 4.29-4.26 (m, 2H) , 3.70-10 3.62 (m, 1H), 2.87-2.79 (m, 1H), 1.99 (s, 3H9, 1.86-1.80 (m, 1H), 1.15-1.00 (m, 2H), 0.87-0.81 (, 1H ); 13C NMR (75 MHz, CDC13) d 143.3, 130.4, 1 C.9, 118.5, 115.4, 6.4.6, 64.1, 44.3, 23.4, 2C.8, 16.3, II.8.
Example 99
N- [[2- (2-methyl-benzofuranyl) -3,3-difluorocyclopropanyl] -me il] acetamide. 'r Ob ob u e 90 * de r. Colorless liquid. Purity = Q- r: r H? .; H? 330 MHz, CDC13) d 2.01 (s, 2., 2.dI.I9 < zt, 1 h, 2.45 (s, 3H), 2.70 (m, 1 H •. 2.1- .T., 1 H, 2 G 2! Rn, 1 H), 5.89 (bs, 1 H), .44 s, :: -., 6.9"« a, = "7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz , 1H), 7.31 (d, J = 7.5 Hz, 1H). 13 C NMR (75 MHz, CDC13) d 14.2, 23.3, 28.4 (t, J = 10.0 Hz), 29.7 (t, J = 10.0 Hz), 37.3, 101.7, 110.2, 114.0 (t, J = 288 Hz), 121.3 , 123.1, 124.4, 129.5, 154.6, 156.0, 170.4.
Example 100
(trans) -N-methyl-N- [[2- (2,3-dihydrobenzofuran-4-yl) cyclopropyl] methyl] propanamide.
To a solution of (t rans) -N- [[2 - (2, 3-dihydrobenzofuran-4- 11 ci cl opcp 11] me 11] ppan ami da (120 mg, 0.6 rr.rpol) in THF «1.5 mL) was added sodium hydride (30 mg, G 5 rrmo I, > The mixture was allowed to stand for 0.5 hours and iodomethane 140 mg, 1 m * r.cl. The solution was concentrated in vacuo, the residue was dissolved and washed with hexane, The acetone solution was concentrated in vacuo and the residue was purified by silica gel chromatography. ethyl acetate and hexane (for e .. c::.: .rz ur. amber oil (90 mg, 69%) Analysis calculated for C16H2? N02-2.2H20: C, 73.08; H, 8.20; N, 5.33. Found: C, 72.91; H, 8.24; N, 5.23.
Example 101
(trans) -N- [[2- (2, 3-dihydro-5,7-diiodobenzofuran- -yl) cyclopropyl] -yl] propanamide.
To a solution of (trans) -N- [[2- (2,3-di idrobenzofuran-4-yl) cyclopropyl] methyl] propanamide (0.245 mg, 1 mmol) and the first te race ao IV (530 mg, 1.2 T.GG.CI, in 1.5 mL of acetic acid, iodine was added, and rr, 1.2 r -.- d, sr 1 was allowed to be dr. : G .: During this time the: e. ::: cr, was screamed.The reaction was diluted with chlorine of * re :: .: the resulting solution was water, water. ys .. ::.:, ae bicarbonate of sodium. * -: * - r J aay se se:: The solution was concentrated i_n • i -. ''. * -: -.-. :: J: s rr ctalizo from isopropyl ether to give the product (500 mg, 99%, mp, 198-199 ° C) Analyzes calculated for Ci5H? 7l2N02: C, 36.24; H, 3.45; N, 2.82. : C, 36.29; H, 3.59;, 2.96.
Example 102
(trans) -N-methyl-N- [[2- (2,3-dihydro-5-iodobenzofuran-yl) cyclop-opyl] -me] propanamide.
At one time. ae C .1 g, (0.6 mmol) of 't r a r. s. - N - [[2- X, 3-d? ? are-benzofuran-4-yl c? cloprcp: i; * :::: prrp r.ar.:da and 0.27 g (0.6 rr.rr.oli of the first step IV in 1 mL of acetic acid) The mixture was then added dropwise to iodine, and the solution was removed by stirring for 1.5 hours, and the solution was extracted with methylene chloride. 1¿ - r '.' C with water and solution
, to caic sa rada and dried. The r. The mixture was purified by chromatography on silica eluting with ethyl acetate-hexane, 3: 7, containing 0.2% methanol to give the product (25 mg, 11%, m.p., 148-149 ° C).
Anal is i s calculated for Ci5H? 8IN02"0.1H20: C, 48.30; H, 4.92; N, 3.75. Found: C, 47.94; H, 4.67; N, 3.70.
Reasonable variations, such as those that can occur to a technical technician, can be made without departing from the scope of the invention.
It is noted that in relation to this date, the best method eer.ccidc by the applicant to carry out the above-mentioned invention, is that the list is clear to the present description of the ention.
Claims (3)
- Claims 1. A compound of Formula I or a pharmaceutically acceptable solvate thereof having the Formula: characterized in that Q "and Q" are each independently hydrogen or halogen; X is CH2, CH or cxi enc; is CR ?, CR3R4 or ÍCHZ) n, with n = 1-4; is CH :, CH or oxygen; is hydrogen, halogen or C 1 .4 alkyl in both cases; e s c .. is alq le C..r, C 3-6 cycloalkyl / haloalkyl C.-3, alkylamino C-, alquer. C 1, C 4, alkoxy (C 4) alkyl, C 1 alkylene (C 4) alkyl, or trigeran-ethylhexyl C: -; it is drogene or C 1 -4 alkyl; and R3 and R4 are each independently hydrogen or C? _4 alkyl.
- 2. The compound according to claim 1, characterized in that Q1 and Q2 are independently hydrogen or iodine and m is 1.
- 3. The compound according to claim 2, characterized in that Rx is C 1 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 3 haloalkyl, 3-alkemyl, C 1 -2 C 1 -2 alkoxy, alkyl or tri-cyuromethylalkyl C 1 2 and R 2 is hydrogen . comp this in accordance with the 1 r. a 1 c a c 1 or p, characterized in that X is CH; Y : > :; aer, or This compliance with the .1, characterized by the fact .choose the g upo ue consisting of: a r o ¡_- e: zofuran-4-il; Cycloprop-1- .T. e t 1 .. j prcpanarria-i; - t r a r. ? -!, '-; [1- d'-d-r drobenzofuran-4- r: :: -l-- r.et d acetam aa; (-) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (-) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl Jmetoxyacetamide; 5 (-) - (trans) -N- [[2- (2-, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] cyclopropanecarboxamide; (-) - (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] -ethyl] trifluoroacetamide; (trans) -N- [[2- (2, 3-dihydro-2,2-dimethyl-benzofuran-10 4-yl) cycloprop-1-yl] methyl] propanamide; (trans-N- [[2- (2, 3-dihydro-2, 2-dimethyl-benzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (-r) - (trans) - N - [[2- (2-methyl-2, 3-dihydrobenzofuran-4-ii) cycloprop-1-yl] methyl] acetamide; fifteen; - < -, - • t ansi - N - [[2 - i 2-met? I-2, 3-dihydrobenzofuran-4- l; c? Clcprop-i-ii] et? I; propanamide; (-) -; t r a n s; - N - [[2- d-met? L-2, 2-dihydrobenzofuran-4-I 'c? Clcprcp-1-d rr.et dbutar. amide; 'd - ítrap s • - N - [2 - 2-met? l-2, 2-dihidrobenzofuran-20 4-il! cycloprop-i-il; r 1e t 1] eiciopropane carbo amide; i - - si - N - [2-l-.t.et.l-2, 3-dihydrobenzofuran-4-1 c clcrrep-1-d) me 1 '. -2-methylpropanamide; - - tra.-. s - '..' - [2-2-met? l-2,3-dihydrobenzofuran-Z? 4-1 c clcpr p-l-? l] .t.et l] chloroacetamide; (- - (trans) -N- [[2- (2-met il-2, 3-dihydrobenzofuran- -il) cic 1-cp rop-1-i 1] me ti 1] propanamide; (-) - ( trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran- -yl) cycloprop-1-yl] methyl] -2-methylpropanamide; (-) - (trans) -N - [[2- (2-methyl-2,3-dihydrobenzofuran- -yl) cycloprop-1-yl] methyl] acetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran- -yl) cycloprop-1-yl] methyl] methoxyacetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran- -yl) c? cloprop-l-yl] methyl] butanamide; (trans) - N - [[2- (2,3-dihydrobenzofuran-4- i; cicioprop-l-ii] methyl] acetamide; - itrar.s! - N - { - .2, 3-d? h idrobenzofuran-4-cycloprop-Ii] methyl] propanamide; a r. s - - - i [2 - «2 3-dih drcbenzofuran-4 eic 1 cp op- 1 - rr.e ría • ar.s • - N- [d-2 arce: aturan- rr. A rr. Aa. - z, "-d yoaobe zofuran-4 cp rep- anamida; ans í - N - -5- odebenzofuran-4- • pa p. a rr. da; -2H-l-de zo iran-5- car.an.ida; (trans) -N- [[2- (3, -dihydro-2H-l-benzopyran-5-yl) cycloprop-1-yl] methyl] cyclopropane carboxamide; (trans) -N- [[2- (3, 4-dihydro-2H-l-benzopyran-5-yl) cycloprop-1-yl] methyl] butanamide; and (+) - (trans) -N - [[2- (3,4-dihydro-2H-1-benzopyran-5-yl) cycloprop-1-yl] methyl] propanamide. 6. The compound according to the rei indication 5, characterized in that it is selected from the group consisting of: (+) - N - [[2- (2, 3-dihydrobe zofuran-4-yl) cycloprop-1-ylmethyl] propanamide; < -. - (rans N- i i -, '? 3-d? idrobenzofuran-4-iI) cieIoprop-I-iljmet? i acetarr. Going; ' -) - (tra s) - N - [[2 - X, 2-a? r. ? drcbenzofuran-4-id ciciocrcD-l-idrr.etd, a m a a - trans '-N-' I rene r. zofuran-4-: rlt rcpa ocarboxamide; - '- - - t r a n s; - - d 1-2, 3-d? h? drobenzofuran-4-1: c? cloprop-1 dtatamide; ~, r a T. S. »! . .-2, 3-dih? Drobenzofuran- -_ - • _ .. ~ l- .. t - * ..- p :: pap am da; - t r a r. s 2 - rr.e t. -2, 3-d? H? Hydrobenzofuran-, cutanamide; (+) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] cyclopropane carboxamide; (+) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] chloroacetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methy1] propanamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] acetamide; (-) - (trans) -N- [[2- (2-methyl-2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] methyl] cyclopropanecarboxamide; . { - - (trans) -N- [[2- (2-met i i -2, 3-dihydrobenzo furan-4-11) cyclopro? -1-ii] methyl 1] butanamide; ' rans) - N - [[2- d, 3-d? hdrobenzofuran-4-ii.ciclcprop-l-i] rr.et l] acetamide; t - • - (trans1-N- [[2 - .2, 3-d? hydrobenzofuran-4-yl c-cloprcp-1-dd.e; :: ^ crcpanarnide; tra s! - N - [[2-. '2, 2-a? R. Zofuran-4-yl c cloprop-1- l] rr.ei; propanamide;' s: - - [[2 - '. 2, _ - a? R. arccenzofuran-4- - c? cloprep -: -? l] rr. »= 1] cutan amide; trans) - N - [2 - - 2, jd: r .: r: -5, 7-diiodobenzof uran- 4-1 e? Elcprcp-1- drr.et? Dpicpanam? Da; and (trans) -N- [[2- (2, 3-dihydro-5-iodobenzofuran-yl) cycloprop-1-yl] methyl] propanamide. 7. The compound according to claim 6, characterized in that it is (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-yl) cycloprop-1-yl] rnetii] propanamide. 8. The compound according to claim 6, characterized in that it is (trans) -N- [[2- (2, 3-dihydrobenzofuran-4-ii) cycloprop-i-yl] me t i 1] propanamide. 9. The compound "" according to claim 3, characterized in that X is or ige or, Y is C C. Z, r, in which n is 1 or 2 and Z is cxiaer.o. 10. The composition according to claim 9, characterized in that it is selected from the group consisting of: • trar. s, -N - [[2- (1, 3-ber.zca oxol-4-yl) cycloprop-1-yl detyl] aceta rr. isa; - - trar. s -. - [2 -:, 3-orth .: cdioxoi-4-yl) cycloprop-1 - 1] .. et? L] aeetamia; (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methyl] propanamide; (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methyl] propanamide; (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-y1] me il] butanamide; i. -) - (trans) - N - [[2- (i, 3-benzodioxol-4-yl) cycloprop-l-yl] methyl] butanamide; (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] methyl] cyclopropane carboxamide; (-) - (trans) -N- [[2- (1,3-benzodioxol-4-yl) cycloprop-1-yl] methyl] cyclopropane carboxamide; (trans - N - [[2 - '1, 3-benzodioxol-4-yl) cycloprop-1-yl] -me 1113 -2-ethyl-proprpane ida; - - 'trar.S'- -; Z-1, 5-ben: hatexol-4-yl) cycloprop -: - .: V.e Vi -l-r.enipr jpar. amide; - - trar. s'-N-di- i, 3-a r. DRO-i, 4-benzodioxin-5-yl cprepre-p-l-l 'retid prepar. am ida; -, - 't r a r. s - N - d - 2, i - a_.r. are-I, 4-benzodioxin-5- l: c cioprep-1- l; r.e t i 1 aeetamide; - '• - Itrar.s1 - N - [Z - 2, 2 - d r. aro-1, 4-benzodioxin-5-:. cicle c ep - 1 - 1 V; : 1 '7 clopropanecarboxamide; - - tro-c - '. "- L 2 - 2,. * - dn? dro-l, 4-benzodioxin-5- -..-_. ir'; -d l.rr, f..Lr ' tanamide; (+) - (trans) -N- [[2- (2, 3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] propanamide; (-) - (trans) -N - [[2- (2,3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] trifluoroacetamide; (-) - (trans) -N- [[2- (-2,3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-l-yl] methyl] -3,3,3-trifluoropropanamide; . { +) - (trans) -N- [[2- (2, 3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] propanamide; (trans; - N - [[2- (2, 3-dihydro-l, 4-benzodioxin-5-yl) cicioprop-1-ii] met il] acetamide; (trans) - N - [[2- (2 , 3-dihydro-l, 4-benzodioxin-5-yl! C cloprop-l-yl] methyl] propanamide; itrans! - N - [2- '2, 3-dihydro-l, Voenzodioxin-5-? Lc clcprep -l- lmethoxy-anamide; traps - / -3 - i? drc-1, Vbenzodioxin-5- - - - - f - or -.-;.-rr.ethylpropanamide; and rans v -benzodioxin-5 - 1. c cyprc -1-d V- --- '. Cyclopropane carboxamide corr.p is t: ae conformance with the d, characterized in that g r _. p.: q u - consis e of: d? - r • _ • r. z e a i o: -: c 1 - 4 - 11} Cycloprop-1- _a ... _. . a (-) - (trans) -N- [[2- (1, 3-benzodioxol-4-yl) cycloprop-1-yl] met-ii] acetamide; (trans) -N- [[2 - (1,3-benzodioxol-4-yl) cycloprop-1-yl] met il] propanamide; and (-) - (trans) -N- [[2- (1,3-benzodioxol-4-yl) cycloprop-1-yl] methyl] propanamide. 12. The compound according to claim 10, characterized in that it is selected from the group consisting of: (-) - (trans) -N- [[2- (2,3-dihydro-l, 4-benzodioxin-5-yl) cycloprop-1-yl] methyl] propanamide; i -) - Itraps! - N - [[2- (2, 3-dihydro-l, 4-benzodioxin-5-yl] cyclcprop-l-ylmethyl] acetamide;! -, -? Trans) -N- [[2- (2 , 3-dihydro-l, 4-benzodiox? N-5- 1; c? Doprop-l-? L] .t.et l3 cyclopropanecarboxamide; ! -; - .traes) -N- [- .2, 3-d? dro-l, 4-benzodioxin-5- l l cyclop c an amide. 13. The commentary in accordance with document 3, characterized in that X is CH, Y 0- v .- is ox i a e r. e. 14. The compound according to claim 13, characterized in that it is selected from the group consisting of: (-) - (trans) -N- [[2- (2-benzofuran-4-yl) cycloprop-1-yljrnethyl] cyclopropane; (-) - (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-yl] methyl] propanamide; (trans) -N- [[2- (2-methyl-benzofuran-4-yl) cycloprop-1-yl] methyl] acetamide; (trans) -N- [[2- (2-methyl-benzofuran-4-yl) cycloprop-1-yl] methyl] propanamide; (trans) - N - [[2- (2-methyl-benzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; (trans) -N- [[2- (benzofuran-4-? i) cycloprop-1-11] me 111] acetara ida; (tra s) - N - [[2-, 'be zofuran -4- l, c? cloprop-1-i I] metii] propar. m (rar. s) -N- [[2- 'ber. zcfurar. - 4 - 11? c? cloprop-1-yl] met? i] butan m aa; trans) -N- ([2- (benzcf * M r .-, - - i - 'l1! cycloprop-1-:! rr.et:] -2-rr.et? lpro dr. a -.da; and trans-4-chloro-1-yl-methyl-1-yl-cyclopropyl-1-yl. 15. The compound according to claim 14, characterized in that it is selected from the group consisting of: (trans) -N- [[2- (2-methyl-l-benzofuran-4-yl) cycloprop-1-yl] methyl] acetamide; (trans) -N- [[2- (2-methyl-benzofuran-4-yl) cycloprop-1-yl] methyl] propanamide; (trans) -N- [[2- (2-methyl-benzofuran-4-yl) cycloprop-1-yl] methyl] butanamide; and (trans) -N- [[2- (benzofuran-4-yl) cycloprop-1-yl] methyl] propanamide. 16. A method for treating sleep disorders in a patient requiring treatment, characterized in that it comprises administering to the patient a therapeutic quality of a compound of claim 1. 17. A composition useful for the treatment of sleep disorders, characterized in that it comprises a therapeutic amount of a compound of the indication and an appropriate amount of a pharmaceutically acceptable carrier. 18. A method for treating disorders related to circadian rhythm in a patient in need of treatment, characterized in that it comprises administering to the patient a therapeutic amount of a compound of claim 1. 19. A composition useful for the treatment of disorders related to the circadian rhythm, characterized in that it comprises a therapeutic amount of a compound of claim 1 and an appropriate amount of a pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/032,689 | 1996-12-10 |
Publications (1)
Publication Number | Publication Date |
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MXPA99005024A true MXPA99005024A (en) | 2000-02-02 |
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