NZ619257B2 - Ketamine derivatives - Google Patents
Ketamine derivatives Download PDFInfo
- Publication number
- NZ619257B2 NZ619257B2 NZ619257A NZ61925713A NZ619257B2 NZ 619257 B2 NZ619257 B2 NZ 619257B2 NZ 619257 A NZ619257 A NZ 619257A NZ 61925713 A NZ61925713 A NZ 61925713A NZ 619257 B2 NZ619257 B2 NZ 619257B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- chlorophenyl
- alkyl
- oxocyclohexyl
- amino
- Prior art date
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- YQEZLKZALYSWHR-UHFFFAOYSA-N Calypsol Chemical class C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 title abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 206010039897 Sedation Diseases 0.000 claims abstract description 23
- 230000036280 sedation Effects 0.000 claims abstract description 23
- 208000002193 Pain Diseases 0.000 claims abstract description 18
- 230000036407 pain Effects 0.000 claims abstract description 18
- 230000001939 inductive effect Effects 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000036592 analgesia Effects 0.000 claims abstract description 7
- FZIHUEMGZWQMJF-UHFFFAOYSA-N ethyl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]butanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCC(=O)OCC)CCCCC1=O FZIHUEMGZWQMJF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 201000008125 pain agnosia Diseases 0.000 claims abstract description 7
- VELFQRXGQQEDQS-UHFFFAOYSA-N propan-2-yl 5-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]pentanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCCC(=O)OC(C)C)CCCCC1=O VELFQRXGQQEDQS-UHFFFAOYSA-N 0.000 claims abstract description 7
- GSLQTNIISBAJKM-UHFFFAOYSA-N propyl 3-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]propanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCC(=O)OCCC)CCCCC1=O GSLQTNIISBAJKM-UHFFFAOYSA-N 0.000 claims abstract description 7
- BEMFAESGNZMDAI-UHFFFAOYSA-N 3-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]propyl acetate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCOC(=O)C)CCCCC1=O BEMFAESGNZMDAI-UHFFFAOYSA-N 0.000 claims abstract description 5
- MLQTZSYHBXPNKI-UHFFFAOYSA-N ethyl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]-methylamino]butanoate Chemical compound C=1C=CC=C(Cl)C=1C1(N(C)CCCC(=O)OCC)CCCCC1=O MLQTZSYHBXPNKI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 69
- 125000005843 halogen group Chemical group 0.000 claims description 55
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 42
- 125000001188 haloalkyl group Chemical group 0.000 claims description 42
- 229910052727 yttrium Inorganic materials 0.000 claims description 40
- -1 2 11 11 15 R Chemical group 0.000 claims description 36
- 150000002431 hydrogen Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 29
- 239000011780 sodium chloride Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 22
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 17
- 206010002091 Anaesthesia Diseases 0.000 claims description 16
- 230000037005 anaesthesia Effects 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 238000001949 anaesthesia Methods 0.000 claims description 15
- 125000001931 aliphatic group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000000969 carrier Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- GNIZNSSNZICSGW-UHFFFAOYSA-N ethyl 3-[[1-(2-chlorophenyl)-2-oxocyclohexyl]-methylamino]propanoate Chemical compound C=1C=CC=C(Cl)C=1C1(N(C)CCC(=O)OCC)CCCCC1=O GNIZNSSNZICSGW-UHFFFAOYSA-N 0.000 claims description 5
- OSYLIDUZSLQOIW-UHFFFAOYSA-N ethyl 3-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]propanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCC(=O)OCC)CCCCC1=O OSYLIDUZSLQOIW-UHFFFAOYSA-N 0.000 claims description 5
- KFZMXHQTFSGYLL-UHFFFAOYSA-N ethyl 5-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]pentanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCCC(=O)OCC)CCCCC1=O KFZMXHQTFSGYLL-UHFFFAOYSA-N 0.000 claims description 5
- DXFKXPYVXFWPHN-UHFFFAOYSA-N methyl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]pentanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NC(C)CCC(=O)OC)CCCCC1=O DXFKXPYVXFWPHN-UHFFFAOYSA-N 0.000 claims description 5
- FRANGXMVILSKAR-UHFFFAOYSA-N methyl 5-[[1-(2-chlorophenyl)-2-oxocyclohexyl]-methylamino]pentanoate Chemical compound C=1C=CC=C(Cl)C=1C1(N(C)CCCCC(=O)OC)CCCCC1=O FRANGXMVILSKAR-UHFFFAOYSA-N 0.000 claims description 5
- OYHDMPDRGZQTIM-UHFFFAOYSA-N propan-2-yl 3-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]propanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCC(=O)OC(C)C)CCCCC1=O OYHDMPDRGZQTIM-UHFFFAOYSA-N 0.000 claims description 5
- UMTAVENMCNHZKS-UHFFFAOYSA-N propan-2-yl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]butanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCC(=O)OC(C)C)CCCCC1=O UMTAVENMCNHZKS-UHFFFAOYSA-N 0.000 claims description 5
- VBIALSIHBKQBCK-UHFFFAOYSA-N propyl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]butanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCC(=O)OCCC)CCCCC1=O VBIALSIHBKQBCK-UHFFFAOYSA-N 0.000 claims description 5
- MDFUNBBVYZXYJZ-UHFFFAOYSA-N propyl 5-[[1-(2-chlorophenyl)-2-oxocyclohexyl]amino]pentanoate Chemical compound C=1C=CC=C(Cl)C=1C1(NCCCCC(=O)OCCC)CCCCC1=O MDFUNBBVYZXYJZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001356 surgical procedure Methods 0.000 claims description 5
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 3
- 238000002695 general anesthesia Methods 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 29
- 229960003299 ketamine Drugs 0.000 description 26
- 239000000243 solution Substances 0.000 description 22
- 125000001309 chloro group Chemical group Cl* 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000001802 infusion Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- BEQZHFIKTBVCAU-UHFFFAOYSA-N Norketamine Chemical compound C=1C=CC=C(Cl)C=1C1(N)CCCCC1=O BEQZHFIKTBVCAU-UHFFFAOYSA-N 0.000 description 13
- 230000003444 anaesthetic Effects 0.000 description 13
- 125000004432 carbon atoms Chemical group C* 0.000 description 13
- 230000002829 reduced Effects 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000003389 potentiating Effects 0.000 description 12
- 230000028527 righting reflex Effects 0.000 description 12
- 238000001990 intravenous administration Methods 0.000 description 11
- 230000001624 sedative Effects 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 9
- 230000000202 analgesic Effects 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 239000008079 hexane Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000011084 recovery Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 230000000875 corresponding Effects 0.000 description 7
- 229940079593 drugs Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 125000005842 heteroatoms Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- VPCDQGACGWYTMC-UHFFFAOYSA-N Nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atoms Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- BEQZHFIKTBVCAU-LBPRGKRZSA-N (2S)-2-amino-2-(2-chlorophenyl)cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(N)CCCCC1=O BEQZHFIKTBVCAU-LBPRGKRZSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 150000002829 nitrogen Chemical group 0.000 description 5
- 230000011514 reflex Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- FGTRLPFQPZJCQO-UHFFFAOYSA-N OC1CCCC1=N Chemical compound OC1CCCC1=N FGTRLPFQPZJCQO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 230000000147 hypnotic Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000006485 reductive methylation reaction Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000932 sedative agent Substances 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- QIJMMRNZBJHXRI-UHFFFAOYSA-N (2-chlorophenyl)-cyclopentylmethanone Chemical compound ClC1=CC=CC=C1C(=O)C1CCCC1 QIJMMRNZBJHXRI-UHFFFAOYSA-N 0.000 description 3
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 3
- OQCDPFUVJUOTNX-UHFFFAOYSA-N 3-bromopropyl acetate Chemical compound CC(=O)OCCCBr OQCDPFUVJUOTNX-UHFFFAOYSA-N 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- AFRWBGJRWRHQOV-UHFFFAOYSA-N ethyl 5-bromopentanoate Chemical compound CCOC(=O)CCCCBr AFRWBGJRWRHQOV-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- KQNJUTDIDREYGN-UHFFFAOYSA-N propan-2-yl 3-bromopropanoate Chemical compound CC(C)OC(=O)CCBr KQNJUTDIDREYGN-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- DDVNLGGCSRULIL-UHFFFAOYSA-N (1-bromocyclopentyl)-(2-chlorophenyl)methanone Chemical compound ClC1=CC=CC=C1C(=O)C1(Br)CCCC1 DDVNLGGCSRULIL-UHFFFAOYSA-N 0.000 description 2
- 229940035676 ANALGESICS Drugs 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L Copper(II) bromide Chemical group [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 230000036499 Half live Effects 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 2
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 2
- YFXSAPARKCXWPV-UHFFFAOYSA-N ethyl 4-[[1-(2-chlorophenyl)-2-oxocyclohexyl]-methylamino]butanoate;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C1(N(C)CCCC(=O)OCC)CCCCC1=O YFXSAPARKCXWPV-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 210000004744 fore-foot Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000002140 halogenating Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000003364 opioid Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N (+)-tartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BEQZHFIKTBVCAU-GFCCVEGCSA-N (2R)-2-amino-2-(2-chlorophenyl)cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@]1(N)CCCCC1=O BEQZHFIKTBVCAU-GFCCVEGCSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- IXTSVDGUKKYTGW-UHFFFAOYSA-N 1-(2-chlorobenzenecarboximidoyl)cyclopentan-1-ol;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(=N)C1(O)CCCC1 IXTSVDGUKKYTGW-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-Chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- PWWKJXJEWPCNHY-LMOVPXPDSA-N 3-[[(1S)-1-(2-chlorophenyl)-2-oxocyclohexyl]amino]propyl acetate;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1[C@@]1(NCCCOC(=O)C)CCCCC1=O PWWKJXJEWPCNHY-LMOVPXPDSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
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- 206010002974 Apnoea Diseases 0.000 description 1
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- 210000004369 Blood Anatomy 0.000 description 1
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- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000001755 vocal Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Abstract
This disclosure relates to a family of compounds of formula (I). These are ketamine derivatives wherein Y1, Y2, X1 and X2 are as defined in the specification. The disclosure also related to pharmaceutical compositions comprising these compounds and methods of providing provide pain relief or analgesia and inducing and maintaining general anesthesia or sedation using these compounds. Examples of the compounds include: 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate, n-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propanoate, ethyl4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)butanoate, isopropyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate and ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)butanoate. ia and inducing and maintaining general anesthesia or sedation using these compounds. Examples of the compounds include: 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate, n-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propanoate, ethyl4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)butanoate, isopropyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate and ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino)butanoate.
Description
COMPLETE SPECIFICATION
KETAMINE DERIVATIVES
KETAMINE DERIVATIVES
TECHNICAL FIELD
The present invention relates to ketamine derivatives, uses thereof, and pharmaceutical
compositions comprising them. Their use as anaesthetics, analgesics, or sedatives is described
herein.
BACKGROUND OF THE INVENTION
(2-o-Chlorophenyl)methylamino-cyclohexanone (ketamine) is an effective non-opioid
anaesthetic/analgesic drug [Laskowski et al., Can J Anesth 2011,58, 911: Carstensen &
Møller, Br J Anaesth. 2010, 104, 401], with the major advantages over opioids in that it shows
no respiratory depression or hyperalgesic effects, and is also free of longer-term effects such
as increased tolerance and immune suppression.
Ketamine is normally used as the racemate, but more recently the more active (S)-enantiomer
has begun to be employed. (S)-Ketamine has similar pharmacological, analgesic and
anaesthetic properties to the racemate, but is about twice as potent [Adams & Werner,
Anaesthetist 1997, 46, 1026].
NHMe
(S)-ketamine
The most important adverse effect of ketamine is its hallucinogenic properties which, together
with its relatively long half-life (2-3 h) means that it is normally administered together with
sedative or hypnotic drugs like midazolam and/or propofol to control the prolonged period of
post-anesthesia hallucinations [Domino, Anesthesiology 2010, 113, 678, Chiaretti et al.,
Pediatric Blood & Cancer 2011, 57, 1163]. While (S)-ketamine has somewhat faster
elimination [Adams & Werner, Anaesthetist 1997, 46, 1026], there is still a need for analogues
with much shorter half-lives to avoid the concomitant use of sedatives/hypnotics.
It is an object of the present invention to go some way to meeting this need, and/or to at least
provide the public with a useful choice.
Other objects of the invention may become apparent from the following description which is
given by way of example only.
Any discussion of documents, acts, materials, devices, articles or the like which has been
included in the present specification is solely for the purpose of providing a context for the
present invention. It is not to be taken as an admission that any or all of these matters form
part of the prior art base or were common general knowledge in the field relevant to the
present invention as it existed before the priority date.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula (I):
wherein
1 1 1
Y is –C aliphaticC(O)OR , –C aliphaticOC(O)R , –C aliphaticC(O)OC
2-6 2-6 1-6 1-
aliphaticC(O)OR , or –C aliphaticC(O)OC aliphaticOR , wherein each aliphatic is
6 1-6 1-6
optionally substituted with one or more R ;
1 11
R is C aliphatic, optionally substituted with one or more halo, CN, NO , NH , NHR ,
1-6 2 2
11 12 11 11 12 11 11
NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR ,
1-6 1-6 2 2
C(O)R , and C aliphatic;
2 11
R is C aliphatic, optionally substituted with one or more halo, OR , or CN;
R is hydrogen or R ;
11 12 11 12
R and R are each independently C aliphatic; or R and R together with the nitrogen
atom to which they are attached are a heteroaryl or heterocyclyl ring;
Y is hydrogen or R ;
1 2 2 11 11 12
X and X are each independently hydrogen, R , halo, NO , NH , NHR , NR R , C
2 2 1-
11 11 12 11 11 11
haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , C(O)R , C
6 1-6 2 2 1-
1 1 1 1 1
aliphaticY , OY , C(O)Y , SO Y , or C(O)NHY at any of the available 2-5 positions;
or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable diluent, excipient, or carrier.
Described herein is a method for treating pain in a subject in need thereof, the method
comprising administering a therapeutically effective amount of a compound of formula (I) to
the subject.
In another aspect, the invention provides use of a compound of formula (I) in the manufacture
of a medicament for treating pain.
In another aspect, the invention provides a compound of formula (I) for treating pain.
In one embodiment, the method, medicament, or compound for treating pain is for providing
analgesia.
Also described herein is a method for anaesthetizing a subject in need thereof, the method
comprising administering a therapeutically effective amount of a compound of formula (II) to
the subject:
(II)
wherein
11 1 1
Y is –C aliphaticC(O)OR , –C aliphaticOC(O)R , –C aliphaticC(O)OC
1-6 1-6 1-6 1-
aliphaticC(O)OR , or –C aliphaticC(O)OC aliphaticOR , wherein each aliphatic is
6 1-6 1-6
optionally substituted with one or more R ; and
1 2 3 2 1 2
R , R , R , Y , X , and X are as defined in the compound of formula (I);
or a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the method is for anaesthetizing a subject for a surgical procedure.
In some embodiments, the method is for inducing general anaesthesia. In other embodiments,
the method is for inducing and maintaining general anaesthesia.
In another aspect, the present invention provides use of a compound of formula (II) in the
manufacture of a medicament for providing anaesthesia.
In one embodiment, the medicament is for providing anaesthesia for a surgical procedure.
In some embodiments, the medicament is for inducing general anaesthesia. In other
embodiments, the medicament is for inducing and maintaining general anaesthesia.
In another aspect, the present invention provides a compound of formula (II) for providing
anaesthesia.
In one embodiment, the compound is for providing anaesthesia for a surgical procedure.
In some embodiments, the compound is for inducing general anaesthesia. In other
embodiments, the compound is for inducing and maintaining general anaesthesia.
Also described herein is a method for sedating a subject in need thereof, the method
comprising administering a therapeutically effective amount of a compound of the formula (II)
to the subject.
In one embodiment, the method is for sedating a subject for a medical procedure. In some
embodiments, method is for providing conscious sedation.
In some embodiments, the method is for inducing conscious sedation. In other embodiments,
the method is for inducing and maintaining conscious sedation.
In another aspect, the present invention provides use of a compound of formula (II) in the
manufacture of a medicament for providing sedation.
In one embodiment, the medicament is for providing sedation for a medical procedure. In
some embodiments, the medicament is for providing conscious sedation.
In some embodiments, the medicament is for inducing conscious sedation. In other
embodiments, the medicament is for inducing and maintaining conscious sedation.
In another aspect, the present invention provides a compound of formula (II) for providing
sedation.
In one embodiment, the compound is for providing sedation is for a medical procedure. In
some embodiments, the compound is for providing conscious sedation.
In some embodiments, the compound is for inducing conscious sedation. In other
embodiments, the compound is for inducing and maintaining conscious sedation.
The following embodiments relate to the compounds of formula (I) and (II), as appropriate.
1 1 1
In one embodiment, Y is –C alkylC(O)OR , –C alkylOC(O)R , –C alkylC(O)OC
2-6 2-6 1-6 1-
alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl is optionally substituted.
6 1-6 1-6
1 1 1
In another embodiment, Y is –C alkylC(O)OR or –C alkylC(O)OC alkylC(O)OR ,
2-6 1-6 1-6
wherein each alkyl is optionally substituted. In one exemplary embodiment, Y is –C
alkylC(O)OR , wherein the alkyl is optionally substituted. In one specifically contemplated
embodiment, Y is –C alkylC(O)OR .
11 1 1
In one embodiment, Y is –C alkylC(O)OR , –C alkylCO(O)R ,–C alkylC(O)OC
1-6 1-6 1-6 1-
alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl is optionally substituted.
6 1-6 1-6
11 1 1
In another embodiment, Y is –C alkylC(O)OR or –C alkylC(O)OC alkylC(O)OR ,
1-6 1-6 1-6
wherein each alkyl is optionally substituted. In one exemplary embodiment, Y is –C
alkylC(O)OR , wherein the alkyl is optionally substituted. In one specifically contemplated
11 1
embodiment, Y is –C alkylC(O)OR .
1 11
In some embodiments, each alkyl in Y or Y is optionally substituted with from one to three
2 1 11
R . In certain embodiments, each alkyl in Y or Y is optionally substituted with one or two
In one embodiment, R is C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl, wherein each
1-6 2-6
alkyl, alkenyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more halo,
11 11 12 11
CN, NO , NH , NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR ,
2 2 1-6 1-6 2
11 12 11 11 11
C(O)NR R , SO R , OR , and C(O)R ; and each alkyl and alkenyl is optionally
substituted with one or more cycloalkyl or cycloalkenyl; and each cycloalkyl and cycloalkenyl
is optionally substituted with one or more C alkyl or C alkenyl.
1-6 2-6
In one embodiment, R is C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl, wherein each
1-6 2-6
alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO , NH , NHR ,
11 12 11 11 12 11 11
NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR ,
1-6 1-6 2 2
and C(O)R ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and
each cycloalkyl is optionally substituted with C alkyl or C alkenyl.
1-6 2-6
In one embodiment, R is C alkenyl or cycloalkenyl, wherein each alkenyl and cycloalkenyl
11 11 12
are optionally substituted with one or more halo, CN, NO , NH , NHR , NR R , C
2 2 1-
11 11 12 11 11
haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , and
6 1-6 2 2
C(O)R ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each
cycloalkyl is optionally substituted with C alkyl or C alkenyl.
1-6 2-6
In other embodiment, R is C alkyl or cycloalkyl, wherein each alkyl and cycloalkyl is
optionally substituted. In one exemplary embodiment R is C alkyl, wherein each alkyl is
optionally substituted. In one specifically contemplated embodiment R is C alkyl.
In some embodiments, each alkyl or cycloalkyl in R is optionally substituted with from one to
three optional substituents. In certain embodiments, each alkyl or cycloalkyl in R is
optionally substituted with one or two optional substituents.
In some embodiment, R is C alkyl or cycloalkyl, optionally substituted with one or more
11 2
halo, OR , or CN. In other embodiments, R is C alkyl, optionally substituted with one or
11 2
more halo, OR , or CN. In certain exemplary embodiments, R is C alkyl.
11 12
In some embodiments, R and R are each independently C alkyl, C alkenyl, cycloalkyl,
1-6 2-6
11 12
or cycloalkenyl; or R and R together with the nitrogen atom to which they are attached are
11 12
a heteroaryl or heterocyclyl ring. In other embodiments, R and R are each independently
11 12
C alkyl or cycloalkyl; or R and R together with the nitrogen atom to which they are
11 12
attached are a heteroaryl or heterocyclyl ring. In certain embodiments, R and R are C
alkyl.
In one embodiment, Y is hydrogen or C alkyl, wherein the alkyl is optionally substituted. In
one exemplary embodiment, Y is hydrogen or C alkyl. In one specifically contemplated
embodiment, Y is hydrogen. In another specifically contemplated embodiment, Y is
hydrogen or methyl.
1 2 2
In some embodiments, X and X are each independently hydrogen, R , halo, NO , NH ,
11 11 12 11 11 12
NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R ,
1-6 1-6 2
11 11 11 1 1 1 1 1
SO R , OR , C(O)R , C alkylY , OY , C(O)Y , SO Y , or C(O)NHY at any of the
2 1-6 2
available 2-5 positions.
1 2 2
In some embodiments, X and X are each independently hydrogen, R , halo, NO , NH ,
11 11 12 11 11 12
NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R ,
1-6 1-6 2
11 11 11
SO R , OR , or C(O)R at any of the available 2-5 positions.
1 2 2
In some embodiments, X and X are each independently hydrogen, R , halo, NO , NH ,
11 11 12 11 11 12
NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R ,
1-6 1-6 2
11 11 11 2 1 1 1 1 1
SO R , OR , or C(O)R ; or X is C alkylY , OY , C(O)Y , SO Y , or C(O)NHY at any of
2 1-6 2
the available 2-5 positions.
1 2 2
In some embodiments, X and X are each independently hydrogen, R , halo, NO , NH ,
11 11 12 11 11 12
NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R ,
1-6 1-6 2
11 11 11
SO R , OR , or C(O)R at any of the available 2-5 positions.
1 2 2
In one embodiment, X and X are each independently hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11 11 2 1 1 1 1
haloalkoxy, SO R , OR , or C(O)R ; or X is C alkylY , OY , C(O)Y , or SO Y at any
6 2 1-6 2
of the available 2-5 positions.
1 2 2
In one embodiment, X and X are each independently hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11 11
haloalkoxy, SO R , OR , or C(O)R at any of the available 2-5 positions.
1 2 2
In one embodiment, X and X are each independently hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11
haloalkoxy, SO R , or OR at any of the available 2-5 positions.
1 2 2
In one embodiment, X and X are each independently hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11
haloalkoxy, SO R , or OR at any of the available 2-5 positions.
1 2 2
In one embodiment, X is halo; and X is independently hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11
haloalkoxy, SO R , or OR at any of the available 2-5 positions.
In one embodiment, X is 2-halo. In another embodiment, X is 2-chloro.
1 2 2
In one embodiment, X is 2-chloro; and X is hydrogen, R , halo, C haloalkyl, C
1-6 1-
11 11
haloalkoxy, SO R , or OR at any of positions 3-5.
In some embodiments, the C haloalkyl is CF , CHF , or CH F. In certain embodiments, the
1-6 3 2 2
C haloalkyl is CF . In some embodiments, the C haloalkoxy is OCF , OCHF , or OCH F.
1-6 3 1-6 3 2 2
In certain embodiments, the C haloalkoxy is CF .
1-6 3
In some embodiments, the halo is F, Cl, or Br. In certain embodiments, the halo is F or Cl.
1 1 1
In one embodiment, Y is –C alkylC(O)OR , –C alkylOC(O)R , –C alkylC(O)OC
2-6 2-6 1-6 1-
alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl is optionally substituted
6 1-6 1-6
with one or more R ; R is C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl, wherein each
1-6 2-6
alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO , NH , NHR ,
11 12 11 11 12 11 11
NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR ,
1-6 1-6 2 2
and C(O)R ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and
each cycloalkyl is optionally substituted with C alkyl or C alkenyl; R is C alkyl or
1-6 2-6 1-6
11 11 12
cycloalkyl, optionally substituted with one or more halo, OR , or CN; R and R are each
11 12
independently C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl; or R and R together with
1-6 2-6
the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring; and X and
2 2 11 11 12
X are each independently hydrogen, R , halo, NO , NH , NHR , NR R , C haloalkyl, C
2 2 1-6 1-
11 11 12 11 11 11 1 1
haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , C(O)R , C alkylY , OY ,
6 2 2 1-6
1 1 1
C(O)Y , SO Y , or C(O)NHY at any of the available 2-5 positions.
11 1 1
In one embodiment, Y is –C alkylC(O)OR , –C alkylCO(O)R ,–C alkylC(O)OC
1-6 1-6 1-6 1-
alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl is optionally substituted
6 1-6 1-6
with one or more R ; R is C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl, wherein each
1-6 2-6
alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO , NH , NHR ,
11 12 11 11 12 11 11
NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR ,
1-6 1-6 2 2
and C(O)R ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and
each cycloalkyl is optionally substituted with C alkyl or C alkenyl; R is C alkyl or
1-6 2-6 1-6
11 11 12
cycloalkyl, optionally substituted with one or more halo, OR , or CN; R and R are each
11 12
independently C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl; or R and R together with
1-6 2-6
the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring; and X and
2 2 11 11 12
X are each independently hydrogen, R , halo, NO , NH , NHR , NR R , C haloalkyl, C
2 2 1-6 1-
11 11 12 11 11 11 1 1
haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , C(O)R , C alkylY , OY ,
6 2 2 1-6
1 1 1
C(O)Y , SO Y , or C(O)NHY at any of the available 2-5 positions.
1 A B C D 1 A B C D 1
In one embodiment, Y is –(CR R ) (CR R ) C(O)OR , –(CR R ) (CR R ) OC(O)R ,–
m n m n
A B C D G H E F 1 A B
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or –(CR R )
m-1 n p o m-
C D G H E F 3
(CR R ) C(O)O(CR R ) (CR R ) OR ; m is an integer from 2 to 6; o is an integer from 1 to
1 n p o
6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p is 6 or
A B C D E F G H
less; and R , R , R , R , R , R , R , and R at each instance of m, n, o, and p are each
independently hydrogen or R .
11 A B C D 1 A B C D 1
In one embodiment, Y is –(CR R ) (CR R ) C(O)OR , –(CR R ) (CR R ) OC(O)R ,–
m n m n
A B C D G H E F 1
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or –
m n p o
A B C D G H E F 3
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) OR ; m and o are each independently an integer
m n p o
from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p
A B C D E F G H
is 6 or less; and R , R , R , R , R , R , R , and R at each instance of m, n, o, and p are each
independently hydrogen or R .
1 11 A B C D 1
In some embodiments, Y or Y is –(CR R ) (CR R ) C(O)OR or –
A B C D G H E F 1
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR .
m n p o
1 11 A B C D 1
In certain embodiments, Y or Y is –(CR R ) (CR R ) C(O)OR .
A B E F
In one embodiment, R , R , R , and R at each instance of m and o are each independently
C D G H
hydrogen; and R , R , R , and R at each instance of n and p are each independently
hydrogen or R .
1 C D 1
In one exemplary embodiment, Y is –(CH ) (CR R ) C(O)OR , –
2 m n
C D 1 G H 1
(CH ) (CR R ) OC(O)R ,–(CH ) C(O)O(CR R ) (CH ) C(O)OR , or –(CH )
2 m n 2 m-1 p 2 o 2 m-
C(O)O(CH ) OR .
1 2 o
11 C D 1
In another exemplary embodiment, Y is –(CH ) (CR R ) C(O)OR , –
2 m n
C D 1 G H 1
(CH ) (CR R ) OC(O)R ,–(CH ) C(O)O(CR R ) (CH ) C(O)OR , or –
2 m n 2 m p 2 o
(CH ) C(O)O(CH ) OR .
2 n 2 o
1 C D 1
In another exemplary embodiment, Y is –(CH ) (CR R ) C(O)OR or –(CH )
2 m n 2 m-
G H 1
C(O)O(CR R ) (CH ) C(O)OR .
1 p 2 o
11 C D 1
In another exemplary embodiment, Y is –(CH ) (CR R ) C(O)OR or –
2 m n
G H 1
(CH ) C(O)O(CR R ) (CH ) C(O)OR .
2 m p 2 o
In one specifically contemplated embodiment, Y is –(CH ) C(O)OR or –(CH )
2 m 2 m-
C(O)O(CH ) C(O)OR .
1 2 o
11 1
In another specifically contemplated embodiment, Y is –(CH ) C(O)OR or –
(CH ) C(O)O(CH ) C(O)OR .
2 m 2 o
1 11 1
In another specifically contemplated embodiment, Y or Y is –(CH ) C(O)OR .
1 A B C D 1
In one exemplary embodiment,Y is –(CR R ) (CR R ) C(O)OR , –
A B C D 1 A B C D G H E F 1
(CR R ) (CR R ) OC(O)R , –(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or –
m n m-1 n p o
A B C D G H E F 3
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) OR .
m-1 n p o
11 A B C D 1
In one exemplary embodiment, Y is –(CR R ) (CR R ) C(O)OR , –
A B C D 1 A B C D
(CR R ) (CR R ) OC(O)R , –(CR R ) (CR R ) C(O)OH, –
m n m n
A B C D G H E F 1
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or –
m n p o
A B C D G H E F 3
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) OR .
m n p o
1 A B C D 1 A B
In another exemplary embodiment, Y is –(CR R ) (CR R ) C(O)OR or –(CR R )
m n m-
C D G H E F 1 1 2
(CR R ) C(O)O(CR R ) (CR R ) C(O)OR ; and X and X are each independently
1 n p o
2 11 11 11
hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , OR , or C(O)R at any of the
1-6 1-6 2
available 2-5 positions.
11 A B C D 1
In another exemplary embodiment, Y is –(CR R ) (CR R ) C(O)OR or –
A B C D G H E F 1 1 2
(CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR ; and X and X are each
m n p o
2 11 11 11
independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , OR , or C(O)R at
1-6 1-6 2
any of the available 2-5 positions.
1 11 A B C D 1
In one specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ; and
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
or OR at any of the available 2-5 positions.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 2
or OR at any of the available 2-5 positions; and Y is hydrogen or C alkyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 2
or OR at any of the available 2-5 positions; and Y is hydrogen or methyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 2
or OR at any of the available 2-5 positions; and Y is hydrogen.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 A B
or OR at any of the available 2-5 positions; R and R at each instance of m are hydrogen;
and Y is hydrogen or C alkyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 A B
or OR at any of the available 2-5 positions; R and R at each instance of m are hydrogen;
and Y is hydrogen or methyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11
X and X are each independently hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R ,
1-6 1-6 2
11 A B
or OR at any of the available 2-5 positions; R and R at each instance of m are hydrogen;
and Y is hydrogen.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11 11
X is 2-chloro; X is hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any
1-6 1-6 2
A B 2
of the available 3-5 positions; R and R at each instance of m are hydrogen; and Y is
hydrogen or C alkyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11 11
X is 2-chloro; X is hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any
1-6 1-6 2
A B 2
of the available 3-5 positions; R and R at each instance of m are hydrogen; and Y is
hydrogen or methyl.
1 11 A B C D 1
In another specifically contemplated embodiment, Y or Y is –(CR R ) (CR R ) C(O)OR ;
1 2 2 11 11
X is 2-chloro; X is hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any
1-6 1-6 2
A B 2
of the available 3-5 positions; R and R at each instance of m are hydrogen; and Y is
hydrogen.
In one embodiment, the compound of formula (I) is
3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propyl acetate,
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
iso-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
n-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
n-propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
n-propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)butanoate, or
methyl 5-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)pentanoate, or
a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the compound of formula (I) is
3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propyl acetate,
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
iso-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
n-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
n-propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, or
n-propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, or
a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the compound is
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
iso-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
n-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
n-propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
n-propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)butanoate, or
methyl 5-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)pentanoate, or
a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the compound is
ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
iso-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
n-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate,
ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
n-propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate,
methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate,
isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, or
n-propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, or
a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the stereochemical configuration at position 2 of the cyclohexyl ring in
the compound is (S).
In some embodiments, the compound comprises 95% or more of a single stereoisomer. In
certain embodiments, the compound is stereoisomerically pure.
In one embodiment, the compound is a pharmaceutically acceptable salt. In one embodiment,
the salt is a hydrochloride salt.
In one embodiment, the compound of formula (II) is a compound of formula (I) as defined in
the first aspect or in any of the embodiments described above.
Asymmetric centers may exist in the compounds of formula (I) and (II). The asymmetric
centers may be designated as (R) or (S), depending on the configuration of substituents in three
dimensional space at the chiral carbon atom. All stereochemical isomeric forms of the
compounds, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers
and l-isomers, and mixtures thereof, including enantiomerically enriched and
diastereomerically enriched mixtures of stereochemical isomers, are included herein.
Individual enantiomers can be prepared synthetically from commercially available enantiopure
starting materials or by preparing enantiomeric mixtures and resolving the mixture into
individual enantiomers. Resolution methods include conversion of the enantiomeric mixture
into a mixture of diastereomers and separation of the diastereomers by, for example,
recrystallization or chromatography, and any other appropriate methods known in the art.
Starting materials of defined stereochemistry may be commercially available or made and, if
necessary, resolved by techniques well known in the art.
The compounds of formula (I) and (II) may also exist as conformational or geometric isomers,
inlcuding cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers. All such isomers and
any mixtures thereof are included herein.
Also included are any tautomeric isomers or mixtures thereof of the compounds. As would be
appreciated by those skilled in the art, a wide variety of functional groups and other structures
may exhibit tautomerism. Examples include, but are not limited to, keto/enol, imine/enamine,
and thioketone/enethiol.
The compounds of formula (I) and (II) may also exist as isotopologues and isotopomers,
wherein one or more atoms in the compounds are replaced with different isotopes. Suitable
1 2 3 12 13 14 16 18
isotopes include, for example, H, H (D), H (T), C, C, C, O, and O. Procedures for
incorporating such isotopes into the compounds described herein will be apparent to those
skilled in the art. Isotopologues and isotopomers of the compounds are thus included herein.
Also included are pharmaceutically acceptable salts and solvates, including hydrates of the
compounds. Such salts include, acid addition salts, base addition salts, and quaternary salts of
basic nitrogen-containing groups. Acid addition salts can be prepared by reacting compounds,
in free base form, with inorganic or organic acids. Examples of inorganic acids include, but
are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and
phosphoric acid. Examples of organic acids include, but are not limited to, lauric, acetic,
trifluoroacetic, formic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic,
maleic, fumaric, pyruvic, aspartic, glutamic, stearic, salicylic, mandelic,methanesulfonic,
benzenesulfonic, isoethonic, sulfanilic, adipic, butyric, oxalic, and pivalic. Base addition salt
can be prepared by reacting compounds, in free acid form, with inorganic or organic bases.
Examples of inorganic base addition salts include alkali metal salts, alkaline earth metal salts,
and other physiologically acceptable metal salts, for example, aluminium, calcium, lithium,
magnesium, potassium, sodium, or zinc salts. Examples of organic base addition salts include
amine salts, for example, salts of trimethylamine, diethylamine, ethanolamine,
diethanolamine, and ethylenediamine. Quaternary salts of basic nitrogen-containing groups in
the compounds may be may be prepared by, for example, reacting the compounds with alkyl
halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl
sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, and the like.
The general chemical terms used in the formulae herein have their usual meaning.
The term “aliphatic” is intended to include saturated and unsaturated, nonaromatic, straight
chain, branched, acyclic, and cyclic hydrocarbons. Those skilled in the art will appreciate that
aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl
groups.
The term “alkyl” is intended to include straight chain and branched chain alkyl groups. In
some embodiments, alkyl groups have from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, or
from 1 to 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited
to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of
branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl,
neopentyl, isopentyl, and 2,2-dimethylpropyl.
The term “alkenyl” is intended to include straight and branched chain alkyl groups having at
least one double bond between two carbon atoms. In some embodiments, alkenyl groups have
from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. In some
embodiments, alkenyl groups have one, two, or three carbon-carbon double bonds. Examples
of alkenyl groups include, but are not limited to, vinyl, allyl, –CH=CH(CH ), –CH=C(CH ) , –
3 3 2
C(CH )=CH , and –C(CH )=CH(CH ).
3 2 3 3
The term “alkynyl” is intended to include straight and branched chain alkyl groups having at
least one triple bond between two carbon atoms. In some embodiments, the alkynyl group
have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. In
some embodiments, alkynyl groups have one, two, or three carbon-carbon triple bonds.
Examples include, but are not limited to, –C≡CH, –C≡CH , –CH C≡CH , and –
3 2 3
C≡CH CH(CH CH ) .
2 2 3 2
The term “cycloalkyl” is intended to include mono-, bi- or tricyclic alkyl groups. In some
embodiments, cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6,
from 3 to 5 carbon atoms in the ring(s). In some embodiments, cycloalkyl groups have 5 or 6
ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some
embodiments, the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from
3 to 5, or from 4 to 5 ring carbon atoms. Bi- and tricyclic ring systems include bridged, spiro,
and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems
include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and
decalinyl.
The term “cycloalkenyl” is intended to include non-aromatic cycloalkyl groups having at least
one double bond between two carbon atoms. In some embodiments, cycloalkenyl groups have
one, two or three double bonds. In some embodiments, cycloalkenyl groups have from 4 to
14, from 5 to 14, from 5 to 10, from 5 to 8, or from 5 to 6 carbon atoms in the ring(s). In some
embodiments, cycloalkenyl groups have 5, 6, 7, or 8 ring carbon atoms. Examples of
cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,
pentadienyl, and hexadienyl.
The term “aryl” is intended to include cyclic aromatic hydrocarbon groups that do not contain
any ring heteroatoms. Aryl groups include monocyclic, bicyclic and tricyclic ring systems.
Examples of aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl,
fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl. In some
embodiments, aryl groups have from 6-14, from 6 to 12, or from 6-10 carbon atoms in the
ring(s). In some embodiments, the aryl groups are phenyl or naphthyl. Aryl groups include
aromatic-aliphatic fused ring systems. Examples include, but are not limited to, indanyl and
tetrahydronaphthyl.
The term “heterocyclyl” is intended to include non-aromatic ring systems containing 3 or
more ring atoms, of which one or more is a heteroatom. In some embodiments, the
heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, the heterocyclyl group
contains one, two, three, or four heteroatoms. In some embodiments, heterocyclyl groups
include mono-, bi- and tricyclic rings having from 3 to 16, from 3 to 14, from 3 to 12, from 3
to 10, from 3 to 8, or from 3 to 6 ring atoms. Heterocyclyl groups include partially unsaturated
and saturated ring systems, for example, imidazolinyl and imidazolidinyl. Heterocyclyl
groups include fused and bridged ring systems containing a heteroatom, for example,
quinuclidyl. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl,
azepanyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, isoxazolidinyl, morpholinyl, piperazinyl,
piperidinyl, pyranyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothienyl, thiadiazolidinyl, and trithianyl.
The term “heteroaryl” is intended to include aromatic ring systems containing 5 or more ring
atoms, of which, one or more is a heteroatom. In some embodiments, the heteroatom is
nitrogen, oxygen, or sulfur. In some embodiments, heteroaryl groups include mono-, bi- and
tricyclic ring systems having from 5 to 16, from 5 to 14, from 5 to 12, from 5 to 10, from 5 to
8, or from 5 to 6 ring atoms. Heteroaryl groups include, but are not limited to, pyrrolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl,
azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, pyrazolopyridinyl, triazolopyridinyl,
benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridinylxanthinyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.
Heteroaryl groups include fused ring systems in which all of the rings are aromatic, for
example, indolyl, and fused ring systems in which only one of the rings is aromatic, for
example, 2,3-dihydroindolyl.
The term “halo” or “halogen” is intended to include F, Cl, Br, and I.
As used herein, the term “substituted” is intended to mean that one or more hydrogen atoms in
the group indicated is replaced with one or more independently selected suitable substituents,
provided that the normal valency of each atom to which the substituent/s are attached is not
exceeded, and that the substitution results in a stable compound.
As used herein, the term “and/or” means “and”, or “or”, or both.
The term “comprising” as used in this specification means “consisting at least in part of”.
When interpreting each statement in this specification that includes the term “comprising”,
features other than that or those prefaced by the term may also be present. Related terms such
as “comprise” and “comprises” are to be interpreted in the same manner.
It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also
incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9,
4, 5, 6, 6.5, 7, 8, 9, and 10) and also any range of rational numbers within that range (for
example, 2 to 8, 1.5 to 5.5, and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly
disclosed herein are hereby expressly disclosed. These are only examples of what is
specifically intended and all possible combinations of numerical values between the lowest
value and the highest value enumerated are to be considered to be expressly stated in this
application in a similar manner.
Although the present invention is broadly as defined above, those persons skilled in the art
will appreciate that the invention is not limited thereto and that the invention also includes
embodiments of which the following description gives examples.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described with reference to the Figures in which:
Figure 1A and Figure 1B are graphs showing time-course for anaesthesia (loss and recovery of
righting reflex) with ketamine and rac-C2nPr (Figure 1A) and rac-C4Me (Figure 1B). The
grey panel shows the duration of drug infusion (measurement taken every minute). ••••: test
compound. : ketamine.
Figure 2A and Figure 2B are graphs showing time-course for analgesia (pedal withdrawal
reflex score) with ketamine and rac-C2nPr (Figure 2A) and rac-C4Me (Figure 2B). The grey
panel shows the duration of drug infusion (measurement taken every minute). Error bars are
SEM. ••••: test compound. : ketamine.
Figure 3 is a plot (log 10) of effective potency (dose [mg/kg] to LRR) vs. duration (time to
RRR) for ketamine and compounds of the invention. The alkyl chain length of compounds is
denoted by symbol: = C2; = C3; = C4; = ketamine. 7 = rac-C3OAc, 7S = (S)-
C3OAC, 8 = rac-C2Et, 8S = (S)-C2Et, 9 = rac-C2iPr, 9S = (S)-C2iPr, 9R = (R)-C2iPr, 10 =
rac-C2nPr, 11 = rac-C3Et, 12 = rac-C3iPr, 13 = rac-C3nPr, 14 = rac-C4Me, 14S = (S)-C4Me,
= rac-C4Et, 16 = rac-C4iPr, and 17 = rac-C4nPr.
DETAILED DESCRIPTION OF THE INVENTION
The present invention generally relates to ketamine derivatives for use as anaesthetics,
analgesics, or sedatives.
The applicants have invented new ketamine derivatives of the formula (I) as defined above
which can provide anaesthetic and/or analgesic effects similar to ketamine, but at least in some
embodiments have the advantage of shortening the period of recovery after administration of
the derivative has ceased.
The applicants have also found that certain known ketamine derivatives, which are
encompassed by the formula (II), can surprisingly be used as anaesthetics and have
advantageous properties similar to those of the compounds of formula (I).
Compounds of formula (I) or (II) may be prepared using methods of synthesis known in the art
or methods analogous thereto.
In one embodiment, the method comprises reacting a compound of the formula (III):
(III)
2 1 2 1
wherein Y , X , and X are as defined above with an alkylating agent of the formula Y –Z or
11 1 11
Y –Z, wherein Z is a suitable leaving group and Y and Y are as defined above, to provide
the compound of the formula (I) or (II), respectively.
In one embodiment, Z is halo.
In some embodiments, the reaction is carried out in the presence of a base. In certain
embodiments, the reaction is carried out in the presence of an inorganic base, for example, a
carbonate base.
In some embodiments, the reaction is carried out in the presence of a suitable solvent, for
example, an aprotic solvent.
The reaction may be carried out at any suitable temperature. In some embodiments, the
reaction is carried out in the presence of a suitable solvent at reflux. In other embodiments,
the reaction is carried out at ambient temperature.
In some embodiments, the compound of formula (III) is prepared by a method comprising
heating a compound of the formula (IV)
(IV)
wherein X and X are as defined above in a suitable liquid reaction medium to provide a
compound of the formula (III), wherein Y is hydrogen.
In some embodiments, the method comprises heating the compound of the formula (IV) in a
suitable solvent. In certain embodiments, the compound is heated at a temperature of 75, 100,
125, 150, 175, or 200 °C or more.
In some embodiments, the compound of formula (IV) is prepared by a method comprising
reacting a compound of the formula (V)
1 2 1
wherein X and X are as defined above and Z is halo with NH /NH OH.
In some embodiments, the compound of formula (V) is prepared by a method comprising
reacting a compound of the formula (VI)
(VI)
wherein X and X are as defined above with a halogenating agent.
In one embodiment, the halogenating agent is copper (II) bromide.
In some embodiments, the reaction is carried out in a suitable solvent.
Schemes 1 to 4 below illustrate the preparation of certain compounds of formula (I) and (II)
wherein X is chloro and X is hydrogen from (2-o-chlorophenyl)amino-cyclohexanone
(norketamine).
(S)-Norketamine (S-24) is synthesized following a reported procedure [Hong & Davisson. J.
Pharm. Sci., 1982, 71, 912].
Commercially available (2-chlorophenyl)(cyclopentyl)methanone (31) is brominated by
refluxing with CuBr in EtOAc. The brominated intermediate (22) is converted to the
corresponding imino cyclopentanol (23) by stirring in NH OH solution saturated with NH
gas. Thermal rearrangement of the hydrochloride salt of imino cyclopentanol in Dowtherm A
at 200 C affords racemic norketamine (rac-24).
Cl O Cl O Cl NH
Br OH
i ii
rac-24, 59 %
31 22, 89 %
23, 69 %
Scheme 1
(i) CuBr , EtOAc, reflux, 3 h; (ii) (a) NH /NH OH, 25 C, 5 days, (b) HCl(g),
2 3 4
isopropanol/diethyl ether, 0 °C, 3 h; (iii) Dowtherm A, 200 C, 12 min.
The (S)-enantiomer of norketamine (S-24) is obtained by resolution with L-(R,R)-(+)-tartaric
acid. The (R)-enantiomer of norketamine (R-24) may be obtained in an analogous fashion
from D-(S,S)-(-)-tartaric acid.
Compounds of formula (I) or (II) are synthesized by treatment of racemic or (S)-norketamine
with alkyl halides corresponding to Y . Enantiopure (R)-norketamine and non-racemic
enantiomeric mixtures of norketamine may be also used.
The compounds may be converted to hydrochloride salts using HCl gas.
Scheme 2.
(iv) 3-bromopropyl acetate, KI, K CO , CH CN, reflux, 24 h; (v) (+) tartaric acid, acetone, 2
2 3 3
days, 3x recrystallization; (vi) NaOH, CH CN, 25 C, 2 h.
Br CO X
Cl Cl
KI, K CO , CH CN
2 3 3
HN CO X
reflux, 24 - 72 h
X = Me, Et, Pr, Pr
rac-24 or S-24
n = 2, 3, 4
Scheme 3
Alkyl halides corresponding to Y are commercially available or may be prepared by methods
known in the art or analogous thereto.
Compounds wherein Y is R may be prepared from compounds of formula (I) or (II) wherein
Y is hydrogen by treatment with an alkylating agent corresponding to R . Such compounds
may also be prepared by reductive amination with an aldehyde (e.g. formaldehyde when R is
methyl) or ketone corresponding to R .
19: Y = (CH ) CO Et
2 2 2
: Y = (CH ) CO Et
2 3 2
21: Y = (CH ) CO Me
2 4 2
Scheme 4.
(i) NaCNBH , HCHO, AcOH, MeOH, 25 C, 24 h.
Compounds of formula (I) and (II) wherein the phenyl ring is substituted with different X and
X may be prepared by, for example, using suitably substituted
(phenyl)(cyclopentyl)methanones.
Certain compounds of formula (II) and methods for their preparation are described in
Preparation of the compounds may involve the protection and deprotection of various
chemical groups. The need for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by a person skilled in the art. Protecting groups
and methods for protection and deprotection are well known in the art [see e.g. T. W. Greene
and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 Ed., Wiley & Sons, Inc., New
York (1999)].
The compounds of formula (I) and (II) have analgesic, anaesthetic, and/or sedative activity
and are therefore useful for treating pain and/or anaesthetizing and/or sedating subjects.
The term “treatment”, and related terms such as “treating” and “treat”, as used herein, in the
context of treating pain, relates generally to treatment, of a human or a non-human subject, in
which some desired therapeutic effect is achieved. The therapeutic effect may, for example,
be inhibition, reduction, amelioration, halt, or prevention of the pain.
Analgesia is the alleviation or elimination of the sensation of pain. As used herein the term
“pain” encompasses a wide range of clinical manifestations, and it has a broad meaning. Pain
perception is highly subjective, and different people experience pain in different ways and
with greatly different intensities. The International Association for the Study of Pain defines
pain as an unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage. Non-limiting types and causes of pain
include neuralgia, myalgia, hyperalgesia, hyperpathia, neuritis, and neuropathy. Pain may also
be caused by physical trauma, such as burns or surgery. In one embodiment, the pain is pain
resistant to treatment with opioids.
The term “anaesthetize” and related terms such as “anaesthetizing” as used herein means to
induce a loss of sensation and usually of consciousness without loss of vital functions
artificially produced by the administration of one or more agents that block responses of the
body to painful stimuli, for example the absence of a response to a surgical incision.
The term “sedate” and related terms such as “sedating” as used herein means to induce a state
of depressed consciousness in which a patient or subject retains the ability to independently
and continuously maintain an open airway and a regular breathing pattern, and to respond
appropriately and rationally to physical stimulation and verbal commands. Sedation may be
evaluated using, for example, the Ramsay Sedation Scale.
The methods described herein comprise administering compounds of formula (I) or (II) to a
subject.
The subject may be a human or non-human animal. Non-human animals include, for example,
production animals, such as, cattle, sheep, swine, deer, and goats; companion animals, such as,
dogs, cats, and horses; zoo animals, such as, zebras, elephants, giraffes, and large cats;
research animals, such as, mice, rats, rabbits, and guinea pigs; fur-bearing animals, such as,
mink; birds, such as, ostriches, emus, hens, geese, turkeys, and ducks; fresh- and salt-water
fish, such as, trout, salmon, carp, and eels; and reptiles, such as lizards and snakes. In one
embodiment, the subject is a human.
The methods comprise administering a therapeutically effective amount of the compound to
the subject. A “therapeutically effective amount” of a compound is an amount effective to
demonstrate a desired therapeutic effect either alone or in combination with other agents.
The therapeutically effective amount of the compound to be administered to a subject depends
on, for example, the purpose for which the compound is administered, mode of administration,
nature and dosage of any co-administered compounds, and characteristics of the subject, such
as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. A
person skilled in the art will be able to determine appropriate dosages having regard to these
any other relevant factors.
In one embodiment, the dose of administered is from about 0.01 mg per kg of body weight (0.
01 mg/kg) to about 100 mg/kg.
The compounds may be administered by any suitable route. The route may depend on the
therapeutic purpose for which the compound is administered.
In one exemplary embodiment, the compound is administered intravenously.
In one specifically contemplated embodiment, the compound is administered by intravenous
bolus. In another specifically contemplated embodiment, the compound is administered
intravenously by continuous infusion.
In certain embodiments, the compound is administered as an intravenous bolus and by
intravenous infusion. In one embodiment, the compound is administered as an intravenous
bolus and by continuous intravenous infusion.
In some embodiments, the compound is administered as an intravenous bolus at a dose from
about 0.01 mg per kg of body weight (0. 01 mg/kg) to about 100 mg/kg.
In some embodiments, the compound is administered by continuous intravenous infusion at a
dose from about 0.1 mg/kg/min to about 10 mg/kg/min.
In one specifically contemplated embodiment, the compound is administered for anesthesia as
an intravenous bolus at a dose from about 0.01 mg per kg of body weight (0. 01 mg/kg) to
about 100 mg/kg and as a continuous intravenous infusion at a dose from about 0.1 mg/kg/min
to about 10 mg/kg/min. Smaller doses would be used for sedation and analgesia.
The compounds of formula (I) and (II) are generally prepared in a formulation or
pharmaceutical composition appropriate for administration by a particular route. Examples of
administration route include transdermal, transmucosal (e.g. nasal, transbuccal, sublingual,
vaginal, and rectal), oral, pulmonary (i.e. inhalation), and parenteral (e.g. intravenous,
intraarterial, intraperitoneal, intradermal, intramuscular, intraventricular, or subcutaneous).
The formulations generally comprise a pharmaceutically acceptable diluent, excipient, or
carrier. Any suitable diluent, excipient, or carrier can be used provided that it is non-toxic and
compatible with the other ingredients of the composition. The diluent, excipient, or carrier
used depends on the intended route of administration.
The formulation or pharmaceutical composition may be manufactured by any method known
in the art, for example, by conventional mixing, dissolving, granulating, levigating,
emulsifying, encapsulating, entrapping, or compression. Numerous diluents, excipients, and
carriers and methods for preparing pharmaceutical compositions are known in the art [see e.g.
Remington’s Pharmaceutical Sciences, Mack Publishing Co., (2000)].
Suitable formulations for administering the compounds include, for example, tablets, capsules,
suppositories, solutions, and powders etc.
The content of the pharmaceutically active compound(s) is typically in the range from 0.05 to
90 wt.-% of the composition as a whole. In one embodiment, the content is from 0.1 to 50
wt.-% of the composition as a whole.
Suitable compositions include for example tablets, capsules, suppositories, solutions and
powders etc. Tablets may comprise a solid carrier or diluent. Liquid pharmaceutical
compositions may comprise a liquid carrier, for example, water, petroleum, animal or
vegetable oils, mineral oil or synthetic oil. Liquid compositions may also comprise
physiological saline solution, dextrose or other carbohydrate solution, glycols e.g. ethylene
glycol, propylene glycol or polyethylene glycol, etc. Capsules may comprise a solid carrier
e.g. gelatin. Such formulations will be well known to a person skilled in the art.
The pharmaceutical composition may be formulated for intravenous, cutaneous or
subcutaneous injection. The active ingredient is generally in the form of a parenterally
acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity and
stability. Those skilled in the art will be able to prepare suitable solutions. The solutions may
comprise isotonic vehicles e.g. sodium chloride injection, Ringer’s injection, etc.
Preservatives, stabilisers, buffers antioxidants and/or other suitable additives may be included
as required.
The composition of the present invention comprises a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent,
excipient, or carrier. The composition may be formulated as described above.
The formulations may comprise or be used or administered in combination, for example
sequentially or simultaneously, with one or more additional therapeutic agents, for example
alpha-2 adrenergic drugs such as clonidine or dexmedetomidine.
In one embodiment, the composition further comprises a buffer, stabiliser, or adjuvant.
The uses of the present invention involve the manufacture of medicaments. The medicaments
are also formulated as described above.
EXAMPLES
The following non-limiting examples are provided to illustrate the present invention and in no
way limit the scope thereof.
The structures and physicochemical properties of selected compounds representative of the
invention are given in Table 1.
Lipophilicities (clogP) were calculated using ChemBioDraw v12.02 (CambridgeSoft, UK).
pKa values were calculated using ACD/PhysChem Suite v12 (ACD/Labs, Toronto, Canada).
Table 1. Details of representative compounds
(I)
1 2 1 2 b c
Compd. X X Y Y Form Purity clogP pKa
rac-C3OAc 2-Cl H (CH ) OAc H R/S 97.2 2.86 6.20
(S)-C3OAc 2-Cl H (CH ) OAc H S 95.8 2.86 6.20
2-Cl H (CH ) CO Et H R/S 97.2 3.05 4.35
rac-C2Et
2 2 2
(S)-C2Et 2-Cl H (CH ) CO Et H S 99.1 3.39 4.35
2 2 2
2-Cl H (CH ) CO Pr H R/S 99.0 3.36 4.35
rac-C2iPr
2 2 2
(S)-C2iPr 2-Cl H (CH ) CO Pr H S 99.5 3.36 4.35
2 2 2
(R)-C2iPr 2-Cl H (CH ) CO Pr H R 99.5 3.36 4.35
2 2 2
2-Cl H (CH ) CO Pr H R/S 99.0 3.58 4.35
rac-C2nPr
2 2 2
rac-C3Et 2-Cl H (CH ) CO Et H R/S 95.3 3.39 5.86
2 3 2
rac-C3iPr 2-Cl H (CH ) CO Pr H R/S 98.4 3.70 5.86
2 3 2
rac-C3nPr 2-Cl H (CH ) CO Pr H R/S 97.2 3.92 5.85
2 3 2
rac-C4Me 2-Cl H (CH ) CO Me H R/S 99.1 2.77 6.29
2 4 2
(S)-C4Me 2-Cl H (CH ) CO Me H S 97.0 2.77 6.29
2 4 2
2-Cl H (CH ) CO Et H S 94.4 3.29 6.29
rac-C4Et
2 4 2
rac-C4iPr 2-Cl H (CH ) CO Pr H R/S 97.6 3.60 6.29
2 4 2
rac-C4nPr 2-Cl H (CH ) CO Pr H R/S 95.4 3.82 6.29
2 4 2
19 2-Cl H (CH ) CO Et Me R/S 93.0 3.69 4.77
2 2 2
2-Cl H (CH ) CO Et Me R/S 94.0 3.48 5.51
2 3 2
21 2-Cl H (CH ) CO Me Me R/S 94.8 3.32 5.74
2 4 2
a b c
Purity by reverse-phase HPLC; ClogP calculated using ChemBioDraw Ultra v12.02; pKa
calculated using ACD/PhysChem Suite v12.
Ketamine has a measured (Volgyi, G. et al. Anal. Chim. Acta 2007, 583, 418-428) aqueous
pKa of 7.49 and a calculated clogP of 2.22. The closest match to this were the acetates (rac-
C3OAc and (S)-C3OAc). Next closest in physicochemical properties were the C4 methyl
esters (rac-C4Me and (S)-C4Me). The esters overall showed a range of both pKa values
(from 4.35 to 6.29) and lipophilicities (from 2.77 to 3.92).
General details
All reagents and solvents were obtained from commercial suppliers and used without further
purification unless otherwise stated. Reactions requiring anhydrous conditions were performed
under nitrogen atmospheres. Reactions were monitored by thin layer chromatography (TLC)
on preloaded silica gel F254 plates (Sigma-Aldrich) with a UV indicator. Column
1 13
chromatography was performed with Merck 230-400 mesh silica gel. H and C NMR
spectra were obtained with a Bruker Avance 400 spectrometer at 400 MHz for H and 100
MHz for C spectra. Spectra were obtained in CDCl or (CD ) SO. The chemical shifts are
3 3 2
reported in parts per million (δ) downfield using tetramethylsilane (SiMe ) as internal
standard. Spin multiplicities are given as s (singlet), d (doublet), dd (double doublet), br
(broad), m (multiplet), and q (quartet). Coupling constants (J values) were measured in hertz
(Hz). All LC/MS data were gathered by direct injection of methanolic solutions into a
Surveyor MSQ mass spectrometer using an atmospheric pressure chemical ionization (APCI)
with a corona voltage of 50 V and a source temperature of 400 C. Final products were
analyzed by reverse-phase HPLC (Alltima C18 5 μm column, 150 mm × 3.2 mm; Alltech
Associated, Inc., Deerfield, IL) using an Agilent HP1100 equipped with a diode array detector.
The mobile phase was 80% CH CN/20% H O (v/v) in 45 mM HCO NH at pH 3.5 and 0.5
3 2 2 4
mL/min. The purity was determined by monitoring at 272 nm and was ≥95% for final products
unless otherwise stated. The enantiomeric purity was analyzed by chiral HPLC (Chiralcel OJ-
H column, 0.46 cm x 45 cm). The mobile phase was 85 % hexanes/15 % EtOH with a flow
rate of 0.6 mL/min. The purity was determined by monitoring at 254 and 280 nm and was
≥95% unless otherwise stated. The final product purity was also assessed by combustion
analysis carried out in the Campbell Micro analytical Laboratory, University of Otago
(Dunedin, New Zealand). Melting points were determined on an Electrothermal 2300 Melting
Point Apparatus and are uncorrected. DCM refers to dichloromethane, DMF refers to N,N-
dimethylformamide, EtOAc refers to ethyl acetate, EtOH refers to ethanol.
Example 1
rac((1-(2-Chlorophenyl)oxocyclohexyl)amino)propyl acetate hydrochloride (rac-
C3OAc). (Scheme 2). (2-chlorophenyl)(cyclopentyl)methanone [US 20080268071] (21) (10
g, 48.0 mmol) was dissolved in ethyl acetate (100 mL) followed by addition of Cu(II)Br (27
g, 120.9 mmol). The solution was refluxed for 2.5 h and cooled to 25 C. The solid was
filtered and the filtrate was evaporated under reduced pressure. Some solid began to form
while evaporating solvent under reduced pressure. DCM (100 mL) was added to the solid
formed and solution cooled to 0 C in an ice bath. After standing for 10 min. the solution was
filtered and the filtrate concentrated under reduced pressure to obtain (1-bromocyclopentyl)(2-
chlorophenyl)methanone (22) as a yellow oil (12.3 g, 89 %). H NMR (400 MHz, CDCl ) δ
7.70 (dd, J = 7.4, 1.8 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz), 7.37 (td, J = 7.4, 1.8 Hz, 1H), 7.30
(td, J = 7.4, 1.3 Hz, 1H), 2.45-2.27 (m, 4H), 2.09-2.01 (m, 2H), 1.89-1.82 (m, 2H); C NMR
(101 MHz, CDCl ) δ 199.47, 138.87, 130.83, 130.55, 130.16, 128.33, 126.49, 74.29, 40.42,
23.26. MS m/z 289.3 (M2H , 24 %) 207.4 (M – Br , 100 %)
Ammonium hydroxide (200 mL) was cooled to 0 C in an ice bath and was saturated with NH
gas for 5 min. The solution was added to a flask containing 22 (12.74 g, 44.5 mmol) and
stirred vigorously at 25 C for 5 days. The brown clumps formed were separated from the
solvent and resuspended in hexanes (150 mL). After stirring in hexanes for 4 h, the precipitate
formed was filtered and dried to obtain 23 (8.15 g, 81%) as a pale yellow solid. This was
suspended in 8 mL of 2-propanol and cooled to 0 C in an ice bath. HCl gas was bubbled
through the solution for 2 min. and diethyl ether (16 mL) was added. Upon standing at 0 C for
3 h a pale yellow precipitate was formed which was filtered, dried under vacuum to obtain 1-
((2-chlorophenyl)(imino)methyl)cyclopentanol hydrochloride (23-HCl) [Parcell, R.F. &
Sanchez, J.P. J. Org. Chem.1981, 46, 5055]. (7.21 g). H NMR (400 MHz, CDCl ) δ 14.05 (br,
1H), 12.28 (br, 1H), 7.61 – 7.32 (m, 4H), 2.23 (br, 2H), 1.98 (m, 4H), 1.69 (br, 2H); C NMR
(101 MHz, CDCl ) δ 195.76, 132.74, 131.42, 130.57, 128.99, 128.85, 126.82, 85.56, 39.47,
38.78, 24.46, 23.85. MS m/z 224.4 (MH ).
To Dowtherm A (142 mL) heated to 200 C was added in portions 23 (18 g, 69.2 mmol). The
heating was continued for 12 min. and cooled to 0 C in an ice bath. The reaction mixture
along with precipitate formed was poured into diethyl ether (500 mL) and allowed to stand
overnight. The white precipitate formed was filtered and washed with diethyl ether (100 mL).
The precipitate was dissolved in water (200 mL) and neutralized with 2 N NaOH. The water
layer was extracted with DCM (3 x 100 mL), dried over Na SO4 and solvent evaporated. The
residue obtained was purified by passing through a short silica gel column eluting with DCM
(100 %) to 10 % MeOH/DCM to give racemic 2-amino(2-chlorophenyl)cyclohexanone
(norketamine) (rac-24) [Parcell, R.F. & Sanchez, J.P. J. Org. Chem.1981, 46, 5055] (9.2g, 59
%). H NMR (400 MHz, CDCl ) δ 7.69 (dd, J = 7.8, 1.7 Hz 1H), 7.39-7.33 (m, 2H), 7.26 (td, J
= 7.6, 1.6 Hz, 1H), 2.79-2.72 (m, 1H), 2.63-2.56 (m, 1H), 2.51-2.43 (m, 1H), 2.08-2.0 (m,
1H), 1.88 (br, 1H), 1.81-1.75 (m, 2H), 1.72-1.63 (m, 1H).
A solution of rac-24 (200 mg, 0.89 mmol), 3-bromopropyl acetate [Demko, Z.P. & Sharpless
K.B. Org. Lett. 2001, 3, 4091] (194 mg, 1.07 mmol), KI (45 mg, 0.27 mmol), K CO (371 mg,
2.7 mmol) was dissolved in CH CN (5 mL). The reaction mixture was heated to reflux for 24
h. After completion of reaction the reaction mixture was cooled to room temperature and
solvent evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel eluting with hexanes (100 %), EtOAc/hexanes (40 %). The
solvent was evaporated under reduced pressure to obtain the desired product as yellow oil (173
mg, 59 %). The yellow oil was dissolved in diethyl ether (5 mL) and was cooled to 0 C in an
ice bath. Dry HCl gas was bubbled through the solution at 0 C for 2 min. The solvent was
evaporated under reduced pressure to obtain a yellow solid. The yellow solid was dissolved in
EtOAc (1 mL) and sonicated at 25 C for 2 min. The white precipitate formed was diluted with
EtOAc (5 mL) and filtered, washed with EtOAc and dried under vacuum to give rac-
C3OAc.HCl (107 mg, 33%), mp 180-183 C. H NMR (400 MHz, CDCl ) δ 11.71 (br, 1H),
8.19 (d, J = 7.6 Hz, 1H), 8.09 (br, 1H), 7.58 (m, 1H), 7.46 (d, J = 4.0 Hz, 2H), 4.15 (m, 1H),
4.08 (m, 1H), 3.81 (dm, J = 12.0 Hz, 1H), 3.19 (br, 1H), 2.74 (d, J = 12.0 Hz, 1H), 2.68-2.60
(m, 2H), 2.47 (br, 1H), 2.28 (t, J = 14 Hz, 1H), 2.12 (br, 2H), 2.09 (s, 3H), 1.84 (br, 2H), 1.54
(br, 1H); C NMR (101 MHz, CDCl ) δ 206.20, 171.04, 135.14, 132.56, 132.34, 131.79,
129.16, 128.92, 77.49, 62.22, 41.87, 40.63, 40.01, 29.91, 25.84, 21.82, 21.02. MS m/z 324.2
(MH ). MS m/z 324.2 (MH ). Anal. calcd for C H Cl NO : C, 56.67; H, 6.43; N, 3.89; Cl,
17 23 2 3
19.68. Found: C, 56.49; H, 6.61; N, 3.69.
Example 2
(S)((1-(2-Chlorophenyl)oxocyclohexyl)amino)propyl acetate hydrochloride [(S)-
C3OAc] (Scheme 2). Resolution of norketamine was achieved by following a published
procedure [Hong & Davisson. J. Pharm. Sci., 1982, 71, 912]. A solution of rac-24 (13.2 g,
59.1 mmol) in MeOH (33 mL) was treated with L-(R,R)-(+)-tartaric acid (8.9 g, 59.1 mmol) in
MeOH (118 mL). The reaction mixture was stirred overnight at 25 C and filtered to remove
any solid impurities. The filtrate was evaporated and the white solid obtained washed with 2-
butanone (264 mL). The white solid was suspended in acetone (1750 mL) and heated to reflux
until most of the solid was dissolved. The solution was cooled to room temperature and
allowed to stand for 2 days. The crystals formed were filtered and recrystallized two additional
times in acetone (1750 mL and 800 mL respectively) to obtain (S)amino(2-
chlorophenyl)cyclohexanone, (S)-norketamine [(S)-24] as the tartrate salt. H NMR (400
MHz, DMSO-d ) δ 7.85 (d, J = 7.8 Hz), 7.39 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 7.5 Hz, 1H), 4.21
(s, 2H), 2.78-2.70 (m, 1H), 2.32 (dt, J = 15.1, 4.4 Hz, 1H), 1.96-1.81 (m, 3H), 1.73-1.60 (m,
2H), one proton submerged with DMSO-d peak; C NMR (101 MHz, DMSO-d ) δ 208.6,
173.320, 131.96, 130.28, 129.1 (2), 128.93, 127.09, 71.93, 64.84, 38.31, 37.5, 25.79, 20.84.
MS m/z 224.2 (MH ). Mp: 190-191 C.
The (S)-norketamine tartrate salt was dissolved in water (200 mL) and neutralized with 2 N
NaOH. The aqueous layer was extracted with DCM (3 x 100 mL). The combined DCM layer
was washed with brine (100 mL) and dried over Na SO . Evaporation of solvent under
reduced pressure afforded (S)-norketamine free base [(S)-24] (4.96 g) as a pale yellow viscous
oil. H NMR (400 MHz, CDCl ) δ 7.70 (dd, J = 7.8, 1.7 Hz), 7.38-7.31 (m, 2H), 7.28-7.23 (m,
1H), 2.79-2.71 (m, 1H), 2.63-2.56 (m, 1H), 2.51-2.43 (m, 1H), 2.08-2.02 (m, 1H), 1.89-1.74
(m, 3H), 1.71-1.63 (m, 1H); C NMR (101 MHz, CDCl ) δ 212.75, 140.49, 133.02, 131.0,
128.97, 128.32, 127.20, 66.42, 41.25, 38.98, 28.32, 22.16. MS m/z 224.2 (MH ).
A solution of (S)-24 (1 g, 4.47 mmol), 3-bromopropyl acetate [Demko, Z.P. & Sharpless K.B.
Org. Lett. 2001, 3, 4091] (971 mg, 5.36 mmol), KI (223 mg, 1.34 mmol), K CO (1.85g, 13.4
mmol) was dissolved in CH CN (12 mL). The reaction mixture was heated to reflux for 24 h.
After completion of reaction the reaction mixture was cooled to room temperature and solvent
evaporated under reduced pressure. The residue was purified by column chromatography on
silica gel eluting with hexanes (100 %), EtOAc/hexanes (40 %). The solvent was evaporated
under reduced pressure to obtain the desired product as yellow oil (695 mg, 48 %). The yellow
oil was dissolved in diethyl ether (20 mL) and was cooled to 0 C in an ice bath. Dry HCl gas
was bubbled through the solution at 0 C for 2 min. The white precipitate formed was filtered
and resuspended in EtOAc (20 mL) and stirred for 10 min at room temperature. The white
precipitate was filtered to give (S)-C3OAc hydrochloride(512 mg, 29%), mp 169-172 C. H
NMR (400 MHz, CDCl ) δ 11.87 (br, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.62 – 7.54 (m, 1H), 7.48
(d, J = 3.8 Hz, 2H), 7.39 (br, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.83 (dm, J = 14.4 Hz, 1H), 3.11-
3.02 (m, 1H), 2.75 (d, J = 12.5 Hz, 1H), 2.70-2.61 (m, 1H), 2.51 (br, 1H), 2.32 (t, J = 7.3 Hz,
2H), 2.24 (t, J = 11.1 Hz, 1H), 2.05 (br, 1H), 1.99-1.88 (m, 2H), 1.83 (d, J = 14.5 Hz, 2H),
1.76 – 1.61 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ) δ 205.41, 173.07,
135.21, 132.58, 132.06, 131.67, 129.34, 128.99, 73.20, 60.57, 43.59, 40.82, 39.62, 33.65,
29.68, 26.07, 22.27, 21.77, 14.31. MS m/z 352.2 (MH ). Anal. calcd for C H Cl NO : C,
19 27 2 3
58.77; H, 7.01; N, 3.61; Cl, 18.26. Found: C, 58.81; H, 7.1, N, 3.51; Cl, 18.31.
General procedure for synthesis of N-alkylated norketamine esters (Scheme 3)
A solution of rac-24 or (S)-24 (1 eq.), the appropriate alkyl halide (1.2 eq. or 6 eq. in case of
ethylbromo propionate), KI (0.3 eq.) and K CO (3 eq.) was dissolved in CH CN (4.5
2 3 3
mL/mmol). The solution was heated to 80 C in a sealed tube for 24 h (72 h in case of ethyl
bromo propionate). The reaction mixture was cooled to room temperature and solvent
evaporated. The residue was purified by column chromatography on silica gel eluting with
hexanes (100 %), EtOAc/hexanes (20-35 %). The solvent was evaporated under reduced
pressure to obtain the desired product as yellow oil. This was dissolved in diethyl ether (5 mL)
and was cooled to 0 C in an ice bath. Dry HCl gas was bubbled through the solution at 0 C
for 2 min. The solvent was evaporated under reduced pressure to obtain a yellow solid. The
yellow solid was dissolved in EtOAc (2 mL) and sonicated at 25 C for 2 min. The white
precipitate formed was diluted with EtOAc (10 mL) and filtered, washed with EtOAc and
dried under vacuum to obtain the product as hydrochloride salt.
The following compounds were prepared according to this general procedure.
Example 3
Ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate hydrochloride (rac-
C2Et). From rac-24 and ethyl 3-bromopropionate (33% yield), mp 199-202 C. H NMR (400
MHz, CDCl ) δ 12.24 (br, 1H, NH ), 8.13 (d, J = 8.0 Hz, 2H, ArH, NH ), 7.61 – 7.54 (m, 1H,
3 2 2
ArH), 7.49 (d, J = 3.8 Hz, 2H,), 4.23 (q, J = 7.2 Hz, 2H), 3.78 (dm, J = 14.3 Hz, 1H), 3.59 –
3.45 (m, 1H), 3.25 (q, J = 5.4 Hz, 1H), 2.73 (br, 2H), 2.68 – 2.54 (m, 2H), 2.23 (td, J = 13.7,
2.5 Hz, 1H), 2.14 – 2.02 (m, 1H), 1.89-1.82 (m, 2H), 1.65 – 1.59 (m, 1H), 1.28 (t, J = 7.2 Hz,
3H,CH CH ); C NMR (101 MHz, CDCl ) δ 206.10, 171.94, 135.27, 132.57, 132.40, 131.85,
2 3 3
129.05, 128. 57, 73.42, 61.67, 40.30, 39.71, 39.63, 30.38, 29.93, 21.86, 14.18; MS m/z 324.2
(MH ). Anal. calcd for C H Cl NO : C, 56.67; H, 6.43; N, 3.89; Cl, 19.68. Found: C, 56.65;
17 23 2 3
H, 6.57; N, 3.89; Cl, 19.90
Example 3A
(S)-Ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl) amino) propanoate hydrochloride [(S)-
C2Et]. From (S)-24 and ethyl 3-bromopropanoate (54 %), mp 208-210 C. H NMR (400
MHz, CDCl ) δ 12.08 (br, 1H), 8.25 (br, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.61-7.56 (m, 1H),
7.49 (br, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.76 (dm, J = 14.3, 3.2 Hz, 1H), 3.55 – 3.46 (m, 1H),
3.28 (q, J = 9.97 Hz, 1H), 2.75-2.56 (m, 4H), 2.26 (td, J = 14.14 Hz, 1H), 2.08 (br, 1H), 1.90-
1.78 (m, 2H), 1.61 (br, 1H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl ) δ 206.35,
172.38, 135.08, 132.39, 132.33, 131.71, 128.91, 128.27, 73.32, 61.75, 40.08, 39.57, 29.91,
29.89, 21.69, 14.02 (1C overlapping). MS m/z 324.2 (MH ). HRMS calculated for
C H ClNO (MH ) 324.1361, found 324.1370.
17 23 3
Example 4
Iso-Propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate hydrochloride
(rac-C2iPr) From rac-24 and isopropyl 3-bromopropanoate (48 %), mp 203 – 205 C. H
NMR (400 MHz, CDCl ) δ 12.0 (br, 1H), 8.27 (br, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.61-7.55
(m, 1H), 7.49 (br, 2H), 5.13 – 5.04 (m, 1H), 3.79 (dm, J = 14.3 Hz, 1H), 3.52 – 3.44 (m, 1H),
3.28 (br, 1H), 2.74 (br, 2H), 2.65 – 2.56 (m, 2H), 2.24 (td, J = 13.8 Hz, 3.2Hz, 1H), 2.07 (br,
1H), 1.89 – 1.78 (m, 2H), 1.65-1.62 (m, 1H), 1.26 (d, J = 5.01 Hz, 6H); C NMR (101 MHz,
CDCl ) δ 206.57, 172.2, 135.23, 132.63, 132.49, 131.84, 129.07, 129.03, 73.51, 69.86, 40.23,
39.85, 30.27, 30.08, 21.93, 21.84. MS m/z 338.2 (MH ). HRMS calculated 338.1517, found
338.1529.
Example 4A
(S)-Isopropyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate hydrochloride
[(S)-C2iPr]. From (S)-24 and isopropyl 3-bromopropanoate (29%), mp 208-211 C. H NMR
(400 MHz, CDCl ) δ 12.22 (br, 1H), 8.14 (dbr, J = 8.1 Hz, 2H), 7.61-7.55 (m, 1H), 7.49 (br,
2H), 5.12-5.06 (m, 1H), 3.79 (dm, J = 14.4 Hz, 1H), 3.52-3.43 (m, 1 H), 3.26 (q, J = 11.9 Hz,
1H), 2.71 (br, 2H), 2.67-2.55 (m, 2H), 2.21 (td, J = 14.1, 3.3 Hz, 1H), 2.07 (br, 1H), 1.89 –
1.78 (m, 2H), 1.63 (br, 1H), 1.27 (app. dd, J = 4.93, 1.25 Hz, 6H); C NMR (101 MHz,
CDCl ) δ 206.62, 172.23, 135.24, 132.62, 132.48, 131.84, 129.08, 128.42, 73.48, 69.86, 40.24,
39.87, 30.28, 30.09, 21.93, 21.87, 21.84. MS m/z 338.2 (MH ). HRMS calculated for
C H ClNO (MH ) 338.1517, found 338.1524.
18 25 3
Example 4B
(R)-Isopropyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate hydrochloride
[(R)-C2iPr]. From (R)-24 and isopropyl 3-bromopropanoate (29%), mp 216-219 C. H
NMR (400 MHz, CDCl ) δ 12.20 (br, 1H), 8.14 (dbr, J = 8.1 Hz, 2H), 7.60-7.56 (m, 1H), 7.49
(br, 2H), 5.14-5.04 (m, 1H), 3.80 (dm, J = 13.6 Hz, 1H), 3.51 – 3.44 (m, 1H), 3.26 (br, 1H),
2.73 (br, 2H), 2.64-2.56 (m, 2H), 2.21 (t, J = 13.2 Hz, 1H), 2.06 (br, 1H), 1.89 – 1.79 (m, 2H),
1.64 (br, 1H), 1.26 (app. dd, J = 4.81, 1.40 Hz, 6H); C NMR (101 MHz, CDCl ) δ 206.71,
172.36, 135.23, 132.67, 132.51, 131.85, 129.11, 128.39, 73.5, 69.94, 40.24, 39.95, 30.26,
.13, 21.95, 21.89, 21.85. MS m/z (MH ). HRMS calculated for C H ClNO (MH )
18 25 3
338.1517, found 338.1521.
(R)-24 was prepared by a procedure analogous to that described above for the preparation of
(S)-24 using D-(S,S)-(-)-tartaric acid, rather than L-(R,R)-(+)-tartaric acid.
Example 5
n-Propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate hydrochloride (rac-
C2nPr). From rac-24 and propyl 3-bromopropanoate (44 %) mp 163 – 165 C. H NMR (400
MHz, CDCl ) δ 11.68 (br, 1H), 8.69 (br, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.61 – 7.54 (m, 1H),
7.49 (br, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.74 (dm, J = 14.3 Hz, 1H), 3.53 – 3.43 (m, 1H), 3.38
(br, 1H), 2.81 – 2.71 (m, 3H), 2.64 – 2.57 (m, 1H), 2.35 (td, J = 13.8, 3.2 Hz, 1H), 2.07 (br,
1H), 1.92 – 1.80 (m, 2H), 1.68 – 1.54 (m, 3H), 0.92 (t, J = 7.4 Hz, 3H); C NMR (101 MHz,
CDCl ) δ 206.03, 172.0, 135.28, 132.48, 132.37, 131.84, 128.99, 128.6, 73.4, 67.22, 40.31,
39.57, 30.28, 29.9, 21.9, 21.81, 10.42. MS m/z 338.2 (MH ). HRMS calculated 338.1517,
found 338.1526.
Example 6
Ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate hydrochloride (rac-
C3Et). From rac-24 and ethyl 4-bromobutanoate (37% yield), mp 186-189 C. H NMR (400
MHz, CDCl ) δ 11.14 (br, 1H, NH ), 9.14 (br, 1H, NH ), 8.26 (d, J = 8.1 Hz, 1H), 7.62 – 7.49
3 2 2
(m, 1H), 7.45 (d, J = 3.8 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.75 (dm, J = 14.4 Hz, 1H), 3.38 –
3.26 (m, 1H), 2.75-2.64 (m, 2H), 2.64 – 2.58 (m, 1H), 2.43 – 2.26 (m, 2H), 2.45-2.28 (m, 2H),
2.14-2.07 (m, 1H), 1.98(br, 2H), 11.79 (m, 1H), 1.58 – 1.44 (m, 1H), 1.23 (t, J = 7.1 Hz,
3H); C NMR (101 MHz, CDCl ) δ 206.03, 173.16, 135.11, 132.76, 132.08, 131.61, 129.19,
129.02, 73.17, 61.04, 43.54, 40.86, 40.00, 32.24, 29.72, 21.64, 14.27. MS m/z 338.2 (MH ).
Anal. calcd for C H Cl NO : C, 57.76; H, 6.73; N, 3.74; Cl, 18.94. Found: C, 57.55; H, 6.92;
18 25 2 3
N, 3.64; Cl, 18.73.
Example 7
Isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate hydrochloride (rac-
C3iPr). From rac-24 and isopropyl 4-bromobutanoate [Fox, M.E., et al. J. Org. Chem. 2005,
70, 1227] (24 % yield), mp 167-169 C. H NMR (400 MHz, CDCl ) δ 11.41 (br, 1H), 8.94
(br, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.68 – 7.50 (m, 1H), 7.45 (d, J = 3.9 Hz, 2H), 4.99 (m, 1H),
3.79 (dm, J = 14.4 Hz, 1H), 3.31 – 3.21 (m, 1H), 2.75-2.68 (m, 1H), 2.66-2.59 (m, 2H), 2.58-
2.49 (m, 1H), 2.42-2.48 (m, 1H), 2.34 (t, J = 10.8 Hz, 2H), 2.11-1.98 (m, 2H), 1.84 (d, J =
.2 Hz, 2H), 1.58 – 1.46 (m, 1H), 1.22 (dd, J = 6.28, 2.2 Hz, 6H) ; C NMR (101 MHz,
CDCl ) δ 206.29, 173.46, 135.04, 132.84, 132.13, 131.62, 129.08, 129.06, 73.11, 68.81, 43.70,
40.84, 40.21, 32.79, 29.90, 21.91, 21.68. MS m/z 352.2 (MH ). Anal. calcd for
C H Cl NO : C, 58.77; H, 7.01; N, 3.61. Found: C, 58.57; H, 7.2; N, 3.54.
19 27 2 3
Example 8
n-Propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate hydrochloride (rac-
C3nPr). From rac-24 and n-propyl 4-bromobutanoate (19%), mp 160-161 C. H NMR (400
MHz, CDCl ) δ 11.10 (br, 1H), 9.23 (br, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.59-7.52 (m, 1H),
7.44 (d, J = 5.1 Hz, 2H), 4.01 (t, J = 6.8 Hz, 2H), 3.76 (dm, J = 14.4 Hz,1H), 3.39-3.28 (m,
1H), 2.70 (t, J = 7.8 Hz, 1H), 2.66 (t, J = 6.9 Hz, 1H), 2.62-2.54 (m, 1H), 2.51 (td, J = 7.0, 2.8
Hz, 2H), 2.47-2.41 (m, 1H), 2.39-2.30 (m, 1H), 2.15-2.06 (m, 1H), 2.0 (br, 1H), 1.85 (td, J =
8.0, 3.9 Hz, 2H), 1.57-1.66 (m, 2H), 1.50 (q, J = 14.4Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H); C
NMR (101 MHz, CDCl ) δ 205.92, 173.47, 135.12, 132.78, 132.05, 131.59, 129.23, 129.0,
73.16, 66.62, 43.54, 40.86, 39.99, 32.19, 29.77, 22.0, 21.78, 21.70, 10.48. MS m/z 352.2
(MH ).
Example 9
rac-Methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate hydrochloride
(rac-C4Me). From rac-24 and ethyl 5-bromopentanoate, followed by purification by
preparative HPLC (41%). H NMR (400 MHz, CDCl ) δ 7.53 (dd, J = 7.8, 1.6 Hz, 1 H), 7.36
(dd, J = 7.8, 1.4 Hz, 1 H), 7.31 (dt, J = 7.8, 7.6, 1.5 Hz, 1 H), 7.25-7.21 (m, 1 H), 3.64 (s, 3
H), 2.77-2.69 (m, 1 H), 2.55-2.42 (m, 2 H), 2.36-2.30 (m. 1 H), 2.26 (t, J = 7.4 H, 2 H), 2.09-
1.73 (m, 7 H), 1.66-1.58 (m, 2 H), 1.55-1.40 (m, 2 H). HPLC 99%.
Example 10
(S)-Methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate hydrochloride [(S)-
C4Me]. From (S)-24 and ethyl 5-bromopentanoate (42%), mp (MeOH/EtOAc) 188-191 °C,
H NMR (400 MHz, CDCl ) δ 7.52 (dd, J = 7.82, 1.68 Hz, 1 H), 7.36 (dd, J = 7.8, 1.4 Hz, 1
H), 7.31 (dt, J = 7.8, 7.60, 1.45 Hz, 1 H), 7.23 (dt, J = 8.0; 1.7 Hz, 1 H), 3.65 (s, 3 H), 2.76-
2.68 (m, 1 H), 2.55-2.42 (m, 2 H), 2.36-2.30 (m, 1 H), 2.26 (t, J = 7.4 Hz, 2 H), 2.08-1.74 (m,
7 H), 1.66-1.58 (M, 2 H), 1.57-1.37 (m, 3 H), Analysis Calc. for C H Cl NO : C, 57.8; H,
18 25 2 3
6.7, Cl, 18.9, N, 3.7; found C, 57.7, H, 6.8 Cl, 18.9 N, 3.7.
Example 11
rac-Ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate hydrochloride (rac-
C4Et). From rac-24 and ethyl 5-bromopentanoate (29%), mp 169-172 C. H NMR (400
MHz, CDCl ) δ 11.87 (br, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.62 – 7.54 (m, 1H), 7.48 (d, J = 3.8
Hz, 2H), 7.39 (br, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.83 (dm, J = 14.4 Hz, 1H), 3.11-3.02 (m,
1H), 2.75 (d, J = 12.5 Hz, 1H), 2.70-2.61 (m, 1H), 2.51 (br, 1H), 2.32 (t, J = 7.3 Hz, 2H), 2.24
(t, J = 11.1 Hz, 1H), 2.05 (br, 1H), 1.99-1.88 (m, 2H), 1.83 (d, J = 14.5 Hz, 2H), 1.76 – 1.61
(m, 3H), 1.24 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ) δ 205.41, 173.07, 135.21,
132.58, 132.06, 131.67, 129.34, 128.99, 73.20, 60.57, 43.59, 40.82, 39.62, 33.65, 29.68, 26.07,
22.27, 21.77, 14.31. MS m/z 352.2 (MH ). Anal. calcd for C H Cl NO : C, 58.77; H, 7.01;
19 27 2 3
N, 3.61; Cl, 18.26. Found: C, 58.81; H, 7.1, N, 3.51; Cl, 18.31.
Example 12
Isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate hydrochloride (rac-
C4iPr) From rac-24 and isopropyl 5-bromovalerate (40 %), mp 161-163 C. H NMR (400
MHz, CDCl ) δ 11.04 (br, 1H), 8.78 (br, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.59-7.53 (m, 1H),
7.47 (br, 2H), 5.01-4.92 (m, 1H), 3.74 (dm, J = 14.4 Hz, 1H), 3.29-3.21 (m, 1H), 2.73 (d, J =
12.2 Hz, 1H), 2.64 (td, J = 13.3 Hz, 6.3, 1H), 2.54-2.42 (m, 2H), 2.26-2.21 (m, 2H), 2.10-1.99
(m, 2H), 1.94-1.83 (m, 2H), 1.78 (d, J = 17.6 Hz, 1H), 1.71-1.47 (m, 3H), 1.20 (dd, J = 6.3,
1.2 Hz, 6H); C NMR (101 MHz, CDCl ) δ 205.7, 172.68, 135.18, 132.61, 132.13, 131.72,
129.26, 129.04, 73.25, 67.95, 43.66, 40.80, 39.76, 33.95, 29.78, 26.12, 22.25, 21.97, 21.8. MS
m/z 366.2 (MH ). HRMS calculated 366.1830, found 366.1842.
Example 13
n-Propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate hydrochloride (rac-
C4nPr). From rac-24 and propyl 5-bromopentanoate (45 %), H NMR (400 MHz, CDCl ) δ
11.23 (br, 1H), 8.49 (br, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.59 -7.52 (m, 1H), 7.46 (br, 2H), 4.0
(t, J = 6.8 Hz, 2H), 3.76 (dm, J = 14.3 Hz, 1H), 3.24 – 3.18 (m, 1H), 2.74 (br, 1H), 2.69 – 2.61
(m, 1H), 2.46 (t, J = 14.0 Hz, 2H), 2.29 (td, J = 7.5, 2.9 Hz, 2H), 2.04 – 1.95 (m, 1H), 1.92 –
1.89 (m, 1H), 1.87 – 1.83 (m, 1H), 1.79 (dbr, J = 15.3 Hz, 1H), 1.73 – 1.57 (m, 5H), 1.54 –
1.47 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); C NMR (101 MHz, CDCl ) δ 205.98, 173. 29,
135.14, 132. 6, 132.19, 131.74, 129.17, 129.08, 73.28, 66.31, 43.68, 40.77, 39.88, 33.58,
29.85, 26.16, 22.16, 22.06, 21.81, 10.5. MS m/z 366.2 (MH ). HRMS calculated 366.1830,
found 366.1839.
General procedure for reductive methylation of N-alkylated norketamine esters (Scheme
Norketamine ester (0.9 mmol) was dissolved in MeOH (20 mL) and cooled to 0 C in an ice
bath. Acetic acid (0.2 mL, 3.6 mmol) and NaCNBH (112 mg, 1.8 mmol) was added to the
above solution and stirred at 0 C for 5 min. Formaldehyde (37 % in H O, 2.2 mmol) was
added at 0 C and reaction mixture allowed to stir at 25 C for 24 h. The reaction mixture was
quenched with NaHCO and diluted with water. The aqueous layer was extracted with CH Cl
3 2 2
(3 x 20 mL), washed with brine and dried over Na SO . The solvent was evaporated under
reduced pressure to obtain the product as yellow oil. The yellow oil was dissolved in Et O (5
mL), cooled to 0 C in an ice bath and treated with HCl gas for 1 min. Solvent was evaporated
and the residue was resuspended in EtOAc (2 mL) and sonicated. The precipitate formed was
diluted with EtOAc (10 mL) and filtered, dried to give the product as the HCl salt.
Example 14
Ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)propanoate (19). From
reductive methylation of rac-C2Et, (97 %). H NMR (400 MHz, CDCl ) δ 7.38 (dd, J = 7.8,
1.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.30 (td, J = 7.9, 1.4 Hz, 1H), 7.25-7.21 (m, 1H), 4.10 (q, J =
7.2 Hz, 2H), 3.11-3.04 (m, 1H), 2.97-2.90 (m, 1H), 2.80-2.73 (m, 1H), 2.58 (t, J = 6.7 Hz,
2H), 2.49-2.45 (m, 2H), 2.43 (s, 3H), 2.05-1.91 (m, 2H), 1.89- 1.72 (m, 2H), 1.65-1.56 (m,
1H), 1.24 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl ) δ 208.1, 172.7, 138.0, 134.07,
131.68, 129.86, 18.64, 126.65, 74.58, 60.37, 47.76, 41.19, 36.97, 36.14, 34.73, 27.28, 22.33,
14.27. MS m/z 338.5 (MH ). HRMS calculated for C H ClNO (MH ) 338.1517, found
18 25 3
338.1514.
Example 15
Ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)butanoate hydrochloride
(20). From reductive methylation of rac-C3Et (97 %). Mixture of rotamers. H NMR (400
MHz, CDCl ) δ 11.97 (br, 1H), 11.79 (br, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.6 Hz,
1H), 7.64- 7.46 (m, 6H), 4.12-4.04 (m, 4H), 3.96 (t, J = 9.3 Hz, 1H), 3.69 (d, J = 14.8 Hz, 1H),
3.47 (1H), 3.25 (d, J = 14.5 Hz, 1H), 3.16 (s, 3H), 2.78 (br, 6H), 2.69-2.55 (m, 5H), 2.48-2.34
(m, 3H), 2.14 (br, 3H), 1.97 (br, 3H), 1.84 (br, 5), 1.48-1.39 (m, 2 H), 1.31-1.19 (m, 6H); C
NMR (101 MHz, CDCl ) δ 205.26, 204.28, 172, 136.05, 135.91, 133.57, 132.87, 132. 77,
132.65, 132.55, 132.11, 129.2, 128.53, 127.69, 60.85, 53.32, 52.16, 42.65, 41.99, 37.37, 37.17,
36.59, 35.39, 31.49, 29.16, 22.22, 22.13, 20.64, 20.55, 14.3 (some C not seen for both
rotamers). MS m/z 352.2 (MH ). HRMS calculated for C H ClNO (MH ) 352.1674, found
19 27 3
352.1687.
Example 16
Methyl 5-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)pentanoate (21). From
reductive methylation of rac-C4Me, (97 %). H NMR (400 MHz, CDCl ) δ 7.41 (d, J = 7.5
Hz, 2H), 7.38-7.29 (m, 2H), 3.66 (s, 3H), 2.83 (br, 2H), 2.61-2.57 (m, 3H), 2.49 (br, 3H), 2.30
(t, J = 7.1Hz, 2H), 2.10-1.94 (m, 3H), 1.88-1.77 (m, 3H), 1.62-1.59 (m, 3H); C NMR (101
MHz, CDCl ) δ 206.75, 173.94, 134.77, 133.19, 132.01, 131.14, 130.12, 127.44, 52.02, 51.62,
41. 63, 37.0, 35.86, 33.66, 28.04, 27.07, 22.58, 22.27 (1C overlapping). MS m/z 352.2 (MH ).
HRMS calculated HRMS calculated for C H ClNO (MH ) 352.1674, found 352.1683.
19 27 3
Biological activity
All animal experiments were conducted at the Ruakura Research Centre, Hamilton, New
Zealand, using experimental protocols reviewed and approved by the Ruakura Animal Ethics
Committee (ethics ref 12604).
Following acquisition of baseline physiologic parameters (heart rate, respiratory rate, PWR,
and righting reflex (RR)) adult female Sprague-Dawley rats of approximately 350-450 g were
put under non-traumatic restraint and the marginal vein of the tail was cannulated. Ketamine
or a compound of the invention at 10mg/ml was administered via a minibore extension tube
adequately secured to the tail. Infusions were commenced at a rate (weight-adjusted) to deliver
20 mg/kg/min initially (until the pedal withdrawal reflex score PWR=1), then were reduced to
a rate of 6.7 mg/kg/min. Infusion rate was then titrated in an up-and-down fashion to maintain
dorsal recumbency and a PWR=1 to 10 minutes before cessation. Three rats were used in each
study, with each group of rats also acting as their own ketamine control. The order of study
drug administration was determined by prior odds/evens randomisation with a recovery
interval of at least one hour afforded between experiments. PWR and RR were recorded at 1
minute intervals throughout. The times from cessation of infusion to return of righting reflex
(RRR), and from cessation of infusion to the animals displaying independent locomotion
(walk) were recorded.
The results are provided in Tables 2 and 3 below.
Pedal Withdrawal Reflex (PWR) scoring: Nociceptive testing in animals was conducted via
1 second application of constant pressure (firm digital pressure) over the forepaw of the
animal. Pedal withdrawal reflex testing is primarily used to assess analgesic effect, and
responses are graded accordingly: 0, absent; 1, flicker; 2, moderate withdrawal; 3, fast
withdrawal; 4, Fast withdrawal with cry/preceding apnoea (modified from Buitrago, S. et al. J.
Amer. Assoc. Lab. Animal. Sci. 2008, 47, 11-17).
Loss of Righting Reflex (LRR): This is primarily used to assess anaesthetic hypnotic effect.
Righting reflex is judged absent when the rat fails to right from a position of dorsal
recumbency to a position of sternal recumbency on three attempts performed in rapid
succession. Dose to LRR is termed effective potency.
Table 2. Anaesthetic effects of ketamine and compounds of the invention in a rat infusion
study
a b c d
Compd LRR PWR=1 RRR Walk
e f e f e e
Time Dose Dose
Time Time Time
(sec) (mg/kg) (mg/kg)
(sec) (sec) (sec)
rac-ketamine 59±5 20±2 93±8 31±2 863±153 1918±518
(S)-C3OAc 81±10 26±3 104±7 34±1 566±30 983±93
rac-ketamine 77±10 27±4 95±13 38±10 1602±549 2536±250
rac-C2Et 135±61 48±23 154±68 55±25 177±51 253±68
rac-ketamine 53±1 20±1 73±3 26±1 1315±215 2163±722
(S)-C2Et 171±54 59±19 185±55 62±20 62±8 80±8
rac-ketamine 62±7 22±2 71±9 24±3 760±144 1100±144
rac-C2iPr 103±17 33±6 127±13 37±6 83±19 153±33
rac-ketamine 65±10 30±4 77±12 34±4 900±60 1200±180
222±18 74±9 247±13 84±4 15±15 224±90
(S)-C2iPr
rac-ketamine 53 24 69 26 1170 1629
(R)-C2iPr 170 71 190 82 0 900
rac-ketamine 51±3 18±1 63±3 21±1 1060±221 1500±5
rac-C2nPr 404±196 131±62 420±180 136±67 0 0
rac-ketamine 59±6 17±2 76±7 24±4 1523±131 2122±131
rac-C3Et 70±6 24±2 137±14 44±5 95±12 170±17
rac-ketamine 69±7 23±2 84±4 28±2 874±81 1384±374
rac-C3iPr 125±21 42±9 192±47 66±17 37±22 110±45
rac-ketamine 69±7 23±2 84±4 28±2 874±81 1384±374
329±106 137±48 558±42 209±20 10±5.5 65±33
rac-C3nPr
rac-ketamine 70±28 20±5 81±23 22±4 1104±95 1462±113
rac-C4Me 92±14 34±7 124±21 44±10 99±16 126±32
rac-ketamine 56±6 17±2 76±7 23±4 1523±131 2122±107
rac-C4Et 97±8 34±4 172±36 57±12 134±22 158±22
rac-ketamine 54 19 66 22 1281 1499
rac-C4iPr 122 38 122 38 180 320
rac-ketamine 65±10 23±3 77±12 26±4 900±60 1200±180
rac-C4nPr 271±97 82±34 277±97 83±34 45±15 90±30
rac-ketamine 60 21 69 25 1230 1475
19 280 95 290 99 0 0
rac-ketamine 75 25 86 29 1500 1920
600 196 600 196 0 0
rac-ketamine 57 20 82 28 2040 2340
420 145 435 148 0 201
LRR: (Loss of righting reflex) assesses anaesthetic effect. Righting reflex is considered
absent when the animal fails to right from a position of dorsal recumbency to a position of
sternal recumbency on three attempts performed in rapid succession. PWR (Pedal withdrawal
reflex) assesses analgesic effect, and is conducted by a 1 second application of firm constant
pressure (for rats, firm digital pressure) over the forepaw of the animal. A PWR=1 (a flicker of
response) indicates a satisfactory level of analgesia (nociception). RRR (Recovery of righting
reflex; ability to right from dorsal recumbency). Walk (ability to sustain independent
locomotion). Time: the time from onset of the infusion of drug to achieve LRR or PWR=1, or
the time from the end of the infusion of drug to achieve RRR or Walk. Dose: The total drug
administered to achieve LRR or PWR=1. Where no errors are given the results are from a
single animal.
Table 3. Head-to-head ratios of anaesthetic effects of compounds of the invention to
ketamine
a b c d
Compd LRR PWR=1 RRR Walk
e f e f e e
Time Dose Time Dose Time Time
(S)-C3OAc 1.37 1.30 1.12 1.10 0.65 0.51
rac-C2Et 1.75 1.78 1.62 1.45 0.11 0.10
(S)-C2Et 3.22 2.95 2.53 2.38 0.05 0.04
rac-C2iPr 1.66 1.50 1.79 1.54 0.11 0.14
(S)-C2iPr 3.41 2.46 3.14 2.47 0.02 0.19
(R)-C2iPr 3.20 2.96 2.75 3.15 NA 0.06
7.92 7.28 6.67 6.48 NC NC
rac-C2nPr
rac-C3Et 1.19 1.41 1.80 1.83 0.062 0.08
(S)-C3Et 3.23 2.95 2.53 2.38 0.05 0.04
rac-C3iPr 1.81 1.83 2.29 2.36 0.042 0.08
rac-C3nPr 4.77 5.95 6.64 7.46 0.012 0.05
1.31 1.70 1.53 2.00 0.090 0.086
rac-C4Me
(S)-C4Me 1.94 1.80 1.81 1.76 0.07 0.51
rac-C4Et 1.73 2.00 2.26 2.48 0.09 0.05
(S)-C4Et 1.73 2.00 2.26 2.48 0.088 0.074
rac-C4iPr 2.26 2.00 1.85 1.73 1.78 1.17
rac-C4nPr 4.17 3.56 3.60 3.19 0.05 0.08
19 4.67 4.50 4.20 3.96 NC NC
8.00 7.84 6.98 6.76 NC NC
21 7.37 7.25 5.30 5.29 NC 0.09
a-f g h
As for Table 2. NA: not active. NC: not calculable.
The results of Tables 2 and 3 clearly show that compounds of the invention show ketamine-
like anaesthetic effects with similarly rapid onset and potency, but with much more rapid (up
to 10-fold faster than ketamine) recovery following discontinuation of infusion.
The average values of the parameters measured for the ketamine standard over the various
experiments is shown below in Table 4. Given the complexity of the experimental protocol,
the pre-sedation data (time and total dose for LRR; Table 2) are very consistent, with ranges of
only 1.5-fold. The consistency of the post-sedation recovery times are expectedly lower, with
ranges of about 2.5-fold.
Representative plots of the performance of two representative compounds of the invention
compared to ketamine in are shown in Figures 1 and 2. Loss of righting (anaesthesia) for rac-
C2nPr and rac-C4Me are shown in Figures 1A and 1B, respectively, and pedal withdrawal
scores are shown in Figures 2A and 2B.
Figure 3 shows a scatter-plot of effective potency (dose [mg/kg] to loss of righting reflex)
versus duration (time to return of righting reflex) for ketamine and representative compounds
of the invention.
Table 4. Average parameters determined for the ketamine standard
Property Average Range
Time to achieve LRR (sec) 61±8 51-75
Total dose to LRR (mg/kg) 21±7 17-27
Time to PWR=1 (sec) 76±9 60-95
Total dose to LRR (mg/kg) 26±4 21-34
Time to RRR (sec) 1212±318 863-2040
Time to walking (sec) 1709±400 1100-2340
Discussion
Acetate (S)-C3OAc was the most potent of the compounds (about as potent as ketamine), but
showed only moderately faster recoveries (1.5-2 fold) than ketamine itself. Without wishing
to be bound by theory, the applicant believes that this is most likely not due to slow acetate
hydrolysis, but to the fact that the corresponding alcohol product is itself a potent
hypnotic/analgesic.
Of the remaining norketamine esters, the more potent compounds (up to 2-fold less dose-
potent than ketamine itself) rac-C2Et, rac-C2iPr, rac-C3Et, rac-C3iPr, rac-C4Me, rac-C4Et
and rac-C4iPr comprised a mixture of chain lengths (thus a range of pKas) and a variety of
Me, Et and iPr esters.
The less dose-potent compounds (from 2-6 fold less than ketamine) rac-C2nPr, rac-C3nPr and
rac-C4nPr were also a mixture of chain lengths, but were all n-Pr esters, and at the higher end
of the lipophilicity range. Since dose-potency and rapidity of recovery from both LRR and
PWR are broadly reciprocal, it is not surprising that these less potent compounds resulted in
the fastest recoveries (20-25 fold faster than ketamine).
Most of the norketamine esters were racemic, but several enantiomers were evaluated, since
(S)-ketamine is known to be as active but about twice as potent as its racemate. Two of the S-
enantiomers ((S)-C2Et, (S)-C2iPr), while active, were only half as potent and showed faster
recoveries than the corresponding racemates, suggesting more rapid hydrolysis of the S-
enantiomer esters. The (R)-C2iPr enantiomer had similar potency and kinetics of recovery to
(S)-C2iPr. rac-C4Me and enantiopure (S)-C4Me had broadly equivalent properties.
Exploratory studies were done (mostly single-animal evaluations) using ketamine esters 19-
21. The racemic C2 ethyl ester 19 was about as potent as the n-Pr norketamine esters, but had
a very weak sedative effect, with very rapid recovery. Longer chain length C3 ethyl and C4
methyl esters 20 and 21, were less potent, with weak sedative activity.
There was no clear effect of pKa on anaesthetic activity, although the weakest bases were
among the least potent of the esters.
In summary, the above results show that short-chain aliphatic ester analogues of ketamine
broadly retain its desirable anaesthetic and analgesic activities, yet are metabolised to the more
polar and inactive acids sufficiently rapidly to minimise the drawbacks of ketamine itself in
this capacity.
Although the invention has been described by way of example and with reference to particular
embodiments, it is to be understood that modifications and/or variations may be made without
departing from the scope of the invention.
All publications referenced in this specification are incorporated herein in their entirety.
WHAT WE
Claims (47)
1. A compound of formula (I): 5 wherein 1 1 1 Y is –C aliphaticC(O)OR , –C aliphaticOC(O)R , –C aliphaticC(O)OC 2-6 2-6 1-6 1- aliphaticC(O)OR , or –C aliphaticC(O)OC aliphaticOR , wherein each aliphatic is 6 1-6 1-6 optionally substituted with one or more R ; R is C aliphatic, optionally substituted with one or more halo, CN, NO , NH , 1-6 2 2 11 11 12 11 11 12 10 NHR , NR R , C haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , 1-6 1-6 2 11 11 11 SO R , OR , C(O)R , and C aliphatic; 2 1-6 2 11 R is C aliphatic, optionally substituted with one or more halo, OR , or CN; R is hydrogen or R ; 11 12 11 12 R and R are each independently C aliphatic; or R and R together with the 15 nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring; Y is hydrogen or R ; 1 2 2 11 11 12 X and X are each independently hydrogen, R , halo, NO , NH , NHR , NR R , C 2 2 1- 11 11 12 11 11 haloalkyl, C haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , 6 1-6 2 2 11 1 1 1 1 1 C(O)R , C aliphaticY , OY , C(O)Y , SO Y , or C(O)NHY at any of the available 1-6 2 20 2-5 positions; or a pharmaceutically acceptable salt or solvate thereof. 1 1 1
2. The compound of claim 1, wherein Y is –C alkylC(O)OR , –C alkylOC(O)R , –C 2-6 2-6 1- alkylC(O)OC alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl 6 1-6 1-6 1-6 is optionally substituted. 25
3. The compound of claim 1 or 2, wherein Y is –C alkylC(O)OR or –C 2-6 1- alkylC(O)OC alkylC(O)OR , wherein each alkyl is optionally substituted. 6 1-6
4. The compound of any one of claims 1-3, wherein Y is –C alkylC(O)OR , wherein the alkyl is optionally substituted.
5. The compound of any one of claims 1-4, wherein R is C alkyl, C alkenyl, 1-6 2-6 cycloalkyl, or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally 11 11 12 5 substituted with one or more halo, CN, NO , NH , NHR , NR R , C haloalkyl, C 2 2 1-6 1- 11 11 12 11 11 11 haloalkoxy, C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , and C(O)R ; and 6 2 2 each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each cycloalkyl is optionally substituted with C alkyl or C alkenyl. 1-6 2-6
6. The compound of any one of claims 1-5, wherein R is C alkyl or cycloalkyl, wherein 10 each alkyl and cycloalkyl is optionally substituted.
7. The compound of any one of claims 1-6, wherein R is C alkyl, wherein each alkyl is optionally substituted.
8. The compound of any one of claims 1-7, wherein R is C alkyl or cycloalkyl, optionally substituted with one or more halo, OR , or CN. 15
9. The compound of claim 8, wherein R is C alkyl, optionally substituted with one or more halo, OR , or CN. 11 12
10. The compound of any one of claims 1-7, wherein R and R are each independently 11 12 C alkyl, C alkenyl, cycloalkyl, or cycloalkenyl; or R and R together with the 1-6 2-6 nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring. 11 12 20 11. The compound of claim 10, wherein R and R are each independently C alkyl or 11 12 cycloalkyl; or R and R together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring.
11 12
12. The compound of claim 10 or 11, wherein R and R are C alkyl.
13. The compound of any one of claims 1-12, wherein Y is hydrogen or C alkyl, 25 wherein the alkyl is optionally substituted.
14. The compound of any one of claims 1-13, wherein X and X are each independently 2 11 11 12 hydrogen, R , halo, NO , NH , NHR , NR R , C haloalkyl, C haloalkoxy, 2 2 1-6 1-6 11 11 12 11 11 11 1 1 C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , C(O)R , C alkylY , OY , 2 2 1-6 1 1 1 C(O)Y , SO Y , or C(O)NHY at any of the available 2-5 positions.
15. The compound of any one of claims 1-14, wherein X and X are each independently 2 11 11 12 hydrogen, R , halo, NO , NH , NHR , NR R , C haloalkyl, C haloalkoxy, 2 2 1-6 1-6 11 11 12 11 11 11 2 1 C(O)NH , C(O)NHR , C(O)NR R , SO R , OR , or C(O)R ; or X is C alkylY , 2 2 1-6 1 1 1 1 OY , C(O)Y , SO Y , or C(O)NHY at any of the available 2-5 positions. 5
16. The compound of any one of claims 1-15, wherein X and X are each independently 2 11 11 11 2 hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , OR , or C(O)R ; or X is 1-6 1-6 2 1 1 1 1 C alkylY , OY , C(O)Y , or SO Y at any of the available 2-5 positions. 1-6 2
17. The compound of any one of claims 1-16, wherein X and X are each independently 2 11 11 hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any of the 1-6 1-6 2 10 available 2-5 positions.
18. The compound of any one of claims 1-17, wherein X is halo; and X is independently 2 11 11 hydrogen, R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any of the 1-6 1-6 2 available 2-5 positions.
19. The compound of any one of claims 1-18, wherein X is 2-chloro; and X is hydrogen, 2 11 11 15 R , halo, C haloalkyl, C haloalkoxy, SO R , or OR at any of positions 3-5. 1-6 1-6 2
20. The compound of any one of claims 1 and 5-19, wherein Y is – A B C D 1 A B C D 1 A B (CR R ) (CR R ) C(O)OR , –(CR R ) (CR R ) OC(O)R ,–(CR R ) m n m n m- C D G H E F 1 A B (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or –(CR R ) 1 n p o m- C D G H E F 3 (CR R ) C(O)O(CR R ) (CR R ) OR ; m is an integer from 2 to 6; o is an integer 1 n p o 20 from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of A B C D E F G H o and p is 6 or less; and R , R , R , R , R , R , R , and R at each instance of m, n, o, and p are each independently hydrogen or R . 1 A B C D 1
21. The compound of claim 20, wherein Y is –(CR R ) (CR R ) C(O)OR or – A B C D G H E F 1 (CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR . m n p o 1 A B C D 1 25
22. The compound of claim 20 or 21, wherein Y is –(CR R ) (CR R ) C(O)OR . A B E F
23. The compound of any or of claims 20-22, wherein R , R , R , and R at each instance C D G H of m and o are each independently hydrogen; and R , R , R , and R at each instance of n and p are each independently hydrogen or R .
24. The compound of claim 1, wherein the compound is 30 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propyl acetate, ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate, iso-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate, n-propyl 3-((1-(2-chlorophenyl)oxocyclohexyl)amino)propanoate, ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate, 5 isopropyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate, n-propyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)butanoate, methyl 4-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, ethyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, isopropyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, 10 n-propyl 5-((1-(2-chlorophenyl)oxocyclohexyl)amino)pentanoate, ethyl 3-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)propanoate, ethyl 4-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)butanoate, or methyl 5-((1-(2-chlorophenyl)oxocyclohexyl)(methyl)amino)pentanoate, or a pharmaceutically acceptable salt or solvate thereof. 15
25. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1- 24, and a pharmaceutically acceptable diluent, excipient, or carrier.
26. Use of a compound of formula (I) according to any one of claims 1-24 in the manufacture of a medicament for treating pain. 20
27. The use of claim 26 for providing analgesia.
28. Use of a compound of formula (II) in the manufacture of a medicament for providing anaesthesia: (II) 25 wherein 11 1 1 Y is –C aliphaticC(O)OR , –C aliphaticCO(O)R , –C aliphaticC(O)OC 1-6 1-6 1-6 1- aliphaticC(O)OR , or –C aliphaticC(O)OC aliphaticOR , wherein each aliphatic is 6 1-6 1-6 optionally substituted with one or more R ; and 1 2 3 2 1 2 R , R , R , Y , X , and X are as defined in the compound of formula (I) according to 5 claim 1; or a pharmaceutically acceptable salt or solvate thereof. 11 1 1
29. The use of claim 28, wherein Y is –C alkylC(O)OR , –C alkylCO(O)R ,–C 1-6 1-6 1- alkylC(O)OC alkylC(O)OR , or –C alkylC(O)OC alkylOR , wherein each alkyl 6 1-6 1-6 1-6 is optionally substituted. 11 1 10
30. The use of claim 28 or 29, wherein Y is –C alkylC(O)OR or –C alkylC(O)OC 1-6 1-6 1- alkylC(O)OR , wherein each alkyl is optionally substituted. 11 1
31. The use of any one of claims 28-30, wherein Y is –C alkylC(O)OR , wherein the alkyl is optionally substituted.
32. The use of any one of claims 28-31, wherein R is as defined in any one of claims 5-7. 15
33. The use of any one of claims 28-32, wherein R is as defined in claim 8 or 9. 11 12
34. The use of any one of claims 28-33, wherein R and R are as defined in any one of claims 10-12.
35. The use of any one of claims 28-34, wherein Y is as defined in claim 13.
36. The use of any one of claims 29-35, wherein X and X are as defined in any one of 20 claims 14-19.
37. The use of any one of claims 28 and 32-36, wherein Y is – A B C D 1 A B C D 1 (CR R ) (CR R ) C(O)OR , –(CR R ) (CR R ) OC(O)R ,– m n m n A B C D G H E F 1 (CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR , or – m n p o A B C D G H E F 3 (CR R ) (CR R ) C(O)O(CR R ) (CR R ) OR ; m and o are each independently an m n p o 25 integer from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the A B C D E F G H sum of o and p is 6 or less; and R , R , R , R , R , R , R , and R at each instance of m, n, o, and p are each independently hydrogen or R . 11 A B C D 1
38. The use of claim 37, wherein Y is –(CR R ) (CR R ) C(O)OR or – A B C D G H E F 1 (CR R ) (CR R ) C(O)O(CR R ) (CR R ) C(O)OR . m n p o 11 A B C D 1 30
39. The use of claim 37 or 38, wherein Y is –(CR R ) (CR R ) C(O)OR . A B E F
40. The use of any one of claims 37-39, wherein R , R , R , and R at each instance of m C D G H and o are each independently hydrogen; and R , R , R , and R at each instance of n and p are each independently hydrogen or R .
41. The use of claim 28, wherein the compound of formula (II) is a compound of formula 5 (I) according to any one of claims 1-24.
42. The use of any one of claims 28-41, wherein the medicament is for providing anaesthesia for a surgical procedure.
43. The use of any one of claims 28-42, wherein the medicament is for inducing and maintaining general anaesthesia. 10
44. Use of a compound of the formula (II) as defined in any one of claims 28-41in the manufacture of a medicament for providing sedation.
45. The use of claim 44, wherein the medicament is for providing sedation for a medical procedure.
46. The use of claim 44 or 45, wherein the medicament is for providing conscious 15 sedation.
47. The use of any one of claims 44-46, wherein the medicament is for inducing and maintaining conscious sedation.
Publications (1)
Publication Number | Publication Date |
---|---|
NZ619257B2 true NZ619257B2 (en) | 2015-11-03 |
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