EP1664010A1 - Antagoniste des canaux calcium type n, de type sulfonamides - Google Patents
Antagoniste des canaux calcium type n, de type sulfonamidesInfo
- Publication number
- EP1664010A1 EP1664010A1 EP04768255A EP04768255A EP1664010A1 EP 1664010 A1 EP1664010 A1 EP 1664010A1 EP 04768255 A EP04768255 A EP 04768255A EP 04768255 A EP04768255 A EP 04768255A EP 1664010 A1 EP1664010 A1 EP 1664010A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- amino
- piperidine
- alkenyl
- carbocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 102000004129 N-Type Calcium Channels Human genes 0.000 title claims abstract description 21
- 108090000699 N-Type Calcium Channels Proteins 0.000 title claims abstract description 21
- 229940124530 sulfonamide Drugs 0.000 title description 2
- 150000003456 sulfonamides Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 208000002193 Pain Diseases 0.000 claims abstract description 32
- 230000036407 pain Effects 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 230000001404 mediated effect Effects 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 172
- 238000000034 method Methods 0.000 claims description 78
- -1 hydroxy, amino, thio Chemical group 0.000 claims description 75
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 229910052731 fluorine Inorganic materials 0.000 claims description 50
- 239000011737 fluorine Substances 0.000 claims description 50
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 48
- 239000000460 chlorine Substances 0.000 claims description 48
- 229910052801 chlorine Inorganic materials 0.000 claims description 48
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 43
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 36
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 36
- 229910052794 bromium Inorganic materials 0.000 claims description 36
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 31
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000004414 alkyl thio group Chemical group 0.000 claims description 22
- 125000003386 piperidinyl group Chemical group 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 18
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 18
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 150000004702 methyl esters Chemical class 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000006190 sub-lingual tablet Substances 0.000 claims description 2
- 229940098466 sublingual tablet Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000004128 high performance liquid chromatography Methods 0.000 description 38
- 230000014759 maintenance of location Effects 0.000 description 38
- 238000001819 mass spectrum Methods 0.000 description 38
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 229940079593 drug Drugs 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 13
- 206010010904 Convulsion Diseases 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 208000000094 Chronic Pain Diseases 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 208000004296 neuralgia Diseases 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000006850 spacer group Chemical group 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- 125000004149 thio group Chemical group *S* 0.000 description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 4
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 208000005298 acute pain Diseases 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 4
- SGBONNFZLBXDIQ-JTQLQIEISA-N (2s)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Cl SGBONNFZLBXDIQ-JTQLQIEISA-N 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- NJXDBSSSDPOAFI-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C(Cl)=C1 NJXDBSSSDPOAFI-UHFFFAOYSA-N 0.000 description 3
- UHIVZTGDOMOBAK-VIFPVBQESA-N 5-ethyl-2-[(2s)-piperidin-2-yl]-1,3-oxazole Chemical compound O1C(CC)=CN=C1[C@H]1NCCCC1 UHIVZTGDOMOBAK-VIFPVBQESA-N 0.000 description 3
- 102000003922 Calcium Channels Human genes 0.000 description 3
- 108090000312 Calcium Channels Proteins 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 3
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 206010071289 Lower urinary tract symptoms Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- 208000026723 Urinary tract disease Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 235000013681 dietary sucrose Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- KPEPDTYCRPLZTI-LBPRGKRZSA-N ethyl (2s)-1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Br KPEPDTYCRPLZTI-LBPRGKRZSA-N 0.000 description 3
- OYRPWFUUSSAJCZ-LBPRGKRZSA-N ethyl (2s)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Cl OYRPWFUUSSAJCZ-LBPRGKRZSA-N 0.000 description 3
- YNJREAKQNRATFU-ZDUSSCGKSA-N ethyl (2s)-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 YNJREAKQNRATFU-ZDUSSCGKSA-N 0.000 description 3
- HSLCPZJPTHTWPC-UHFFFAOYSA-N ethyl 1-(4-formylphenyl)sulfonylpiperidine-2-carboxylate Chemical compound CCOC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C=O)C=C1 HSLCPZJPTHTWPC-UHFFFAOYSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 229940071648 metered dose inhaler Drugs 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- XJLSEXAGTJCILF-UHFFFAOYSA-N nipecotic acid Chemical compound OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 3
- 229960003081 probenecid Drugs 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 208000014001 urinary system disease Diseases 0.000 description 3
- BKPHVZFLBKRBIR-JTQLQIEISA-N (2s)-1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Br BKPHVZFLBKRBIR-JTQLQIEISA-N 0.000 description 2
- OYFYHVHYJYCOSA-NSHDSACASA-N (2s)-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 OYFYHVHYJYCOSA-NSHDSACASA-N 0.000 description 2
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 2
- KODLUXHSIZOKTG-UHFFFAOYSA-N 1-aminobutan-2-ol Chemical compound CCC(O)CN KODLUXHSIZOKTG-UHFFFAOYSA-N 0.000 description 2
- XDIAMRVROCPPBK-UHFFFAOYSA-N 2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)CN XDIAMRVROCPPBK-UHFFFAOYSA-N 0.000 description 2
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- KPHUMZIZPQNGCL-UHFFFAOYSA-N n-ethyl-n-methyl-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide Chemical compound CCN(C)C(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 KPHUMZIZPQNGCL-UHFFFAOYSA-N 0.000 description 1
- SAVQQRYWWAGSQW-UHFFFAOYSA-N n-methyl-n-(trifluoro-$l^{4}-sulfanyl)methanamine Chemical compound CN(C)S(F)(F)F SAVQQRYWWAGSQW-UHFFFAOYSA-N 0.000 description 1
- WQPXEHNENKLSPO-UHFFFAOYSA-N n-pentan-3-yl-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide Chemical compound CCC(CC)NC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 WQPXEHNENKLSPO-UHFFFAOYSA-N 0.000 description 1
- QTRMZHOJZDLYIR-UHFFFAOYSA-N n-propan-2-yl-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide Chemical compound CC(C)NC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 QTRMZHOJZDLYIR-UHFFFAOYSA-N 0.000 description 1
- DSLNJJQGMUZNGA-UHFFFAOYSA-N n-propyl-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide Chemical compound CCCNC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 DSLNJJQGMUZNGA-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HYQCZNNQQAISHR-UHFFFAOYSA-N piperidin-1-yl-[1-[4-(trifluoromethyl)phenyl]sulfonylpiperidin-2-yl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)N1C(C(=O)N2CCCCC2)CCCC1 HYQCZNNQQAISHR-UHFFFAOYSA-N 0.000 description 1
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- UPNLKOKBLCSFOU-UHFFFAOYSA-N propan-2-yl 1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CC(C)OC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 UPNLKOKBLCSFOU-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 239000008109 sodium starch glycolate Substances 0.000 description 1
- XFTALRAZSCGSKN-UHFFFAOYSA-M sodium;4-ethenylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=C(C=C)C=C1 XFTALRAZSCGSKN-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- KVVPBMZBZZGWGC-CQSZACIVSA-N tert-butyl (2r)-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@H]1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 KVVPBMZBZZGWGC-CQSZACIVSA-N 0.000 description 1
- DOCGRGSXNFSJEK-LLVKDONJSA-N tert-butyl (3r)-1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonylpiperidine-3-carboxylate Chemical compound C1[C@H](C(=O)OC(C)(C)C)CCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Br DOCGRGSXNFSJEK-LLVKDONJSA-N 0.000 description 1
- CDNNMAYRGJHGSJ-LLVKDONJSA-N tert-butyl (3r)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonylpiperidine-3-carboxylate Chemical compound C1[C@H](C(=O)OC(C)(C)C)CCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Cl CDNNMAYRGJHGSJ-LLVKDONJSA-N 0.000 description 1
- ZTQVKQKUSNGQHA-GFCCVEGCSA-N tert-butyl (3r)-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-3-carboxylate Chemical compound C1[C@H](C(=O)OC(C)(C)C)CCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 ZTQVKQKUSNGQHA-GFCCVEGCSA-N 0.000 description 1
- KVVPBMZBZZGWGC-UHFFFAOYSA-N tert-butyl 1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCCN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 KVVPBMZBZZGWGC-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
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- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000005289 uranyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to specific sulphonylpiperidine derivatives which act as inhibitors of N-type calcium channels.
- Mammalian ion channels are becoming increasingly well characterised, and this is especially true of calcium channels.
- Voltage-gated calcium channels are critical components for the functioning of the nervous system, and they signal a painful event.
- 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non- neuronal cells (Perez-Reyes, E.; Schneider, T. DrugDev. Res., 1994, 33, 295-318). These channels are now recognised as valid targets for pain therapeutics and as neuroprotective agents (Cox, B.; Denyer, J.C.
- the present invention provides the use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,
- R 1 is Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, -L-Het-Y, -L-X-Y, 5- to 6-membered heteroaryl, -CONH or -X-Y, wherein: - X is -CO-, -CO-O-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR-, wherein each R is the same or different and represents hydrogen, -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; Het is -O-, -S- or -NR-, wherein R is as defined above; L represents a C C 6 alkyl, C 2 -C 6 alkenyl or C -C 6 alkynyl moiety; Y is C 1 -Q 5 alkyl, C 2 -C 6 alkenyl,
- R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, halogen, hydroxy, thio, amino, cyano, nitro, -C ⁇ alkyl, C -C 6 alkenyl, C -C 6 alkynyl, Ci-C 6 alkoxy, -C ⁇ alkylthio, mono(C 1 -C 6 alkyl)amino and di(C 1 -C 6 alkyl)amino; and n is from 0 to 4, the alkyl, alkenyl and alkynyl groups and moieties in R 1 to R 5 being unsubstituted or substituted by one, two or three substituents which are
- the present invention further provides the use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: one of R 1 and R 6 is hydrogen and the other is C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein: - X is -CO-, -CO-O-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR-, wherein each R is the same or different and represents hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and Y is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C
- the substituents on the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in formulae (I) and (II) are typically unsubstituted.
- the orientation of the group X in formulae (I) and (II) is such that the left hand side of the depicted group is attached to the piperidinyl ring.
- the group -X-Y is -CONR-Y.
- R 2 is an oxo group the line linking R 2 to the piperidinyl ring depicts a double bond.
- a Ci-C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms.
- -C ⁇ alkyl groups or moieties include methyl, ethyl, iso-propyl, n-propyl, t-butyl, iso-butyl, sec-butyl, n-butyl, 3 -methyl-butyl, 1,2-dimethyl-butyl, 1-ethyl-pro ⁇ yl, 2,2-dimethyl- propyl and 3,3-dimethyl-butyl.
- C!-C 6 alkyl groups or moieties include -C 4 alkyl groups or moieties, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.
- Preferred -Ce alkyl groups include methyl, ethyl, n-propyl, iso-propyl and t-butyl.
- a divalent alkyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
- a C 2 -C 6 alkenyl group is a linear or branched C 2 -C 6 alkylene group.
- an alkenyl group or moiety is saturated except for one double bond.
- it is an ethenyl, propenyl or butenyl group.
- it is an ethenyl group.
- a divalent alkenyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
- a C 2 -C 6 alkynyl group is a linear or branched C 2 -C 6 alkynyl group.
- an alkynyl group or moiety is saturated except for one triple bond. Typically, it is an ethynyl, propynyl or butynyl group.
- a divalent alkynyl group can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
- a C 6 -C 10 aryl group or moiety is typically a phenyl or naphthyl group or moiety. Preferably, it is a phenyl group.
- a 5- to 10-membered heteroaryl group is a 5- to 10-membered aromatic ring containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N.
- Preferred 5- to 10-membered heteroaryl groups are 5- to 6-membered heteroaryl groups.
- Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
- Preferred 5- to 6-membered heteroaryl groups are furanyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl and imidazolyl.
- a 5- to 10-membered heteroaryl group is typically a monocyclic 5- to 10-membered heteroaryl group.
- a 5- to 10-membered heteroaryl group or moiety is a monocyclic group or moiety or a bicyclic fused group or moiety.
- Preferred bicyclic fused groups and moieties are 5- to 10-membered moieties in which a 5- to 6- membered ring is fused to a phenyl ring, to form a 9- to 10-membered heteroaryl group.
- suitable such 5- to 6-membered heteroaryl groups are pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl and thiozolyl groups.
- a 9- to 10-membered heteroaryl group or moiety is therefore typically a 5- to 6- membered heteroaryl group fused to a phenyl ring.
- Examples of such 9- to 10- membered heteroaryl groups and moieties are benzimidazolyl, benzoxazolyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl and benzothiazolyl.
- a preferred such group is benzoxazolyl.
- a halogen is typically fluorine, chlorine, bromine or iodine and is preferably fluorine, chlorine or bromine.
- a said Ci-C 6 alkoxy group is typically a said -C O alkyl group attached to an oxygen atom.
- a said - alkylthio group is typically a said Ci-C 6 alkyl group attached to a thio group.
- a C C 6 haloalkyl group is typically a said -C ⁇ alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
- haloalkyl groups include perhaloalkyl groups such as -CX 3 wherein X is a said halogen atom.
- Preferred haloalkyl groups are fluoroalkyl groups such as -CF 3 , -CHF 2 and -CH 2 F.
- a Ci-C 6 haloalkoxy group is typically a said -C ⁇ alkoxy group substituted by one or more said halogen atoms.
- haloalkoxy groups include perhaloalkoxy groups such as -OCX 3 wherein X is a said halogen atom.
- a Ci-C ⁇ hydroxyalkyl group is typically a said Ci-C ⁇ alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by 1, 2 or 3 hydroxy groups.
- Preferred hydroxyalkyl groups are monohydroxyalkyl groups.
- a Ci-C ⁇ haloalkylthio group is typically a said C C 6 alkylthio group substituted by one or more said halogen atoms.
- haloalkylthio groups include perhaloalkylthio groups such as -SCX 3 wherein X is a said halogen atom.
- a C 3 -C 8 carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms.
- the carbocyclyl group is saturated, for example a C 3 -C 6 cycloalkyl group. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- a preferred carbocyclyl group is cyclopropyl.
- a C 3 -C 8 carbocyclyl group or moiety is typically a monocyclic C 3 -C 8 carbocyclyl group or moiety.
- a 5- to 10-membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 5 -C 10 carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred.
- heterocyclyl groups examples include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolanyl, dithiolanyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, morpholinyl and thiomorpholinyl.
- Preferred heterocyclic groups are pyrrolidinyl and piperidinyl.
- An example of a preferred heterocyclic group is piperidinyl.
- a 5- to 10-membered heterocyclyl group or moiety is a monocyclic group or moiety or a bicyclic fused group or moiety.
- Preferred bicyclic fused groups and moieties are 5- to 10-membered moieties in which a 5- to 6- membered ring is fused to a phenyl ring, to form a 9- to 10-membered heterocyclic group.
- suitable such 5- to 6-membered heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl.
- a 9- to 10-membered heterocyclic group or moiety is therefore typically a 5- to 6-membered heterocyclyl group fused to a phenyl ring.
- 9- to 10-membered heterocyclyl groups and moieties are 1,3-dihydroisobenzo uranyl, 2,3-dihydrobenzofuranyl, 1,3- dihydrobenzo[c]thiophenyl, 2,3-dihydrobenzo[b]thio ⁇ henyl, 1,3-dihydroisoindolyl, 2,3-dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isochromanyl, isothiochromanyl and thiochromanyl.
- a preferred such group is 1,3-dihydroisoindolyl and, in particular, l,3-dihydroisoindol-2-yl.
- the alkyl, alkenyl and alkynyl groups and moieties in R to R are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents.
- the alkyl, alkenyl and alkynyl groups and moieties in R 1 to R 6 , in the formulae (I) and (II), are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine or chlorine.
- R' in the formula (I), is hydrogen or - alkyl.
- R' is hydrogen or Ci-C 2 alkyl. More preferably, R' is hydrogen or methyl.
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R and R , in the formula (I), are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, C ⁇ -C 4 alkyl, Q-C 4 alkoxy, Ci-C 4 alkylthio, mono(C 1 -C 4 alkyl)amino, di(C 1 -C 4 alkyl)amino, C 1 -C 4 haloalkyl, C C haloalkoxy, -C 4 haloalkylthio, -C 4 hydroxyalkyl, -(C 1 -C alkyl)-O-(C 1 -C 4 alkyl), -(d-C 4 alkyl)-S-(d-C 4 alkyl), -(C C 4 alkyl)
- substituents on an aryl, heteroaryl, carbocyclyl or heterocyclyl group or moiety is a -(C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), -(d-C 4 alkyl)-S-(C 1 -C 4 alkyl), -(C 1 -C 4 alkyl)-NR'-(C 1 -C 4 alkyl), -CO-(C ! -C 4 alkyl), -CO-O-(C 1 -C 4 alkyl)or -CONRHQ- alkyl) substituent.
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R and R , in the formula (I), are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Q-C 4 haloalkyl, Q-C 4 haloalkoxy, d-C 2 hydroxyalkyl, -(C 1 -C 2 alkyl)-O-(C 1 -C 2 alkyl), or -CO-O-(C ⁇ -C 4 alkyl) substituents.
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R 1 and R 2 , in the formula (I), are unsubstituted or are substituted by a single methyl, ethyl, t-butyl, trifluoromethyl, -CH 2 -OH, -CH 2 -O-CH 3 or -CO-O-t-butyl substituent.
- each R in the moiety X or Het, in the formulae (I) and (II) is the same or different and represents hydrogen or C C ⁇ alkyl.
- each R is the same or different and represents hydrogen or Q-C 2 alkyl.
- each R is the same or different and represents hydrogen or methyl.
- Het in the formula (I), represents -O-, -S- or -NR-, wherein R is as defined above.
- Het represents -O- or -NR-, wherein R is as defined above.
- Het represents -O-, -NH- or -NMe-.
- L in the formulae (I) and (II), represents a Ci-C 6 alkyl moiety.
- L represents a Q-C 4 alkyl moiety. More preferably, L represents a Cj . -C alkyl moiety.
- A in the formulae (I) and (II) represents a phenyl, 5- to 6- membered heteroaryl, C -C 6 carbocyclyl or 5- to 6-membered heterocyclyl moiety.
- A represents a phenyl, 5- to 6-membered heteroaryl or C 3 -C 6 carbocyclyl moiety.
- A represents thienyl, furanyl or phenyl.
- An example of a more preferred A group is phenyl.
- X in the formulae (I) and (II) is -CO-, -CO-O-, -CONR-, -O-CO- or -NR-CO-, wherein R is as defined above.
- X is -CO-, -CO-O- or -CONR-, wherein R is as defined above. More preferably, X is -CO-, -CO-O-, -CONH- or -CON e-.
- Y is -L-A, it is typically -( -C ⁇ alkyl)-A where A is as defined above. It is preferably -( -C 4 alkyl)- A, where A is a phenyl, 5- to 6-membered heteroaryl or C 3 -C 6 carbocyclyl moiety.
- Y in the formulae (I) and (II) is - 5 alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- to 10-membered heterocyclyl or -L-A, wherein L and A are as defined above.
- Examples of typical Y groups are Ci-C ⁇ alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- to 6-membered heterocyclyl and -L-A, wherein L and A are as defined above.
- Y is -C ⁇ alkyl, C -C 6 carbocyclyl, 5- to 6 membered heterocyclyl, 9- to 10-membered heterocyclyl or -L-A, wherein L and A are as defined above.
- Examples of preferred Y groups are - alkyl, C 3 -C 6 carbocyclyl and -L-A, wherein L and A are as defined above.
- Y is C C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -(C 1 -C 2 alkyl)-thienyl, -( -C 2 alkyl)-furanyl or -(CrC 2 alkyl)-phenyl.
- Examples of more preferred Y groups are C ⁇ alkyl, cyclopropyl, cyclobutyl and -(Ci-C alkyl)-phenyl.
- Examples of more preferred Y groups are Ci-C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1,3-dihydroisoindolyl, -(C 1 -C 2 alkyl)-thienyl, -(d-C 2 alkyl)- furanyl or -(C 1 -C 2 alkyl)- ⁇ henyl.
- Further examples of more preferred Y groups are C C 6 alkyl, cyclopropyl, cyclobutyl and -(C 1 -C 2 alkyl)-phenyl.
- Y When Y is a heterocyclyl moiety which comprises nitrogen, it may be attached to X via either a carbon or nitrogen atom. Typically, when X is -CO-O-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR- and Y is a heterocyclyl moiety which comprises nitrogen, Y is attached to X via a carbon atom.
- R 1 or R 6 in the formulae (I) and (II) is -X-Y, it is typically -CO-Y,
- Y is C ⁇ -C 6 alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- toT ⁇ -membered heterocyclyl or -L-A, wherein L, A and R are as defined above.
- Y is Q-Cs alkyl, C 3 -C 6 carbocyclyl, 5- to 6 membered heterocyclyl, 9- to 10-membered heterocyclyl or -L-A, wherein L, A and R are as defined above.
- preferred groups are -CO-Y, -CO-O-Y or -CONR-Y, wherein Y is C C 6 alkyl, C 3 -C 6 carbocyclyl or -L-A, wherein L, A and R are as defined above.
- Y is C C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -( -C2 alkyl)-thienyl, -( -C 2 alkyl)-furanyl or -(CrC 2 alkyl)-phenyl.
- Examples of more preferred groups are -CO-Y, -CO-O-Y, -CONH-Y or -CONMe-Y, wherein Y is -Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1,3-dihydroisoindolyl, -(C 1 -C 2 alkyl)-thienyl, -(CrC 2 alkyl)- furanyl or -(CrC 2 alkyl)-phenyl.
- R 1 in the formula (I), is C ⁇ -C 6 alkyl, cyano, -L-Het-Y, -L-X-Y, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein X, Y, Het and L are as defined above.
- R 1 is C 1 -C4 alkyl, cyano, -(C1-C2 alkyl)-NR-(C 1 -C 6 alkyl), -(C 1 -C 2 alkyl)-NR-(C 3 -C 6 carbocyclyl), oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, imidazolyl, benzoxazolyl, -CONH , -CO-Y, -CO-O-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is C C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -(C 1 -C 2 alkyl)-thienyl, -(0 ⁇ 0
- R 2 When R 2 is -X-L, it is typically -CO-L, -CO-O-L or -CONR-L, wherein R and L are as defined above. It is preferably -CO-O-( -C 6 alkyl) and more preferably -CO-O-( C1-C4 alkyl).
- R 2 in the formula (I), represents fluorine, chlorine, bromine, hydroxy, amino, thio, C; ⁇ -C 6 alkyl, oxo, -Het-L, -Het-A, -X-L or X-A, wherein Het, L, A and X are as defined above.
- R 2 represents fluorine, chlorine, hydroxy, -C ⁇ alkyl, oxo, -Het-L or -X-L, wherein Het represents -O-, -NH- or - NMe-, X represents -CO-, -CO-O-, -CONH- or -CONMe- and L represents C ⁇ -C 6 alkyl. More preferably, R 2 represents fluorine, chlorine, hydroxy, C 1 -C 4 alkyl, oxo or -CO-O-(C ⁇ -C alkyl). Typically, in the formulae (I) and (II), only one of R to R represents a nitro or cyano group.
- R 3 , R 4 and R 5 in the formulae (I) and (II), are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, hydroxy, thio, amino, cyano, -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, -C 4 alkylthio, mono(C 1 -C 4 alkyl)amino and di(C C 4 alkyl)amino.
- R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 2 alkoxy, -C2 alkylthio, mono(C 1 -C 2 alkyl)amino and di(C ⁇ -C 2 alkyl)amino. More preferably, R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, -C 4 alkyl, C 1 -C 2 alkoxy or ethenyl.
- R 3 , R 4 and R 5 groups are hydrogen, fluorine, chlorine, bromine, cyano, C 1 -C 4 alkyl or ethenyl.
- n in the formula (I), represents 0,1 or 2.
- Preferred compounds of formula (I) are those wherein: R 1 is C 1 -C 6 alkyl, cyano, -L-Het-Y, -L-X-Y, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein: X is -CO-, -CO-O-, -CONR-, -O-CO- or -NR-CO-, wherein R represents hydrogen or C C 6 alkyl; Het represents -O-, -S- or -NR-, wherein R is as defined above; L represents a Ci-C ⁇ alkyl moiety; and Y is Ci -C 6 alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- to 10-membered heterocyclyl or -L-A, wherein L ia as defined above and A represents a phenyl, 5- to 6-membered heteroaryl, C -C 6 carbocycl
- R 1 is C1-C4 alkyl, cyano, -(C1-C 2 alkyl)-NR-(C 1 -C 6 alkyl), -(C1-C2 alkyl)-NR- (C 3 -C 6 carbocyclyl), oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, imidazolyl, benzoxazolyl, -CONH 2 , -CO-Y, -CO-O-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is Ci-C ⁇ alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -(CrC 2 alkyl)-thieny
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R 1 and R 6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, hydroxy, amino, thio, C 1 -C 4 alkyl, -C 4 alkoxy, -C 4 alkylthio, mono(Ci-C 4 alkyl)amino, di(C C 4 alkyl)amino, C 1 -C 4 haloalkyl, -C 4 haloalkoxy or -C 4 haloalkylthio substituents.
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R 1 and R 6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C Q haloalkyl or -C 4 haloalkoxy substituents.
- substituents are fluorine, chlorine, bromine, C C 2 alkyl, C C 2 alkoxy, C C 2 haloalkyl and C C 2 haloalkoxy substituents.
- the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R and R are unsubstituted or are substituted by a single methyl, ethyl or t-butyl substituent.
- substituents are a single methyl or ethyl substituent.
- one of R 1 and R 6 is hydrogen and the other is C C 6 alkyl, cyano, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein X and Y are as defined above.
- one of R 1 and R 6 is hydrogen and the other is
- Examples of preferred groups are those wherein one of R 1 and R 2 is hydrogen and the other is Ci-C alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl, -CONH 2 , -CO-Y, -CO-O-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is CrC 6 alkyl, cyclopropyl, cyclobutyl or -( -C 2 alkyl)-phenyl.
- Preferred compounds of formula (II) are those wherein: one of R 1 and R 6 is hydrogen and the other is -C ⁇ alkyl, cyano, phenyl, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein: X is -CO-, -CO-O-, -CONR-, -O-CO- or -NR-CO-, wherein R is hydrogen or C C 6 alkyl; and Y is C C 6 alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- to 10-membered heterocyclyl or -L-A, wherein: L represents a Ci-C 6 alkyl moiety; and A represents a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl moiety; and R 3 , R 4 and R 5 are the same or different and are selected from hydrogen
- Examples of preferred compounds of formula (II) are the preferred compounds of formula (II) as defined above wherein Y is d-C 6 alkyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl, 5- to 6-membered heterocyclyl or -L-A, wherein L and A are as defined for said preferred compounds.
- More preferred compounds of formula (II) are those wherein: one of R and R is hydrogen and the other is d-C 6 alkyl, cyano, phenyl, 5- to 6-membered heteroaryl, -CONH 2 or -X-Y, wherein: X is -CO-, -CO-O- or -CO-NR-, wherein R represents hydrogen or d- alkyl; and - Y is d-C 6 alkyl, C 3 -C 6 carbocyclyl, 5- to 6-membered heterocyclyl, 9- to 10-membered heterocyclyl or -L-A, where L represents a d-d alkyl moiety and A represents a phenyl, 5- to 6-membered heteroaryl or C 3 -C 6 carbocyclyl moiety; and R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano, d- alkyl, C2-C 4 alken
- Examples of more preferred compounds of formula (II) are those more preferred compounds of formula (II) as defined above wherein Y is d-C 6 alkyl, C -C 6 carbocyclyl or -L-A, where L represents a d- alkyl moiety and A represents a phenyl, 5- to 6-membered heteroaryl or C 3 -C 6 carbocyclyl moiety, and wherein the phenyl, heteroaryl and carbocyclyl groups and moieties in R 1 and R 6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, d- alkyl, d-d alkoxy, d-C 2 haloalkyl or d-C 2 haloalkoxy substituents.
- Particularly preferred compounds of formula (II) are those wherein: one of R 1 and R 6 is hydrogen and the other is d-d alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, -CONH 2 , -CO-Y, -CO-O-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is d-C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, 1,3-dihydroisoindolyl, -(d-C 2 alkyl)-thienyl, -(d-C 2 alkyl)-furanyl or -(C 1 -C2 alkyl)-phenyl; and R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, cyano,
- particularly preferred compounds of formula (II) are the particularly preferred compounds of formula (II) as defined above wherein one of R 1 and R 6 is hydrogen and the other is d- alkyl, cyano, oxadiazolyl, oxazolyl, isoxazolyl, -CONH 2 , -CO-Y, -CO-O-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is d-C 6 alkyl, cyclopropyl, cyclobutyl or -(d-C 2 alkyl)-phenyl, and wherein the phenyl, heteroaryl and carbocyclyl groups and moieties in R 1 and R 6 are unsubstituted or substituted by one, two or three unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, d-C 2 alkyl, d-C 2 alkoxy, d-C 2 haloal
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I), provided that when R 1 is ⁇ to the nitrogen of the piperidinyl ring and n is 0, then:
- R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 ;
- R 1 when the phenyl ring substituted by R 3 , R 4 and R 5 is a para- fluorophenyl group, then R 1 is not a 5-membered heteroaryl group; or (ii) R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl, l,2,4-oxadiazol-3-yl or l,2-imidazol-2-yl group.
- provisos (a) and (b)(i) apply.
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I), provided that, when R 1 is ⁇ to the nitrogen of the piperidinyl ring and n is 0, R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 and when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5-membered heteroaryl group.
- R 1 is not a -CO-O-(d-C 6 ) alkyl group.
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) provided that R 1 is not -CO-O-CH 2 -CH 3 ,
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) provided that R 1 is not -CO-O-(C 1 -C 6 alkyl) or a 5- to 6-membered heteroaryl group.
- R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) and R 1 is d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, -L-Het-Y, -L-X-Y, -CONH 2 or -X-Y, wherein: X is -CO-, -CONR-, -O-CO-, -NR-CO- or -NR-CO-NR-, wherein each R is the same or different and represents hydrogen, d-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; Het is -O-, -S- or -NR-, wherein R is as defined above; L represents a d-C 6 alkyl, d-C 6 alkenyl or C 2 -C 6 alkynyl mo
- R 1 is d-d alkyl, cyano, -(d-C 2 alkyl)-NR-(d-C 6 alkyl), -(d-C 2 alkyl)-NR- (C 3 -C 6 carbocyclyl), -CONH 2 , -CO-Y, -CO-NH-Y or -CO-NMe-Y, wherein Y is d- alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -(d- alky ⁇ -tbienyl, -(d-d alkyl)-furanyl or -(d-d alkyl)-phenyl and R is hydrogen or methyl; R 2 represents fluorine, chlorine, hydroxy, d- alkyl, oxo or -CO-O-
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that: (a) R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 ; and either (b) (i) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para- fluorophenyl group, then R 1 is not a 5-membered heteroaryl group; or (ii) R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl or l,2,4-oxadiazol-3-yl group.
- provisos (a) and (b)(i) apply.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that R 1 is not -CO-O-CH 2 -CH 3 or -CO-O-CH(CH 3 ) 2 and when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5-membered heteroaryl group.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II) provided that R 1 is not -CO-O-CH 2 -CH 3 , -CO-O- CH(CH 3 ) 2 or a 5-membered heteroaryl group.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II) provided that R 1 is not -CO-O-(C 1 -C 6 alkyl) or a 5- to 6-membered heteroaryl group.
- the present invention also provides a compound of formula (IN A), a tautomer thereof or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body,
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that: (a) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5-membered heteroaryl group; or
- R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl or l,2,4-oxadiazol-3-yl group.
- proviso (a) applies.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that when the phenyl ring substituted by R 3 , R and R 5 is a para-fluorophenyl group, then R 1 is not a 5-membered heteroaryl group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a para-fluorophenyl group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a para-halophenyl group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a phenyl group substituted by a halogen substituent.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a phenyl group substituted by a halogen, haloalkyl or haloalkoxy substituent.
- R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, thio, amino, cyano, nitro, C 2 -C 6 alkenyl, C -C 6 alkynyl, d-C 6 alkylthio, mono(C ⁇ -C 6 alkyl)amino and di(d-C 6 alkyl)amino, provided that R 3 , R 4 and R 5 are not all hydrogen.
- Examples of particularly preferred compounds of formulae (I) to (INA) are: l-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-3 -carboxylic acid ethyl ester l-(4-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; 2-Methyl- 1 -(4-trifluoromethyl-benzenesulfonyl)-piperidine; l-(2,4,6-Trimethyl-benzenesulfonyl)-piperidme-2-carboxylic acid ethyl ester; l-(2,4,6-Triisopropyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethyl ester; l-(4-Bromo-2-methyl-benzenesulfonyl)-piperidine-2-carboxylic acid ethy
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I), provided that when n is 0 then:
- R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 , and either
- R 1 when the phenyl ring substituted by R 3 , R 4 and R 5 is a para- fluorophenyl group, then R 1 is not a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group; or (ii) R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl, l,2,4-oxadiazol-3-yl or 1,3- imidazoly-2-yl group.
- provisos (a) and (b)(i) apply.
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I), provided that, when n is 0, then R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 , and when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group.
- R 1 is not a -CO-O-(d-d) alkyl group.
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) provided that R 1 is not -CO-O-CH 2 -CH 3 , -CO-O-
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) provided that R 1 is not -CO-O-(d-C 6 alkyl), a 5- to 6-membered heteroaryl, -CO-NH 2 , -CO-NH-(d-C 6 alkyl) or cyano group.
- R 2 , R 3 , R 4 , R 5 and n are as defined for formula (I) and R 1 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -L-Het-Y, -L-X-Y or -X-Y, wherein: X is -CO-, -O-CO-, -NR-CO- or -NR-CO-NR-, wherein each R is the same or different and represents hydrogen, d-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; Het is -O-, -S- or -NR-, wherein R is as defined above; - L represents a d-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl moiety; Y is d-C 6 alkyl
- R 1 is d-d alkyl, -(d-C 2 alkyl)-NR-(C ⁇ -C 6 alkyl), -(d-C 2 alkyl)-NR-(C 3 -C 6 carbocyclyl) or -CO-Y, wherein Y is d-C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, pyrrolidinyl, 1,3-dihydroisoindolyl, -(d-C alkyl)-thienyl, -(d-C 2 alkyl)-furanyl or -(d-C 2 alkyl)-phenyl and R is hydrogen or methyl; R represents fluorine, chlorine, hydroxy, d- alkyl, oxo or -CO-O-(d-C 4 alkyl); R 3 , R and R 5 are the same or different
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that:
- R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 , and either
- R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl or l,2,4-oxadiazol-3-yl group.
- provisos (a) and (b)(i) apply.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that R 1 is neither -CO-O-CH 2 -CH 3 nor -CO-O-CH(CH 3 ) 2 , and when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5- membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2- hydroxypropylamido group.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II) provided that R 1 is not -CO-O-CH 2 -CH 3 , -CO-O-CH(CH 3 ) 2 , a 5-membered heteroaryl, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group.
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II) provided that R 1 is not -CO-O-(d-C 6 alkyl), a 5- to 6-membered heteroaryl, -CO- ⁇ H 2 , -CO-NH-(C 1 -C 6 alkyl) or cyano group.
- the present invention provides a compound of formula (VIA), a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that either: (a) (i) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para- 1 trifluoromethylphenyl group, neither R nor R is -CO-O-CH 2 -CH 3 ; and (ii) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para- fluorophenyl group, then R 1 is not a 5-membered heteroaryl, carboxylic acid, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group, or
- R 1 , R 3 , R 4 , R 5 and R 6 are as defined for formula (II), provided that: (i) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-trifluoromethylphenyl group, neither R 1 nor R 2 is -CO-O-CH 2 -CH 3 ; and (ii) when the phenyl ring substituted by R 3 , R 4 and R 5 is a para-fluorophenyl group, then R 1 is not a 5- membered heteroaryl, carboxylic acid, amido, methyl ester, methyl amido, cyano or 2-hydroxypropylamido group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a para-trifluoromethylphenyl or para- fluorophenyl group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a para-trihalomethylphenyl or para-halophenyl group.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a phenyl group substituted by a trihalomethyl or halogen substituent.
- the phenyl ring substituted by R 3 , R 4 and R 5 is not a phenyl group substituted by a halogen, haloalkyl or haloalkoxy substituent. More preferably still, R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, thio, amino, cyano, nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-C 6 alkylthio, mono(d-C 6 alky ⁇ )amino and di(d-d alkyl)amino, provided that R 3 , R 4 and R 5 are not all hydrogen.
- R 1 is a 1,3- oxazol-2-yl, l,2-isoxazol-3-yl, l,2,4-oxadiazol-3-yl or l,3-imidazol-2-yl group it is unsubstituted or substituted by one or two unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, d- alkyl, -d alkoxy, -d haloalkyl, d-d haloalkoxy, d-d hydroxyalkyl and -(d-C 2 alkyl)-O-(d-C2 alkyl) substituents.
- R 1 is a l,3-oxazol-2-yl, 1,2- isoxazol-3-yl, l,2,4-oxadiazol-3-yl or l,3-imidazol-2-yl group it is unsubstituted or substituted by a single methyl, ethyl, t-butyl, trifluoromethyl, -CH 2 -OH or -CH 2 -O-CH 3 substituent.
- R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl or l,2,4-oxadiazol-3-yl group it is unsubstituted or substituted by one or two unsubstituted substituents which are the same or different and are selected from fluorine, chlorine, bromine, - alkyl, d- alkoxy, d-d haloalkyl or d-d haloalkoxy substituents.
- R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl, 1,2,4- oxadiazol-3-yl or l,3-imidazol-2-yl group it is unsubstituted or substituted by a single methyl, ethyl or t-butyl substituent.
- R 1 is a l,3-oxazol-2-yl, l,2-isoxazol-3-yl or l,2,4-oxadiazol-3-yl group it is preferably unsubstituted or substituted by a single methyl, ethyl or t-butyl substituent. Examples of preferred substituents are a single methyl or ethyl substituent.
- the compounds of formulae (N), (NI) and (VIA) do not include 2- piperidine carboxylic acid-l-[(4-fluorophenyl)sulphonyl]-phenyl methyl ester.
- a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
- Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
- Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
- the compounds of the invention can contain one or more chiral centre.
- the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non- racemic mixtures and pure enantiomers and/or diastereoisomers.
- Preferred compounds of the invention are optically active isomers.
- preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (III), (IN) or (INA), as defined above, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the said pharmaceutically acceptable carrier or diluent is not DMSO.
- Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
- Preferred pharmaceutical compositions are sterile and pyrogen free.
- the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
- the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula (III), (NI) or (VIA) or a tautomer thereof.
- the compounds of formulae (I) to (VIA) may be prepared by conventional routes, for example those set out in any of Schemes 1, 2 or A to F shown below.
- Compounds of formula (I) may be prepared by the reaction of a piperidine (I') and a phenyl sulphonyl chloride (I"), wherein R 1 to R 5 and n are as defined above.
- the coupling of the piperidine and the sulphonyl chloride may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, N-ethylmorpholine or diisopropylethylamine.
- a suitable solvent such as toluene or dichloromethane
- a base for example triethylamine, N-ethylmorpholine or diisopropylethylamine.
- Both piperidine T) and phenyl sulphonyl chloride (I") are either known compounds or can be prepared by the skilled person using known methods.
- R 1 and R 3 to R 6 are as defined above.
- ethyl-piperidine carboxylate or carboxylate hydrochloride
- a solvent such as dichloromethane
- a non-nucleopliilic organic amine base such as triethylamine, N-ethylmorpholine or diisopropylethylamine.
- Saponification of the ethyl ester may be accomplished using standard methods familiar to one skilled in the art, typically employing an aqueous metal hydroxide base such as LiOH or ⁇ aOH in the presence of water miscible solvents such as tetrahydrofuran and MeOH. After activating the resultant carboxylic acid it may be utilized for the synthesis of a variety of products by reaction with a nucleophile of type Y-M.
- Y-M (wherein Y is as defined above) may be an organometallic agent such as an organolithium compound (whereby M is Li) or a Grignard reagent (whereby M is MgHal).
- Reaction with an organometallic agent must be accomplished by first generating a suitable leaving group on the carboxylic acid.
- a typical method for achieving this would be to use a chlorinating reagent such as oxalyl chloride or thionyl chloride, in a solvent such as dichloromethane (with catalytic DMF added) to generate of the acid chloride species in situ.
- Reaction with the organometallic agent can then be carried out in suitable solvent such as tetrahydrofuran.
- Alternative methods for preparing ketones of formula (2) include conversion of acids of formula (3) either to the Weinreb amide or the 2-pyridine carbothiolate as described by Wu et al, (J. Med. Chem., 2002, 45(16), 3558-3568).
- Esters of formula (2) may be prepared from acids of formula (3) by standard methods such as refluxing with alcohols of formula YOH (wherein Y is as defined above) in the presence of catalytic concentrated HC1.
- Y-M is dimethylformamide di-tert-butyl acetal and the reaction typically carried out using toluene as solvent.
- an amide such as t-butyl amide, may be generated from the carboxylic acid intermediate, by reacting with primary or secondary amines (of generic formula RYN-H, wherein R and Y are as defined above).
- R is d-C 6 alkyl, d- alkenyl or d-C 6 alkynyl may be generated from intermediate acids of formula (3) by employing the reaction sequences outlined in Schemes B to D.
- Scheme B oxidation
- the acid may be coupled to primary amines of general formulae R 8 CH(OH)CH 2 NH2.
- the reaction is effected using standard amide coupling conditions, familiar to one skilled in the art, such as EDC.HCl/HOBt, HATU or HBTU.
- the resultant hydroxy-amide may then be oxidized to the keto-amide by employing l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one as described by Dess, D.B. and Martin, J.C., J. Org. Chem., 1983, 48(22), 4155-6, or dimethyl sulphoxide as described by Omura, K. et ah, J. Org.
- Intermediate acid (3) may be further utilized to synthesize heterocyclic compounds of general formulae (5).
- Hydrazine may be coupled to the acid using a standard amide coupling procedure, familiar to one skilled in the art. Typically iso- butylchloroformate was employed, in a suitable solvent such as tetrahydrofuran, using a non-nucleophilic base such as N-ethylmorpholine.
- the resulting hydrazide may then be coupled to an acid chloride, such as acetyl chloride. Heating with Lawesson's reagent in toluene may generate the thiohydrazide which spontaneously cyclises to the desired thiadiazole.
- the intermediate carboxylic acid (3) may be converted to the corresponding amide by employing standard methods familiar to one skilled in the art.
- a typical procedure uses ethyl chloroformate in a suitable solvent such as THF, in the presence of an organic base such as triethylamine followed by ammonium hydroxide.
- Reduction of the amide to a nitrile may typically be accomplished using diphosgene and trimethylphosphate as described by Echavarren, A. et al, Helv. Chim. Acta, 1988, 71, 685-97.
- Refluxing with hydroxylamine hydrochloride, in a protic solvent such as ethanol, in the presence of an inorganic base such as sodium carbonate yields the hydroxyamidine.
- Acylation of this intermediate may be accomplished using standard methods familiar to one skilled in the art, for example by reacting with an acid chloride, in the presence of an organic base such as triethylamine. Cyclisation of this intermediate to the oxadiazole may be typically accomplished by heating in pyridine.
- Scheme E employs a suitably protected piperidine carboxylic acid of general formula (6), whereby P is, for example, t- butyloxycarbonyl or benzyloxycarbonyl.
- P is, for example, t- butyloxycarbonyl or benzyloxycarbonyl.
- P is, for example, t- butyloxycarbonyl or benzyloxycarbonyl.
- the N- piperdine protected ketone, ester or amide may then be de-protected using standard conditions, familiar to one skilled in the art.
- the sulphonyl chloride may then be coupled to the free amine in an analogous manner to previously described in Scheme A.
- Scheme F several (6)
- Scheme F employs a suitably protected piperidine carboxylic acid of general formula (5), whereby P is, for example, t-butyloxycarbonyl or benzyloxycarbonyl.
- P is, for example, t-butyloxycarbonyl or benzyloxycarbonyl.
- This may be subjected to similar conditions as described for the generation of heterocycles in Schemes B to D, to yield the N-piperdine protected heterocycle. Deprotection may be accomplished using standard conditions, familiar to one skilled in the art.
- the sulphonyl chloride may then be coupled to the free amine in an analogous manner to previously described in Scheme A.
- heterocycles may be synthesized from acids of general formula (2) or (5), by employing methods, familiar to one skilled in the art as outlined, for example, in Joule, J.A. and Mills, K.A., Heterocyclic Chemistry (Fourth edition), 2000, Blackwell Science Ltd, Oxford, UK, ISBN 0-632-05453-0.
- the thus obtained compounds of formulae (I), (II) and (III) may be salif ⁇ ed by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techinques, for example elution on a chiral chromatography column.
- the compounds of the invention are found to be inhibitors of N-type calcium channels.
- the compounds of the invention exhibit selectivity over L-type calcium channels.
- the compounds of the invention are therefore therapeutically useful.
- the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
- Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
- the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
- the compounds may also be administered as suppositories.
- One preferred route of administration is inhalation.
- inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
- Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation.
- the present invention also provides an inhalation device containing such a pharmaceutical composition.
- said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
- said propellant is a fluorocarbon.
- Further preferred inhalation devices include nebulizers.
- Nebulizers are devices capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.
- Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.
- said inhalation device contains a spacer.
- a spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat.
- Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses.
- the pharmaceutical compositions of the invention are typically suitable for intranasal administration.
- the present invention also provides an intranasal device containing such a pharmaceutical composition.
- a further preferred route of administration is transdermal administration.
- the present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof.
- sublingual administration is also provides a sub- lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.
- a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
- solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
- Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
- the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
- Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
- Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
- the compounds of the present invention are therapeutically Useful in the treatment or prevention of conditions mediated by N-type calcium channels. Accordingly, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. These compounds are useful as calcium channel antagonists thereby inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder.
- N-type calcium channels are known to be closely involved in the mediation of pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. N-type calcium channels have been identified as being particularly important in the transmission of pain signals in the spinal cord (Chaplan S.R., Pogrel J,W., Yaksh T.L. J. Pharm. Exp. Ther., 1994, 269, 1117-1123; Diaz, A., Dickenson, A.H. Pain, 1997, 69, 93-100).
- the compounds of the invention are accordingly particularly effective in alleviating pain.
- said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain.
- the compounds of the invention are effective in alleviating both chronic and acute pain.
- Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease.
- Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system.
- Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.
- Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal.
- Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system.
- Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb" pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIN, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.
- neurogenic pain Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain.
- One non-limiting definition of neuro genie pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease.
- the compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain.
- blockers of N-type calcium channels inhibit the release of excitatory amino acids, they can be used ter alia to inhibit damage to neuronal cells during anoxia, and function as neuroprotective agents, useful in the treatment of cerebral ischaemia or central nervous system injuries (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).
- the compounds can also be utilised for the treatment of eye diseases (Chu, T-C; Potter, D.E. Research Communications in Pharmacology and Toxicology, 2001, 6, 263-275).
- cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrhage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.
- central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.
- eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.
- the compounds of the invention can be used in the treatment of seizure disorders.
- seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndrome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).
- partial epilepsy simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures
- generalised seizures including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndrome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).
- the compounds of the invention can be utilised in the treatment of tinnitus, itch such as pruritoceptive, neuropathic, neurogenic and psychogenic itch, as well as urinary tract disorders such as urinary incontinence, and irritable bowel syndrome.
- the compounds of the invention may also have application in disorders which are generally associated with blocking of L-type calcium channels, such as cardiovascular, antiasthmatic and antibronchoconstriction disorders for example in the prevention and treatment of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, premature labour, gastrointestinal motility disorders and cardiovascular disorders wherein the cardiovascular disorder is selected from the group consisting of hypertension, myocardial ischemia, angina, congestive heart failure, myocardial infarction and stroke.
- the compounds of the invention can be utilised in the treatment of hypersensitivity disorders such as urinary tract disorders.
- urinary tract disorders include in particular bladder dysfunctions such as overactive (or unstable) bladder (OAB) more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia; bladder hyper-reflexia; urinary tract inflammation specifically bladder inflammation e.g interstitial cystitis; and urinary tract infection.
- OAB overactive (or unstable) bladder
- the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.
- the compounds of the invention can also be utilised in the treatment of anxiety-related disorders and mood disorders, Bipolar disorder and post traumatic stress disorders.
- the compounds of the invention the invention can also be used in the treatment of lower urinary tract symptoms (LUTS).
- LUTS lower urinary tract symptoms
- LUTS comprises three groups of symptoms, which are irritative, which comprises urgency, frequency and nocturia and which can be associated with OAB and benign prostatic hyperplasia (BHP), obstructive and post micturition symptoms.
- the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.
- a therapeutically effective amount of a compound of the invention is administered to a patient.
- a typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
- daily dosage levels are from 5 mg to 2 g.
- the following Examples illustrate the invention. They do not, however, limit the invention in any way.
- Step 2 A mixture of (2S)-ethyl- 1 -(4-trifluoromethylbenzenesulphonyl)piperidine-2- carboxylate (0.638g, 1.75mmol) and lithium hydroxide monohydrate (0.011 g, 1.83mmol) in ethanol (8mL) and water (2mL) was stirred at room temperature for 3 Oh. The solvent was removed in vacuo and the residue dissolved in water. The aqueous layer was acidified and extracted with dichloromethane. The organic layer was washed with brine and dried over MgSO 4 .
- Step 1 starting from ethyl-2-piperidinecarboxylate hydrochloride (1.98g, 10.2rmnol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (4:1) gave Ethyl- l-(4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylate as a pale yellow oil
- Step 2 To a solution of ethyl- 1 -(4-trifluoromethylbenzenesulphonyl)piperidine-2- carboxylate (l.OOg, 2.7mmol) in tetrahydrofuran (20mL) and methanol (lOmL) was added 2M aqueous sodium hydroxide (2.75mL, 5.5mmol) and the reaction mixture stirred at room temperature for 15h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was washed with 10% aqueous hydrochloric acid followed by brine. The organic layer was dried over MgSO 4 .
- Step 3 Using an analogous method to that described for Example 1, Step 3 starting from 1 -(4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylic acid (0.135g, 0.4mmol) and triturating the residue with isohexane gave the title compound as a colourless solid (0.073g, 46%). HPLC (Method A) retention time 4.60min. Mass spectrum (ES+) m/z 338 (M-'Bu+H).
- Step 2 Using an analogous method to that described for Example 2, Step 2 starting from (2S)-ethyl-l-(2-chloro-4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylate gave (2S)- 1 -(2-Chloro-4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylic acid as a colourless oil (0.097g, 89%). HPLC (Method B) retention time 2.53min. Mass spectrum (ES-) m/z 370 (M-H).
- Step 1 starting from (2S)-ethyl-2-piperidinecarboxylate hydrochlori.de (0.50g, 2.58mmo ⁇ ) and 2-bromo-4- (trifluoromethyl)benzenesulphonyl chloride (0.84g, 2.58mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (19:1) gave (2S)- ethyl- l-(2-bromo-4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylate as a colourless oil (0.554g, 48%). HPLC (Method B) retention time 4.62min. Mass spectrum (ES+) m/z 444/446 (M+H).
- Step 2 Using an analogous method to that described for Example 2, Step 2 starting from (2S)-ethyl-l-(2-bromo-4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylate (0.50g, 1.13mmol) gave (2S)-l-(2-bromo-4-trifluoromethylbenzenesulphonyl) piperidine-2-carboxylic acid as a colourless solid (0.353g, 75%). HPLC (Method B) retention time 2.52min. Mass spectrum (ES-) m/z 414/416 (M-H).
- Step 3 starting from (2S)- 1 -(2-bromo-4-trifluoromethylbenzenesulphonyl)piperidine-2-carboxylic acid (0.104g, 0.25mmol) and purifying by flash column chromatography, eluting with isohexane/ethyl acetate (19:1) gave the title compound as a colourless oil (0.095g, 81%). HPLC (Method B) retention time, 4.86 min. Mass spectrum (ES+) m/z 416/418 (M-'Bu+H).
- Step ! Using an analogous method to that described for Example 2, Step 2 starting from (3i?)-ethyl-l-(2-bromo-4-trifluoromethylbenzenesulphonyl)piperidine-3-carboxylate gave (3i-)-l-(2-Bromo-4-trifluoromethylbenzenesulphonyl)piperidine-3-carboxylic acid as a pale yellow solid (0.985g, 82%). HPLC (Method B) retention time 2.51min. Mass spectrum (ES-) m/z AIAIAX6 (M-H).
- Step 3 l-(4-Trifluoromethylbenzenesulphonyl)piperidine-2-carboxylic acid (2- oxobutyl)amide (0.334g, 0.82mmol) was dissolved in phosphorus oxychloride (2.46mL, 26.5mmol) and heated to 110°C. The reaction was quenched by addition to an ice/saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane and the organic layer dried over MgSO 4 . The MgSO 4 was removed by filtration and the filtrate evaporated to dryness.
- Step 3 Using an analogous method to that described for example 9, step 3, starting from (2S)-benzyl-2-(2-oxobutylcarbamoyl)piperidine-l-carboxylate (2.607g, 8.25mmol), quenching with water and purifying by flash column chromatography, eluting with ethyl acetate/methanol (95:5) gave (2S)-Benzyl-2-(5-ethyloxazol-2-yl)piperidine-l- carboxylate (0.324g, 13%). HPLC (Method B) retention time 2.65min. Mass spectrum (ES+) m/z 167 (M+H), (ES-) m/z 165 (M-H).
- (2S)-Benzyl-2-(5-ethyloxazol-2-yl)piperidine-l-carboxylate (0.324g, 1.03mmol) was dissolved in ethanol (20mL) with 10% palladium on charcoal (0.050g), and subjected to hydrogenation (1 atm) over a period of 7h. The catalyst was removed by filtration and washed with water. The aqueous ethanol filtrate was evaporated to afford (2S)-2- (5-Ethyloxazol-2-yl)piperidine as a yellow solid in quantitative yield (0.190g). HPLC (Method B) retention time 3.03min. Mass spectrum (ES+) m/z 181 (M+H).
- step 4 starting from (2S)-2-(5-ethyloxazol-2-yl)piperidine (0.095g, 0.528mmol), stirring the reaction for 3h and purifying by flash column chromatography, eluting with dichloromethane gave the title compound as a yellow solid (0.075g, 34%). HPLC (Method B) retention time 4.63min. Mass spectrum (ES+) m/z 423 (M+H).
- step 4 starting from (2S)-2-(5-ethyloxazol-2-yl)piperidine (0.095g, 0.528mmol) and 4- trifluoromethylbenzenesulphonyl chloride (0.129g, 0.528mmol) and purifying by flash column chromatography, eluting with dichloromethane and then dichloromethane/methanol (95:5) gave the title compound as a pale yellow oil (0.086g, 42%). HPLC (Method A) retention time 4.43min. Mass spectrum (ES+) m/z 389 (M+H).
- reaction was stirred under nitrogen for 16h.
- the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate then 5% aqueous citric acid followed by brine.
- the organic layer was dried over MgSO 4 .
- step 3 starting from ethyl-l-(4-hydroxymethylbenzenesulphonyl)piperidine-2-carboxylate (0.038g, O.llmmol) gave the title compound as a colourless gum (0.025g, 69%).
- HPLC Method A retention time 3.95min.
- the human neuroblastoma cell line IMR32 has been used by a number of groups to investigate calcium ion channels either by electrophysiological or fluorescent techniques in low throughput assays (Carbone, E., et al. (1990) Pfl ⁇ gers Arch
- undifferentiated IMR32 cells constitutively express L-type calcium channels, whilst differentiated IMR32 cells express both N- and L-type channels. Therefore, undifferentiated IMR32 cells can be used to assay the L-type calcium channel and differentiated cells assayed in the presence of 5 ⁇ M nitrendipine can be used to study the N-type channels.
- the Molecular Devices Corp FLEXstationTM was utilised to develop a medium throughput assay with undifferentiated and differentiated IMR32 cells labelled with Fluo-4. Opening of voltage-activated calcium channels was stimulated by depolarisation of cells with KC1, which was added by the FLEXstation' s fluidics system. The resulting influx of calcium into the cells was recorded by an increase in fluorescence. The assays were validated with known ion channel blockers.
- IMR32 cells were grown in EMEM supplemented with 10% foetal bovine serum, 2 mM lutamine, 1% NEAA, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin. To differentiate the IMR32 cells, 1 mM dibutyryl cAMP and 2.5 ⁇ M bromodeoxyuridine were added to the cell culture media and cells maintained for 7-9 days.
- HBSS Free cell dissociation buffer
- the cells were then resuspended in assay buffer (HBSS containing Ca 2+ /Mg 2+ and supplemented with 20 mM HEPES, pH 7.4) to give a total volume of 40 ml. 2 ⁇ M Fluo-4 and 50 ⁇ M probenecid were added and then the cells were incubated at 25 °C for 30 min.
- the cell pellet was resuspended in 40 ml assay buffer supplemented with 50 ⁇ M probenecid and incubated at 25 °C for a further 30 min.
- the cells were centrifuged as before and again resuspended in assay buffer supplemented with probenecid.
- 200,000 cells were aliquoted into each well of a 96- well plate containing 0.001-100 ⁇ M compound to be tested (for the N-type assay 5 ⁇ M nitrendipine was also added to each well), in triplicate.
- the final volume of compound and cells in assay buffer was 200 ⁇ l.
- the plate containing cells was centrifuged at 300 rpm for 1 min with no brake in a Heraeus Labofuge 400E (rotor 8177).
- the plate was then assayed using the FLEXstation (Molecular Devices Corp).
- the excitation and emission wavelengths were 494 and 525 nm, respectively.
- the calcium response was stimulated by the addition of 50 ⁇ l 250 mM KC1 (50 inM final concentration) by the FLEXstation fluidics system.
- SOFTmax Pro (Molecular Devices Corp).
Abstract
L'invention concerne des composés de formule générale (I), leurs tautomères et leurs sels pharmaceutiquement acceptables, qui présente une action antagoniste de canaux calcium de type N. Lesdits composés s'utilisent dans le traitement ou la prévention d'un état induit par canaux calcium de type N, comme la douleur.
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GB0320294A GB0320294D0 (en) | 2003-08-29 | 2003-08-29 | Chemical compounds |
GB0330044A GB0330044D0 (en) | 2003-12-24 | 2003-12-24 | Chemical compounds |
PCT/GB2004/003705 WO2005068448A1 (fr) | 2003-08-29 | 2004-08-31 | Sulfonamides a action antagoniste sur des canaux calcium de type n |
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US20060035884A1 (en) * | 2004-05-20 | 2006-02-16 | Elan Pharmaceuticals, Inc. | N-cyclic sulfonamido inhibitors of gamma secretase |
GB0420424D0 (en) * | 2004-09-14 | 2004-10-20 | Ionix Pharmaceuticals Ltd | Therapeutic compounds |
GB0525068D0 (en) | 2005-12-08 | 2006-01-18 | Novartis Ag | Organic compounds |
WO2007125398A2 (fr) * | 2006-04-27 | 2007-11-08 | Pfizer Japan Inc. | Sulfonamides |
PL2066659T3 (pl) * | 2006-09-29 | 2014-01-31 | Gruenenthal Gmbh | Podstawione pochodne sulfonamidowe |
US8563732B2 (en) * | 2007-05-31 | 2013-10-22 | Shionogi & Co., Ltd. | Oxyimino compounds and the use thereof |
EP2676956A1 (fr) | 2008-08-01 | 2013-12-25 | Purdue Pharma L.P. | Composés de tétrahydro-pyridinyle et de dihydropyrrolyle et leur utilisation |
US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
WO2010091721A1 (fr) * | 2009-02-11 | 2010-08-19 | Glaxo Group Limited | Dérivés de 1-arylsulfonylpipéridine substitués en position 3 destinés au traitement de la douleur |
WO2010096371A2 (fr) * | 2009-02-18 | 2010-08-26 | Boehringer Ingelheim International Gmbh | Composés hétérocycliques qui modulent le récepteur cb2 |
NZ598269A (en) * | 2009-09-18 | 2014-12-24 | Zalicus Pharmaceuticals Ltd | Aryl sulphone derivatives as calcium channel blockers |
US9315454B2 (en) | 2010-01-15 | 2016-04-19 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
AR080056A1 (es) | 2010-02-01 | 2012-03-07 | Novartis Ag | Derivados de ciclohexil-amida como antagonistas de los receptores de crf |
US20120295942A1 (en) | 2010-02-01 | 2012-11-22 | Nicholas James Devereux | Pyrazolo[5,1b]oxazole Derivatives as CRF-1 Receptor Antagonists |
ES2527849T3 (es) | 2010-02-02 | 2015-01-30 | Novartis Ag | Derivados de ciclohexilamida como antagonistas del receptor de CRF |
WO2012012307A1 (fr) | 2010-07-22 | 2012-01-26 | Boehringer Ingelheim International Gmbh | Composés sulfonylés qui modulent le récepteur cb2 |
AR086554A1 (es) | 2011-05-27 | 2014-01-08 | Novartis Ag | Derivados de la piperidina 3-espirociclica como agonistas de receptores de la ghrelina |
AU2013255458A1 (en) | 2012-05-03 | 2014-10-09 | Novartis Ag | L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists |
EP2803668A1 (fr) | 2013-05-17 | 2014-11-19 | Boehringer Ingelheim International Gmbh | Nouveau (cyano-dimethyl-methyl)-isoxazoles et - [1,3,4] thiadiazoles |
WO2016107542A1 (fr) * | 2014-12-29 | 2016-07-07 | 成都先导药物开发有限公司 | Composé pyrrole amide, son procédé de préparation et son utilisation |
CN105801464B (zh) * | 2014-12-29 | 2019-05-28 | 成都先导药物开发有限公司 | 吡咯酰胺类化合物及其制备方法与用途 |
WO2016107541A1 (fr) * | 2014-12-29 | 2016-07-07 | 成都先导药物开发有限公司 | Composé de pyrrole-amide, son procédé de préparation et son utilisation |
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