DE69933147T2 - Sustiuierte cyclische verbindungen, verfahren zu ihrer herstellung sowie sie enthaltende pharmazeutische zusammesetzungen - Google Patents
Sustiuierte cyclische verbindungen, verfahren zu ihrer herstellung sowie sie enthaltende pharmazeutische zusammesetzungen Download PDFInfo
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- DE69933147T2 DE69933147T2 DE69933147T DE69933147T DE69933147T2 DE 69933147 T2 DE69933147 T2 DE 69933147T2 DE 69933147 T DE69933147 T DE 69933147T DE 69933147 T DE69933147 T DE 69933147T DE 69933147 T2 DE69933147 T2 DE 69933147T2
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- 238000000034 method Methods 0.000 title claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title description 79
- 150000001923 cyclic compounds Chemical class 0.000 title 1
- 230000002459 sustained effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 194
- 238000002360 preparation method Methods 0.000 claims description 88
- 239000002253 acid Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- 230000009471 action Effects 0.000 claims description 33
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 29
- -1 cyano, carboxy, nitro, amino Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000001193 melatoninergic effect Effects 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 150000001540 azides Chemical class 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 125000006685 (C1-C6) polyhaloalkyl group Chemical group 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 150000002475 indoles Chemical class 0.000 claims description 6
- KYSCWFKYUJDVHS-UHFFFAOYSA-N methyl n-[3-[2-(cyclopropanecarbonylamino)ethyl]-1-benzofuran-5-yl]carbamate Chemical compound C12=CC(NC(=O)OC)=CC=C2OC=C1CCNC(=O)C1CC1 KYSCWFKYUJDVHS-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- SUSDQVARBLWNKJ-UHFFFAOYSA-N n-[3-(2-acetamidoethyl)-1-benzofuran-5-yl]-2,2,2-trifluoroacetamide Chemical compound C1=C(NC(=O)C(F)(F)F)C=C2C(CCNC(=O)C)=COC2=C1 SUSDQVARBLWNKJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- CQWNTRFWWAONMJ-UHFFFAOYSA-N methyl n-[3-[2-(2-methylpropanoylamino)ethyl]-1-benzofuran-5-yl]carbamate Chemical compound COC(=O)NC1=CC=C2OC=C(CCNC(=O)C(C)C)C2=C1 CQWNTRFWWAONMJ-UHFFFAOYSA-N 0.000 claims description 3
- VFPAHXTUSUVJEM-UHFFFAOYSA-N methyl n-[3-[2-(furan-2-carbonylamino)ethyl]-1-benzofuran-5-yl]carbamate Chemical compound C12=CC(NC(=O)OC)=CC=C2OC=C1CCNC(=O)C1=CC=CO1 VFPAHXTUSUVJEM-UHFFFAOYSA-N 0.000 claims description 3
- GCBBVRLFMIQTAY-UHFFFAOYSA-N n-[2-(5-acetamido-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide Chemical compound C12=CC(NC(=O)C)=CC=C2OC=C1CCNC(=O)C1CC1 GCBBVRLFMIQTAY-UHFFFAOYSA-N 0.000 claims description 3
- UZFMTPZFMOXXAE-UHFFFAOYSA-N n-[2-(5-acetamido-1-benzothiophen-3-yl)ethyl]benzamide Chemical compound C12=CC(NC(=O)C)=CC=C2SC=C1CCNC(=O)C1=CC=CC=C1 UZFMTPZFMOXXAE-UHFFFAOYSA-N 0.000 claims description 3
- TXEOZOYTOBMLJS-UHFFFAOYSA-N n-[2-(7-acetamidonaphthalen-1-yl)ethyl]acetamide Chemical compound C1=C(NC(C)=O)C=C2C(CCNC(=O)C)=CC=CC2=C1 TXEOZOYTOBMLJS-UHFFFAOYSA-N 0.000 claims description 3
- ZZZMEMOYMVCOBE-UHFFFAOYSA-N n-[8-[2-[(2-bromoacetyl)amino]ethyl]naphthalen-2-yl]cyclohexanecarboxamide Chemical compound C1=C2C(CCNC(=O)CBr)=CC=CC2=CC=C1NC(=O)C1CCCCC1 ZZZMEMOYMVCOBE-UHFFFAOYSA-N 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- DRERKYSJZHRXKG-UHFFFAOYSA-N tert-butyl n-[3-(2-acetamidoethyl)-1-benzofuran-5-yl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=C2OC=C(CCNC(C)=O)C2=C1 DRERKYSJZHRXKG-UHFFFAOYSA-N 0.000 claims description 3
- CKDITILKVSNWTR-UHFFFAOYSA-N tert-butyl n-[3-(2-acetamidoethyl)-1-benzofuran-5-yl]carbamate Chemical compound C1=C(NC(=O)OC(C)(C)C)C=C2C(CCNC(=O)C)=COC2=C1 CKDITILKVSNWTR-UHFFFAOYSA-N 0.000 claims description 3
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000006553 (C3-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 claims description 2
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- 229910002056 binary alloy Inorganic materials 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- 239000007822 coupling agent Substances 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000022244 formylation Effects 0.000 claims description 2
- 238000006170 formylation reaction Methods 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002346 iodo group Chemical class I* 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 238000006138 lithiation reaction Methods 0.000 claims description 2
- ZINMQJVLELNGRZ-UHFFFAOYSA-N methyl n-[3-(2-acetamidoethyl)-1-benzofuran-5-yl]carbamate Chemical compound COC(=O)NC1=CC=C2OC=C(CCNC(C)=O)C2=C1 ZINMQJVLELNGRZ-UHFFFAOYSA-N 0.000 claims description 2
- YNHBPUMTCUKQHD-UHFFFAOYSA-N methyl n-[3-(2-benzamidoethyl)-1-benzofuran-5-yl]carbamate Chemical compound C12=CC(NC(=O)OC)=CC=C2OC=C1CCNC(=O)C1=CC=CC=C1 YNHBPUMTCUKQHD-UHFFFAOYSA-N 0.000 claims description 2
- BGFIBWAZAGTWQA-UHFFFAOYSA-N methyl n-[8-(2-acetamidoethyl)-6-phenylnaphthalen-2-yl]carbamate Chemical compound C1=C(CCNC(C)=O)C2=CC(NC(=O)OC)=CC=C2C=C1C1=CC=CC=C1 BGFIBWAZAGTWQA-UHFFFAOYSA-N 0.000 claims description 2
- SHZBHGJUHWSBAF-UHFFFAOYSA-N methyl n-[8-(2-acetamidoethyl)naphthalen-2-yl]carbamate Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(NC(=O)OC)=CC=C21 SHZBHGJUHWSBAF-UHFFFAOYSA-N 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 238000005949 ozonolysis reaction Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 6
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 claims 3
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 claims 3
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical class C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 claims 2
- 125000003367 polycyclic group Chemical group 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 238000004873 anchoring Methods 0.000 claims 1
- 125000001309 chloro group Chemical class Cl* 0.000 claims 1
- QOSYUBJFWXZYIK-UHFFFAOYSA-N ethyl n-[8-[2-[(2-bromoacetyl)amino]ethyl]naphthalen-2-yl]carbamate Chemical compound C1=CC=C(CCNC(=O)CBr)C2=CC(NC(=O)OCC)=CC=C21 QOSYUBJFWXZYIK-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- VNBHAJFCYIDHKM-UHFFFAOYSA-N hexyl n-[8-(2-acetamidoethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]carbamate Chemical compound C1CCC(CCNC(C)=O)C2=CC(NC(=O)OCCCCCC)=CC=C21 VNBHAJFCYIDHKM-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- WPUVYHBPRBDQLZ-UHFFFAOYSA-N methyl n-[3-[2-(cyclopentanecarbonylamino)ethyl]-1-benzofuran-5-yl]carbamate Chemical compound C12=CC(NC(=O)OC)=CC=C2OC=C1CCNC(=O)C1CCCC1 WPUVYHBPRBDQLZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 230000033764 rhythmic process Effects 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 13
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 230000027455 binding Effects 0.000 description 11
- 229960003987 melatonin Drugs 0.000 description 11
- 239000012429 reaction media Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 230000006978 adaptation Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 5
- 0 C*=C(*)N(C)* Chemical compound C*=C(*)N(C)* 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 5
- 210000001367 artery Anatomy 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 5
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Classifications
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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| PCT/FR1999/001101 WO1999058496A1 (fr) | 1998-05-12 | 1999-05-10 | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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| AUPO274596A0 (en) * | 1996-10-04 | 1996-10-31 | Armstrong, Stuart Maxwell | Method for the treatment of neurological or neuropsychiatric disorders |
| FR2778662B1 (fr) * | 1998-05-12 | 2000-06-16 | Adir | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| US6569879B2 (en) * | 2000-02-18 | 2003-05-27 | Merck & Co., Inc. | Aryloxyacetic acids for diabetes and lipid disorders |
| FR2814165B1 (fr) | 2000-09-15 | 2002-11-22 | Adir | Nouveaux derives biphenyles substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| AU2001297717B2 (en) * | 2000-12-11 | 2006-02-23 | Amgen Inc. | CXCR3 antagonists |
| US6794379B2 (en) * | 2001-06-06 | 2004-09-21 | Tularik Inc. | CXCR3 antagonists |
| FR2853649B1 (fr) * | 2003-04-09 | 2006-07-14 | Servier Lab | Nouveaux derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2857011B1 (fr) * | 2003-07-04 | 2005-09-16 | Servier Lab | Nouveaux derives du benzothiophene 2-thiosubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| GB0330043D0 (en) | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them |
| GB0330042D0 (en) | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions them |
| JP2007536302A (ja) * | 2004-05-05 | 2007-12-13 | エフ.ホフマン−ラ ロシュ アーゲー | 5−ht6受容体、5−ht2a受容体、又はその両方の調節に有用なアリールスルホニルベンゾジオキサン類 |
| US7393865B2 (en) | 2004-06-17 | 2008-07-01 | Neurocrine Biosciences, Inc. | Sleep inducing compounds and methods relating thereto |
| US7271271B2 (en) * | 2004-06-28 | 2007-09-18 | Amgen Sf, Llc | Imidazolo-related compounds, compositions and methods for their use |
| US7375102B2 (en) * | 2004-06-28 | 2008-05-20 | Amgen Sf, Llc | Tetrahydroquinazolin-4(3H)-one-related and tetrahydropyrido[2,3-D]pyrimidin-4(3H)-one-related compounds, compositions and methods for their use |
| US7939538B2 (en) * | 2004-06-28 | 2011-05-10 | Amgen Inc. | Compounds, compositions and methods for prevention and treatment of inflammatory and immunoregulatory disorders and diseases |
| HRP20100181T1 (hr) * | 2004-12-21 | 2010-05-31 | F. Hoffmann - La Roche Ag | Derivati tetralina i indana i njihove upotrebe |
| CA2591810A1 (en) | 2004-12-21 | 2006-06-29 | F.Hoffmann-La Roche Ag | Chroman derivatives and uses thereof in the treatment of cns disorders |
| WO2006066746A1 (en) * | 2004-12-21 | 2006-06-29 | F. Hoffmann-La Roche Ag | Chroman derivatives and their use as 5-ht receptor ligands |
| ATE409179T1 (de) * | 2004-12-21 | 2008-10-15 | Hoffmann La Roche | Tetralin- und indanderivate und deren anwendungen als 5-ht-antagonisten |
| MX2007007481A (es) | 2004-12-21 | 2007-07-20 | Hoffmann La Roche | Derivados de tetralina e indano y usos de los mismos. |
| ATE499355T1 (de) * | 2005-11-03 | 2011-03-15 | Hoffmann La Roche | Arylsulfonylchromane als 5-ht6-inhibitoren |
| US8337721B2 (en) | 2005-12-02 | 2012-12-25 | Vanderbilt University | Broad-emission nanocrystals and methods of making and using same |
| AU2007215247B2 (en) * | 2006-02-10 | 2012-12-13 | Transtech Pharma, Llc | Benzazole derivatives, compositions, and methods of use as Aurora kinase inhibitors |
| MX2008015511A (es) | 2006-06-20 | 2008-12-18 | Hoffmann La Roche | Derivados de arilsulfonilnaftaleno y usos de los mismos. |
| MX2008015510A (es) * | 2006-06-20 | 2008-12-18 | Hoffmann La Roche | Derivados de arilsulfonamidiltetralina y usos de los mismos. |
| CN101472884A (zh) * | 2006-06-20 | 2009-07-01 | 弗·哈夫曼-拉罗切有限公司 | 1,2,3,4-四氢化萘和茚满衍生物及其用途 |
| JP2010540630A (ja) * | 2007-10-04 | 2010-12-24 | メルク・シャープ・エンド・ドーム・コーポレイション | ヒストン脱アセチル化酵素阻害剤としてのn−ヒドロキシ−ナフタレンジカルボキサミド及びn−ヒドロキシ−ビフェニル−ジカルボキサミド化合物 |
| ATE533752T1 (de) | 2008-09-08 | 2011-12-15 | Cadila Pharmaceuticals Ltd | Verbesserter herstellungsprozess für nebivolol- hydrocholorid |
| CN101481321B (zh) * | 2009-02-27 | 2012-04-18 | 上海医药工业研究院 | 阿戈美拉汀卤化氢复合物及其制备方法 |
| UA121309C2 (uk) | 2014-02-03 | 2020-05-12 | Вітае Фармасьютікалс, Ллс | Дигідропіролопіридинові інгібітори ror-гамма |
| CN104292125B (zh) * | 2014-08-14 | 2016-06-01 | 广东东阳光药业有限公司 | 萘衍生物及其在药物上的应用 |
| BR112017007460A2 (pt) | 2014-10-14 | 2017-12-19 | Vitae Pharmaceuticals Inc | inibidores de di-hidropirrolopiridina de ror-gama |
| US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
| US9657020B2 (en) * | 2015-01-20 | 2017-05-23 | Xoc Pharmaceuticals, Inc. | Ergoline compounds and uses thereof |
| JP2018502889A (ja) | 2015-01-20 | 2018-02-01 | エックスオーシー ファーマシューティカルズ インコーポレイテッドXoc Pharmaceuticals, Inc | イソエルゴリン化合物およびその使用 |
| ES2856931T3 (es) | 2015-08-05 | 2021-09-28 | Vitae Pharmaceuticals Llc | Moduladores de ROR-gamma |
| MX385332B (es) | 2015-11-20 | 2025-03-18 | Vitae Pharmaceuticals Llc | Moduladores de ror-gamma. |
| TW202220968A (zh) | 2016-01-29 | 2022-06-01 | 美商維它藥物有限責任公司 | ROR-γ調節劑 |
| US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| AU2018275873A1 (en) | 2017-06-01 | 2019-12-19 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
| CN111225914B (zh) | 2017-07-24 | 2022-10-11 | 生命医药有限责任公司 | RORγ的抑制剂 |
| WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | INHIBITORS OF ROR GAMMA |
| CN108156986A (zh) * | 2018-01-04 | 2018-06-15 | 山东农业大学 | 外源褪黑素对苹果矮化自根砧木幼苗臭氧胁迫缓解效应的应用 |
| IL309232A (en) | 2021-06-14 | 2024-02-01 | Scorpion Therapeutics Inc | Urea derivatives which can be used to treat cancer |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4663347A (en) * | 1983-10-31 | 1987-05-05 | Merck Frosst Canada, Inc. | Benzofuran 2-carboxylic acid esters useful as inhibitors of leukotriene biosynthesis |
| FR2680507B1 (fr) * | 1991-08-23 | 1993-10-08 | Adir Cie | Nouvelles naphtylethylurees et naphtylethylthiourees, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
| FR2689124A1 (fr) * | 1992-03-27 | 1993-10-01 | Adir | Nouvelles naphtylalkylamines, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
| FR2705095B1 (fr) * | 1993-05-12 | 1995-06-23 | Adir | Nouveaux indoles substitués, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
| GB9313913D0 (en) * | 1993-07-06 | 1993-08-18 | Smithkline Beecham Plc | Novel compounds |
| US5350748A (en) * | 1993-08-18 | 1994-09-27 | Warner-Lambert Company | 3-thio or amino substituted-benzo[b]thiophene-2-carboxamides and 3-oxygen, thio, or amino substituted-benzofuran-2-carboxamides as inhibitors of cell adhesion |
| FR2713636B1 (fr) * | 1993-12-07 | 1996-01-05 | Adir | Nouveaux dérivés naphtaléniques, leur procédé de préparation, et les compositions pharmaceutiques qui les contiennent. |
| ATE193700T1 (de) * | 1994-09-12 | 2000-06-15 | Takeda Chemical Industries Ltd | Benzozykloalkenverbindungen, deren herstellung und verwendung |
| JP3908798B2 (ja) * | 1994-09-12 | 2007-04-25 | 武田薬品工業株式会社 | ベンゾシクロアルケン類、その製造法および剤 |
| JPH08268987A (ja) * | 1995-02-24 | 1996-10-15 | Bristol Myers Squibb Co | テトラリニル−,及びインダニル−エチルアミド誘導体 |
| US5863936A (en) * | 1995-04-18 | 1999-01-26 | Geron Corporation | Telomerase inhibitors |
| FR2734815B1 (fr) * | 1995-05-31 | 1997-07-04 | Adir | Nouveaux composes arylalkyl (thio) carboxamides, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2734814B1 (fr) * | 1995-05-31 | 1997-07-04 | Adir | Nouveaux composes alkoxy-aryles, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO1997020833A1 (en) * | 1995-12-05 | 1997-06-12 | Darwin Discovery Limited | Benzofuran carboxamides and sulphonamides |
| FR2778662B1 (fr) * | 1998-05-12 | 2000-06-16 | Adir | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| KR101012391B1 (ko) | 2008-11-11 | 2011-02-09 | 엘지전자 주식회사 | 무선 통신 시스템에 있어서, 하향링크로 서브프레임 지정 정보를 전송하는 방법 |
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1998
- 1998-05-12 FR FR9805957A patent/FR2778662B1/fr not_active Expired - Fee Related
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1999
- 1999-05-10 BR BR9911783-5A patent/BR9911783A/pt not_active Application Discontinuation
- 1999-05-10 PL PL99344048A patent/PL195613B1/pl unknown
- 1999-05-10 BR BR9911771-1A patent/BR9911771A/pt not_active Application Discontinuation
- 1999-05-10 CA CA002331877A patent/CA2331877C/fr not_active Expired - Fee Related
- 1999-05-10 US US09/700,056 patent/US6605632B1/en not_active Expired - Fee Related
- 1999-05-10 ES ES99918036T patent/ES2255260T3/es not_active Expired - Lifetime
- 1999-05-10 DE DE69933147T patent/DE69933147T2/de not_active Expired - Fee Related
- 1999-05-10 EP EP99918037A patent/EP1077928B1/fr not_active Expired - Lifetime
- 1999-05-10 CN CN99806830A patent/CN1304400A/zh active Pending
- 1999-05-10 AU AU36104/99A patent/AU747301B2/en not_active Ceased
- 1999-05-10 AT AT99918037T patent/ATE312073T1/de not_active IP Right Cessation
- 1999-05-10 WO PCT/FR1999/001100 patent/WO1999058495A1/fr not_active Ceased
- 1999-05-10 NZ NZ507691A patent/NZ507691A/en unknown
- 1999-05-10 CA CA002331870A patent/CA2331870C/fr not_active Expired - Fee Related
- 1999-05-10 US US09/700,098 patent/US6872851B1/en not_active Expired - Fee Related
- 1999-05-10 NZ NZ507692A patent/NZ507692A/en unknown
- 1999-05-10 AT AT99918036T patent/ATE312072T1/de not_active IP Right Cessation
- 1999-05-10 DK DK99918036T patent/DK1077927T3/da active
- 1999-05-10 HU HU0101800A patent/HUP0101800A3/hu unknown
- 1999-05-10 ES ES99918037T patent/ES2255261T3/es not_active Expired - Lifetime
- 1999-05-10 PL PL99344012A patent/PL344012A1/xx unknown
- 1999-05-10 DE DE69933149T patent/DE69933149T2/de not_active Expired - Fee Related
- 1999-05-10 JP JP2000548300A patent/JP2002514620A/ja active Pending
- 1999-05-10 HU HU0101813A patent/HUP0101813A3/hu unknown
- 1999-05-10 EP EP99918036A patent/EP1077927B1/fr not_active Expired - Lifetime
- 1999-05-10 DK DK99918037T patent/DK1077928T3/da active
- 1999-05-10 CN CN99806053A patent/CN1300277A/zh active Pending
- 1999-05-10 JP JP2000548299A patent/JP2002514619A/ja active Pending
- 1999-05-10 AU AU36103/99A patent/AU748567B2/en not_active Ceased
- 1999-05-10 WO PCT/FR1999/001101 patent/WO1999058496A1/fr not_active Ceased
-
2000
- 2000-11-10 ZA ZA200006528A patent/ZA200006528B/en unknown
- 2000-11-10 ZA ZA200006529A patent/ZA200006529B/en unknown
- 2000-11-13 NO NO20005714A patent/NO20005714D0/no not_active Application Discontinuation
- 2000-11-13 NO NO20005715A patent/NO20005715D0/no not_active Application Discontinuation
-
2003
- 2003-06-16 US US10/462,331 patent/US7183318B2/en not_active Expired - Fee Related
- 2003-06-16 US US10/462,326 patent/US20040002490A1/en not_active Abandoned
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2004
- 2004-09-23 US US10/947,757 patent/US7126012B2/en not_active Expired - Fee Related
- 2004-09-23 US US10/948,410 patent/US7115752B2/en not_active Expired - Fee Related
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