NO143993B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMASOYTIC ACTIVE GUANIDINE DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMASOYTIC ACTIVE GUANIDINE DERIVATIVES Download PDFInfo
- Publication number
- NO143993B NO143993B NO762774A NO762774A NO143993B NO 143993 B NO143993 B NO 143993B NO 762774 A NO762774 A NO 762774A NO 762774 A NO762774 A NO 762774A NO 143993 B NO143993 B NO 143993B
- Authority
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- Norway
- Prior art keywords
- bicyclo
- formula
- hept
- exo
- radical
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 7
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 33
- 239000007858 starting material Substances 0.000 claims description 23
- -1 cyclohexyl- Chemical group 0.000 claims description 21
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 150000002357 guanidines Chemical class 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- 241000709661 Enterovirus Species 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 13
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 5
- 229940101209 mercuric oxide Drugs 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- QMBYPRSCPXSELE-UHFFFAOYSA-N 1-(1-adamantyl)-3-(4-chlorophenyl)thiourea Chemical compound C1=CC(Cl)=CC=C1NC(=S)NC1(C2)CC(C3)CC2CC3C1 QMBYPRSCPXSELE-UHFFFAOYSA-N 0.000 description 3
- MZZVFXMTZTVUFO-UHFFFAOYSA-N 1-chloro-4-isothiocyanatobenzene Chemical compound ClC1=CC=C(N=C=S)C=C1 MZZVFXMTZTVUFO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000005180 public health Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 2
- ASHRQSXKUANWOC-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-cyclohexylthiourea Chemical compound C1=CC(Cl)=CC=C1NC(=S)NC1CCCCC1 ASHRQSXKUANWOC-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010039105 Rhinoviral infections Diseases 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- 230000008722 morphological abnormality Effects 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ISJBQSJDQZLCSF-UHFFFAOYSA-N (4-chlorophenyl)azanium;chloride Chemical compound [Cl-].[NH3+]C1=CC=C(Cl)C=C1 ISJBQSJDQZLCSF-UHFFFAOYSA-N 0.000 description 1
- GKFFFNUVYUGXEW-UHFFFAOYSA-N (4-chlorophenyl)cyanamide Chemical compound ClC1=CC=C(NC#N)C=C1 GKFFFNUVYUGXEW-UHFFFAOYSA-N 0.000 description 1
- UWQWPBFCCCMRRV-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-cyclohexylguanidine Chemical compound C1=CC(Cl)=CC=C1NC(=N)NC1CCCCC1 UWQWPBFCCCMRRV-UHFFFAOYSA-N 0.000 description 1
- VITGOPDLKOHBNZ-UHFFFAOYSA-N 2-(1-adamantyl)-1-(4-chlorophenyl)guanidine Chemical compound C1=CC(Cl)=CC=C1NC(=N)NC1(C2)CC(C3)CC2CC3C1 VITGOPDLKOHBNZ-UHFFFAOYSA-N 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical group C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 206010061494 Rhinovirus infection Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910003439 heavy metal oxide Inorganic materials 0.000 description 1
- LFXAECSQJSRSTP-UHFFFAOYSA-N hydron;methyl carbamimidothioate;iodide Chemical compound I.CSC(N)=N LFXAECSQJSRSTP-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229910000464 lead oxide Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- IATJWQHWZUYXGC-UHFFFAOYSA-N nonane;hydrochloride Chemical compound Cl.CCCCCCCCC IATJWQHWZUYXGC-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940117953 phenylisothiocyanate 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
- 239000006187 pill Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- QXKXDIKCIPXUPL-UHFFFAOYSA-N sulfanylidenemercury Chemical compound [Hg]=S QXKXDIKCIPXUPL-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000003253 viricidal effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61P31/12—Antivirals
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Description
Denne oppfinnelse vedrører analogifremgangsmåte for This invention relates to analog method for
fremstilling av nye guanidinderivater som har antivirale egenskaper. preparation of new guanidine derivatives that have antiviral properties.
I henhold til oppfinnelsen er det tilveiebragt analogifremgangsmåte for fremstilling av et guanidinderivat med formelen: According to the invention, there is provided an analogous method for the production of a guanidine derivative with the formula:
hvor R1 er et cykloheksyl-, adamantyl^, bicyklo[2,2,1]heptanyl-, bicyklo[2,2,l]hept-5-enyl-, tricyklo[2,2,1,0<2>'<6>]heptanyl- eller tetracyklo[4,3,0,0 2 ' 4 ,0 3 ' 7 ]nonanyl-radikal, og R 2 er et fenyl-eller pyridylradikal som eventuelt er substituert med 1 eller 2 substituenter valgt fra halogenatomer, alkyl- og cyanoalkylradikaler med 1 til 6 karbonatomer, alkoksykarbonylradikaler med 2 til 6 karbonatomer og aminoradikaler, og de farmasøytisk akseptable syreaddisjonssalter derav. where R 1 is a cyclohexyl-, adamantyl^, bicyclo[2,2,1]heptanyl-, bicyclo[2,2,1]hept-5-enyl-, tricyclo[2,2,1,0<2>'< 6>]heptanyl or tetracyclo[4,3,0,0 2 ' 4 ,0 3 ' 7 ]nonanyl radical, and R 2 is a phenyl or pyridyl radical which is optionally substituted with 1 or 2 substituents selected from halogen atoms, alkyl and cyanoalkyl radicals of 1 to 6 carbon atoms, alkoxycarbonyl radicals of 2 to 6 carbon atoms and amino radicals, and the pharmaceutically acceptable acid addition salts thereof.
Formlene, ved 3-dimensjonal fremstilling, for adamantyl- (II), bicyklo[2,2,l]heptanyl- (III), bicyklbt2,2,l]hept-5-enyl- (IV), tricyklo[2,2,l,0<2>,<6>]heptanyl- (V) og tetracyklo[4,3,0,0<2>'<4>,0<3>'<7>]-nonanyl- (VI) radikalene, er følgende: The formulas, in 3-dimensional representation, for adamantyl- (II), bicyclo[2,2,1]heptanyl- (III), bicyclbt2,2,1]hept-5-enyl- (IV), tricyclo[2,2 ,1,0<2>,<6>]heptanyl-(V) and tetracyclo[4,3,0,0<2>'<4>,0<3>'<7>]-nonanyl-(VI) the radicals, are the following:
Tilknytningspunktet til radikalene II, III, IV, V eller VI kan være ved hvilken som helst av de viste nummererte stillinger, hvorav noen er identiske med hverandre, og kan være i hvilken som helst av de mulige stereokjemiske konfigurasjoner. For eksempel kan bindingene i stillingene 2, 3, 5 eller 6 i formel III, stillingene 5 eller 6 i formel IV, stillingene 3 eller 5 i formel V og stillingene 8 eller 9 i formel VI ha enten exo- eller endo-konfigurasjon, det vil si de kan være henholdsvis cis eller trans med hensyn til bro-stillingen (7 i formlene III, IV og V og 5 i formel VI). The point of attachment to radicals II, III, IV, V or VI may be at any of the numbered positions shown, some of which are identical to each other, and may be in any of the possible stereochemical configurations. For example, the bonds at positions 2, 3, 5 or 6 of formula III, positions 5 or 6 of formula IV, positions 3 or 5 of formula V and positions 8 or 9 of formula VI may have either exo or endo configuration, the that is, they can be respectively cis or trans with respect to the bridging position (7 in formulas III, IV and V and 5 in formula VI).
Man vil se at når R<1> er et bicyklot2,2,l]heptanyl-, bicyklo[2,2,l]hept-5-enyl-, tricyklo[2,2,1,0<2>'<6>]heptanyl- eller tetracyklo[4,3,0,0 2 ' 4 ,0 3 ' 7]nonanyl-radikal og molekylet ikke inneholder noe symmetriplan, vil guanidinderivatet fremstilt i henhold til oppfinnelsen inneholde et optisk aktivt senter og kan derfor oppspaltes i to optiske enantiomere former. Det skal forstås, at i slike tilfeller omfatter denne oppfinnelse den racemiske form og begge optisk aktive enantiomerer av et slikt derivat. It will be seen that when R<1> is a bicyclo2,2,1]heptanyl-, bicyclo[2,2,1]hept-5-enyl-, tricyclo[2,2,1,0<2>'<6 >]heptanyl or tetracyclo[4,3,0,0 2 ' 4 ,0 3 ' 7]nonanyl radical and the molecule contains no plane of symmetry, the guanidine derivative produced according to the invention will contain an optically active center and can therefore be split into two optical enantiomeric forms. It should be understood that in such cases this invention encompasses the racemic form and both optically active enantiomers of such a derivative.
Spesielle grupper av forbindelser fremstilt i henhold til Special groups of compounds prepared according to
- oppfinnelsen, som er innenfor.ovennevnte definisjon, er følgende: De hvor R"*" er et adamantyl-, bicyklo [ 2, 2 ,1 ]heptanyl-, bicyklo[2,2,l]hept-5-enyl- eller tricyklot2,2,1,0<2>'<6>]heptanyl-radikal. - the invention, which is within the above definition, is the following: Those where R"*" is an adamantyl, bicyclo[2,2,1]heptanyl, bicyclo[2,2,1]hept-5-enyl or tricyclo2,2,1,0<2>'<6>]heptanyl radical.
De hvor R er et cykloheksyl-, adamant-l-yl-, exo-bicyklo[2,2,l]heptan-2-yl-, endo-bicyklo[2,2,1]heptan-2-yl-, exo-bicyklo[2,2,1]hept-5-en-2-yl-, tricyklo[2,2,1,0<2>'<6>]heptan-3-yl-eller tetracyklo[4,3,0,0<2>'<4>,0<3>'<7>]nonan-8-yl-radikal, og R<2> er et pyridylradikal eller et fenylradikal som eventuelt er substituert med 1 eller 2 fluoratomer, med et klor- eller bromatom, eller med et metyl-, cyanometyl-, metoksykarbonyl- eller amino-radikal. Those where R is a cyclohexyl-, adamant-1-yl-, exo-bicyclo[2,2,1]heptan-2-yl-, endo-bicyclo[2,2,1]heptan-2-yl-, exo -bicyclo[2,2,1]hept-5-en-2-yl-, tricyclo[2,2,1,0<2>'<6>]heptan-3-yl-or tetracyclo[4,3, 0,0<2>'<4>,0<3>'<7>]nonan-8-yl radical, and R<2> is a pyridyl radical or a phenyl radical optionally substituted with 1 or 2 fluorine atoms, with a chlorine or bromine atom, or with a methyl, cyanomethyl, methoxycarbonyl or amino radical.
De hvor R^" er i exo-konf iguras jon. Those where R^" is in exo-conf iguras ion.
2 2
De hvor R bærer en eventuell substituent. Those where R carries a possible substituent.
De hvor R"<*>" er et exo-bicyklo [ 2 , 2 ,1 ] hept-5-en-2-yl- eller exo[2,2,1]heptan-2-yl-radikal og R 2et eventuelt substituert fenylradikal. Those where R"<*>" is an exo-bicyclo[2,2,1]hept-5-en-2-yl or exo[2,2,1]heptan-2-yl radical and R 2 is optionally substituted phenyl radical.
De hvor R"<*>" er et exo-bicyklo[2,2,1]hept-5-en-2-yl-radikal og R 2 et fenylradikal som bærer en enkelt eventuell substituent, som for eksempel kan være i 4-stillingen og som for eksempel kan være et fluor-, klor- eller bromatom. Those where R"<*>" is an exo-bicyclo[2,2,1]hept-5-en-2-yl radical and R 2 a phenyl radical bearing a single optional substituent, which can for example be in 4 -position and which can, for example, be a fluorine, chlorine or bromine atom.
Spesielle forbindelser fremstilt i henhold til oppfinnelsen er beskrevet i eksemplene og av disse er 2-exo-[3-(p-klorfenyl)-guanidino]bicyklo[2,2,1]hept-5-en og de farmasøytisk akseptable syreaddisjonssalter derav foretrukne forbindelser. Special compounds produced according to the invention are described in the examples and of these 2-exo-[3-(p-chlorophenyl)-guanidino]bicyclo[2,2,1]hept-5-ene and the pharmaceutically acceptable acid addition salts thereof are preferred connections.
Et egnet farmasøytisk akseptabelt syreaddisjonssalt A suitable pharmaceutically acceptable acid addition salt
av guanidinderivatet fremstilt i henhold til oppfinnelsen, er for eksempel et hydroklorid, fosfat eller sulfat eller et citrat, acetat, succinat eller fumarat. of the guanidine derivative produced according to the invention, is for example a hydrochloride, phosphate or sulphate or a citrate, acetate, succinate or fumarate.
De nye guanidinderivater med formel I fremstilles The new guanidine derivatives of formula I are prepared
i henhold til oppfinnelsen ved: according to the invention by:
(a) omsetning av et tiourinstoff med formelen: eller et tiouroniumsalt derav, med ammoniakk i nærvær av en katalysator; (b) omsetning av et cyanamid med formelen R^-NHCN eller R 2 NHCN med et amin med henholdsvis formelen R 2-NI^ eller R<1->NH2; (c) omsetning av et karbodiimid med formelen: (a) reaction of a thiourea of the formula: or a thiouronium salt thereof, with ammonia in the presence of a catalyst; (b) reacting a cyanamide of the formula R 2 -NHCN or R 2 NHCN with an amine of the formula R 2 -NI 2 or R<1->NH 2 respectively; (c) reacting a carbodiimide of the formula:
med ammoniakk; eller with ammonia; or
(d) for de forbindelser hvor R"*" er et cykloheksyl- eller bicyklo[2,2,1]heptanylradikal, reduksjon av en forbindelse med formelen (d) for those compounds where R"*" is a cyclohexyl or bicyclo[2,2,1]heptanyl radical, reduction of a compound of the formula
hvor R 3 er et cykloheksenyl- eller bicyklo[2,2,1]heptenylradikal. where R 3 is a cyclohexenyl or bicyclo[2,2,1]heptenyl radical.
1 2 1 2
I hvert av alternativene a) - d) har R og R de inn-ledningsvis angitte betydninger. In each of the alternatives a) - d) R and R have the meanings indicated at the beginning.
Eventuelt oppspaltes den racemiske forbindelse med formel I i sine optisk aktive isomerer. Eventuelt omdannes de fremstilte forbindelser til syreaddisjonssaltene derav. Optionally, the racemic compound of formula I is split into its optically active isomers. Optionally, the compounds produced are converted to their acid addition salts.
Fremgangsmåte (a) blir fortrinnsvis utført i et fortynningsmiddel eller oppløsningsmiddel, så som etanol. En foretrukket katalysator for anvendelse ved fremgangsmåten, er et tungmetalloksyd, for eksempel gult merkurioksyd eller blyoksyd, og omsetningen blir fortrinnsvis utført ved en temperatur mellom 0 og 100°C eller ved kokepunktet til fortynningsmidlet eller opp-løsningsmidlet, det som er lavest. Anvendelse av en temperatur over romtemperatur kan nødvendiggjøre konstant tilsetning av ammoniakk i form av en gass-strøm. Tiouroniumsaltet anvendt som eventuelt utgangsmateriale, kan ha formelen: Method (a) is preferably carried out in a diluent or solvent, such as ethanol. A preferred catalyst for use in the method is a heavy metal oxide, for example yellow mercury oxide or lead oxide, and the reaction is preferably carried out at a temperature between 0 and 100°C or at the boiling point of the diluent or solvent, whichever is the lowest. Use of a temperature above room temperature may necessitate the constant addition of ammonia in the form of a gas stream. The thiouronium salt used as possible starting material can have the formula:
hvor R 4 er et alkylradikal med 1 til 4 karbonatomer, for eksempel where R 4 is an alkyl radical with 1 to 4 carbon atoms, for example
et metylradikal, og X er et anion, for eksempel et halogenid-anion, så som et klorid-, bromid- eller jodid-anion. a methyl radical, and X is an anion, for example a halide anion, such as a chloride, bromide or iodide anion.
Fremgangsmåte (b) kan utføres i nærvær eller fravær av et fortynningsmiddel eller oppløsningsmiddel ved en temperatur på mellom 50 og 250°C, idet den øvre grense er begrenset til kokepunktet for det eventuelle fortynnings- eller oppløsningsmiddel. Et egnet eventuelt fortynnings- eller oppløsningsmiddel er for eksempel n-butanol. Amin-komponenten ved omsetningen blir fortrinnsvis anvendt i form av et salt, for eksempel et hydroklorid. Method (b) can be carried out in the presence or absence of a diluent or solvent at a temperature of between 50 and 250°C, the upper limit being limited to the boiling point of the possible diluent or solvent. A suitable diluent or solvent is, for example, n-butanol. The amine component in the reaction is preferably used in the form of a salt, for example a hydrochloride.
Fremgangsmåte (c) kan utføres under de samme forhold som fremgangsmåte (a), selv om det selvsagt ikke er nødvendig med noen katalysator. Method (c) can be carried out under the same conditions as method (a), although of course no catalyst is necessary.
Fremgangsmåte (d) kan utføres ved anvendelse av hydrogen Method (d) can be carried out using hydrogen
i et fortynnings- eller oppløsningsmiddel, for eksempel etanol, in a diluent or solvent, such as ethanol,
i nærvær av en katalysator, for eksempel en palladium-på-trekull-katalysator så som f.eks. en 5%ig vekt/vekt palladium-på-trekull-katalysator. Hydrogenet kan være ved atmosfæretrykk eller ved et trykk på opptil 5 atmosfærer. in the presence of a catalyst, for example a palladium-on-charcoal catalyst such as e.g. a 5% w/w palladium-on-charcoal catalyst. The hydrogen can be at atmospheric pressure or at a pressure of up to 5 atmospheres.
Oppspaltingen i isomerer kan for eksempel utføres The splitting into isomers can be carried out, for example
ved fraksjonert krystallisasjon av et salt av det racemiske derivat med formel I med en optisk aktiv syre, for eksempel (+)- eller (-)-mandelsyre eller (+)-0,O-dibenzoylvinsyre. by fractional crystallization of a salt of the racemic derivative of formula I with an optically active acid, for example (+)- or (-)-mandelic acid or (+)-0,O-dibenzoyltartaric acid.
Utgangsmaterialet med formel VII for anvendelse ved fremgangsmåte (a) kan erholdes ved omsetning av et amin med formelen The starting material with formula VII for use in method (a) can be obtained by reacting an amine with the formula
R 2 -NH_ eller R 1-NH_ med et isotiocyanat med henholdsvis formelen R 1 -NCS eller R 2-NCS. Isotiocyanatet selv kan erholdes ved omsetning av et amin med formelen R 1 -NH- eller R 2-NH„ med tiofosgen. R 2 -NH_ or R 1-NH_ with an isothiocyanate of the formula R 1 -NCS or R 2-NCS, respectively. The isothiocyanate itself can be obtained by reacting an amine with the formula R 1 -NH- or R 2-NH„ with thiophosgene.
Utgangsmaterialet med formelen R 1-NHCN for anvendelse ved fremgangsmåte (b) kan erholdes ved omsetning av en forbindelse med formelen R<1->NCS med ammoniakk for å oppnå tiourinstoff The starting material with the formula R 1-NHCN for use in method (b) can be obtained by reacting a compound with the formula R<1->NCS with ammonia to obtain thiourea
som så omsettes med gult merkurioksyd for å gi det ønskede produkt, eller ved omsetning av et amin med formelen R<1->NH2 med cyanogen-bromid. which is then reacted with yellow mercuric oxide to give the desired product, or by reacting an amine of the formula R<1->NH2 with cyanogen bromide.
Utgangsmaterialet med formelen VIII for anvendelse ved fremgangsmåte (c) kan erholdes ved omsetning av en forbindelse med formel VII med trifenylfosfin i nærvær av karbontetraklorid og trietylamin. The starting material of formula VIII for use in method (c) can be obtained by reacting a compound of formula VII with triphenylphosphine in the presence of carbon tetrachloride and triethylamine.
De nye forbindelsene fremstilt i henhold til oppfinnelsen har antiviral aktivitet, og de er spesielt aktive mot rhinoviruser, som for eksempel bebor og formerer seg i de øvre åndedrettsorganer på varmblodsdyr, innbefattet mennesker. Denne aktivitet blir vist ved en vev-kultur-prøve med menneskelige embryo-lungeceller, hvorved det kan vises at forbindelsene inhiberer voksteren av minst 16 forskjellige rhinoviruser ved en konsentrasjon som ikke frembringer noen morfologiske abnormiteter på vev-kultur-cellene. Alle de forbindelser som det er gitt eksempler på i beskrivelsen, er 50% aktive mot rhinovirus type 2 ved eller under en konsentrasjon på 5 yg/ml, mens de ikke frembringer noen morfologiske abnormiteter i sammenflytende monoskikt av vev-kultur-celler ved en konsentrasjon på minst 4 ganger den aktive dose. Således er for eksempel en forbindelse fremstilt i henhold til oppfinnelsen, 2-exo-[3-(p-fluorfenyl)guanidino]bicyklo[2,2,l]hept-5-en, 50% aktiv mot rhinovirus type 2 ved en konsentrasjon på 0,02 yg/ml, mens den forårsaker at 50% av cellene i vevkultur-platen viser abnormiteter bare ved en konsentrasjon på 2 5 yg/ml, og dette er et terapeutisk forhold på 1250. The new compounds produced according to the invention have antiviral activity, and they are particularly active against rhinoviruses, which for example inhabit and multiply in the upper respiratory organs of warm-blooded animals, including humans. This activity is shown by a tissue culture test with human embryo lung cells, whereby it can be shown that the compounds inhibit the growth of at least 16 different rhinoviruses at a concentration that does not produce any morphological abnormalities on the tissue culture cells. All of the compounds exemplified in the specification are 50% active against rhinovirus type 2 at or below a concentration of 5 µg/ml, while producing no morphological abnormalities in confluent monolayers of tissue culture cells at a concentration of at least 4 times the active dose. Thus, for example, a compound prepared according to the invention, 2-exo-[3-(p-fluorophenyl)guanidino]bicyclo[2,2,1]hept-5-ene, is 50% active against rhinovirus type 2 at a concentration of 0.02 yg/ml, whereas it causes 50% of the cells in the tissue culture plate to show abnormalities only at a concentration of 25 yg/ml, and this is a therapeutic ratio of 1250.
En forbindelse fremstilt i henhold til oppfinnelsen kan innlemmes som aktiv bestanddel i en farmasøytisk blanding med det formål å behandle en rhinovirus-infeksjon i varmblodsdyr. På grunn av at dens antivirale spektrum har en sterkt selektiv natur, kan en forbindelse fremstilt i henhold til oppfinnelsen også anvendes ved diagnostiske studier og i offentlige helselaboratorier for selektivt å inhibere voksteren av rhinoviruser, mens den tillater at andre viruser, så som enterovirusene, arborvirusene, myxovirusene og DNA-holdige viruser, mot hvilke forbindelsen fremstilt i henhold til oppfinnelsen ikke har noen virkning, formerer seg normalt i vev-kulturen.. A compound produced according to the invention can be incorporated as an active ingredient in a pharmaceutical mixture for the purpose of treating a rhinovirus infection in warm-blooded animals. Because its antiviral spectrum has a highly selective nature, a compound prepared according to the invention can also be used in diagnostic studies and in public health laboratories to selectively inhibit the growth of rhinoviruses, while allowing other viruses, such as the enteroviruses, the arborviruses , the myxoviruses and DNA-containing viruses, against which the compound produced according to the invention has no effect, multiply normally in the tissue culture.
Ved anvendelse i varmblodsdyr for å frembringe den ønskede effekt, er det ønskelig med en daglig oral dose på fra 1 til 15 mg/kg av en forbindelse fremstilt i henhold til oppfinnelsen. Ved anvendelse på mennesker er dette ekvivalent med en daglig dose på mellom 70 mg og 1 g. Til mennesker er det foretrukket med en daglig dose på mellom 70 og 250 mg som gis i oppdelte doser. Til-mennesker er det ønskelig med en daglig nasal dose på 1 til 12 5 yg, og det er foretrukket med 1 til 25 yg. When used in warm-blooded animals to produce the desired effect, a daily oral dose of from 1 to 15 mg/kg of a compound produced according to the invention is desirable. When applied to humans, this is equivalent to a daily dose of between 70 mg and 1 g. For humans, a daily dose of between 70 and 250 mg given in divided doses is preferred. For humans, a daily nasal dose of 1 to 125 yg is desirable, and 1 to 25 yg is preferred.
En forbindelse fremstilt i henhold til oppfinnelsen kan anvendes i form av en farmasøytisk blanding som som aktiv bestanddel omfatter et guanidinderivat i henhold til oppfinnelsen sammen med et farmasøytisk akseptabelt fortynningsmiddel eller en bærer. A compound produced according to the invention can be used in the form of a pharmaceutical mixture which as active ingredient comprises a guanidine derivative according to the invention together with a pharmaceutically acceptable diluent or a carrier.
Den farmasøytiske blanding med en forbindelse fremstilt i henhold til oppfinnelsen kan være i form av konvensjonelle tabletter, terninger, kapsler, vandige eller oljeaktige oppløsninger eller suspensjoner, emulsjoner, nesedråper, spray, aerosol (enten våt eller tørr-pulver) eller inhalgeringsmidler, og de kan fremstilles ved konvensjonelle teknikker og innlemme konvensjonelle inerte formgivningsmidler. The pharmaceutical mixture with a compound produced according to the invention can be in the form of conventional tablets, cubes, capsules, aqueous or oily solutions or suspensions, emulsions, nasal drops, sprays, aerosols (either wet or dry powder) or inhalants, and the can be produced by conventional techniques and incorporate conventional inert forming agents.
Foretrukne blandinger med forbindelser fremstilt i henhold til oppfinnelsen, er slike som frembringer en virucidal mengde av guanidinderivatet fremstilt i henhold til oppfinnelsen i de deler av kroppen hvor rhinoviruser vanligvis vokser, for eksempel i slimet i nese, strupe, munn og bronkier, enten ved direkte applikasjon av blandingen til slike deler eller indirekte ved å frembringe en tilstrekkelig mengde av guanidinderivatet i blodet efter oral administrasjon. Preferred mixtures with compounds prepared according to the invention are those which produce a virucidal amount of the guanidine derivative prepared according to the invention in the parts of the body where rhinoviruses usually grow, for example in the mucus of the nose, throat, mouth and bronchi, either by direct application of the mixture to such parts or indirectly by producing a sufficient amount of the guanidine derivative in the blood after oral administration.
Slike foretrukne blandinger for direkte applikasjon er Such preferred compositions for direct application are
for eksempel terninger som kan oppløses sakte i munnen for å bade munnen og tilknyttede ganger med en oppløsning av den aktive bestanddel, nasale sprayer eller våte aerosoler i form av en opp-løsning eller suspensjon av guanidin-derivatet i en inert farmasøytisk akseptabel væske eller en tørr pulver-aerosol som inneholder et guanidinderivat fremstilt i henhold til oppfinnelsen i finpulverisert form, og hvilke som helst av disse kan inhaleres for example, cubes that can be dissolved slowly in the mouth for bathing the mouth and associated passages with a solution of the active ingredient, nasal sprays or wet aerosols in the form of a solution or suspension of the guanidine derivative in an inert pharmaceutically acceptable liquid or a dry powder aerosol containing a guanidine derivative prepared according to the invention in finely powdered form, any of which can be inhaled
og avsettes i de nasale og bronkiale ganger, og foretrukne blandinger for oral administrering er f.eks. tabletter. and is deposited in the nasal and bronchial passages, and preferred mixtures for oral administration are e.g. pills.
En egnet tablett eller terning inneholder fra 2 5 til 100 mg med antiviral forbindelse fremstilt i henhold til oppfinnelsen, A suitable tablet or cube contains from 25 to 100 mg of antiviral compound prepared according to the invention,
og den normale kur for forebyggelse eller behandling av en rhinoviral infeksjon er en tablett 2 til 4 ganger pr. dag. and the normal regimen for the prevention or treatment of a rhinoviral infection is one tablet 2 to 4 times a day. day.
En egnet nasal spray eller aerosol inneholder fra 5 til A suitable nasal spray or aerosol contains from 5 to
50 yg av en antiviral forbindelse fremstilt i henhold til oppfinnelsen pr. ml oppløsning eller suspensjon, og for forebygging eller behandling av en rhinoviral infeksjon blir ca. 0,01 ml av en slik oppløsning sprøytet inn i nesen på pasienten 3 til 6 ganger pr. dag. 50 yg of an antiviral compound produced according to the invention per ml of solution or suspension, and for the prevention or treatment of a rhinoviral infection, approx. 0.01 ml of such a solution injected into the nose of the patient 3 to 6 times per day.
Blandingene med forbindelser fremstilt i henhold til oppfinnelsen kan også inneholde andre kjente farmasøytisk nyttige forbindelser, for eksempel nasale antikongestive, antipyretiske eller antiseptiske midler. På grunn av at det antivirale spektrum til forbindelsene har sterkt selektiv natur, er forbindelsene fremstilt i henhold til oppfinnelsen også nyttige i sykehus og offentlige helsestasjoner for selektivt å inhibere voksteren av rhinovirus i vev-kulturer, og således kan andre viruser som kan være tilstede, påvises lettere. For eksempel kan kliniske prøver fra pasienter med sykdom i åndedrettsorganene dyrkes i nærvær av en forbindelse fremstilt i henhold til oppfinnelsen. Rhinoviruser vokser i de øvre åndedrettsorganer hos mennesker, og rhinoviruser vil derfor ofte være tilstede i slike prøver. Vokster av rhinovirus blir forhindret under inkubasjonen, men andre viruser som kan være tilstede, så som influensavirus, adenovirus og syncytial åndedrettsvirus, vokser ugenert. På lignende måte kan, i virke-feltet for offentlig helsestell, voksteren av rhinoviruser under-trykkes mens andre viruser så som enteroviruser, arborviruser, myxoviruser og DNA-holdige viruser, mot hvilke forbindelsene fremstilt i henhold til oppfinnelsen ikke har noen virkning, fortsetter å formere seg normalt i vev-kultur. The mixtures with compounds produced according to the invention may also contain other known pharmaceutically useful compounds, for example nasal anticongestive, antipyretic or antiseptic agents. Due to the fact that the antiviral spectrum of the compounds has a highly selective nature, the compounds prepared according to the invention are also useful in hospitals and public health centers to selectively inhibit the growth of rhinovirus in tissue cultures, and thus other viruses that may be present, is more easily detected. For example, clinical samples from patients with disease in the respiratory organs can be cultured in the presence of a compound prepared according to the invention. Rhinoviruses grow in the upper respiratory tract of humans, and rhinoviruses will therefore often be present in such samples. Growth of rhinovirus is prevented during incubation, but other viruses that may be present, such as influenza virus, adenovirus and respiratory syncytial virus, grow unhindered. Similarly, in the field of public health care, the growth of rhinoviruses can be suppressed while other viruses such as enteroviruses, arborviruses, myxoviruses and DNA-containing viruses, against which the compounds prepared according to the invention have no effect, continue to multiply normally in tissue culture.
Som et ytterligere alternativ tilveiebringer den evne som en forbindelse fremstilt i henhold til oppfinnelsen har til selektivt å inhibere voksteren av rhinoviruser i nærvær av andre viruser, et diagnostisk verktøy for rask identifisering av rhinoviruser der hvor det er en blandet virus-utbredelse. As a further alternative, the ability of a compound of the invention to selectively inhibit the growth of rhinoviruses in the presence of other viruses provides a diagnostic tool for the rapid identification of rhinoviruses where there is a mixed virus distribution.
Ved anvendelse blir en forbindelse fremstilt i henhold til oppfinnelsen tilsatt som en suspensjon eller oppløsning i et egnet fortynningsmiddel eller oppløsningsmiddel, som vanligvis er vann eller vev-kultur-mediet, til vev-kulturen som skal undersøkes. In use, a compound prepared according to the invention is added as a suspension or solution in a suitable diluent or solvent, which is usually water or the tissue culture medium, to the tissue culture to be examined.
Den endelige konsentrasjon av forbindelsen fremstilt i henhold til oppfinnelsen kan variere over et vidt område, men den ligger vanligvis i området på 0,04 til 4 5 pg/ml. Kulturen blir så inkubert i en passende tidsperiode ved en passende temperatur før under-søkelse med hensyn til viral vokster. The final concentration of the compound prepared according to the invention can vary over a wide range, but it is usually in the range of 0.04 to 45 pg/ml. The culture is then incubated for an appropriate period of time at an appropriate temperature before testing for viral growth.
Menneskelige embryoniske lunge-celler som vokser i Eagel's medium i glassrør på 101,6 mm x 12,7 mm ble for eksempel dobbelt-infisert med 100 TCD5Q av herpes simpleks type 1 virus og 100 TCD5^ med rhinoviruser type 2 og inkubert ved 33°C. To dager senere kunne man se at cellene var degenerert på grunn av vokster av virusene og kultur-fluidene viste seg ved infektivitets- For example, human embryonic lung cells growing in Eagel's medium in 101.6 mm x 12.7 mm glass tubes were double-infected with 100 TCD5Q of herpes simplex type 1 virus and 100 TCD5^ with rhinovirus type 2 and incubated at 33° C. Two days later it could be seen that the cells had degenerated due to growth of the viruses and the culture fluids showed by infectivity
titreringer å inneholde minst 100 ganger mer av hver virus enn den opprinnelige innpodning. titrations to contain at least 100 times more of each virus than the original inoculation.
Ved et parallelt forsøk ble det dannet et kultur-medium inneholdende 2-exo-[3-(p-klorfenyl)guanidino]bicyklo[2,2,l]hept-5-en med en konsentrasjon på 2,5 ug/ml. Dette medium ble satt til dobbelt infiserte celle-kulturer som ble inkubert ved 33°C i 2 dager, som ovenfor. Man kunne igjen se at cellene var degenerert på grunn av virus-vokster, men kultur-fluidene viste seg å inneholde bare en høy konsentrasjon av herpesvirus, idet voksteren av rhinovirus var blitt undertrykket. In a parallel experiment, a culture medium was formed containing 2-exo-[3-(p-chlorophenyl)guanidino]bicyclo[2,2,1]hept-5-ene with a concentration of 2.5 µg/ml. This medium was added to doubly infected cell cultures which were incubated at 33°C for 2 days, as above. One could again see that the cells had degenerated due to virus growth, but the culture fluids were found to contain only a high concentration of herpes virus, as the growth of rhinovirus had been suppressed.
Oppfinnelsen blir nå illustrert av de følgende eksempler hvori temperaturene er angitt i celsiusgrader. The invention is now illustrated by the following examples in which the temperatures are indicated in degrees Celsius.
Eksempel 1 Example 1
En oppløsning av 2-exo-[3-(p-fluorfenyl)tioureido]-bicyklo-[2,2,1]hept-5-en (2 g) i mettet etanolisk ammoniakk (60 ml) ble rørt ved romtemperatur sammen med gult merkurioksyd (1,74 g) i 16 timer. Reaksjonsblandingen ble kokt på et dampbad i 15 minutter for å avdrive overskudd av ammoniakk og koagulere den fine utfelning av merkurisulfid. Dette faste stoff ble filtrert ut, vasket med kokende etanol (10 ml) to ganger, og de forenede filtrater ble inndampet til tørrhet. Det faste residuum ble omkrystallisert fra etylacetat for å gi 2-exo[3-(p-fluorfenyl)guanidino]bicyklo[2,2,1 ] - hept-5-en, sm.p. 192-194°C. A solution of 2-exo-[3-(p-fluorophenyl)thioureido]-bicyclo-[2,2,1]hept-5-ene (2 g) in saturated ethanolic ammonia (60 ml) was stirred at room temperature with yellow mercuric oxide (1.74 g) for 16 hours. The reaction mixture was boiled on a steam bath for 15 minutes to drive off excess ammonia and coagulate the fine precipitate of mercury sulfide. This solid was filtered off, washed with boiling ethanol (10 mL) twice, and the combined filtrates were evaporated to dryness. The solid residue was recrystallized from ethyl acetate to give 2-exo[3-(p-fluorophenyl)guanidino]bicyclo[2,2,1]-hept-5-ene, m.p. 192-194°C.
Den som utgangsmateriale anvendte 2-exo[3-(p-fluorfenyl)-tioureido]bicyklo[2,2,1]hept-5-en kan fremstilles på følgende måte: The 2-exo[3-(p-fluorophenyl)-thioureido]bicyclo[2,2,1]hept-5-ene used as starting material can be prepared in the following way:
En oppløsning av p-fluoranilin (2,6 g) i 25 ml kloroform A solution of p-fluoroaniline (2.6 g) in 25 ml of chloroform
ble satt til 2-exo-isotiocyanatobicyklo[2,2,1]hept-5-en (3,0 g)og was added to 2-exo-isothiocyanatobicyclo[2,2,1]hept-5-ene (3.0 g) and
blandingen ble rørt ved romtemperatur i 16 timer. Blandingen ble så oppvarmet under tilbakeløpskjøling i 5 timer for å fullføre omsetningen, og ble så avkjølt, og det faste produkt ble filtrert ut, vasket med litt kald kloroform og tørket. Omkrystallisering fra toluen ga 2-exo-[3-(p-fluorfenyl)tioureidojbicyklo[2,2,1]-hept-5-en, sm.p. 201-203°C. the mixture was stirred at room temperature for 16 hours. The mixture was then heated under reflux for 5 hours to complete the reaction, then cooled, and the solid product was filtered off, washed with some cold chloroform and dried. Recrystallization from toluene gave 2-exo-[3-(p-fluorophenyl)thioureidobicyclo[2,2,1]-hept-5-ene, m.p. 201-203°C.
Eksempel 2 Example 2
Fremgangsmåten beskrevet i eksempel 1 ble gjentatt ved anvendelse av passende substituerte utgangsmaterialer, og man erholdt følgende forbindelser: The procedure described in Example 1 was repeated using suitably substituted starting materials, and the following compounds were obtained:
Utgangsmaterialene for ovennevnte fremgangsmåte ble erholdt ved gjentagelse av fremgangsmåten beskrevet i andre del av eksempel 1, ved anvendelse av et passende substituert anilin i stedet for p-fluoranilin som utgangsmateriale, og cykloheksan i stedet for kloroform som oppløsningsmiddel, og man erholdt følgende forbindelser: The starting materials for the above process were obtained by repeating the process described in the second part of Example 1, using a suitably substituted aniline instead of p-fluoroaniline as starting material, and cyclohexane instead of chloroform as solvent, and the following compounds were obtained:
Eksempel 3 Example 3
En oppløsning av 2-exo[3-(p-fluorfenyl)guanidino]-bicyklo-[2,2,l]hept-5-en (0,5 g) i etanol (25 ml) ble hydrogenert ved rom-' temperatur og trykk i nærvær av 5% vekt/vekt palladium-på-trekull (0,05 g) inntil det ikke ble tatt opp mer hydrogen. Blandingen ble riltrert og oppløsningsmidlet inndampét i vakuum. Det gjenværende faste stoff ble omkrystallisert fra etylacetat for å gi 2-exo-[3-(p-fluorfenyl)guanidino]bicyklo[2,2,ljheptan, sm.p. 186°C A solution of 2-exo[3-(p-fluorophenyl)guanidino]-bicyclo-[2,2,1]hept-5-ene (0.5 g) in ethanol (25 ml) was hydrogenated at room temperature and press in the presence of 5% w/w palladium-on-charcoal (0.05 g) until no more hydrogen was taken up. The mixture was filtered and the solvent evaporated in vacuo. The remaining solid was recrystallized from ethyl acetate to give 2-exo-[3-(p-fluorophenyl)guanidino]bicyclo[2,2,1heptane, m.p. 186°C
Eksempel 4 Example 4
Fremgangsmåten beskrevet i eksempel 3 ble gjentatt, ved anvendelse av passende substituerte utgangsmaterialer, og man erholdt følgende forbindelser: The procedure described in Example 3 was repeated, using suitably substituted starting materials, and the following compounds were obtained:
Eksempel 5 Example 5
En oppløsning av 1-(p-fluorfenyl)-3-(2-exo-bicyklo[2,2,1]-hept-5-enyl)-karbodiimid (0,9 g) i mettet etanolisk ammoniakk (10 ml) ble hensatt ved romtemperatur i 48 timer. Oppløsningsmidlet ble inndampét i vakuum fra suspensjonen, og det gjenværende faste stoff ble omkrystallisert fra etylacetat for å gi 2-exo-[3-(p- A solution of 1-(p-fluorophenyl)-3-(2-exo-bicyclo[2,2,1]-hept-5-enyl)-carbodiimide (0.9 g) in saturated ethanolic ammonia (10 ml) was set aside at room temperature for 48 hours. The solvent was evaporated in vacuo from the suspension, and the remaining solid was recrystallized from ethyl acetate to give 2-exo-[3-(p-
fluorfenyl)guanidino]bicyklot2,2,l]hept-5-en, sm.p. 194°C. fluorophenyl)guanidino]bicyclo2,2,1]hept-5-ene, m.p. 194°C.
Det som utgangsmateriale anvendte 1-(p-fluorfenyl)-3-(2-exo-bicyklo[2,2,l]hept-5-enyl)karbodiimid ble erholdt på følgende måte: Til en oppløsning av 2-exo-[3-(p-fluorfenyl)tioureido]-bicyklo[2,2,l]hept-5-en (1,55 g) i tørr metylenklorid (6 ml) ble satt karbontetraklorid (0,9 g), trietylamin (0,58 g) og trifenylfosfin (1,8 g). Blandingen ble oppvarmet til 40°C. Efter 20 minutter var det dannet en klar oppløsning. Efter ytterligere lh time ved 40°C var oppløsningen avkjølt. Oppløsningsmidlet ble fjernet ved inndampning og residuet ble ekstrahert med kald petrol-eter (k.p. 60-80°C, 3 x 10 ml). Ved inndampning av ekstraktet erholdt man det ønskede 1-(p-fluorfenyl)-3-(2-exo-bicyklo[2,2,1]-hept-5-enyl)karbodiimid som en gul olje, og det ble identifisert ved massespektrometri (masse-ion 228) og infrarød spektrometri (N=C=N svært sterk absorpsjon ved 2100 cm "*") , og ble anvendt uten ytterligere rensing. The 1-(p-fluorophenyl)-3-(2-exo-bicyclo[2,2,1]hept-5-enyl)carbodiimide used as starting material was obtained in the following way: To a solution of 2-exo-[3 -(p-fluorophenyl)thioureido]-bicyclo[2,2,1]hept-5-ene (1.55 g) in dry methylene chloride (6 ml) was added carbon tetrachloride (0.9 g), triethylamine (0.58 g) and triphenylphosphine (1.8 g). The mixture was heated to 40°C. After 20 minutes, a clear solution had formed. After a further 1 hour at 40°C, the solution had cooled. The solvent was removed by evaporation and the residue was extracted with cold petroleum ether (b.p. 60-80°C, 3 x 10 ml). Evaporation of the extract afforded the desired 1-(p-fluorophenyl)-3-(2-exo-bicyclo[2,2,1]-hept-5-enyl)carbodiimide as a yellow oil, which was identified by mass spectrometry (mass ion 228) and infrared spectrometry (N=C=N very strong absorption at 2100 cm "*"), and was used without further purification.
Eksempel 6 Example 6
Fremgangsmåten beskrevet i eksempel 1 ble gjentatt, ved anvendelse av 1-(3-p-klorfenyltioureido)adamantan som utgangsmateriale, og således erholdt man 1-[3-(p-klorfenyl)guanidino]-adamantan, sm.p. 19 6°C. The procedure described in example 1 was repeated, using 1-(3-p-chlorophenylthioureido)adamantane as starting material, and thus 1-[3-(p-chlorophenyl)guanidino]-adamantane was obtained, m.p. 19 6°C.
Det som utgangsmateriale anvendte 1-[3-(p-klorfenyl)-tioureido]adamantan erholdt man på følgende måte: Adskilte oppløsninger av 1-aminoadamantan (0,9 g) og p-klorfenylisotiocyanat (0,9 g) i kloroform (10 ml) ble blandet og rørt ved 20°C i 3 dager. Oppløsningsmidlet ble inndampét i vakuum, og det gjenværende faste stoff ble omkrystallisert fra toluen for å gi 1-[3-(p-klorfenyl)-tioureido]adamantan, sm.p. 185°C. The 1-[3-(p-chlorophenyl)-thioureido]adamantane used as starting material was obtained in the following way: Separate solutions of 1-aminoadamantane (0.9 g) and p-chlorophenyl isothiocyanate (0.9 g) in chloroform (10 ml) were mixed and stirred at 20°C for 3 days. The solvent was evaporated in vacuo and the remaining solid was recrystallized from toluene to give 1-[3-(p-chlorophenyl)-thioureido]adamantane, m.p. 185°C.
Eksempel 7 Example 7
Fremgangsmåten beskrevet i eksempel 1 ble gjentatt, ved anvendelse av passende substituerte utgangsmaterialer, og man erholdt følgende forbindelser: The procedure described in Example 1 was repeated, using suitably substituted starting materials, and the following compounds were obtained:
Fotnoter Footnotes
1. Omkrystallisert fra etylacetat. 1. Recrystallized from ethyl acetate.
2. Omkrystallisert fra toluen 2. Recrystallized from toluene
3. Hydroklorid, omkrystallisert fra isopropanol/etylacetat. 3. Hydrochloride, recrystallized from isopropanol/ethyl acetate.
Utgangsmaterialene for ovennevnte fremgangsmåte ble erholdt ved å gjenta fremgangsmåten beskrevet i andre del av eksempel 1, ved anvendelse av det passende substituerte anilin som utgangsmateriale i stedet for p-fluor-anilin, og cykloheksan i stedet for kloroform som oppløsningsmiddel, og man erholdt følgende forbindelser: The starting materials for the above process were obtained by repeating the process described in the second part of Example 1, using the appropriately substituted aniline as the starting material instead of p-fluoroaniline, and cyclohexane instead of chloroform as the solvent, and the following compounds were obtained :
Fotnoter Footnotes
1. Omkrystallisert fra toluen. 1. Recrystallized from toluene.
2. Omkrystallisert fra eter. 2. Recrystallized from ether.
3. Omkrystallisert fra etylacetat. 3. Recrystallized from ethyl acetate.
4. Anvendt uten ytterligere rensing. 4. Used without further purification.
Eksempel 8 Example 8
Fremgangsmåten beskrevet i eksempel 1 ble gjentatt, ved anvendelse av 2-exo-[3-(4-pyridyl)tioureido]bicyklo[2,2,l]hept-5-en-hydroklorid i stedet for 2-exo-[3-(p-fluorfenyl)tioureido]-bicyklo[2,2,1]hept-5-en. Man erholdt således 2-exo-[3-(4-pyridyl)-guanidino]bicyklo[2,2,1]hept-5-en som ble omdannet til dens hydroklorid-salt og omkrystallisert fra en blanding av etanol og etylacetat, og dette ga et produkt som smelter ved 282° med spaltning. The procedure described in Example 1 was repeated, using 2-exo-[3-(4-pyridyl)thioureido]bicyclo[2,2,1]hept-5-ene hydrochloride instead of 2-exo-[3- (p-Fluorophenyl)thioureido]-bicyclo[2,2,1]hept-5-ene. 2-exo-[3-(4-pyridyl)-guanidino]bicyclo[2,2,1]hept-5-ene was thus obtained, which was converted to its hydrochloride salt and recrystallized from a mixture of ethanol and ethyl acetate, and this gave a product melting at 282° with cleavage.
Utgangsmaterialet ble erholdt ved gjentagelse av fremgangsmåten beskrevet i andre del av eksempel 1, ved anvendelse av 4-amino-pyridin i stedet for p-fluoranilin og ved tilbakeløpskjøling i 3 dager i stedet for i 5 timer. Produktet ble isolert som^dets hydroklorid-salt og det hadde et smeltepunkt på 200-201°C. The starting material was obtained by repeating the procedure described in the second part of example 1, using 4-amino-pyridine instead of p-fluoroaniline and by refluxing for 3 days instead of 5 hours. The product was isolated as its hydrochloride salt and it had a melting point of 200-201°C.
Eksempel 9 Example 9
Fremgangsmåten i eksempel 1 ble gjentatt, ved anvendelse The procedure in Example 1 was repeated, by application
av 2-endo-(3-fenyltioureido)bicyklo[2,2,1]heptan som utgangsmateriale i stedet for 2-exo-[3-(p-fluorfenyl)tioureido]bicyklo[2,2,1]-hept-5-en. Man erholdt således 2-endo-(3-fenylguanidino)bicyklo-[2,2,1]heptan, sm.p. 132-133° ved omkrystallisering fra toluen. of 2-endo-(3-phenylthioureido)bicyclo[2,2,1]heptane as starting material instead of 2-exo-[3-(p-fluorophenyl)thioureido]bicyclo[2,2,1]-hept-5 -one. 2-endo-(3-phenylguanidino)bicyclo-[2,2,1]heptane was thus obtained, m.p. 132-133° by recrystallization from toluene.
Utgangsmaterialet kan fremstilles på følgende måte: The starting material can be produced in the following way:
En oppløsning av 2-endo-aminonorbornan i cykloheksan A solution of 2-endo-aminonorbornane in cyclohexane
(erholdt ved ekstrahering av en alkalisk oppløsning i vann av 2-endo-aminonorbornan-hydrobromid (1,5 g) med cykloheksan fulgt av tørking over vannfritt magnesiumsulfat) ble satt til en opp-løsning av fenylisotiocyanat (1,38 g) i cykloheksan og rørt i 10 timer ved romtemperatur. Det utfelte produkt ble utfiltrert, vasket med cykloheksan og så omkrystallisert fra cykloheksan for å gi 2-endo-(3-fenyltioureido)bicyklo[2,2,l]heptan, sm.p. 154°. (obtained by extracting an alkaline aqueous solution of 2-endo-aminonorbornane hydrobromide (1.5 g) with cyclohexane followed by drying over anhydrous magnesium sulfate) was added to a solution of phenyl isothiocyanate (1.38 g) in cyclohexane and stirred for 10 hours at room temperature. The precipitated product was filtered off, washed with cyclohexane and then recrystallized from cyclohexane to give 2-endo-(3-phenylthioureido)bicyclo[2,2,1]heptane, m.p. 154°.
Eksempel 10 Example 10
l-cykloheksyl-3-(p-klorfenyl)tiourinstoff (2,0 g) ble opp-løst i absolutt etylalkohol mettet med ammoniakk (40 ml). Dertil ble satt gult merkurioksyd (1,7 g) og blandingen ble rørt ved romtemperatur i 16 timer. Blandingen ble så tilbakeløpskjølt i 15 minutter for å koagulere den fine utfelning av merkurisulfid, blir så filtrert og det klare filtrat blir inndampét til tørrhet. Residuet ble omkrystallisert fra toluen for å gi l-cykloheksyl-3-(p-klorfenyl)guanidin, sm.p. 187-190°C. 1-cyclohexyl-3-(p-chlorophenyl)thiourea (2.0 g) was dissolved in absolute ethyl alcohol saturated with ammonia (40 ml). Yellow mercury oxide (1.7 g) was added thereto and the mixture was stirred at room temperature for 16 hours. The mixture was then refluxed for 15 minutes to coagulate the fine precipitate of mercuric sulphide, then filtered and the clear filtrate evaporated to dryness. The residue was recrystallized from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)guanidine, m.p. 187-190°C.
Utgangsmaterialet kan erholdes på følgende måte: Til en oppløsning av cykloheksylamin (1,75 g) i kloroform (15 ml) ble under omrøring dråpevis satt en oppløsning av p-klorfenylisotiocyanat (3,0 g) i kloroform (15 ml) ved romtemperatur. Efter røring i 3 timer ble det hvite faste stoff utfiltrert, The starting material can be obtained in the following way: To a solution of cyclohexylamine (1.75 g) in chloroform (15 ml) a solution of p-chlorophenyl isothiocyanate (3.0 g) in chloroform (15 ml) was added dropwise with stirring at room temperature. After stirring for 3 hours, the white solid was filtered out,
vasket med litt CHCl^ og omkrystallisert fra toluen for å gi 1-cykloheksyl-3-(p-klorfenyl)tiourinstoff, sm.p. 179-180°C. washed with a little CHCl^ and recrystallized from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)thiourea, m.p. 179-180°C.
Eksempel 11 Example 11
Til en oppløsning av 3-[3-(p-klorfenyl)tioureido]tricyklo [2,2,1,0 2 ' 6]heptan (0,25 g) i etanol mettet med ammoniakk (10 ml) ble det satt 0,2 g med gult merkurioksyd, og blandingen ble rørt ved romtemperatur i 16 timer. Det faste stoff ble frafiltrert og det klare filtrat ble inndampét til tørrhet. Det gjenværende faste stoff ble omkrystallisert fra toluen for å gi 3-[3-(p^klorfenyl)guanidino]tricyklo[2,2,1,0 2 ' 6 ]heptan, sm.p. 204-205 o. To a solution of 3-[3-(p-chlorophenyl)thioureido]tricyclo [2,2,1,0 2 ' 6]heptane (0.25 g) in ethanol saturated with ammonia (10 ml) was added 0, 2 g of yellow mercuric oxide, and the mixture was stirred at room temperature for 16 hours. The solid was filtered off and the clear filtrate was evaporated to dryness. The remaining solid was recrystallized from toluene to give 3-[3-(p-chlorophenyl)guanidino]tricyclo[2,2,1,0 2 ' 6 ]heptane, m.p. 204-205 etc.
Det som utgangsmateriale anvendte tiourinstoff kan fremstilles på følgende måte: 3-aminotricyklo[2,2,1,0 2 ' 6]heptan (21 g) (fremstilt som beskrevet i britisk patentskrift nr. 1.051.319) ble oppløst i kloroform (2 5 ml) og satt sakte, under 10°, til en omrørt oppløsning av tLofosgen (22 g) i kloroform (20 ml). Efter fullført tilsetning ble blandingen hensatt for å oppnå omgivelsenes temperatur og ble rørt i ytterligere 2 timer. Kloroformoppløsningen ble i rekkefølge vasket med 20 ml's porsjoner av vann, IN NaOH og igjen vann, og ble tørket over vannfritt MgS04 og filtrert og kloroformen ble avdampet i vakuum. Den gjenværende olje ble underkastet fraksjonert destillasjon i vakuum for å gi 3-isotiocyanatotricyklo[2,2,1,0 2 ' 6]-heptan, k.p. 70-76° ved et trykk på 0,4 mm Hg. The thiourea used as starting material can be prepared in the following way: 3-aminotricyclo[2,2,1,0 2 ' 6]heptane (21 g) (prepared as described in British patent document no. 1,051,319) was dissolved in chloroform (2 5 ml) and added slowly, below 10°, to a stirred solution of tLophosgene (22 g) in chloroform (20 ml). After the addition was complete, the mixture was allowed to reach ambient temperature and was stirred for a further 2 hours. The chloroform solution was in order washed with 20 ml portions of water, 1N NaOH and again water, and was dried over anhydrous MgSO 4 and filtered and the chloroform was evaporated in vacuo. The remaining oil was subjected to fractional distillation in vacuo to give 3-isothiocyanatotricyclo[2,2,1,0 2 ' 6 ]-heptane, m.p. 70-76° at a pressure of 0.4 mm Hg.
Dette isocyanat (1,2 g) ble oppløst i kloroform (30 ml) og dertil ble det satt p-kloranilin (2,1 g). Sistnevnte ble hurtig oppløst og blandingen ble tilbakeløpskjølt i 3 timer. Den av-kjølte oppløsning ble ekstrahert med 2N HCl (10 ml), vasket med vann (10 ml) og tørket over vannfritt MgSO^. Efter filtrering ble oppløsningsmidlet inndampét i vakuum og det faste residuum ble omkrystallisert fra toluen for å gi 3-[3-(p-klorfenyl)tioureido]-tricyklo[2,2,l,0<2>,<6>]heptan, sm.p. 164-166°. This isocyanate (1.2 g) was dissolved in chloroform (30 ml) and p-chloroaniline (2.1 g) was added thereto. The latter was quickly dissolved and the mixture was refluxed for 3 hours. The cooled solution was extracted with 2N HCl (10 mL), washed with water (10 mL) and dried over anhydrous MgSO 4 . After filtration, the solvent was evaporated in vacuo and the solid residue was recrystallized from toluene to give 3-[3-(p-chlorophenyl)thioureido]-tricyclo[2,2,1,0<2>,<6>]heptane, sm.p. 164-166°.
Eksempel 12 Example 12
8-[3-(p-klorfenyl)tioureido]tetracyklo[4,3,0,0<2>'4,03'<7>]-nonan (0,30 g) ble oppløst i etanol mettet med ammoniakk (100 ml) ved romtemperatur og rørt sammen med gult merkurioksyd (0,43 g) 8-[3-(p-chlorophenyl)thioureido]tetracyclo[4,3,0,0<2>'4,03'<7>]-nonane (0.30 g) was dissolved in ethanol saturated with ammonia (100 ml) at room temperature and stirred with yellow mercuric oxide (0.43 g)
i 6 timer. Blandingen ble,så kokt i 15 minutter for å fjerne overskudd av ammoniakk, ble så filtrert og filtratet ble inndampét til tørrhet. Det faste residuum ble omkrystallisert fra toluen/ cykloheksan (1:2 volum/volum) for å gi 8-[3-(p-klorfenyl)-guanidino]tetracyklo!4,3,0,0<2>'<4>,03'7]nonan, sm.p. 170-171°. for 6 hours. The mixture was then boiled for 15 minutes to remove excess ammonia, then filtered and the filtrate evaporated to dryness. The solid residue was recrystallized from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)-guanidino]tetracyclo!4,3,0,0<2>'<4>, 03'7]nonane, m.p. 170-171°.
Det som utgangsmateriale anvendte tiourinstoff kan fremstilles på følgende måte: 8-aminotetracyklo[4,4,0,0 2 ' 4 ,0 3 ' 7]nonan-hydroklorid (0,5 g) The thiourea used as starting material can be prepared in the following way: 8-aminotetracyclo[4,4,0,0 2 ' 4 ,0 3 ' 7]nonane hydrochloride (0.5 g)
(fremstilt som beskrevet i britisk patentskrift nr. 1.180.749) ble oppløst i en blanding av kloroform (25 ml) og trietylamin (0,33 g). Til denne oppløsning ble det satt p-klorfenylisotiocyanat (0,5 g) og blandingen ble tilbakeløpskjølt i 16 timer. Kloroform-opp-løsningen ble efter avkjøling suksessivt vasket med 10 ml's porsjoner av 2N HCl, vann og mettet saltoppløsning, og ble så tørket over vannfritt MgSO^. Efter filtrering ble oppløsningsmidlet inndampét i vakuum og residuet ble omkrystallisert fra toluen/cykloheksan (1:2 volum/volum) for å gi 8-[3-(p-klorfenyl)tioureido]-tetracyklo[4,3,0,0<2>'<4>,0<3>'<7>]nonan, sm.p. 168-170°C (prepared as described in British Patent No. 1,180,749) was dissolved in a mixture of chloroform (25 ml) and triethylamine (0.33 g). To this solution was added p-chlorophenyl isothiocyanate (0.5 g) and the mixture was refluxed for 16 hours. After cooling, the chloroform solution was successively washed with 10 ml portions of 2N HCl, water and saturated salt solution, and was then dried over anhydrous MgSO 4 . After filtration, the solvent was evaporated in vacuo and the residue was recrystallized from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)thioureido]-tetracyclo[4,3,0,0<2 >'<4>,0<3>'<7>]nonane, m.p. 168-170°C
Eksempel 13 Example 13
2-endo-aminobicyklo[2,2,1]heptan-hydrobromid (0,96 g) ble intimt blandet med p-klorfenylcyanamid (0,76 g) og oppvarmet ved 200-220° i 15 minutter. Blandingen ble raskt flytende og den ble 2-endo-aminobicyclo[2,2,1]heptane hydrobromide (0.96 g) was intimately mixed with p-chlorophenylcyanamide (0.76 g) and heated at 200-220° for 15 minutes. The mixture quickly liquified and it stayed
rørt nå og da. Den ble hensatt til avkjøling og ble så behandlet med etylacetat (10 ml) og vann (5 ml) som oppløste residuet. Den organiske fase ble ekstrahert tre ganger med 5 ml vann hver gang. touched now and then. It was allowed to cool and then treated with ethyl acetate (10 ml) and water (5 ml) which dissolved the residue. The organic phase was extracted three times with 5 ml of water each time.
De vandige faser ble forenet og gjort basisk med vandig ION NaOH. The aqueous phases were combined and basified with aqueous ION NaOH.
Det utfelte faste stoff ble filtrert ut, vasket med vann, tørket The precipitated solid was filtered off, washed with water, dried
og viste seg ved t.l.c. å være rent guanidin. Etylacetat-skiktet viste seg ved t.l.c. fortsatt å inneholde det fordrede guanidin. and appeared at t.l.c. to be pure guanidine. The ethyl acetate layer appeared at t.l.c. still contain the required guanidine.
Det ble derfor ekstrahert med 2N NaOH (3x5 ml), tørket over vannfritt I^CO^f filtrert og inndampét og residuet ble omkrystallisert fra toluen for å gi 2-endo-[3-(p-klorfenyl)guanidino]-bicyklo[2,2,l]heptan, sm.p. 179-181°. It was therefore extracted with 2N NaOH (3x5 mL), dried over anhydrous I^CO^f filtered and evaporated and the residue recrystallized from toluene to give 2-endo-[3-(p-chlorophenyl)guanidino]-bicyclo[2 ,2,1]heptane, m.p. 179-181°.
Eksempel 14 Example 14
p-kloranilin-hydroklorid (1,25 g) ble oppløst i n-butanol p-Chloraniline hydrochloride (1.25 g) was dissolved in n-butanol
(10 ml) og oppvarmet til tilbakeløp. Det ble så sakte og dråpevis tilsatt en kald oppløsning av 2-exo-cyanamidobicyklo[2,2,i]hept-5-en i butanol (10 ml) slik at blandingen fortsatte med tilbake- (10 mL) and heated to reflux. A cold solution of 2-exo-cyanamidobicyclo[2,2,i]hept-5-ene in butanol (10 ml) was then added slowly and dropwise so that the mixture continued with reflux
løp. En time efter at tilsetningen var fullført ble blandingen avkjølt, butanol ble avdampet i vakuum og residuet ble oppløst i etylacetat (10 ml). Den organiske fase ble ekstrahert med vann , (4x5 ml). De forenede vandige faser ble bragt til en pH-verdi på 7 med vandig Na2C02~oppløsning og ble ekstrahert med eter. run. One hour after the addition was complete, the mixture was cooled, the butanol was evaporated in vacuo and the residue was dissolved in ethyl acetate (10 mL). The organic phase was extracted with water (4x5 ml). The combined aqueous phases were brought to a pH value of 7 with aqueous Na 2 CO 2 ~ solution and were extracted with ether.
Dette fjernet uomsatt p-kloranilin. Den gjenværende vandige fase This removed unreacted p-chloroaniline. The remaining aqueous phase
ble bragt til en pH-verdi på 12 med vandig ION NaOH, hvilket utfelte rent produkt. Det ble utfiltrert, vasket med vann, tørket og omkrystallisert fra etylacetat for å gi 2-exo-[3-(p-klorfenyl)-guanidino]bicyklo[2,2,1]hept-5-en, sm.p. 206-207°. was brought to a pH of 12 with aqueous ION NaOH, which precipitated pure product. It was filtered off, washed with water, dried and recrystallized from ethyl acetate to give 2-exo-[3-(p-chlorophenyl)-guanidino]bicyclo[2,2,1]hept-5-ene, m.p. 206-207°.
Det som utgangsmateriale anvendte 2-exo-cyanamidobicyklo-[2,2,1]hept-5-en kan erholdes på følgende måte: 2-exo-isotiocyanatobicyklo[2,2,l]hept-5-en (50 g) ble opp-løst i etanol (200 ml) og det ble tilsatt konsentrert vandig ammoniakk (S.G. 0,88, 10 ml). Denne blanding ble tilbakeløps-behandlet og det ble i løpet av 30 minutter dråpevis tilsatt ytterligere 50 ml med konsentrert vandig ammoniakk. Efter til-sammen 3 timers tilbakeløpsbehandling, ble oppløsningen avkjølt og det ønskede produkt krystalliserte ut for å gi 2-exo-tioureido-bicyklo[2,2,l]hept-5-en (50,35 g), sm.p. 158-159,5°. The 2-exo-cyanamidobicyclo[2,2,1]hept-5-ene used as starting material can be obtained in the following way: 2-exo-isothiocyanatobicyclo[2,2,1]hept-5-ene (50 g) was dissolved in ethanol (200 ml) and concentrated aqueous ammonia (S.G. 0.88, 10 ml) was added. This mixture was refluxed and a further 50 ml of concentrated aqueous ammonia was added dropwise over the course of 30 minutes. After refluxing for a total of 3 hours, the solution was cooled and the desired product crystallized out to give 2-exo-thioureido-bicyclo[2,2,1]hept-5-ene (50.35 g), m.p. 158-159.5°.
Dette tiourinstoff (1,0 g) ble oppløst i absolutt etanol This thiourea (1.0 g) was dissolved in absolute ethanol
(50 ml) ved romtemperatur og friskt fremstilt gult merkurioksyd (1,29 g) ble tilsatt. Blandingen ble rørt i 24 timer ved romtemperatur og det ble tilsatt en ytterligere porsjon av HgO (1,29 g). (50 mL) at room temperature and freshly prepared yellow mercuric oxide (1.29 g) was added. The mixture was stirred for 24 hours at room temperature and a further portion of HgO (1.29 g) was added.
Efter røring i ytterligere 48 timer ble de faste stoffer filtrert ut og vasket godt med etanol. Filtratet ble bragt til tørrhet i en roterende inndamper hvorved temperaturen ble holdt så lav som mulig. Det således erholdte 2-exo-cyanamidobicyklo[2,2,l]hept-5-en, som en svært lysebrun gummi, ble oppløst i kald n-butanol (10 ml) og anvendt øyeblikkelig. After stirring for a further 48 hours, the solids were filtered out and washed well with ethanol. The filtrate was brought to dryness in a rotary evaporator whereby the temperature was kept as low as possible. The 2-exo-cyanamidobicyclo[2,2,1]hept-5-ene thus obtained, as a very light brown gum, was dissolved in cold n-butanol (10 ml) and used immediately.
Eksempel 15 Example 15
2-exo-1 3-(p-klorfenyl)tioureido]bicyklo[2,2,1]hept-5-en (0,5 g) ble oppløst i etanol (10 ml), og jodmetan (0,255 g) ble tilsatt. Blandingen ble tilbakeløpsbehandlet i 3 timer hvorunder tiourinstoffet ble fullstendig omdannet til S-metyltiouroniumjodid. Blandingen ble avkjølt og så mettet med ammoniakk-gass. Blandingen ble tilbakeløpsbehandlet med gjennomføring av en konstant strøm av ammoniakk i 10 timer, ble avkjølt til romtemperatur, igjen mettet med ammoniakk og så hensatt i 3 dager. 2-exo-1 3-(p-chlorophenyl)thioureido]bicyclo[2,2,1]hept-5-ene (0.5 g) was dissolved in ethanol (10 mL), and iodomethane (0.255 g) was added . The mixture was refluxed for 3 hours during which the thiourea was completely converted to S-methylthiouronium iodide. The mixture was cooled and then saturated with ammonia gas. The mixture was refluxed with a constant flow of ammonia for 10 hours, cooled to room temperature, again saturated with ammonia and then allowed to stand for 3 days.
Oppløsningsmidlet ble avdampet og residuet ble tatt opp i etylacetat (10 ml). Det ble frafiltrert en uoppløselig del (ammoniumjodid), og den organiske fase ble ekstrahert med vann (4 x 10 ml). De samlede vandige ekstrakter ble gjort basisk med ION NaOH og utfelningen ble filtrert ut, vasket med vann og tørket. Efter omkrystallisering fra etylacetat erholdt man 2-exo-[3-(p-klorfenyl)guanidino]bicyklo[2,2,1]hept-5-en, sm.p. 202-203°. The solvent was evaporated and the residue was taken up in ethyl acetate (10 ml). An insoluble part (ammonium iodide) was filtered off, and the organic phase was extracted with water (4 x 10 ml). The combined aqueous extracts were basified with 1N NaOH and the precipitate was filtered off, washed with water and dried. After recrystallization from ethyl acetate, 2-exo-[3-(p-chlorophenyl)guanidino]bicyclo[2,2,1]hept-5-ene was obtained, m.p. 202-203°.
Eksempel 16 Example 16
En oppløsning av 2-exo-[3-(p-klorfenyl)guanidino]bicyklo-[2,2,1]hept-5-en (6,1 g) i varm etanol (75 ml) ble rørt mens det dråpevis ble tilsatt en oppløsning av (+)-mandelsyre (3,54 g) i varm etanol (25 ml). Blandingen ble hensatt for å avkjøles sakte i løpet av 16 timer, og da ble utfelningen filtrert ut, så rørt sammen med 10 ml etanol og filtrert på nytt. De to filtratene ble forenet og tatt vare på. Det utfUtrerte faste stoff ble omkrystallisert 3 ganger fra etanol, og hadde da et smeltepunkt på 159-162°. Dette faste stoff ble rørt sammen med 2N NaOH (20 ml) A solution of 2-exo-[3-(p-chlorophenyl)guanidino]bicyclo-[2,2,1]hept-5-ene (6.1 g) in hot ethanol (75 mL) was stirred while adding dropwise added a solution of (+)-mandelic acid (3.54 g) in hot ethanol (25 ml). The mixture was allowed to cool slowly over 16 hours, at which time the precipitate was filtered off, then stirred with 10 ml of ethanol and filtered again. The two filtrates were combined and stored. The precipitated solid was recrystallized 3 times from ethanol, and then had a melting point of 159-162°. This solid was stirred with 2N NaOH (20 mL)
i 15 minutter, hvilket ga den frie base av det spaltede guanidin, som ble utfiltrert, vasket med vann (10 ml) og tørket. Det faste stoff ble omkrystallisert frå etylacetat og dette ga (+)-2-exo-[3-(p-klorfenyl)guanidino]bicyklo[2,2,1]hept-5-en, sm.p. 205-207° for 15 minutes, yielding the free base of the cleaved guanidine, which was filtered off, washed with water (10 mL) and dried. The solid was recrystallized from ethyl acetate and this gave (+)-2-exo-[3-(p-chlorophenyl)guanidino]bicyclo[2,2,1]hept-5-ene, m.p. 205-207°
[a]<2>)<1>= + 73° (c, 1,0 i metanol). [a]<2>)<1>= + 73° (c, 1.0 in methanol).
Filtratene fra (+)-mandelat-saltet som ble tatt vare på, ble inndampét til tørrhet i vakuum og basen ble frigjort ved røring med kald 2N NaOH (20 ml). Basen ble filtrert ut, vasket med vann og tørket, og dette ga 3,0 g med fast stoff. Dette ble oppløst i varm etanol (45 ml) og det ble tilsatt en oppløsning av (-)-mandelsyre (1,75 g) i varm etanol (29 ml). De blandede oppløsninger ble hensatt for å avkjøles sakte i 16 timer. Utfelningen ble utfiltrert, vasket med etanol (10 ml) og så omkrystallisert to ganger fra etanol, og dette ga et salt med sm.p. 159,5-162°. The filtrates from the (+)-mandelate salt which were retained were evaporated to dryness in vacuo and the base liberated by stirring with cold 2N NaOH (20 mL). The base was filtered off, washed with water and dried to give 3.0 g of solid. This was dissolved in hot ethanol (45 ml) and a solution of (-)-mandelic acid (1.75 g) in hot ethanol (29 ml) was added. The mixed solutions were allowed to cool slowly for 16 hours. The precipitate was filtered off, washed with ethanol (10 mL) and then recrystallized twice from ethanol to give a salt of m.p. 159.5-162°.
Den frie base ble frigjort som ovenfor, og ga efter én krystallisering fra etylacetat (-)-2-exo-[3-(p-klorfenyl)guanidino]-bicyklo[2,2,l]hept-5-en, sm.p. 205-207°, [a]<21> = "73° (c, 1,0 i metanol). The free base was liberated as above, and after one crystallization from ethyl acetate (-)-2-exo-[3-(p-chlorophenyl)guanidino]-bicyclo[2,2,1]hept-5-ene, m.p. p. 205-207°, [α]<21> = "73° (c, 1.0 in methanol).
i in
Claims (2)
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Application Number | Priority Date | Filing Date | Title |
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GB33435/75A GB1492678A (en) | 1975-08-11 | 1975-08-11 | Guanidine derivatives |
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NO762774L NO762774L (en) | 1977-02-14 |
NO143993B true NO143993B (en) | 1981-02-16 |
NO143993C NO143993C (en) | 1981-05-27 |
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NO762774A NO143993C (en) | 1975-08-11 | 1976-08-10 | ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMASOYTIC ACTIVE GUANIDINE DERIVATIVES |
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JP (1) | JPS5225743A (en) |
AT (1) | AT351045B (en) |
AU (1) | AU497534B2 (en) |
BE (1) | BE845052A (en) |
CA (1) | CA1087180A (en) |
CH (1) | CH625207A5 (en) |
DE (1) | DE2635932A1 (en) |
DK (1) | DK362576A (en) |
FI (1) | FI762158A (en) |
FR (1) | FR2320736A1 (en) |
GB (1) | GB1492678A (en) |
IE (1) | IE43488B1 (en) |
NL (1) | NL7608903A (en) |
NO (1) | NO143993C (en) |
PL (1) | PL98956B1 (en) |
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ZA814307B (en) * | 1980-07-01 | 1983-02-23 | Nat Res Dev | Prostaglandins |
EP0082646B1 (en) * | 1981-12-23 | 1989-11-15 | National Research Development Corporation | Prostaglandins |
CH660964A5 (en) * | 1982-06-21 | 1987-06-30 | Inst Organicheskogo Sinteza Ak | MEDICINAL PRODUCT WITH ANTI-MEDICINAL EFFECT. |
WO2005095345A2 (en) * | 2004-03-23 | 2005-10-13 | Achillion Pharmaceuticals, Inc. | Heteroaryl guanidines as inhibitors of viral replication |
-
1975
- 1975-08-11 GB GB33435/75A patent/GB1492678A/en not_active Expired
-
1976
- 1976-07-08 IE IE1510/76A patent/IE43488B1/en unknown
- 1976-07-12 ZA ZA764126A patent/ZA764126B/en unknown
- 1976-07-12 CA CA256,739A patent/CA1087180A/en not_active Expired
- 1976-07-16 AU AU15956/76A patent/AU497534B2/en not_active Expired
- 1976-07-28 FI FI762158A patent/FI762158A/fi not_active Application Discontinuation
- 1976-08-04 PL PL1976191619A patent/PL98956B1/en unknown
- 1976-08-10 AT AT592976A patent/AT351045B/en not_active IP Right Cessation
- 1976-08-10 FR FR7624440A patent/FR2320736A1/en active Granted
- 1976-08-10 SE SE7608929A patent/SE7608929L/en not_active Application Discontinuation
- 1976-08-10 DE DE19762635932 patent/DE2635932A1/en not_active Withdrawn
- 1976-08-10 NO NO762774A patent/NO143993C/en unknown
- 1976-08-10 BE BE169700A patent/BE845052A/en unknown
- 1976-08-10 CH CH1019576A patent/CH625207A5/en not_active IP Right Cessation
- 1976-08-11 DK DK362576A patent/DK362576A/en not_active Application Discontinuation
- 1976-08-11 JP JP51095896A patent/JPS5225743A/en active Pending
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JPS5225743A (en) | 1977-02-25 |
NL7608903A (en) | 1977-02-15 |
DE2635932A1 (en) | 1977-03-03 |
CH625207A5 (en) | 1981-09-15 |
FR2320736B1 (en) | 1980-11-07 |
SE7608929L (en) | 1977-02-12 |
ZA764126B (en) | 1977-06-29 |
FR2320736A1 (en) | 1977-03-11 |
BE845052A (en) | 1977-02-10 |
NO762774L (en) | 1977-02-14 |
DK362576A (en) | 1977-02-12 |
AU1595676A (en) | 1978-01-19 |
GB1492678A (en) | 1977-11-23 |
AU497534B2 (en) | 1978-12-14 |
NO143993C (en) | 1981-05-27 |
FI762158A (en) | 1977-02-12 |
IE43488B1 (en) | 1981-03-11 |
PL98956B1 (en) | 1978-06-30 |
CA1087180A (en) | 1980-10-07 |
ATA592976A (en) | 1978-12-15 |
AT351045B (en) | 1979-07-10 |
IE43488L (en) | 1977-02-11 |
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