IE920138A1 - Amide derivatives and their therapeutic use - Google Patents
Amide derivatives and their therapeutic useInfo
- Publication number
- IE920138A1 IE920138A1 IE013892A IE920138A IE920138A1 IE 920138 A1 IE920138 A1 IE 920138A1 IE 013892 A IE013892 A IE 013892A IE 920138 A IE920138 A IE 920138A IE 920138 A1 IE920138 A1 IE 920138A1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- cyclopropyl
- butenamide
- january
- Prior art date
Links
- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000001408 amides Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 137
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims description 56
- 238000009472 formulation Methods 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- MCPQKPJCSVFCQO-CMDGGOBGSA-N (e)-3-(2-bromophenyl)-n-cyclopropylbut-2-enamide Chemical compound C=1C=CC=C(Br)C=1C(/C)=C/C(=O)NC1CC1 MCPQKPJCSVFCQO-CMDGGOBGSA-N 0.000 claims description 7
- 230000036506 anxiety Effects 0.000 claims description 7
- -1 bromo, chloro, iodo Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 210000003205 muscle Anatomy 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000002920 convulsive effect Effects 0.000 claims description 6
- HHWRQXXWKQACMN-CMDGGOBGSA-N (e)-n-cyclopropyl-3-(2-iodophenyl)but-2-enamide Chemical compound C=1C=CC=C(I)C=1C(/C)=C/C(=O)NC1CC1 HHWRQXXWKQACMN-CMDGGOBGSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000011321 prophylaxis Methods 0.000 claims description 5
- CZNOEBGQSDGBGW-BQYQJAHWSA-N (e)-n-cyclopropyl-3-(2,3-dichlorophenyl)but-2-enamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(/C)=C/C(=O)NC1CC1 CZNOEBGQSDGBGW-BQYQJAHWSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- LNFZKEQFLHGENA-CMDGGOBGSA-N (e)-3-(2-chlorophenyl)-n-cyclopropylbut-2-enamide Chemical compound C=1C=CC=C(Cl)C=1C(/C)=C/C(=O)NC1CC1 LNFZKEQFLHGENA-CMDGGOBGSA-N 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000013160 medical therapy Methods 0.000 claims description 3
- ICZGZHIGSLVNHS-VOTSOKGWSA-N (e)-3-(2-bromophenyl)but-2-enamide Chemical compound NC(=O)\C=C(/C)C1=CC=CC=C1Br ICZGZHIGSLVNHS-VOTSOKGWSA-N 0.000 claims description 2
- DTVWEZDUUUIWOO-UHFFFAOYSA-N 3-(4-chlorophenyl)but-2-enamide Chemical compound NC(=O)C=C(C)C1=CC=C(Cl)C=C1 DTVWEZDUUUIWOO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003158 myorelaxant agent Substances 0.000 abstract description 12
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 7
- 230000000949 anxiolytic effect Effects 0.000 abstract description 7
- 229940035363 muscle relaxants Drugs 0.000 abstract description 7
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 6
- 239000002249 anxiolytic agent Substances 0.000 abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 229940125681 anticonvulsant agent Drugs 0.000 abstract description 3
- 229940005530 anxiolytics Drugs 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 30
- 239000002585 base Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 10
- PIMNFNXBTGPCIL-UHFFFAOYSA-N 1-(2-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Br PIMNFNXBTGPCIL-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 8
- 229940069328 povidone Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- BJUYTGDIEOUJRY-VOTSOKGWSA-N (e)-3-(2-bromophenyl)but-2-enoic acid Chemical compound OC(=O)\C=C(/C)C1=CC=CC=C1Br BJUYTGDIEOUJRY-VOTSOKGWSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 5
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000538 analytical sample Substances 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 230000036461 convulsion Effects 0.000 description 4
- CRTDYPTXLDRNQX-CMDGGOBGSA-N ethyl (e)-3-(2-bromophenyl)but-2-enoate Chemical compound CCOC(=O)\C=C(/C)C1=CC=CC=C1Br CRTDYPTXLDRNQX-CMDGGOBGSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 206010003591 Ataxia Diseases 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 206010010947 Coordination abnormal Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000007101 Muscle Cramp Diseases 0.000 description 3
- 206010039897 Sedation Diseases 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000007963 capsule composition Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical class ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 208000016290 incoordination Diseases 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
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- 230000036280 sedation Effects 0.000 description 3
- 229940080313 sodium starch Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- KEGBPCDPXDEOEZ-VOTSOKGWSA-N (e)-3-(2-bromophenyl)but-2-enoyl chloride Chemical compound ClC(=O)\C=C(/C)C1=CC=CC=C1Br KEGBPCDPXDEOEZ-VOTSOKGWSA-N 0.000 description 2
- DYJMPABDBIPXPM-MDZDMXLPSA-N (e)-3-(2-chlorophenyl)-n-cyclopropylpent-2-enamide Chemical compound C=1C=CC=C(Cl)C=1C(/CC)=C/C(=O)NC1CC1 DYJMPABDBIPXPM-MDZDMXLPSA-N 0.000 description 2
- MCPQKPJCSVFCQO-HJWRWDBZSA-N (z)-3-(2-bromophenyl)-n-cyclopropylbut-2-enamide Chemical compound C=1C=CC=C(Br)C=1C(/C)=C\C(=O)NC1CC1 MCPQKPJCSVFCQO-HJWRWDBZSA-N 0.000 description 2
- ZDOYHCIRUPHUHN-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Cl ZDOYHCIRUPHUHN-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- ZPWIVSGEQGESFF-UHFFFAOYSA-N 2-chloro-n-cyclopropylacetamide Chemical compound ClCC(=O)NC1CC1 ZPWIVSGEQGESFF-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
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- 238000011065 in-situ storage Methods 0.000 description 2
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- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- VWYYSLUEZNSXBN-BQYQJAHWSA-N methyl (e)-3-(2-bromophenyl)but-2-enoate Chemical compound COC(=O)\C=C(/C)C1=CC=CC=C1Br VWYYSLUEZNSXBN-BQYQJAHWSA-N 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- RJLVURPNEWDHCV-UHFFFAOYSA-N n-cyclopropyl-2-diethoxyphosphorylacetamide Chemical compound CCOP(=O)(OCC)CC(=O)NC1CC1 RJLVURPNEWDHCV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- SNYDMZJXWYXCKT-UHFFFAOYSA-M sodium propane-1,2,3-triol benzoate Chemical compound [Na+].OCC(O)CO.[O-]C(=O)c1ccccc1 SNYDMZJXWYXCKT-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Anesthesiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to certain 3-phenyl-2-alkenamide derivatives, base salts and other physiologically functional derivatives thereof, pharmaceutical preparations containing them and the use of such compounds and preparations thereof in therapy, particularly as muscle relaxants, anxiolytics and anti-convulsants. Processes for the preparation of these 3-phenyl-2-alkenamides are also disclosed.
Description
AMIDE DERIVATIVES AND THEIR THERAPEUTIC USE The present invention relates to 3-phenyl-2-alkenamide derivatives, physiologically functional derivatives thereof, pharmaceutical preparations containing them and the use of such compounds and preparations in therapy, particularly as muscle relaxants, anxiolytics and anti-convulsants.
The hypnotic derivatives, cinnamamides Pharm.Assoc. and sedative effects of certain 3-phenyl-2-alkenamide usually referred to by their trivial chemical name have been disclosed by Lott and Christiansen, J.Am. 23.,788 (1934) and Van Heyningen et al. . J.Med. Chem., .9,675 (1966) respectively.
In US patent no. 4,190,674 there is disclosed cinnamamide derivatives which are active in the treatment of convulsion of a mammal and their use in relaxing muscles, for example, treatment of increased skeletal muscle tone.
European patent specification no. 0381508 describes the use of certain cinnamamides for relaxing muscle tone, for example, in the treatment of muscle spasm or spastic paralysis such as cerebral injuries.
The major limiting side effects of many clinically effective muscle relaxants and anticonvulsants are the induction of sedation and incoordination in the recipient, which severely limits the usefulness of these compounds. Similar side effects have been found with drugs used in the treatment of anxiety, such as, benzodiazepines. Although these effects may be transient, patients on such therapy are often unable to drive or participate in certain occupations.
This side-effect liability of potential muscle relaxant compounds can be determined experimentally from studies on the efficacy and depressant potential of muscle relaxants (Drug Dev. Res., 2,383 (1982)).
LL/JJ/7th January, 1992.
PB1216 We have now surprisingly found that certain 3-phenyl-2-alkenamides have potent muscle relaxant activity bu- with significantly reduced liability to the sedation and incoordination side-effects observed with known muscle relaxants. These compounds have also been found to have anxiolytic and anti-convulsant activity.
According to the present invention there is provided 3-phenyl-2-alkenamide derivatives of general formula (I) : 2 wherein R represents g alkyl, R represents hydrogen or g cycloalkyl and R3 represents one or more ring substituents selected from halogen (for example, Cl,Br,I,F) and perhaloC^ ^alkyl (for, example trifluoromethyl); with the following provisos that: 3 (i) when R is methyl and R is cyclopropyl then the or one of R is in the 2-position; and (ii) said compound of formula (I) is not 3-(4-chlorophenyl)-2-butenamide ; or a base salt or other physiologically functional derivative thereof.
As used herein the term alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have 1 to 3 carbon atoms and are more preferably methyl or ethyl, most preferably methyl.
LL/JJ/7th January, 1992.
PB1216 Preferred compounds of formula (I) include those wherein represents 3 methyl and/or, R represents cyclopropyl and/or the or one of R is a ring substituent at the 2-position, preferably bromo, chloro or iodo or a perhalomethyl, for example trifluoromethyl; or a base salt or other physiologically functional derivative thereof.
Particularly preferred compounds of formula (I) include those wherein 3 R represents methyl and/or, R represents cyclopropyl and/or R is a single ring substituent at the 2-position, preferably bromo, chloro, iodo or trifluoromethyl; or a base salt or other physiologically functional derivative thereof.
The (E) isomers of compounds of formula (I) or a base salt or other physiologically functional derivative thereof are preferred.
Especially preferred compounds of formula (I) are: 1. (E)-3 -(2-bromophenyl)-N-cyclopropyl-2-butenamide; 2. (E)-N-cyclopropyl-3-(2-(trifluoromethyl)phenyl))-2-butenamide; 3. (E)-N-cyclopropyl-3-(2 - iodophenyl)-2-butenamide; 4. (E)-N-cyclopropyl-3-(2,3-dichlorophenyl)-2-butenamide; . (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide; and 6. (E)-3-(2-bromophenyl)-2-butenamide.
The compounds of formula (I) above and their base salts, or other physiologically functional derivatives are hereinafter referred to as the compounds according to the invention.
LL/JJ/7th January, 1992.
PB1216 It will be appreciated that the compounds of formula (I) may exist in various geoisomeric forms and as mixtures thereof in any proportions. The present invention includes within its scope the use of such geoisomeric forms or mixtures of geoisomers, including the individual E and Z isomers of the compounds of formula (I) as well as mixtures of such isomers, in any proportions.
By other physiologically functional derivatives is meant any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the said compound or an active metabolite or residue thereof.
Examples of base salts according to the invention include salts, for example, derived from an appropriate base, such as alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts, ammonium and NX^+ (wherein X is alkyl).
For therapeutic use, salts of compounds of formula (I) will be physiologically acceptable, i.e. physiologically acceptable base. they will be salts derived from a However, salts of bases which are not physiologically acceptable may also find use, for example in the preparation or purification of the compound. All base salts whether or not derived from a physiologically acceptable base are to be considered as being within the scope of the present invention.
According to further aspects of the invention there are provided the compounds according to the invention for use in medical therapy, in particularly for the treatment or prophylaxis of - conditions associated with abnormally raised muscle tone, - convulsive states, and - anxiety.
The compounds are thus of particular value in the relaxation of skeletal muscle in spastic, hypertonic and hyperkinetic conditions.
LL/JJ/7th January, 1992.
PB1216 In particular the compounds may be used in the treatment and symptomatic relief of conditions such as spinal cord injury, parkinsonism, chorea, arthritis, athetosis, status epilepticus and tetanus and especially in the relief of muscle spasm in conditions such as myositis, spondylitis, cerebral palsy, cerebrovascular disease amd multiple sclerosis.
The compounds may also be used for the treatment of exertion-induced skeletal muscle spasm, for example, lower back pain.
Convulsive states for which the compounds may be employed include grand mal, petit mal, psychomotor epilepsy and focal seizure. The compounds according to the invention may also be used in the treatment of anxiety including generalised anxiety disorders, obsessive compulsive disorder, panic disorder, phobic anxiety, separation anxiety and post-traumatic stress disorder.
A further use of such compounds is as presurgical muscle relaxants and anti-anxiety agents.
In a further aspect of the present invention there is included: a) a method for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states or anxiety in a host, for example, a mammal including man, and mice which comprises treating said mammal with an effective non-toxic amount of a compound according to the invention. b) use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states or anxiety.
The above compounds according to the invention may be employed in combination with other therapeutic agents for the treatment of the LL/JJ/7th January, 1992.
PB1216 conditions associated with abnormally raised muscle tone. Examples of such therapeutic agents include analgesics, such as, codeine, acetaminophen, phenacetin or ibuprofen.
The present invention further provides pharmaceutical formulations of the compounds according to the invention, also referred to herein as active ingredients, which may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will also be appreciated that the preferred route will vary with the conditions and age of the recipient, the nature of the disorder and the chosen active ingredient.
The amount required of the individual active ingredient for the treatment of, for example, increased muscle tone, convulsive states and anxiety of course depends upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician.
In general, for the foregoing conditions a suitable dose of a compound of formula (I) or a base salt or other physiologically functional derivatives thereof (estimated as the parent compound) is in the range of 0.05 to lOOmg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 50mg per kilogram body weight per day, most preferably in the range 0.5 to 20mg per kilogram body weight per day and optimally 3mg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 1 to 1500mg, preferably 5 to lOOOmg, and most preferably 10 to 700mg of active ingredient per unit dosage form.
LL/JJ/7th January, 1992.
PB1216 While it is possible for the active ingredient to be administered alone it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprises at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, dis integrant (e.g. sodium LL/JJ/7th January, 1992.
PB121 starch glycollate, cross-linked povidone, cross-linked SOdium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for oral use as described above may also include buffering agents designed to neutralize stomach acidity. Such buffers may be chosen from a variety of organic or inorganic agents such as weak acids or bases admixed with their conjugated salts.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injections solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render LL/JJ/7th January, 1992.
PB1216 the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, as liposomes or other microparticulate systems which are designed to target the compounds to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound as an optionally buffered, aqueous solution of, for example, 0.1 to 0.2M concentration with respect to the said compound. As one particular possibility, the active compound may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research. 1/6, 318 (1986).
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
LL/JJ/7th January, 1992.
PB12 The compounds of formula (I) may be prepared in any convention manner and in accordance with the present invention, may, for examplt be prepared by any method hereinafter described.
Thus, the present invention further includes a process for the preparation of compounds of formula (I) and base salts, and other physiologically functional derivatives thereof which comprises:A) reacting a compound of formula (II) (II) (wherein R is as hereinbefore defined and X is a suitable leaving group, for example a halogen atom such as bromine or iodine or a sulphonate such as CF^SiO^O- with a compound of formula (III) R^CH : :CHCOR (III) / 9 19 (wherein R represents -NHR and R and R are as hereinbefore defined); B) reacting a compound of formula (IV) LL/JJ/7th January, 1992.
PB1216 (IV) (wherein R and R are as hereinbefore defined) reagent of formula (V) with a Wittig YCH2C0R4 (V) (wherein R is as hereinbefore defined and Y is -P(-0)(OR)2 wherein R is a alkyl, aryl or aralkyl group, or Y is a triarylphosphine) under Wittig conditions; C) dehydrating a compound of formula (VII) (VII) (wherein Rx, R and R are as hereinbefore defined) D) reacting a compound of formula (VIII) (VIII) LL/JJ/7th January, 1992.
PB1216 (wherein R and R are as hereinbefore defined and Z is a suitable leaving group, for example, a halogen atom, such as bromine or chlorine, azido, amino, or a ROC(O)0- group wherein R represents C, , alkyl, for example, CH_CH-OC(O)O- or an alkanoyloxy group, such as acetyloxy) with a compound of formula (IX) H-R4 (IX) (wherein R is as hereinbefore defined). and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions : (i) converting the compound of formula (I) so formed into a base salt, or other physiologically functional derivative thereof; (ii) when a base salt, or other physiologically functional derivative of a compound of formula (I) is formed, converting the said derivative into a compound of formula (I), or a different derivative thereof.
In process A), a compound of formula (II), is reacted with a compound of formula (III), typically in the presence of a catalyst, such as a transition metal catalyst, for example, a palladium catalyst, in particular, palladium acetate, conveniently in the presence of an organic base such as triethylamine (TEA) and in a suitable polar solvent, for example, acetonitrile, dimethylformamide (DMF) or methanol, preferably at an elevated temperature. The reaction may be carried out in the presence of a phosphorus reagent such as tri-o-toluyl phosphine or another triarylphosphine.
LL/JJ/7th January, 1992.
PB1216 Compounds of formula (II) may be obtained commercially or, may be prepared by methods known in the art for tne synthesis of compounds of analogous structure and in this regard reference is made, by way of illustration only to the following texts:i) Protective Groups in Organic Chemistry'' ed. J. F.W.McOmie, Plenum Press (1973), ISBN 0-306-30717-0; ii) Compendium of Organic Synthetic Methods ed. I.T.Harrison and S.Harrison, Wiley-lnterscience, Vol.I (1971) ISBN 0,471-35550-X, Vol.II (1974) ISBN 0-471-35551-8 and Vol.Ill (ed. L.S.Hegedus and L.Wade) (1977) ISBN 0-471-36752-4; and iii) Rodd's Chemistry of Carbon Compounds'1 second edition, Elsevier Publishing Company. 4 Compounds of formula (III) wherein R and R are as hereinbefore defined may conveniently be prepared either directly from a compound 4 of formula (III) wherein R is as hereinbefore defined and R represents hydroxy, for example, by treatment with the appropriate amine in the presence of a reagent such as dicyclohexylcarbodiimide (DCC) or by conversion of the latter compound of formula (III) to an activated derivative, such as an acid halide, for example, the acid chloride, or an acid anhydride. In the case of the acid chloride, by reaction with thionyl chloride, followed by reaction with the appropriate amine in the presence of an organic base such as TEA or an excess of the amine itself.
Compounds of formula (III) wherein is as hereinbefore defined and R* is hydroxy may be obtained commercially or by methods known to a skilled person.
In process B), a compound of formula (IV), is reacted with a Wittig reagent of formula (V), generally in the presence of a strong base such as sodium hydride or lithium hydride and conveniently in an inert LL/JJ/7th January, 1992. •Ε 920138 - 14 - ΡΒ1216 solvent, for example, dimethoxyethane (DME). The relative proportions of E and Z isomers in the compound of formula (I) so formed will depend on the nature of the alkyl, aryl or aralkyl group in the phosphorus-containing group of the Wittig reagent.
Compounds of formula (IV) may be obtained commercially or prepared by methods well known to a skilled person.
Compounds of formula (V) where Y and R are as hereinbefore defined may be prepared by methods well known in the art, but are typically prepared from compounds of formula (V) wherein R is as hereinbefore defined and Y is a suitable leaving group, for example, a halogen atom, such as chlorine or bromine, by treatment with a suitable phosphorylating agent such as a trialkylphosphite or a triarylphosphine. Compounds of formula (V) wherein R is as hereinbefore defined and Y is a leaving group may be prepared from compounds of formula (V) wherein Y is the aforementioned leaving group and R is another suitable leaving group, for example a halogen atom such as chlorine or bromine. Such compounds, for example, CICOCHjCl, may be obtained from commercial sources or prepared by methods known to a skilled person or readily available from the chemical literature.
In process C), dehydration of a compound of formula (VII), may be effected with a suitable dehydrating agent, such as acetic anhydride, typically in the presence of an acid such as £-toluenesulphonic acid.
Compounds of formula (VII) may conveniently be prepared by reacting a compound of formula (IV) as defined In process B) with a compound of formula (V) wherein R is as hereinbefore defined and Y is bromine, in the presence of zinc (Reformatski reaction). The compound of formula (VII) obtained may be isolated or dehydrated in situ.
Compounds of formula (V) wherein R is as hereinbefore defined and Y is bromine may be prepared by methods analogous to those described 4 , above for the preparation of compounds of formula (V) wherein R is as LL/JJ/7th January, 1992.
PB1216 hereinbefore defined and Y is a suitable leaving group, in this case bromine and compounds of formula (IV) may be obtained commercially or by methods known to a skilled person.
Process D) may be carried out by treating a compound of formula (VIII) with a compound of formula (IX), typically in an inert solvent such as THF or benzene.
Compounds of formula (IX) may be obtained commercially or made by methods well known to a skilled person. 3 Compounds of formula (VIII) wherein R , R and Z are as hereinbefore defined may be prepared from compounds of formula (VIII) wherein R^ 3 and R are as hereinbefore defined and Z is hydroxy, for example where Z is to be halogen, by treatment with a halogenating agent such as oxalyl chloride in an inert solvent such as benzene or, where Z is to be a ROC(O)0- group wherein R is as hereinbefore defined, by treatment with the appropriate alkylchloroformate in the presence of an organic base such as TEA and in an inert solvent such as THF. The compound of formula (VIII) obtained may be isolated or aminated in situ.
Compounds of formula (I) may also be prepared directly from a compound 1 3 of formula (VIII) wherein R and R are as hereinbefore defined and Z 4 is hydroxy by treatment with a compound of formula (IX) wherein R is as hereinbefore defined in a suitable solvent. 3 Compounds of formula (VIII) where R and R are as hereinbefore defined and Z is hydroxy may conveniently be prepared by the 1 3 hydrolysis of a compound of formula (VIII) wherein R and R are as hereinbefore defined and Z is a suitable leaving group, such as alkoxy, for example, (E)-methyl-3-(2-bromophenyl)-2-butenoate wherein 1 3 R is methyl, R is 2-bromo and Z is methoxy, in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid and in a polar solvent, for example, ethanol. Compounds of formula (VIII) wherein Z is alkoxy may be made by the dehydration of a compound of LL/JJ/7th January, 1992. - 16 - PB1216 4 formula (VII) wherein R and R are as hereinbefore defined and R = Z. Such compounds may be prepared by <-he Reformatski reaction described in process C) above.
The compound of formula (I) may be converted into a pharmaceutically acceptable base salt in a conventional manner, for example, by treatment with the appropriate base.
The present invention further includes the following novel intermediates which are of particular value for the preparation of 1 2 compounds of formula (I) wherein R and R are as hereinbefore defined and is 2-bromo: 1. (E)-3-(2-Bromophenyl)-2-butenoic acid. 2. (E)-Ethyl-3-(2-bromophenyl)-2-butenoate. 3. (E)-Methyl-3-(2-bromophenyl)-2-butenoate. 4. (E)-3-(2-Bromophenyl)-2-butenoylchloride.
The following examples illustrate the present invention but should not be construed as limitations thereof.
Example 1 Preparation of (E)-3-(2-Bromophenyl)-N-cyclopropyl-2-butenamide A) Preparation of 2-chloro-N-cvclopropylacetamide A solution of chloroacetyl chloride (33.8g, 0.3moles) In 100ml of ethyl ether was added dropwise over 30 minutes to cyclopropyl amine (34.2g, 0.6moles, Aldrich) in 400ml of ethyl ether at 0°C with stirring. After and additional 30 minutes at this temperature, the ether was evaporated with a stream of nitrogen LL/JJ/7th January, 1992.
PB1216 while heating on a steam bath. The residue was dissolved in dichloromethane (400ml) and washed successively with 100ml portions of dilute hydrochloric acid (IN), aqueous sodium bicarbonate (5%), and distilled water. The volatiles were removed by spin evaporation in vacuo. and the residue was recrystallized from dichloromethane/hexanes to give 26.4g (66%) of 2 - chloro-N-cyclopropylacetamide, m.p. 80-83°C.
Anal. Calcd. for CcH0ClNO: C, 44.96; H, 6.04; N, 10.48; Cl, 26.54 o Found: C, 45.04; H, 6.06; N, 10.45; Cl, 26.52.
B) Preparation of Diethylf(cvclopropvlcarbamoyl)methyl)phosphonate 2-Chloro-N-cyclopropylacetamide (20g, 0.15moles) was added in portions with stirring to triethyl phosphite (28g, 0.17moles, Aldrich) at 110°C. The solution was then heated to 155°C for 30 minutes, cooled to 125°C, and the volatiles were removed by distillation under aspirator vacuum (15mm Hg) at this temperature. The residual oil was stirred with pentane (200ml) while cooling in an ice bath to induce crystallization. Filtration gave 5.2g (14%) of diethyl((cyclopropylcarbamoyl)methyl)phopsphonate as white crystals; m.p. 51-56°C. The liquor was concentrated and cooled to give 25.3g (71%) of a second crop; m.p. 50-56°C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55-57°C.
Anal. Calcd. for C^gNO^: C, 45.96; H, 7.71; N, 5.95.
Found. C, 45.85; H, 7.76; N, 5.90.
C) Preparation of (E)-3-f2-Bromophenvl)-N-cyclopropvl-2-butenamide To an ice-cold, stirred suspension of NaH (80% dispersion in mineral oil, (0.67g, 28mmoles, Aldrich) in dimethoxyethane (25ml) was added a solution of diethyl((cyclopropylcarbamoyl)methyl)phosphonate (5.0g, 21mmoles) in dimethoxyethane (60ml). After LL/JJ/7th January, 1992.
PB1216 1.5 hours, a solution of 2'-bromoacetophenone (4.0g, 20mmoles, Aldrich) in dimethoxyethane (60ml) was added, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into IL of ice water and the mixture was extracted with dichloromethane. The residue was chromatographed on Silica Gel 60 using dichloromethane-ethyl acetate (9:1) as eluent. The fractions containing only (E)-3-(2-bromophenyl)-Ncyclopropyl-2-butenamide were combined and spin evaported in vacuo to give 2.2g of a colorless oil. Trituration with pentane gave 1.85g (33%) of (E)-3-(2-bromophenyl)-N-cyclopropyl2-butenamide, m.p. 82-84°C; NMR (DMSO-dg): 8.04 (d, 1H, J - 4.02 Hz, NH), 7.64-7.19 (m, 4H, Ar), 5.64 (d, 1H, J - 1.36 Hz, -CH), 2.68 (m, 1H, NCH), 2.36 (d, 3H, J - 1.17 Hz, CH3), 0.68-0.35 (2m's, 4H, CH^CHj); steady-state nOe: irradiation at 2.36, observed 4.9% nOe at 7.25 and 1.3% nOe at 5.64.
Anal. Calcd. for C H^BrNO: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.82; H, 5.09; N, 4.95.
Example 2 Preparation of (E)-3-(2-Bromophenvl)-N-cvclopropyl-2-butenamide (A) Preparation of (E)-N-Cvclopropvl-2-butenamide Thionyl chloride (24mL, 0.33mol) was added dropwise during 15 minutes to a stirred solution of crotonic acid (25.8g, 0.30mol, Aldrich) in benzene (400mL) protected from moisture by a drying tube containing Drierite. The resulting clear solution was heated at reflux for 3 hours before a portion of the solvent (lOOmL) was removed by distillation (atmospheric pressure). The remaining solution was stirred, chilled (ice bath) and treated dropwise with cyclopropylamine (20.6g, 0.36mol, Aldrich) followed by triethylamine (41.8mL, 0.30mol). A white solid precipitated. Water (50mL) was added to the mixture and the resulting layer; LL/JJ/7th January, 1992.
PB1216 were separated. The aqueous layer was saturated with NaCl and extracted with methylene chloride (5 x lOOmL). The organic layers were combined, dried over Na^SO^, filtered and concentrated to a solid residue, which subsequently was subjected to bulb to bulb distillation (pot temperature 90-110°C) at 0.1 torr; yield, 31.2g (83%), m.p. 63-65°C; NMR (DMSO-dg): S 7.91 (br s, 1H, NH), 6.48-6.66 (m, 1H, -CHCH3), 5.79 (d x d, J - 1.6, J - 15.2 Hz; 1H, -CHCO), 2.65 (m, 1H, NCH), 1.74 (d x d, J - 1.7, J - 6.8 Hz, 3H, CH3), 0.39 and 0.60 (2 m's, 4H, CH^Hp .
Anal. Calcd. for C^^O.0.1 H20: C, 66.22; H, 8.89; N, 11.03. Found: C, 66.10; H, 8.90; N, 11.07.
(B) Preparation of (E~)-3-(2-BromophenyI)-N-cyclopropyl-2-butenamide A stirred mixture of 1,2-dibromobenzene (Aldrich) (2.36g, lO.Ommol), (E)-N-Cyclopropyl-2-butenamide (1.30g, lO.Ommol), triethylamine (l.Olg, lO.Ommol), tri-o-tolylphosphine (Aldrich) (0.24g, 0.8mmol), palladium acetate (Aldrich) (0.04g, 0.2mmol) and acetonitrile (25mL) was heated in a stoppered flask at 120°C for 18 hours. The mixture was cooled to ambient temperature, filtered, concentrated and chromatographed on Silica Gel 60 using ethyl acetate-hexanes (1:4 to 1:1 gradient) as eluent. Fractions containing only (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide were combined and spin evaporated in vacuo to give 1.2g (42.8%) of the product. An analytical sample obtained by recrystallization from dichloromethane/hexanes was identical to the compound prepared in Example 1 by mixed m.p. (82-84°C) and NMR.
Anal. Calcd. for C.,H1zBrNO: C, 55.73; H, 5.04; N, 5.00; 14 Br, 28.52.
Found: C, 55.81; H, 5.06; N, 5.01; Br, 28.44.
LL/JJ/7th January, 1992.
PB1216 Example 3 Preparation of (E)-3-(2 - Bromophenyl)-N-cyclopropyl-2-butenamide A) Preparation of (E)-Ethyl 3-(2-Bromophenvl)-2-butenoate A stirred mixture of 2'-bromoacetophenone (Aldrich) (14.7g, 74mmol), zinc powder (Mallinckrodt) (9.0g), ethyl bromoacetate (Aldrich) (18.5g, lllmmol), a crystal of iodine, benzene (lOOmL) and diethyl ether (lOOmL) was heated at reflux under nitrogen for 2 hours. The resulting grey suspension was cooled to ambient temperature, filtered and the filtrate was concentrated to a yellow foam. The residue was dissolved in acetic anhydride (50mL) with cooling, treated with £-toluenesulfonic acid (50mg, Aldrich) and heated at 70-80°C for 0.5 hours. The solution was cooled to ambient temperature, concentrated in vacuo and chromatographed on a Waters Prep 500 using ethyl acetate-hexanes (1:133) as eluent. Fractions containing only (E)-ethyl 3-(2-bromophenyl)-2-butenoate were combined and spin evaporated in vacuo to give 3.Og (15%) of a clear oil; NMR (DMSO-dg): 5 7.67-7.23 (m, 4H, Ar), 5.72 (d, IH, J-1.4 Hz, -CH), 4.13 (q, 2H, CH2O), 2.37 (d, 3H, J-1.4 Hz, CHp, 1.21 (t, 3H, CH3CH2O); steady-state nOe: irradiation at 2.37 δ, observed 2% nOe at 7.45 δ and 1% nOe at 5.72 δ.
Anal. Calcd. for C^H^BrO^ C, 53.55; H, 4.87; Br, 29.69.
Found: C, 53.61; H, 4.83; Br, 29.76.
B) Preparation of (E)-3-(2-Bromophenvl)-2-butenoic Acid A mixture of (E)-ethyl 3-(2-bromophenyl)-2-butenoate (2.7g, lO.Ommol), ethanol (20mL) and IN NaOH (ll.OmL) was stirred overnight at ambient temperature. The solution was concentrated in vacuo. diluted with water (30mL) and extracted with diethyl ether. The aqueous layer was acidified by adding cone HCl LL/JJ/7th January, 1992.
PB1216 (1.2mL) and extracted with diethyl ether. The ether layer was dried over Na^O^, filtered, concentrated and chromatographed on Silica Gel 60 using ethyl acetate-dichloromethane (1:4). The fractions containing only (E)-3-(2-bromophenyl)-2-butenoic acid were combined and concentrated to give white crystals (l.Og, 41.7%) of the product, m.p. 109-lll°C; NMR (DMSO-d.): S 12.43 o (br s, 1H, COOH), 7.67-7.22 (m, 4H, Ar), 5.66 (d, 1H, J-1.4 Hz, —CH), 2.34 (d, 3H, J—1.4 Hz, CH^); steady-state nOe: irradiation at 2.34 5, observed 1% nOe at 7.29 6 and 1% nOe at 5.66 S.
Anal. Calcd. for C1()HgBrO2: C, 49.82; H, 3.76; Br, 33.14.
Found: C, 49.92; H, 3.77; Br, 33.21.
C) Preparation of (E)-3-(2-Bromophenyl)-N-cvclopropvl-2-butenamide A solution of (E)-3-(2-bromophenyl)-2-butenoic acid (l.Og, 4.0mmol) and oxalyl chloride (1.7g, 13.8mmol, Aldrich) in benzene (50mL) was refluxed for 2 hours and concentrated to give (E)-3-(2-bromophenyl)-2-butenoylchloride as a pale yellow oil; IR: 1773, 1611 cm \ Cyclopropylamine (0.9g, 16mmol, Aldrich) was added to the acid chloride in benzene (60mL), and the mixture was stirred overnight at room temperature. The solution was washed sequentially with saturated NaHCO^ (50mL), IN HCl (50mL) and brine (50mL), dried over Na2SO^, filtered and concentrated in vacuo to a cloudy oil (0.9g). Recrystallization from dichloromethane-hexanes gave white crystals (0.3g, 30%) of the product identical to the compound prepared in Example 1 by mixed m.p. (82-84°C) and NMR.
Anal. Calcd. for C^H^BrNO: C, 55.73; H, 5.04; N, 5.00; Br, 28.52.
Found: C, 55.77; H, 5.02; N, 5.01; Br, 28.44.
LL/JJ/7th January, 1992. Έ920138 ΡΒ1216 Example 4 Preparation of (E)-3-(2-Bromophenyl)-N-cyclopropyl-2-butenamide Ethyl chloroformate (Aldrich) (0.13g, 1.24mmol) was added dropwise to a stirred solution of (E)-3-(2-bromophenyl)-2-butenoic acid (0.30g, 1.24mmol), triethylamine (0.12g, 1.24mmol) and tetrahydrofuran (5mL) at 0°C. After 2h at 0°C, the precipitated triethylamine hydrochloride was removed by filtering and a solution of cyclopropylamine (7lmg, 1.24mmol) in tetrahydrofuran (lmL) was added dropwise to the ice-cold filtrate. The mixture was stirred overnight at ambient temperature, concentrated and chromatographed on Silica Gel 60 using ethyl acetate-dichloromethane (1:19) as eluent. The fractions containing only (E)-3-(2-Bromophenyl)-N-cyclopropyl-2-butenamide were combined and spin evaporated in vacuo to give 0.21g (60%) of the product. An analytical sample obtained by recrystallization from dichloromethane/ hexanes was identical to the compounds prepared in Example 1 by mixed m.p. (82-84°C) and NMR.
Anal. Calcd. for C H BrNO: C, 55.73; H, 5.04; N, 5.00; Br, 28.52. Found: C, 55.71; H, 5.04; N, 5.01; Br, 28.60.
Example 5 Preparation of (Z)-3-(2-Bromophenyl)-N-cyclopropvl-2-butenamide The fractions from Example 1C containing only (Z)-3-(2-bromophenyl)-Ncyclopropyl-2-butenamide were combined and spin evaporated in vacuo to give 1.7g of a white solid. Trituration with pentane gave 1.31g (23%) of (Z)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide, m.p. 144-146°C; NMR (DMSO-dr): δ 7.82 (d, 1H, NH), 7.55-7.05 (m, 4H, Ar), 5.90 (d, o 1H, J - 1.47 Hz, -CH), 2.48 (m, 1H, NCH), 1.97 (d, 3H, J - 1.47 Hz, CHp 0.57-0.27 (2m's, 4H, CI^CHp; steady-state nOe; irradiation at 1.97, observed 8.2% nOe at 7.1 and 17.0% nOe at 5.90.
LL/JJ/7th January, 1992.
PB1216 Anal. Calcd. for C^H^BrNO: C, 55.73; H, 5.04; N, 5.00.
Found: C, 55.73; H, 4.99; N, 4.99.
Example 6 Preparation of (E)-N-Cyclopropyl-3-(2-(trifluoromethyl))phenvl)-2butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2'-(trifluoromethyl)acetophenone (Aldrich). The chromatography solutions that contained (E)-N-cyclopropyl-3-(2-(trifluoromethyl))-2phenyl)-2-butenamide were spin evaporated in vacuo. The solid was collected and recrystallized from ethanol-water to give 0.74g (10%) of (E)-N-cyclopropyl-3-(2-(trifluoromethyl))phenyl)-2-butenamide, m.p. — 114-116°C; NMR (DMSO-d,): δ 8.06 (d, 1H, J - 4.16 Hz, NH), 7.76-7.36 o (m, 4H, Ar), 5.62 (d, 1H, J - 1.31 Hz, -CH), 2.70 (m, 1H, NCH), 2.40 (d, 3H, J - 1.07 Hz, CHj), 0.66-0.40 (2m's, 4H, CH^H^; steady-state nOe: irradiation at 2.40 δ, observed 4.9% nOe at 7.4 and 1.4% nOe at 5.628 δ.
Anal. Calcd. for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20.
Found: C, 62.37; H, 5.28; N, 5.19.
Example 7 Preparation of (E)-N-Cyclopropyl-3-(2.3-dichlorophenvl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2',3'-(dichloro)acetophenone (Maybridge). The chromatography solutions that contained (E)-N-cyclopropyl-3-(2,3-dichlorophenyl)-2butenamide were spin evaporated, and the solid was collected and dried; yield, 6.73g (47%), m.p. 111-113°C; NMR (DMS0-d6): δ 8.08 (d, 1H, J - 4.06 Hz, NH), 7.62-7.21 (m, 3H, Ar), 5.69 (d, 1H, JLL/JJ/7th January, 1992.
PB1216 1.22 Hz, -CH), 2.67 (m, IH, NCH), 2.63 (d, 3H, J - 0.97 Hz, CHg), 0.66-0.37 (2m's, 4H, CH2CH ).
Anal. Calcd. for C H^C^NO: C, 57.80; H, 4.85; N, 5.18; Cl, 26.25. Found: C, 57.71; H, 4.83; N, 5.13; Cl, 26.34.
Example 8 Preparation of (E)- 3 -(2-Chlorophenvl)-N-cvclopropyl-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2'-chloroacetophenone (Aldrich). The chromatography solutions that contained (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide were spin evaporated in vacuo. The solid was collected and dried; yield, 28.30g (32%), m.p. 92.5-94°C; NMR (DMSO-dJ: 5 8.05 (d, IH, J - 3.86 Hz, NH), o 7.48-7.22 (m, 4H, Ar), 5.68 (d, IH, J -1.28 Hz, -CH), 2.68 (m, IH, NCH), 2.38 (d, 3H, J - 1.44 Hz, CHg), 0.68-0.37 (2m's, 4H, C^C^) ; steady-state nOe: irradiation at 2.38 S, observed 4% nOe at 7.3 and 1% nOe at 5.68 S.
Anal. Calcd. for C H^CINO: C, 66.24; H, 5.99; N, 5.94; Cl, 15.04. Found: C, 66.34; H, 6.03; N, 5.90; Cl, 15.10.
Example 9 Preparation of (Z)-3-(2-Chlorophenyl)-N-cvclopropyl-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2’-chloroacetophenone (Aldrich). The chromatography solutions that contained (Z)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide were spin evaporated and the solid was collected and dried; yield, 3.52g (4%), m.p. 125-132°C; NMR (DMSO-dg): & 7.83 (d, IH, NH), 7.38-7.06 (m, 4H, Ar), 5.92 (d, IH, J - 1.45 Hz, -CH), 2.48 (m, IH, NCH), LL/JJ/7th January, 1992.
PB1216 1.98 (d, 3H, J - 1.41 Hz, CH^ , 0.57-0.24 (2m's, 4H, CH^H^ ; steady-state nOe: irradiation at 1.98 6, observed 5% nOe at 7.1 and 14% nOe at 5.92 S.
Anal. Calcd. for C^H^CINO: C, 66.24; H, 5.99; N, 5.94; Cl, 15.04. Found: C, 66.33; H, 6.04; N, 5.88; Cl, 15.11.
Example 10 Preparation of (E)-N-Cyclopropyl-3-(2-fluorophenyl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2'-fluoroacetophenone (Aldrich). The chromatography solutions were spin evaporated, and the solid was collected and dried; yield, 8.50g (55%), m.p. 59-5.62°C; NMR (DMSO-dg): S 8.08 (d, 1H, J - 3.82 Hz, NH), 7.37-7.15 (m, 4H, Ar), 5.89 (d, 1H, J - 1.21 Hz, -CH), 2.67 (m, 1H, NCH), 2.40 (s, 3H, CH ), 0.66-0.37 (2m's, 4H, CH^H^ ; steady-state nOe: irradiation at 2.49 S, observed 5.3% nOe at 7.3 and 0.7% nOe at 5.89 5.
Anal. Calcd. for C^-H-.FNO: C, 71.21; H, 6.44; N, 6.39. 14 Found; C, 71.30; H, 6.46; N, 6.35.
Example 11 Preparation of (E)-3-(3-Chlorophenvl)-N-cvclobutyl-2-butenamide (E)-3-(3-chlorophenyl)-2J.Med.Chem, 9, 675 (1966) (2.57g, 254mmole) in chloroformate (2.76g, To a stirred, ice bath-cooled solution of butenoic acid (E. Van Heyningen et al. (5.00g, 254mmole) and triethylamine tetrahydrofuran (120ml) was added ethyl 254mmole) in tetrahydrofuran (20ml). After 30 minutes cyclobutylamine (l.lg, 254mmole, Aldrich) in tetrahydrofuran (30ml) was added slowly. The reaction mixture was stirred at ambient temperature for 15 hours.
LL/JJ/7th January, 1992.
PB1216 The reaction mixture was spin evaporated in vacuo. and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate layer was washed with IN hydrochloric acid and brine. The ethyl acetate solution was dried (sodium sulfate) and spin evaporated in vacuo. The residual yellow solid was purified by flash chromatography on silica gel 60 (40-63 m, E. Merck No. 9385) using ethyl acetate-hexane (1:4) as eluent. The fractions that contained (E)-3-(3-chlorophenyl)-N-cyclobutyl-2-butenamide were combined and Λ evaporated to give 3.93g (61%) of product, (DMSO-d,): 6 (d, 1H, J 8.2 (br d, 1H, NH), 1.3 Hz, -CH), 4.28 7.54-7.35 (m, 1H, NCH), m.p. 89-90 C; NMR (m, 4H, Ar), 6.21 2.45 (d, 3H, J 1.2 Hz, CHp , 2.32-1.55 (m, 6H, (CH,^); steady-state nOe: irradiation at 2.45, observed 18.1% nOe at 7.5 and -0.2% nOe at 6.21.
Anal. Calcd. for C H &C1NO: C, 67.33: H, 6.46; N, 5.61. Found: C, 67.34; H, 6.46; N, 5.58.
Example 12 Preparation of (E)-3-(2-Bromophenvl)-N-cyclobutvl-2-butenamide This compound was prepared in an analogous manner to that of Example 3 with the replacement of cyclopropylamine in Example 3C with cyclobutylamine (Aldrich). The solid was recrystallized from dichloromethane-hexanes to give off white crystals (1.lg, 64%) of the product, m.p. 128-13O°C; NMR (DMSO-d&): £ 8.22 (d, 1H, J - 7.7 Hz, NH), 7.66-7.20 (m, 4H, Ar), 5.68 (d, 1H, J - 1.4 Hz, - CH), 4.25 (m, 1H, NCH), 2.36 (d, 3H, J - 1.3 Hz, CH ), 2.20-1.58 (3 m's, 6H, (CH2)3); steady-state nOe: irradiation at 2.36 S, observed 4% nOe at 7.24 6 and 1% nOe at 5.68 S.
Anal. Calcd. for C H BrNO: C, 57.16; H, 5.48; N, 4.76; Br, 27.16. Found: C, 57.08; H, 5.50; N, 4.72; Br, 27.08.
LL/JJ/7th January, 1992.
PB1216 Example 13 Preparation of (E)-3-(2-Chlorophenyl)-N-cvclopropyl-2-pentenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2'-choropropiophenone (B.L.Jenson, S.E. Burke and S.E.Thomas, Tetrahedron, 34. 1627-1631 (1978)). The chromatography solutions that contained (E)-3-(2-Chlorophenyl)-N-cyclopropyl-2-pentenamide were combined and spin evaporated in vacuo to give 6.60g (37%) of (E)-3(2-Chlorophenyl)-N-cyclopropyl-2-pentenamide, m.p. - 148-150°C; NMR (DMSO-dg): δ 8.06 (d, IH, J - 3.9 Hz, NH), 7.50-7.22 (3 m's, 4H, Ar), .64 (s, 1H, - CH), 3.01 (q, 2H, J - 7.5 Hz, C^C-), 2.70 (m, IH, NCH), 0.86 (t, 3H, J - 7.5 Hz, CH3), 0.68-0.40 (2 m's, 4H, CH^H^; steady-state mOe: irradiation at 3.01 δ, observed 19.7% nOe at 0.86 δ and 1.1% nOe at 5.64 δ .
Anal. Calcd. for C^H^Cl.N.O: C, 67.33; H, 6.46; N, 5.61; Cl, 14.19.
Found: C, 67.35; H, 6.48; N, 5.62; Cl, 14.12.
Example 14 Preparation of (E)-N-Cyclopropyl-3-(2-iodophenyl)2-butenamide A) Preparation of DiisopropyK(cvclopropvlcarbamoyl)methvl)phosphonate This compound was prepared (3.0 molar scale) in a manner analogous to that of Example IB with the replacement of triethyl phosphite with triisopropylphosphite (Aldrich) and pentane with hexane: yield, 385g (48.7%) as a fluffy white solid, m.p. 58-60°C; the analytical sample was recrystallized from hexane.
LL/JJ/7th January, 1992.
PB1216 Anal. Calcd. for C^H^NO^P: C, 50.18; H, 8.42; N, 5.32 Found: C, 50.08; H, 8.44; N, 5.26.
B) Preparation of (E)-N-Cyclopropyl-3-(2-iodophenyl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with (Aldrich) the replacement of 2'-bromoacetophenone in Example 1C with 2'-iodoacetophenone (Aldrich) and the replacement of diethyl((cyclopropylcarbamoyl)methyl)phosphonate with diisopropyl((cyclopropylcarbamoyl)methyl)phosphonate. The chromatography solutions that contained (E)-N-cyclopropyl-3-(2iodophenyl)-2-butenamide were spin evaporated in vacuo. The residue was recrystallized from dichloromethane-hexanes to give 1.7g (51%) of the product as white crystals, m.p. 120-122°C; NMR (DMSO-dg): S 8.04 (d, 1H, J - 4.0 Hz, NH), 7.88-7.00 (m, 4H, Ar), 5.57 (d, 1H, J - 1.4 Hz, -CH), 2.68 (m, 1H, CH), 2.34 (d, 3H, J - 1.3 Hz, CH ), 0.68-0.35 (2 m's, 4H, ; steady-state nOe: irradiation at 2.34 5, observed 5% nOe at 7.04 S and 1% nOe at 5.57 6.
Anal. Calcd. for C H^INO: C, 47.73; H, 4.31; N, 4.28; I, 38.79. Found: C, 47.63; H, 4.33; N, 4.26; I, 38.86.
Pharmaceutical Formulations In the following formulation Examples, the Active Ingredient may be any compound of formula (I) or base salt or other physiologically functional derivative thereof, for example, compounds of Examples 1 to 14.
LL/JJ/7th January, 1992.
PB1216 Example 15 Tablet Formulations The following formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
Formulation A me/tablet me/tablet (a) Active ingredient 250 250 (b) Lactose B.P. 210 26 (c) Povidone B.P. 15 9 (d) Sodium Starch Glycollate 20 12 (e) Magnesium Stearate 5 _3 500 300 Formulation B me/tablet me/tablet (a) Active ingredient 250 250 (b) Lactose 150 - (c) Avicel PH 101 60 26 (d) Povidone B.P. 15 9 (e) Sodium Starch Glycollate 20 12 (f) Magnesium Stearate 5 3 500 300 LL/JJ/7th January, 1992.
PB1216 Formulation C mg/tablet Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Magnesium Stearate _4 359 The following formulations, D and E, are prepared by direct compression of the admixed ingredients. The lactose in formulation E is of the direct compression type (Dairy Crest - Zeparox).
Formulation D mg/tablet Active ingredient Pregelatinized Starch NF15 250 150 400 Formulation E mg/tablet Active ingredient Lactose Avicel 250 150 100 500 Formulation F (Controlled Release Formulation) The formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
LL/JJ/7th January, 1992.
PB1216 mg/tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose (Methocel K4M Premium) 112 (c) Lactose B.P. 53 (d) Povidone B.P. 28 (e) Magnesium Stearate _7 700 Example 16 Capsule Formulations Formulation A A capsule formulation is prepared by admixing the ingredients of Formulation D in Example 15 above and filling into a two-part hard gelatin capsule. Formulation B (infra) is prepared in a similar manner.
Formulation B mg/capsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycollate 25 (d) Magnesium Stearate _2 420 LL/JJ/7th January, 1992. - 32 PB1216 Formulation C mg/capsule (a) Active ingredient (b) Macrogol 4000 B.P. 250 350 600 Formulation D mg/capsule Active ingredient Lecithin Arachis Oil 250 100 100 450 Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
Formulation E (Controlled Release Capsule) The following controlled release capsule formulation is prepared by extruding ingredients a, b and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 513 LL/JJ/7th January, 1992.
PB1216 Example 17 Injectable Formulation Active ingredient 0.200 g 95% Ethanol and PEG 400, 1:1 ratio Sterile water q.s. to 10 mL The active ingredient is dissolved in 95% Ethanol and PEG 400 (1:1).
The batch is then made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 mL amber glass vial (type 1) and sealed with sterile closures and overseals.
Example 18 Syrup Active ingredient Sorbitol Solution Glycerol Sodium Benzoate Flavor, Peach 17.42.3169 Purified Water 0.25 g 1.50 g 2.00 g 0.005 g 0.0125 mL q.s. to 5.00 mL The active ingredient is dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavor. The volume is made up with purified water and mixed well.
LL/JJ/7th January, 1992.
PB1216 Example 19 Suppository mg/suppository Active ingredient 250 Hard Fat, B.P. (Witepsol H15 - Dynamit NoBel) 1770 2020 One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45*C maximum. The active ingredient is sifted through a 200 M sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix. The entire suspension is passed through a 250 M stainless steel screen and, with continuous stirring, is allowed to cool to 40°C. At a temperature of 38°C to 40°C, 2.02 g of the mixture is filled into suitable, 2 mL plastic molds. The suppositories are allowed to cool to room temperature.
Example 20 Pessaries mg/pessarv Active ingredient 250 Anhydrate Dextrose 380 Potato Starch 363 Magnesium Stearate 7 The above ingredients are mixed directly and pessaries prepared by direct compression of the resulting mixture. 1000 LL/JJ/7th January, 1992. - 35 - PB1216 Example 21 Muscle Relaxant Activity Muscle relaxant activity of compounds of formula (I) was determined using a Straub tail test based on that described by K.O. Ellis and J.F. Carpenter Neuropharmacol, .13, 211 (1974).
The Straub tail test result is reported as an Εϋ^θ in mg/kg. The Εϋ^θ is defined as the dose of compound administered, which prevents Straub tail in 50% of mice. The compound is administered by oral gavage (po) 60 min. prior to scoring.
The side effect potential of these compounds was determined using the mouse rotorod test as described by G.D. Novak and J.M.-Zwolshei, J. Pharmacological. Methods, 10, 175 (1983). Rotorod result is reported as Εϋ^θ in mg/kg. The Εϋ^θ is the dose which causes 50% of the animals to fail to maintain position on a cylinder rotating at 11 r.p.m.
Antagonism of morphine - induced Straub tail reflects muscle relaxant efficacy while failure in the rotorod test reflects sedation and incoordination. Determination of the ratio of rotorod failure to antagonism of morphine-induced Straub tail is a means of assessing side effect liability of muscle relaxants (G.D. Novak, Drug Dev. Res., 2, 383 (1982). Compound of Straub Rotorod Rotorod/ Example No. Tail Straub Tai p.°. ed50, p.o. ED50, ratio mg/kg. mg/kg. 45 1.8 LL/JJ/7th January, 1992.
PB1216 Example 22 Anticonvulsant Activity Anticonvulsant activity of compounds of formula (I) was determined using a method described by Mehta et al.. J.Med.Chem., 24. 465 (1981).
The anticonvulsant activity is reported as an Εϋ^θ in mg/kg. The Εϋ^θ for protection against maximal electroshock-induced convulsions was the dose which prevented hind limb extension in 50% of the animals. The ED^q for protection against Metrazol-induced convulsions was the dose which prevented? convulsions in 50% of the animals.
Compound of Example No. i.p. ED5Q, mg/kg (rat) MES MET 9.6 3.6 MES - maximal electroshock MET - metrazol Example 23 Anxiolytic Activity Anxiolytic activity of the compounds according to the invention was measured using method of Geller and Seifter, J.Psychopharmacolgia, 1, 482 (1960) as modified by Pollard and Howard, Psychopharmacology, 62. 117 (1979). Clinically efficacious anxiolytics increase punished responding. The anxiolytic activity of the compound is reported as LL/JJ/7th January, 1992.
PB1216 the dose necessary to produce a 50% increase in punished responding in rats.
Compound of Example No. Ρ,ο,. EPS0, mg/kR LL/JJ/7th January, 1992.
Claims (17)
1. A compound of formula (I): 1 2 wherein R represents C- , alkyl, R 3 cycloalkyl and R represents one selected from halogen and perhaloC^ represents hydrogen or C^ & or more ring substituents alkyl; with the following provisos that: 1 2 (I) when R is methyl and R is cyclopropyl then the or one of 3 R is in the 2-position; and (ii) said compound of formula (I) is not 3-(4-chlorophenyl)-2butenamide; or a base salt or other physiologically functional derivative thereof.
2. A compound according to claim 1 wherein R^ represents methyl 2 3 and/or, R represents cyclopropyl and/or the or one of R as defined in formula (I) is in the 2-position; or a base salt or other physiologically functional derivative thereof.
3. A compound according to claims 1 or 2 wherein R^ represents 2 3 methyl and/or, R represents cyclopropyl and/or the or one of R represents bromo, chloro, iodo or trifluoromethyl and is in the LL/JJ/7th January, 1992. PB1216CC -392-position; or a base salt or other physiologically functional derivative thereof.
4. A compound according to any one of claims 1 to 3 wherein R^ 2 3 represents methyl and/or, R represents cyclopropyl and/or R is as hereinbefore defined and is in the 2-position; or a base salt or other physiologically functional derivative thereof.
5. (E) isomers of compounds of formula (I) or a base salt or other physiologically functional derivative thereof according to any one of claims 1 to 4.
6. A compound according to claim 1 which compound is : 1. (E)-N-cyclopropyl-3-(2-(trifluoromethyl)phenyl)) -2-butenamide; 2. (E)-N-cyclopropyl-3-(2-iodophenyl) -2-butenamide; 3. (E)-N-cyclopropyl-3- (2,3-dichlorophenyl)-2-butenamide; 4. (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-butenamide ; 5. (E)-3-(2-bromophenyl)-2-butenamide; or a base salt or other physiologically functional derivatives thereof.
7. (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide.
8. A base salt or other physiologically functional derivative of a compound according to any one of claims 1 to 7.
9. A compound according to any one of claims 1 to 8 for use in medical therapy. LL/JJ/7th January, 1992. -40PB1216CC
10. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prophylaxis of the conditions associated with abnormally raised muscle tone.
11. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prophylaxis of convulsive states.
12. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of anxiety.
13. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, together with a pharmaceutically acceptable carrier therefor.
14. A formulation according to claim 13 adapted for oral administration.
15. A formulation according to claim 14 in the form of a tablet or capsule .
16. A process for the preparation of a compound according to any one of claims 1· to 8 which comprises :A) reacting a compound of formula (II) (II) LL/JJ/7th January, 1992. PB1216CC -413 (wherein R is as defined in formula (I) and X is a leaving group) with a compound of formula (III) R 1 CH ==CHC0R 4 (HI) 4 2 12 (wherein R represents -NHR and R and R are as defined in formula (I)); B) reacting a compound of formula (IV) (IV) 1 3 (wherein R and R are as defined in formula (I)) with a Wittig reagent of formula (V) YCH 2 COR 4 (V) (wherein R is as hereinbefore defined and Y is -P(-O)(OR) 2 wherein R is a alkyl, aryl or aralkyl group, or Y is a triarylphosphine) under Wittig conditions; C) dehydrating a compound of formula (VII) LL/JJ/7th January, 1992. PB1216CC (VII) (wherein R , R and R are as hereinbefore defined). D) reacting a compound of formula (VIII) (VIII) 1 3 (wherein R and R are as hereinbefore defined and Z is a leaving group) with a compound of formula (IX) H-R 4 (IX) (wherein R is as hereinbefore defined). and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions: (i) converting the compound of formula (I) so formed into a base salt, or other physiologically functional derivative thereof; LL/JJ/7th January, 1992. PB1216CC -43(ii) when a base salt, or other physiologically functional derivative of a compound of formula (I) is formed, converting the said derivative into a compound of formula (I), or a different derivative thereof. LL/JJ/7th January, 1992, -44 23.
17. . 23. A compound substantially as hereinbefore described with reference to the Examples. (E) isomers of a compound substantially as hereinbefore described with reference to the Examples. A base salt substantially as hereinbefore described with reference to the Examples. A compound substantially as hereinbefore described with reference to the Examples for use in medical therapy. A use substantially as hereinbefore described with reference to the Examples. A pharmaceutical formulation substantially as hereinbefore described with reference to the Examples. A process substantially as hereinbefore described with reference to the Examples.
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JPH09512813A (en) * | 1994-05-10 | 1997-12-22 | ザ、ウェルカム、ファンデーション、リミテッド | Amide derivatives and their therapeutic use |
US5917038A (en) * | 1996-11-22 | 1999-06-29 | Eli Lilly And Company | Process of preparing substituted acrylamides |
US6159943A (en) * | 1999-09-24 | 2000-12-12 | Bioenergy, Inc. | Use of ribose to prevent cramping and soreness in muscles |
EP3498273A1 (en) * | 2017-12-14 | 2019-06-19 | Universität Wien | Pharmaceutical composition for modulating the response of a gaba-a receptor |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2132547A1 (en) * | 1971-04-08 | 1972-11-24 | Clin Byla Ets | Substd phenyl alkyl or alkenyl amides - useful as analgesics and antiinflammatories |
US4190674A (en) * | 1976-02-03 | 1980-02-26 | Burroughs Wellcome Co. | 3-Fluoro-N-cyclopropylcinnamide |
JPH0714871B2 (en) * | 1989-02-02 | 1995-02-22 | 大正製薬株式会社 | Muscle relaxant |
-
1991
- 1991-01-19 GB GB919101244A patent/GB9101244D0/en active Pending
-
1992
- 1992-01-17 AU AU11710/92A patent/AU655000B2/en not_active Ceased
- 1992-01-17 CA CA002101783A patent/CA2101783A1/en not_active Abandoned
- 1992-01-17 HU HU9302052A patent/HUT65231A/en unknown
- 1992-01-17 IL IL100689A patent/IL100689A0/en unknown
- 1992-01-17 TW TW081100323A patent/TW212170B/zh active
- 1992-01-17 NZ NZ241331A patent/NZ241331A/en unknown
- 1992-01-17 JP JP4503564A patent/JPH06506916A/en active Pending
- 1992-01-17 EP EP92903260A patent/EP0569409A1/en not_active Withdrawn
- 1992-01-17 WO PCT/GB1992/000108 patent/WO1992012959A1/en not_active Application Discontinuation
- 1992-01-17 ZA ZA92357A patent/ZA92357B/en unknown
- 1992-01-17 IE IE013892A patent/IE920138A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
HU9302052D0 (en) | 1993-10-28 |
ZA92357B (en) | 1993-07-19 |
TW212170B (en) | 1993-09-01 |
AU655000B2 (en) | 1994-12-01 |
CA2101783A1 (en) | 1992-07-20 |
IL100689A0 (en) | 1992-09-06 |
WO1992012959A1 (en) | 1992-08-06 |
EP0569409A1 (en) | 1993-11-18 |
AU1171092A (en) | 1992-08-27 |
HUT65231A (en) | 1994-05-02 |
JPH06506916A (en) | 1994-08-04 |
GB9101244D0 (en) | 1991-02-27 |
NZ241331A (en) | 1994-08-26 |
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Legal Events
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FA9A | Application withdrawn section 33(1) |