CS248738B2 - Production method of the new 2-substituted derivatives of ergoline - Google Patents
Production method of the new 2-substituted derivatives of ergoline Download PDFInfo
- Publication number
- CS248738B2 CS248738B2 CS252685A CS252685A CS248738B2 CS 248738 B2 CS248738 B2 CS 248738B2 CS 252685 A CS252685 A CS 252685A CS 252685 A CS252685 A CS 252685A CS 248738 B2 CS248738 B2 CS 248738B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- group
- carbon
- formula
- methyl
- palladium
- Prior art date
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- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- -1 acrylic ester Chemical class 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 17
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- XECWCWOFFBIAKZ-PRHODGIISA-N (6ar,10ar)-5-bromo-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline Chemical compound C([C@@H]12)CCN[C@@H]1CC1=C(Br)NC3=CC=CC2=C31 XECWCWOFFBIAKZ-PRHODGIISA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001955 cumulated effect Effects 0.000 abstract 1
- 238000007336 electrophilic substitution reaction Methods 0.000 abstract 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229960002896 clonidine Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229960004046 apomorphine Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- JUAFFCYJDFGDSA-DXCKQFNASA-N 3-[(6ar,9s,10ar)-5-iodo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=C(I)NC3=C1 JUAFFCYJDFGDSA-DXCKQFNASA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002631 hypothermal effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 3
- UJGQBDHUJZTVRD-DXCKQFNASA-N (6ar,9s,10ar)-9-(diethylcarbamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-5-carboxylic acid Chemical class C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=C(C(O)=O)NC3=C1 UJGQBDHUJZTVRD-DXCKQFNASA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZMADCGSDJKHDCB-YYFZDKIDSA-N 3-[(6ar,9s,10ar)-5-ethynyl-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=C(C#C)NC3=C1 ZMADCGSDJKHDCB-YYFZDKIDSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methyl urea Chemical compound CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001253 acrylic acids Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229960003587 lisuride Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- OTYPIDNRISCWQY-UHFFFAOYSA-L palladium(2+);tris(2-methylphenyl)phosphane;dichloride Chemical compound Cl[Pd]Cl.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C OTYPIDNRISCWQY-UHFFFAOYSA-L 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000028016 temperature homeostasis Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOIXEDCJSGJMDR-WPLVIQRKSA-N (6ar,10ar)-7,9-dimethyl-8-(2-phenylethynyl)-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound C([C@@H]1C=2C=CC=C3NC=C(C=23)C[C@H]1N1C)=C(C)C1C#CC1=CC=CC=C1 JOIXEDCJSGJMDR-WPLVIQRKSA-N 0.000 description 1
- JSNKGWSJEOFBET-DXCKQFNASA-N (6ar,9s,10ar)-9-(diethylcarbamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-5-carboxamide Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=C(C(N)=O)NC3=C1 JSNKGWSJEOFBET-DXCKQFNASA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- PERGOYKXBIQUFH-GUVBGQPJSA-N 3-[(6ar,9s,10ar)-7-methyl-5-[3-(oxan-2-yloxy)prop-1-ynyl]-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound C([C@@H]1[C@@H](C=2C=CC=C(C3=2)N2)C[C@@H](CN1C)NC(=O)N(CC)CC)C3=C2C#CCOC1CCCCO1 PERGOYKXBIQUFH-GUVBGQPJSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- PSVNDADZQOUXMI-LUQKVYGDSA-N C(#CC)C1=C2C[C@H]3N(C[C@H](C[C@@H]3C=3C=CC=C(N1)C=32)NC(N(CC)CC)=O)C Chemical compound C(#CC)C1=C2C[C@H]3N(C[C@H](C[C@@H]3C=3C=CC=C(N1)C=32)NC(N(CC)CC)=O)C PSVNDADZQOUXMI-LUQKVYGDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
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- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
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- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
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- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZGNPLWZYVAFUNZ-UHFFFAOYSA-N tert-butylphosphane Chemical compound CC(C)(C)P ZGNPLWZYVAFUNZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
(54) Způsob výroby nových 2-substituovaných derivátů ergolinu(54) A method for producing the novel 2-substituted ergoline derivatives
Předložený vynález se týká způsobu výroby nových derivátů ergolinu, které jsou substituovány v poloze 2. Uvedené sloučeniny mají cenné íarmakologické vlastnosti a mohou se tudíž používat jako účinné složky léčiv.The present invention relates to a process for the preparation of novel ergoline derivatives which are substituted in the 2-position. The compounds have valuable pharmacological properties and can therefore be used as active pharmaceutical ingredients.
Předmětem předloženého vynálezu je způsob výroby v poloze 2 substituovaných ergolinů obecného vzorce I znamenají jednoduchou vazbu uhlík—uhlík nebo dvojnou vazbu uhlík—uhlík, avšak nikoli kumulovanou dvojnou vazbu a substituent v poloze 8 zaujímá a- nebo β-polohu, jestližeAn object of the present invention is a process for the preparation of the 2-position of substituted ergolines of formula I is a carbon-carbon single bond or a carbon-carbon double bond but not a cumulative double bond and the substituent at position 8 occupies the α- or β-position
znamená jednoduchou vazbu uhlík—uhlík, R2 znamená skupinu vzorce COR‘, přičemž v němž (OR 2 represents a group of formula COR ', wherein (O
R‘ znamená hydroxyskupinu, alkoxyskupinu s 1 až 4 atomy uhlíku nebo aminoskupinu, dále znamená skupinu vzorceR‘ is hydroxy, C 1 -C 4 alkoxy or amino, furthermore, R is
CH=CH—CO2R“ aCH = CH — CO 2 R a
CH2—CH2—COR“, přičemžCH 2 —CH 2 — COR ", wherein
R“ znamená alkylovou skupinu s 1 až 4 atomy uhlíku, dále znamená skupinu vzorce cQ я c2 aR " is C1-C4alkyl, furthermore a group of formula c- Q and c- 2a
C=C—R“‘C = C — R “‘
HC=CH—R“‘, přičemž znamená atom vodíku, alkylovou skuskuR“‘ pinu s 1 až 4 atomy uhlíku, fenylovou pinu nebo skupinu vzorce CH2OH,HC = CH — R “‘, which is hydrogen, C1-C4 alkyl, R “‘, phenyl or CH 2 OH,
CH2NR2“ aCH2NR2 'a
MeMe
Si—R“,Si — R “,
Me přičemžMe taking
R“ znamená alkylovou skupinu s 1 atomy uhlíku, .R "represents an alkyl group having 1 carbon atoms,.
R6 znamená nižší alkylovou skupinu atomy uhlíku - aR 6 represents a lower alkyl group by carbon atoms - and
R8 znamená methylovou skupinu nebo- skupinu vzorce až 4 s ažR 8 represents a methyl group or a group of the formula up to 4 to 4
NH—CO—NEt2 neboNH — CO — NEt2 or
NH—CS—NEÍ2, přičemžNH - CS - NE2, wherein
Et ' znamená ethyl, jakož i jejich solí, který spočívá v tom,··, že se nechá reagovat 2-jodergolin nebo 2-bromergolin obecného vzorce IIEt 'means ethyl, and salts thereof, by reacting 2-iodergoline or 2-bromergoline of formula II
(II) v němž(II) in which:
C9I mají shora uvedený význam, s elektrofilním činidlem zvoleným , ze skupiny, tvořené - - směsí benzylalkoholu a oxidu uhelnatého, - esterem akrylové kyseliny vzorce CH2=Ch—CO2R“ - a - ethinylderivátem vzorce - CH=C—R“‘, přičemž R“ a R“‘ mají shora - uvedený - . význam, v přítomnosti - paládiového- - katalyzátoru a seknudářního - - - nebo terciárního - aminu bez rozpouštědla nebo v aprotickém - - rozpouštědle mísitelném s vodou při - teplotách nad teplotu místnosti v rozsahu - od 40 - °C - do - - teploty varu - reakční směsi, načež se popřípadě; 2-benzylová - - skupina hydrogenuje paládiem za vzniku karboxyderivátu- nebo - se nechá reagovat - -s amoniakem za vzniku 2-karboxamidoskupiny nebo se exocyklická násobná vazba hydrogenuje pomocí - Raney-niklu nebo paládia na nosiči - na - jednoduchou nebo dvojnou vazbu uhlík—uhlík nebo se chránící skupina SiMezR“ - . působením báze nebo se tetrahydropyranylová chránící skupina - od- . štěpí působením pyridinium-p-toluensulfonátu - a pořípadě se takto získané sloučeniny převedou působením fyziologicky snášenlivé - kyseliny na - . adiční -.sůl s kyselinou. C 9I is as defined above, with an electrophilic agent selected from the group consisting of: - a mixture of benzyl alcohol and carbon monoxide, - an acrylic ester of formula CH 2 = CH-CO 2 R ", and - an ethynyl derivative of formula - CH = C-R" wherein R "and R"'have the aforementioned -. meaning, in the presence of - a palladium - catalyst and a secondary - - - or tertiary - amine without solvent or in an aprotic - water miscible solvent - at temperatures above room temperature in the range of - from 40 ° C to - boiling point - the reaction mixture, optionally; 2-benzyl - - hydrogenates with palladium to form a carboxy derivative - or - reacts - with ammonia to form a 2-carboxamido group, or exocyclic multiple bond is hydrogenated with - Raney nickel or palladium on a support - to - single or double carbon bonding— carbon or a protecting group SiMezR '-. by treatment with a base or with a tetrahydropyranyl protecting group. it is cleaved by the action of pyridinium p-toluenesulfonate - and, if necessary, the compounds thus obtained are converted into - by the action of a physiologically tolerable acid. acid addition salt.
Alkylovými skupinami s až 4 atomy uhlíku jsou takové skupiny, které se odvozují od alifatických uhlovodíků. Takovými zbytky jsou například methyl, ethyl, n-propyl, isopropyl, n-butyl a terc.butyl.Alkyl groups of up to 4 carbon atoms are those derived from aliphatic hydrocarbons. Such residues are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
Solemi - sloučenin vzorce - I, které se vyrábějí - - -postupem - -podle vynálezu, - jsou adiční soli - š kyselinami, a odvozují - se od - fyziologicky - nezávadných - kyselin. Takovými- fyziologicky nezávadnými kyselinami jsou - anorganické kyseliny, jako například chlorovodíková - kyselina, dusičná- - kyselina, fosforečná - kyselina, - sírová -kyselina, - bromovodíková kyselina, jodovodíková kyselina, - - dusitá'· kyselina nebo fosforitá kyselina, nebo- organické kyseliny, jako například alifatické monokarboxylové nebo dikarboxylové kyseliny, fenylsubstituované alkankarboxylové kyseliny, hydroxyalkankarboxylové kyseliny nebo alkandikarboxylové - kyseliny, aromatické kyseliny nebo- alifatické nebo aromatické sulfonové kyseliny. Fyziologicky nezávadnými solemi těchto kyselin jsou tudíž například následující:The salts of the compounds of the formula I which are produced by the process of the invention are acid addition salts and are derived from physiologically acceptable acids. Such physiologically acceptable acids are - inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, or organic acids such as aliphatic monocarboxylic or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids or alkanedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids. Thus, the physiologically acceptable salts of these acids are, for example, as follows:
sulfát, pyrosulfát, hydrogensulfát, sulfit, hydrogensulfit, nitrát, fosfát, monohydrogenfosfát, dihydrogenfosfát, metafosfát, pyrrofosfát, chlorid, bromid, jodid, fluorid, acetát, propionát, dekaonát, kaprylát, akrylát.·. formiát, isobutyrát, kaproát, heptanoát, propionát, malonát, sukcinát, suberát, sebakát, fumarát, maleát, mandlát, butin-l,4-dioát, hexin-l,6-dioát, benzoát, chlorbenzoát, methylbenzoát, dinitrobenzoát, hydroxybenzoát,sulphate, pyrosulphate, hydrogen sulphate, sulphite, hydrogen sulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decaonate, caprylate, acrylate. formate, isobutyrate, caproate, heptanoate, propionate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,
4 8 7 3 8 methokybenzoát, ftalát, tereftalát, -benzensulfonát, toluensulfonát, chlorbenzensulfonát, xylensulfonát, fenylacetát, fenylpropionát, fenylbutyrát, citrát, Taktát, f-hydroxybutyrát, glykolát, malát, tartrát, methansulfonát, propansulfonát, naftalen-l-sulfonát, nebo naftalen-2-sulfonát.4 8 7 3 8 Methoxycarbenzoate, phthalate, terephthalate, -benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, Tactate, f-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate 1-methanesulfonate or naphthalene-2-sulfonate.
Ve -srovnání -se známými ergoliny, které nejsou . substituovány v poloze 2, jako -na.příklad s Lisuridem nebo s Te-rguridem se sloučeniny vzorce I vyráběné postupem -podle - vynálezu vyznačují centrálními - anidoparainergními účinky nebo/a účinky projevujícími se v blokování a'2-receptorů.In comparison to known ergolines which are not. Substituted at the 2-position, such as, for example, with Lisuride or Terururide, the compounds of formula I produced by the process of the invention are characterized by central anidoparainergic and / or α 2 -receptor blocking effects.
Centrální blokádu dopaminových -receptorů, například l,l-dietbyl-{G-methyl-2-ethlnyl-b/a-ergollnyl)močoviny (A) je - možno· ilustrovat -pomocí -interakčního testu za použití agonisty -receptorů, kterým je v daném -případě -apomorfin, na myších po jednorázovém - -předběžném intraperitoneálním . -podání, - přičemž se uvedený test hodnotí -na -základě potlačení hypotermie vyvolané -intraperitoneálním podáním 5 mg/kg apornorfinu. Samci myší (kmen -NMRI) se předběžně - - ošetří podáním různých dávek látky - A, která sama neovlivňuje termoregulaci pokusných -zvířat, popřípadě nosnou -látkou. O 30 minut -později se všem -zvířatům podá apomorfin v dávce 5 mg/kg i. p. -60 -minut po podání látky A, popřípadě nosné látkv (= 30 minut po podání apomorfinu·) se měří teplota v konečníku pomocí termosondy. Zatímco zvířata, - -' kterým byla podána pouze nosná látka vykazují hypotermii, -byl u - zvířat - ošetřených podáním 2-ethínyI-T-DHL - v závislosti na - dávce -potlačen -účinek apornorfinu -na pokles tělesné teploty. Účinek látky A, jakožto antagonisty -apomorfinu byl statisticky významný již při dávce 0,2 mg/kg.The central blockade of dopamine-receptors, for example 1,1-dietbyl- (G-methyl-2-ethnyl-b / α-ergollnyl) urea (A), can be illustrated by the interaction test using an agonist -receptors which are: in a given case, apomorphine, in mice following a single pre-intraperitoneal injection. administration, said assay being evaluated for suppression of hypothermia induced by intraperitoneal administration of 5 mg / kg apornorphine. Male mice (strain -NMRI) are pre-treated with various doses of substance A, which itself does not affect the thermoregulation of the test animals or the vehicle. 30 minutes later, all animals are given apomorphine at a dose of 5 mg / kg i.p. -60 minutes after administration of Compound A or vehicle (= 30 minutes after administration of apomorphine), the rectal temperature is measured using a thermosonde. While the vehicle-only animals exhibited hypothermia, the animals treated with 2-ethynyl-T-DHL were dose-suppressed by the effect of apornorphine on a decrease in body temperature. The effect of substance A as an antagonist-apomorphine was statistically significant at the 0.2 mg / kg dose.
Centtální blokáda a2-receptorů látky A -byHa ilustrována pomocí interakčního- testu - za použití -Clonidinu, jakožto· antagonisty - «2^re· ceptorů, na myších po jednorázovém intraperitoneálním předběžném podání - (parametr: potlačení -hypotermie vyvolané podáním - 0,1 mg/kg i. p. eionidinu). -Samcům- myší - (kmen NMRI) byly předběžně podány různé -látky - A, která sama neovlivňuje termoregulaci pokusných zvířat, -popřípadě nosné -látky. O -30 -minut později byl všem zvířatům -podán Clonidin v- dávce - 0,1 -mg/ /kg i. p. 60 minut po podání A, popřípadě nosné -látky ( - = 30 -minut -po podání Clonidinu) se měří teplota v - konečníku pomocí termosondy. -Zatímco -myši, které byly - ošetřeny pouze podáním nosné látky, vykazovaly hypotermii, byl u zvířat ošetřených předem látkou A potlačen v závislosti na dávce -účinek Clonidinu na pokles tělesné teploty. Účinek -látky A - jako - antagonisty Clonidinu, byl statisticky významný již při dávce 0,2 mg/kg.The central blockade of? 2 -receptors of? -ByHa is illustrated by an interaction test using -Clonidine as an antagonist of? 2 receptors in mice following a single intraperitoneal pre-administration (parameter: suppression of administration-induced hyperthermia - 0, 1 mg / kg ip eionidine). The mouse mice - (NMRI strain) were pre-administered with various substances - A, which does not itself affect the thermoregulation of the test animals, or the carrier substance. -30 minutes later, all animals were administered Clonidine at a dose of 0.1 mg / kg ip 60 minutes after administration of A or the carrier substance (- = 30 minutes after administration of Clonidine) and the temperature in - rectum by thermosonde. While mice that were treated with vehicle only showed hypothermia, dose-dependent effects of Clonidine on body temperature decrease were suppressed in animals pretreated with substance A. The effect of Compound A as a Clonidine antagonist was statistically significant as early as 0.2 mg / kg.
Na základě těchto zjištění se mohou sloučeniny vyráběné postupem podle -vynálezu používat -jako neuroleptika k léčení - psychóz schizofrenního typu nebo jako antidepresiva.Based on these findings, the compounds produced by the process of the invention can be used as neuroleptics for the treatment of schizophrenic-type psychoses or as antidepressants.
Výroba sloučenin obecného vzorce -I -ze sloučenin obecného- vzorce II -se provádí - - o sobě známými metodami.The preparation of the compounds of formula (I) from the compounds of formula (II) is carried out by methods known per se.
.Za tím účelem se -nechá -reagovat 2-jodnebo -2-brom-ergoIin -s elektrofilním -činidlem, jako je benzylalkohol pod atmosférou oxidu uhelnatého, -ester akrylové -kyseliny nebo monosubstituovaný acetylen buď bez rozpouštědla, v -odpovídajícímu aminu, nebo v - - aprotickém rozpouštědle mísitelném s - vodou, v přítomnosti sekundárního nebo· terciárního - - aminu, - při teplotách nad --teplotou místnosti v -rozsahu od - 40 CC až - do -teploty varu -reakční směsi - v přítomnosti paládiového - -katalyzátoru.For this purpose, 2-iodo-2-bromo-ergoline is reacted with an electrophilic reagent such as benzyl alcohol under a carbon monoxide atmosphere, an acrylic ester or a monosubstituted acetylene either without a solvent in the corresponding amine, or - in an aprotic solvent miscible with - water, in the presence of a secondary or tertiary - amine, - at temperatures above - room temperature ranging from - 40 ° C to - to the boiling point of the - reaction mixture - in the presence of palladium - -catalyst.
stt^iry akrylové kyseliny - se rozumí -takové estery - akrylové - kyseliny, - které se -získají esterifikací - pomocí - nižších - alifatických alkoholů - s až - 3 atomy uhlíku, jako je například ethylester - akrylové - kyseliny.Acrylic acid esters are to be understood as being those esters of acrylic acids which are obtained by esterification by means of - lower - aliphatic alcohols - with up to - 3 carbon atoms, such as, for example, ethyl ester of acrylic acid.
Jako -monosubstituovaný acetylen se označují takové ethinylderiváty, -u kterých - je 1 atom -vodíku substituován -alkylovou skupinou s 1 až 3 atomy - uhlíku, fenylovou skupinou, hydroxymethylovou skupinou, - -tetrahydroρyranyloxytkupinou, - alkoxyka-rbonylovou skupinou s 1 - až 3 atomy uhlíku v alkoxylové -části, dialkylaminomethylovou skupinou s 1 -až -3 -atomy -uhlíku v -alkylových cásit^ch -a -alkyldimethylsil^ylovou - skupinou s 1 až 3 atomy uhlíku v- alkylové části.-Monosubstituted acetylene are those ethinylderivatives in which - 1-hydrogen atom is substituted by - C1-C3-alkyl, phenyl, hydroxymethyl, - -tetrahydro-rhyranyloxy, - alkoxycarbonyl-1 to 3 the carbon atoms in the alkoxy moiety, the C 1 -C 3 dialkylaminomethyl group in the alkyl moieties and the C 1 -C 3 alkyldimethylsilyl moiety.
Jako - aprotícká rozpouštědla, - která jsou nlísstelná s -vodou, -lze jmenovat -například dimethylformamid, - N-methylpyrrolidon, tetrahydrofuran, acetonitril . -a dioxan.Examples of aprotic solvents which are miscible with water may be mentioned, for example, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile. -and dioxane.
Sekundárními - a terciárními aminy jsou například - dimethylamin, . - diethylamin, -piperldin, triethylamin - a - tri-n-butylamin.Secondary and tertiary amines are, for example, dimethylamine,. - diethylamine, -piperldine, triethylamine - and - tri-n-butylamine.
Jako- paládiové katalyzátory přicházejí v úvahu -soli paládia -a komplexní sloučeniny paládia. Jako - příklad - -lze uvést - octan paladnatý, trans-di-chlor-bis-- (tri-o-tolylf osf in) paládium - (II) nebo -transldlchlor-bit-(tI^i^I^et^ylfosfin)paládium (II) a -paládium(O j-tetrakit-trifenylfotfin. Katalyzátor se -používá v množství od - 0,01 -až -do 0,1 mol, vztaženo na použitý - 2-halogenergolin.Suitable palladium catalysts include palladium salts and complex palladium compounds. By way of example, palladium acetate, trans-di-chloro-bis- (tri-o-tolylphosphine) palladium (II) or -transldlchloro-bit- (tert -butylphosphine) palladium (II) -butylphosphine may be mentioned. The catalyst is used in an amount of from - 0.01 - to 0.1 mol, based on the - 2-haloenergoline used.
Při mnohých reakcích je výhodný přídavek jodidu měďnatého nebo tri-o-tolylfosfinu.In many reactions, the addition of copper (I) iodide or tri-o-tolylphosphine is preferred.
Reakce se účelně provádějí za vyloučení vzduchu, částečně však -také za zvýšeného tlaku, tj. pod - -atmosférou inertního plynu a v autoklávu.The reactions are expediently carried out with the exclusion of air, but partly also under elevated pressure, i.e. under the atmosphere of the inert gas and in an autoclave.
Znamená-li substituent R‘ popřípadě -hydroxyskuplnu, -pak se odpovídající benzylester 2-karboxylové -kyseliny hydrogenuje vodíkem -za - atmosférického tlaku -při teplotě místnosti v -protickém -rozpouštědle, jako v alifatickém alkoholu, například v -methanolu, v -přítomnosti jemně dispergovaného - paládia, jako- paládia -na - uhlí.When R @ 1 is -hydroxy-group, the corresponding 2-carboxylic acid benzyl ester is hydrogenated with hydrogen at atmospheric pressure at room temperature in a protic solvent such as an aliphatic alcohol, for example methanol, in the presence of finely dispersed palladium, such as palladium-on-coal.
Znamená-li substituent R‘ popřípadě aminoskupinu, - pak - se -odpovídající Z-benzylester uvádí v reakci s - amoniakem v protickém rozpouštědle, jako v - -alkoholu, výhod248738 ně v ethylenglykolu, při zvýšené teplotě za vzniku odpovídajícího karboxamidu.When R @ 1 is optionally amino, the corresponding Z-benzyl ester reacts with ammonia in a protic solvent such as an alcohol, preferably in ethylene glycol, at elevated temperature to give the corresponding carboxamide.
Obsahuje-li substituent v poloze 2 exocyklickou dvojnou vazbu uhlík=uhlík nebo trojnou vazbu uhlík=uhlík, pak lze tuto nenasycenou vazbu snadno redukovat například za použití Raney-niklu nebo paládia na uhlí v alifatickém alkoholu při teplotě místnosti a atmosférickém tlaku úplně nebo parciárně za vzniku odpovídajícího hydrogenačního produktu.If the substituent at the 2-position contains an exocyclic carbon = carbon double bond or a carbon = carbon triple bond, this unsaturated bond can be readily reduced, for example, using Raney-nickel or palladium on carbon in an aliphatic alcohol at room temperature and atmospheric pressure completely or partially. formation of the corresponding hydrogenation product.
Obsahuje-li ethinylový substituent v poloze 2 chránící skupinu, jako skupinu SiMežR“, pak je možno tuto skupinu odstranit působením slabé báze, jako je uhličitanu sodného nebo uhličitanu draselného, při teplotě místnosti, nebo také působením kyselin nebo fluoridových iontů (fluoridu česného nebo tetrabutylamoniumfluoridu). Je-li ethinylová skupina jednostranně chráněna jako acetonový adiční produkt, pak se taková chránící skupina odstraní povařením se silnou bází, jako s hydroxidem draselným nebo s hydroxidem sodným při teplotě 100 °C.If the ethynyl substituent in the 2-position contains a protecting group such as SiMe2R, it may be removed by treatment with a weak base such as sodium carbonate or potassium carbonate at room temperature, or with acids or fluoride ions (cesium fluoride or tetrabutylammonium fluoride) ). If the ethynyl group is unilaterally protected as an acetone addition product, then such a protecting group is removed by boiling with a strong base such as potassium hydroxide or sodium hydroxide at 100 ° C.
Je-li chránící skupinou tetrahydropyranylová skupina, pak se к odštěpení této skupiny používá kyseliny, jako například pyridinium-p-toluensulfonátu nebo zředěné sírové kyseliny, v alkoholu při teplotě 70 až 100 °C.When the protecting group is a tetrahydropyranyl group, an acid such as pyridinium p-toluenesulfonate or dilute sulfuric acid in an alcohol at 70 to 100 ° C is used to cleave the group.
Takto získané sloučeniny vzorce I se bud ve formě volných bází nebo popřípadě ve formě svých adičních solí s kyselinami, které se získávají reakcí s fyziologicky snášenlivou kyselinou, jako například s kyselinou vinnou nebo s kyselinou maleinovou, čistí překrystalováním nebo/a chromatografií.The compounds of the formula I thus obtained are purified by recrystallization and / or chromatography, either in the form of the free bases or, optionally, in the form of their acid addition salts, obtained by reaction with a physiologically compatible acid such as tartaric acid or maleic acid.
Za účelem tvorby solí se sloučeniny vzorce I rozpustí v malém množství methanolu nebo methylenchloridu a přidá se koncentrovaný roztok žádané kyseliny v methanolu při teplotě místnosti.To form salts, the compounds of formula I are dissolved in a small amount of methanol or methylene chloride and a concentrated solution of the desired acid in methanol is added at room temperature.
Výchozí látky potřebné pro provádění postupu podle vynálezu jsou buď známé nebo se mohou vyrábět metodami, které jsou pro odborníka známé.The starting materials required for carrying out the process of the invention are either known or can be prepared by methods known to those skilled in the art.
Výroba výchozí látky mmol Terguridu se rozpustí ve 20 ml bezvodého dioxanu, přidá se asi 1,5 ml N-jodsukcinimidu při teplotě místnosti a směs se míchá 30 minut. oPtom se reakční směs vylije do nasyceného roztoku hydrogenuhličitanu, provede se extrakce methylenchloridem a organická fáze se vysuší síranem hořečnatým. Po odpaření rozpouštědla se zbytek chromatografuje na silikagelu. Získá se v 76% výtěžku l,l-diethyl-3-(2-jod-6-methyl-8a.-ergolinyl J močovina.Preparation of the mmol mmol of terguride is dissolved in 20 ml of anhydrous dioxane, about 1.5 ml of N-iodosuccinimide is added at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is then poured into a saturated bicarbonate solution, extracted with methylene chloride and the organic phase is dried over magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel. Obtained in 76% yield of 1,1-diethyl-3- (2-iodo-6-methyl-8α-ergolinyl) urea.
[a]D = +37,3° (c = 0,2 v pyridinu).[α] D = + 37.3 ° (c = 0.2 in pyridine).
Analogickým způsobem se z Lisuridu aIn an analogous manner, from Lisuride a
N-bromsukcinimidu získá l,l-diethyl-3-(2-brom-6-methyl-9,10-didehydro-8a-ergolinylmočovina.N-bromosuccinimide affords 1,1-diethyl-3- (2-bromo-6-methyl-9,10-didehydro-8α-ergolinylurea).
Výtěžek 23 % teorie.Yield: 23%.
[«]□ = +247° (c = 0,2 v pyridinu).[Α] D = + 247 ° (c = 0.2 in pyridine).
Za účelem použití sloučenin vyráběných postupem podle vynálezu jakožto léčiv se tyto sloučeniny převádějí na farmaceutické přípravky, které vedle účinné látky obsahují některou farmaceutickou, organickou nebo anorganickou inertní nosnou látku vhodnou pro enterální nebo parenterální aplikaci, jako například vodu, želatinu, arabskou gumu, mléčný cukr, škrob, hořečnatou sůl, stearové kyseliny, mastek, rostlinné oleje, polyalkylenglykoly atd. Farmaceutické přípravky se mohou vyskytovat v pevné formě, například ve formě tablet, dražé, čípků, kapslí nebo v kapalné formě, například ve formě roztoků, suspenzí nebo emulzí. Popřípadě obsahují také ještě pomocné látky, jako konzervační prostředky, stabilizátory, smáčedla nebo emulgátory, soli к ovlivňování osmotického tlaku nebo pufry.In order to use the compounds according to the invention as medicaments, they are converted into pharmaceutical preparations which contain, in addition to the active substance, a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration, such as water, gelatin, acacia, milk sugar , starch, magnesium salt, stearic acids, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. If desired, they also contain auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers.
Následující příklady postup podle vynálezu blíže objasňují, avšak jeho rozsah v žádném směru neomezují.The following examples illustrate the process in more detail, but do not limit its scope in any way.
Příklad 1Example 1
300 mg (0,644 mmol) 3-(2-jod-6-methyl-8a-ergolinyl)-l,l-diethylmočoviny se zahřívá ve 4 ml benzylalkoholu po přidání 0,169 ml (0,709 mmol) tri-n-butylaminu, pod atmosférou oxidu uhelnatého se přidá 7 mg (0,031 mmol) octanu paladnatého a reakční směs se po dobu 2,5 hodiny udržuje za intenzivního míchání na teplotě 100 až 110 stupňů C. Po ochlazení na teplotu místnosti se reakční roztok zředí ethylacetátem a provede se extrakce nasyceným roztokem hydrogenuhličitanu sodného a na syceným roztokem chloridu sodného. Po vysušení síranem hořečnatým se ethylacetát oddestiluje za sníženého tlaku a poté se oddestiluje benzylalkohol ve vysokém vakuu. Za surového produktu se sloupcovou chromatografií na 150 g silikagelu za použití směsi dichlormethanu a ethanolu v poměru 10 : 1 jako elučního činidla a po překrystalování ze směsi ethanolu a hexanu získá 166 mg benzylesteru 8a- (3,3-diethylureido) -6-methylergolin-2-karboxylové kyseliny. Výtěžek 54,5 % teorie.300 mg (0.644 mmol) of 3- (2-iodo-6-methyl-8α-ergolinyl) -1,1-diethylurea were heated in 4 ml of benzyl alcohol after addition of 0.169 ml (0.709 mmol) of tri-n-butylamine under an atmosphere of oxide 7 mg (0.031 mmol) of palladium (II) acetate are added and the reaction mixture is maintained at 100-110 degrees C with vigorous stirring for 2.5 hours. After cooling to room temperature, the reaction solution is diluted with ethyl acetate and extracted with a saturated solution of bicarbonate. sodium carbonate solution. After drying over magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and then benzyl alcohol was distilled off under high vacuum. The crude product was chromatographed on 150 g of silica gel with dichloromethane / ethanol (10: 1) as the eluent and recrystallized from ethanol / hexane to give 166 mg of 8a- (3,3-diethylureido) -6-methylergoline- 2-carboxylic acids. Yield 54.5% of theory.
Teplota tání 226 až 229 °C.Mp 226-229 ° C.
[a]D = +43,2° (c = 0,25 % v pyridinu).[α] D = + 43.2 ° (c = 0.25% in pyridine).
Příklad 2Example 2
104 mg (0,22 mmol) benzylesteru 8a-(3,3-diethy lureido)-6-methylergoIin-2-kar boxy248738 lové kyseliny se rozpustí ve 20 ml methanolu a po přidání . 50 mg paládiové černi se směs hydrogenuje 30 minut při teplotě místnosti a při atmosférickém tlaku. Po odfiltrování katalyzátoru a po zahuštění se získá 8a- (3,3-diethylureido) -6-methylergolin-2-karboxylová kyselina ve 100% výtěžku.104 mg (0.22 mmol) of 8α- (3,3-diethyl -ureido) -6-methyl-amino-2-carboxylic acid benzyl ester are dissolved in 20 ml of methanol and added. 50 mg of palladium black are hydrogenated at room temperature and atmospheric pressure for 30 minutes. Filtration of the catalyst and concentration gave 8α- (3,3-diethylureido) -6-methylergoline-2-carboxylic acid in 100% yield.
Teplota tání: rozklad od 230 °C.Melting point: decomposition from 230 ° C.
Příklad 3Example 3
150 mg (0,31 mmol) benzylesteru 8a-(3,3-diethylureido)-6-methylergolin-2-karboxylové kyseliny se zahřívá ve 3 ml nasyceného roztoku amoniaku v ethylenglykolu 3 hodiny na teplotu 100 °C. Po zředění vodou se provede extrakce ethylacetátem - a organická fáze se promyje nasyceným roztokem chloridu sodného, vysuší se síranem hořečnatým, zfiltruje a zahustí se. Zbytek se chromatografuje na silikagelu za použití směsi methylenchloridu a ethanolu v poměru 8 -: - 1 jako· elučního činidla. Po roztírání zbytku ve směsi ethanolu, hexanu a etheru se získá 90 mg amidu 8a- (3,3-diethylureido )-6-methylergolin-2-karboxylové kyseliny o teplotě tání 171 až 173 - °C.150 mg (0.31 mmol) of 8α- (3,3-diethylureido) -6-methylergoline-2-carboxylic acid benzyl ester were heated to 100 ° C in 3 mL of saturated ammonia in ethylene glycol for 3 h. After dilution with water, extraction is performed with ethyl acetate - and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (8: 1). After trituration of the residue in a mixture of ethanol, hexane and ether, 90 mg of 8a- (3,3-diethylureido) -6-methylergoline-2-carboxylic acid amide is obtained, m.p. 171-173 ° C.
[a]D -= +42,5° (c = 0,2 -% v pyridinu).[ .alpha. ] D = + 42.5 DEG (c = 0.2% in pyridine).
P říklad 4Example 4
261 mg (0,56 mmol) 3-(2-jod-6-methyl-8í^.-<^rgolinyl)-]^,l-dlě3tt^ym^c^č^c^v^i^n^y, 7,0 mg (0,023 mmol) tri-o-tolylfosfinu, 4,7 mg (0,006 mmol) trans-dichlor-bis-(tri-o-tolylfosfin)paládium(II) a 0,075 ml (0,69 mmol) ethylesteru akrylové kyseliny se rozpustí v 1,5 ml dimehylformamidu a 0,7 ml triethylaminu a po výplachu argonem se reakční směs zahřívá v autoklávu 4 hodiny na teplotu 100 °C.- Po zahuštění reakčního roztoku za sníženého tlaku se zbytek vyjme ethylacetátem a ethylacetátový roztok se promyje nasyceným roztokem chloridu sodného. Po vysušení ethylacetátové fáze síranem hořečnatým - a po zahuštění roztoku se získá surový produkt, který se chromatografuje na 150 g silikagelu za použití směsi dichlormethanu a ethanolu v poměru 10 : 1 jako elučního činidla. Získá se 3-(2-ethoxykarbonylvinyl-6-methyl-8a-ergolinyl) -1,1-^bcethylmočovina.261 mg (0.56 mmol) of 3- (2-iodo-6-methyl-8H-pyrrolidinyl) -1,1,1-dihydro-3- (2-iodo-6-methyl-8 H-) , 7.0 mg (0.023 mmol) of tri-o-tolylphosphine, 4.7 mg (0.006 mmol) of trans-dichloro-bis- (tri-o-tolylphosphine) palladium (II), and 0.075 mL (0.69 mmol) of ethyl ester The acrylic acids are dissolved in 1.5 ml of dimethylformamide and 0.7 ml of triethylamine and after flushing with argon, the reaction mixture is heated in an autoclave at 100 DEG C. for 4 hours. After concentrating the reaction solution under reduced pressure, the residue is taken up with ethyl acetate. washed with saturated sodium chloride solution. After drying the ethyl acetate phase with magnesium sulfate and concentrating the solution, a crude product is obtained which is chromatographed on 150 g of silica gel using a 10: 1 mixture of dichloromethane and ethanol as eluent. 3- (2-ethoxycarbonylvinyl-6-methyl-8a-ergolinyl) -1,1-methylurea is obtained.
Výtěžek: 115 mg (47 % teorie).Yield: 115 mg (47% of theory).
Teplota tání: 223 až 225 °C (ze směsi ethanolu -a hexanu).223-225 ° C (from ethanol-hexane).
[a]D = +115° (c = 0,2 % v pyridinu).[α] D = + 115 ° (c = 0.2% in pyridine).
Příklad 5Example 5
178- mg (0,406 mmol) 3-(2-ethoxykarbonylvinyl) -6-methyl-8α,-etgoClnyl)-1,1-diethyl močoviny se rozpustí ve 20 ml ethanolu a po přidání 0,1 g Raney-niklu se směs -hydrogenuje 1 hodinu při teplotě místnosti za atmosférického tlaku. Po odfiltrování katalyzátoru se překrystalováním ze směsi ethylacetátu a hexanu získá 86 mg 3-[2-(2-ethoxy к arbon у leehy i ) -6-methyl-8a-ergolinyl ] -1,1diethylmočoviny (48 % teorie). .178- mg (0.406 mmol) of 3- (2-ethoxycarbonylvinyl) -6-methyl-8α, -ethoClnyl) -1,1-diethyl urea are dissolved in 20 ml of ethanol and after addition of 0.1 g of Raney-nickel, hydrogenation for 1 hour at room temperature under atmospheric pressure. After filtering off the catalyst, recrystallization from ethyl acetate / hexane gave 86 mg of 3- [2- (2-ethoxycarbonyl) -6-methyl-8α-ergolinyl] -1,1-diethylurea (48% of theory). .
Teplota tání 160 až 161 °C.Melting point 160-161 ° C.
[a]0 -= +22° (c = 0,2 - '% v- pyridinu).[α] D = + 22 ° (c = 0.2% v-pyridine).
Příklad 6Example 6
933 mg (2,0 mmol) 3-(2-jod-6-methyl-8a-ergolinyl)-l,l-diethylmočoviny se rozpustí ve směsi 5 ml dimethylformamidu a 10 ml triethylaminu a po přidání 0,610 ml (4,4 mmol) ethinyltrimethylsilanu, 19 mg (0,1 mmol) jodidu měďného a 47,2 mg (0,06 mmol) trans-dichlor-bis- (tri-o-tolylfosfin)paládia (II) se - reakční - směs zahřívá- 3 hodiny pod atmosférou argonu na - teplotu 60 stupňů C. Po zahuštění za sníženého tlaku a po vyjmutí zbytku směsí ethylacetátu a vody se organická fáze promyje nasyceným roztokem chloridu sodného, vysuší se síranem hořečnatým a odpaří se. Po sloupcové chromatografií na 150 g silikagelu za použití směsi methylenchloridu a ethanolu v poměru 10 : 1 jako elučního činidla se získá 486 mg 3-(2-tthinyltrimethylsllyl-6-methyl-8a-ergolinyl) -1,1-diethylmočoviny (55,7 procenta teorie) ve formě oleje.933 mg (2.0 mmol) of 3- (2-iodo-6-methyl-8α-ergolinyl) -1,1-diethylurea were dissolved in a mixture of 5 ml of dimethylformamide and 10 ml of triethylamine and after addition of 0.610 ml (4.4 mmol) of ethynyltrimethylsilane, 19 mg (0.1 mmol) of copper (I) iodide and 47.2 mg (0.06 mmol) of trans-dichloro-bis- (tri-o-tolylphosphine) palladium (II) - the reaction mixture was heated for 3 hours under argon to 60 degrees C. After concentration under reduced pressure and removal of the residue with a mixture of ethyl acetate and water, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. Column chromatography on 150 g of silica gel eluting with methylene chloride / ethanol (10: 1) gave 486 mg of 3- (2-thynyltrimethylsilyl-6-methyl-8α-ergolinyl) -1,1-diethylurea (55.7 g). percent of theory) in the form of an oil.
Analogickým způsobem se vyrobí následující sloučeniny:The following compounds were prepared in an analogous manner:
3-!6-m ethyl-2- [ 3- (tetr ahydropyran-2-yloxy) propinyl ] -8a-ergolinyl|-l,l-diethylmočovina, teplota tání 188 °C, [a]n -= -+64° (c = 0,2 % v pyridinu);3- [6-methyl-2- [3- (tetr ahydropyran-2-yloxy) propynyl] -8a-ergolinyl] -1,1-diethylurea, m.p. 188 [deg.] C., [[alpha]] D = = + 64 ° (c = 0.2% in pyridine);
3- (2-pr opinyl-6-methy l-8a-ergolinyl) -1,1-diethylmočovina;3- (2-propynyl-6-methyl-8a-ergolinyl) -1,1-diethylurea;
3-(2-( l-dimethylaminopropin-3-yl) -6-methyl-8a-ergolinyl ] +1-diethylmočovina;3- (2- (1-dimethylaminopropin-3-yl) -6-methyl-8α-ergolinyl) + 1-diethylurea;
3-(2-( l-ethoxykarbonylethin-2-yl) -6-methyl-8a-ergolinyl ] -1,1-diethylmočovina;3- (2- (1-ethoxycarbonylethin-2-yl) -6-methyl-8α-ergolinyl) -1,1-diethylurea;
3- (2-trimethylsilylethinyl-6-methy--83-ergolinyl)-l,l-diethylmočovina;3- (2-trimethylsilylethynyl-6-methyl-83-ergolinyl) -1,1-diethylurea;
3- (2-trimethylsilylethinyl-6-methyl-8a-ergolinyl)-l,l-diethylthčomočovina;3- (2-trimethylsilylethynyl-6-methyl-8α-ergolinyl) -1,1-diethylthiourea;
3- (2-trimethylsilylethinyl-l,6-dimethyl-8a-ergolinyl) -1,1-diethylmočovina;3- (2-trimethylsilylethynyl-1,6-dimethyl-8α-ergolinyl) -1,1-diethylurea;
8,9-didehydro-6,8-dimethyl-2-fenylethinylergolin, teplota tání od 118 °C (za rozkladu) a8,9-didehydro-6,8-dimethyl-2-phenylethynylergoline, m.p. 118 ° C (dec.); And
3-.(2-ΐΓΐΜβΐύγ1811γ1Θΐ^Ι^·1Γ^5^1·^£^-η^-ρΐ^^Θρ^ν^]^-8α^-fergollnyl) -1,1-diethylmočovina.3- (2-β-γ1811γ1ΘΐΘΐΙΘΐ · ·ΓΓΓ 5 5 5 5 5 5 5 5 5 5ΐΐΐΐΐΐΐΐΐΐΐ ^ ^ferferferferferferferferferferferferfer) - 1,1-diethylurea.
P 'ř í klad 6 aExample 6 a
Za použití 3-(2-brom-6-methyl-8a-ergo'liny1)-l,l-diethylmočoviny jako výchozí látky se reakcí s 3-(tetrahydropyran-2-yloxy]-.I-propinem získá 3J(9,10-didehydro-6-methyl-2- [ 3- (tetra hydropyran-2-yloxy) -1-proplnyl ] -8a-ergoTmylj-lll-diethylmo6ovina (výtěžek 25 % teorie);Using 3- (2-bromo-6-methyl-8a-ergo'liny1) -l, l-diethylurea as a starting material by reaction with 3- (tetrahydropyran-2-yloxy] -. I-propyne gives 3 J (9 10-didehydro-6-methyl-2- [3- (tetrahydro-pyran-2-yloxy) -1-propynyl] -8a-ergomethyl-11-diethylurea (25% yield);
reakcí s 3-hydroxy-3-merhylIl-butmem získáby reaction with 3-hydroxy-3-methyl-1-butyl
3-[ ' 9,10--lidehydr o-2- (3-hydr oxy-3-m ethyl-l-butinyl) -6-methyl-8oajergolinyl ] -l^-^t^^itethylmočovina (výtěžek 31 '% teorie).3- [ '9,10 - lidehydr of 2- (3-hydroxy-3-m ethyl-l-butynyl) -6-methyl-ergolinyl 8oa j] -l ^^ ^^ t itethylmočovina (yield 31 '% theory).
Příklad 7Example 7
262 mg - (0,6 mmol) 3-(2-ethinyltrimethyl'sílyl-6-methyll8a-ergollnyl) -1,1-diethylmočoviny se rozpustí ve směsi 9 ml ethanolu a 1 ml' vody a po přidání 104 mg (0,75 - mmol) bezvodého uhličitanu draselného se -reakční směs míchá 16 hodin při teplotě místnosti. Rozpouštědlo se oddestiluje, zbytek se vyjme eťhylacetátem a -ethylacetátový roztok se dále vytřepává s nasyceným -roztokem chloridu sodného. Po -vysušení ethylacetátového roztoku -síranem horečnatým, po oddestilování rozpouštědla -a po -sloupcové chromatografii surového produktu -na 150 g silikagelu za použití směsi toluenu, ethanolu, vody v poměru 80 : 20 : 1 jako eiučního činidla se získá 81 mg 3-(2-ethinyl-6-methyl-8a-ergΘ1lnyl)-l,l-diethylmočoviny (37 % teorie) překrystalováním ze směsi ethanolu a hexanu.262 mg - (0.6 mmol) of 3- (2-ethynyltrimethylsilyl-6-methyl-8α-ergolinyl) -1,1-diethylurea are dissolved in a mixture of 9 ml of ethanol and 1 ml of water and after the addition of 104 mg (0, Anhydrous potassium carbonate (75 mmol) was stirred at room temperature for 16 hours. The solvent was distilled off, the residue was taken up in ethyl acetate and the ethyl acetate solution was further shaken with a saturated sodium chloride solution. After drying the ethyl acetate solution with magnesium sulphate, distilling off the solvent, and after column chromatography of the crude product on 150 g of silica gel with toluene / ethanol / water 80: 20: 1 as eluent, 81 mg of 3- ( 2-ethynyl-6-methyl-8a-ergolinyl) -1,1-diethylurea (37% of theory) by recrystallization from ethanol / hexane.
Teplota tání 192 °C.Mp 192 ° C.
[ajD = 4-60,6° (c = 0,175 % v pyridinu).[J and D = 4-60,6 ° (c = 0.175% in pyridine).
Analogickým způsobem se vyrobí následující sloučeniny:The following compounds were prepared in an analogous manner:
3- (2-ethinyl-6-méthyl18α-lrgoΘ1nyl) -1.1-diethylthiomočovina,3- (2-ethynyl-6-methyl-18α-1-benzoyl) -1,1-diethylthiourea,
3- (2-ethinyl-l,6-dimethyl-8a-er goliny!) -1,1-diethylmočovina a3- (2-ethynyl-1,6-dimethyl-8α-erolinyl) -1,1-diethylurea; and
3- (2-ethinyl-6-n-prop yl-8 α-ergolln ) -1,1-diethylmočovina, teplota tání 126 °C.3- (2-ethynyl-6-n-propyl-8α-ergoline) -1,1-diethylurea, m.p. 126 ° C.
Příklad 8Example 8
122 mg -(0,29 - mmol) 3-[9,10-didehydro-2- (3-ltydrΘxy-3-merhyl1llbutiny1 )-6-methyl-8<a-ergolinyl]-1,l-diethylπюčΘvmy se zahřívá v ' 15 ml absolutního toluenu - po' přidání 64 mg - (1,6 mmol) práškového hydroxidu sodného 2 hodiny pod atmosférou dusíku a pod zpětným chladičem. Potom se rozpouš tědlo oddestiluje -a - zbytek se 'extrahuje ethylacetátem - a vodou - a - nasyceným - roztokem chloridu sodného. Surový produkt - 'Získaný z - ethylacetátového - -roztoku - 'po vysušení síranem hořečnatým a po -zahuštění se čistí chromatografií - na - -sloupci ' 80 g silikagelu za použití - -směsi - -ethylacetátu -a -ethanolu v poměru 2 : 1 jako eiučního činidla. Překrystalováním - ze --směsi - ěthylaeeitátu, etheru a hexanu se získá ve 25% výtěžku 3- (9,10-didehydro-2-ethinyl-8a-srgblinyl )-1,1-diethylmočovina.122 mg - (0.29 - mmol) of 3- [9,10-didehydro-2- (3-ethyloxy-3-methyl-11-butynyl) -6-methyl-8α-ergolinyl] -1,1-diethyl-piperidine was heated in 15 ml of absolute toluene - after addition of 64 mg of sodium hydroxide powder (1.6 mmol) under nitrogen and reflux for 2 hours. Then the solvent is distilled off - and the residue is extracted with ethyl acetate - and water - and saturated sodium chloride solution. The crude product obtained from the ethyl acetate solution after drying over magnesium sulphate and concentration is purified by chromatography on a 80 g silica gel column using a 2: 1 mixture of ethyl acetate and ethanol. as the eluent. Recrystallization - of a mixture of ethyl acetate, ether and hexane gave 3- (9,10-didehydro-2-ethynyl-8a-pyrrinyl) -1,1-diethylurea in 25% yield.
Příklad 9Example 9
213 mg (0,45 - ’шмИ) -'3-{6-m¢r1hy1l2-[- Htótrahydropy ran-2-yloxy^)proplnyl;]-81ale·rgo1iinyl}-l,lldlethy1mΘČΘvtay - -se - - zahřívá -v - --10. - - ml ethanolu spolu - se - - -2 '-mil - - vody - -a - 1-76 mg (0,7 - m-mol)' - -pyridininn^-^^-tt^oluMK^t^l^l^^i^i^látu- - 1 hodinu k varu -pod - - zpětným - cWádičem>-- а pod - atmosférou -argonu.· - 'Po - odpaření - a- rozdělení - mezi ethylacetát - - - - a - -nasycený - roztok hydrogenuhličitanu - se - - organická - fáze -pro myje -nasyceným roztokem - -chloridu sodného, - vysuší - - se - síranem hořečnatým, zfiltruje se a zahustí se. ' -Zbytek - se -chrΘmatΘgraf^uje nejprve na silikagelu - za použití - ‘směsi - acetonu a rthy1acrtátu v poměru 1:1a později za použití směsi methylenchloridu- a - acetonu v poměru 12 : 1 jako eiučního činidla. Po překrystalování ze směsi e>thy1aΘétál tu a hexanu se získá 90 mg (51 - % teorie) 3- [ 2- '(l-hydr oxypropin-3-yl )-ů-mfirtly4-8α*ergolinyl -] -1,1-diethylmočcwiny.213 mg (0.45 - 'шмИ) -'3- {6-m ¢ r1hy1l2 - [- Htótrahydropy dihydrofuran-2-yloxy ^) propynyl] - 81ale · i rgo1 ynyl} -l, lldlethy1mΘČΘvtay - -with - - heats -v - --10. - - ml of ethanol together with - - 2'-mil - - water - -a - 1-76 mg (0,7-m-mol) - pyridinine - - - - - - - - - - - - - - After 1 hour of boiling under reflux, under an atmosphere of argon, after evaporation, the a-partition between ethyl acetate and the like. - saturated - bicarbonate solution - is - - organic - phase - washed with - saturated sodium chloride solution, - dried - - with magnesium sulphate, filtered and concentrated. The residue is first chromatographed on silica gel using a 1: 1 mixture of acetone and ethyl acetate later using a 12: 1 mixture of methylene chloride and acetone as the eluent. Recrystallization from ethyl acetate and hexane gave 90 mg (51% of theory) of 3- [2- '(1-hydroxypropin-3-yl) -amino-4- [4-] ergolinyl-] -1,1 -diethylmočcwiny.
Teplota - tání 151 --až - '154 - -°C.Mp 151-154 ° C.
![a]n = 4-71,2° - - (c = -0,21 - '% - v - - pyridinu!)·.[α] D = 4-71.2 ° - - (c = -0.21 -% in v-pyridine!) ·.
Analogickým způsobem se vyrobí:The following are produced in an analogous manner:
3-(2- - (^Ьу-г’ОХУРГВфШ-З-уН-ЭДО^йгЬу-г©l6-merhyУ8α’ergolinnl]jl,l-diethytalčovlna.3- (2- - (Ьу-г'О -УРГВфШ-З-уН-ЭДО ^ йгЬу-г © 16-merhyУ8α´ergolinnl)], l-diethythalcine.
Teplota tání: větší - -než '129 ' °C.Melting point: greater than -129 ° C.
[a]D = 4-404° - (c = -0,2 - '% v pyridinu). Přikladl![α] D = 4-404 ° - (c = -0.2 -% in pyridine). He did!
140 mg - '(0,084 - mmol) - 3-(2jethinyl-6-methyl-Ba-eirgollnyi)-1 ,l-diethiylmoěoviny - se hydrogenuje ve 20 ml - ěthawshr - po· 'přidání 0,1 g Raney-niklu 45 minut při teplotě místnosti a za atmosférického' tteak-u. filtrování katalyzátoru a po zahuštění roztoku se zbytek -přékrystaluje 'ze - -směsi- - ethanolu a hexanu. Získá se 119 mg 3lt2eιth¢yk6J4»el thyl-8a-ergolinyl)-l,l-diethylmočoviny (84 % teorie).140 mg - (0.084 mmol) -3- (2-ethynyl-6-methyl-B-glycololyl) -1,1-diethiylurea were hydrogenated in 20 ml of methanol - after addition of 0.1 g of Raney nickel. minutes at room temperature and under atmospheric temperature. filtration of the catalyst, and after concentration of the solution, the residue is recrystallized from a mixture of ethanol and hexane. There were obtained 119 mg of 3-methyl-4-methyl-8α-ergolinyl) -1,1-diethylurea (84% of theory).
Teplota tání 165 až 168 °C.Melting point 165-168 ° C.
[a]D -= 4-'25° .(se - - = - 0,22' %- v- pyridinu).[α] D - = 4 - 25 ° (with - = = 0.22% v-pyridine).
Příklad 11Example 11
200 mg 3- (2-ethinyl-6-methyl-8a<-ergOlinyl]-l,l-diethylmočoviny se hydrogenuje. ve ml ethanolu za přídavku 200 mg paládia t na uhličitanu vápenatém (2%) a 200 mg chinolinu při teplotě místnosti a při atmo2 4 8'7 3'8 sférickém: tlaku.: Po odf iltrQvám:katal.yžá-t< toru se reakčhí směs odpaří. Zbytek se obrou . matografuje :přes silikagel >za-použití. směsfc&. methylenchloridu da ethanolu v poměru 6 :31. ·. Získá se 30 mg .3-(6-methylr2-Vinýb8aaepgos’í linyl)-l,l-diethylmbčovinyve formě oleje. e200 mg of 3- (2-ethynyl-6-methyl-8α-ergolinyl) -1,1-diethylurea were hydrogenated in ml of ethanol with the addition of 200 mg of palladium t on calcium carbonate (2%) and 200 mg of quinoline at room temperature. After filtration, the reaction mixture was evaporated and the residue was chromatographed over silica gel using a mixture of methylene chloride and ethanol in ethanol. 6: 31 ratio to give 30 mg of 3- (6-methyl-2-ynyl-epoxy) -1,1-diethylbutyric acid as an oil.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843413659 DE3413659A1 (en) | 1984-04-09 | 1984-04-09 | Novel 2-substituted ergoline derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS248738B2 true CS248738B2 (en) | 1987-02-12 |
Family
ID=6233290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS252685A CS248738B2 (en) | 1984-04-09 | 1985-04-04 | Production method of the new 2-substituted derivatives of ergoline |
Country Status (3)
| Country | Link |
|---|---|
| CS (1) | CS248738B2 (en) |
| DE (1) | DE3413659A1 (en) |
| ES (1) | ES542069A0 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE107647T1 (en) * | 1984-04-09 | 1994-07-15 | Schering Ag | 2-SUBSTITUTED ERGOLINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS. |
| DE3528584A1 (en) * | 1985-08-06 | 1987-02-19 | Schering Ag | NEW 1-ALKYL-ERGOLIN-THIOURINE DERIVATIVES |
| DE3535929A1 (en) * | 1985-10-04 | 1987-04-09 | Schering Ag | 1,2-DISUBSTITUTED ERGOL DERIVATIVES |
| DE3535930A1 (en) * | 1985-10-04 | 1987-04-09 | Schering Ag | NEW 2-SUBSTITUTED ERGOL DERIVATIVES |
| DK338789A (en) * | 1988-07-15 | 1990-01-16 | Schering Ag | 2-SUBSTITUTED ERGOLINYLURINE DERIVATIVES AND PROCEDURES FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINES AND INTERMEDIATES FOR THE PRODUCTION THEREOF |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3101535A1 (en) * | 1981-01-14 | 1982-08-12 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW (2-HALOGEN-ERGOLINYL) -N'.N'-DIETHYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| DE3151912A1 (en) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW ERGOLIN AMINO DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
-
1984
- 1984-04-09 DE DE19843413659 patent/DE3413659A1/en not_active Withdrawn
-
1985
- 1985-04-04 CS CS252685A patent/CS248738B2/en unknown
- 1985-04-09 ES ES542069A patent/ES542069A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES8603182A1 (en) | 1985-12-16 |
| DE3413659A1 (en) | 1985-10-17 |
| ES542069A0 (en) | 1985-12-16 |
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