US3055902A - Bis-(1-piperidino) alkanes - Google Patents
Bis-(1-piperidino) alkanes Download PDFInfo
- Publication number
- US3055902A US3055902A US831459A US83145959A US3055902A US 3055902 A US3055902 A US 3055902A US 831459 A US831459 A US 831459A US 83145959 A US83145959 A US 83145959A US 3055902 A US3055902 A US 3055902A
- Authority
- US
- United States
- Prior art keywords
- amino
- acid
- compounds
- bis
- piperidino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001335 aliphatic alkanes Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 51
- -1 alkylene radical Chemical class 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000002253 acid Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 150000003839 salts Chemical class 0.000 description 33
- 238000000034 method Methods 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 20
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 125000003277 amino group Chemical group 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 150000007513 acids Chemical class 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012458 free base Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000012279 sodium borohydride Substances 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- 125000001302 tertiary amino group Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000001453 quaternary ammonium group Chemical group 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 150000001450 anions Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 229960004979 fampridine Drugs 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000003385 bacteriostatic effect Effects 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 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 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DKEGCUDAFWNSSO-UHFFFAOYSA-N 1,8-dibromooctane Chemical compound BrCCCCCCCCBr DKEGCUDAFWNSSO-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229940107816 ammonium iodide Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- PFZCOWLKXHIVII-UHFFFAOYSA-N pyridin-1-ium-1-amine Chemical group N[N+]1=CC=CC=C1 PFZCOWLKXHIVII-UHFFFAOYSA-N 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GTQHJCOHNAFHRE-UHFFFAOYSA-N 1,10-dibromodecane Chemical compound BrCCCCCCCCCCBr GTQHJCOHNAFHRE-UHFFFAOYSA-N 0.000 description 1
- ZJJATABWMGVVRZ-UHFFFAOYSA-N 1,12-dibromododecane Chemical compound BrCCCCCCCCCCCCBr ZJJATABWMGVVRZ-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- WGAXVZXBFBHLMC-UHFFFAOYSA-N 1,9-dibromononane Chemical compound BrCCCCCCCCCBr WGAXVZXBFBHLMC-UHFFFAOYSA-N 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical group CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- GNCLPNMQEGMNTG-UHFFFAOYSA-N 2-methylpyridin-4-amine Chemical compound CC1=CC(N)=CC=N1 GNCLPNMQEGMNTG-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OVFUUSPKWADLNJ-UHFFFAOYSA-N 5-methyl-4-nitro-2-(4-nitrophenyl)-4h-pyrazol-3-one Chemical compound O=C1C([N+]([O-])=O)C(C)=NN1C1=CC=C([N+]([O-])=O)C=C1 OVFUUSPKWADLNJ-UHFFFAOYSA-N 0.000 description 1
- 229910000761 Aluminium amalgam Inorganic materials 0.000 description 1
- 229910000497 Amalgam Inorganic materials 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- 238000006085 Schmidt reaction Methods 0.000 description 1
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- 241000295644 Staphylococcaceae Species 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
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- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
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- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
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- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004653 carbonic acids Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
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- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
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- 238000000909 electrodialysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- FCQJEPASRCXVCB-UHFFFAOYSA-N flavianic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FCQJEPASRCXVCB-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical group CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 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
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
- C07D295/30—Nitrogen atoms non-acylated
Definitions
- Ciba Corporation a corporation of Delaware No Drawing. Filed Aug. 4, 1959, Ser. No. 831,459 10 Ciaims. (Cl. 260-293)
- the present invention concerns bis-piperidino-alkane compounds.
- Alk represents an alkylene radical separating group Pi from group Pi by four to twenty carbon atoms
- each of the groups Pi and Pi stands for an amino-1- piperidino group, N-acyl-ated derivatives, salts and quaternary ammt inium compounds thereof.
- the alkylene radical Alk which separates the amino-lpiperidino radicals by from four to twenty carbon atoms, contains from four to twenty, more especially from six to fourteen, particularly from eight to twelve, primarily ten, carbon atoms, which may be arranged in a straight or in a branched chain.
- alkylene chains are, for example, 1,4-butylene, 1,5'-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,l4-tetradecylene 1,15-pentadecylene, 1,16-hexadecylene, l,17-heptadecylene, 1,18-octadecylene, 1,19-nonadecylene, 1,20- eicosylene, I-methyLLS-pentylene, 3,3-di-methyl-l,5- pentylene, 3,4-dimethyl-1,6-hexylene,4,4-dimethyl 1,7 hept ylene, 2,7-dimethyl-1,8-octylene, S-ethyl 1,9
- the amino group is located primarily in the 4 position of the piperidyl nucleus, but may also be attached to the 3position of the ring.
- the amino group of the amino-l-piperidino portion represents above all a primary amino group.
- Amino may also stand for secondary amino, particularly N-lower alkyl-amino, e.g. N-methylamino, N-ethylamino, N-nqpropylamino, N-isopropylarnino and the like, N-carbocyclic arylamino, such as N-monocyclic carbocyclic aryl-amino, e.g. N-phenylamino and the like, or N-bicyclic carbocyclic aryl-amino, e.g.
- N-carbocyclic aryl-lower alkyl-amino such as Nmonocyclic carbocyclic aryl-lower aIkyLamino, e. g. N-benzylamino, N-lphenylethylarnino or N-Z-phenylethyl-amino and the like, or bicyclic carbocyclic aryl-lower alkyl-amino, e.g. N-lnaphthyl-methylamino and the like.
- amino groups are tertiary amino groups, such as, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N-ethyl-Namethyl-amino, N,N- diethylamino, N,N-dipropylamino or N,N-di-isopropylamino and the like, N-lower alkyl-N-carbocyclic aryllower alkyl-amino, e.g.
- Other tertiary amino groups are, for example, N,N- alkylene-imino groups, in which alkylene contains preferably from four to eight carbon atoms, e.g.
- l-pyrrolidino Zmethyl-l-pyrrolidino, l-piperidino, 2-methyl-1-piperidino, S-methyl-lpiperidino, 4amethyl-1-piperidino, 3-hydroxy-lpiperidino, 3-acetoxy-1 piperidino, 3 hydroxymethyl-l-piperidino, N,N-l hexamethyleneimino, N,N,-lheptamethyleneimino and the like, N,N-lower oxa-alkyleneirnino, in which alkylene contains preferably four carbon atoms, e.g.
- alkylene contains preferably four carbon atoms, e.g. piper'azino, 4-methyl-piperazino, 4-benzyl- 2 piperazino, 4-(2-hydroxyethyl)-piperazino, 4-(2-acetoxyethyl)apiperazino and the like.
- N-acyl-amino may also represent the amino group of the amino-l-pipeiidyl portion of the bis-(amino-l-piperidino)-alkanes of this invention.
- 'Acyl represents primarily the acyl radical of organic carboxylic acids.
- Such acids are, for example, aliphatic carboxylic acids, such as carbonic acids, especially O-lower alkyl-carbonic acids, e.g. oamethyl-carbonic or O-ethyl-carbonic acid and the like, O-carbocyclic aryl-lower alkyl-carbonic acids, e.g.
- lower alkane carboxylic acids which may contain other functional groups, e.g. formic, acetic, propionic, butyric, pivalic or trifluoroacetic acid and the like, carbocyclic aryl carboxylic acids, which may contain additional substituents, such as monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic acid and the like, or carbocyclic aryl-lower alkane carboxylic acids, which may contain other groups, such as monocyclic carbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, or 3+phenyl-propionic acid and the like, or other organic carboxylic acids.
- lower alkane carboxylic acids which may contain other functional groups, e.g. formic, acetic, propionic, butyric, pivalic or trifluoroacetic acid and the like
- carbocyclic aryl carboxylic acids which may contain additional substituents, such as
- the piperidino nucleus of the amino-l-piperidino group is preferably unsubstituted, or may contain one or more than one additional isubstituent, which may be attached to any of the positions available for substitution in the aminol-piperidino nucleus.
- substituents are particularly lower alkyl, e. g. methyl or ethyl and the like, halogen, e.g. fluorine, chlorine or bromine and the like, lower alkoxy, e.g. methoxy or ethoxy and the like, or other substituents.
- the two amino-l-piperidino groups Pi and Pi, connected through the alkylene radical may be of different nature, they are preferably identical.
- Salts of the compounds of this invention are particularly therapeutically acceptable acid addition salts with inorganic acids, such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like, with organic carboxylic acids, e.g.
- Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by hydroxylated compounds and strong acids, particularly mineral acids, e.g. hydrochloric, hydrobromic or hydriodic acid and the like, or strong organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic or Z-hydroxyethane sulfonic acid and the like.
- Such esters are, for example, lower alkyl halides, e.g. methyl, ethyl, n propyl or isopropyl chloride, bromide or iodide and the like, lower alkyl lower alkane sulfonates, e.g.
- quaternary ammonium compounds include the quaternary ammonium hydroxides, and the salts obtained by reacting the latter with inorganic, or more particularly with organic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts.
- Monoor poly-quaternary ammonium compounds may be formed, depending to exterminate bacteria in an alkane dicarboxylic acids,
- the compounds may be in the form of mixtures of racemate's, which may be separated into single racemates, or in the form of racemates, which may be resolved into the antipodes.
- the compounds of the present invention have COIlSlderable bacteriostatic and bactericidal effects and may, therefore, be used to prevent the propagation and possibly animal or human host, without noticeable adverse effects to the latter.
- the previously-described compounds and their salts show bacteriostatic and bactericidal activities against streptococci, such as Streptococcus pyogenes, and staphylococci, such as Staphyloccus aureus, and may, therefore, be used as bacteriostatic and bactericidal agents to prevent and/or combat infections of such bacteria in animals or humans.
- the new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new bis-(amino-l-piperidino)-alkane compounds or their salts, especially their pharmacologically compatible acid addition salts, in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, parenteral or topical administration.
- a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, parenteral or topical administration.
- substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier for medicaments.
- the pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees and the like, in liquid form, for example, as solutions, e.g. isotonic saline solutions, or as suspensions, emulsions or creams and the like.
- solutions e.g. isotonic saline solutions
- suspensions emulsions or creams and the like.
- auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buflfers, and the like. They may also contain, in combination, other therapeutically useful substances.
- the compounds of the present invention may be prepared by treating compounds of the formula in which Alk has the above-given meaning, each of the radicals Py and Py represents an amino-l-pyridinium group (amino having the previously-given meaning), and
- An stands primarily for the anion of a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, especially hydrobromic acid, or of a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, particularly p-toluene sulfonic acid.
- a strong inorganic acid such as a mineral acid, particularly a hydrohalic acid, especially hydrobromic acid
- a strong organic sulfonic acid such as a monocyclic carbocyclic aryl sulfonic acid, particularly p-toluene sulfonic acid.
- Anions of other inorganic or organic acids may also be conceivable, whereby anions of di-basic acids, such as, for example, sulfuric or tartaric acid may satisfy two positive pyridinium ions.
- Reducing reagents capable of converting the bis-(amino- 1-pyridinium)-alkane compounds into the desired bis- (amino-l-piperidino)-alkanes are primarily hydrides, especially borohydrides, such as alkali metal borohydride, e.g. lithium borohydride, sodium borohydride or potassium borohydride, alkaline earth metal borohydrides, e.g. calcium borohydride, strontium borohydride or barium borohydride, or alkali metal tri-lower alkoxy-borohydrides, e.g. sodium trimethoxy-borohydride. Alkali metal tri-lower alkoxy-aluminumhydrides, e.g.
- lithium tri-propyloxy-aluminumhydride may also be used as reducing agents. If desired, these reagents may be used together with an activator, such as, for example, aluminum chloride and the like.
- Solvents used in the reaction are, for example, lower alkanols, e.g. methanol or ethanol, or any other solvent compatible with the above-mentioned metal hydride compounds.
- the reaction may be carried out under cooling or at room temperature, and, if necessary, may be completed at an elevated temperature. If desired, it may be performed in the atmosphere of an inert gas, e.g. nitrogen.
- Another reducing reagent capable of converting bis- (amino -l-pyridinium)-alkane compounds into the corresponding amino-l-piperidino derivatives may be catalytically activated hydrogen, whereby the catalyst contains a metal of the eighth group of the periodic system, such as platinum or palladium; preferred catalysts are, for example, platinum oxide and palladium on charcoal.
- This hydrogenation may be carried out in the presence of a solvent, such as a lower alkanoic acid, e.g. acetic acid, or a lower alkanol, e.g. methanol or ethanol, and the like; it may be performed under atmospheric or increased pressure, and, if desired, at an elevated temperature.
- a solvent such as a lower alkanoic acid, e.g. acetic acid, or a lower alkanol, e.g. methanol or ethanol, and the like; it may be performed under atmospheric or increased pressure, and, if desired, at an elevated temperature.
- Nascent hydrogen such as generated by a metal or a metal amalgam in the presence of a hydrogen donor, may also be used in the above-described reduction procedure; zinc in the presence of acetic acid or aluminum amalgam in the presence of a moist ether, e.g. tetrahydrofuran, are examples of sources of nascent hydrogen capable of performing the desired reaction.
- a moist ether e.g. tetrahydrofuran
- the resulting bis(amino l-piperidino)-alkanes may be isolated according to conventional methods; for example, an alcoholic solvent used in the metal hydride reduction may be evaporated, the residue suspended in a small amount of water and salted out into a supernatant, only partially water-miscible solvent, e.g. ether, by adding, for example, a solid carbonate, e.g. sodium or potassium carbonate, or an alkali metal halide, e.g. sodium chloride. .
- a solid carbonate e.g. sodium or potassium carbonate
- an alkali metal halide e.g. sodium chloride.
- the separated and dried organic, e.g. ether, phase may be evaporated and the liquid may be decanted from a,
- the resulting free base may be purified by distillation, for example, in a molecular still, or, more advantageously, by conversion into a salt or into another derivative thereof, which may be further purified, for example, by recrystallization, if desired, in the presence of an adsorbent, e.g. charcoal, diatomaceous earth and the like.
- an adsorbent e.g. charcoal, diatomaceous earth and the like.
- the bis-amino-l-pyridinium-alkane compounds of the previously-given formula, which are used as the starting materials, are known or, if new, may be prepared according to the procedures used for the known compounds. They may be prepared, for example, by reacting two mols of an amino-pyridine compound with one mole of a reactive ester formed by a dihydroxy-alkane, in which the two hydroxyl groups are separated by at least four carbon atoms, and a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, e.g. hydrobromic acid, or a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g.
- a strong inorganic acid such as a mineral acid, particularly a hydrohalic acid, e.g. hydrobromic acid, or a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic
- the reaction may be carried out in the presence of an inert solvent, such as, for example, a carbocyclic aryl hydrocarbon, e.g. benzene, toluene or xylene, a highboiling aliphatic hydrocarbon, e.g. hexane and the like, a lower alkanone, e.g. Z-butanone, or a lower alkanol, e.g. isopropanol. It is advantageously performed at an elevated temperature, preferably at the boiling temperature of the solvent.
- an inert solvent such as, for example, a carbocyclic aryl hydrocarbon, e.g. benzene, toluene or xylene, a highboiling aliphatic hydrocarbon, e.g. hexane and the like, a lower alkanone, e.g. Z-butanone, or a lower alkanol, e.g. isopropanol
- Particularly useful as starting materials are compounds of the formula in which Alk represents an alkylene radical containing from six to fourteen carbon atoms and separating the two groups Py by four to fourteen carbon atoms, and in which Py represents a 4-amino-l-pyridinium and Hal stands for the anion of a hydrohalic acid.
- This group of starting materials may be represented by compounds of the formula in which Alk" represents an alkylene radical containing from eight to twelve carbon atoms and separating the two 4-amino-1-pyridinium groups by the same number of carbon atoms.
- primary or secondary amino groups may be converted into secondary or tertiary amino groups according to conventional methods.
- compounds vvith primary amino groups may be treated with an aldehyde to form so-called Schiif bases, which upon reduction (for example, with sodium borohydride) yield compoundscontaining secondary amino groups.
- Such groups may also be obtained by reducing in N-acy-lated amino groups the amido into a methylene-amino group; the reduction may be carried out, for example, by treatment with an alkali metal aluminum hydride, e.g. lithium aluminum hydride, in an inert solvent, e.g. ether, whereby it may be advantageous to use an activator, such as aluminum chloride.
- the reduction of amides into amino groups is also suitable for the preparation of tertiary amino groups; upon treatment of an N-acylated secondary amino group with aluminum hydride, the tertiary amino group may be formed.
- Tertiary, as Well as secondary, amino groups may be formed from primary amino groups, for example, by treatment of the amino compounds with catalytically activated hydrogen in the presence of an aldehyde or a ketone.
- a catalyst contains a metal of the eighth group of the periodic system, such as palladium (palladium on charcoal), platinum (platinum oxide or platinum black) or nickel (Raney nickel) and the like; hydrogen may be applied under atmospheric, as well as under increased pressure.
- Any aldehyde or ketone compound suitable in the formation of the previously-shown secondary or tertiary amino groups may be used; for example the use of formaldehyde in the above reaction furnishes methyl groups, whereas acetone yields isopropyl groups.
- secondary and tertiary amino groups from primary or secondary amino groups may also be achieved by treatment of the latter with esters, formed by hydroxylated compounds and strong acids, particularly hydrohalic acids; this reaction may be carried out according to known procedures, such as, for example, according to the conditions used for the alkylation of primary and secondary amino groups with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like.
- esters formed by hydroxylated compounds and strong acids, particularly hydrohalic acids
- hydrohalic acids particularly hydrohalic acids
- N-acylation may be carried out, for example, by treating the amino compound with a reactive functional derivative of one of the carboxylic acids mentioned hereinbefore, such as a halide, e.g. chloride, or an anhydride.
- a reactive functional derivative of one of the carboxylic acids mentioned hereinbefore such as a halide, e.g. chloride, or an anhydride.
- the reaction may be carried out according to known procedures, for example, in the absence or presence of a condensing reagent, such as a liquid organic base, for example, a tri-lower alkyl-amine, e.g. trimethylamine or triethylamine, or preferably a pyridine derivative, e.g.
- pyridine or collidine particularly if an anhydride, e.g. acetic acid anhydride is used.
- Solvents are anhydrous inert organic solvents, such as, for example, lower aliphatic ketones, e.g. acetone.
- Liquid basic condensation reagents such as, for example, pyridine or collidine, may simultaneously serve as solvents.
- a liquid acylation reagent, such as, for example, acetic acid anhydride may be used without an additional solvent.
- the conditions of the reaction, and/or the molar ratios of the reactants monoor poly-acylated products may be obtained.
- N-acylated derivatives may be converted into nonacylated compounds, for example, by acidic or basic hydrolysis.
- Particularly susceptible to hydrolytic cleavage are N-acylated amino compounds, in which the acyl group is derived from an O-lower alkyl-carbonic acid, e.g. O- methyl-carbonic or O-ethyl carbonic acid, or a polyhalogene-lower alkane carboxylic acid, e.g. trifluoroacetic acid.
- N-acylated amino groups may also be converted to non-acylated amino groups by hydrogenolysis; for example, compounds containing N-acyl-amino groups, in which acyl represents the acyl radical of an O-benzyl-carbonic, e.g. O-benzyl-carbonic acid, may be treated with hydrogen in the presence of a catalyst, such as palladium on charcoal, to cleave the N-acylated amino group.
- a catalyst such as palladium on charcoal
- N-acyl-amino groups particularly those which are easily cleaved by hydrolysis or hydrogenolysis
- reactions on compounds containing N-acylated amino may be carried out, which otherwise would affect free primary or secondary amino groups; thetemporary protection of the latter by way of removable acyl groups makes such reactions possible.
- compounds containing N-acylated groups may then be reconverted into compounds containing free primary or secondary amino groups.
- Acylation and deacylation may be carried out according to the previouslydescribed or analogous procedures.
- the compounds of this invention may be obtained in the form of free bases or as thesalts thereof.
- a salt may be converted into the free base, for example, by reacting the former with an alkaline, particularly an aqueous alkaline, reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, or ammonia.
- a free base may be converted into its therapeutically useful acid addition salts by reacting the free base with one of the inorganic or organic acids outlined hereinbefore; salt formation may be carried out, for example, by treating a solution of the free base in a solvent, such as a lower alkanol, e.g.
- salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.
- Quaternary ammonium compounds may be formed from the compounds of this invention. Prior to quaternization, groups, such as primary or secondary amino groups, may temporarily be protected, for example, by easily removable acyl groups, such as those shown hereinbefore.
- the quaternization reaction may be carried out, for example, by treating the free base with an ester formed by a hydroxylated compound and a strong inorganic or organic acid. Hydroxylatcd compounds are primarily lower alkanols containing from one to seven carbon atoms, and esters thereof are more especially those with mineral acids, such as hydrohalic acids, e.g.
- esters are, for example, lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, or lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate, ethane sulfonate or Z-hydroxy-ethane sulfonate.
- lower alkyl halides e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like
- lower alkyl lower alkane sulfonates e.g. methyl or ethyl methane sulfonate, ethane sulfonate or Z-hydroxy-ethane sulfonate.
- the reaction may be performed advantageously in the presence of a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol, a lower alkanone, e.g. acetone or methyl ethyl ketone, or an organic acid amide, e.g. formarnide or dimethylformamide, if necessary, at an elevated temperature, and/or in a closed vessel under pressure.
- a solvent such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol, a lower alkanone, e.g. acetone or methyl ethyl ketone, or an organic acid amide, e.g. formarnide or dimethylformamide, if necessary, at an elevated temperature, and/or in a closed vessel under pressure.
- a solvent such as
- Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quarternary ammonium halide with silver oxide, or a quarternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared therapeutically suitable quaternary ammonium salts by reacting the former with an acid, for example, with one of those described hereinbefore as being suitable for the preparation of the acid addition salts.
- a quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without forming the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as hydrates, e.g. hemihydrates, monohydrates, sesquihydrates or polyhydrates.
- the new compounds of this invention may be obtained as mixtures of racemates, which mixtures may be separated into the individual racemates on the basis of physico-chemical differences, such as solubility; such separation may be carried out, for example, by fractionated crystallization or distillation.
- racemates of the compounds of this invention may be resolved into the optically active dand l-forms according to procedures known for the resolution of racemic compounds.
- the free base of a racemic d,lcompound may be dissolved in a solvent, such as, for
- a lower alkanol e.g. methanol or ethanol
- one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof, for example, in the same lower alkanol or in another solvent may then be added, whereupon a salt can be isolated, which is formed by the optically active acid with one of the optically active form of the base.
- optically active forms of salt-forming acids having an asymmetric carbon atom are D- and L-tartaric acid; the optically active forms of malic, mandelic, camphor sulfonic or quinic acid may also be employed.
- the free and optically active base may be obtained according to processes known for the conversion of a salt into a base, for example, 'as outlined hereinbefore.
- An optically active base may be converted into acid addition salts with one of the acids mentioned hereinbefore, or may be converted into other derivatives thereof.
- Optically active forms may also be isolated by biochemical methods.
- the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.
- Example 1 A solution of 31.1 g. of 1,10-bis-(4-amino-1-pyridinium)-decane dibromide in about 500 ml. of methanol is treated with a large excess of sodium borohydride (a total of about g.) in portions and over a period of several hours. At the beginning, the reaction proceeds exothermically and causes some evaporation of the methanol, which is replenished. After the initial exothermic reaction subsides, the reaction mixture is heated on the steam bath; additional sodium borohydride is added while heating. The solvent is then allowed to evaporate until a thick suspension is formed, which is cooled and treated with 150 ml. of water.
- sodium borohydride sodium borohydride
- the hydrogen chloride may be replaced by other acids, such as, for example, sulfuric, phosphoric, maleic, tartaric or citric acid and the like may be used as salt-forming acids, whereupon the corresponding sulfate, phosphate, maleate, tartrate or citrate and the like of l,lO-bis-(4-amino-l-piperidino)-decane may be isolated.
- acids such as, for example, sulfuric, phosphoric, maleic, tartaric or citric acid and the like may be used as salt-forming acids, whereupon the corresponding sulfate, phosphate, maleate, tartrate or citrate and the like of l,lO-bis-(4-amino-l-piperidino)-decane may be isolated.
- the starting material may be prepared as follows: A mixture of 15.5 g. of Z-aminopyridine, 25 g. of l,l0-dibromodecane and 250 ml. of toluene is refluxed for five hours. A crystalline, tan precipitate is formed, the reaction mixture is cooled and the solid material is collected, dried and recrystallized from ethanol to give the colorless l,lO-bis-(4-amino-l-pyridinium)-decane dibromiide, M.P. 247; yield of crude material; 41.4 g.
- Example 2 The 1,4-bis-(4-amino-1-piperidino)-butane tetrahydrochloride, M.P. 305, may be prepared by reacting 1,4-dibromobutane with 4-amino-pyridine, reducing a methanol solution of the resulting 1,4-bis-(4-amino-l-pyridinium)- butane di bromide, M.P. 275, with sodium borohydride and converting the resulting free base into the salt according to the procedure described in Example 1.
- Example 3 Treatment of 1,6-bis(4-amino-l-pyridinium) -hexane dibromide, M.P. 305, which may be prepared by reacting l,6-dibnomohexane with 4-amino-pyridine, with sodium borohydride in the presence of ethanol gives rise to the formation of 1,6-bis-(4-amin-o-l-piperidino)-hexane, identified as the tetrahydrochloride melting at 204.
- Example 4 A solution of 1,8-dibromooctane and 4-amino-pyridine, when refluxed according to the procedure of Example 1, yields the 1,8bis-(4-amino-l-pyridinium)-octane dibromide, M.P. 302, which is reduced to the desired 1,8bis- (4-amino-1-piperidino)octane by treatment of a methan- 01 solution of the former with sodium borohydrid according to the process described in Example 1; the free base is converted to the tetnahydrochloride, M.P. 306, by treatment with hydrogen chloride.
- Example 5 The reduction of 1,9-bis-(4-amino-l-pyridinium)-non- 'ane dibromid'e, M.P. 222 (prepared from 1,9-dibromononane and 4-amino-pyridine), with sodium borohydride in the presence of methanol yields the 1,9-bis-(4-aminopiperidino)-nonane, characterized as the tetrahydrochloride, M.P. 321.
- the reactions are carried out according to the procedure of Example 1.
- Example 6 The 1,12-bis-(4-amino-1-piperidino)-dodecane may be prepared by treating a methanol solution of 1,12-bis-(4- amino-Lpyridinium)-dodecane dibromide, M.P. 210, with sodium borohydride according to the pnocedure described in Example 1; the free base may be characterized as its tetra-hydrochloride.
- the starting material may be prepared as previously shown, i.e. by refluxing a toluene solution of 1,12-dibromododecane With 4-amino-pyridine.
- Example 7 1,8-dibromo-octane and 4amino-2methyl-pyridine, when refluxed in a toluene solution, yields the 1,8-bis-(4- amino 2 methyl pyridinium)-octane dibromide, M.P. 308, which is reduced by treatment of methanol solution thereof with sodium borohydride, to yield the desired 1,8-bis- 4-amino-2-methyll-piperidino -o ctane, characterized as the tetrahydrochloride.
- Example 8 The reaction of a methanol solution of 1,10-bis-(3- amino-1-pyridinium)-decane dibromide, which is prepared by reacting 3-amino-pyridine with 1,10-dibromodecane in toluene, with hydrogen in the presence or platinum yields the desired 1, 1 O-bis- 3-amino- 1 apiperidino -decane, identified as its tetrahydrochloride.
- Example 9 10 thereof with sodium borohydride according to the procedure of Example 1 yields the 1,10-bis-(4-amino-1- piperidinO)-undecane; the tree base may be converted and characterized as the tetrahydrochloride.
- Example 1 Treatment of an ethanol solution of 1,10-bis-(4 amino- 1-piperidino)-deoane with hydrogen in the presence of palladium on charcoal and an excess of an aqueous solution of formaldehyde results in the formation of the 1,10- bis-(4-dimethylamino-1-piperidino) -decane.
- Example 12 Upon reacting the 1,10-bis-(4-amino-1-piperidino)- decane with trifluoroacetic acid anhydride in the presence of pyridine the 1,10-bis-[4-(N-trifluoroacetylamino)-l piperidino1-decane may be obtained, which, when treated with methyl iodide, yield-s the 1,10-bis-[4-(N-trifluoroacetylarnino)-1-piperidinium]-decane di-iodide.
- N- trifluoroacetylamino groups of the resulting compound may be hydrolyzed by treatment With sodium hydroxide to yield the desired 1,10-bis-(4-amino-1-piperidinium)- decane di-iodide.
- the compounds of the present invention may also be prepared according to other procedures.
- the piperidino groups in which the piperidino groups contain functional substituents capable of being converted into amino groups of the previously- :mentioned type, such groups may be converted into amino groups, and, if desired, the optional steps may be carried out.
- Functional groups which may be converted into amino groups are primarily carboxyl groups, or particularly functional derivatives thereof.
- Functional derivatives of carboxyl groups are primarily their esters With lower alkanols, e.g. methanol or ethanol, which are capable of being converted via hydrazides into azides; under the congroup may also be obtained directly from the carboxyl group by treatment with hydrazoic acid; this reaction may be carried out in the presence of sulfuric acid and directly furnish the desired amino group. This latter modification is carried out according to the conditions of the Schmidt reaction.
- Carbamyl represents another functional derivative of a carboxylic acid, which may be converted to an amino group, for example, according to the Hofmann degradation reaction. This reaction involves bromination of the carbamyl group and rearrangement of the brominated cgrbomyl group in the presence of an alkali metal hydroxi e.
- ' 11 dino)-alkanes may then contain secondary or tertiary amino groups in the piperidyl moiety.
- Previously-described bis-(1-piperidino)-alkane compounds which contain N-acylamino groups in the piperidino moieties, may also be used for the preparation of the desired bis-(amino-l-piperidino)-alkane derivatives; the hydrolysis may be carried out as previously described.
- These bis-(N-acylamino-l-piperindo)-alkanes may be obtained by treating a reactive ester of a bis-hydroxy-alkane, in which the hydroxyl groups are separated by at least four carbon atoms, for example, a bis-dihalogeno-alkane, e.g. a bis-bromo-alkane, with an (N-acylamino)-piperidine.
- the resulting compounds may then be hydrolyzed to the amino derivatives according to previously-described procedures.
- the compounds of the presentainvention may also be obtained by reacting a bis-amino-alkane, in which the amino groups are separated by at least four carbon atoms, with a reactive ester of a 1,5-dihydroXy-pentane, such as a 1,5-dihalogeno-pentane, e.g. a 1,-5-dibromo-pentane, which contains, in addition to the ester groupings, an amino group; this reaction, in which piperidino-nuclei are formed, may be carried out according to known conditions.
- a 1,5-dihydroXy-pentane such as a 1,5-dihalogeno-pentane, e.g. a 1,-5-dibromo-pentane
- Pi-AlkPi' O-phenyl-lower alkyl-carbonic acid, lower alkane car- 4 boxylic acid, trifluoroacetic acid, benzoic acid and phenyllower alkanoic acid, therapeutically acceptable acid addition salts thereof, quaternary ammonium hydroxides thereof, lower alkyl quaternary ammonium halides there- 12 of and lower alkyl quaternary ammonium sulfonates thereof.
- Alk represents an alkylene radical containing from six to fourteen carbon atoms and separating the two groups Pi, by four to fourteen carbon atoms, and Pi, represents 4-amino-l-piperidino.
- Alk represents an alkylene radical containing from eight to twelve carbon atoms and separating the two 4-amino-1-piperidino groups by the same number of carbon atoms.
- Alk represents an alkylene radical separating group Pi from group Pi by four to twenty carbon atoms
- each of the groups Pi and Pi stands for a member selected from the group consisting of 3-amino-1-piperidino and 4-amino-1-piperidino, which comprises contacting a compound, in an inert solvent, of the formula:
- each of Py and Py represents a member selected from the group consisting of 3-amino-l-pyridino and 4-amin0-1-pyridino, and An stands for the anion of an acid, with an alkali metal borohydride reducing agent.
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Description
United States 3,055,902 Patented Sept. 25, 1962 ICQ 3,055,902 BIS-(l-PIPERIDINO) ALKANES Gordon Northrop Walker, Gillette, N.J., assignor to Ciba Corporation, a corporation of Delaware No Drawing. Filed Aug. 4, 1959, Ser. No. 831,459 10 Ciaims. (Cl. 260-293) The present invention concerns bis-piperidino-alkane compounds. More particularly, it relates to compounds of the formula in which Alk represents an alkylene radical separating group Pi from group Pi by four to twenty carbon atoms, and ,each of the groups Pi and Pi stands for an amino-1- piperidino group, N-acyl-ated derivatives, salts and quaternary ammt inium compounds thereof.
The alkylene radical Alk, which separates the amino-lpiperidino radicals by from four to twenty carbon atoms, contains from four to twenty, more especially from six to fourteen, particularly from eight to twelve, primarily ten, carbon atoms, which may be arranged in a straight or in a branched chain. Such alkylene chains are, for example, 1,4-butylene, 1,5'-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,l4-tetradecylene 1,15-pentadecylene, 1,16-hexadecylene, l,17-heptadecylene, 1,18-octadecylene, 1,19-nonadecylene, 1,20- eicosylene, I-methyLLS-pentylene, 3,3-di-methyl-l,5- pentylene, 3,4-dimethyl-1,6-hexylene,4,4-dimethyl 1,7 hept ylene, 2,7-dimethyl-1,8-octylene, S-ethyl 1,9 nonylene, l-methyl-1,l-decylene, 5,6-diethyl-l,lO-decylene, 3,8-dimethyl-1,10-decylene and the like.
In the amino-lpiperidino moieties the amino group is located primarily in the 4 position of the piperidyl nucleus, but may also be attached to the 3position of the ring.
The amino group of the amino-l-piperidino portion represents above all a primary amino group.
Amino may also stand for secondary amino, particularly N-lower alkyl-amino, e.g. N-methylamino, N-ethylamino, N-nqpropylamino, N-isopropylarnino and the like, N-carbocyclic arylamino, such as N-monocyclic carbocyclic aryl-amino, e.g. N-phenylamino and the like, or N-bicyclic carbocyclic aryl-amino, e.g. N-1-naphthyl-' amino or N-Z-naphthyl-amino and the like, or N-carbocyclic aryl-lower alkyl-amino, such as Nmonocyclic carbocyclic aryl-lower aIkyLamino, e. g. N-benzylamino, N-lphenylethylarnino or N-Z-phenylethyl-amino and the like, or bicyclic carbocyclic aryl-lower alkyl-amino, e.g. N-lnaphthyl-methylamino and the like.
=1Also included as amino groups are tertiary amino groups, such as, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N-ethyl-Namethyl-amino, N,N- diethylamino, N,N-dipropylamino or N,N-di-isopropylamino and the like, N-lower alkyl-N-carbocyclic aryllower alkyl-amino, e.g. N-benzyl-N-methyl-amino or N- methyl-N-(2-phenylethyl)-amino and the like, or N-lower 'alkyl-N-lower cycloalkyl-amino, e.g. N-cyclopentyl-N- methyl-amino or N-cyclohexyl-N-methyl-amino and the like. Other tertiary amino groups are, for example, N,N- alkylene-imino groups, in which alkylene contains preferably from four to eight carbon atoms, e.g. l-pyrrolidino, Zmethyl-l-pyrrolidino, l-piperidino, 2-methyl-1-piperidino, S-methyl-lpiperidino, 4amethyl-1-piperidino, 3-hydroxy-lpiperidino, 3-acetoxy-1 piperidino, 3 hydroxymethyl-l-piperidino, N,N-l hexamethyleneimino, N,N,-lheptamethyleneimino and the like, N,N-lower oxa-alkyleneirnino, in which alkylene contains preferably four carbon atoms, e.g. morpholino, or N,N-lower aza-alkyleneimino, in which alkylene contains preferably four carbon atoms, e.g. piper'azino, 4-methyl-piperazino, 4-benzyl- 2 piperazino, 4-(2-hydroxyethyl)-piperazino, 4-(2-acetoxyethyl)apiperazino and the like.
N-acyl-amino may also represent the amino group of the amino-l-pipeiidyl portion of the bis-(amino-l-piperidino)-alkanes of this invention. 'Acyl represents primarily the acyl radical of organic carboxylic acids. Such acids are, for example, aliphatic carboxylic acids, such as carbonic acids, especially O-lower alkyl-carbonic acids, e.g. oamethyl-carbonic or O-ethyl-carbonic acid and the like, O-carbocyclic aryl-lower alkyl-carbonic acids, e.g. O-benzyl-carbonic acid and the like, lower alkane carboxylic acids, which may contain other functional groups, e.g. formic, acetic, propionic, butyric, pivalic or trifluoroacetic acid and the like, carbocyclic aryl carboxylic acids, which may contain additional substituents, such as monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic acid and the like, or carbocyclic aryl-lower alkane carboxylic acids, which may contain other groups, such as monocyclic carbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, or 3+phenyl-propionic acid and the like, or other organic carboxylic acids.
The piperidino nucleus of the amino-l-piperidino group is preferably unsubstituted, or may contain one or more than one additional isubstituent, which may be attached to any of the positions available for substitution in the aminol-piperidino nucleus. Such substituents are particularly lower alkyl, e. g. methyl or ethyl and the like, halogen, e.g. fluorine, chlorine or bromine and the like, lower alkoxy, e.g. methoxy or ethoxy and the like, or other substituents.
Although the two amino-l-piperidino groups Pi and Pi, connected through the alkylene radical, may be of different nature, they are preferably identical.
Salts of the compounds of this invention are particularly therapeutically acceptable acid addition salts with inorganic acids, such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like, with organic carboxylic acids, e.g. formic, acetic, pro- ,pionic, glycolic, lactic, pyruvic, malonic, suocinic, maleic, hydroxymaleic, dihydydromaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicyclic, 4-a-minosalicylic, Z-phenoxybenzoic or 2-acetoxybenzoic, and the like, or with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic or 2-hydroxyethane sulfonic acids. Salts, which are primarily used for identification purposes, are particularly those with acidic organic nitro compounds, e.g. picric, picrolonic or flavianic acid, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic or Reinecke acid. Mono-, more particularly poly-, such as bisor tetra-salts may be formed, depending on the procedure used for the preparation of the salts and/ or the number of salt-forming groups present.
Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by hydroxylated compounds and strong acids, particularly mineral acids, e.g. hydrochloric, hydrobromic or hydriodic acid and the like, or strong organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic or Z-hydroxyethane sulfonic acid and the like. Such esters are, for example, lower alkyl halides, e.g. methyl, ethyl, n propyl or isopropyl chloride, bromide or iodide and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate and the like, or lower alkyl lower hydroxy-alkane sulfonate, e.g. methyl Z-hydroxyethane sulfonate. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts obtained by reacting the latter with inorganic, or more particularly with organic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts. Monoor poly-quaternary ammonium compounds may be formed, depending to exterminate bacteria in an alkane dicarboxylic acids,
on the procedure used for their formation and/or the number of tertiary amino groups present in the molecule.
The compounds may be in the form of mixtures of racemate's, which may be separated into single racemates, or in the form of racemates, which may be resolved into the antipodes.
The compounds of the present invention have COIlSlderable bacteriostatic and bactericidal effects and may, therefore, be used to prevent the propagation and possibly animal or human host, without noticeable adverse effects to the latter. Thus, the previously-described compounds and their salts show bacteriostatic and bactericidal activities against streptococci, such as Streptococcus pyogenes, and staphylococci, such as Staphyloccus aureus, and may, therefore, be used as bacteriostatic and bactericidal agents to prevent and/or combat infections of such bacteria in animals or humans. Particularly good bacteriostatic and bactericidal effects are shown by compounds of the formula represented by compounds of the formula in which Alk" represents a lower alkylene radical containing from eight to twelve carbon atoms and separating the two 4-amino-1-piperidino groups by the same number of carbon atoms, and their addition salts with mineral jacids, e.g. hydrochloric, sulfuric or phosphoric acid, lower alkane carboxylic acids, e.g. acetic or propionic acid, lower alkane dicarboxylic acids, e.g. maleic acid, lower hydroxye.g. tartaric acid, or lower hydroxy-alkane tricarboxylic acids, e.g. citric acid. This group of compounds may be represented by 1,10-bis-(4- amino-l-piperidino)-decane of the formula and the salts, particularly salts with the above-mentioned monobasic and dibasic acids.
.The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new bis-(amino-l-piperidino)-alkane compounds or their salts, especially their pharmacologically compatible acid addition salts, in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, parenteral or topical administration. For making up the preparations there may be employed substances, which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees and the like, in liquid form, for example, as solutions, e.g. isotonic saline solutions, or as suspensions, emulsions or creams and the like. If desired, they may contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buflfers, and the like. They may also contain, in combination, other therapeutically useful substances.
Advantageously the compounds of the present invention may be prepared by treating compounds of the formula in which Alk has the above-given meaning, each of the radicals Py and Py represents an amino-l-pyridinium group (amino having the previously-given meaning), and
An stands for the anion of an acid, with a reducing reagent, and, if desired, converting a primary or a secondary amino group in a resulting compound into a secondary or a tertiary amino, or, if desired, acylating a resulting compound, containing primary or secondary amino groups, and/or, if desired, hydrolyze compounds containing N- acyl groups, and/ or, if desired, converting a resulting salt into the free base, and/ or, if desired, converting a free base into its salts, and/or, if desired, converting in a resulting compound tertiary amino groups into quaternary ammonium groups, while temporarily protecting any primary or secondary amino groups, and/ or, if desired, separating resulting mixtures of racemates into single racemates, and/or, if desired, resolving resulting racemates into antipodes.
In the above formula, depicting the starting materials, An stands primarily for the anion of a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, especially hydrobromic acid, or of a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, particularly p-toluene sulfonic acid. Anions of other inorganic or organic acids may also be conceivable, whereby anions of di-basic acids, such as, for example, sulfuric or tartaric acid may satisfy two positive pyridinium ions.
Reducing reagents capable of converting the bis-(amino- 1-pyridinium)-alkane compounds into the desired bis- (amino-l-piperidino)-alkanes are primarily hydrides, especially borohydrides, such as alkali metal borohydride, e.g. lithium borohydride, sodium borohydride or potassium borohydride, alkaline earth metal borohydrides, e.g. calcium borohydride, strontium borohydride or barium borohydride, or alkali metal tri-lower alkoxy-borohydrides, e.g. sodium trimethoxy-borohydride. Alkali metal tri-lower alkoxy-aluminumhydrides, e.g. lithium tri-propyloxy-aluminumhydride, may also be used as reducing agents. If desired, these reagents may be used together with an activator, such as, for example, aluminum chloride and the like. Solvents used in the reaction are, for example, lower alkanols, e.g. methanol or ethanol, or any other solvent compatible with the above-mentioned metal hydride compounds. The reaction may be carried out under cooling or at room temperature, and, if necessary, may be completed at an elevated temperature. If desired, it may be performed in the atmosphere of an inert gas, e.g. nitrogen.
Another reducing reagent capable of converting bis- (amino -l-pyridinium)-alkane compounds into the corresponding amino-l-piperidino derivatives, may be catalytically activated hydrogen, whereby the catalyst contains a metal of the eighth group of the periodic system, such as platinum or palladium; preferred catalysts are, for example, platinum oxide and palladium on charcoal. This hydrogenation may be carried out in the presence of a solvent, such as a lower alkanoic acid, e.g. acetic acid, or a lower alkanol, e.g. methanol or ethanol, and the like; it may be performed under atmospheric or increased pressure, and, if desired, at an elevated temperature.
Nascent hydrogen, such as generated by a metal or a metal amalgam in the presence of a hydrogen donor, may also be used in the above-described reduction procedure; zinc in the presence of acetic acid or aluminum amalgam in the presence of a moist ether, e.g. tetrahydrofuran, are examples of sources of nascent hydrogen capable of performing the desired reaction.
The resulting bis(amino l-piperidino)-alkanes may be isolated according to conventional methods; for example, an alcoholic solvent used in the metal hydride reduction may be evaporated, the residue suspended in a small amount of water and salted out into a supernatant, only partially water-miscible solvent, e.g. ether, by adding, for example, a solid carbonate, e.g. sodium or potassium carbonate, or an alkali metal halide, e.g. sodium chloride. .The separated and dried organic, e.g. ether, phase may be evaporated and the liquid may be decanted from a,
residue after standing. The resulting free base may be purified by distillation, for example, in a molecular still, or, more advantageously, by conversion into a salt or into another derivative thereof, which may be further purified, for example, by recrystallization, if desired, in the presence of an adsorbent, e.g. charcoal, diatomaceous earth and the like.
The bis-amino-l-pyridinium-alkane compounds of the previously-given formula, which are used as the starting materials, are known or, if new, may be prepared according to the procedures used for the known compounds. They may be prepared, for example, by reacting two mols of an amino-pyridine compound with one mole of a reactive ester formed by a dihydroxy-alkane, in which the two hydroxyl groups are separated by at least four carbon atoms, and a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, e.g. hydrobromic acid, or a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonic acid. The reaction may be carried out in the presence of an inert solvent, such as, for example, a carbocyclic aryl hydrocarbon, e.g. benzene, toluene or xylene, a highboiling aliphatic hydrocarbon, e.g. hexane and the like, a lower alkanone, e.g. Z-butanone, or a lower alkanol, e.g. isopropanol. It is advantageously performed at an elevated temperature, preferably at the boiling temperature of the solvent.
Particularly useful as starting materials are compounds of the formula in which Alk represents an alkylene radical containing from six to fourteen carbon atoms and separating the two groups Py by four to fourteen carbon atoms, and in which Py represents a 4-amino-l-pyridinium and Hal stands for the anion of a hydrohalic acid. This group of starting materials may be represented by compounds of the formula in which Alk" represents an alkylene radical containing from eight to twelve carbon atoms and separating the two 4-amino-1-pyridinium groups by the same number of carbon atoms.
In the compounds resulting from the above-described procedure, primary or secondary amino groups may be converted into secondary or tertiary amino groups according to conventional methods. For example, compounds vvith primary amino groups may be treated with an aldehyde to form so-called Schiif bases, which upon reduction (for example, with sodium borohydride) yield compoundscontaining secondary amino groups. Such groups may also be obtained by reducing in N-acy-lated amino groups the amido into a methylene-amino group; the reduction may be carried out, for example, by treatment with an alkali metal aluminum hydride, e.g. lithium aluminum hydride, in an inert solvent, e.g. ether, whereby it may be advantageous to use an activator, such as aluminum chloride. The reduction of amides into amino groups is also suitable for the preparation of tertiary amino groups; upon treatment of an N-acylated secondary amino group with aluminum hydride, the tertiary amino group may be formed.
Tertiary, as Well as secondary, amino groups may be formed from primary amino groups, for example, by treatment of the amino compounds with catalytically activated hydrogen in the presence of an aldehyde or a ketone. A catalyst contains a metal of the eighth group of the periodic system, such as palladium (palladium on charcoal), platinum (platinum oxide or platinum black) or nickel (Raney nickel) and the like; hydrogen may be applied under atmospheric, as well as under increased pressure. Any aldehyde or ketone compound suitable in the formation of the previously-shown secondary or tertiary amino groups may be used; for example the use of formaldehyde in the above reaction furnishes methyl groups, whereas acetone yields isopropyl groups.
The formation of secondary and tertiary amino groups from primary or secondary amino groups may also be achieved by treatment of the latter with esters, formed by hydroxylated compounds and strong acids, particularly hydrohalic acids; this reaction may be carried out according to known procedures, such as, for example, according to the conditions used for the alkylation of primary and secondary amino groups with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like.
Compounds, prepared according to the procedure of this invention, which contain primary or secondary amino groups, may be converted into acylated derivatives according to procedures used for the preparation of nitrogen-acylated derivatives. N-acylation may be carried out, for example, by treating the amino compound with a reactive functional derivative of one of the carboxylic acids mentioned hereinbefore, such as a halide, e.g. chloride, or an anhydride. The reaction may be carried out according to known procedures, for example, in the absence or presence of a condensing reagent, such as a liquid organic base, for example, a tri-lower alkyl-amine, e.g. trimethylamine or triethylamine, or preferably a pyridine derivative, e.g. pyridine or collidine, particularly if an anhydride, e.g. acetic acid anhydride is used. Solvents are anhydrous inert organic solvents, such as, for example, lower aliphatic ketones, e.g. acetone. Liquid basic condensation reagents, such as, for example, pyridine or collidine, may simultaneously serve as solvents. A liquid acylation reagent, such as, for example, acetic acid anhydride, may be used without an additional solvent. Depending on the number of available primary or secondary amino groups, the conditions of the reaction, and/or the molar ratios of the reactants, monoor poly-acylated products may be obtained.
N-acylated derivatives may be converted into nonacylated compounds, for example, by acidic or basic hydrolysis. Particularly susceptible to hydrolytic cleavage are N-acylated amino compounds, in which the acyl group is derived from an O-lower alkyl-carbonic acid, e.g. O- methyl-carbonic or O-ethyl carbonic acid, or a polyhalogene-lower alkane carboxylic acid, e.g. trifluoroacetic acid. Certain N-acylated amino groups may also be converted to non-acylated amino groups by hydrogenolysis; for example, compounds containing N-acyl-amino groups, in which acyl represents the acyl radical of an O-benzyl-carbonic, e.g. O-benzyl-carbonic acid, may be treated with hydrogen in the presence of a catalyst, such as palladium on charcoal, to cleave the N-acylated amino group.
Compounds of the present invention, which contain N- acyl-amino groups, particularly those which are easily cleaved by hydrolysis or hydrogenolysis, are, therefore, particularly suitable as intermediary compounds. Thus, reactions on compounds containing N-acylated amino may be carried out, which otherwise would affect free primary or secondary amino groups; thetemporary protection of the latter by way of removable acyl groups makes such reactions possible. After completion of the latter, compounds containing N-acylated groups may then be reconverted into compounds containing free primary or secondary amino groups. Acylation and deacylation may be carried out according to the previouslydescribed or analogous procedures.
The compounds of this invention may be obtained in the form of free bases or as thesalts thereof. A salt may be converted into the free base, for example, by reacting the former with an alkaline, particularly an aqueous alkaline, reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, or ammonia. A free base may be converted into its therapeutically useful acid addition salts by reacting the free base with one of the inorganic or organic acids outlined hereinbefore; salt formation may be carried out, for example, by treating a solution of the free base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, n-propanol or isopropanol and the like, or other suitable solvents with the acids or a solution thereof and isolating the resulting salt, for example, by adding another solvent, such as an ether, e.g. diethylether, and thus precipitating the salt, or by any other standard procedure. The salts (monoor poly-salts) may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.
Quaternary ammonium compounds may be formed from the compounds of this invention. Prior to quaternization, groups, such as primary or secondary amino groups, may temporarily be protected, for example, by easily removable acyl groups, such as those shown hereinbefore. The quaternization reaction may be carried out, for example, by treating the free base with an ester formed by a hydroxylated compound and a strong inorganic or organic acid. Hydroxylatcd compounds are primarily lower alkanols containing from one to seven carbon atoms, and esters thereof are more especially those with mineral acids, such as hydrohalic acids, e.g. hydrochloric, hydrobromic or hydriodic acid, or with organic sulfonic acids, such as lower alkane sulfonic acids, e.g. methane, ethane or Z-hydroxy-ethane sulfonic acid and the like. Such esters are, for example, lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, or lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate, ethane sulfonate or Z-hydroxy-ethane sulfonate. The reaction may be performed advantageously in the presence of a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol, a lower alkanone, e.g. acetone or methyl ethyl ketone, or an organic acid amide, e.g. formarnide or dimethylformamide, if necessary, at an elevated temperature, and/or in a closed vessel under pressure.
Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quarternary ammonium halide with silver oxide, or a quarternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared therapeutically suitable quaternary ammonium salts by reacting the former with an acid, for example, with one of those described hereinbefore as being suitable for the preparation of the acid addition salts. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without forming the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as hydrates, e.g. hemihydrates, monohydrates, sesquihydrates or polyhydrates.
The new compounds of this invention may be obtained as mixtures of racemates, which mixtures may be separated into the individual racemates on the basis of physico-chemical differences, such as solubility; such separation may be carried out, for example, by fractionated crystallization or distillation.
The racemates of the compounds of this invention may be resolved into the optically active dand l-forms according to procedures known for the resolution of racemic compounds. For example, the free base of a racemic d,lcompound may be dissolved in a solvent, such as, for
example, a lower alkanol, e.g. methanol or ethanol, and one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof, for example, in the same lower alkanol or in another solvent may then be added, whereupon a salt can be isolated, which is formed by the optically active acid with one of the optically active form of the base. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D- and L-tartaric acid; the optically active forms of malic, mandelic, camphor sulfonic or quinic acid may also be employed. From resulting salts, the free and optically active base may be obtained according to processes known for the conversion of a salt into a base, for example, 'as outlined hereinbefore. An optically active base may be converted into acid addition salts with one of the acids mentioned hereinbefore, or may be converted into other derivatives thereof. Optically active forms may also be isolated by biochemical methods.
The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.
Example 1 A solution of 31.1 g. of 1,10-bis-(4-amino-1-pyridinium)-decane dibromide in about 500 ml. of methanol is treated with a large excess of sodium borohydride (a total of about g.) in portions and over a period of several hours. At the beginning, the reaction proceeds exothermically and causes some evaporation of the methanol, which is replenished. After the initial exothermic reaction subsides, the reaction mixture is heated on the steam bath; additional sodium borohydride is added while heating. The solvent is then allowed to evaporate until a thick suspension is formed, which is cooled and treated with 150 ml. of water. Several hundred grams of potassium carbonate is added, and the organic material is extracted with three portions of ether (a total of about 2500 ml.). The ether solution is dried over potassium carbonate, filtered and evaporated. The residue is allowed to stand for several days; the liquid portion, representing the 1,10- bis-(4-amino-l-piperidino)-decane, is decanted from the solid phase.
It is converted into the salt as follows: A solution of the base in ethanol is treated with an excess of dry hydrogen chloride, the precipitate is filtered ofi, washed with ethanol (yield: about 5 g.) and recrystallized from the same solvent yielding the l,10-bis-(4-amino-l-piperidino)- decane tetrahydrochloride, M.P. 285. The hydrogen chloride may be replaced by other acids, such as, for example, sulfuric, phosphoric, maleic, tartaric or citric acid and the like may be used as salt-forming acids, whereupon the corresponding sulfate, phosphate, maleate, tartrate or citrate and the like of l,lO-bis-(4-amino-l-piperidino)-decane may be isolated.
The starting material may be prepared as follows: A mixture of 15.5 g. of Z-aminopyridine, 25 g. of l,l0-dibromodecane and 250 ml. of toluene is refluxed for five hours. A crystalline, tan precipitate is formed, the reaction mixture is cooled and the solid material is collected, dried and recrystallized from ethanol to give the colorless l,lO-bis-(4-amino-l-pyridinium)-decane dibromiide, M.P. 247; yield of crude material; 41.4 g.
Example 2 The 1,4-bis-(4-amino-1-piperidino)-butane tetrahydrochloride, M.P. 305, may be prepared by reacting 1,4-dibromobutane with 4-amino-pyridine, reducing a methanol solution of the resulting 1,4-bis-(4-amino-l-pyridinium)- butane di bromide, M.P. 275, with sodium borohydride and converting the resulting free base into the salt according to the procedure described in Example 1.
Example 3 Treatment of 1,6-bis(4-amino-l-pyridinium) -hexane dibromide, M.P. 305, which may be prepared by reacting l,6-dibnomohexane with 4-amino-pyridine, with sodium borohydride in the presence of ethanol gives rise to the formation of 1,6-bis-(4-amin-o-l-piperidino)-hexane, identified as the tetrahydrochloride melting at 204.
Example 4 A solution of 1,8-dibromooctane and 4-amino-pyridine, when refluxed according to the procedure of Example 1, yields the 1,8bis-(4-amino-l-pyridinium)-octane dibromide, M.P. 302, which is reduced to the desired 1,8bis- (4-amino-1-piperidino)octane by treatment of a methan- 01 solution of the former with sodium borohydrid according to the process described in Example 1; the free base is converted to the tetnahydrochloride, M.P. 306, by treatment with hydrogen chloride.
Example 5 The reduction of 1,9-bis-(4-amino-l-pyridinium)-non- 'ane dibromid'e, M.P. 222 (prepared from 1,9-dibromononane and 4-amino-pyridine), with sodium borohydride in the presence of methanol yields the 1,9-bis-(4-aminopiperidino)-nonane, characterized as the tetrahydrochloride, M.P. 321. The reactions are carried out according to the procedure of Example 1.
Example 6 The 1,12-bis-(4-amino-1-piperidino)-dodecane may be prepared by treating a methanol solution of 1,12-bis-(4- amino-Lpyridinium)-dodecane dibromide, M.P. 210, with sodium borohydride according to the pnocedure described in Example 1; the free base may be characterized as its tetra-hydrochloride.
The starting material may be prepared as previously shown, i.e. by refluxing a toluene solution of 1,12-dibromododecane With 4-amino-pyridine.
Example 7 1,8-dibromo-octane and 4amino-2methyl-pyridine, when refluxed in a toluene solution, yields the 1,8-bis-(4- amino 2 methyl pyridinium)-octane dibromide, M.P. 308, which is reduced by treatment of methanol solution thereof with sodium borohydride, to yield the desired 1,8-bis- 4-amino-2-methyll-piperidino -o ctane, characterized as the tetrahydrochloride.
Example 8 The reaction of a methanol solution of 1,10-bis-(3- amino-1-pyridinium)-decane dibromide, which is prepared by reacting 3-amino-pyridine with 1,10-dibromodecane in toluene, with hydrogen in the presence or platinum yields the desired 1, 1 O-bis- 3-amino- 1 apiperidino -decane, identified as its tetrahydrochloride.
Example 9 10 thereof with sodium borohydride according to the procedure of Example 1 yields the 1,10-bis-(4-amino-1- piperidinO)-undecane; the tree base may be converted and characterized as the tetrahydrochloride.
Example 1] Treatment of an ethanol solution of 1,10-bis-(4 amino- 1-piperidino)-deoane with hydrogen in the presence of palladium on charcoal and an excess of an aqueous solution of formaldehyde results in the formation of the 1,10- bis-(4-dimethylamino-1-piperidino) -decane.
Example 12 Upon reacting the 1,10-bis-(4-amino-1-piperidino)- decane with trifluoroacetic acid anhydride in the presence of pyridine the 1,10-bis-[4-(N-trifluoroacetylamino)-l piperidino1-decane may be obtained, which, when treated with methyl iodide, yield-s the 1,10-bis-[4-(N-trifluoroacetylarnino)-1-piperidinium]-decane di-iodide. The N- trifluoroacetylamino groups of the resulting compound may be hydrolyzed by treatment With sodium hydroxide to yield the desired 1,10-bis-(4-amino-1-piperidinium)- decane di-iodide.
The compounds of the present invention may also be prepared according to other procedures. For example, in bis-l-piperidino-alkane compounds, in Which the piperidino groups contain functional substituents capable of being converted into amino groups of the previously- :mentioned type, such groups may be converted into amino groups, and, if desired, the optional steps may be carried out.
Functional groups Which may be converted into amino groups are primarily carboxyl groups, or particularly functional derivatives thereof. Functional derivatives of carboxyl groups are primarily their esters With lower alkanols, e.g. methanol or ethanol, which are capable of being converted via hydrazides into azides; under the congroup may also be obtained directly from the carboxyl group by treatment with hydrazoic acid; this reaction may be carried out in the presence of sulfuric acid and directly furnish the desired amino group. This latter modification is carried out according to the conditions of the Schmidt reaction.
Carbamyl represents another functional derivative of a carboxylic acid, which may be converted to an amino group, for example, according to the Hofmann degradation reaction. This reaction involves bromination of the carbamyl group and rearrangement of the brominated cgrbomyl group in the presence of an alkali metal hydroxi e. T
' 11 dino)-alkanes may then contain secondary or tertiary amino groups in the piperidyl moiety.
Previously-described bis-(1-piperidino)-alkane compounds, which contain N-acylamino groups in the piperidino moieties, may also be used for the preparation of the desired bis-(amino-l-piperidino)-alkane derivatives; the hydrolysis may be carried out as previously described. These bis-(N-acylamino-l-piperindo)-alkanes may be obtained by treating a reactive ester of a bis-hydroxy-alkane, in which the hydroxyl groups are separated by at least four carbon atoms, for example, a bis-dihalogeno-alkane, e.g. a bis-bromo-alkane, with an (N-acylamino)-piperidine. The resulting compounds may then be hydrolyzed to the amino derivatives according to previously-described procedures.
The compounds of the presentainvention may also be obtained by reacting a bis-amino-alkane, in which the amino groups are separated by at least four carbon atoms, with a reactive ester of a 1,5-dihydroXy-pentane, such as a 1,5-dihalogeno-pentane, e.g. a 1,-5-dibromo-pentane, which contains, in addition to the ester groupings, an amino group; this reaction, in which piperidino-nuclei are formed, may be carried out according to known conditions.
Compounds of this invention, which have the previously-given formula in which Alk has the above-mentioned meaning, and the two radicals Pi and Pi are amino-l-piperidyl radicals, but of difierent structure, may be obtained, whenever the starting materials are prepared stepwise.
What is claimed is:
1. A member of the group consisting of compounds of the formula:
Pi-AlkPi' O-phenyl-lower alkyl-carbonic acid, lower alkane car- 4 boxylic acid, trifluoroacetic acid, benzoic acid and phenyllower alkanoic acid, therapeutically acceptable acid addition salts thereof, quaternary ammonium hydroxides thereof, lower alkyl quaternary ammonium halides there- 12 of and lower alkyl quaternary ammonium sulfonates thereof.
2. Compounds of the formula:
in which Alk represents an alkylene radical containing from six to fourteen carbon atoms and separating the two groups Pi, by four to fourteen carbon atoms, and Pi, represents 4-amino-l-piperidino.
3. Compounds of the formula:
in which Alk represents an alkylene radical containing from eight to twelve carbon atoms and separating the two 4-amino-1-piperidino groups by the same number of carbon atoms.
4. 1,8-bis-(4-amino-1-piperidino)-octane.
5. l,9-bis-(4amino11-piperidin0)-n0nane.
6. 1,10-bis-(4-amino-1-piperidino)-decane.
7. 1,10-bis-(4-amino-l-piperidino)-decane tetrahydrochloride.
8. 1,-10-bis-(4-amino-1-piperidino)-undecane.
9. 1,12-bis-(4-amino-1-piperidino)-dodecane.
10. Process for the preparation of a compound of the formula:
Pi-Alk-Pi in which Alk represents an alkylene radical separating group Pi from group Pi by four to twenty carbon atoms, and each of the groups Pi and Pi stands for a member selected from the group consisting of 3-amino-1-piperidino and 4-amino-1-piperidino, which comprises contacting a compound, in an inert solvent, of the formula:
[PyAlkPy1 21 in which Alk has the above-given meaning, each of Py and Py represents a member selected from the group consisting of 3-amino-l-pyridino and 4-amin0-1-pyridino, and An stands for the anion of an acid, with an alkali metal borohydride reducing agent.
References Cited in the file of this patent UNITED STATES PATENTS 2,261,002 Ritter Oct. 28, 1941 2,271,378 SeaIle Jan. 27, 1942 2,716,134 Reynolds et a1 Aug. 23, 1955 FOREIGN PATENTS 536,017 Great Britain Apr. 30, 1941
Claims (1)
1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA:
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US831459A US3055902A (en) | 1959-08-04 | 1959-08-04 | Bis-(1-piperidino) alkanes |
Publications (1)
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US3055902A true US3055902A (en) | 1962-09-25 |
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Application Number | Title | Priority Date | Filing Date |
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US831459A Expired - Lifetime US3055902A (en) | 1959-08-04 | 1959-08-04 | Bis-(1-piperidino) alkanes |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4206215A (en) * | 1976-02-25 | 1980-06-03 | Sterling Drug Inc. | Antimicrobial bis-[4-(substituted-amino)-1-pyridinium]alkanes |
US4542125A (en) * | 1984-03-23 | 1985-09-17 | Sterling Drug Inc. | Antimicrobial surface degerming compositions and method of use thereof |
US4707507A (en) * | 1985-09-04 | 1987-11-17 | Adeka Argus Chemical Co., Ltd. | 2,2,6,6-tetramethyl quaternary ammonium halides and synthetic resin and stabilizer compositions |
JP2007510672A (en) * | 2003-11-13 | 2007-04-26 | ザ・ユニバーシティ・オブ・シドニー | Bis-cationic compounds and their use |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB536017A (en) * | 1938-08-30 | 1941-04-30 | Du Pont | Polymeric quaternary ammonium salts from ditertiary diamines and dihalides |
US2261002A (en) * | 1941-06-17 | 1941-10-28 | Du Pont | Organic nitrogen compounds |
US2271378A (en) * | 1939-08-30 | 1942-01-27 | Du Pont | Pest control |
US2716134A (en) * | 1950-04-19 | 1955-08-23 | Eastman Kodak Co | N, n, n', n'-tetrasubstituted diamines |
-
1959
- 1959-08-04 US US831459A patent/US3055902A/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB536017A (en) * | 1938-08-30 | 1941-04-30 | Du Pont | Polymeric quaternary ammonium salts from ditertiary diamines and dihalides |
US2271378A (en) * | 1939-08-30 | 1942-01-27 | Du Pont | Pest control |
US2261002A (en) * | 1941-06-17 | 1941-10-28 | Du Pont | Organic nitrogen compounds |
US2716134A (en) * | 1950-04-19 | 1955-08-23 | Eastman Kodak Co | N, n, n', n'-tetrasubstituted diamines |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4206215A (en) * | 1976-02-25 | 1980-06-03 | Sterling Drug Inc. | Antimicrobial bis-[4-(substituted-amino)-1-pyridinium]alkanes |
US4542125A (en) * | 1984-03-23 | 1985-09-17 | Sterling Drug Inc. | Antimicrobial surface degerming compositions and method of use thereof |
US4707507A (en) * | 1985-09-04 | 1987-11-17 | Adeka Argus Chemical Co., Ltd. | 2,2,6,6-tetramethyl quaternary ammonium halides and synthetic resin and stabilizer compositions |
JP2007510672A (en) * | 2003-11-13 | 2007-04-26 | ザ・ユニバーシティ・オブ・シドニー | Bis-cationic compounds and their use |
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