US3352912A - Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes - Google Patents
Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes Download PDFInfo
- Publication number
- US3352912A US3352912A US376259A US37625964A US3352912A US 3352912 A US3352912 A US 3352912A US 376259 A US376259 A US 376259A US 37625964 A US37625964 A US 37625964A US 3352912 A US3352912 A US 3352912A
- Authority
- US
- United States
- Prior art keywords
- undecane
- tricycle
- adamantane
- tricyclo
- ether
- 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
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical class CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 title description 171
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical class C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 title description 55
- 150000001875 compounds Chemical class 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
- 239000000243 solution Substances 0.000 description 60
- -1 alkyl radical Chemical class 0.000 description 46
- 239000000203 mixture Substances 0.000 description 45
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000012280 lithium aluminium hydride Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- UPWLURAENVJIJL-UHFFFAOYSA-N adamantane;hydrochloride Chemical compound Cl.C1C(C2)CC3CC1CC2C3 UPWLURAENVJIJL-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 150000001805 chlorine compounds Chemical class 0.000 description 5
- 239000012259 ether extract Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XSOHXMFFSKTSIT-UHFFFAOYSA-N 1-adamantylmethanamine Chemical compound C1C(C2)CC3CC2CC1(CN)C3 XSOHXMFFSKTSIT-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 229910021529 ammonia Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- NAQQTJZRCYNBRX-UHFFFAOYSA-N n-pentan-3-ylidenehydroxylamine Chemical compound CCC(CC)=NO NAQQTJZRCYNBRX-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- MVYBXAPKYZVQTR-UHFFFAOYSA-N 1-(1-adamantyl)-n,n-dimethylmethanamine Chemical compound C1C(C2)CC3CC2CC1(CN(C)C)C3 MVYBXAPKYZVQTR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 2
- MIBQYWIOHFTKHD-UHFFFAOYSA-N adamantane-1-carbonyl chloride Chemical compound C1C(C2)CC3CC2CC1(C(=O)Cl)C3 MIBQYWIOHFTKHD-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 description 2
- UJYLYGDHTIVYRI-UHFFFAOYSA-N cadmium(2+);ethane Chemical compound [Cd+2].[CH2-]C.[CH2-]C UJYLYGDHTIVYRI-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 244000144972 livestock Species 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
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- DYUWTXWIYMHBQS-UHFFFAOYSA-N n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCNCC=C DYUWTXWIYMHBQS-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RSJKGSCJYJTIGS-BJUDXGSMSA-N undecane Chemical group CCCCCCCCCC[11CH3] RSJKGSCJYJTIGS-BJUDXGSMSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- SNJMEUDNDRSJAS-UHFFFAOYSA-N 2-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(CCN)C3 SNJMEUDNDRSJAS-UHFFFAOYSA-N 0.000 description 1
- PXQHUVHSOLQIQZ-UHFFFAOYSA-N 2-(1-adamantylmethylamino)ethanol Chemical compound C1C(C2)CC3CC2CC1(CNCCO)C3 PXQHUVHSOLQIQZ-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical class 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- NZXLSJFSECATQY-UHFFFAOYSA-N Cl.CN(C)CC12CC3CC(CC(C1)C3)C2 Chemical compound Cl.CN(C)CC12CC3CC(CC(C1)C3)C2 NZXLSJFSECATQY-UHFFFAOYSA-N 0.000 description 1
- TWDJIKFUVRYBJF-UHFFFAOYSA-N Cyanthoate Chemical compound CCOP(=O)(OCC)SCC(=O)NC(C)(C)C#N TWDJIKFUVRYBJF-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000662429 Fenerbahce Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010069767 H1N1 influenza Diseases 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- UYVNICMJTSQMPP-UHFFFAOYSA-N N-(1-adamantylmethyl)-N-ethylethanamine hydrochloride Chemical compound Cl.C(C)N(CC)CC12CC3CC(CC(C1)C3)C2 UYVNICMJTSQMPP-UHFFFAOYSA-N 0.000 description 1
- 208000009620 Orthomyxoviridae Infections Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
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- 238000006434 Ritter amidation reaction Methods 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 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 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- CKBZJTAMRPPVSR-UHFFFAOYSA-N adamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2CC1(C(=O)N)C3 CKBZJTAMRPPVSR-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 description 1
- 229960000892 attapulgite Drugs 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- OWAQXCQNWNJICI-UHFFFAOYSA-N benzene;chloroform Chemical compound ClC(Cl)Cl.C1=CC=CC=C1 OWAQXCQNWNJICI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- JMSRBKPMLUGHCR-UHFFFAOYSA-N bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical class OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- YGLLICRFEVEWOZ-UHFFFAOYSA-L disodium;3-carboxy-1-[(3-carboxy-2-oxidonaphthalen-1-yl)methyl]naphthalen-2-olate Chemical compound [Na+].[Na+].C1=CC=C2C(CC3=C4C=CC=CC4=CC(=C3O)C([O-])=O)=C(O)C(C([O-])=O)=CC2=C1 YGLLICRFEVEWOZ-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229910000286 fullers earth Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- ZQWHHCSEGLAVTC-UHFFFAOYSA-N n,n-diethyladamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2CC1(C(=O)N(CC)CC)C3 ZQWHHCSEGLAVTC-UHFFFAOYSA-N 0.000 description 1
- RMRZPLJAVNSFCJ-UHFFFAOYSA-N n,n-dimethyladamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2CC1(C(=O)N(C)C)C3 RMRZPLJAVNSFCJ-UHFFFAOYSA-N 0.000 description 1
- YGEUBHFQORJDLZ-UHFFFAOYSA-N n-(1-adamantylmethyl)-2-methylpropan-2-amine Chemical compound C1C(C2)CC3CC2CC1(CNC(C)(C)C)C3 YGEUBHFQORJDLZ-UHFFFAOYSA-N 0.000 description 1
- IOXXVNYDGIXMIP-UHFFFAOYSA-N n-methylprop-2-en-1-amine Chemical compound CNCC=C IOXXVNYDGIXMIP-UHFFFAOYSA-N 0.000 description 1
- RGSODMOUXWISAG-UHFFFAOYSA-N n-prop-2-ynylprop-2-yn-1-amine Chemical compound C#CCNCC#C RGSODMOUXWISAG-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 229910052625 palygorskite Inorganic materials 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-OUBTZVSYSA-N potassium-40 Chemical compound [40K] ZLMJMSJWJFRBEC-OUBTZVSYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- OADNVNPVQYWJMK-UHFFFAOYSA-N undecane;hydrochloride Chemical compound Cl.CCCCCCCCCCC OADNVNPVQYWJMK-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005303 weighing Methods 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
- C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/29—Saturated compounds containing keto groups bound to rings
- C07C49/313—Saturated compounds containing keto groups bound to rings polycyclic
- C07C49/323—Saturated compounds containing keto groups bound to rings polycyclic having keto groups bound to condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- the com-pounds of this invention are adamantanes of the formula and tricyclo[4.3.l.l ]undecanes of the formula 3,352,912 Patented Nov. 14, 1967 where X and Y can be the same or different and are hydrogen,
- n 2, 3, 4, 5, or 6; NR R or N CHR wherein R is hydrogen; alkyl of 1 through 6 carbon atoms; mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2 carbon atoms, NH NHR or -NR R where R and R can be the same or different and each is an alkyl radical of 1 through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; cyclobutylmethyl;
- R is R chlorine; bromine; for-myl; CH COOH or CH COOC H with the proviso that when R is alkenyl or alkynyl having the unsaturated bond in the 1-position, R is alkyl or mono-substituted alkyl as above defined;
- substituent is aromatic or heterocyclic; aromatic; or heterocyclic containing not more than 12 carbon atoms.
- compounds of the invention are preferred Where the amine on the adamantane or undecane moiety is substituted with dialkyl (N,N-dialkylated compounds) because they provide a very favorable balance of antiviral activity with reduced stimulant activity.
- dialkyl N,N-dialkylated compounds
- the lower alkyl substituents such as the dimethyl and diethyl derivatives are most preferred from considerations of higher anti-viral activity.
- Compounds of the invention where the amine on the adamantane or undecane moiety is monoalkylated also demonstrate reduced stimulant acanti-viral activity than the dialkylated amine derivatives.
- R is aliphatic; mono-substituted aliphatic where the zit-substituted compounds exhibit higher anti-viral activity but less favorable drug dynamics in comparison to the :,oL-Sllb5iil1lll6d compounds.
- the compounds of this invention can be prepared by a variety of methods.
- l-adamantane carboxylic acid and 3-tricyclo[4.3.1.1 undecane carboxylic acid can be converted to the corresponding acid chlorides with thionyl chloride.
- the unsubstituted amides and a variety of N-alkyland N,N-dialkylsubstituted amides can be prepared from the acidchlorides by reaction with the appropriately substituted amines and ammonia. These amides are then reduced with lithium aluminum hydride to the corresponding amino-, N-alkylaminoand N,N-dialkylaminomethyl-adamantanes .and tricycloundecanes.
- Thea-alkyl-l-adamantanemethylamines and a-alkyl-3- tricyclo[4.3.1.1 ]undecanemethylamines are prepared by reduction of adamantyl-(l) alkyl ketone oximes and tricyclo[4.3.1.1 ]undecyl-(3) alkyl ketone oximes with lithium aluminum hydride.
- the ketones from which these oximes are derived are conveniently made by the reaction of the appropriate dialkyl cadmium with l-adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoy1 chloride.
- the u,a-dialkyl-l-adamantanemethylamines and .ot,oL- dialkyl 3 tricyclo[4.3.1.1 ]undecanemethylamines are made by the reaction of acetonitrile and sulfuric acid (Ritter reaction) with the corresponding a,a-dialkyl-1-adamantanemethanol or (1,0: dialkyl 3 tricycl0[4.3.1.l ]undecanemethanol, which gives the N acetyl a,ot dialkyll adamantanemethylamine or N acetyl 04,0: dialkyl 3 tricyclo[4.3.l.1 ]undecanemethylamine.
- the amine is obtained by alkaline hydrolysis.
- the starting alcohols for these reactions are made by the reaction of 1 adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoyl chloride with alkyl Grignard reagents.
- reactions of the acid chlorides with allylamine and diallylamine give the N-allyl and N,N-diallyl compounds after reduction.
- Reactions of the acid chlorides with propargylamine and dipropargylamine give the N-propargyl and N,N-dipropargy1 compounds after reduction.
- Some substituted alkyl amino compounds are more easily made by other routes. Hydroxyethyland bis-hydroxyethyl compounds are made by reaction of the amine with ethylene oxide. N-carbalkoxymethylamino compounds are made by alkylation with alkyl chloroacetate and base.
- Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylation with appropriate aminoalkyl halides and base, although they can be made by treating the corresponding hydroxyalkyl compound with a thionyl halide to replace the hydroxyl group with a halogen and then replacing the halogen with the amino, alkylamino, or dialkylamino group by reaction with ammonia or a primary or secondary amine.
- N-alkyland N,N-dialkyl-compounds are easily made by alkylation of l-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.l ]undecane with alkylating agents (such as alkyl halides), without resorting to reduction of N-alkyland N,N-dialkyl-amides.
- the monoalkylamino compound When the reagents are used in molar amounts, the monoalkylamino compound is generally formed as the major product, whereas greater amounts of the reagents give the dialkylamino compound.
- This method is not as clean-cut as reduction of the amides which is Why it is less preferred. However, it sometimes becomes the method of choice because it involves fewer steps.
- Ethylene chloroand bromo-hydrin, and alkoxyalkyl halides can be used. to alkylate the amino nitrogen, to give the hydroxyethyland alkoxyalkyl-substitutions. For the reasons just given, these reactions are less preferable than other methods but. may be preferred in certain instances, and they illustrate an alternate route to substituted alkylaminomethyltricyclo[4.3.1.1 ]undecanes and adamantanes by ordinary alkylation with a substituted alkylating reagent.
- Reactions of l-(aminomethyl)adamantane and 3- (aminomethyl)tricyclo[4.3.1.1 ]undecane with aldehydes give the corresponding alkylidene, arylidene or heterocyclicylidene aminomethyladamantanes and aminomethyltricycloundecancs.
- reaction of l-(aminomethyl)adamantane with formaldehyde gives N-(l-adamantylmethyl)azomethine.
- Reaction of 3-(aminomethyl) tricyclo[4.3.l.l ]undecane with benzaldehyde gives 3- (benzylideneaminomethyl)tricyclo [4.3.1.1 ]undecane.
- undecane 3- [N- 2-rnethylamineethyl) aminemethyl] tricycle [4.3 .1.1 ]undecane 3 [N- 3-dirnethylamineprepyl aminemethyl] tricycle [4.3 .1 1 undecane 3 [N- (2-dimethylarnineethyl -N-methylaminomethyl] tricycle [4.3.
- undecane 3- (N-chlere-Nhexylarninemethyl) tricycle [4.3 1 1 undecane 3- (N-bremeaminernethyl) tricycle [4.3.1. 1 ]undecane 3- (N-brome-N-methylaminemethyl tricycle [4.3 .1. 1
- undecane 3- (N-brerno-N-hexylaminemethyl) tricycle [4.3 1 1 undecane 3-(fermamidernethyl) tricycle [4.3.1.1 undecane 3- (N rnethylfermarnidemethyl) tricycle [4.3 1 1 undecane 3 -(N-hexylfermamidernethyl)tricycle[4.3.l.1
- Example 1 A solution of 6 parts of I-adamantane carbexamide in 200 parts of tetrahydrefuran is added slowly to a wellstirred suspension of 6.15 parts of lithium aluminum hydride in 200 parts of dry diethyl ether. After completion of addition, the mixture is refluxed for one hour and the solvent distilled 01f. The residue is subjected to steam distillation. The waxy l-aminomethyl adamantane is extracted from the steam distillate with ether and the ethereal solution dried with solid potassium hydroxide. Dry hydrogen chloride is then passed into the ether solution to precipitate the amine hydrochloride. The yield is 5.25 parts of l-(aminomethyl)adamantane hydrochloride which melts at 337-340 C. after recrystallization from chloroform-benzene.
- the free l-aminomethyl adamantane melts at 128.5 C. and can be converted to an acetyl derivative by treatment with acetic anhydride which, after recrystallization from n-hexane, melts at 123-124".
- Example 2 A solution of 17 parts of l-adamantoyl chloride in 150 parts of acetone is treated with 15 parts of a 40% aqueous solution of methylarnine at C. After complete addition, the mixture is warmed gently and diluted with Water. The crystalline l-N-methyl adamantane carboxamide is isolated by filtration as 11.27 parts of material melting at 137138 C. In an alternative synthesis of this compound, dry methylamine, 2 equivalents, is distilled into an ethereal solution of adamantoyl chloride, 1 equivalent, and the resulting solution evaporated to dryness.
- Example 3 A solution of 19.85 parts of l-adamantoyl chloride in 100 parts of dry diethyl ether is stirred at 0 C. and an ethereal solution of 9 parts of dimethylamine added slowly. The mixture is then stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed. This gives 19.5 parts (94.2%) of 1-N,N-dimethyl adamantane carboxamide which melts at 76-78 C. The 19.5 parts of amide is dissolved in 100 parts of ether and added slowly to a well stirred suspension of 4.5 parts of LiAlH in 300 parts of ether.
- Example 4 A solution of 19.85 parts of l-adamantoyl chloride is treated with 9 parts of ethylamine under the condi- 10 tions outlined in the previous example to give 19.56 parts, 94.5%, of l-N-ethyl adamantane carboxamide melting at 138 C.
- Example 5 A solution of 19.85 parts of l-adamantoyl chloride in other is reacted with an ethereal solution of 12 parts of propylamine by the procedure of Example 3 to give 21.38 parts of l-(N-propyl)adamantane carboxamide melting at 140141 C. Twenty-one parts of this amide is reduced with LiAlH as shown in the previous example to give 19.4 parts of l-(N-propylamino-rnethyl)adamantane hydrochloride. After recrystallization from methanol, this melts at 342 C.
- Example 6 Under the conditions of the previous example, 19.85 parts of l-adamantoyl chloride and 14.67 parts of diethylamine give 22.8 parts of 1-N,N-diethyladamantane carboxamide, M.P. 6263 C.
- Example 7 A solution of 5.8 parts of 3-carboxytricyclo[4.3.1.1 undecane in 10 parts of thionyl chloride is refluxed until hydrogen chloride evolution ceases.
- the crude acid halide thus prepared is isolated by distilling off the excess thionyl chloride under reduced pressure, adding a small amount of benzene and removing this under reduced pressure.
- the acid chloride is then dissolved in 200 parts of ether and an excess of dry methylamine passed into the stirred solution at 0 C.
- the reaction is then stirred for 30 minutes and diluted with water.
- the layers are separated, the ether layer washed with water and dried over calcium chloride. Removal of the solvent gives 3.7 parts of white leaflets, melting at 133 C., of N-methyltricyclo [4.3. l.1 ]undecyl-3 -carboxamide.
- Example 8 The amine hydrochloride of Example 2, 5.4 parts, is dissolved in 20 parts of pyridine and 5 parts of acetic anhydride is added. The mixture is warmed gently until a clear solution is obtained, then heated on a steam bath for 30 minutes and diluted with cold water.
- the solid Example 9 A sample of B-carboxamidotricyclo [4.3.l.1 ]undecane is prepared by convertin the 3-carboxytricyclo[4.3.1. 1 ]undecane of Stetter, Ber., 92, 1629-1635 (1959), to
- Example 10 A solution of 19.85 grams (0.10 mole) of l-adamantoyl chloride in 100 milliliters of dry diethyl ether is stirred at C. and an ethereal solution of 12.7 grams (0.15 mole) of piperidine is added slowly. The mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed to leave 1-adamantoylpiperidide.
- Example 11 A mixture of 3.6 g. of magnesium turnings, a small crystal of iodine,,1l ml. of anhydrous benzene and 1 ml. of absolute ethanol is heated until a reaction begins. Then heating is discontinued and a mixture of 24.0 g. of diethyl malonate, 7.0 g. of absolute ethanol and 30 ml. of benzene is added dropwise at a rate which causes the reactionmixture to reflux. After addition is completed, the mixture is heated at reflux until the magnesium has dissolved. The excess ethanol is removed by azeotropic distillation with some of the benzene. To the resultant solution of ethoxymagnesiumdiethylmalonate is added a solution of 19.8 g.
- a mixture of 14 g. of hydroxylamine hydrochloride, 65 ml. of anhydrous pyridine and 65 ml. of anhydrous ethanol is heated on a steam bath until a clear solution is obtained.
- 13.4 g. of adamantyl-(l) methyl ketone is added to this is added 13.4 g. of adamantyl-(l) methyl ketone, and the mixture is heated at reflux for 2 hours, then cooled. It is concentrated to dryness in a vacuum at 70, and the residue is suspended in 150 ml. of water and stirred well.
- the solids are filtered and dried to yield 14.2 g. of adamantyl-( 1) methyl ketone oxime, a white, crystalline compound melting at 180.5 182 C. This can be recrystallized from a dioxane-water mixture without affecting the melting point.
- oxime is added to a mixture of 3.3 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran, and the mixture is stirred and heated at reflux for 3 hours. It is cooled in an ice bath and the excess of lithium aluminum hydride is destroyed with a water-tetrahydrofuran mixture. Several ml. of 10% sodium hydroxide solution is added to aid in the coagulation of the solids, which are removed by filtration, washed with 50 ml. of chloroform, and discarded. The filtrate, which includes the tetrahydrofuran solution and the chloroform solution, is saturated with dry hydrogen chloride and then concentrated to dryness in a vacuum at 50 C.
- Example 12 Substitution of 21.3 g. of 3-tricyclo[4.3.1.1 ]-undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 11 and repetition of the procedure of that example leads to tricyclo[4.3.l.1 ]undecyl-(3) methyl ketone, then to tricyclo[4.3.1.1 ]undecyl-(3) methyl ketone oxime, and, after the reduction, to u-methyl-3- tricyclo [4.3 1. 1 -undecanemethylamine hydrochloride.
- Example 13 To a solution of 31.5 g. of l-adamantoyl chloride in 500 ml. of anhydrous ether under a nitrogen atmosphere is added, dropwise, ml. of commercial 3 M methyl magnesium bromide at a rate which maintains a gentle reflux. The reaction mixture is heated for 1 hour after the addition, then cooled. To decompose the metal complex, 300 ml. of saturated ammonium chloride is added. The ether layer is separated and the aqueous layer is extracted with 100 ml. of chloroform. This extract is combined with the ether layer, and the mixture is dried with anhydrous magnesium sulfate and vacuum-concentrated to dryness at 35 C.
- Example 14 Substitution of 33.7 g. of 3-tricyclo[4.3.1.1 ]undecoyl chloride for the 31.5 g. of l-adamantoyl chloride in Example 13 and repetition of the procedure of that example leads to a,a-dimethyl-3-tricyclo[4.3.1.l ]undecanemethanol, then to N-acetyl-u,ot-din1ethyl-3-tricyclo[4.3.1.1 undecanemethylamine, and, after hydrolysis, to aux-(limethyl-3-tricyclo[4.3.l.1 Jundecane methylamine hydrochloride.
- Example 15 To a mixture of 1.5 g. of lithium aluminum hydride in 100 ml. of anhydrous diethylene glycol, dimethyl ether is added 4.1 g. of N-acetyl-a,a-dimethyl-1-adamantanemethylamine, prepared in Example 13. The reaction mixture is stirred and heated at reflux for 3 hours, then cooled in an ice bath. The excess lithium aluminum hydride is decomposed by adding wet diethylene glycol, dimethyl ether. Several ml. of 10% sodium hydroxide is added to coagulate the precipitate, which is then filtered and washed with 50 ml. of ether. The filtrate is treated with dry hydrogen chloride until no additional precipitate forms. This is filtered, dissolved in 100 ml.
- Example 17 A solution of diethyl cadmium in benzene is prepared by adding 19.6 g. of powdered anhydrous cadmium chloride over a 5-minute period to 0.2 mole of ethyl magnesium bromide in ml. of anhydrous ether at ice bath temperature. The mixture is heated at reflux with vigorous stirring for 30 minutes. Then, the ether is removed by distillation on a steam bath, and 65 ml. of benzene is added to the nearly dry, brown, pasty residue. Distillation is continued until the vapor temperature of the distillate reaches 61 C. An additional 100 ml. of benzene is added to the diethyl cadmium solution, and the solution is again heated to reflux.
- a mixture of 75 ml. of anhydrous ethanol, 75 ml. of anhydrous pyridine, 16 g. of hydroxylamine hydrochloride and 16.0 g. of adamantyl-(l) ethyl ketone is heated at reflux for 2 hours and then vacuum concentrated to semi-dryness .at 80 C.
- a ZOO-ml. amount of water is added, and the mixture is again concentrated to semidryness.
- the residue is suspended in 300 ml. of water, and the solids are filtered.
- the melting point of this crude material is -177 C. Recrystallization from a mixture of dioxane and acetonitrile gives 10.3 g. of white, crystalline adamantyl-(l) ethyl ketone oxime, M.P. 177- 179 C.
- a 7.7-g. quantity of adamantyl-(l) ethyl ketone oxime is added to a mixture of 3.0 g. of lithium aluminum hydride and 150 ml. of anhydrous diethylene glycol dimethyl ether, and the mixture is stirred and heated at reflux for three hours. It is cooled to 10 C. with an ice bath and the excess lithium aluminum hydride is destroyed with wet diethylene glycol dimethyl ether. Five ml. of 10% sodium hydroxide is added to coagulate the solids, which are then filtered, washed with 50 m1. of ether and discarded. The filtrate is saturated with dry hydrogen chloride and vacuum concentrated until precipitation is complete.
- the concentrated filtrate is cooled and the solids are filtered, washed with ether and dried.
- the dried salt is dissolved in 150 ml. of Water and the solution is treated with excess 50% sodium hydroxide and extracted with two 50-ml. portions of ether.
- the ether extracts are combined, dried with potassium hydroxide pellets, and treated with dry hydrogen chloride until precipitation is complete.
- the precipitate is filtered and dried to give 5.2 g. of white, crystalline a-ethyl-ladamantanemethylamine hydrochloride, M.P. 278-282" C. (sealed tube).
- Example 18 Substitution of 21.3 g. of 3-tricyclo[4.3.l.l ]undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 17, and repetition of the procedure of that example leads to tricyclo[4.3.l.l ]undecyl-(3) ethyl ketone, then to tricyclo [4.3.1.1 ]undecyl-( 3) ethyl ketone oxime, and, after the reduction, to a-ethyl-3-tricyclo [4.3.1.1 ]undecanemethylamine hydrochloride.
- Example 19 Use of 0.10 mole of 3-tricyclo[4.3.1.l ]undecoylchlo-
- Example 21 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (see Example 7) and 0.15 mole of diallylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N,N-di-allylaminomethyl)tricyclo [4.3.1.1 ]undecane hydrochloride.
- Example 22 Use of 0.15 mole of propargylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N-propargylaminomethyhadamantane hydrochloride.
- Example 23 Use of 0.15 mole of cyclopropylmethylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N- cyclopropyl-methylaminomethyl)adamantane hydrochloride.
- Example 24 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (See Example 7) and 0.15 mole of cyclobutylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N-cyclobutylaminoethyl) -tricycl [4.3. 1 1 undecane hydrochloride.
- Example 25 A milliliter flask with magnetic stirrer and reflux condenser is charged with 0.050 mole of l-(aminomethyl) adamantane, 6.13 grams (0.050 mole) of ethyl chloroacetate, 5.00 grams (0.060 mole) of sodium bicarbonate and 20 milliliters of methanol. The insoluble material is filtered and the filtrate is evaporated to dryness. The residue is dissolved in 60 millilitersof 1N hydrochloric acid, and 10 milliliters of, 70% perchloric acid is added. The precipitated perchlorate salt is filtered, Washed with cold water, and dried. The free base is regenerated with 10% sodium hydroxide and distilled to remove unchanged starting material. The higher boiling fraction is N( l-adamantylmethyl) glycine, ethyl ester.
- Example 26 fate, and concentrated in vacuo to give l-[N-Z-diethylaminoethyl) -N-methylaminomethyl] adamantane.
- Example Product of Example 16 Example 27 A flask equipped with a Dean-Stark water separator is charged with 0.10 mole. of 3-(aminomethyl)tricyclo- [4.3.1.l ]undecane (see Example 9), 15.4 grams (0.10 mole) of freshly distilled benzaldehyde, and 50 milliliters of toluene. The solution is allowed to reflux for 45 hours. The toluene is evaporated and the residue is recrystallized to give N-(3-tricyclo[4.3.1.1 ]undecylmethyl)benzaldimine.
- Example 28 A solution of 0.5 mole of l-(aminomethyl)adamantane in 120 milliliters of tetrahydrofuran and 30 milliliters of Water is charged into a 400 milliliter stainless steel autoclave and 5.0 grams (0.11 mole) of ethylene oxide is injected. The autoclave is heated to C. for 24 hours after which time it is cooled and cautiously vented. Solvent is removed at reduced pressure, and the residue is extracted with ether. The ether extract is dried with anhydrous potassium carbonate. Solvent is removed at reduced pressure and the residue is subjected to sublimation at 100 C./20 mm. in order to remove unreacted l-(aminomethyl)adamantane. The residue from the sublimation is distilled under vacuum to yield 1-[N-(2-hydroxyethyl)aminomethyl]adamantane.
- Example 29 A solution of 0.10 mole of 1-(aminomethyl)adamantane in milliliters of 98% formic acid is allowed to stand 48 hours at room temperature. The formic acid is removed by concentration in vacuo to leave the residue, l-(formamidomethyl)adamantane.
- this compound is prepared by refluxing 0.05 mole of l-(aminomethyl)adamantane for 19 hours in 25 ml. of butyl formate. The excess butyl formate is removed by vacuum concentration to leave a residue of l-(formamidomethyl)adamantane.
- Example 30 A suspension of 0.1 mole of 3-(aminomethyl)tricyclo- [4.3.1.1 ]undecane in 100 milliliters of ice water is placed in a 500 milliliter flask equipped with mechanical stirrer and thermometer. The flask is cooled in an ice bath, and 142 grams of 5.25% sodium hypochlorite solution (commercial Chl0rox) is added at such a rate that the temperature does not exceed 10 C.
- sodium hypochlorite solution commercial Chl0rox
- Example 31 A mixture of 0.10 mole of 1-(aminomethyl)adaman tame and 9.87 grams (0.10 mole) of 38% hydrochloric acid in 100 milliliters of water is concentrated in vacuo at 60 C. The resulting salt, l-(aminomethyl)adamantane hydrochloride, is dried in vacuo at 60 C.
- Example 18 is repeated, substituting the following indicated reactants for those of that example, .to obtain the indicated product.
- Acid Product 1 (free base) 2 (free base) 0.10 mole). 3 (free base) (0.10 mole) 4 (free base) (0.10 mole). 5 (free base) (0.10 mole). 6 (tree base) (0.10 mole).
- Lactic acid (0.10 mole) 1 7
- Example 41 A solution of 0.20 mole of l-(aminoethyl)adamantane hydrochloride in 100 milliliters of water is added to a solution of 0.10 mole of pamoic acid, disodium salt [44'- methylene bis(3-hydroxy-2naphthoic acid), disodium salt] in 500 milliliters of water. The resulting precipitate is filtered, washed well with water, and dried in vacuo to give l-(aminomethyl)adamantane, pamoate.
- Example 42 Carbon dioxide is passed into a solution of 0.10 mole of l-(aminomethyl)adamantane in 100 milliliters of ethyl ether until precipitation is complete. The precipitate is filtered and dried in vacuo to give l-(aminoethyl) adamantane, bicarbonate.
- the compounds of this invention can be administered in the antiviral treatment according to this invention by any means that effects contact of the active ingredient compound with the site of virus infection in the body. It will be understood that this includes the site prior to infection setting in as well as after.
- administration can be parenterally, that is subcutaneously, intraveneously, intramuscularly, or intraperitoneally. Alternatively or concurrently, administration can be by the oral route.
- the dosage administered will be dependent upon the virus being treated, the age, health and weight of the recipient, the extent of infection, kind of concurrent treatment if any, frequency of treatment, and the nature of the effect desired.
- a daily dosage of active ingredient compound will be from about 1 to 50 milligrams per kilogram of body weight, although lower, such as 0.5 milligram, per kilogram or higher amounts can be used. Ordinarily, from 1 to 20 and preferably 1 to 10 milligrams per kilogram per day, in one or more applications per day is effective to obtain the desired result.
- the active ingredient of this invention can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous).
- the active ingredient will ordinarily always be present in an amount of at least 0.5% by weight based on the total weight of the composition and not more than 90% by weight.
- the antiviral composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.
- the solid carrier is a capsule which can be of the ordinary gelatin type.
- the capsule will be from about 30-60% by weight of a compound of Formulas 1 and 2 and 70-40% of a carrier.
- the active ingredient is tableted with or without adjuvants.
- the active ingredient is put into powder packets and employed.
- These capsules, tablets and powders will generally constitute from about 5% to about 95% and preferably from 25% to 90% by weight.
- These dosage forms preferably contain from about 5 to about 500 milligrams of active ingredient, with from about 25 to about 250 most preferred.
- the pharmaceutical carrier can, as previously indicated, he a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like.
- a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like.
- water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carries, particularly for injectible solutions.
- Sterile 18 injectible solutions such as saline will ordinarily contain from about 0.5% to 25%, and preferably about 1 to 10% by weight of the active ingredient.
- oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.5 to 10%, and preferably about 2 to 5%, by weight.
- the pharmaceutical carrier in such composition can be a Watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
- Suitable pharmaceutical carriers are described in Rem ingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.
- Example 43 A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules weighing about 50 milligrams each with 50 milligrams of powdered 1- (aminoethyl)adamantane, hydrochloride, 125 milligrams of lactose and 1 milligram of Cab-o-sil.
- Example 44 Example 43 is repeated except that soft gelatin capsules are used and powdered l-(aminomethyl)adamantane is first dissolved in mineral oil.
- Example 45 Example 43 is repeated except that the dosage unit is 50 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose, mixed and formed into a tablet by a conventional tableting machine. Slow release pills or tablets can also be used, .by applying appropriate coatings. A sugar coating may be applied to increase palatability.
- Example 46 A parenteral composition suitable for administration by injection is prepared by stirring 5% by weight of the active ingredient of Example 43 in sterile aqueous 0.9% saline.
- compositions according to this invention can thus readily be made by substituting other compounds of thisinvention, and including specifically but not limited to compounds of this invention that have specifically been named hereinbefore.
- the compounds will "be used in the amounts indicated in accordance with procedures well known and described in the Martin and Cook text mentioned above. f
- Compounds within the scope of Formulae 1 and 2 of the invention are anti-viral agents in domestic animals and livestock.
- compounds within the'scope of Formulae 1 and 2 are effective against swine influenza and an embodiment of the intlention, therefore, is a control of this infection by incorporating an active ingredient compound in the diet of the affected animal.
- an amount of active compound will be used to provide from about 0.0001% to 0.1% by weight of the active compounds based on the total weight of feed intake.
- Preferably, from 0.001% to 0.02% by weight will be used.
- compositions which comprise at least one active ingredient compound within the scope of this invention in admixture with an animal feed.
- suitable feeds can be found in the book Feeds and Feeding by Frank B. Morrison, published by the Morrison Publishing Company of Ithaca, N.Y., 1948, 21st edition. The selection of the particular feed is within the knowledge of the art and will depend of course on the animal, the economics, natural materials available, the surrounding circumstances and the nature of the effect desired, as will be readily understood.
- the feed compositions can additionally contain other components of feed concentrates or animal feeds, as will be readily understood.
- Other particularly important additives include proteins, carbohydrates, fats, vitamins, minerals, antibiotics, etc.
- a compound selected from the group consisting of those of the formula 20 and A is hydrogen
- X and Y are each hydrogen, methyl, or ethyl; and R is m -N H2).
- R is alkenyl or alkynyl having the unsaturated bond in the l-position, R is alkyl of 1 through 6 carbon atoms or mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2 carbon atoms,
- -NH NHR and --NR R and R is hydrogen, alkyl of 1 through 5 carbon atoms,
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Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
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US376259A US3352912A (en) | 1963-07-24 | 1964-06-18 | Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes |
DE19641793207 DE1793207A1 (de) | 1963-07-24 | 1964-07-18 | Nicht-toxische Saeureadditionssalze von 1-(Aminomethyl)adamantan |
DE19641793208 DE1793208A1 (de) | 1963-07-24 | 1964-07-18 | Neue cyclische Kohlenwasserstoffverbindungen |
DE19641792295 DE1792295B1 (de) | 1963-07-24 | 1964-07-18 | Pharmazeutisches Praeparat enthaltend 1-Aminomethyladamantan |
DE19641468769 DE1468769C (de) | 1963-07-24 | 1964-07-18 | Alkylaminoadamantandenvate und ihre Salze |
BR160975/64A BR6460975D0 (pt) | 1963-07-24 | 1964-07-20 | Processo para a preparacao de compostos triciclicos |
CH946964A CH476673A (de) | 1963-07-24 | 1964-07-20 | Verfahren zur Herstellung von Salzen von Adamantan- und Tricyclo(4,3,1,13,8)undecanverbindungen |
CH1457468A CH479535A (de) | 1963-07-24 | 1964-07-20 | Verfahren zur Herstellung von a-Alkyl-l-adamantanmethylaminen und a-Alkyl-3-tricyclo(4,3,1,1 3,8)undecanmethylaminen |
AT1064666A AT269836B (de) | 1964-06-18 | 1964-07-22 | Verfahren zur Herstellung von neuen basischen, tricyclischen Verbindungen und deren Salzen |
AT1064566A AT269835B (de) | 1964-06-18 | 1964-07-22 | Verfahren zur Herstellung von neuen basischen, tricyclischen Verbindungen und deren Salzen |
BE650919D BE650919A (de) | 1963-07-24 | 1964-07-23 | |
IL21753A IL21753A (en) | 1963-07-24 | 1964-07-23 | Adamantanes and tricycloundecanes |
DK367964AA DK112027B (da) | 1963-07-24 | 1964-07-23 | Fremgangsmåde til fremstilling af basiske tricycliske forbindelser eller salte, formamider eller N-halogenaminer deraf. |
SE9752/67A SE320363B (de) | 1963-07-24 | 1964-07-23 | |
FI1584/64A FI42322B (de) | 1963-07-24 | 1964-07-23 | |
SE09751/67A SE330693B (de) | 1963-07-24 | 1964-07-23 | |
ES0302369A ES302369A1 (es) | 1963-07-24 | 1964-07-23 | Metodo de preparacion de compuestos triciclicos. |
SE8987/64A SE321924B (de) | 1963-07-24 | 1964-07-23 | |
NL6408505A NL6408505A (de) | 1963-07-24 | 1964-07-24 | |
FR1572956D FR1572956A (de) | 1963-07-24 | 1964-07-24 | |
GB30940/64A GB1069563A (en) | 1963-07-24 | 1964-08-04 | Adamantane and tricyclo[4,3,1,1]undecane derivatives |
AT06819/68A AT279581B (de) | 1963-07-24 | 1964-08-07 | Verfahren zur herstellung von neuen, basischen, tricyclischen verbindungen und deren salzen |
DK353265AA DK114769B (da) | 1963-07-24 | 1965-07-09 | Fremgangsmåde til fremstilling af basiske tricycliske forbindelser eller salte deraf. |
DK353365AA DK114199B (da) | 1963-07-24 | 1965-07-09 | Fremgangsmåde til fremstilling af basiske tricycliske forbindelser eller salte deraf. |
FI0197/69A FI42548B (de) | 1963-07-24 | 1969-01-22 | |
FI0198/69A FI42211B (de) | 1963-07-24 | 1969-01-22 | |
NL7102097A NL7102097A (de) | 1963-07-24 | 1971-02-17 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US29723363A | 1963-07-24 | 1963-07-24 | |
US376259A US3352912A (en) | 1963-07-24 | 1964-06-18 | Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes |
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US3352912A true US3352912A (en) | 1967-11-14 |
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US376259A Expired - Lifetime US3352912A (en) | 1963-07-24 | 1964-06-18 | Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes |
Country Status (14)
Country | Link |
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US (1) | US3352912A (de) |
AT (1) | AT279581B (de) |
BE (1) | BE650919A (de) |
BR (1) | BR6460975D0 (de) |
CH (2) | CH476673A (de) |
DE (3) | DE1793207A1 (de) |
DK (3) | DK112027B (de) |
ES (1) | ES302369A1 (de) |
FI (3) | FI42322B (de) |
FR (1) | FR1572956A (de) |
GB (1) | GB1069563A (de) |
IL (1) | IL21753A (de) |
NL (2) | NL6408505A (de) |
SE (3) | SE320363B (de) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3449422A (en) * | 1966-02-09 | 1969-06-10 | Smithkline Corp | Pentacycloundecane amines |
US3624086A (en) * | 1969-11-10 | 1971-11-30 | Searle & Co | Adamantanecarboxamidoalkanoic acid amides |
US3682922A (en) * | 1969-01-16 | 1972-08-08 | Searle & Co | N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines |
US3852339A (en) * | 1970-06-15 | 1974-12-03 | Squibb & Sons Inc | Aminoalkoxyphenylurea derivatives |
US3870759A (en) * | 1969-07-19 | 1975-03-11 | Yoshiaki Inamoto | 1-Adamantyl alkyl ketones and their preparation |
US3879400A (en) * | 1973-11-16 | 1975-04-22 | Upjohn Co | 1-Lower alkyl-(1-adamantylmethyl)piperidines and process for their preparation |
US4111990A (en) * | 1976-10-12 | 1978-09-05 | Kao Soap Co., Ltd. | 1-Acetylaminotricyclo [4.3.1.12,5 ] undecane and process for the preparation thereof |
US4351847A (en) * | 1981-06-26 | 1982-09-28 | Pennwalt Corporation | Antiviral alpha, alpha-dialkyl adamantylethylamines |
US4551552A (en) * | 1984-05-23 | 1985-11-05 | E. I. Du Pont De Nemours And Company | Process for preparing rimantadine |
US4751245A (en) * | 1986-06-25 | 1988-06-14 | E. R. Squibb & Sons, Inc. | Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same |
US5576355A (en) * | 1993-06-04 | 1996-11-19 | Mobil Oil Corp. | Diamondoid derivatives for pharmaceutical use |
US5684024A (en) * | 1996-01-25 | 1997-11-04 | Viropharma Incorporated | Pyrazole dimers compositions and methods for treating influenza |
US5821243A (en) * | 1996-07-22 | 1998-10-13 | Viropharma Incorporated | Compounds compositions and methods for treating influenza |
WO2003004461A1 (en) * | 2001-07-02 | 2003-01-16 | Schering Corporation | Drugs for treating viral infections |
US20060287317A1 (en) * | 2005-06-17 | 2006-12-21 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
WO2007062272A1 (en) | 2005-11-28 | 2007-05-31 | Omega-Biopharma (H.K.) Limited | Materials and methods for treating viral infections with a cysteamine compound |
CN100450994C (zh) * | 2002-12-23 | 2009-01-14 | 詹森药业有限公司 | 制备1-羟基-4-氨基金刚烷的方法 |
WO2015086428A1 (en) * | 2013-12-09 | 2015-06-18 | Unilever Plc | Process of making adamantanamides |
US9227990B2 (en) | 2012-10-29 | 2016-01-05 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
WO2017093354A1 (en) | 2015-11-30 | 2017-06-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nmdar antagonists for the treatment of diseases associated with angiogenesis |
WO2019018185A1 (en) * | 2017-07-15 | 2019-01-24 | Arisan Therapeutics Inc. | ENANTIOMERICALLY PURE ADAMATANE DERIVATIVES FOR THE TREATMENT OF FILOVIRUS INFECTIONS |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1294371B (de) * | 1966-12-21 | 1969-05-08 | Penicillin Ges Dauelsberg & Co | Verfahren zur Herstellung von 1-Aminoadamantan und dessen N-Alkyl- bzw. N-Cyclohexylderivaten |
US3489802A (en) * | 1967-01-23 | 1970-01-13 | Du Pont | Preparation of alpha-methyl-1-adamantane-methylamine and alpha,4 - dimethyl - 1 - bicyclo(2,2,2)octane methylamine |
NL6900004A (de) * | 1969-01-02 | 1970-07-06 | ||
ES2175614T3 (es) * | 1997-04-10 | 2002-11-16 | Pfizer | Derivados fluorosustituidos de adamantano. |
GB0013737D0 (en) | 2000-06-07 | 2000-07-26 | Astrazeneca Ab | Novel compounds |
WO2003079972A2 (en) | 2002-02-22 | 2003-10-02 | New River Parmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
SE0103836D0 (sv) * | 2001-11-16 | 2001-11-16 | Astrazeneca Ab | Novel compounds |
SE0300480D0 (sv) | 2003-02-21 | 2003-02-21 | Astrazeneca Ab | Novel compounds |
GB0312609D0 (en) | 2003-06-02 | 2003-07-09 | Astrazeneca Ab | Novel compounds |
PE20091225A1 (es) | 2007-03-22 | 2009-09-16 | Astrazeneca Ab | Derivados de quinolina como antagonistas del receptor p2x7 |
PE20091036A1 (es) | 2007-11-30 | 2009-08-15 | Astrazeneca Ab | Derivado de quinolina como antagonista del receptor p2x7 |
-
1964
- 1964-06-18 US US376259A patent/US3352912A/en not_active Expired - Lifetime
- 1964-07-18 DE DE19641793207 patent/DE1793207A1/de active Pending
- 1964-07-18 DE DE19641793208 patent/DE1793208A1/de active Pending
- 1964-07-18 DE DE19641792295 patent/DE1792295B1/de not_active Withdrawn
- 1964-07-20 CH CH946964A patent/CH476673A/de not_active IP Right Cessation
- 1964-07-20 BR BR160975/64A patent/BR6460975D0/pt unknown
- 1964-07-20 CH CH1457468A patent/CH479535A/de not_active IP Right Cessation
- 1964-07-23 BE BE650919D patent/BE650919A/xx unknown
- 1964-07-23 SE SE9752/67A patent/SE320363B/xx unknown
- 1964-07-23 DK DK367964AA patent/DK112027B/da unknown
- 1964-07-23 SE SE09751/67A patent/SE330693B/xx unknown
- 1964-07-23 FI FI1584/64A patent/FI42322B/fi active
- 1964-07-23 IL IL21753A patent/IL21753A/xx unknown
- 1964-07-23 ES ES0302369A patent/ES302369A1/es not_active Expired
- 1964-07-23 SE SE8987/64A patent/SE321924B/xx unknown
- 1964-07-24 NL NL6408505A patent/NL6408505A/xx unknown
- 1964-07-24 FR FR1572956D patent/FR1572956A/fr not_active Expired
- 1964-08-04 GB GB30940/64A patent/GB1069563A/en not_active Expired
- 1964-08-07 AT AT06819/68A patent/AT279581B/de not_active IP Right Cessation
-
1965
- 1965-07-09 DK DK353365AA patent/DK114199B/da unknown
- 1965-07-09 DK DK353265AA patent/DK114769B/da unknown
-
1969
- 1969-01-22 FI FI0197/69A patent/FI42548B/fi active
- 1969-01-22 FI FI0198/69A patent/FI42211B/fi active
-
1971
- 1971-02-17 NL NL7102097A patent/NL7102097A/xx unknown
Non-Patent Citations (1)
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None * |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3449422A (en) * | 1966-02-09 | 1969-06-10 | Smithkline Corp | Pentacycloundecane amines |
US3682922A (en) * | 1969-01-16 | 1972-08-08 | Searle & Co | N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines |
US3870759A (en) * | 1969-07-19 | 1975-03-11 | Yoshiaki Inamoto | 1-Adamantyl alkyl ketones and their preparation |
US3624086A (en) * | 1969-11-10 | 1971-11-30 | Searle & Co | Adamantanecarboxamidoalkanoic acid amides |
US3852339A (en) * | 1970-06-15 | 1974-12-03 | Squibb & Sons Inc | Aminoalkoxyphenylurea derivatives |
US3879400A (en) * | 1973-11-16 | 1975-04-22 | Upjohn Co | 1-Lower alkyl-(1-adamantylmethyl)piperidines and process for their preparation |
US4111990A (en) * | 1976-10-12 | 1978-09-05 | Kao Soap Co., Ltd. | 1-Acetylaminotricyclo [4.3.1.12,5 ] undecane and process for the preparation thereof |
US4351847A (en) * | 1981-06-26 | 1982-09-28 | Pennwalt Corporation | Antiviral alpha, alpha-dialkyl adamantylethylamines |
US4551552A (en) * | 1984-05-23 | 1985-11-05 | E. I. Du Pont De Nemours And Company | Process for preparing rimantadine |
US4751245A (en) * | 1986-06-25 | 1988-06-14 | E. R. Squibb & Sons, Inc. | Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same |
US5576355A (en) * | 1993-06-04 | 1996-11-19 | Mobil Oil Corp. | Diamondoid derivatives for pharmaceutical use |
US5684024A (en) * | 1996-01-25 | 1997-11-04 | Viropharma Incorporated | Pyrazole dimers compositions and methods for treating influenza |
US5821243A (en) * | 1996-07-22 | 1998-10-13 | Viropharma Incorporated | Compounds compositions and methods for treating influenza |
US5935957A (en) * | 1996-07-22 | 1999-08-10 | Viropharma Incorporated | Compounds, compositions and methods for treating influenza |
US6180628B1 (en) | 1996-07-22 | 2001-01-30 | Viropharma Incorporated | Compounds, compositions and methods for treating influenza |
US6271373B1 (en) | 1996-07-22 | 2001-08-07 | Viropharma Incorporated | Compounds, compositions and methods for treating influenza |
WO2003004461A1 (en) * | 2001-07-02 | 2003-01-16 | Schering Corporation | Drugs for treating viral infections |
CN100450994C (zh) * | 2002-12-23 | 2009-01-14 | 詹森药业有限公司 | 制备1-羟基-4-氨基金刚烷的方法 |
US20060287317A1 (en) * | 2005-06-17 | 2006-12-21 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
US7338961B2 (en) * | 2005-06-17 | 2008-03-04 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
US20080167352A1 (en) * | 2005-06-17 | 2008-07-10 | Apogee Biotechnology Corporation | Sphingosine Kinase Inhibitors |
US8063248B2 (en) | 2005-06-17 | 2011-11-22 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
US8557800B2 (en) | 2005-06-17 | 2013-10-15 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
USRE49811E1 (en) * | 2005-06-17 | 2024-01-23 | Apogee Biotechnology Corporation | Sphingosine kinase inhibitors |
WO2007062272A1 (en) | 2005-11-28 | 2007-05-31 | Omega-Biopharma (H.K.) Limited | Materials and methods for treating viral infections with a cysteamine compound |
US9227990B2 (en) | 2012-10-29 | 2016-01-05 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
CN105829284A (zh) * | 2013-12-09 | 2016-08-03 | 荷兰联合利华有限公司 | 制备金刚烷甲酰胺类化合物的方法 |
JP2016540774A (ja) * | 2013-12-09 | 2016-12-28 | ユニリーバー・ナームローゼ・ベンノートシヤープ | アダマンタンアミド製造方法 |
US9840466B2 (en) | 2013-12-09 | 2017-12-12 | Conopco, Inc. | Process of making adamantanamides |
CN105829284B (zh) * | 2013-12-09 | 2019-01-22 | 荷兰联合利华有限公司 | 制备金刚烷甲酰胺类化合物的方法 |
EA031458B1 (ru) * | 2013-12-09 | 2019-01-31 | Юнилевер Н.В. | Способ получения адамантанамидов |
WO2015086428A1 (en) * | 2013-12-09 | 2015-06-18 | Unilever Plc | Process of making adamantanamides |
WO2017093354A1 (en) | 2015-11-30 | 2017-06-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nmdar antagonists for the treatment of diseases associated with angiogenesis |
WO2019018185A1 (en) * | 2017-07-15 | 2019-01-24 | Arisan Therapeutics Inc. | ENANTIOMERICALLY PURE ADAMATANE DERIVATIVES FOR THE TREATMENT OF FILOVIRUS INFECTIONS |
US11548893B2 (en) | 2017-07-15 | 2023-01-10 | Arisan Therapeutics Inc. | Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection |
Also Published As
Publication number | Publication date |
---|---|
ES302369A1 (es) | 1965-03-16 |
DE1792295B1 (de) | 1971-05-27 |
DK114769B (da) | 1969-08-04 |
NL6408505A (de) | 1965-01-25 |
BE650919A (de) | 1964-11-16 |
AT279581B (de) | 1970-03-10 |
BR6460975D0 (pt) | 1973-08-09 |
DK112027B (da) | 1968-11-04 |
FI42211B (de) | 1970-03-02 |
CH479535A (de) | 1969-10-15 |
DE1468769B1 (de) | 1972-06-29 |
NL7102097A (de) | 1971-05-25 |
CH476673A (de) | 1969-08-15 |
FI42548B (de) | 1970-06-01 |
SE330693B (de) | 1970-11-30 |
DE1793207A1 (de) | 1972-03-30 |
FR1572956A (de) | 1969-07-04 |
DE1793208A1 (de) | 1972-04-06 |
FI42322B (de) | 1970-03-31 |
DK114199B (da) | 1969-06-09 |
IL21753A (en) | 1968-01-25 |
SE321924B (de) | 1970-03-23 |
GB1069563A (en) | 1967-05-17 |
SE320363B (de) | 1970-02-09 |
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