NZ286164A

NZ286164A - 2-[4-1h-imidazol-4-yl)piperidin-1-yl-4,5-dihydroimidazo--[4,5,1-ij]qu ioline or -[1,5,4-de][1,4]benzoxazine derivatives

Info

Publication number: NZ286164A
Application number: NZ286164A
Authority: NZ
Inventors: Luc Even; Samir Jegham; Gerard Defosse; Michel Aletru
Original assignee: Synthelabo
Priority date: 1995-03-13
Filing date: 1996-03-12
Publication date: 1996-11-26
Also published as: NO961000D0; AU4800896A; HUP9600624A2; EP0732334A1; NO961000L; JPH08269058A; IL117455A0; CA2171579A1; HU9600624D0; CZ75496A3; SK34196A3; PL313204A1; ZA961994B; CN1140174A; FR2731708A1; FR2731708B1; KR960034205A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £86164 286164 No: Date: Priority Date(s):.... Complete Specification Fit ad: ...V a\3.1qu. Class. (S) Col W.a ft \p!q\ . Gs?l Ji Mrl.!. Publication Date: 2..&..N.Q.V..1996" P.O. Journal No: )"rir. NEW ZEALAND PATENTS ACT, 1953 1 n^P^LSl^-'P \ 2 MAR 1996 received COMPLETE SPECIFICATION PIPERIDINE DERTVATTVES, PROCESS FOR THE PREPAR ATION THEREOF AND APPLICATION THEREOF IN THERAPEUTICS We, SYNTHELABO, a French body corporate, 22 Avenue Galilee, 92350 Le Plessis-Robinson, Cedex, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1- (followed by page la) 286164 Iq The present invention relates to piperidine derivatives/ a process for their preparation and their application in therapeutics. The present invention provides a compound of formula (I) (I) in which X represents an oxygen atom or a methylene group, R, represents a chlorine or fluorine atom or a methyl, methoxy or amino group, and 10 R2 and R3 independently represent a hydrogen atom or a methyl group, in the form of the free base or an addition salt with a pharmaceutically acceptable acid. The preferred compounds according to the invention are those in which, 15 x represents an oxygen atom and R, is at position 8 on the phenyl ring. The particularly preferred compounds of formula (I) are (fi)-8-fluoro-4-methyl-2-[4-(5-methyl-lg-imidazol-4-yl)piperidin-l-yl]-20 4.5-dihvdroimidazorl.5.4-delr1.41benzoxazine and <g)-8-fluoro~4-aethyl-i'2-[4-(lH-imidazol-4-yl)piperidin-l-yl]-4.5-dihydroimidazo fl.5,4-delT1.41benzoxazine. Some compounds of formula (I) contain an asymmetric 286164 2 asymmetric carbon atom. They can therefore exist in the form of enantiomers. These en&ntiomers, pure or in the form of mixtures, including racemic mixtures, form part of the invention. The mesomeric forms of the oompounds of formula (X) also form part of the invention. The compounds of formula (I) can be prepared by reaction of a compound of formula (XX), in which X, Rj and R2 are as defined in formula (X) and Y represents a halogen atom, in particular a chlorine atom, with a compound of formula (XXX), in which R3 is is defined in formula (X), according to Scheme 1. Scheme 1 -<ry - -Op. - ^QCK>p~ (U) (W) <n The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to the person skilled in the art. Thus, the compound of formula (XXX) in which B, is i hydrogen atom is described in Arch. Pharmaz., 306 (12), 934-942 (1973). The compound of formula (XXX) in which R, it a methyl group can be prepared according to the process 286164 3 described in EP-A-O,507,650. The compounds of formula (II)/ in which Y is a chlorine atom and X, R, and R2 are as defined in formula (I), can be prepared by the reduction of a compound of formula 5 (IV) (IV) which is then reacted with urea to give a compound of formula (V) (V) which is then treated with phosphoryl chloride. The compounds of formula (IV) can be prepared 10 by reaction of a compound of formula (VI) H (VI) -CO with bis(lfl-dimethylethyl) dicarbonate, nitration of a compound of formula (VII) 286164 "OCT COOt-Bu I (VII) and Hydrolysis of a compound of formula (VIII) NO. COOt-Bu (VIII) Some compounds of formula (IV) can also be prepared from compounds of formula (IX) (IX) in which X and Rj are as defined in formula (I) 5 in particular, compounds of formula (IVa) (IVa) can be prepared by chlorination of the compounds of formula (IX). The preparation of the compound of formula (XX), in which Rj is a methyl group and X an oxygen 10 atom, is described in EP-A-0,646,583. The compound of formula (IX) in which Rj is a hydrogen atom and X an oxygen atom can be prepared by 286164 5 an analogous process. Compounds of formula (IVb) (XVb) in which R2 is as defined in formula (I) can also be prepared by nitration of a compound of formula (X) (X) The compounds of formula (X) are typically prepared by cyclization of 2-bromo-5-fluorophenol with a compound of formula (XI) HO Y ^COOtBu (XI) The following Examples illustrate the 10 preparation of compounds according to the present invention. Microanalyses and NMR spectra have confirmed the structures of the products obtained. The (y:x) ratios correspond to the (base:acid) ratio. The numbers between brackets refer to the table given later which 2861 6 illustrates the chemical structures and the physical properties of some compounds according to the invention. Example l (Compound No. l) 5 (§.) -8-chloro-4-methyl-2-[4- (5-methyl-lg-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo-[1/5,4-de][1,4]benzoxazine 1.1. (g)-7-chloro-3-methyl-5-nitro-3,4-dihydro-2g-1,4-benzoxazine 10 5.82 g (0.030 mol) of (S)-3-methyl-5-nitro- 3,4-dihydro-2H-i,4-benzoxazine are dissolved in 135 ml of acetic acid at 45°C. 5.16 g (0.038 mol) of £-chlorosuccinimide are rapidly added and the reaction mixture is stirred for 4 hours at 50°C. Zt is then 15 poured into water and extracted 3 times with diethyl ether. The organic phases are combined, washed with water and then with an aqueous sodium hydroxide solution and dried. The solvent is evaporated to dryness. 20 6.7 g of product are obtained. Melting point : 95®C 1.2. (fi)-8-chloro-4-methyl-4#5-dihydroimidazo-[1,5,4-fli][l,4]benzoxazin-2(lS)-one A suspension between 8.9 g (0.039 mol) of 25 (fi)-7-ehloro-3-methyl-5-nitro-3/4-dihydro-2l-l/4- benzoxazine in 250 ml of ethanol and a catalytic amount 2881 of R«.n«y nickel are introduced into a Parr apparatus. Eydrogenation is carried out for 2 hours at room temperature under a pressure of 70 kPa (10 psi). The catalyst is then filtered off and washed vith ethanol, 5 the filtrate is recovered and the solvent is evaporated to dryness. 3.4 g (0.056 mol) of urea are added to the residue thus obtained and heating is carried out with an oil bath at 170-180°c for l hour. The solid obtained is then taken 10 up in a mixture of water and diethyl ether (.50:50), and the precipitate formed is filtered off, washed with diethyl ether and then with water and dried under vacuum over phosphorous pentoxide. 6.3 g of product are obtained, which product is purified by chromatography 15 on a silica gel column with a mixture of dichloromethane and methanol (97:3). 5.2 g of product are obtained. 1.3 (S)-2,8-dichloro-4-methyl- 4,5-dihydroimidaso[1,5,4-de][1,4]benzoxazine 20 100 ml of phosphoryl chloride are poured onto 5.2 g (0.023 mol) of (£)-8-chloro-4-methyl-4 , 5—dihydroimidazo[ l, 5 , 4-de] [ l, 4 ] benzoxazin-2 (l]{)-one. The mixture is heated at reflux for 2 hours, the solvent is then evaporated to dryness and the residue 25 is taken up in ice-cold water and then in a concentrated agueous ammonia solution. Extraction is then carried out with diethyl ether, the organic phases COO | o 8 ara combined and dried and tbe solvent is evaporated to dryness. 4.5 g of residue are obtained, which residue is purified by chromatography en a silica gel column with a mixture of hexane and ethyl acetate (97:3). 5 4.1 g of product are obtained in the form of an oil. 1.4. (g)-8-chloro-4-methyl-2-[4-(5-methyl-lS-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine A mixture of 1.35 g (0.0082 mol) of 10 4-(5-methyl-lg—imidazol-4-yl)piperidine, l g (0.0041 mol) of (8)-2,8-dichloro-4-methyl-4.5-dihvdroimidazori#S.4-de1fl.41benzoxazine and 4.5 ml of isoamyl alcohol is heated at 120°C for 12 hours with stirring. The solvent is then evaporated to dryness and 15 the residue is purified by chromatography on a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5). After recrystallization from acetone, 0.7 g of product is obtained in the base form. 20 Melting point : 208*C [a]" = -23.8* (c.s o.oi, methanol) Example 2 (compound No. 2) (fi) -8-chloro-2-[4-(iH-imidazol-4-yl)piperidin-l-yl]-4-nethyl-4,5-dihydroimidazo[l,5,4-£a][1,4][benzoxazine 25 There is obtained, from a mixture of (£)- 2,8-dichloro-4-methyl-4,5-dihydroimidazo- 2861 9 [l,S,4-de][1,4]benzoxazine and 4-(lH-imidazol-4-yl)piperidine, treated under tbe conditions of Example 1.4, after recryst&liization from acetone, 0.6 g of product in the bass form. 5 Melting point : 215"C [a]£° = -3.7" (e = 0.01, methanol) ExampIs 3 (Compound Mo. 5) 8-fluoro-2-[4-(lg-imidazol-4-yl)piperidin-l-yl]-4-methy1-5,6-dihydro-4g-imidazo[4,5,l-ij]quinoline 10 3.1. l,l-dimethylethyl 6-fluoro-2-methyl- 1,2,3,4-tetrahydroquinoline-i-carboxylate A mixture of 16.5 g (0.1 mol) of 6-fluoro-2-methyl-l,2,3,4-tetrahydroquinoline and 32 g (0.146 mol) of bis(1,1-dimethylethyl) dicarbonate in 100 ml of 15 tetrahydrofuran is heated at 60*C for 3 days. The solvent is then evaporated to dryness and the remaining dicarbonate is driven off using a vane pump. The residue is purified by chromatography on silica gel vith a mixture of hexane and ethyl acetate (90:10). 20 24.5 g of product are obtained in the form of an oil. 3.2 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroguinoline-l-carboxylate A solution of 18.4 g (0.0697 mol) of 1,l-dimethylethyl 6-fluoro-2-methy1-25 l,2,3,4-tetrahydroquinoline-l-carboxylate and 13.8 ml 286 10 of anhydrous K. K. N', M'-tetramethvlethvlenediamine in 350 nl of anhydrous diethyl ether is cooled to -78#c. 64.2 Bl of a 1.3N solution of sec-butvl iodide in a mixture of cyclohexane and pentane are then added over 5 30 Binutes. The reaction mixture is stirred for 1 hour at —78*c and then 12.3 g (0.103 boI) of isobutyl nitrate are added. The reaction Bixture is stirred for 1.5 hours at -70*c and is then neutralised by being poured into ice-cold vater. Extraction is carried out 10 vith diethyl ether, the organic phases are combined, vasbed vith vater and dried and the solvent is then evaporated to dryness. Tbe residue is purified by chromatography on a silica gel column, elution being carried out vith a mixture of hexane and ethyl acetate 15 (90:10). 8.1 g of product are obtained. 3.3. 6-fluoro-2-Bethyl-8-nitro-1,2,3,4-tetrahydroquinoline A mixture of 8.6 g (0.0261 mol) of 20 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro- 1,2,3,4-tetrahydroquinoline-l-carboxylate, 30 Bl of concentrated hydrochloric acid, 20 ml of toluene and 30 Bl of vater is heated at the reflux temperature for one day. The Bixture is then alloved to return to room 25 temperature, separation is carried out by settling and extraction is carried out vith toluene. The organic phases are combined, vashed vith vater and dried and / 286164 11 the solvent is then evaporated to dryness. 5.6 9 of product are obtained. Melting point: 56*C 3.4. 8-fluoro-4-ethyl-5,6-dihydro-4g-imidazo-5 £4,5/l-ij.]quinol-2 (lg)-one A suspension of 5.5 g (0.026 sol) of 6-fluoro-2-methyl-8-nitro-l,2,3,4-tetrahydroquinoline in 150 ml of ethanol and a catalytic amount of Raney nickel are introduced into a Parr apparatus and 10 hydrogenation is then carried out for 1 hour at room temperature tinder a pressure of 0.21 MPa (30 psi). Tbe catalyst is then filtered off and washed with ethanol/ the filtrate is recovered and the solvent is evaporated to dryness. The residue is added to 2.6 g (0.043 mol) 15 of urea and heating is carried out with an oil bath at 175°C for 1.5 hours. The solid obtained is taken up in a mixture of water and diethyl ether (50:50) and the precipitate formed is then filtered off, washed with diethyl ether and with water and dried under vacuum 20 over phosphorus pentoxide. 4.2 g of product are obtained. 3.5. 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4g-imidazo T4.5.1-iilauinoline 100 ml of phospboryl chloride are poured onto 25 4.2 g (0.02 mol) of 8-fluoro-4-methyl-5/6-dihydro-4B-imidazor 4.5.1-ii Jquinol-2(1H)-one and the mixture is 286 12 then heated at reflux for 2 hours. The solvent is then evaporated to dryness and the residue is taken up in ice-oold water and then in a concentrated aqueous ammonia solution. Extraction is carried out with 5 diethyl ether, the organic phases are combined and dried and the solvent is then evaporated to dryness. The residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of hexane and ethyl acetate (70:30). 10 2.4 g of product are obtained. Melting point : 80#C 3.6. 8-fluoro-2-[4-(lg-imidazol-4-yl)piperidin-l-yl]- 4-methyl-5,6-dihydro-4g-imidazo[4,5,l-ij Jquinoline A mixture of 0.94 g (0.00625 mol) of 4-(lg-15 imidazol-4-yl)piperidine, 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4g-imidazo-[4,5,l-AA]quinoline and 3.5 ml of isoamyl alcohol is heated at 120°C for 18 hours with stirring. The solvent is then evaporated to dryness and the residue is 20 purified by chromatography on a silica gel colium with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5). After recrystallization from acetone, 0.85 g of product is obtained in the base form. 25 Melting point : 175-177*C 286164 13 Example 4 (Compound No. 6) 8-fluoro-4-methyl-2-[4-(5-methyl-lII-imidazol-4 -yl) piper idin-l-yl ] -5,6-dihydro-4g- imidazo-[ 4,5,1-li] quinoline 5 There is obtained, from 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4g-imid&zo[4,5,l-iJ.]quinoline and 1 g (0.00623 mol) of 4-(5-methyl-lg-imidazol-4—yl)piperidine, treated under the conditions of Example 3.6, after recrystallization 10 from acetone, 0.7 g of product in the base form. Melting point t 255°C Fvamplft s (Compound NO. 8) (S) -4-metbyl-2-[4-(5-methyl-i-iinidazol-4-yl)piperidin-l-yll"4.S-dihydroimidazofl.5.4-del[l,4]benzoxazin-15 8-amine 5.1. (S)-5,7-dinitro-3-methyl-3/4-dihydro-2|I-1,4-benzoxazine 7.7 g (0.04 mol)of(S)-3-methyl-5-nitro-3,4-dihydro-2g-l,4-benzoxazine are dissolved in 176 ml 20 of acetic acid at 60°C. 2.8 ml (0.044 mol) of nitric acid are added dropwise, the reaction mixture is stirred for 45 minutes at 60*c and then 176 ml of water are added. The reaction mixture is cooled to o°c and the precipitate fbrmed is filtered off, washed with 25 water and dried under vacuum. 8.13 g of product are obtained. 286164 14 Melting point : 170°c 5.2. (fi)-3-aethyl-7-nitro-3,4-dihydro-2g-l,4-benzoxazin-5-aaine 7.(3 9 (0.032 aol) of (£)-5,7-dinitro-5 3-methyl-3,4-dihydro-2g-l,4-benzoxazine are heated to 50°c and a solution of 30.52 g (0.391 aol) of sodiua sulphide and of 10.70 g of sodiua hydrogencarbonate dissolved in 46 al of water is added dropwise. This reaction aixture is slowly brought to the reflux 10 temperature and then, after stirring for 30 ainutes, a quantity of water is poured in. The reaction aixture is allowed to cool and is extracted three times with ethyl ether. The organic phases are combined, washed with water and dried and the solvent is then evaporated to 15 dryness. 5.98 g of product are obtained. 5.3. (S)-4-methyl-8-nitro-4,5-dihydr©imidazo-[1,5,4-fle][l,4]benzoxazin-2(lg)-one 3.43 g (0.057 aol) of urea are added to 20 5.98 g (0.029 aol) of (g)-3-aethyl-7-nitro-3,4-dihydro-2g-l,4-benzoxazin-5-amine and the aixture is heated for 2 hours at 175*C. It is taken up in boiling water and the precipitate is filtered off and washed with water. The filtrate is extracted with dichloroaethane and the 25 organic extracts are washed with water, dried and evaporated under vacuua. The residue is purified by j i 286 15 chromatography on a silica gal column, slution being carried out vith a dichloromithane:methanol (98:2) mixture. 3.86 g of product are obtained. 5.4. (£)-2-chloro-4-methyl-8-nitro-4,5-dihvdroimidazofi.5„4-de7 f1.47benzoxazine 3.86 g of (0.021 mol) of (fi)-4-methyl-8-nitro-4.S-dihvdroimidazo f1.S.4-delfl.4Ibenzoxazin-2(iH)-one are heated at the reflux temperature for 3 hours in the presence of 76 ml of phosphoryl chloride. The solvent is evaporated to dryness and the residue is taken up in ice. The reaction mixture is basified vith aqueous ammonia and the precipitate formed is filtered off, rinsed vith vater and pulled dry. It is dried in a vacuum oven. The residue is purified by chromatography on a silica gel column, elution being carried out vith a dichloromethane:methanol (99:l) mixture. 3.6 g of product are obtained. 5.5. (S)-4-methyl-8-nitro-2-t4-(5-methyl-lg-imidazol-4-y1)piperidin-1-yl]-4,5-dihydroimidazo-fl.5.4-de1f1.41benzoxazine A mixture of 1.87 g (0.00788 mol) of 4-(5-methyl-lg-imidazol-4-yl)piparidine, l g (0.00394 mol) of (g)-2-chloro-4-methyl-8-aitro-4.5-dihvdroimidazor1.5,4-deJ T1.4Ibenzoxazine and 5 ml of isoamyl alcohol is heated at 120 *C for 5 hours vith 286164 16 stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel column, elution being carried out vith a mixture of dichloromethane, methanol and aqueous ammonia 5 (94:6:0.6). After recrystallization from ethanol, 1.3 g of product are obtained in the base form. Melting point s 125°C 5.6. (S) -4-methyl-2-[4-(5-methyl-lH-imidazol-10 4-yl)piperidin-l-yl]-4,5-dihydroimidazo- [l,5,4-ge][l,4]benzoxazin-8-amine A suspension of 1.1 g (0.00287 mol) of (£)-4-methyl-8-nitro-2-[4-(5-methyl-lg-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo-15 [1,5,4 -de][1,4]benzoxazine in 50 ml of ethanol and a catalytic amount of platinum oxide are introduced into a Parr flask and hydrogenation is then carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and vashed vith 20 ethanol and vith ethyl acetate, the filtrate is recovered and the solvent is evaporated to dryness. 0.8 g of product is obtained, vhich product crystallizes in the base form. Melting point t 245*C 25 [a]£° = -23.4* (c = 0.01, methanol). I 286 17 Example 6 (Compound Mo. 7) (S)-2-[4-(11-imidazol-4-yl)piperidin-l-yl]-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-8-amine There are obtained, from a mixture of (g)-2-chloro-4-methyl-8-nitro-4,5-dihydroi]iiidazo-[1,5,4-fie][1,4]benzoxazine and 4-(lfi-iittidazol-4-yl)piperidine, treated under tbe conditions of Example 5.5, after chromatography on a silica gel column, elution being carried out vith a mixture of dichloromethane, methanol and aqueous ammonia (94:6:0.6), 1.3 g of product, vhich product is treated under the conditions of Example 5.6. 0.7 g of product is obtained in the base form. Melting point : 235-238°C [ot]p° = - 1.4° (c = 0.01, methanol) Example 7 (Compound No. 14) (8)-8-fluoro-4-m«thyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo-fl.5,4-de1f1,41benzoxazine 7.1. 1,1-dimethylethyl (g)-[2-(2-bromo- 5-fluorophenoxy)-l-methylethyl]carbamate 130 g (0.74 mol) of 1,1-dimethylethyl (£)-(2-hydroxy-l-methylethyl)carbamate and 191 g (0.728 mol) of triphenylphosphine are placed in a 4-litre three-necked, round-bottomed flask containing 2.3 litres of toluene. The mixture is cooled vith an ice £8616 4 18 bath and 115 ml (0.726 mol) of diethyl azodicarboxylate are added dropwise. The reaction mixture is left stirring for l hour, 100 g (0.52 mol) of 2-bromo-5-fluorophenol are added dropwise, the reaction mixture 5 is stirred for 2 hours at o*c, the temperature of the reaction mixture is allowed to return to room temperature and the reaction mixture is left stirring overnight. The precipitate obtained is then filtered off and the filtrate is washed with IN sodium hydroxide 10 solution and water, dried and evaporated. The residue obtained is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane and heptane (70:30). 170 g of product are obtained. 15 [®1d° = - 45.6° (c = 0.01, dichloromethane) 7.2. (S)-l-(2-bromo-5-fluorophenoxy)propan-2-amine 170 g (0.48 mol) of 1,1-dimethylethyl (8)-[2-(2-bromo-5-fluorophenoxy)-l-methylethyl]carbamate dissolved in 520 ml of water and 260 ml of 12N 20 hydrochloric acid are heated at reflux for 2 hours. 500 ml of ice-cold water are poured in and extraction is carried out once with 600 ml of toluene and once with 400 ml of ether. The aqueous phase is cooled in an ice-cold water bath and is basified with 10N sodium 25 hydroxide solution. Extraction is carried out three times with 500 ml of ether and the organic phases are combined, washed twice with water and once with a 2861 19 saturated aqueous sodium chloride solution, dried and evaporated under reduced pressure. 118 g of product are obtained in the form of an oil. [<x]d° = + 2.8" (o = 0.01, dichloromethane) 5 7.3. (g)-7-fluoro-3-methyl-3,4-dihydro-2fi-1,4-bensoxaz ine 72 9 (0.768 mol) of sodium tert-butoxide are placed in 1 litre of toluene in a 4-litre three-necked flask under an inert atmosphere. 5 9 of 10 tetrakis(triphenylphosphine)palladium and then a solution of 120 g (0.48 mol) of (g)-1-(2-bromo-5-fluorophenoxy)propan-2-amine in 250 ml of toluene are added. The reaction mixture is heated to 110°C and is left stirring for 2.5 hours. 3 g of catalyst are again 15 added and, after stirring for 5.5 hours at 110°C, the reaction mixture is allowed to cool and 1 litre of water is added. The reaction mixture is stirred, is allowed to separate by settling and the aqueous layer is extracted with toluene. The organic phases are 20 combined, washed with water and dried and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a silica gel column, elution being carried out with dichloromethane. 21.5 g of product are obtained. 25 [<0»# = - 4.8* (c = 0.01, methanol) £80 1 fc)4 20 7.4. (S)-4-acetyl-7-fluoro-3-Bethyl-3,4-dihydro-2g-1,4-benzoxazin® A solution of 21.5 g (0.128 mol) of (&)-7-fluoro-3-Bethyl-3,4-dihydro-2g-l,4-benzoxazine in 5 60 ml of pyridine is cooled with an ioe bath, 15.1 g (0.15 sol) of acetic anhydride are added and the Bixture is allowed to return to room teaperature and is stirred for 48 hours, it is poured onto ice-cold water and extracted twice with ether. The organic phases are 10 combined, washed successively with vater, with dilute hydrochloric acid, with water and with brine and are then dried and the solvent is evaporated under reduced pressure. 24.2 g of product are obtained. 15 [a]£° = -I- 102.9° (c = 0.01, dichloromethane) 7.5. (8)-7-fluoro—3—aethyl-5-nitro—3,4-dihydro-2g-1,4-benzoxazine 24 g (0.114 mol) of (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydro-2H-l,4-benzoxazine are dissolved 20 in 350 ml of acetic acid. 8.4 ml (0.134 boI) of nitric acid are added dropwise and the reaction mixture is left stirring for 4 hours at approximately lOO'C. The acetic acid is evaporated under reduced pressure, 100 Bl of toluene and 500 ml of 3N sodium hydroxide 25 solution are added and the reaction Bixture is left stirring at the reflux teaperature for 3 hours. The reaction mixture is separated by settling and the 286164 21 aqueous layer is extracted vith toluene. The organic phases are combined, vasbed vith vatar, dried and avaporatad under reduced pressure. Tha residue obtained is purified by chromatography on a silica gel column, 5 elution being carried out vith a mixture of dichloromethane and heptane (50:50). Two products are separated. 3.8 g of (S)-7-fluoro-3-iaethyl-5-nitro-3,4-dihydro-2g-1,4-benzoxazine are obtained 10 Melting point : 1166C [a]p° = - 65° (c = 0.016, dichloromethane) and 15 g of its regioisomer, (£)-7-fluoro-3-methyl- 6-nitro-3,4-dihydro-2H-l,4-benzoxazine are obtained Melting point : 132°c 15 [<k]d° = -79.7° (c = 0.01, dichloromethane) 7.6. (£)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine A solution of 3.45 g (0.0162 mol) of (£)- 7-fluoro—3-methyl-5-nitro-3,4-dihydro-2H-i,4- 20 benzoxazine in 90 ml of ethanol and a catalytic amount of platinum oxide are introduced into a Parr flask. Eydroganation is carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and vashed vith ethanol, the 25 filtrate ia recovered and the solvent is evaporated to dryness. 2.9 g of crystalline product are obtained. Melting point : 72*C 286164 22 [ot3d" = "" ?s.3° (c = 0.01, dichloromethane) 7.7. (8)-8-fluoro-4-methyl-4,5-dihydroimidazo-[l,5,4-£g][l,4]benzoxazin-2(lg)-one 2.9 g (0.0162 mol) of (g)-7-fluoro-3-methyl-5 3,4-dihydro-2g-i,4-benzoxazin-5-amine ara heated at 175°c vith an oil bath for 1.5 houra in the presence of 1.8 g (0.03 mol) of urea. The residue is taken up in a vater:ether (50:50) mixture and is triturated in order to obtain a precipitate vhich is filtered off, washed 10 vith vater and vith ether and then dried. 3.1 g of product are obtained. Melting point : 175°C [a]£° = + 33.9° (c = 0.01, dimethylformamide) 7.8. (g)-2-chloro-8-fluoro-4-methyl- 15 4,5-dihydroimidazo[l,5,4-de][1,4]benzoxazine 3.1 g (0.0148 mol) of (£)-8-fluoro-4-methyl-4/5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(lg)-one are heated at the reflux temperature for 3 hours in 70 ml of phosphoryl chloride. The solvent is evaporated 20 to dryness, the residue is taken up in ice-eold vater and the pH of the mixture is adjusted to 8 vith aqueous ammonia. Extraction is carried out tvice vith ether, the organic phases ara combined, vashad vith vater and dried and the aolvent is evaporated to dryness. 25 Purification is carried out by chromatography on a silica gel column, elution being carried out vith a 286164 23 mixture of ethyl acetate and heptane (50:50). 1.85 g of product are obtained. Melting point : 102°C [a]£° = - 15.85* (c = 0.01, dichloromethane) 5 7.9. (g)-8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine A mixture of 1.47 g (0.00617 mol) of 4-(5—methyl—IH—imidazol—4-yl)piperidine, 0.7 g (0.00308 10 mol) of (g)-2-chloro-8-fluoro-4-methyl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine and 4 ml of isoamyl alcohol is heated at 12 0°C for 24 hours vith stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel 15 column, elution being carried out vith a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5). After recrystallization from ethanol, 0.6 g of product is obtained in the base form. 20 Melting point: 224*c [<*]" = - 11.0° (e = 0.991, methanol) Example 8 (Compound Mo. 13) (£)-8-fluoro-2-[4-(lg-imidazol-4-yl)piperidin-l-yl]-4-methyl-4.S-dihydroimidazofl.5.4-del[1,4]benzoxazine 25 (2)-but-2-enedioate (1:2) There is obtained, from a mixture of (g)- 286164 24 2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo-fl.5.4-da1r1.41benzoxazine and 4-(lg-imidazol-4-yl)piperidine, treated under the conditions of Example 7.9., the product in the base form which is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5). By adding to the base two equivalents of maleic acid in methanol, 0.26 g of maleate is obtained. Melting point : 142°C [«3d° = + 8.13° (c = 0.504, methanol) Kev to the table : in the "Salt" ^r>i»mn j the ratio between brackets represents the ratio (salt:base); the absence of any mention means that tbe product is in tbe base form; "HC1" corresponds to a hydrochloride and "mal." corresponds to a maleate No. X R. r3 Salt M.p. < °C) tali* (C=0.01, nethanol) 1 0 8-Cl (s)-ch3 -ch3 208 - 23.8 2 0 8-Cl (8) —chj -H - 215 - 3.7 3 0 8-Cl -H -H hc1 275 - 4 O 8-Cl -H -ch3 hc1 234 - 5 ch2 h 1 CO -ch3 -H - 175-177 - 6 ch2 8-f -CH3 -ch3 - 255 - 7 0 8-NH2 (8)-ch3 -h 235-238 - 1.4 8 0 8-NH2 (8)-ch3 -ch3 - 245 - 23.4 M (II no o> Mo. X R1 R3 Gait M.p. C°C) t«]£° (O=0.01, methanol) 9 0 8-F -h -h - 187 - 10 0 8-F -h -ch3 - 210-217 - 11 0 8-F -chj -h Ml 174 - 12 0 8-F -ch3 -ch3 - 242 - 13 0 8-F (8) -ch3 -h mal. 142 + 8.13* 14 0 8-F (8)-ch3 -ch3 - 224 - llb 15 0 8-F (B)-ch3 -ch3 - 224 +11.1 16 0 8-F (s) -ch3 -h mal. 142 -8.7* o = 0.504, methanol, o = 0.991, methanol. PO oo o> o> 286164 27 The compounds of the invention formed the subject of pharmacological tests which demonstrated their advantage as therapeutically active substances. They were In particular tested for their 5 inhibitory effects on the binding of i'hj-(S)-zacopride to type 5-HTj serotoninergic receptors of the rat cortex, according to the method described by M.M. Barnes et al., in J. Pharm. Pharmacol., 40, 548-551 (1988). 10 Male Sprague-Dawley rats (OFA, Iffa credo) weighing 200 to 250 g are humanely killed and their brains are removed. The cortex is dissected and is homogenized using a Polytron" mill (7.20 s position) in 20 volumes of 25 mM Tris buffer (pH = 7.4, 22°C). The homogenate 15 is centrifuged for 10 min at 45000 x g (in a Sorvall centrifuge equipped with an SS34 rotor) and the pellet is then resuspended in 10 volumes of Tris buffer and incubated at 37°C for 10 min with stirring. The suspension is then diluted to 20 volumes using Tris 20 buffer and centrifuging is carried out under the same conditions as above. The pellet obtaiaed is resuspeaded in 5 volumes of Tris buffer and thea divided into 5 ml aliquot fractions which are frozen at -80°C. On the day of the experiment, the preparation is defrosted to 4*c 25 and then dilutnd 1.2 times using Tris-NaCl incubation buffer (25 mK Tris, ISO mM MaCl, pH =7.4, 22*C). The membrane suspension (100 ill, l mg of proteins) is incubated at 25*C for 25 min in the preseace of 0.5 nM 28 of ['H]-(g)-zacopride (specific activity : 75-85 ci/mmol, Amersham, Little Chalfont, United Kingdom) in a final volume of 500 pi Tris-NaCl buffer, in the absence or in the presence of the test compound. 5 Incubation is halted by filtration using Whatman GF/B filters pretreated with polyethyleneimine (0.1%). Each reaction tube is prediluted with 4 ml of Tris-NaCl buffer and then rinsed 3 times with 4.5 ml of Tris-NaCl buffer. 10 The filters are cut up beforehand before drying in an oven (120°c, 5 min). The radioactivity retained on tbe filters is measured by liquid scintigraphy. The nonspecific binding is determined in the presence of 10 ftM of HDL 72222. 15 For each concentration of study compound, the percentage of inhibition of the specific binding of -(g)-zacopride and then the concentration of the compound which inhibits 50% of the specific binding of C3!!]-(g)-zacopride (ic^) are determined. 20 The ICjq values of the compounds of the invention lie between 0.5 nX and l mM. The compounds of the invention were also studied for their affinity with respect to 5-HT4 receptors in the striatum of guinea pigs according to 25 the method described by Grossman et al. in Br. J. Pharmacol., 109, 618-624 (1993). Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are humanely killed and their brains are removed. 28 6 1 6 4 I 286 29 The striata are excised and are frozen at -80*C. On the day of the experiment, the tissue is defrosted to +4"C in 33 volumes of 50 mM Hepes-NaOH buffer (pH 7.4 at 20*c) and is homogenised using a Polytron® mill. The homogenate ia oentrifuged for 10 min at 48,000 x g, the pellet is recovered, is resuspended and is recentrifuged under the same oonditions. The final pellet is suspended in Hepes-NaOH buffer (30 mg of fresh tissue/ml). This membrane suspension is used as is. 100 nl of the membrane suspension are incubated at 0*C for 120 minutes, in the presence of 0.1 nM of [^GRllSSOS (specific activity 80-85 Ci/mmol), in a final volume of l ml of Hepes-NaOH buffer (50 mM, pH = 7.4), in the absence or in the presence of the compound under test. Incubation is halted by filtration through Whatman GF/B* filters pretreated with 0.1% polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0°c and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 30 pMserotonin. The specific binding represents 90% of the total radioactivity recovered on the filter. For each concentration of study compound, the percentage of inhibition of the specific binding of [3H3GR118808 and then the concentration of the tested compound which inhibits 50% of the specific binding 30 (XCso) are determined. The IC50 values of tbe compounds of the invention lie between 0.02 and 2 jiM. The results of the biological tests show that 5 the compounds of the invention are antagonists of 5-HT3 and/or 5-HT4 serotoninergic receptors. They may hence be used for the treatment and prevention of disorders in which 5-HT3 and 5-HT4 receptors are involved, such as nausea and vomiting, for example 10 following antitumour treatment or the administration of an anaesthetic; disorders of the central nervous system such as schizophrenia, mania, anxiety and depression; disorders of cognition such as senile dementia or Alzheimer's presenile dementia; dyskinesia, pain, 15 migraine and headache; disorders associated with alcohol or drug dependence or withdrawal; disorders of gastrointestinal function such as dyspepsia, peptic ulcer, heartburn, flatulence; disorders of the cardiovascular system and respiratory disorders. 20 They may also be used for the treatment and prevention of disorders such as diarrhoea, irritable colon, oesophageal reflux, intestinal motor disorders, disorders of intestinal secretion, cystic fibrosis of the pancreas, carcinoid syndrome and incontinence. 25 The present invention also provides a pharmaceutical composition which comprises a compound of formula (X) and an exeipient, which may be in any form suitable for oral or parenteral administration, 286164 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 286164 31 such as a tablet, drag£e, capsule, including a hard gelatin capsule, or a suspension or solution to be swallowed or injected, and in doses that enable 0.005 to 5 mg/kg to be administered 1 to 4 times a day. 5 The present invention also provides a compound of formula (I) for use in a method of treatment of the human or animal body. The present invention further provides the use of a compound of formula (Z) in the manufacture of a 10 medicament for use in the treatment or prevention of a disorder in which 5~HT3 and/or 5-HT4 receptors are involved. There is also disclosed a method of treatment of a subject suffering from a disorder in which 5-HT3 and/or 15 5-HT4 receptors are involved which comprises administering to that subject an effective amount of a compound of formula (I). The present invention also provides a composition for treating or preventing a disorder in which 5-HT3 20 and/or 5-HT4 receptors are involved comprising a compound of formula (X) and a pharmaceutically acceptable adjuvant. 28616 NZ, ZA 32 WHAT -tfWE CLAIM IS

1. A compound of formula (I) in which 10 X represents an oxygen atom or a methylene group, Rj represents a chlorine or fluorine atom or a methyl, methoxy or amino group, and R2 and R3 independently represent a hydrogen atom or a methyl group, 15 in the form of the free base or an addition salt with a pharmaceutically acceptable acid.

2. A compound according to claim 1 which is in the form of a pure enantiomer.

3. A compound according to claim 1 or 2, in 20 which X represents an oxygen atom and Rj is at position 8 on the phenyl ring.

4. (5) -8-Fluoro-4-methyl-2-[4-(5-methyl-ifr-imidazol-4-yl)piperidin-l-yl]-4,5-dihydroimidazo- 25 [1,5,4-de][1,4]benzoxazine in the form of the free base or an addition salt with a pharmaceutically acceptable acid.

5. (S)-8-Fluoro-4-methyl-2-[4-(lff-imidazol-4- 286 i04 10 15 NZ, ZA 33 yl)piperidin-l-yl]-4,5-dihydroimidazo- [ 1,5,4-<Je] [1/4]benzoxazine in thfe form of the free base or an addition salt with a pharmaceutically acceptable acid.

6. A process for the preparation of a compound of formula (I) according to claim 1, in which process a compound of formula (II) (II) in which X, I*! and R2 are as defined in claim 1 and Y represents a halogen atom, is reacted with a compound of formula (III) (III) in which R3 is as defined in claim 1 to give a compound of 20 formula (I) and optionally converting the compound obtained into a salt thereof with a pharmaceutically acceptable acid.

7. A process according to claim 6 substantially as described in any of Examples 1 to 8. 25

8. A compound of formula (I) according to claim 1 whenever prepared by the process of claim 6 or 7. 34 286164

9. A compound of formula I as defined in claim 1 substantially as herein described with reference to the examples.

10. A pharmaceutical composition which comprises a compound of formula (I) according to any one of claims 1 to 5, 8 and 9 and an excipient

11. A compound of formula (I) as defined in any one of claims 1 to 5, 8 and 9 for use in a method of treatment of the human or animal body.

12. Use of a compound of formula (I) as defined in any one of claims 1 to 5, 8 and 9 in the manufacture of a medicament for use in the treatment or prevention of a disorder in which 5-HT3 and/or 5-HT4 receptors are involved. '"y ib.3 authorised agents ^ A J PARK & SON :sr IkttdcnL </div>