CH529762A - 5 azatricyclo (4 3 11) undecane derivs with antiviral - Google Patents
5 azatricyclo (4 3 11) undecane derivs with antiviralInfo
- Publication number
- CH529762A CH529762A CH226071A CH226071A CH529762A CH 529762 A CH529762 A CH 529762A CH 226071 A CH226071 A CH 226071A CH 226071 A CH226071 A CH 226071A CH 529762 A CH529762 A CH 529762A
- Authority
- CH
- Switzerland
- Prior art keywords
- alkyl
- formula
- less
- azatricyclo
- group
- Prior art date
Links
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 title abstract 4
- 230000000840 anti-viral effect Effects 0.000 title abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 14
- OKDJIRNQPPBDKJ-UHFFFAOYSA-N 4-azatricyclo[4.3.1.13,8]undecan-5-one Chemical compound C1C(C2)C(=O)NC3CC1CC2C3 OKDJIRNQPPBDKJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 5
- 230000005792 cardiovascular activity Effects 0.000 abstract description 2
- 230000001741 anti-phlogistic effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
- -1 pyrrolidino, piperidino Chemical group 0.000 description 32
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RWMIUVLOQIOJGB-UHFFFAOYSA-N 3-(chloromethyl)isoquinoline Chemical compound C1=CC=C2C=NC(CCl)=CC2=C1 RWMIUVLOQIOJGB-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- CTGAFDHGTYGPAI-UHFFFAOYSA-N 4-[3-(4-methylpiperazin-1-yl)propyl]-4-azatricyclo[4.3.1.13,8]undecane Chemical compound C1CN(C)CCN1CCCN1C(C2)CC(C3)CC2CC3C1 CTGAFDHGTYGPAI-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 2
- IYKFYARMMIESOX-UHFFFAOYSA-N adamantanone Chemical compound C1C(C2)CC3CC1C(=O)C2C3 IYKFYARMMIESOX-UHFFFAOYSA-N 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- CRKHNIDATUGNFE-UHFFFAOYSA-N sbb013443 Chemical compound C1C(C2)CC3CC2NCC1C3 CRKHNIDATUGNFE-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- NBSLHMOSERBUOV-UHFFFAOYSA-N undecan-4-one Chemical compound CCCCCCCC(=O)CCC NBSLHMOSERBUOV-UHFFFAOYSA-N 0.000 description 2
- WAXWAIBJJHOUBZ-UHFFFAOYSA-N 1-(3-bromopropyl)-4-methylpiperazine;dihydrobromide Chemical compound Br.Br.CN1CCN(CCCBr)CC1 WAXWAIBJJHOUBZ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UIOUQNKJSDPBTG-UHFFFAOYSA-N 4-[3-(4-methyl-1-piperazinyl)propyl]-4-azatricyclo[4.3.1.13,8 ]undecan-5-one Chemical compound C1CN(C)CCN1CCCN1C(=O)C(C2)CC3CC2CC1C3 UIOUQNKJSDPBTG-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JCMWSVNNSPUNER-UHFFFAOYSA-N N,O-dimethyltyramine Chemical compound CNCCC1=CC=C(OC)C=C1 JCMWSVNNSPUNER-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940039748 oxalate 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
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/32—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems containing carbocyclic rings other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
5-azatricyclo (4.3.1.1) undecane derivs with antiviral, cardiovascular or antiphlogistic activity. G3A. Cpds. of formula (I) and their salts (where R is H, alkenyl, cycloalkylalkyl, aralkyl, -(CH2)m-COOH or -(CH2)n-B, m is 1-10, n is 2-10 and B is a basic N-contng. residue with up to 15 C atoms which contains either a 5- to 7-membered N-contng. heterocycle or a residue in which R1 and R2 are H, alkyl or hydroxyalkyl or R1 and R2 together with the N-atom form an opt. subst. heterocycle which in addition to the N-atom contains a further N, O or S atom) ("alkyl" is C1-7 and "cycloakyl" is C3-7) are new. - (I) are prepared by the following process:- (R' = R other than H) - Intermediates (V) and (VI) are new and are claimed per se.
Description
Procédé de préparation du 5-azatricyclo (4.3.1.13,8)undécane La présente invention a pour objet un procédé de préparation des 5-azatricyclo(4.3.1.13,8)undécan-4-ones de formule
EMI0001.0001
par réaction de la 5-azatricyclo(4.3.1.13,8)undécan-4-one de formule suivante
EMI0001.0003
avec un composé de formule R-hal.
On peut utiliser les composés de formule (1) pour préparer, par réduction, les 5-azatricyclo(4.3.1.13,8)undé- canes de formule :
EMI0001.0006
Dans les formules ci-dessus, hal représente un halo gène, de préférence le chlore ou le brome, R représente un groupe alcoyle ayant moins de 8 C, alcényle ayant moins de 8 C, cycloalcoyle-alcoyle ayant moins de 8 C, le groupe cycloalcoyle ayant de 3 à 7 atomes de carbone, aralcoyle, -(CH2)m-COOH ou - :714).-B, m est un nombre entier ayant la valeur 1 à 10 et n est un nombre entier ayant la valeur 2 à 10.
B est un radical basique contenant de l'azote ayant 15 atomes ou moins et il consiste en un radical N-hétéro- cyclique ayant 5 à 7 membres, ou un groupe de formule
EMI0001.0011
dans laquelle R1 et R. sont identiques ou différents et représentent un atome d'hydrogène, un groupe alcoyle ayant moins de 8 C ou hydroxyalcoyle ayant moins de 8 C. En outre, les fragments R1 et R2 peuvent être reliés à l'azote pour former un groupe hétérocyclique, par exemple un groupe pyrrolidino, pipéridino, homopipé- ridino, pipérazino, morpholino ou thiamorpholino.
En outre, le groupe hétérocyclique peut porter un ou deux groupes tels qu'un groupe alcoyle Cl-CI, alcoxy Cl-C7, halogéno, trihalogénométhyle, alcanoyloxy C1-C7 - alcoyle C1-C7 ou hydroxy-alcoyle C1-C7.
Les groupes alcoyle représentés par les symboles ci- dessus incluent des radicaux hydrocarbure saturé à chaîne droite ou ramifiée ayant moins de 8 atomes de carbone, par exemple, les groupes méthyle, éthyle, pro pyle, isopropyle, butyle, isobutyle et t-butyle et les grou pes alcényle C1-C7 incluent des groupes mono- non satu rés analogues, par exemple les groupes vinyle, allyle, isopropényle, butényle et isobutényle. Les groupes cyclo- alcoyle incluent les groupes cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle et cycloheptyle.
Ces groupes sont fixés aux groupes alcoyle C1-C7 du type décrit. Les groupes aralcoyle sont en premier lieu les groupes phé nyle-alcoyle C1-C7 dans lesquels le radical phényle peut être substitué, par exemple par un ou deux atomes d'ha logène, qui peuvent être n'importe lequel des quatre halogènes, mais particulièrement le chlore ou le brome, et des groupes alcoyle C1-C7 tels que ceux indiqués plus haut ou des groupes alcoxy C1-C7 tels que les groupes méthoxy, éthoxy et propoxy.
Des exemples du groupe
EMI0002.0009
sont les groupes amino, méthylamino, éthylamino, dimé- thylamino, diéthylamino, dipropylamino, méthyléthyl- amino et di(hydroxyéthyl)amino.
Comme noté plus haut, le groupe
EMI0002.0014
peut aussi former un radical hétérocyclique, cependant, du moment que R1 et R2 ensemble peuvent représenter les atomes de carbone (et d'hydrogène), de soufre ou d'azote qui, avec l'atome d'azote dans le groupe ci- dessus, forment le radical N-hétérocyclique ayant 5, 6 ou 7 membres, il peut y avoir plus d'un autre atome autre que le carbone en plus de l'atome d'azote, déjà indiqué dans le groupe.
Néanmoins, il ne doit pas y avoir plus d'un autre atome différent du carbone en plus de l'atome d'azote qui se trouve dans ledit noyau hétéro- cyclique. Ces radicaux hétérocycliques peuvent aussi porter un à trois des substituants suivants: halogéno ;
trifluorométhyle, alcoxy C1-C7, alcoyle C1-C7; hydroxy- alcoyle C1-C7; par exemple hydroxyméthyle ou 2-hy- droxyéthyle ; hydroxy-alcoxy C1-C7 - alcoyle C1-C7, par exemple, 2-(2-hydroxyéthoxy)éthyle; alcanoyloxy-alcoyle C1-C7 (jusqu'à environ 14 atomes de carbone dans le groupe alcanoyle) tel que 2-heptanoyloxyéthyle ; carbo- alcoxy C1-C7, par exemple, carbométhoxy, carboéthoxy, ou carbopropoxy ; ou 2-(alcanoyloxy-alcoxy inférieur) alcoyle C1-C7 (jusqu'à environ 14 atomes de carbone dans le groupe alcanoyle) par exemple, 2-(décanoyloxy- éthoxy)éthyle.
Des exemples des radicaux hétérocycliques repré sentés par
EMI0002.0031
sont les suivants: pipéridino ; (alcoyle C1-C7)pipéridino [par exemple, 2-, 3-, ou 4-(alcoyle C1-C7)pipéridino] ; di(alcoyle C1-C7)pipéridino [par exemple, 2,4-, 2,5-, 3,5- di(alcoyle C1-C7)pipéridino] ; (alcoxy C1-C7)pipéridino [par exemple, 2-méthoxypipéridino ou 3-méthoxypipéri- dino] ; hydroxypipéridino [par exemple, 3-hydroxy- ou 4-hydroxypipéridino] ; pyrrolidino ;
(alcoyle C1-C7)pyr- rolidino [par exemple, 3-méthylpyrrolidino] ; di(alcoyle C1-C7)pyrrolidino [par exemple, 3,4-diméthylpyrrolidi- no] ; (alcoxy C1-C7)pyrrolidino [par exemple, 2-méthoxy- pyrrolidino] ; morpholino ; (alcoyle C1-C7)morpholino [par exemple 3-méthylmorpholino] ; di(alcoyle C1-C7)- morpholino [par exemple, 3,5-diméthylmorpholino] ; (al- coxy C1-C7)morpholino [par exemple, 2-méthoxymorpho- lino] ; thiamorpholino ;
(alcoyle C1-C7)thiamorpholino [par exemple, 3-méthylthiamorpholino] ; di(alcoyle Cl- C7)thiamorpholino [par exemple, 3,5-diméthylthiamor- pholino] ; (alcoxy C1-C7)thiamorpholino [par exemple, 3-méthoxythiamorpholino] ; pipérazino ; (alcoyle C1-C7)- pipérazino [par exemple, N4-méthylpipérazino] ; di(al- coyle C1-C7)pipérazino [par exemple, 2,5-diméthylpipé- razino ou 2,6-diméthylpipérazino] ;
(alcoxy C1-C7)pipé- razino [par exemple, 2-méthoxypipérazino] ; hydroxy- alcoyle C1-C7)pipérazino [par exemple, N4-(2-hydroxy- éthyl)pipérazino] ;
(alcanoyloxy-alcoyle C1-C7)pipérazino dans lequel le groupe alcanoyloxy a jusqu'à 14 atomes de carbone [par exemple, N4-(2-heptanoyloxyéthyle)pipé- razino ou N4-(2-dodécanoyloxyéthyle)pipérazino] ; (hy- droxy-alcoxy C1-C7 - alcoyle C1-C7)pipérazino [par exem ple, N4-(2-hydroxyéthoxyéthyle)pipérazino] ; et (carbo- alcoxy C1-C7)pipérazino [par exemple, N4-(carbomé- thoxy-, carboéthoxy-, ou carbopropoxy)pipérazino] ; ho- mopipérazino ; ou N4-(2-hydroxyéthyle)homopipérazino].
Les composés que l'on préfère particulièrement sont ceux dans lesquels R est un atome d'hydrogène, un groupe 3-(4-méthyle-1-pipérazinyl)propyle, allyle ou phé- néthyle.
Les composés de formule (111) forment des sels d'ad dition d'acide avec divers acides inorganiques et orga niques. Souvent ces sels fournissent un moyen pratique de séparation du produit, du mélange réactionnel dans lequel ils sont préparés ou du solvant dont on les extrait, à cause de leur insolubilité dans divers milieux. Ainsi on peut précipiter le produit sous forme de sel insoluble, puis le convertir, selon des techniques connues, en base libre ou en un autre sel si on le désire.
Des exemples de sels incluent les halogènhydrates, par exemple le chlorhydrate, le bromhydrate ou l'iodhy- drate, surtout les deux premiers, d'autres sels d'acides minéraux, par exemple le phosphate, le sulfate, le nitrate, etc., des sels d'acides organiques tels que l'oxalate, le tartrate, le malate, le maléate, le citrate, le camphre- sulfonate, le méthanesulfonate, le benzènesulfonate, le toluènesulfonate, le salicylate, le benzoate, l'ascorbate, le mandélate, le pamoate, etc.
Les composés de formule (111) et leurs sels physiolo giquement acceptables sont utiles comme agents anti- virus, cardiovasculaires ou anti-inflammatoires pour trai ter ou atténuer les symptômes chez divers animaux à sang chaud.
Bien que toute la classe en général présente ces propriétés, les composés dans lesquels R est un groupe alcényle Cl-C7, cycloalcoyle-alcoyle Cl-C7 ou aralcoyle ont une activité antivirus comme propriété pré dominante, les composés dans lesquels R est un groupe
EMI0002.0099
ont une activité cardiovasculaire comme propriété pré dominante et les composés dans lesquels R est un groupe -(CH2)m-COOH ont une activité anti-inflammatoire comme propriété prédominante.
Pour préparer le composé de départ de formule (11), on peut traiter le 1-hydroxyadamantane avec de l'acide sulfurique concentré pour obtenir la 2-adamantanone. On fait réagir cette dernière avec le chlorhydrate ou le sul fate d'hydroxylamine pour obtenir la 2-adamantanone- oxime. Après une transposition de Beckmann , en traitant la 2-adamantanone-oxime avec un excès d'acide polyphosphorique, de pentachlorure de phosphore, etc., à 120 -1300 C, on obtient la 5-azatricyclo(4.3.1.13,8)undé- can-4-one de formule (11).
L'exemple suivant illustre l'invention. Toutes les tem pératures sont en degrés centigrades.
A. - Matière de départ Oxime de 2-adamantanone A une solution refroidie de 8,5 g (0,05 mole) de 2-ada- mantanone, 6,2 g (0,09 mole) de chlorhydrate d'hydroxyl- amine et 16 ml d'eau, on additionne 11,2g (0,28 mole) d'hydroxyde de sodium en agitant. On chauffe au reflux le mélange pendant 10 minutes. Après l'avoir refroidi, on verse le contenu sur 300 ml d'HCl 1 N.
On filtre le préci pité formé et obtient 5,3 g (57 %) de l'oxime de 2-ada- mantanone sous forme de cristaux blancs qui fondent à
EMI0003.0010
5-azatricyclo(4.3.1.13,8)undécan-4-one On met un mélange, agité à la main, de 3 g (0,0l8 mole) de l'oxime de 2-adamantanone et 90 g d'acide polyphosphorique dans un bain d'huile préalablement chauffé à 140o C. On maintient la température du mé lange entre 120 et 130 C pendant 10 minutes. A la fin de cette période, on refroidit la solution brun foncé et la traite avec 500 ml d'eau.
On extrait le mélange avec 500 ml de chloroforme, le sèche sur du MgSO4 et l'éva pore pour obtenir 1,4 g de solide blanc brut, après subli mation du produit on obtient 1,17 g (39 %) de cristaux blancs de 5-azatricyclo(4.3.1.13,8)undécan-4-one qui fon dent au-dessus de 270o C et ont un
EMI0003.0014
de 1650 cm-1 (C = O), un i CDC13 de 7,5 à 8,4 (protons d'adaman- tyle), de 6,4 à 7,5 (N-H et hydrogène de méthine adja cent au carbonyle).
EMI0003.0017
<I>Analyse</I>
<tb> Calculé <SEP> pour <SEP> C10H15NO <SEP> : <SEP> C <SEP> 72,69 <SEP> ; <SEP> H <SEP> 9,15 <SEP> ; <SEP> N <SEP> 8,48
<tb> Trouvé <SEP> : <SEP> C <SEP> 72,98 <SEP> ; <SEP> H <SEP> <B>9,00;</B> <SEP> N <SEP> 8,43 B. - Mise en auvre du procédé 5-[3-(4-méthyl-1-pipérazinyl)propyl]-5-aza- tricyclo[4.3.1.13,8]undécan-4-one A une solution bien agitée de 2,4 g (0,02 mole) de 5-azatricyclo(4.3.1.13,8)undécan-4-one dans 300 ml de to luène, on additionne 3,2 g d'hydroxyde de sodium pulvé risé.
Après avoir agité fortement pendant 5 minutes, on additionne 12 g de dibromhydrate de 1-(3-bromopropyl)- 4-méthylpipérazine et chauffe le mélange pendant 20 mi nutes au bain-marie. On refroidit le mélange réactionnel et l'agite avec 50 ml d'eau froide. On sépare la couche de toluène, la lave avec deux fois 50 ml d'eau et l'extrait avec trois fois 100 ml d'HCl 5 N. On réunit les extraits acides, les lave avec 100 ml d'éther, les refroidit et les alcalinise avec NaOH 2 N.
On extrait la base libre avec trois fois 250 ml de chloroforme, la sèche sur MgS04 et l'évapore sous vide pour obtenir la 5-[3-(4-méthyl-1-pipé- razinyl)propyl]-5-azatricyclo(4.3.1.13,8)undécan-4-one.
Le produit ci-dessus peut être utilisé pour la prépa ration suivante 5-[3-(4-méthyl-1-pipérazinyl)propyl]-5-aza- tricyclo(4.3.1.13,8)undécane A une suspension refroidie de 1,5 g d'hydrure de lithium-aluminium dans 50 ml de tétrahydrofuranne, on additionne goutte à goute en agitant 1,5 g (0,01 mole) de 5-[3-(4-méthyl-1-pipérazinyl)propyl]-5-azatricyclo- (4.3.1.13,8)undécan-4-one dans 50 ml de tétrahydrofu- ranne. On chauffe au reflux le mélange pendant une nuit. On décompose l'excès d'hydrure de lithium-alumi nium en additionnant avec précaution de l'eau au mé lange refroidi.
Le précipité gélatineux devient granulaire après l'addition de 30 ml d'hydroxyde de sodium à 10/0. On sépare le précipité par filtration et sépare le tétra- hydrofuranne du filtrat sous vide. On extrait la matière résiduelle avec trois fois 50 ml d'éther. On sèche l'extrait éthéré sur du sulfate de magnésium et isole le produit, c'est-à-dire le 5-[3-(4-méthyl-1-pipérazinyl)propyl]-5-aza- tricyclo(4.3.1.13,8)undécane par évaporation de la solu tion éthérée sous vide.
On peut obtenir les autres produits de formules (1) et (111) suivants en substituant, dans le procédé de l'exem ple, le composé de la colonne du milieu du tableau ci- dessous au dibromhydrate -de 1-(3-bromopropyl)-4-mé- thylpipérazine. En procédant par ailleurs comme dans cet exemple, on obtient le composé de formule (1) dans laquelle R est le groupe indiqué dans la colonne de droite ci-dessous. Ensuite, en utilisant ce produit, on obtient le produit de formule (111) dans laquelle R est le même groupe indiqué dans la colonne de droite.
On peut obte nir tout sel d'addition d'acide en utilisant de l'acide chlorhydrique ou un autre acide inorganique ou orga nique.
EMI0003.0046
EMI0004.0000
Process for preparing 5-azatricyclo (4.3.1.13,8) undecane The present invention relates to a process for preparing 5-azatricyclo (4.3.1.13,8) undecan-4-ones of formula
EMI0001.0001
by reaction of 5-azatricyclo (4.3.1.13,8) undecan-4-one of the following formula
EMI0001.0003
with a compound of formula R-hal.
The compounds of formula (1) can be used to prepare, by reduction, the 5-azatricyclo (4.3.1.13,8) undecanes of formula:
EMI0001.0006
In the above formulas, hal represents a halogen, preferably chlorine or bromine, R represents an alkyl group having less than 8 C, alkenyl having less than 8 C, cycloalkyl-alkyl having less than 8 C, the group cycloalkyl having 3 to 7 carbon atoms, aralkyl, - (CH2) m-COOH or -: 714) .- B, m is an integer having the value 1 to 10 and n is an integer having the value 2 to 10.
B is a basic nitrogen-containing radical having 15 atoms or less and it consists of an N-heterocyclic radical having 5 to 7 members, or a group of the formula
EMI0001.0011
wherein R1 and R. are the same or different and represent a hydrogen atom, an alkyl group having less than 8 C or hydroxyalkyl having less than 8 C. In addition, the R1 and R2 moieties can be linked to nitrogen for forming a heterocyclic group, for example a pyrrolidino, piperidino, homopiperidino, piperazino, morpholino or thiamorpholino group.
Further, the heterocyclic group may carry one or two groups such as C1-C1 alkyl, C1-C7 alkoxy, halo, trihalomethyl, C1-C7 alkanoyloxy-C1-C7 alkyl or C1-C7 hydroxyalkyl.
The alkyl groups represented by the above symbols include straight or branched chain saturated hydrocarbon radicals having less than 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups and C1-C7 alkenyl groups include analogous monounsaturated groups, for example vinyl, allyl, isopropenyl, butenyl and isobutenyl groups. Cycloalkl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
These groups are attached to C1-C7 alkyl groups of the type described. The aralkyl groups are in the first place the phenyl-C1-C7 alkyl groups in which the phenyl radical can be substituted, for example by one or two halogen atoms, which can be any of the four halogens, but particularly chlorine or bromine, and C1-C7 alkyl groups such as those indicated above or C1-C7 alkoxy groups such as methoxy, ethoxy and propoxy groups.
Examples of the group
EMI0002.0009
are amino, methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino and di (hydroxyethyl) amino groups.
As noted above, the group
EMI0002.0014
can also form a heterocyclic radical, however, as long as R1 and R2 together can represent carbon (and hydrogen), sulfur or nitrogen atoms which together with the nitrogen atom in the above group , form the N-heterocyclic radical having 5, 6 or 7 members, there may be more than one other atom other than carbon in addition to the nitrogen atom, already indicated in the group.
However, there should not be more than one other atom other than carbon in addition to the nitrogen atom which is in said heterocyclic ring. These heterocyclic radicals can also carry one to three of the following substituents: halo;
trifluoromethyl, C1-C7 alkoxy, C1-C7 alkyl; C1-C7 hydroxyalkyl; for example hydroxymethyl or 2-hydroxyethyl; hydroxy-C1-C7 alkoxy-C1-C7 alkyl, for example, 2- (2-hydroxyethoxy) ethyl; C1-C7 alkanoyloxyalkyl (up to about 14 carbon atoms in the alkanoyl group) such as 2-heptanoyloxyethyl; C1-C7 carboalkoxy, for example, carbomethoxy, carboethoxy, or carbopropoxy; or 2- (alkanoyloxy-lower alkoxy) C1-C7 alkyl (up to about 14 carbon atoms in the alkanoyl group) for example, 2- (decanoyloxyethoxy) ethyl.
Examples of heterocyclic radicals represented by
EMI0002.0031
are as follows: piperidino; (C1-C7 alkyl) piperidino [eg, 2-, 3-, or 4- (C1-C7 alkyl) piperidino]; di (C1-C7 alkyl) piperidino [eg, 2,4-, 2.5-, 3,5- di (C1-C7 alkyl) piperidino]; (C1-C7 alkoxy) piperidino [eg, 2-methoxypiperidino or 3-methoxypiperidino]; hydroxypiperidino [eg, 3-hydroxy- or 4-hydroxypiperidino]; pyrrolidino;
(C1-C7 alkyl) pyrrolidino [eg, 3-methylpyrrolidino]; di (C1-C7 alkyl) pyrrolidino [eg, 3,4-dimethylpyrrolidino]; (C1-C7 alkoxy) pyrrolidino [eg, 2-methoxy-pyrrolidino]; morpholino; (C1-C7 alkyl) morpholino [eg 3-methylmorpholino]; di (C1-C7 alkyl) - morpholino [eg, 3,5-dimethylmorpholino]; (C1-C7 alkoxy) morpholino [eg, 2-methoxymorpholino]; thiamorpholino;
(C1-C7 alkyl) thiamorpholino [eg, 3-methylthiamorpholino]; di (C1-C7 alkyl) thiamorpholino [eg, 3,5-dimethylthiamorpholino]; (C1-C7 alkoxy) thiamorpholino [eg, 3-methoxythiamorpholino]; piperazino; (C1-C7 alkyl) - piperazino [eg, N4-methylpiperazino]; di (C1-C7 alkyl) piperazino [eg, 2,5-dimethylpiperazino or 2,6-dimethylpiperazino];
(C1-C7 alkoxy) piperazino [eg, 2-methoxypiperazino]; (C1-C7 hydroxyalkyl) piperazino [eg, N4- (2-hydroxyethyl) piperazino];
(C1-C7 alkanoyloxy-alkyl) piperazino in which the alkanoyloxy group has up to 14 carbon atoms [eg, N4- (2-heptanoyloxyethyl) piperazino or N4- (2-dodecanoyloxyethyl) piperazino]; (hydroxy-C1-C7 alkoxy-C1-C7 alkyl) piperazino [eg, N4- (2-hydroxyethoxyethyl) piperazino]; and (C1-C7 carboalkoxy) piperazino [eg, N4- (carbomethoxy-, carboethoxy-, or carbopropoxy) piperazino]; homopiperazino; or N4- (2-hydroxyethyl) homopiperazino].
Particularly preferred compounds are those in which R is hydrogen, 3- (4-methyl-1-piperazinyl) propyl, allyl or phenethyl.
Compounds of formula (111) form acid addition salts with various inorganic and organic acids. Often these salts provide a convenient means of separating the product, the reaction mixture from which they are prepared or the solvent from which they are extracted, due to their insolubility in various media. Thus, the product can be precipitated in the form of an insoluble salt and then converted, according to known techniques, into free base or into another salt if desired.
Examples of salts include hydrohalides, for example hydrochloride, hydrobromide or iodide, especially the first two, other salts of mineral acids, for example phosphate, sulfate, nitrate, etc., salts of organic acids such as oxalate, tartrate, malate, maleate, citrate, camphorsulfonate, methanesulfonate, benzenesulfonate, toluenesulfonate, salicylate, benzoate, ascorbate, mandelate , pamoate, etc.
The compounds of formula (111) and their physiologically acceptable salts are useful as anti-virus, cardiovascular or anti-inflammatory agents for treating or alleviating symptoms in various warm-blooded animals.
Although the whole class in general exhibits these properties, compounds in which R is a C1-C7 alkenyl, C1-C7 cycloalkyl-alkyl or aralkyl group have antivirus activity as a predominant property, compounds in which R is a group
EMI0002.0099
have cardiovascular activity as a predominant property and compounds in which R is a - (CH2) m-COOH group have anti-inflammatory activity as a predominant property.
To prepare the starting compound of formula (11), 1-hydroxyadamantane can be treated with concentrated sulfuric acid to obtain 2-adamantanone. The latter is reacted with the hydrochloride or hydroxylamine sulfate to obtain 2-adamantanone oxime. After a Beckmann transposition, by treating 2-adamantanone-oxime with an excess of polyphosphoric acid, phosphorus pentachloride, etc., at 120-1300 C, 5-azatricyclo (4.3.1.13,8) undé is obtained - can-4-one of formula (11).
The following example illustrates the invention. All temperatures are in degrees centigrade.
A. - Starting material 2-adamantanone oxime A a cooled solution of 8.5 g (0.05 mole) of 2-adamantanone, 6.2 g (0.09 mole) of hydroxylamine hydrochloride and 16 ml of water, 11.2 g (0.28 mol) of sodium hydroxide are added with stirring. The mixture is refluxed for 10 minutes. After cooling it, the contents are poured into 300 ml of 1N HCl.
The precipitate formed is filtered off and 5.3 g (57%) of 2-adamantanone oxime are obtained in the form of white crystals which melt at
EMI0003.0010
5-azatricyclo (4.3.1.13,8) undecan-4-one A mixture, stirred by hand, of 3 g (0.018 mol) of 2-adamantanone oxime and 90 g of polyphosphoric acid is placed in an oil bath previously heated to 140 ° C. The temperature of the mixture is maintained between 120 and 130 ° C. for 10 minutes. At the end of this period, the dark brown solution is cooled and treated with 500 ml of water.
The mixture is extracted with 500 ml of chloroform, dried over MgSO4 and evaporated to obtain 1.4 g of crude white solid, after subli mation of the product 1.17 g (39%) of white crystals of 5-azatricyclo (4.3.1.13,8) undecan-4-one which melts above 270o C and has a
EMI0003.0014
from 1650 cm-1 (C = O), an i CDC13 from 7.5 to 8.4 (adamantyl protons), from 6.4 to 7.5 (NH and methine hydrogen adja cent to the carbonyl) .
EMI0003.0017
<I> Analysis </I>
<tb> Calculated <SEP> for <SEP> C10H15NO <SEP>: <SEP> C <SEP> 72.69 <SEP>; <SEP> H <SEP> 9.15 <SEP>; <SEP> N <SEP> 8.48
<tb> Found <SEP>: <SEP> C <SEP> 72.98 <SEP>; <SEP> H <SEP> <B> 9.00; </B> <SEP> N <SEP> 8.43 B. - Implementation of the process 5- [3- (4-methyl-1-piperazinyl) propyl] -5-aza- tricyclo [4.3.1.13,8] undecan-4-one To a well-stirred solution of 2.4 g (0.02 mol) of 5-azatricyclo (4.3.1.13,8) undecan-4 -one in 300 ml of toluene, 3.2 g of pulverized sodium hydroxide are added.
After stirring vigorously for 5 minutes, 12 g of 1- (3-bromopropyl) - 4-methylpiperazine dihydrobromide are added and the mixture is heated for 20 minutes in a water bath. The reaction mixture is cooled and stirred with 50 ml of cold water. The toluene layer is separated, washed with twice 50 ml of water and extracted with three times 100 ml of 5N HCl. The acid extracts are combined, washed with 100 ml of ether, cooled and. alkalinizes them with 2N NaOH.
The free base is extracted with three times 250 ml of chloroform, dried over MgSO4 and evaporated in vacuo to give 5- [3- (4-methyl-1-piperazinyl) propyl] -5-azatricyclo (4.3. .1.13,8) undecan-4-one.
The above product can be used for the following preparation 5- [3- (4-methyl-1-piperazinyl) propyl] -5-aza-tricyclo (4.3.1.13,8) undecane In a cooled suspension of 1, 5 g of lithium aluminum hydride in 50 ml of tetrahydrofuran, 1.5 g (0.01 mol) of 5- [3- (4-methyl-1-piperazinyl) propyl] - are added dropwise while stirring. 5-azatricyclo- (4.3.1.13,8) undecan-4-one in 50 ml of tetrahydrofuran. The mixture is refluxed overnight. The excess lithium aluminum hydride is decomposed by carefully adding water to the cooled mixture.
The gelatinous precipitate becomes granular after the addition of 30 ml of 10/0 sodium hydroxide. The precipitate is filtered off and the tetrahydrofuran is separated from the filtrate in vacuo. The residual material is extracted with three times 50 ml of ether. The ethereal extract is dried over magnesium sulfate and the product is isolated, i.e. 5- [3- (4-methyl-1-piperazinyl) propyl] -5-aza-tricyclo (4.3.1.13 , 8) undecane by evaporation of the ethereal solution in vacuo.
The following other products of formulas (1) and (111) can be obtained by substituting, in the process of the example, the compound in the middle column of the table below for 1- (3-bromopropyl dihydrobromide). ) -4-methylpiperazine. Further proceeding as in this example, the compound of formula (1) is obtained in which R is the group indicated in the right column below. Then, using this product, one obtains the product of formula (111) in which R is the same group shown in the right column.
Any acid addition salt can be obtained by using hydrochloric acid or other inorganic or organic acid.
EMI0003.0046
EMI0004.0000
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75446068A | 1968-08-21 | 1968-08-21 | |
| CH1270069A CH505100A (en) | 1968-08-21 | 1969-08-21 | Process for preparing 5-azatricyclo (4.3.1.1 3,8) undecane |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH529762A true CH529762A (en) | 1972-10-31 |
Family
ID=25710759
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH226071A CH529762A (en) | 1968-08-21 | 1969-08-21 | 5 azatricyclo (4 3 11) undecane derivs with antiviral |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH529762A (en) |
-
1969
- 1969-08-21 CH CH226071A patent/CH529762A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |