US007964593B2
(12) United States Patent (10) Patent No.: US 7.964,593 B2 Starck et al. (45) Date of Patent: Jun. 21, 2011
(54) INDOLONE-ACETAMIDE DERIVATIVES, FOREIGN PATENT DOCUMENTS PROCESSES FOR PREPARING THEMAND EP O 022,317 A1 1, 1981 THEIR USES EP O 445 781 A1 9, 1991 EP O610553 A1 8, 1994 (75) Inventors: Jean-Philippe Starck, Gougenheim JP O1095766 4f1989 SU 841 264 A1 11F1995 (FR); Benoit Kenda, Emines (BE) WO 94.29272 A1 12, 1994 WO 98/O1428 A1 1, 1998 (73) Assignee: UCB Pharma, S.A., Brussels (BE) WO WOO1f87887 A 11, 2001 WO WO 2004/087658 A 10, 2004 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Parkinson's disease online retrieved on Nov. 4, 2010 from the internet. (
R6 N NR3R3a R7 R2 RI O 50 wherein R" is hydrogen, wherein 55 R" is hydrogen, R’ is hydrogen or C1-20-alkyl, R’ is hydrogen or C1-20-alkyl, R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy cloalkenyl, aryl, aromatic or non aromatic heterocycle, cloalkenyl, aryl, aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group of formula – W. R. C1-20-alkoxy, or a group of formula R is hydrogen, C1-20 R" is hydrogen, C1-20-alkyl or a group of formula: 60 alkyl or a group of formula:
65 US 7,964,593 B2 3 4 or NRR" is a group of formula able group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups. Preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex R10 R11 3-en-1-yl. The term “aryl', as used herein, is defined as including an /-y-R" /f organic radical derived from an aromatic hydrocarbon con -N Y or -X sisting of 1-3 rings and containing 6-30 carbon atoms by ln removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently R" is hydrogen, 10 selected from halogen, hydroxy, nitro, C1-6-alkyl, C1-6- R is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridiny Substituted by halogen; lalkyl. Aryl radicals are preferably phenyl radicals. Preferred or C1-20-alkoxy unsubstituted or substituted by halogen, aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, R is hydrogen, C1-20-alkyl or halogen, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hy 15 droxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4- R’ is hydrogen, C1-20-alkyl or halogen, dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfonylphe W is C1-12-alkylene, NH- or - NHC(=O) , nyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, X is O, S or NH, 2-(trifluoromethyl)thiophenyl, 2-chlorophenyl or 4-bro Y is O, S, CR'R' NR' or C(=O) , mophenyl. R is aryl or heterocycle, The term “halogen', as used herein, includes an atom of Cl, R. R', R'' and R'' are independently selected from hydro Br, F, I. gen, C1-4-alkyl, halogen, hydroxy or methoxycarbonyl, The term “nitro, as used herein, represents a group of the or R'' and R' together form a C3-6-alkylene, formula - NO. R" is hydrogen, C1-4-alkyl, halogen or hydroxy, The term "hydroxy’, as used herein, represents a group of R" is hydrogen, 25 the formula—OH. or CR'R' is dioxolanyl, The term “alkoxy’, as used herein, represents a group of R'' is aryl, heterocycle or a group of formula - V R', formula -OR wherein R is an alkyl group, as defined V is C1-12-alkylene, above. R" is aryl or heterocycle, The term “ester', as used herein, represents a group of m is 1 to 4. 30 formula —COOR wherein R is an alkyl group or an aryl n is 0 or 1, group, as defined above. and at least one of R, R or R is different from hydrogen The term “alkoxycarbonyl', as used herein, represents a when R is hydrogen, R is H or 2,6-diisopropylphenyl, and group of formula—COOR wherein R is an alkyl group, as R is H. defined above. The term “alkyl, as used herein, is defined as including 35 The term "amino', as used herein, represents a group of the saturated, monovalent hydrocarbon radicals having straight, formula - NH. branched or cyclic moieties or combinations thereof and con The term “alkylamino', as used herein, represents a group taining 1-20 carbon atoms, preferably 1-6 carbon atoms and of formula-NHR or - NR'R' wherein R and Rare alkyl more preferably 1-4 carbon atoms for non-cyclic alkyl and group as defined above. 3-8 carbon atoms for cycloalkyl. Alkyl moieties may option 40 The term alkylsulfonyl, as used herein is defined as repre ally be substituted by 1 to 5 substituents independently senting a group of formula—SO R, wherein R is C1-4- selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, alkyl. ester or alkylamino. Preferred alkyl groups are methyl, ethyl, The term "heterocycle', as used herein is defined as includ n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, ing an aromatic or non aromatic cycloalkyl or cycloalkenyl 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hy 45 moiety as defined above, having at least one O, S and/or N droxymethyl)propyl. 3,3,3-trifluoro-2-hydroxypropyl, atom interrupting the carbocyclic ring structure and option 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3-(dimethy ally, one of the carbon of the carbocyclic ring structure may be lamino)propyl. replaced by a carbonyl. The term “cycloalkyl, as used herein, refers to a monova Non-limiting examples of aromatic heterocycles are pyra lent group of 3 to 18 carbon atoms, preferably 4-8 carbon 50 Zolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrro atoms, derived from a saturated cyclic or polycyclic hydro lyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isoox carbon which may be substituted by any suitable group azolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, including but not limited to one or more moieties selected pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, triazolopy from groups as described above for the alkyl groups. Pre ridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopy ferred cycloalkyl group is cycloheptyl. 55 rimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, The term “alkylene', as used herein, represents a divalent quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, alkyl group, having straight or branched moieties, containing indolyl, indolizinyl, purinyl, carbazolyl, thieno (2,3-b)fura 1-12 carbon atoms, preferably 1-6 carbon atoms, and being nyl, thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, optionally Substituted with any Suitable group, including but quinoxalinyl, phenothiazinyl, isochromanyl and Xanthenyl, not limited to one or more moieties selected from groups as 60 optionally substituted by 1 to 5 substituents independently described above for the alkyl groups. Preferred alkylene selected from halogen, hydroxy, thiol, amino, nitro, cyano, groups are methylene, ethylene, hydroxyethylene, trimethyl azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-ha ene or propylene. loalkyl, formyl or ester. More preferred aromatic hetero The term “cycloalkenyl', as used herein, is defined as a cycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyland cyclic unsaturated hydrocarbon radical having at least one 65 pyridinyl. double bond, containing 4-20 carbon atoms, preferably 5-8 Non-limiting examples of non aromatic heterocycles are carbonatoms, and being optionally substituted with any Suit tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imida US 7,964,593 B2 5 6 Zolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thia romen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or Zolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisoch 4.5-dihydro-1H-imidazol-2-ylamino. More preferably, R is romenyl, tetrahydropyranyl, oxooctahydroquinolinyl, hydrogen. dioxolanyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo Generally, R is hydrogen, C1-4-alkyl or a group of for pyrrolidinyl, 8-thiabicyclo[3.2.1 cyclooctanyl, 1,4-dithiepa mula nyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl. optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-ha 1sy loalkyl, formyl or ester. More preferred non aromatic hetero 10 cycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazi nyl, imidazolidinyl, morpholinyl, thiomorpholinyl, wherein m is 1 to 4. pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazo Preferably, R is hydrogen, methyl or tetrahydrofuran-2- cin-1 (2H)-y1, 3,4-dihydro-1H-isochromen-1-yl, tetrahydro ylmethyl. More preferably, R is hydrogen. 15 In another embodiment, NR'R'' is piperidinyl unsubsti pyranyl, oxooctahydroquinolinyl and dioxolanyl. The term tuted or substituted by hydroxy; thiomorpholinyl; thiazolidi "heterocycle” also includes bicyclic, tricyclic and tetracyclic, nyl unsubstituted or substituted by C1-4-alkoxycarbonyl: spiro groups in which any of the above heterocyclic rings is 2,5-dihydro-1H-pyrrol-1-yl: 1,4-dioxa-8-azaspiro4.5 dec fused to one or two rings independently selected from an aryl 8-yl, 4-oxooctahydro-1 (2H)-quinolinyl; or a group of for ring, a cycloalkyl ring, a cycloalkenyl ring or another mono mula cyclic heterocyclic ring or where a monocycle heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-Oxabicyclo(2.2.1)heptanyl and 8-azabicyclo(3.2.1)octanyl. -N N-R1 The term "pyridinylalkyl, as used herein, represents a 25 group of formula - R - pyridinyl in which R" is C1-4- alkylene. wherein R'' is pyridinyl; phenyl unsubstituted or substi The term “azido” as used herein, represents a group of the tuted by halogen, hydroxy, C1-4-alkyl; or a group of formula formula—N3. The term “cyano” as used herein, represents a V R' wherein V is unsubstituted C1-4-alkylene and R' group of the formula—CN. 30 is phenyl or morpholinyl. Generally, R is hydrogen or C1-4-alkyl. In a preferred embodiment, NRR" is 4-pyridin-2-ylpip Preferably, R is hydrogen, methyl or ethyl. More prefer erazin-1-yl 4-(3-methylphenyl)piperazin-1-yl 4-(4-hydrox ably, R is hydrogen or methyl. yphenyl)piperazin-1-yl 4-(2-phenylethyl)piperazin-1-yl, Generally, R is hydrogen; C1-6-alkyl unsubstituted or 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperi substituted by 1 to 5 substituents selected from halogen, 35 din-1-yl, thiomorpholin-4-yl 4-methoxycarbonyl-1,3-thia hydroxy, alkoxy, alkoxycarbonyl or alkylamino: C5-7-cy Zolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-aza cloalkyl: (hydroxymethyl)cyclohexenyl; phenyl unsubsti spiro4.5 dec-8-yl or 4-oxooctahydro-1 (2H)-quinolinyl. tuted or substituted by 1 to 5 substituents selected from halo Generally, R is hydrogen, nitro, halogen, C1-4-alkyl, gen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl, unsubstituted or substituted by halogen, or C1-4-alkoxy unsubstituted or substituted by halogen. trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted 40 Preferably, R is hydrogen, methyl, ethyl, trifluoromethyl, or Substituted by methoxy; triazolyl; C1-4-alkoxy; or a group trifluoromethoxy, n-propyl, isopropyl. nitro, or halogen. of formula - W R wherein: More preferably, R is halogen or trifluoromethyl. Generally, Wis C1-4-alkylene unsubstituted or substituted Generally, R is hydrogen, C1-6-alkyl or halogen. by halogen, hydroxy, C1-4-alkyl or alkoxy; —NH-; or Preferably, R is hydrogen, methyl or C1. More preferably, —NHC(=O) ; and 45 R is hydrogen. Risphenyl unsubstituted or substituted by 1 to 5 substituents Generally, R is hydrogen, methyl or halogen. selected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro, Preferably, R is hydrogen, methyl, Br, F or C1. More methylsulfonyl or trifluoromethylthio; furyl unsubstituted or preferably, R is hydrogen, Br or F. substituted by methyl; pyrazolyl pyridinyl; morpholinyl; tet Combinations of one or more of these preferred compound rahydrobenzazocinyl; piperidinyl unsubstituted or substi 50 tuted by methyl; dihydroisochromenyl or dihydroimidazolyl. groups are especially preferred. Preferably, R is hydrogen, n-butyl, cycloheptyl, 2-fluoro In a preferred embodiment, the invention provides a com ethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl. pound having the formula I or a pharmaceutically acceptable 1-(hydroxymethylpropyl. 3,3,3-trifluoro-2-hydroxypropyl, salt thereof or stereoisomeric forms thereof, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino) 55 propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydrox (I) yphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4- R4 dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3- methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, R 2-chloro-6-fluorobenzyl, 2-(trifluoromethyl)thiobenzyl, 60 2-hydroxy-2-phenylethyl 2-(3,4-dimethoxyphenyl)ethyl, O 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bro 6 N mophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl, R NR3 R3a 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-fu R R5 RI ryl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-yl 65 O ethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl)propyl. 2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isoch
US 7,964,593 B2 11 12 cated in the above formula, such forms are intended to be This reaction may be carried out with a strong base, for included within the scope of the present invention. example Sodium hydride, at a temperature comprised The compounds of formula I according to the invention can between 0 and 40° C. and in an inert solvent, for example be prepared analogously to conventional methods as under DMF under an inert atmosphere, or as described in patent GB 1,309,692 (UCB). stood by the person skilled in the art of synthetic organic Compounds of formula III may be prepared by reaction of chemistry. a compound of formula V with 1.2-ethanedithiol according to A. According to one embodiment, some compounds hav the equation: ing the general formula I may be prepared by desulfurization of a compound of formula II according to the equation: 10 R4 O R SH R S O + Her SH 15 6 N O R H R6 N R7 NR3R3a -- (V) R R5 R4 R1 S O R S (II) R4 O R R6 NH 25 O R7 6 N (III) R NR3R3a R R5 30 wherein R. RandR have the same definitions as described R1 above. O This reaction may be carried out at a temperature com prised between 25 and 100°C. in an inert solvent or in acetic acid, in the presence of a Lewis acid, preferably BF.Et2O under an inert atmosphere. This reaction may be carried out using Raney nickel in an 35 Compounds of formula V are commercially available or inert solvent, preferably THF, at a temperature comprised may be prepared according to methods described in: Smith between 0° C. and 40° C., or as described in: Mehta L., K., El-Hiti G. A., Hawes A. C., Synlett (1999), 945-947: Parrick J., Payne F., J. Chem. Research (S) (1998), 190-191. Lackey K., Sternbach D. D., Synthesis (1993), 10,993; or Compounds of formula II may be prepared by alkylation of Organic Synthesis, Collective Volume I, Second Edition, Gil a compound of formula III with a compound of formula IV 40 man H. & Blatt A. H., J. Wiley & Sons Inc., 327-330. according to the equation: B. According to another embodiment, some compounds having the general formula I may be prepared by oxidative bromination of the corresponding indole of formula (VI) followed by the reduction of compound (VII) according to the R4 equation: S 45 R S Hal O + R2 -- R4 NR3R3a R6 N R1 50 N R7 O -- (III) (IV) N R4 S R S 55 O (VI) R4 6 N Br Br R NR3R3a R R7 R2 R1 60 O O 6 N (II) R R2 R R2- R3a wherein Halisahalogenatom, preferably Bror C1, and R', 65 O R. R. R. R. R. and R7 have the same definitions as (VII) described above. US 7,964,593 B2 13 14 -continued R4 R4 R R O 5 o NHRR3a N R6 NR3R3a R6 N O
O 10 R bit (I) (IX) R4 This reaction may be carried out as described in: Marfat A. R Carta M. P., Tetrahedron Lett. (1987), 28, 4027-4031. 15 Compounds of formula VI may be prepared by alkylation O of a compound of formula VIII with a compound of formula R6 N IV according to the equation: O R. R. R2 R4 2O NNR3a R3 R N Hall (I) -- R2 --- R6 N R1 NR3R3a 25 In one embodiment, O 1ment, theth present invention concerns a lsoSOthe th H synthesis intermediates of formula II or stereoisomeric forms R7 O thereof, (VIII) (IV) R4 30 (II) R R4 S N R S
6 N R NR3R3a 35 O R 7 R 2 R 6 N O O R7 R 2 (VI) R NNR3a 40 R3 wherein Hal is an halogen atom, preferably Br or Cl. wherein This reaction may be carried out in the presence of a strong base, preferably sodium hydride, at a temperature comprised RR" is hydrogen or C1-20-alkyl between 0 and 40°C., in an inert solvent, for example DMF, R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy under an inert atmosphere, or as described in patent GB 45 cloalkenyl, aryl, aromatic or non aromatic heterocycle, 1,309,692 (UCB). C1-20-alkoxy, or a group of formula W R, C. According to another embodiment, some compounds R" is hydrogen, C1-20-alkyl or a group of formula: having the general formula I may be prepared by halogena tion of the corresponding compound of formula I wherein R is a hydrogen with a N-halosuccinimide according to the 50 X procedure described in: Castanet A.-S., Colobert F., Broutin Y P.-E., Tetrahedron Lett. (2002), 43, 5047-5048. -R9, According to another embodiment, some compounds hav ing the general formula I may be prepared analogously from 33 the corresponding compound of formula I wherein ss or NRR" is a group of formula R=R’—H by using two equivalents of N-halosuccinimide. R10 D. According to another embodiment, Some compounds 0. R11 having the general formula I may be prepared by nitration of / y Rive or /f s the corresponding compound of formula I wherein R is a -N Y o O hydrogen according to procedure described in: Sun L. Rubin 60 \-M, J. R. Kraker A. J., Showalter H. D., J. Heterocyclic Chem. (1997), 34, 1399-1405. R" is hydrogen, E. According to another embodiment, some compounds R is hydrogen; nitro; halogen; azido; cyano; -S-C1-4- having the general formula I may be prepared by coupling of alkyl; SO C1-4-alkyl: an amine of formula NHR'R'" with a carboxylic acid deriva- 65 - SO C1-4-alkyl, -SONH; C1-20-alkyl unsubstituted tive of formula IX in the presence of a coupling agent such as or substituted by halogen; or dicyclohexylcarbodiimide in dichloromethane or THF. C1-20-alkoxy unsubstituted or substituted by halogen, US 7,964,593 B2 15 16 R is hydrogen, C1-20-alkyl or halogen, W is C1-12-alkylene, NH- or - NHC(=O) , R’ is hydrogen, C1-20-alkyl or halogen, X is O, S or NH, W is C1-12-alkylene, NH- or - NHC(=O) , X is O, S or NH, Y is O, S, CR'R' , NR' or C(=O) , Y is O, S, CR'R' NR' or C(=O) , R is aryl or heterocycle, R is aryl or heterocycle, R. R', R'' and R'' are independently selected from hydro R. R', R'' and R'' are independently selected from hydro gen, C1-4-alkyl, halogen, hydroxy or methoxycarbonyl, gen, C1-4-alkyl, halogen, hydroxy or methoxycarbonyl, or R'' and R' together form a C3-6-alkylene, or R'' and R' together form a C3-6-alkylene, R" is hydrogen, C1-4-alkyl, halogen or hydroxy, 10 R' is hydrogen, C1-4-alkyl, halogen or hydroxy, R" is hydrogen, R" is hydrogen, or CR'R' is dioxolanyl, or CR'R' is dioxolanyl, R'' is aryl, heterocycle or a group of formula - V R', V is C1-12-alkylene, R'' is aryl, heterocycle or a group of formula - V R', R" is aryl or heterocycle, 15 V is C1-12-alkylene, m is 1 to 4. R" is aryl or heterocycle, n is 0 or 1, and at least one of R, R or R is different from hydrogen m is 1 to 4. when R is hydrogen, R is H or 2,6-diisopropylphenyl, and n is 0 or 1, R is H. and at least one of R, R or R7 is different from hydrogen In another embodiment, the present invention concerns when R is hydrogen, R is H or 2,6-diisopropylphenyl, and also the synthesis intermediates of formula II or stereoiso R is H. meric forms thereof, Preferably, the synthesis intermediates of formula II are 25 selected from the group consisting of: 2-(5'-methyl-2'-OX (II) ospiro 1,3-dithiolane-2,3'-indol-1'(2H)-yl)acetamide: 2-2'-oxo-5'-(trifluoromethyl)oxyspiro 1,3-dithiolane-2,3'- R S indol-1'(2H)-yl)acetamide: 2-5'-(1-methylethyl)-2-ox 30 ospiro 1,3-dithiolane-2,3'-indol-1'(2H)-yl)acetamide: O 2-(5'-ethyl-2'-oxospiro 1,3-dithiolane-2,3'-indol-1'(2H)-yl) R6 N acetamide: 2-(5'-fluoro-2'-oxospiro 1,3-dithiolane-2,3'-in O dol-1'(2H)-yl)acetamide: 2-(5',7-dimethyl-2'-oxospiro1, R7 R1 R2 35 3-dithiolane-2,3'-indol-1'(2H)-yl)acetamide: 2-(2-oxo-5'- NN R3a propylspiro 1,3-dithiolane-2,3'-indol-1'(2H)-yl)acetamide: R3 (trifluoromethyl)spiro 1,3-dithiolane-2,3'-indol-1'(2H)-yl) acetamide; and 2-(5',6'-dimethyl-2'-oxospiro 1,3-dithiolane wherein 2.3'-indol-1'(2H)-yl)acetamide. R" is hydrogen, 40 R’ is hydrogen or C1-20-alkyl, In one embodiment, the invention concerns also the Syn R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy thesis intermediates of formula III or stereoisomeric forms cloalkenyl, aryl, aromatic or non aromatic heterocycle, thereof, C1-20-alkoxy, or a group of formula – W. R. 45 R" is hydrogen, C1-20-alkyl or a group of formula: (III)
50 or NRR" is a group of formula
55 R10 R11 wherein R" is hydrogen, /x" O o C R is hydrogen; nitro; azido; cyano, -S-C1-4-alkyl: \ / —SO—C1-4-alkyl; 60 —SO C1-4-alkyl; —SONH; C1-20-alkyl unsubstituted R" is hydrogen, or substituted by halogen; or R is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or C1-20-alkoxy unsubstituted or substituted by halogen, Substituted by halogen; R is hydrogen, C1-20-alkyl or halogen, or C1-20-alkoxy unsubstituted or substituted by halogen, 65 R is hydrogen, C1-20-alkyl or halogen, R’ is hydrogen, C1-20-alkyl or halogen, R’ is hydrogen, C1-20-alkyl or halogen, and at least one of R, R or R is different from hydrogen. US 7,964,593 B2 17 18 In another embodiment, the invention concerns also the or NRR" is a group of formula: synthesis intermediates of formula III or stereoisomeric forms thereof, R10 R11 (III) -/ .." - C \-4.
10 R" is hydrogen, R is hydrogen; halogen; azido; cyano; -S-C1-4-alkyl: —SO—C1-4-alkyl; —SO C1-4-alkyl; —SONH; or C1-20-alkyl unsubsti 15 tuted or substituted by halogen, wherein R is hydrogen, C1-20-alkyl or halogen, R" is hydrogen, R’ is hydrogen, C2-20-alkyl or halogen, R is hydrogen; nitro; C1-20-alkyl unsubstituted or substi W is C1-12-alkylene, NH- or - NHC(=O) , tuted by halogen; or C1-20-alkoxy unsubstituted or substi X is O, S or NH, tuted by halogen, Y is O, S, CR'R' , NR' or C(=O) , R is hydrogen, C1-20-alkyl or halogen, R is aryl or heterocycle, R’ is hydrogen, C1-20-alkyl or halogen, R. R', R'' and R'' are independently selected from hydro and at least one of R, R or R is different from hydrogen. gen, C1-4-alkyl, halogen, hydroxy or methoxycarbonyl, Preferably, the synthesis intermediates of formula III are or R'' and R' together form a C3-6-alkylene, selected from the group consisting of 5'-methylspiro1.3- 25 R" is hydrogen, C1-4-alkyl, halogen or hydroxy, dithiolane-2,3'-indol-2(1H)-one; 5'-(trifluoromethyl)oxy R" is hydrogen, spiro 1,3-dithiolane-2,3'-indol-2(1H)-one; 5'41-methyl or CR'R' is dioxolanyl, ethyl)spiro 1,3-dithiolane-2,3'-indol-2(1H)-one: R'' is aryl, heterocycle or a group of formula - V R', 5'-ethylspiro 1,3-dithiolane-2,3'-indol-2(1H)-one; 5'-fluo V is C1-12-alkylene, rospiro 1,3-dithiolane-2,3'-indol-2(1H)-one; 5,7-dimeth 30 R" is aryl or heterocycle, ylspiro1,3-dithiolane-2,3'-indol-2(1H)-one; 5'-propyl m is 1 to 4. spiro 1,3-dithiolane-2,3'-indol-2(1H)-one: 5'- n is 0 or 1, (trifluoromethyl)spiro 1,3-dithiolane-2,3'-indol-2(1H)- and at least one of R, R or R is different from hydrogen one; and 5',6'-dimethylspiro 1,3-dithiolane-2,3'-indol-2 35 when R is hydrogen, R is H or 2,6-diisopropylphenyl, and (1H)-one. R is H. In one embodiment, the present invention concerns also the In another embodiment, the present invention concerns the synthesis intermediates of formula VI or stereoisomeric synthesis intermediates of formula VI or stereoisomeric forms thereof, forms thereof, 40
4 (VI) R R 45
R6 N O R7 50 RI R2 N R^ rs R 3 wherein wherein R" is hydrogen, 55 R" is hydrogen, R’ is hydrogen or C1-20-allyl, R’ is hydrogen or C1-20-alkyl, R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cy cloalkenyl, aryl, aromatic or non aromatic heterocycle, cloalkenyl, aryl, aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group of formula – W. R. C1-20-alkoxy, or a group of formula – W. R. R" is hydrogen, C1-20-alkyl or a group of formula: 60 R" is hydrogen, C1-20-alkyl or a group of formula:
65 US 7,964,593 B2 19 20 or NRR" is a group of formula: R is hydrogen, C1-20-alkyl or halogen, R’ is hydrogen, C1-20-alkyl or halogen, and at least one of R, R or R is different from hydrogen R10 R11 When R’ is hydrogen, R is H or 2,6-diisopropylphenyl, and R. S. H. In another embodiment, the present invention concerns the /x" O C synthesis intermediates of formula IX or stereoisomeric \-4. forms thereof,
10 R" is hydrogen, (IX) R is hydrogen; halogen; or C1-20-alkyl unsubstituted or R4 Substituted by halogen, R is hydrogen, C1-20-alkyl or halogen, R O R’ is hydrogen, C2-20-alkyl or halogen, 15 W is C1-12-alkylene, NH- or - NHC(=O) , R6 N X is O, S or NH, O Y is O, S, CR'R' NR' or C(=O) , R is aryl or heterocycle, k RI - R. R', R'' and R'' are independently selected from hydro R bit gen, C1-4-alkyl, halogen, hydroxy or methoxycarbonyl, wherein or R'' and R' together form a C3-6-alkylene, R" is hydrogen, R'' is hydrogen, C1-4-alkyl, halogen or hydroxy, R’ is hydrogen or C1-20-alkyl, R" is hydrogen, R" is hydrogen, or CR'R' is dioxolanyl, 25 R is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or R" is aryl, heterocycle or a group of formula - V R', Substituted by halogen; V is C1-12-alkylene, or C1-20-alkoxy unsubstituted or substituted by halogen, R" is aryl or heterocycle, R is hydrogen, C1-20-alkyl or halogen, m is 1 to 4. R’ is hydrogen, C1-20-alkyl or halogen, n is 0 or 1, 30 and at least one of R, R or R is different from hydrogen and at least one of R, R or R is different from hydrogen When R’ is hydrogen, R is H or 2,6-diisopropylphenyl, and when R is hydrogen, R is H or 2,6-diisopropylphenyl, and R’ is H. R is H. Preferably, the synthesis intermediate of formula IX is Preferably, the synthesis intermediates of formula VI are (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid. selected from the group consisting of: 2-(5-chloro-1H-indol 35 The present invention also concerns the synthesis interme 1-yl)propanamide: 2-(7-chloro-1H-indol-1-yl)acetamide: diates 2-(7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)aceta 2-(6-chloro-1H-indol-1-yl)acetamide, 2-(5-chloro-1H-in mide and ethyl (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) dol-1-yl)butanamide: 2-(5-methyl-1H-indol-1-yl)propana acetate. mide: 2-(5-bromo-1H-indol-1-yl)propanamide: 2-(7-fluoro It has now been found that compounds of formula I and 1H-indol-1-yl)acetamide: 2-(5-bromo-1H-indol-1-yl) 40 their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications. acetamide: 2-(5-fluoro-1H-indol-1-yl)acetamide; and 2-(5- For example, the compounds according to the invention are chloro-1H-indol-1-yl)acetamide. useful for the treatment of epilepsy, epileptogenesis, seizure In one embodiment, the present invention concerns also the disorders and convulsions. synthesis intermediates of formula IX or stereoisomeric These compounds may also be used for the treatment of forms thereof, 45 Parkinson's disease. These compounds may also be used for the treatment of dyskinesia induced by dopamine replacement therapy, tar (IX) dive dyskinesia induced by administration of neuroleptic R4 drugs or Huntington Chorea. R 50 In addition, the compounds according to the invention may also be used for treating other neurological disorders includ O ing bipolar disorders, mania, depression, anxiety, attention R6 N deficit hyperactivity disorder (ADHD), migraine, trigeminal O and other neuralgia, chronic pain, neuropathic pain, cerebral R7 55 ischemia, cardiac arrhythmia, myotonia, cocaine abuse, R stroke, myoclonus, tremor, essential tremor, simple or com R. H. plex tics, Tourette syndrome, restless leg syndrome and other movement disorders, neonatal cerebral haemorrhage, amyo wherein trophic lateral sclerosis, spasticity and degenerative diseases, R" is hydrogen, 60 bronchial asthma, asthmatic status and allergic bronchitis, R’ is hydrogen or C1-20-alkyl, asthmatic syndrome, bronchial hyperreactivity and broncho R" is hydrogen, spastic syndromes as well as allergic and vasomotor rhinitis R is hydrogen; nitro; halogen; azido: cyano; -S-C1-4- and rhinoconjunctivitis. alkyl; —SO C1-4-alkyl: Thus, the present invention also concerns a compound —SO C1-4-alkyl; —SONH; C1-20-alkyl unsubstituted 65 having the formula I or a pharmaceutically acceptable salt or substituted by halogen; or C1-20-alkoxy unsubstituted or thereof or stereoisomeric forms thereofas defined above for Substituted by halogen, use as a medicament. US 7,964,593 B2 21 22 In a further aspect, the present invention concerns also the movements. One way in which dyskinesias may arise is as a use of a compound of formula I or a pharmaceutically accept side effect of dopamine replacement therapy for parkin able salt thereof for the manufacture of a medicament for the Sonism or other basal ganglia-related movement disorders. treatment of neurological and other disorders such as men The term “migraine' as used herein means a disorder char tioned above. acterised by recurrent attacks of headache that vary widely in In particular, the present invention concerns the use of a intensity, frequency, and duration. The attacks are commonly compound of formula I or a pharmaceutically acceptable salt unilateral and are usually associated with anorexia, nausea, thereof for the manufacture of a medicament for the treatment Vomiting, phonophobia, and/or photophobia. In some cases of epilepsy, Parkinson's disease, dyskinesia, migraine, bipo they are preceded by, or associated with, neurological and lar disorders, chronic pain, neuropathic pain, or bronchial, 10 mood disturbances. Migraine headache may last from 4 hours asthmatic or allergic conditions. to about 72 hours. The International Headache Society (IHS, The methods of the invention comprise administration to a 1988) classifies migraine with aura (classical migraine) and mammal (preferably human) Suffering from above men migraine without aura (common migraine) as the major types tioned conditions or disorders, of a compound according to of migraine. Migraine with aura consists of a headache phase the invention in an amount Sufficient to alleviate or prevent 15 preceded by characteristic visual, sensory, speech, or motor the disorder or condition. symptoms. In the absence of Such symptoms, the headache is The compound is conveniently administered in any Suit called migraine without aura. able unit dosage form, including but not limited to one con The term “bipolar disorders' as used herein refers to those taining 3 to 3000 mg, preferably 25 to 500 mg of active disorders classified as Mood Disorders according to the Diag ingredient per unit dosage form. nostic and Statistical Manual of Mental Disorders, 4th edition The term “treatment as used herein includes curative (Diagnostic and Statistical Manual of Mental Disorders treatment and prophylactic treatment. (DSM-IV TM), American Psychiatry Association, Washing By "curative' is meant efficacy in treating a current symp ton, D.C., 1994). Bipolar disorders are generally character tomatic episode of a disorder or condition. ised by spontaneously triggered repeated (i.e. at least two) By “prophylactic' is meant prevention of the occurrence or 25 episodes in which the patient’s hyperexcitability, activity and recurrence of a disorder or condition. mood are significantly disturbed, this disturbance consisting The term “epilepsy” as used herein refers to a chronic on some occasions of an elevation of mood and increased neurologic condition characterised by unprovoked, recurrent energy and activity (mania or hypomania), and in other occa epileptic seizures. An epileptic seizure is the manisfestation sions a lowering of mood and decreased energy and activity of an abnormal and excessive synchronised discharge of a set 30 (depression). Bipolar disorders are separated into four main of cerebral neurons; its clinical manifestations are Sudden and categories in the DSM-IV (bipolar I disorder, bipolar II dis transient. The term "epilepsy” as used herein can also refer to order, cyclothymia, and bipolar disorders not otherwise a disorder of brain function characterised by the periodic specified). occurrence of seizures. Seizures can be “nonepileptic' when The term “manic episode', as used herein refers to a dis evoked in a normal brain by conditions such as high fever or 35 tinct period during which there is an abnormally and persis exposure to toxins or “epileptic' when evoked without evi tently elevated, expansive, or irritable mood with signs of dent provocation. pressured speech and psychomotor agitation. The term “seizure' as used herein refers to a transient The term “hypomania’, as used herein refers to a less alteration of behaviour due to the disordered, synchronous, extreme manic episode, with lower grade of severity. and rhythmic firing of populations of brain neurones. 40 The term “major depressive episode', as used herein refers The term “Parkinsonian symptoms’ relates to a syndrome to a period of at least 2 weeks during which there is either characterized by slowness of movement (bradykinesia), depressed mood or the loss of interest or pleasure in nearly all rigidity and/or tremor. Parkinsonian symptoms are seen in a activities with signs of impaired concentration and psycho variety of conditions, most commonly in idiopathic Parkin motor retardation. sonism (i.e. Parkinson's Disease) but also following treat 45 The term “mixed episode', as used herein refers to a period ment of schizophrenia, exposure to toxins/drugs and head of time (lasting at least 1 week) in which the criteria are met injury. It is widely appreciated that the primary pathology both for a manic episode and for a major depressive episode underlying Parkinson's disease is degeneration, in the brain, nearly every day. of the dopaminergic projection from the Substantia nigra to The term "chronic pain” as used herein refers to the con the striatum. This has led to the widespread use of dopamine 50 dition gradually being recognised as a disease process distinct replacing agents (e.g. L-3,4-dihydroxyphenylalanine from acute pain. Conventionally defined as pain that persists (L-DOPA) and dopamine agonists) as symptomatic treat beyond the normal time of healing, pain can also be consid ments for Parkinson's disease and such treatments have been ered chronic at the point when the individual realises that the Successful in increasing the quality of life of patients suffer pain is going to be a persistent part of their lives for the ing from Parkinson's disease. However, dopamine-replace 55 foreseeable future. It is likely that a majority of chronic pain ment treatments do have limitations, especially following syndromes involves a neuropathic component, which is usu long-term treatment. Problems can include a wearing-off of ally harder to treat than acute Somatic pain. the anti-parkinsonian efficacy of the treatment and the The term “neuropathic pain” as used herein refers to pain appearance of a range of side-effects which manifest as due to a dysfunctional nervous system, sometimes occurring abnormal involuntary movements. Such as dyskinesias. 60 following injury to the central nervous system (central pain), The term 'dyskinesia” is defined as the development in a but more often caused by damage to peripheral nerves (pain Subject of abnormal involuntary movements. This appears in ful peripheral neuropathy). Neuropathic pain is most likely patients with Huntington's disease, in Parkinson's disease caused by neural hyperexcitation in partially damaged patients exposed to chronic dopamine replacement therapy, nerves. Several types of painful peripheral neuropathy, which and in Schizophrenia patients exposed to chronic treatment 65 may share some underlying pathogenic mechanisms, have with neuroleptics. Dyskinesias, as a whole, are characterised been distinguished, such as: (1) postraumatic painful periph by the development in a subject of abnormal involuntary eral neuropathy; (2) phantom limb pain; (3) facial (trigemi US 7,964,593 B2 23 24 nal) pains; (4) postherpetic neuralgia; (5) painful diabetic Activity in any of the above-mentioned indications can of neuropathy; (6) neuropathies due to cancer tumors; (7) neu course be determined by carrying out Suitable clinical trials in ropathies induced by treatment with anti-neoplastic agents; a manner known to a person skilled in the relevant art for the and (8) nerve damage associated with demyelinating disease, particular indication and/or in the design of clinical trials in Such as multiple Sclerosis. In neuropathic pain, painful reac general. tions appear in response to normally neutral stimuli (allo For treating diseases, compounds of formula I or their dynia) or as exaggerated reactions to painful stimuli (hyper pharmaceutically acceptable salts may be employed at an algesia). Spontaneous pain, not provoked by external stimuli, effective daily dosage and administered in the form of a also occurs in neuropathic pain, and is the most difficult form pharmaceutical composition. of pain to measure and treat. 10 Therefore, another embodiment of the present invention The term “tics' refers to common and often disabling neu concerns a pharmaceutical composition comprising an effec rological disorders. They are frequently associated with tive amount of a compound of formula I or a pharmaceutically behaviour difficulties, including obsessive-compulsive disor acceptable salt thereof in combination with a pharmaceuti der, attention deficit hyperactivity disorder and impulse con cally acceptable diluent or carrier. trol. Tics are involuntary, Sudden, rapid, repetitive, nonrhyth 15 To prepare a pharmaceutical composition according to the mic stereotype movements or Vocalizations. Tics are invention, one or more of the compounds of formula I or a manifested in a variety of forms, with different durations and pharmaceutically acceptable salt thereof is intimately degrees of complexity. Simple motor tics are brief rapid admixed with a pharmaceutical diluent or carrier according to movements that often involve only one muscle group. Com conventional pharmaceutical compounding techniques plex motor tics are abrupt movements that involve either a known to the skilled practitioner. cluster of simple movements or a more coordinated sequence Suitable diluents and carriers may take a wide variety of of movements. Simple Vocal tics include sounds such as forms depending on the desired route of administration, e.g., grunting, barking, yelping, and throat clearing. Complex oral, rectal, parenteral or intranasal. Vocal tics include syllables, phrases, repeating other people's 25 Pharmaceutical compositions comprising compounds words and repeating one’s own words. according to the invention can, for example, be administered The term “tremor” refers to an involuntary, rhythmical, orally or parenterally, i.e., intravenously, intramuscularly or oscillatory movement of a body part. Tremor can be phenom Subcutaneously, intrathecally, by inhalation or intranasally. enologically defined as tremor at rest or associated with an Pharmaceutical compositions suitable for oral administra action. Such an action can be postural (maintenance of a limb 30 tion can be solids or liquids and can, for example, be in the position), kinetic (movement-related), or intentional (at the form of tablets, pills, dragees, gelatin capsules, Solutions, end of a purposeful movement). Etiologically, tremor most Syrups, chewing-gums and the like. often occurs in Parkinson's disease (Parkinsonian rest To this end the active ingredient may be mixed with an inert tremor) and in essential tremor (postural and kinetic tremor), diluent or a non-toxic pharmaceutically acceptable carrier which consists of hereditary and age-related forms. Tremor 35 Such as starch or lactose. Optionally, these pharmaceutical may also occur in dystonia and in multiple Sclerosis. Other compositions can also contain a binder Such as microcrystal tremors, which can arise from various etiologies, are cerebel line cellulose, gum tragacanth or gelatine, a disintegrant Such lar (intentional tremor) and Holmes' midbrain tremor (pos as alginic acid, a lubricant such as magnesium Stearate, a tural tremor). Tremor can also be an exaggerated form of glidant such as colloidal silicon dioxide, a Sweetener Such as normal physiological tremor. Apart from the behavioral con 40 Sucrose or saccharin, or colouring agents or a flavouring agent text in which tremor occurs, tremor frequency is an important Such as peppermint or methyl salicylate. criterion to distinguish between various forms of tremor. The invention also contemplates compositions which can Essential tremor has the highest incidence of all tremors. As it release the active Substance in a controlled manner. Pharma is age-related, it can be expected to increase in aging popu ceutical compositions which can be used for parenteral lations. Animal model and clinical data indicate that essential 45 administration are in conventional form such as aqueous or tremor may be primarily based on a brainstem (inferior oli oily solutions or Suspensions generally contained in vary nucleus)-cerebellar dysfunction, whereas Parkinsonian ampoules, disposable Syringes, glass or plastics vials or infu tremor probably originates from abnormal activity within the sion containers. basal ganglia. Excessive synchronization and/or hyperexci In addition to the active ingredient, these solutions or Sus tation in neuronal circuits may underlie tremor activity. 50 pensions can optionally also contain a sterile diluent such as The activity of the compounds of formula I, or their phar water for injection, a physiological saline solution, oils, poly maceutically acceptable salts, as anticonvulsants can be ethylene glycols, glycerine, propylene glycol or other syn determined in the audiogenic seizures model. The objective thetic solvents, antibacterial agents such as benzyl alcohol, of this test is to evaluate the anticonvulsant potential of a antioxidants such as ascorbic acid or sodium bisulphite, compound by means of audiogenic seizures induced in 55 chelating agents such as ethylene diamine-tetra-acetic acid, Sound-Susceptible mice, a genetic animal model with reflex buffers such as acetates, citrates orphosphates and agents for seizures. In this model of primary generalised epilepsy, sei adjusting the osmolarity, such as Sodium chloride or dextrose. Zures are evoked without electrical or chemical stimulation These pharmaceutical forms are prepared using methods and the seizure types are, at least in part, similar in their which are routinely used by pharmacists. clinical phenomenology to seizures occurring in man 60 The amount of active ingredient in the pharmaceutical (Löscher W. & Schmidt D., Epilepsy Res. (1998), 2, p. 145 compositions can fall within a wide range of concentrations 181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41). and depends on a variety of factors such as the patient’s sex, Results obtained with compounds of formula I are indicative age, weight and medical condition, as well as on the method of a strong pharmacological effect. of administration. Thus the quantity of compound of formula Another assay indicative of potential anticonvulsant activ 65 I in compositions for oral administration is at least 0.5% by ity is binding to levetiracetam binding site (LBS) as herein weight and can be up to 80% by weight with respect to the after described. total weight of the composition. US 7,964,593 B2 25 26 In accordance with the invention it has also been found that In compositions for parenteral administration, the quantity the compounds of formula I or the pharmaceutically accept of compound of formula I present is at least 0.5% by weight able salts thereof can be administered alone or in combination and can be up to 33% by weight with respect to the total with other pharmaceutically active ingredients. Non-limiting weight of the composition. For the preferred parenteral com examples of Such additional compounds which can be cited 5 positions, the dosage unit is in the range 3 mg to 3000 mg of for use in combination with the compounds according to the compounds of formula I. invention are antivirals, antispastics (e.g. baclofen), antiemet The daily dose can fall within a wide range of dosage units ics, antimanic mood Stabilizing agents, analgesics (e.g. aspi of compound of formula I and is generally in the range 3 to rin, ibuprofen, paracetamol), narcotic analgesics, topical 3000 mg. However, it should be understood that the specific anesthetics, opioid analgesics, lithium salts, antidepressants 10 doses can be adapted to particular cases depending on the (e.g. mianserin, fluoxetine, traZodone), tricyclic antidepres individual requirements, at the physician's discretion. sants (e.g. imipramine, desipramine), anticonvulsants (e.g. The LBS binding compounds provided by this invention valproic acid, carbamazepine, phenyloin), antipsychotics and labelled derivatives thereof may be useful as standards (e.g. risperidone, haloperidol), neuroleptics, benzodiaz and reagents in determining the ability of tested compounds epines (e.g. diazepam, clonazepam), phenothiazines (e.g. 15 (e.g., a potential pharmaceutical) to bind to the LBS receptor. chlorpromazine), calcium channel blockers, amphetamine, Labelled derivatives of LBS ligands provided by this clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiap invention may also be useful as radiotracers for positron ine, serotonin antagonists, B-blockers, antiarrhythmics, trip emission tomography (PET) imaging or for single photon tans, ergot derivatives and amantadine. emission computerized tomography (SPECT). Of particular interest in accordance with the present inven The following examples are provided for illustrative pur tion are combinations of at least one compound of formula I poses. or a pharmaceutically acceptable salt thereof and at least one Unless specified otherwise in the examples, characteriza compound inducing neural inhibition mediated by GABA tion of the compounds is performed according to the follow receptors. The compounds of formula I exhibit a potentiating ing methods: effect on the compounds inducing neural inhibition mediated 25 NMR spectra are recorded on a BRUKERAC 250 Fourier by GABA receptors enabling, in many cases, effective treat Transform NMR Spectrometer fitted with an Aspect 3000 ment of conditions and disorders under reduced risk of computer and a 5 mm 'H/C dual probehead or BRUKER adverse effects. DRX 400 FTNMR fitted with a SG Indigo computer and a 5 Examples of compounds inducing neural inhibition medi mm inverse geometry 'H/C/N triple probehead. The com ated by GABA receptors include the following: benzodiaz 30 pound is studied in DMSO-d CDC1) solution at a probe epines, barbiturates, steroids, and anticonvulsants such as temperature of 313 K or 300 K and at a concentration of 20 valproate, viagabatrine, tiagabine or pharmaceutical accept mg/ml. The instrument is locked on the deuterium signal of able salts thereof. DMSO-d (or CDC1). Chemical shifts are given in ppm Benzodiazepines include the 1,4-benzodiazepines, such as downfield from TMS taken as internal standard. diazepam and clonazepam, and the 1.5-benzodiazepines, 35 HPLC analyses are performed using one of the following Such as clobazam. Preferred compound is clonazepam. systems: Barbiturates include phenobarbital and pentobarbital. Pre an Agilent 1100 series HPLC system mounted with an ferred compound is phenobarbital. INERTSILODS3 C18, DP5um, 250x4.6 mm column. Steroids include adrenocorticotropic hormones such as tet The gradient runs from 100% solvent A (acetonitrile, racosactide acetate, etc. 40 water, HPO (5/95/0.001, V/v/v)) to 100% solvent B Anticonvulsants include hydantoins (phenyloin, ethotoin, (acetonitrile, water, HPO (95/5/0.001, V/v/v)) in 6 min etc), oxazolidines (trimethadione, etc.). Succinimides (etho with a hold at 100% B of 4 min. The flow rate is set at 2.5 Suximide, etc.), phenacemides (phenacemide, acetylphenetu ml/min. The chromatography is carried out at 35° C. ride, etc.), Sulfonamides (Sulthiame, acetoazolamide, etc.), a HP 1090 series HPLC system mounted with a HPLC aminobutyric acids (e.g. gamma-amino-beta-hydroxybutyric 45 Waters Symetry C18, 250x4.6 mm column. The gradi acid, etc.), sodium valproate and derivatives, carbamazepine ent runs from 100% solvent A (MeOH, water, HPO. and so on. (15/85/0.001M, V/v/M)) to 100% solvent B (MeOH, Preferred compounds include valproic acid, valpromide, water, HPO (85/15/0.001 M, V/v/M)) in 10 min with a valproate pivoxil, Sodium valproate, semi-sodium valproate, hold at 100% B of 10 min. The flow rate is set at 1 divalproex, clonazepam, phenobarbital, vigabatrine, tiagab 50 ml/min. The chromatography is carried out at 40°C. ine and amantadine. Mass Spectrometric Measurements in LC/MS Mode are Of particular interest in accordance with the present inven Performed as Follows: HPLC Conditions tion are combinations of at least one compound of formula I Analyses are performed using a WATERS Alliance HPLC or a pharmaceutically acceptable salt thereof and at least one system mounted with an INERTSIL ODS 3, DP 5 um, 250x compound modulating neurotransmission mediated by 55 4.6 mm column. glutamate receptors. The compounds of formula I exhibit a The gradient runs from 100% solvent A (acetonitrile, potentiating effect on the compounds modulating neurotrans water, TFA (10/90/0.1, V/v/v)) to 100% solvent B (acetoni mission mediated by glutamate receptors enabling, in many trile, water, TFA (90/10/0.1, V/v/v)) in 7 min with a hold at cases, effective treatment of conditions and disorders under 100% B of 4 min. The flow rate is set at 2.5 ml/min and a split reduced risk of adverse effects. 60 of/25 is used just before API source. Examples of compounds modulating neurotransmission MS Conditions mediated by glutamate receptors include the following: Samples are dissolved in acetonitrile/water, 70/30, V/v at NBQX and MK-801 or pharmaceutical acceptable salts the concentration of about 250 ugr/ml. API spectra (+ or -) are thereof. performed using a FINNIGAN (San Jose, Calif., USA) LCQ For the preferred oral compositions, the daily dosage is in 65 ion trap mass spectrometer. APCI source operates at 450° C. the range 3 to 3000 milligrams (mg) of compounds of and the capillary heater at 160° C. ESI source operates at 3.5 formula I. kV and the capillary heater at 210°C. US 7,964,593 B2 27 28 Mass spectrometric measurements in DIP/EI mode are configuration at that center. The letter (A, B) in front is a way performed as follows: samples are vaporized by heating the of distinguishing the various enantiomers of the same struc probe from 50° C. to 250° C. in 5 min. EI (Electron Impact) ture. spectra are recorded using a FINNIGAN (San Jose, Calif., USA) TSQ 700 tandem quadrupole mass spectrometer. The EXAMPLE 1. source temperature is set at 150° C. Mass spectrometric measurements on a TSQ 700 tandem Synthesis of 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol quadrupole mass spectrometer (Finnigan MAT, San Jose, 1-yl)acetamide 2 Calif., USA) in GC/MS mode are performed with a gas chro 10 matograph model 3400 (Varian, Walnut Creek, Calif., USA) fitted with a split/splitless injector and a DB-5MS fused-silica column (15 mx0.25 mm I.D., 1 um) from J&W Scientific (Folsom, Calif., USA). Helium (purity 99.999%) is used as O Her carrier gas. The injector (CTC A200S autosampler) and the 15 transfer line operate at 290 and 250°C., respectively. Sample N (1 ul) is injected in splitless mode and the oven temperature is programmed as follows: 50° C. for 5 min., increasing to 280° \" C. (23°C/min) and holding for 10 min. The TSQ 700 spec O trometer operates in electron impact (EI) or chemical ioniza tion (CI/CH) mode (mass range 33-800, scan time 1.00 sec). The source temperature is set at 150° C. O Specific rotation is recorded on a Perkin-Elmer 341 pola N rimeter. The angle of rotation is recorded at 25° C. on 1% 25 solutions in MeOH. For some molecules, the solvent is CHCl, or DMSO, due to solubility problems. \" Melting points are determined on a Bichi:535 or 545 Tot O toli-type fusionometre, and are not corrected, or by the onset temperature on a PerkinElmer DSC 7. 30 Preparative chromatographic separations are performed on 2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 1 is syn silicagel 60 Merck, particle size 15-40 um, reference thesized according to the method described by Valenta et al. 1.15111.9025, using Novasep axial compression columns (80 (Valenta, V.; Holubeck, J.; Svatek, E.; Valchar, M. Krejci, I.: mm flow rates between 70 and 150 ml/min. Amount of sili 35 Protiva, M.: Collect. Czech. Chem. Commun. (1990), 55, cagel and solvent mixtures as described in individual proce 2756-2764). dures. Oxindole 1 (1 g, 5.25 mmol) was dissolved in CHCN (20 Preparative Chiral Chromatographic separations are per ml). After addition of the MS (1.3 g 5.78 mmol), the TFA formed on a DAICEL Chiralpak AD 20 um, 100*500 mm (217 ul, 1.57 mmol) was added and the reaction was allowed column using an in-house build instrument with various mix 40 at room temperature for 16h. After evaporation of the solvent, tures of lower alcohols and C5 to C8 linear, branched or cyclic the mixture was triturated in a 10% aqueous solution of alkanes at +350 ml/min. Solvent mixtures as described in NaSO. The beige solid formed was filtered, washed with individual procedures. water and with ether. After cristallization from 90% aqueous The following abbreviations are used in the examples: EtOH, and re-cristallization from acetonitrile, 2-(5-iodo-2- 45 oxo-2,3-dihydro-1H-indol-1-yl)acetamide 2 was obtained as AcOEt Ethyl acetate a white solid. CHCN Acetonitrile Yield: 166 mg (10%). DMF N,N-Dimethylformamide MS (GC-MS, M*): 316. NBS N-bromosuccinimide 50 NCS N-chlorosuccinimide EXAMPLE 2 MSN-iodosuccinimide TFA Trifluoroacetic acid Synthesis of 2-(5-chloro-2-oxo-2,3-dihydro-1H-in THF Tetrahydrofuran 55 dol-1-yl)acetamide 3 In the tables, the stereochemical information is contained in the two columns headed “configuration'. The second col umn indicates whether a compound has no stereogenic center (achiral), is a pure enantiomer (pure), a racemate (rac) or is a mixture of two stereoisomers, possibly in unequal propor 60 O --- tions (MIXT). The first column contains the stereochemical N assignment for the recognised center, following the IUPAC numbering used in the “IUPAC name column. A number alone indicates the existence of both configurations at that \" O center. A number followed by R or 'S' indicates the known 65 absolute configuration at that center. A number followed by ‘S’ indicates the existence of only one but unknown absolute US 7,964,593 B2 29 -continued -continued C ON O O N\" N\" O O
10 Oxindole 1 (1.77 g., 9.3 mmol) was dissolved in 90% HSO (6 ml) at room temperature, and NCS (1.24 g, 9.3 To a stirred solution of 2-(2-oxo-2,3-dihydro-1H-indol-1- mmol) was slowly added with stirring. After 2 hours, the yl)acetamide 1 (400 mg, 2.1 mmol) in TFA (20 ml) was added mixture was poured into cold water. The precipitate was collected, washed several times with water and then with 15 fuming nitric acid (170 ul, 2.7 mmol) over 10 minutes. Fol EtO. After cristallization from EtOH, 2-(5-chloro-2-oxo-2, lowing addition, the ice bath was removed and the mixture 3-dihydro-1H-indol-1-yl)acetamide 3 was obtained as a was stirred at room temperature for 5 minutes, then poured white solid. carefully into ice water. The precipitate was collected, Yield: 479 mg (23%). washed with water until pH 7 and dried to give a crude solid. MS (LC-MS, MH): 225/227. Cristallization in a mixture acetonitrile/MeCH afforded the MP: 226 C. 2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 5 as a green-gray Solid. EXAMPLE 3 Yield: 150 mg (30%). Synthesis of 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H MS (DIPM): 235. indol-1-yl)acetamide 4 25 EXAMPLE 5 O --- N Synthesis of 2-(5-methyl-2-oxo-2,3-dihydro-1H \" 30 indol-1-yl)acetamide 24 O 1 Br 35
O
N N NH2 H Br 40 / O S
He O
2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)aceta 45 N mide 4 was obtained as described in example 1 by using 2 H equivalents of NBS. The crude material was purified by silica 6 gel chromatography. Yield: 129 mg (10%). S MS (LC-MS, MH): 259/261. 50 Ho O EXAMPLE 4 N Synthesis of 2-(5-nitro-2-oxo-2,3-dihydro-1H-indol 1-yl)acetamide 5 55 \" O 15
O 60 N\" O 65 24 US 7,964,593 B2 31 32 5.1 Synthesis of 5'-methylspiro 1,3-dithiolane-2,3'- TABLE 2-continued indol-2(1H)-one 6 No IUPACNAME 5-methyl-1H-indole-2,3-dione (6 g., 37 mmol) was sus 22 2-2'-oxo-5'-(trifluoromethyl)spiro1,3-dithiolane-2,3'-indol-1'(2H)- pended in 100 ml of AcOH. The heterogenous mixture was 5 yl)acetamide 23 2-(5",6'-dimethyl-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)- heated at 60° C. After complete solubilisation, 1.2- yl)acetamide ethanedithiol (3.15 ml, 37 mmol) was added and then neat BF.OEt (9.5 ml, 75 mmol) was added dropwise. The reac tion was stirred for 25 minutes, in which time the reaction mixture became homogenous. After 20 minutes at room tem 10 5.3 Synthesis of 2-(5-methyl-2-oxo-2,3-dihydro-1H perature, the reaction was quenched by addition of water, the indol-1-yl)acetamide 24 Solid washed several times with large amounts of water and air dried affording 5'-methylspiro 1,3-dithiolane-2,3'-indol The Raney Nickel was prepared as an aqueous slurry after 2(1H)-one 6 as a brown solid. removing four fifth of water of the commercial solution. 15 Aqueous Raney nickel (10 ml) was added to a solution of Yield: 8.65 g (98%). compound 15 (4.06 g. 13.8 mmol) in 40 ml of distilled THF MS (DIP, Mt): 237. and the mixture was further vigourously stirred at room tem Compounds listed in table 1 can be synthesised according perature. When no starting material was detected by thin layer to the same method. chromatography, the mixture was diluted with THF and fil tered through a Celite pad. After removal of the solvent, the TABLE 1. crude material was purified by silica gel chromatography No IUPACNAME (CHC1/MeoH95/5 then 90/10), and the solvent was evapo rated to yield the 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol 6 5'-methylspiro1,3-dithiolane-2,3'-indol-2'(1H)-one 1-yl)acetamide 24 as a white solid. 7 5'-(trifluoromethyl)oxyspiro1,3-dithiolane-2,3'-indol-2'(1H)- 25 Ole Yield: 697 mg (21%). 8 5'-(1-methylethyl)spiro1,3-dithiolane-2,3'-indol-2'(1H)-one 9 5'-ethylspiro1,3-dithiolane-2,3'-indol-2'(1H)-one MS (LC-MS, MH): 205. 10 5'-fluorospiro1,3-dithiolane-2,3'-indol-2'(1H)-one 11 5,7-dimethylspiro1,3-dithiolane-2,3'-indol-2(1H)-one EXAMPLE 6 12 5'-propylspiro1,3-dithiolane-2,3'-indol-2'(1H)-one 13 5'-(trifluoromethyl)spiro1,3-dithiolane-2,3'-indol-2'(1H)-one 30 14 5",6'-dimethylspiro1,3-dithiolane-2,3'-indol-2(1H)-one Synthesis of 2-(5-chloro-2-oxo-2,3-dihydro-1H-in dol-1-yl)propanamide 32, 33 and 34
5.2 Synthesis of 2-(5'-methyl-2'-oxospiro 1,3-dithi 35 olane-2,3'-indol-1'(2H)-yl)acetamide 15 C Compound 6 (8g, 33.7 mmol) was dissolved in dry DMF (80 ml) under a nitrogen atmosphere. The solution was cooled N O)H - at 0°C. and NaH (1.62 g, 37.13 mmol. 60% dispersion) was 40 C carefully added portionwise. When the nitrogen evolution N ceased, bromoacetamide (5.6 g., 37.13 mmol) was added. --- After 30 minutes, the mixture was poured into cold water and N the solid filtered off, washed with water and hexane. The crude material was directly cristallized in acetonitrile afford 45 ing 2-(5'-methyl-2'-oxospiro 1,3-dithiolane-2,3'-indol-1 2 xNH2 (2H)-yl)acetamide 15 as a white solid. O Yield: 4.86 g (49%). 25 MS (LC-MS, MH): 295. Br Br Compounds listed in table 2 can be synthesised according 50 C to the same method. O N TABLE 2 No IUPACNAME 55 2 ( NH2 15 2-(5'-methyl-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)- O yl)acetamide 31 16 2-2'-oxo-5'-(trifluoromethyl)oxyspiro1,3-dithiolane-2,3'- indol-1'(2H)-yl)acetamide C 17 2-5'-(1-methylethyl)-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)- 60 O yl)acetamide Her 18 2-(5'-ethyl-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)-yl)acetamide N 19 2-(5'-fluoro-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)- yl)acetamide 20 2-(5",7'-dimethyl-2'-oxospiro1,3-dithiolane-2,3'-indol-1'(2H)- 2 ( NH2 yl)acetamide O 21 2-(2-oxo-5'-propylspiro1,3-dithiolane-2,3'-indol-1'(2H)- 65 yl)acetamide 32 US 7,964,593 B2 34 -continued AcOEt. Organic layers were dried over NaSO and concen C trated. The beige solid was cristallized in AcOEtandafforded O 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide 32 as a white solid. N Yield: 2.5 g (18%). MS (LC-MS, MH): 239/241. Compound 32 (2.5 g, 10.5 mmol) was resolved into its O enantiomers by chiral chromatography (DAICEL, Chiralcel 33 OD phase, eluent: 50/50 ethanol/hexane) to afford enanti 34 10 omers 33 (first eluted) and 34 (second eluted) as white solids. Compound 33: Yield: 977 mg (39 W. 6.1 Synthesis of MS (LC-MS, MH): 239/241. 2-(5-chloro-1H-indol-1-yl)propanamide 25 15 MP; 171-1720 C. Compound 34: A dispersion of 60% NaH (6.85g, 0.17 mol) was added to Yield: 941 mg (37%). an ice-cooled solution of 5-chloroindole (20g, 0.13 mol) in MS (LC-MS, MH): 239/241. 250 ml of dry DMF. The stirring was continued for 20 minutes MP; 171-1720 C. at room temperature, and the mixture was cooled again with an ice bath. After portionwise addition of solid 2-bromopro EXAMPLE 7 panamide (24.1 g, 0.15 mol), the reaction mixture was stirred for 1 ha.0 at room temperature, then poured into cold water Synthesis of N-(4-tert-Butyl-phenyl)-2-(5-chloro-2- and extracted 3 times with AcOEt. The combined organic oxo-2,3-dihydro-indol-1-yl)-acetamide 85 phases were dried over NaSO, filtered and concentrated in 25 vacuo. The crude material was purified by silica gel chroma tography (AcOEt/hexane 50/50) to give pure 2-(5-chloro-1H indol-1-yl)propanamide 25 as a white Solid. C Yield: 13.45 g (46%). MS (LC-MS, MH): 223/225. 30 N Compounds listed in table 3 can be synthesised according O)H - to the same method. C
TABLE 3 O He 35 N No Configuration IUPACNAME 25 2 rac 2-(5-chloro-1H-indol-1-yl)propanamide 26 achiral 2-(7-chloro-1H-indol-1-yl)acetamide \" 27 achiral 2-(6-chloro-1H-indol-1-yl)acetamide O 28 2 rac 2-(5-chloro-1H-indol-1-yl)butanamide 40 58 29 2 rac 2-(5-methyl-1H-indol-1-yl)propanamide C 30 2 rac 2-(5-bromo-1H-indol-1-yl)propanamide 55 achiral 2-(7-fluoro-1H-indol-1-yl)acetamide O 112 achiral 2-(5-bromo-1H-indol-1-yl)acetamide Ho 113 achiral 2-(5-fluoro-1H-indol-1-yl)acetamide N 114 achiral 2-(5-chloro-1H-indol-1-yl)acetamide 45 \-" O 6.2 Synthesis of 2-(5-chloro-2-oxo-2,3-dihydro-1H 59 indol-1-yl)propanamide 32 C 50 Pyridinium bromide perbromide (38.8 g., 117 mmol) was O added in portions over a period of 30 minutes to a stirred N solution of 2-(5-chloro-1H-indol-1-yl)propanamide 25 (13 g, 58.4 mmol) intert-butanol (100 ml) at room temperature. The reaction mixture was stirred for 30 minutes, then poured into 55 - water and diluted with AcOEt. After removal of the organic layer, the aqueous phase was extracted twice with AcOEt. 85 Combined organic phases were dried over Na2SO and con centrated. 2-(3,3-dibromo-5-chloro-2-oxo-2,3-dihydro-1H indol-1-yl)propanamide 31 was obtained as a crude oil and 60 was directly used in the next step, without further purification. 7.1 Synthesis of ethyl (5-chloro-2-oxo-2,3-dihydro Zinc dust (23.71 g, 0.58 mol) was added to a stirred solu 1H-indol-1-yl)acetate 58 tion of compound 31 (theorical: 58.4 mmol) in AcOH (110 ml) at 0°C. After 1 hour, the reaction mixture was filtered The ester 58 was obtained from 5-chloroindole and ethyl through a Celite pad. The filtrate was diluted with AcOEt and 65 bromoacetate (instead of bromo-acetamide) using the meth cold water. The pH was adjusted to 7 and the layers were odology described in example 6. separated. The aqueous phase was extracted again with MS (GC-MS, M*): 253/255.
US 7,964,593 B2 39 40 TABLE 4-continued Compounds of formula I. No Configuration IUPAC NAME MS (LC-MS, MH) C (MeOH, 25°C., 1%) 105 achiral N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H- 367369,371 indol-1-yl)acetamide 106 achiral N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N- 329,311 methylacetamide 107 achiral 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2- 415,417 (trifluoromethyl)thiobenzyl)acetamide 108 achiral 5-chloro-1-(2-(1,4-dioxa-8-azaspiro[4.5 dec-8-yl)-2-oxoethyl- 351,353 1,3-dihydro-2H-indol-2-one 109 achiral 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N- 321,323 cycloheptylacetamide 110 achiral 5-chloro-1-(2-4-(2-morpholin-4-ylethyl)piperazin-1-yl)-2- 407,409 oxoethyl-1,3-dihydro-2H-indol-2-one 111 achiral 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3- 302,304 ylacetamide
EXAMPLE 8 9206, Camberra Packard, Belgium, or any other equivalent counter). Data analysis is performed by a computerized non LBS Binding Assay linear curve fitting method using a set of equations describing several binding models assuming populations of independent LBS stands for Levetiracetam Binding Site cf. M. Noyer non-interacting receptors, which obey to the law of mass. et al., Eur. J. Pharmacol. (1995), 286, 137-146. 25 The inhibition constant (K) of a compound is determined in competitive binding experiments by measuring the binding EXAMPLE 9 of a single concentration of a radioactive ligand at equilib rium with various concentrations of the unlabeled test Sub Animal Model of Sound-Susceptible Mice stance. The concentration of the test substance inhibiting 50% 30 of the specific binding of the radioligand is called the ICso. The equilibrium dissociation constant K, is proportional to The aim of this test is to evaluate the anticonvulsant the ICs and is calculated using the equation of Cheng and potency of a compound in Sound-Susceptible mice, a genetic Prusoff (Cheng Y. et al., Biochem. Pharmacol. (1972), 22. animal model with reflex seizures. In this model of primary 3099-3108). 35 generalised epilepsy, seizures are evoked without electrical or The concentration range usually encompasses 6 log units chemical stimulation and the seizure types are, at least in part, with variable steps (0.3 to 0.5 log). Assays are performed in similar in their clinical phenomenology to seizures occurring mono- or duplicate, each K, determination is performed on in man (Löscher W. & Schmidt D., Epilepsy Res. (1998), 2. two different samples of test substance. 145-181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41). Cerebral cortex from 200-250 g male Sprague-Dawley rats 40 Male or female genetically sound-sensitive mice (14-28 g; are homogenised using a Potter Shomogeniser (10 strokes at N=10), derived from a DBA strain originally selected by Dr. 1,000 rpm; Braun, Germany) in 20 mmol/l Tris-HCl (pH 7.4), Lehmann of the Laboratory of Acoustic Physiology (Paris) 250 mmol/l sucrose (buffer A); all operations are performed and bred in the UCB Pharma Sector husbandry unit since at 4°C. The homogenate is centrifuged at 30,000xg for 15 1978, are used. The experimental design consists of several min. The crude membrane pellet obtained is resuspended in 45 groups, one group receiving the vehicle control and the other 50mmol/l Tris-HCl (pH 7.4), (buffer B) and incubated 15 min groups different doses of the test-compound. The compounds at 37° C. centrifuged at 30,000xg for 15 min and washed are administered intraperitoneally 60 minutes before the twice with the same buffer. The final pellet is resuspended in induction of audiogenic seizures. The range of the doses buffer A at a protein concentration ranging from 15 to 25 administered has a logarithmic progression, generally mg/ml and stored in liquid nitrogen. 50 between 1.0x10 mol/kg and 1.0x10 mol/kg, but lower or Membranes (150-200 ug of protein/assay) are incubated at higher doses are tested if necessary. 4°C. for 120 minin0.5 ml of a 50mmol/l Tris-HCl buffer (pH 7.4) containing 2 mmol/l MgCl2, 10 to 2.10 mol/l of For testing, the animals are placed in Small cages, one H-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinylbutana mouse per cage, in a Sound-attenuated chamber. After a mide and increasing concentrations of the test Substance. The 55 period of orientation of 30 seconds, the acoustic stimulus (90 non specific binding (NSB) is defined as the residual binding dB, 10-20 kHz) is delivered for 30 seconds via loudspeakers observed in the presence of a concentration of reference sub positioned above each cage. During this interval, the mice are stance (e.g. 10 mol/l levetiracetam) that binds essentially all observed and the presence of the 3 phases of the seizure the receptors. Membrane-bound and free radioligands are activity namely wild running, clonic and tonic convulsions, is separated by rapid filtration through glass fiber filters (equiva 60 recorded. The proportion of mice protected against wild run lent to Whatman GF/C or GF/B: VEL, Belgium) pre-soaked ning, clonic and tonic convulsions, respectively, is calculated. in 0.1% polyethyleneimine and 10 mol/l levetiracetam to For active compounds, an EDso value, i.e. the dose produc reduce non specific binding. Samples and filters are rinsed by ing 50% protection relative to the control group, together with at least 6 ml of 50 mmol/l Tris-HCl (pH 7.4) buffer. The entire 95% confidence limits, was calculated using a Probit Analysis filtration procedure does not exceed 10 seconds per sample. 65 (SAS/STATR Software, version 6.09, PROBIT procedure) of The radioactivity trapped onto the filters is counted by liquid the proportions of protected mice for each of the 3 phases of scintillation in a (3-counter (Tri-Carb 1900 or TopCount the seizure activity. US 7,964,593 B2 41 42 The invention claimed is: wherein 1. A compound of formula I or a pharmaceutically accept R" is hydrogen, able salt thereof or stereoisomeric forms thereof, R is hydrogen or C-alkyl, is NRR" is piperidinyl unsubstituted or substituted by (I) hydroxy; thiomorpholinyl: 4-oxooctahydro-1 (2H)- R4 quinolinyl; or a group of formula R O 10 / \ -N N-R10 N R6 NR3R3a R7 R2 R O R" is hydrogen, 15 R is hydrogen; nitro; halogen; Cla-alkyl, unsubstituted or wherein Substituted by halogen; or C-alkoxy unsubstituted or R" is hydrogen, substituted by halogen, R is hydrogen or Co-alkyl, R is hydrogen, C1-c-alkyl or halogen, NRR" is a group of formula 20 R is hydrogen, methyl or halogen, R'' is pyridinyl; phenyl unsubstituted or substituted by halogen, hydroxy, Ca-alkyl; or a group of formula R10 V R's, /-y-R,10a 25 V is unsubstituted C-alkylene, -N Y R" is phenyl or morpholinyl. \-/ 3. A compound according to claim 1 wherein R is hydro gen or methyl. R" is hydrogen, 4. A compound according to claim 1 wherein R is halogen R is hydrogen; nitro; halogen; azido; cyano; —S-C- 30 or trifluoromethyl. alkyl; —SO-Ca-alkyl; —SO Ca-alkyl; 5. A compound according to claim 1 wherein R is hydro —SONH2: Co-alkyl unsubstituted or substituted by gen. halogen; or Co-alkoxy unsubstituted or substituted by 6. A compound according to claim 1 wherein R is hydro halogen, R is hydrogen, C1-20-alkyl or halogen, 35 gen, Br, or F. R’ is hydrogen, Co-alkyl or halogen, 7. A compound according to claim 1 wherein R is Co Y is O, S, CR'R' NR' or C(=O) alkyl and the carbon atom to which R is attached is in the R" and R" are independently selected from hydrogen, “S”-configuration. Ca-alkyl, halogen, hydroxy or methoxycarbonyl, 8. A compound selected from or R'' and R" together form a C-alkylene, 40 5-chloro-1-(2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl) R" is hydrogen, Ca-alkyl, halogen or hydroxy, ethyl-1,3-dihydro-2H-indol-2-one: R" is hydrogen, 5-chloro-1-(2-4-(3-methylphenyl)piperazin-1-yl)-2- or CR'R' is dioxolanyl, oxoethyl-1,3-dihydro-2H-indol-2-one; R'' is aryl, heterocycle or a group of formula V. R. V is C2-alkylene, 5(chloro-1-(2-(3-hydroxypiperidin-1-yl)-2-oxoethyl-1, R" is aryl or heterocycle, 3-dihydro-2H-indol-2-one: n is 1. 5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihy 2. A compound of formula I or a pharmaceutically accept dro-2H-indol-2-one: so 5-chloro-1-(2-oxo-2-[4-(2-phenylethyl)piperazin-1-yl) able salt thereof or stereoisomeric forms thereof, ethyl-1,3-dihydro-2H-indol-2-one: 5-chloro-1-(2-[4-(4-hydroxyphenyl)piperazin-1-yl)-2- (I) oxoethyl-1,3-dihydro-2H-indol-2-one; and 5-chloro-1- {2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl)- 2-oxoethyl-1,3-dihydro-2H-indol-2-one. 9. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination 60 with a pharmaceutically acceptable diluent or carrier.