DK168487B1 - 12- og 13-substituerede ergolinderivater samt en fremgangsmåde til fremstilling deraf - Google Patents
12- og 13-substituerede ergolinderivater samt en fremgangsmåde til fremstilling deraf Download PDFInfo
- Publication number
- DK168487B1 DK168487B1 DK449986A DK449986A DK168487B1 DK 168487 B1 DK168487 B1 DK 168487B1 DK 449986 A DK449986 A DK 449986A DK 449986 A DK449986 A DK 449986A DK 168487 B1 DK168487 B1 DK 168487B1
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- ergolinyl
- diethyl
- urea
- methylthio
- 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 abstract description 4
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 30
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000004202 carbamide Substances 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- -1 1,1-diethyl-3- (2,3-dihydro-12-formyl-6-methyl-8-ergolinyl) urea Chemical compound 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- PFDOIIKNUZUWCE-ZYHUDNBSSA-N (6ar,10ar)-2-bromo-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline Chemical class C([C@@H]12)CCN[C@@H]1CC1=CNC3=CC(Br)=CC2=C31 PFDOIIKNUZUWCE-ZYHUDNBSSA-N 0.000 claims description 2
- PVCVGMVUIGAEAF-XYJFISCASA-N C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC=C(C([C@H]2C1)=C34)SCC)C)CC Chemical compound C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC=C(C([C@H]2C1)=C34)SCC)C)CC PVCVGMVUIGAEAF-XYJFISCASA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- BESPKSYERKGHPB-ZSZQSSIHSA-N 3-[(6aR,9S,10aR)-7-methyl-2-methylsulfanyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinolin-9-yl]-1,1-diethylurea Chemical compound C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC(=CC([C@H]2C1)=C34)SC)C)CC BESPKSYERKGHPB-ZSZQSSIHSA-N 0.000 claims 1
- PSEDBCDMBCWQRS-YQQAZPJKSA-N 3-[(6ar,9s,10ar)-7-methyl-1-methylsulfanyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound C1=C(SC)C([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=CNC3=C1 PSEDBCDMBCWQRS-YQQAZPJKSA-N 0.000 claims 1
- DURDUBSSYNROIT-FRQCXROJSA-N C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC(=CC([C@H]2C1)=C34)C)C)CC Chemical compound C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC(=CC([C@H]2C1)=C34)C)C)CC DURDUBSSYNROIT-FRQCXROJSA-N 0.000 claims 1
- YSOBDGDQFPGDQO-LSSORACZSA-N C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3CNC4=CC=C(C([C@H]2C1)=C34)SC)C)CC Chemical compound C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3CNC4=CC=C(C([C@H]2C1)=C34)SC)C)CC YSOBDGDQFPGDQO-LSSORACZSA-N 0.000 claims 1
- FLVIGYVXZHLUHP-UHFFFAOYSA-N N,N'-diethylthiourea Chemical compound CCNC(=S)NCC FLVIGYVXZHLUHP-UHFFFAOYSA-N 0.000 claims 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 claims 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 229960001701 chloroform Drugs 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 229960002896 clonidine Drugs 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 5
- 150000002168 ethanoic acid esters Chemical class 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229940049920 malate Drugs 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOAHPSVPXZTVEP-UHFFFAOYSA-N 1,1-diethyl-3-(7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl)urea Chemical compound C1=CC(C2CC(CN(C)C2C2)NC(=O)N(CC)CC)=C3C2=CNC3=C1 JOAHPSVPXZTVEP-UHFFFAOYSA-N 0.000 description 3
- TUMNHQRORINJKE-UHFFFAOYSA-N 1,1-diethylurea Chemical compound CCN(CC)C(N)=O TUMNHQRORINJKE-UHFFFAOYSA-N 0.000 description 3
- ORLXWYWZAITENH-HDMKZQKVSA-N 3-[(6ar,9s,10ar)-2-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound BrC1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=CNC3=C1 ORLXWYWZAITENH-HDMKZQKVSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- RYECOJGRJDOGPP-UHFFFAOYSA-N Ethylurea Chemical compound CCNC(N)=O RYECOJGRJDOGPP-UHFFFAOYSA-N 0.000 description 3
- 101100518501 Mus musculus Spp1 gene Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001430 anti-depressive effect Effects 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
- 229960004046 apomorphine Drugs 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002631 hypothermal effect Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 2
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- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
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- SPIBFHPWXQIEPM-YRISNDGFSA-N 3-[(6aR,9S,10aR)-7-methyl-2-propylsulfanyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinolin-9-yl]-1,1-diethylurea Chemical compound C(C)N(C(=O)N[C@@H]1CN([C@@H]2CC3=CNC4=CC(=CC([C@H]2C1)=C34)SCCC)C)CC SPIBFHPWXQIEPM-YRISNDGFSA-N 0.000 description 1
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 230000028016 temperature homeostasis Effects 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
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
i DK 168487 B1
Opfindelsen angår hidtil ukendte 12- og 13-substituerede ergolinderivater med den almene formel I samt en fremgangsmåde til fremstilling heraf-
5 Forbindelserne ifølge opfindelsen er ejendommelige ved den almene formel I
R3 4» io r1 Pi N _R 2 ^ 3; i < 15 HN“-^ hvori
Ri betegner lavere alkyl, SR5 (r5 “ lavere alkyl), CN, Cl eller J, R2 betegner en lavere alkylgruppe og 20 R3 betegner NH-C0-NEt2 eller NH-CS-NEt2 og
Cg---Cio og C2---C3 betegner en CC-enkelt- eller en C=C- dobbeltbinding, og hydrogenatomet i 10-sti11 ingen er a-stillet, når Cg C^q er en CC-enkeltbinding, og hydrogenatomet i 3-stillingen er a- eller β-stillet, når C2 C3 25 er en CC-enkeltbinding, samt syreadditionssalte deraf.
Ved lavere alkylrester forstås rester med indtil 6 carbonato-mer, hvor Cj_4-alkyl rester foretrækkes såsom methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, te.rt.-buty 1.
30
Saltene af forbindelserne i følge opfi ndel sen med formlen I er syreadditionssalte og hidrører fra sædvanligvis anvendte syrer. Sådanne syrer er f.eks. uorganiske syrer, som f.eks. saltsyre, salpetersyre, phosphorsyre, svovlsyre, hydrogenbromid-35 syre, hydrogenjodidsyre, salpetersyrling eller phosphorsyr-ling, eller organiske syrer som f.eks. alifatiske mono- eller dicarboxylsyrer, phenylsubstituerede alkancarboxylsyrer, hydro- DK 168487 Bl 2 xyalkancarboxylsyrer eller alkendicarboxylsyrer, aromatiske syrer eller alifatiske eller aromatiske sulfonsyrer. Fysiologisk acceptable salte af disse syrer er derfor f.eks. sulfat, pyrosulfat, bisulfat, sulfit, bisulfit, nitrat, phosphat, mono-5 hydrogenphosphat, dihydrogenphosphat, met-aphosphat, pyrophos-phat, chlorid, bromid, jodid, fluorid, acetat, propionat, deca-noat, caprylat, acrylat, formiat, isobutyrat, caproat, hepta-noat, propiolat, malonat, succinat, suberat, sebacat, fumarat, maleat, mandelat, butyn-1,4-dioat, hexyn-1,6-dioat, benzoat, 10 chlorbenzoat, methylbenzoat, dinitrobenzoat, hydroxybenzoat, methoxybenzoat, phthalat, terephthalat, benzensul fonat, tolu-ensulfonat, chlorbenzensulfonat, xylensulfonat, phenyl acetat, phenylpropionat, phenylbutyrat, citrat, lactat, /3-hydroxybuty-rat, glycollat, malat, tartrat, methansulfonat, propansulfo-15 nat, naphthalen-l-sulfonat eller naphthalen-2-sulfonat.
I sammenligning med kendte, i 13-stillingen ikke-substi tuerede ergoliner, som f.eks. trans-dihydrolisurid, besidder forbindelserne ifølge opfindelsen med formlen I en stærkere eller 20 mindst lige så stærk central a2--receptorblokerende virkning ved svagere eller manglende antidopaminerge virkninger. Denne virkningsprofil frembyder forbindelserne som værdifulde stoffer til behandling af psykiske forstyrrelser inden for depressionsområdet. Den antidepressive virkning af forbindelserne 25 ifølge opfindelsen beror på en central a2-recePtorblokade, som bevirker en forøget noradrenalinfrigørelse i hjernen og derved medfører den antidepressive virkning.
Den centrale a2-receptorblokade blev fastslået i et interak-30 ti ons forsøg med <X2-r*eceptoragonisten clonidin hos mus efter en enkelt i.p.-forbehandl ing (parameter: ophævelse af den af clonidin 0,1 mg/kg i.p. forårsagede hypotermi). NMRI-hanmus blev forbehandlet med forskellige doser af l,l-diethyl-(6-methyl-8a-ergoli ny1)-uri nstof (TDHL) eller 13-substituerede ergoli-35 nylurinstofforbindelser, som ikke selv påvirker forsøgsdyrenes termoregulering, eller med bærermedium. 30 minutter senere modtog alle dyr clonidin 0,1 mg/kg i.p.. 60 minutter efter 3 DK 168487 B1 prøvestof eller bærermedium (= 30 minutter efter clonidin) blev rekta1 temperaturen målt ved hjælp af en termosonde. Mens de med bærermedium forbehandlede mus udviste en hypotermi, var den legemstemperatursænkende virkning af clonidin afhængigt af 5 dosen ophævet hos dyr, der var forbehandlet med TDHL eller 13-substituerede ergo!inylurinstofforbindelser. Som det fremgår af tabel 1, var den clonidinantagonistiske virkning efter I3-SCH3-TDHL statistisk signifikant ved doseringen 0,78 mg/kg.
10 øen centrale dopaminreceptorblokade blev fastslået i et inter-akti onsforsøg med dopaminreceptoragonisten apornorf in hos mus efter en enkelt i.p.-forbehandling. (Parameter: ophævelse af den af apomorfin 5 mg/kg i.p. forårsagede hypotermi). Den videre fremgangsmåde er den samme som den for den centrale a>i~ 15 receptorblokade angivne fremgangsmåde.
Som det fremgår af tabel 2, var den apomorfinantagonistiske virkning efter TDHL statistisk stærk signifikant ved doseringen 3,13 mg/kg. I3-SCH3-TDHL virkede ikke apomorfinantagoni-20 stisk i doseringerne 0,1-3,13 mg/kg.
På grund af disse undersøgelsesresul tater kan forbindelserne ifølge opfindelsen derfor anvendes som neuroleptika til behandling af psykoser indenfor det skizofrene område eller som anti-25 depressiva.
Desuden udviser forbindelserne ifølge opfindelsen blodtrykssænkende virkning og egner sig derfor som lægemiddel til behandling af forhøjet blodtryk.
30 I dyrefarmakologiske undersøgelser viste f.eks. 1,1-diethyl-(13-hydroxy-6-methy1-8a-ergolinyl)-uri nstof (13-OH-TDHL) en dosisafhængig blodtrykssænkning hos spontant hypertensive rotter, som var blevet præpareret efter en metode, der var modifi-35 ceret efter Weeks (Weeks, J.R., Routine Direct Measurement of Arterial Pressure in Anaesthetized Rats. Proc.S.Exp.Biol. Med. 104:646-648, 1960).
4 DK 168487 B1
Til undersøgelse af den blodtrykssænkende virkning og dennes dosisafhængighed udførtes følgende farmakologiske forsøg:
Hos ca. 300 g tunge SH-hanrotter fastlagdes det arterielle 5 middelblodtryk og hjertefrekvensen ved hjælp af et implanteret aortakateter.
Prøvestoffet blev indgivet intravenøst via et i vena jugularis placeret kateter i bolus i doseringerne 0,01 mg/kg, 0,1 mg/kg 10 og 1,0 mg/KM, efter at det var blevet opløst i DMSO og fyldt op med destilleret vand til det volumen, der skulle indgives.
Den maksimale blodtrykssænkning efter indgift af 1,0 mg/kg KM andrager med 13-0H-TDHL som eksempel 35% af udgangsværdien. 15 ved denne dosis vedvarer den blodtrykssænkende virkning indtil slutningen af forsøget efter 120 minutters forløb. Hjertefrekvensen sænkes ved dosen 1 mg/kg KM maksimalt 30%.
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7 DK 168487 B1 På samme måde som angivet for de i tabel 1 opnåede resultater blev forskellige 12- og 13-substi tuerede ergo!in(thi o)ur in-stoffer undersøgt for clonidinantagonist-isk virkning. Resultaterne fremgår af tabel 3.
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5 9 DK 168487 B1
Forbindelserne med den almene formel I ifølge opfindelsen kan fremstilles efter en fremgangsmåde, som er ejendommelig ved det i krav 3's kendetegnende del anførte.
Fremstillingen af forbindelserne med den almene formel I foregår efter i og for sig kendte fremgangsmåder ved, at man omsætter et 12- eller 13-Br-ergoli nderivat med den almene formel II
10 R3 ζ
Br A-, "" N- / 20 r4 hvori R2, R3 og C---C har den ovenfor angivne betydning, og R4
betegner hydrogen eller en beskyttelsesgruppe, med en lithium-25 organyl og omsætter det således opnåede 12- eller 13-Li-ergo-linderivat med den almene formel III
R3 Λ Λ
30 Li ✓N
ψτ .....
/ R4 35 N- 10 DK 168487 B1 hvori R4, R2, R3 og C C har den ovenfor angivne betydning, med et elektrofilt reagens valgt blandt en thiosulfon-syre-S-alkylester, et isocyanat, et formamid, et alkylhaloge-5 nid og et halogeneringsmiddel og om ønsket derpå omdanner et carboxyl syreamid eller et formylderivat til en nitril, oxiderer et svovlatom og/eller omdanner en urinstofforbindelse til en thiourinstofforbindelse og om ønsket omdanner forbindelsen med en syre til et fysiologisk forligeligt syreadditionssalt.
10
Til fremstillingen af forbindelserne med den almene formel III kan anvendes alle kendte 1ithiumorganyler, hvor 1ithiumalkyl-forbindelser og 1 i thiumpheny1 foretrækkes. Som lithiumalkyl kommer især tert.-buty11 ithium på tale, hvorved man anvender l 15 til 10 ækvivalenter.
Reaktionen gennemføres i et aprotisk opløsningsmiddel såsom ether eller hydrocarbon, f.eks. i tetrahydrofuran, dioxan, diethylether, toluen, hexan og andre.
20
Tilsætningen af en støkiometrisk mængde tetramethylethylendi-amin, beregnet på lithiumalkyl, har vist sig egnet.
R4 kan betyde en sædvanligvis anvendt beskyttelsesgruppe, som 25 f.eks. en acyl- eller silylrest, hvor trialkylsilylresten, især tert.-butyldimethylsilylgruppen, foretrækkes.
Brom-1i thi umudbytni ngen foretages ved temperaturer fra 20®C til -110°C, hvor temperaturer fra -70°C til -110°C foretrækkes 30 i nærværelse af en beskyttelsesgruppe og temperaturer fra 20®C til -70°C foretrækkes i fravær af beskyttelsesgruppe.
For at undgå bireaktioner kan protonen i urinstoffet før bromli thi umudbytni ngen fjernes ved de sædvanlige metoder som 35 f.eks. tilsætning af 1 ithiumdiisopropy1amid eller lithium-bis-(trimethylsilyl)-amid i støkiometriske mængder.
11 DK 168487 B1
Reaktionen er afsluttet efter ca, 5 minutter til 2 timer og gennemføres hensigtsmæssigt under en inaktiv gas som f.eks. argon eller nitrogen.
5 Det således opnåede 1 ithiumergolinderivat med den almene formel III omsættes uden yderligere oparbejdning med det elektro-file reagens i det aprotiske opløsningsmiddel.
Som elektrofilt reagens egner sig f.eks.: 10 thiosulfonsyre-S-estere som f.eks. methanthiosulfonsyre-S-me-thyl ester, toluenthiosul fonsyre-S-ethyl ester og toluenthiosul-fonsyre-S-n-propylester, isocyanater og isothiocyanater som f.eks. trimethylsilyliso-15 cyanat og methyl i sothiocyanat, formamider som f.eks. dimethyl formamid, alkylhalogenider, f.eks. methyl jodid, isopropyl jodid og alkyl-bromid, halogeneringsmidler som f.eks. N-chlorsuccinimid, N-jodsuccin-20 imid og halogen, f.eks. jod, Såfremt reaktanten under normale betingelser er en gas, så indføres denne gasformigt eller bringes til reaktion i fast form.
25
Den elektrofile substitution gennemføres ved lave temperaturer (0°C til -90°C), og derefter efterrøres der eventuelt ved stuetemperatur i ca. 2 timer.
30 Såfremt beskyttelsesgruppen R4 er til stede, kan den fraspaltes efter de sædvanlige metoder ved behandling med syrer, såsom fortyndet uorganisk syre eller trif1uoreddikesyre, eller uorganiske baser såsom KOH, NaOH eller fluorid såsom tetrabu-tylammoniumfluorid i inaktive opløsningsmidler, f.eks. vand, 35 alkoholer eller hydrocarboner og andre, ved stuetemperatur.
Om ønsket kan substituenterne i 12- og i 13-sti 11 i ngen derefter omsættes efter i og for sig kendte metoder.
12 DK 168487 B1
Carboxylsyreamider kan omdannes til nitriler, f.eks. ved omsætning med phosphoroxychlorid uden opløsningsmiddel eller i et aprotisk opløsningsmiddel såsom ethere eller methylenchlo-rid ved stuetemperatur eller forhøjet temperatur.
5 Såfremt Ri betegner en alkylmercaptangruppe, så kan denne oxideres til sulfinylgruppen ved, at man f.eks. oxiderer til sulf-oxidet med Na-metaperjodat i et inaktivt opløsningsmiddel såsom acetonitril, dioxan eller THF, ved stuetemperatur eller 10 forhøjet temperatur.
Omdannelsen af 8<x-urinstofderivaterne til de tilsvarende thio-ner foregår ved omsætning med phosphoroxychlorid og efterfølgende reaktion med kaliumxanthogenat. Reaktionen foretages ved 15 lave temperaturer med temperaturforøgelse i mellemtiden i inaktive opløsningsmidler såsom ethere.
Til dannelsen af salte opløses forbindelserne med formlen I i lidt methanol eller methylenchlorid og tilsættes en koncentre-20 ret opløsning af den ønskede syre i methanol ved stuetemperatur.
Til anvendelsen af forbindelserne ifølge opfindelsen som lægemiddel bringes disse på en farmaceutisk præparatform, som ud 25 over det virksomme stof indeholder et til den enterale eller parenterale applikation egnet farmaceutisk, organisk eller uorganisk, inaktivt bærermateriale som f.eks. vand, gelatine, gummi arabicum, mælkesukker, stivelse, magnesiumstearat, talkum, vegetabilske olier, polyalkylenglykoler osv. De farmaceu-30 tiske præparater kan foreligge i fast form, f.eks. som tabletter, drageer, stikpiller eller kapsler eller i flydende form, f.eks. som opløsninger, suspensioner eller emulsioner. Eventuelt indeholder de derudover hjælpestoffer såsom konserverings-, stabiliserings- og befugtningsmidler eller emulgatorer, salte 35 til forandring af det osmotiske tryk eller puffere.
Fremstillingen af udgangsforbindelserne er kendt eller foregår efter kendte metoder.
13 DK 168487 B1
De efterfølgende eksempler skal belyse fremgangsmåden ifølge opfindelsen.
Fremstilling af udqanqsforbindelserne 5 3-(13-brom-l-tert.-buty 1 dimethy1 s i 1y1-6-methy1-8a-ergoli ny 1)- 1.1- diethylurinstof
Der fremsti lies en opløsning af 1 ithiumdi isopropyl amid ud fra 10 400 ml frisk destilleret, vandfrit THF, 12,9 ml vandfri diiso- propylamin og 42,8 ml n-butyl1ithium (i hexan) ved 0°C. Denne opløsning afkøles til -20eC, tilsættes 8,21 g 3-{13-brom-6-me-thyl-8a-ergolinyl)-1,1-diethylurinstof (19,5 mmol), opløst i 200 ml frisk destilleret, vandfrit THF, ved -20°C, og der om-15 røres i 15 minutter. Ved den samme temperatur tilsættes opløsningen af 10,7 g tert.-butyldimethylsilylchlorid i 150 ml frisk destilleret, vandfrit THF, og der omrøres igen i 15 minutter. Derpå hældes blandingen på is, gøres alkalisk med 25% ammoniak og udrystes med methylenchlorid. Der kromatograferes 20 på kieselgel med hexan, di isopropy1 ether, methylenchlorid og methanol og der opnås efter krystallisation fra eddikesyreester og diisopropylether 7,3 g (70% af det tetoretiske).
[<x]D = -12° (0,5% i chloroform) 25 På analog måde fremstilles de følgende silylforbindelser: 3-(13-brom-l-tert.-butyl di methyl silyl-6-n-propyl-8a-ergoli nyl)- 1.1- diethyl uri nstof, 30 3-(12-brom-l-tert.-butyldimethylsilyl-6-methy1-8a-ergo!inyl)— 1.1- di ethyl ur i nstof, [a]o - +34° (0,5% i chloroform) 3-(12-brom-l-tert.-butyldimethylsilyl-9,10-di dehydro-6-methy1-3g 8a-ergoli ny1)—1,1—di ethylurinstof, 3-(13-brom-l.tert.-butyldimethylsilyl -2,3 -.di hydro-6-me thy 1 -8a-ergolinyl)-l,1-diethylur i nstof og . DK 168487 B1 14 3-(12-brom-l-tert.-butyldi methyIsily1-2,3-di hydro-6-methyl-8a-ergolinyl)-1,1-diethyl urinstof,
Eksempel 1 5 1,l-diethvl-3-(6-methvl-13-methvlthio-8a-erqo1inyl)-uri nstof 3,2 ml (15 mmol) destilleret hexamethyldisilazan anbringes i 40 ml vandfri, frisk destilleret toluen under argon. Efter 10 afkøling af denne blanding til 0°C tildryppes 8,5 ml (14 mmol) 15% n-butylli thium i hexan, og der omrøres endnu 15 minutter ved 0eC. Derefter tildryppes opløsningen af 5,33 g 3-(13-brom-1-tert.-butyl dimethyl si ly1-6-methy1-8a-ergolinyl)-l,l-diethyl-urinstof (10 mmol) i 200 ml vandfri, frisk destilleret toluen, 15 og der omrøres efter i 15 minutter ved 0°C. Derefter tilsættes 10 ml destilleret tetramethylethylendiamin og afkøles til -90eC. Nu tilsættes 50 ml 1,4 M tert.-butyllithium (70 mmol), og der omrøres i 2 minutter.
20 Til opløsningen af 13-lithiumergolinylurinstofforbindelsen sættes opløsningen af 6,3 g methanthiosulfonsyre-S-methylester (10 mmol) i 50 ml frisk destilleret, vandfrit THF. Efter 10 minutters omrøring anbringer man blandingen på is, gør alkalisk med 25% ammoniakopløsning og udryster med methylenchlo-25 rid.
Råproduktet opløses til afsilyleringen i · 500 ml methanol og omrøres med 250 ml 7 N kalilud i 15 minutter ved stuetemperatur. Blandingen anbringes igen på is og udrystes med methy-30 lenchlorid. Efter afdest i 11 at i on af opløsningsmidlet kromato-graferes remanensen (udbytte 1,27 g, 33% af det teoretiske) og krystalliserer fra eddikesyreester og diisopropylether. Udbytte 0,7 g(18% af det teoretiske).
35 [<x]D = -13° (0,25% i chloroform).
På fuldstændig analog måde fremstilles ud fra de følgende 12-og 13-bromergolinylurinstofforbindelser med methanthiosul-
—V
15 DK 168487 B1 fonsyre-S-methylester:
Ud fra 3-(12-brom-l-tert.-butyldimethylsi]yl-6-methyl-8a-ergo-1 i ny1)-1,1-di ethyl ur i nstof l,l-diethyl-3-(6-methyl-12-methyl-5 thio-8a-ergolinyl)-ur i nstof, udbytte 44% af det teoretiske, [a]g » +24° (0,5% i chloroform), ud fra 3-(12-brom-l-tert.-butyldimethylsilyl~2,3-dihydro-6-methyl-8a-ergo!i ny1)-1,1-di ethylurinstof l,l-diethyl-3-(2,3- 10 dihydro-6-methyl-12-methylthio-8a-ergolinylurinstof, udbytte 80% af det teoretiske, [a]o = +41,7° (0,5% i chloroform), ud fra 3-(13-brom~l-tert.-butyldimethylsilyl-2,3-dihydro-6-methyl-8a-ergolinyl)-l,l-diethylurinstof 1,1-di ethy1-3-(2,3-15 di hydro-6-methyl-13-methyl thi o-8a-ergo 1inyl)-urinstof, ud fra 3-(12-brom-l-tert.-butyldimethylsilyl-9,10-didehydro-6-methy1-8a-ergolinyl)-l,l-diethylurinstof ·3-(9,10-didehydro-6-methy1-12-methy1 thi o-8a-ergo1 i ny1)-1,1-di ethylurinstof, 20 ud fra 3-(13-brom-l-tert.-butyldimethylsilyl-6-n-propy1-8a-ergoli nyl)-1,1-diethyl urinstof l,l-diethyl-3-(13-methylthio-6-n-propy1-8a-ergolinyl)-urinstof og 25 ud fra 3-(13-brom-l-tert.-butyldimethylsilyl-2,3-dihydro-6-n- propyl-8a-ergoli ny1)-1,1-diethyluri nstof 1,1-diethy1-3-(2,3- dihydro-13-methylthio-6-n-propyl-8a-ergolinyl)-urinstof.
Såfremt man erstatter methanthiosulfonsyre-S-methylester med 30 andre elektrofile reagenser, så opnås de følgende forbindel ser : med toluenthiosulfonsyre-S-ethylester og· 3-(12-brom-1-tert.-butyldimethylsilyl-6-methyl-8a-ergoli nyl)-l,l-diethylurinstof 35 1,1-diethyl-3-(12-ethyl thio-6-methyl-8a-ergolinyl)-urinstof, udbytte 48% af det teoretiske, [a]o = +98° (0,5% i chloro form ), DK 168487 Bl 16 med toluenthiosulfonsyre-S-n-propylester og 3-(13-brom-l-tert.-butyldimethyl silyl-6-methy1-8a-ergolinyl)-1,1-diethyl uri nstof 1,1-diethy1-3-(6-methy1-13-n-propylthio-8a-ergolinyl)-uri nstof, 5 med trimethylsilylisocyanat og 3-(12-brom-l-tert.-butyIdime-thylsilyl-6-methyl-8a-ergoli ny1)-1,1-diethy1 uri nstof 8ct- (3,3-diethy1 ureido)-6-methy1-ergo1 i n-12-carboxy1 syreamid, udbytte 15% af det teoretiske 10 med dimethyl formamid og 3-(l3-brom-l-tert.-butyldimethylsilyl- 6-methyl-8a-ergoli ny1)-1,1-diethyluri nstof 1,1-diethyl-3-{13-formyl-6-methyl-8a-ergolinyl)-urinstof, udbytte 13%, [a]p = -11° (0,5% i chloroform) 15 med methyljodid og 3-(12-brom-l-tert.-butyldimethylsilyl-6-me- thyl-8a-ergolinyl)-1,1-diethyl uri nstof 1,1-diethy1-3-(6,12-di-methyl-8a-ergolinyl)-urinstof, udbytte 31%, [a]p = +5,5® (0,5% i chloroform), 20 med methyljodid og 3-(13-brom-l-tert.-butyIdimethylsily1-6-methyl-8a-ergolinyl)-1,1-diethyl urinstof 1,1-diethy1-3-(6,13-dimethyl-8a-ergo1inyl)-urinstof, med isopropyl jodid og 3-(13-brom-l-tert-butyldimethylsi lyl-25 2,3-di hydro-6-methyl-8a-ergoli ny1)-1,1-diethyluri nstof 1,1- diethyl-3-(6-methy1-13-isopropyl-8α-ergo!inyl)-uri nstof, med isopropyl jodid og 3-(l3-brom-l-tert.-butyldimethylsilyl- 6-n-propyl-8a-ergolinyl)-l,1-diethylur i nstof 1,1-diethyl-3- 30 (13-isopropy1-6-n-propyl-8a-ergo!inyl)-urinstof, med N-chlorsuccinimid og 3-{12-brom-l-tert.-butyldimethylsilyl- 6-methy1-8a-ergoli nyl)-1,1-diethy1 ur i nstof 3-(12-chlor-6-me-thyl-8a-ergolinyl)-1,1-diethyl uri nstof, med N-chlorsuccinimid og 3-(13-brom-l-tert.-butyldimethylsi-lyl-6-methy1-8a-ergolinyl)-1,1-diethyl ur i nstof 3-{13-chlor-6-methyl-8a-ergolinyl)-1,1-diethyl uri nstof, 35 5 17 DK 168487 B1 med N-chlorsuccinimid og 3-(13-brom-l-tert.-butyldimethylsilyl--2,3-dihydro-6-methyl-8a-ergolinyl)-1,1-di ethyl urinstof 3-(13-chlor-2,3-dihydro-6-methyl-8<x-ergolinyl)-l,l-diethylurinstof, med N-chlorsuccinimid og 3-(12-brom-l-tert.-buty1dimethylsily1- 9,10-d idehydro-6-methy1-8a-ergo1 i ny1)-1,1-di ethyl ur i nstof 3- (12-chlor-9,10-didehydro-6-methyl-8a-ergolinyl)-l,l-diethyl-uri nstof, 10 med N-jodsuccinimid og 3-(12-brom-l-tert.-butyldimethylsilyl- 6-methyl-8a-ergoli ny1)-1,1-diethylurinstof 1,1-diethy1-3-(12-jod-6-methy1-8a-ergoli ny1)-uri nstof, 15 med jod og 3-(13-brom-l-tert.-butyldimethylsilyl-6-methyl-8a~ ergoli nyl)-1,1-diethyl urinstof 1,1-diethyl-3-(13-jod-6-methy1-8a-ergolinyl)-urinstof, med N-jodsuccinimid og 3-(12-brom-l-tert.-butyldimethylsily1-2 0 2,3-dihydro-6-methy1-8a-ergolinyl)-1,1-diethy1 ur i nstof 1,1- diethyl-3-(2,3-dihydro-12-jod-6-methyl-8a-ergolinyl)-urinstof, med jod og 3-(13-brom-l-tert.-butyldimethylsilyl-2,3-dihydro- 6-methyl-8a-ergolinyl)-l,l-diethylurinstof 1,1-diethy1-3-(2,3-25 di hydro-13-jod-6-methyl-8a-ergoli ny1)-uri nstof, med jod og 3-(12-brom-l-tert.-butyldimethylsilyl-9,10-didehy-dro-6-methyl-8a-ergoli ny1)-1,1-di ethylurinstof 3-(9,10-dide- hydro-12-jod-6-methyl-8a-ergoli nyl)-1,1-di ethyl uri nstof og 30 med jod og 3-(13-brom-l-tert.-butyldimethylsilyl-6-n-propyl-8a-ergoli ny1)-1,1-diethyl uri nstof l,l-diethyl-3-(13-jod-6-me-thyl-8a-ergoli nyl)-ur i nstof.
35 18 DK 168487 B1
Referenceeksempel 1,1-diethy1-3-(13-hvdroxv-6-methy1-6a-erqolinyl)-urinstof 5 419 mg 3-(13-brom-6-methyl-8a-ergolinyl)-l,1-diethylurinstof (1 mmol) opløses i 15 ml vandfrit, frisk destilleret THF under argon, afkøles til -20°C og tilsættes 5 ml af en 1,4 molær opløsning af tert.-butyllithium i hexan. Det omrøres i 2 timer ved 0*0, hvorpå der afkøles til -70°C og tilsættes 0,5 nitro-10 benzen i 10 ml vanfrit, frisk destilleret THF. Efter 10 minutters omrøring sættes blandingen på is, gøres alkalisk med 25¾ ammoniakopløsning og udrystes med methylenchlorid. Remanensen renses ved kromatografi på kieselgel og krystalliserer fra ed-dikesyrester og di isopropylester, udbytte 131 mg (37% af det 15 teoretiske) [a]ø = 11° (0,5% i methanol).
Analogt fremstilles: med methanthiosulfonsyre-S-methylester og 3-(13-brom-6-methy1-20 8a-ergolinyl)-1,1-diethyl uri nstof 1,1-diethyl-3-(6-methy1-13-methylthio-8a-ergolinyl)-urinstof med 46% udbytte, [<x]ø = -13° (0,25% i chloroform), med dimethyl formamid og 3-(12-brom-6-methyl-8a-ergolinyl)-1,1~ 25 diethylurinstof 1,1-di ethyl-3-(12-formyl-6-methy1-8a-ergoli" nyl)-urinstof med 70% udbytte, [«Id = +20,6° (0,5% i chloro form) , med dimethyl formamid og 3-(12-brom-2,3-dihydro-6-methy1-8a-30 ergo!inyl)-l,1-diethylurinstof l,l-diethyl-3-(12-formyl-2,3-dihydro-6-methy1-8a-ergolinyl)-urinstof med 65% udbytte, [a]p = +14® (0,5% i chloroform), 35 19 DK 168487 B1
Eksempel 2 3-(12-cyan-6-methv1-8a-ergolinyl)-l,l-diethylurinstof 5 383 mg [8a-(3,3-diethy1ureido)-6-methy1 ergo 1 in-12-y1]-carbon- syreamid ( 1 mmol) opløses i 25 ml chloroform, og der tilsættes 3 ml phosphoroxychlorid og omrøres i 16 timer ved 55°C. Blandingen hældes på is, venter i 30 minutter og gøres derpå alkalisk med IN kalilud og ekstraheres med methylenchlorid. Den 10 organiske fase tørres med natriumsulfat og inddampes. Remanensen krystalliserer fra eddikesyreester med 43% udbytte, [α]β = +16® (0,5% i chloroform).
Eksempel 3 15 1.1- diethyl-3-(6-methvl-12-methvlthio-8a-erqolinvl)-thiourin-stof 5,79 g 1,1-diethy1-3-(6-methy1-12-methylthio-8a-ergolinyl)-20 urinstof (15 mmol) opløses i en blanding af 4,13 g frisk destilleret phosphoroxychlorid (45 mmol) og 50 ml vandfrit methylenchlorid ved -20°C, og temperaturen kommer op på +10°C i løbet af 4 timer. Natten over omrøres ved stuetemperatur og derefter i endnu 2 timer ved 40®C, og derpå afdesti 1 leres op-25 løsningsmidlet i vakuum. Remanensen opløses i 50 ml vandfri acetonitril, afkøles til -10°C, tilsættes 7,2 g kaliumethyl-xanthogenat (45 mmol) og omrøres i 20 timer ved stuetemperatur. Opløsningsmidlet afdesti1 leres i vist omfang, og derpå fordeles blandingen mellem eddieksyreester og mættet natrium-30 carbonatopløsning, og den vandige fase tørres med natriumsulfat og inddampes. Remanensen krystalliserer fra eddikesyreester, udbytte 82%, [a]g = +48° (0,5% i chloroform).
De følgende thiourinstofforbindelser fremstilles analogt ud 35 fra de påfølgende urinstofforbindelser: 1.1- diethy1-3-(6-methyl-13-methylthio-8a-ergolinyl)-thiourin-stof,
Claims (9)
- 20 DK 168487 B1 1.1- diethy1-3-(2,3-dihydro-6-methy1-13-methy1thio-8a-ergo 1 i -ny1)-thi ourinstof, 3-(9,10-didehydro-6-methy1-12-methylthio-8a-ergoli nyl)-1,1-5 diethylthiourinstof og 1.1- diethy1-3-(13-methy1 thio-6-n-propyl-8a-ergolinyl)-thiourin-stof.
- 10 Eksempel 4 3-(12-cyan-2,3-dihydro-6-methyl-8a-ergolinvl)-l,l-diethvlurin-stof
- 15 En suspension af 500 mg l,l-diethyl-3-(2,3-dihydro-12-formyl- 6-methyl-8o-ergolinyl)-urinstof og 460 mg hydroxylamin-O-sulfon-syre i 5 ml vand omrøres i 20 timer ved stuetemperatur. Reaktionsblandingen sættes på is, gøres alkalisk med 25% ammoniakopløsning og ekstraheres med dichlormethan. Den organiske fase 20 tørres (Na2S04) og inddampes, og remanensen kromatograferes på kieselgel med dichlormethan/methanol = 95:5 som elueringsmid-del og krystalliserer fra ethylacetat/pentan, udbytte 26% af det teoretiske, [a]g = +26° (0,5% i chloroform).
- 25 Patentkrav. 1 35 12- og 13-substituerede ergolinderivater, kende tegnet ved den almene formel I 30 21 DK 168487 B1 R3 w9·'·· jjT HN-^ 10 hvori R1 betegner lavere alkyl, SR5 (R5 = lavere alkyl), CN, Cl eller J, R2 betegner en lavere alkylgruppe og R3 betegner NH-C0-NEt2 eller NH-CS-NEt2 og 15 c9---Cio °9 c2---c3 betegner en CC-enkelt- eller en C=C- dobbeltbinding, og hydrogenatomet i 10-stillingen er omstillet, når Cg Cjo er en CC-enkeltbinding, og hydrogenatomet i 3-stillingen er a- eller β-stillet, når C2 C3 er en CC-enkeltbi nding, samt syreadditionssalte deraf. 20
- 2. Forbindelse, kendetegnet ved, at den er 1.1- diethy1-3-(6-methy1-13-methy1thio-8a-ergoli ny1)-uri nstof, 25 1,l-diethyl-3-(6-methyl-12-methylthio-8a-ergolinyl)-urinstof, 1.1- diethyl-3-(2,3-dihydro-6-methyl-12-methylthio-8a-ergoli-nyl)-urinstof, 30 l,l-diethyl-3-(12-ethylthio-6-methy1-8a-ergolinyl)-urinstof, 1.1- diethy1-3-(6,13-di methyl-8α-ergolinyl)-urinstof, 1.1- diethyl-3-(13-jod-6-methyl-8a-ergolinyl)-urinstof, 35 1.1- diethy1-3-(6-methy1-13-methy1 thio-8a-ergolinyl)-urinstof, 22 DK 168487 B1 3 - (12-cyan-6-me thy 1 -8<x-er gol inyl)-l,l-diethylurinstof og 1f1-diethy1-3-(6-methy1-12-methylthio-8a-ergoli nyl)-thi our i n-stof. 5
- 3. Fremgangsmåde til fremstilling af forbindelser med den almene formel I, kendetegnet ved, at man omsætter et 12- eller 13-Br-ergolinderivat med den almene formel II 10 j?3 Br N-r2 (Uf j <m / 20 r4 hvori R2, R3 og c---C har den ovenfor angivne betydning, og R4 betegner hydrogen eller en beskyttelsesgruppe, med en lithium-25 organylforbindelse og omsætter det således opnåede 12- eller
- 13-Li-ergo!i nderivat med den almene formel III bi?" 3 5 ^-i R4 23 DK 168487 B1 hvori R4, R2, r3 0g C --- C har den ovenfor angivne betydning, med et elektrofilt reagens valgt blandt en thiosu1fonsyre-S-alkylester, et isocyanat, et formamid, et ‘alkylhalogenid og et 5 halogeneringsmiddel og om ønsket derefter omdanner et carbo-xylsyreamid eller et formylderivat til en nitril, oxiderer et svovlatom eller omdanner en urinstofforbindelse til en thiou-rinstofforbindelse og eventuelt omdanner med en syre til et fysiologisk forligeligt syreadditionssalt. - O X *-» 15 20 25 30 35 DK 168487 B1 BILAG. CM σ> o co co oo ro rH 1— I— I— I— I— (I) <D QJ O) 0) Ώ Δ JD Λ .Ω re ro ro ro ro +j -p +j +j . 0) i. + ε — 3 4- £ — C E £- — E r- i- Ε O E i. O O L. 4- S- O Ε α 4- 0 0 0 4- IL E 0 4-5-4- O O O
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853533672 DE3533672A1 (de) | 1985-09-19 | 1985-09-19 | Neue 12- und 13-substituierte ergolinderivate |
| DE3533672 | 1985-09-19 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK449986D0 DK449986D0 (da) | 1986-09-19 |
| DK449986A DK449986A (da) | 1987-03-20 |
| DK168487B1 true DK168487B1 (da) | 1994-04-05 |
Family
ID=6281549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK449986A DK168487B1 (da) | 1985-09-19 | 1986-09-19 | 12- og 13-substituerede ergolinderivater samt en fremgangsmåde til fremstilling deraf |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4863929A (da) |
| EP (1) | EP0220129B1 (da) |
| JP (1) | JPH0717640B2 (da) |
| AT (1) | ATE66478T1 (da) |
| AU (1) | AU582275B2 (da) |
| CA (1) | CA1289948C (da) |
| CS (1) | CS261246B2 (da) |
| DE (2) | DE3533672A1 (da) |
| DK (1) | DK168487B1 (da) |
| ES (1) | ES2003101A6 (da) |
| HU (1) | HU201548B (da) |
| IE (1) | IE59340B1 (da) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3533672A1 (de) * | 1985-09-19 | 1987-03-26 | Schering Ag | Neue 12- und 13-substituierte ergolinderivate |
| DE3806374A1 (de) * | 1988-02-25 | 1989-09-07 | Schering Ag | Neue ergolin-derivate, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| DK338789A (da) * | 1988-07-15 | 1990-01-16 | Schering Ag | 2-substituerede ergolinylurinstofderivater og fremgangsmaade til fremstilling deraf, deres anvendelse som laegemidler samt mellemprodukter til fremstilling deraf |
| DE4001323A1 (de) * | 1990-01-15 | 1991-07-18 | Schering Ag | 2,13-disubstituierte ergoline, deren herstellung und verwendung in arzneimitteln |
| FR2662439B1 (fr) * | 1990-05-23 | 1993-11-19 | Rhone Poulenc Chimie | Reactif et procede de perfluoroalkylation de substrats nucleophiles par les perfluoroalcanesulfinates de sodium en milieu oxydant. |
| DE4123587A1 (de) * | 1991-07-12 | 1993-01-14 | Schering Ag | 2,14-disubstituierte ergoline, deren herstellung und verwendung in arzneimitteln |
| CA2125288C (en) * | 1992-12-24 | 2004-11-23 | Sergio Mantegani | Serotoninergic ergoline derivatives |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0021206B1 (de) * | 1979-06-13 | 1983-06-22 | Schering Aktiengesellschaft | Neue (Ergolin-yl)-N', N'-diäthylharnstoff-Derivate, ihre Herstellung und sie enthaltende Arzneimittel |
| CH644606A5 (de) * | 1980-09-23 | 1984-08-15 | Sandoz Ag | Verfahren zur isomerisierung von 9,10-dihydrolysergsaeurederivaten. |
| DE3101535A1 (de) * | 1981-01-14 | 1982-08-12 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue (2-halogen-ergolinyl)-n'.n'-diethyl-harnstoffderivate, verfahren zu ihrer herstellung und deren verwendung als arzneimittel |
| DE3205169A1 (de) * | 1981-02-24 | 1982-10-14 | Sandoz-Patent-GmbH, 7850 Lörrach | Neue ergolinderivate, deren herstellung und deren pharmazeutische zusammensetzungen |
| GB2112382B (en) * | 1981-11-06 | 1985-03-06 | Erba Farmitalia | Ergoline derivatives |
| DE3151912A1 (de) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue ergolin-aminoderivate, verfahren zu ihrer herstellung und deren verwendung als arzneimittel |
| DE3309493A1 (de) * | 1983-03-14 | 1984-09-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue ergolin-derivate, verfahren zu ihrer herstellung sowie verwendung als arzneimittel |
| DE3587860D1 (de) * | 1984-04-09 | 1994-07-28 | Schering Ag | 2-substituierte Ergolin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. |
| DE3528584A1 (de) * | 1985-08-06 | 1987-02-19 | Schering Ag | Neue 1-alkyl-ergolin-thioharnstoffderivate |
| DE3533675A1 (de) * | 1985-09-19 | 1987-03-26 | Schering Ag | Neue 12- und 13-brom-ergolinderivate |
| DE3533672A1 (de) * | 1985-09-19 | 1987-03-26 | Schering Ag | Neue 12- und 13-substituierte ergolinderivate |
-
1985
- 1985-09-19 DE DE19853533672 patent/DE3533672A1/de not_active Withdrawn
-
1986
- 1986-09-16 AU AU62731/86A patent/AU582275B2/en not_active Ceased
- 1986-09-18 DE DE8686730147T patent/DE3680986D1/de not_active Expired - Lifetime
- 1986-09-18 IE IE248686A patent/IE59340B1/en not_active IP Right Cessation
- 1986-09-18 AT AT86730147T patent/ATE66478T1/de active
- 1986-09-18 HU HU863990A patent/HU201548B/hu not_active IP Right Cessation
- 1986-09-18 EP EP86730147A patent/EP0220129B1/de not_active Expired - Lifetime
- 1986-09-18 CA CA000518527A patent/CA1289948C/en not_active Expired - Lifetime
- 1986-09-19 JP JP61219892A patent/JPH0717640B2/ja not_active Expired - Lifetime
- 1986-09-19 US US06/909,838 patent/US4863929A/en not_active Expired - Fee Related
- 1986-09-19 DK DK449986A patent/DK168487B1/da active
- 1986-09-19 ES ES8602018A patent/ES2003101A6/es not_active Expired
- 1986-09-19 CS CS866751A patent/CS261246B2/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU201548B (en) | 1990-11-28 |
| ATE66478T1 (de) | 1991-09-15 |
| IE59340B1 (en) | 1994-02-09 |
| EP0220129A3 (en) | 1987-08-05 |
| DE3680986D1 (de) | 1991-09-26 |
| DK449986A (da) | 1987-03-20 |
| DK449986D0 (da) | 1986-09-19 |
| HUT41782A (en) | 1987-05-28 |
| AU582275B2 (en) | 1989-03-16 |
| CA1289948C (en) | 1991-10-01 |
| CS261246B2 (en) | 1989-01-12 |
| CS675186A2 (en) | 1988-04-15 |
| EP0220129A2 (de) | 1987-04-29 |
| AU6273186A (en) | 1987-03-26 |
| EP0220129B1 (de) | 1991-08-21 |
| US4863929A (en) | 1989-09-05 |
| JPS6270373A (ja) | 1987-03-31 |
| JPH0717640B2 (ja) | 1995-03-01 |
| ES2003101A6 (es) | 1988-10-16 |
| DE3533672A1 (de) | 1987-03-26 |
| IE862486L (en) | 1987-03-19 |
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