DERIVATIVES OF IMIDAZO [5,1-C][1, 4]BENZOXAZIN-1-ONE AS 5 HT3 ANTAGONISTS

Abstract: The invention provides derivatives of 2,3,3a,4-tetrahydro-2-azabicyclo alkyl-1H-imidazo [5,1-C][1,4]benzoxazin-1-one of general formula (I), in which inter alia R3 represents (a) or (b) wherein n is an integer or 1 or 2 and R8 is hydrogen, C1-C6 alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2-C6 alkanoyl; and the pharmaceutically acceptable salts thereof, which are useful in the treatment of CNS disorders, gut motility disorders, emesis and migraine, as cognition activators, anti-drug addiction agents and analgesics.

Description: DERIVATIVES OF IMIDAZO ~ ' [ 5 , l-C] [l , 4 ]BENZOXAZIN-l-ONE AS 5 HT3 ANTAGONISTS The present invention relates to new derivatives of 2,3,3a,4-Tetrahydro-2-azabicycloalkYl-lH-imidazo [5,1-cJ pL,4]benzoxazin-l-one f to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents. The present invention provides novel compounds having the general formula (I) wherein each of R, R and R , which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C,-C, alkyl, CF„, I D 3 alkylthio, formyl, C -C alkanoyl, carboxy, C,-C, alkoxy-carbonyl, nitro, -N(H. R_) in 1 O A D which each of R and R_ independently is hydrogen, C,-C c alkyl, formyl or C--C. alkanoyl; or a (R_ R_)N-S0„ 1 o ά o o 7 2 group, in which each of R and R independently is hydrogen or C,-C, alkyl; 1 6 R is a group a ) or b ) wherein n is an integer of 1 or 2 and R_ is hydrogen, C,-C, 8 l o alkyl unsubstituted or substituted by phenyl,. C -C alkenyl, C -C alkynyl, formyl or C -C alkanoyl; and the pharmaceutically acceptable salts thereof. The formula reported above for the compounds according to the present invention includes all the possible isomers, in particular stereoiso ers, typically diastereoisomers, as well as their mixtures. In the compounds of the invention wherein the substi- tuent R is a group a), as defined above, such group w may be in the R- or S- configuration, or in mixtures thereof. Similarly wr-εn the substituent R is a group b), as defined above, such group may be in the endo- or exo- configuration or mixtures thereof, the endo being the preferred. The invention includes within its scope the metabolites ' and the metabolic precursors or bio-precursors (other¬ wise known as pro-drugs) of the compounds of formula (I). Namely the invention includes compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). A halogen atom may be a fluorine, chlorine, bromine or iodine atom, preferably it is chlorine or bromine. The alkyl, alkenyl, alkynyl, alkoxy and alkylthio group may be a branched or straight chain groups. A C -C alkyl group is preferably a C -C alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. butyl or tert butyl, in particular methyl or ethyl. A C -C alkoxy group is preferably a C -C . alkoxy grocp e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy, preferably methoxy and ethoxy. A Cl-Co, alkylthio group is preferably a C1-C.alkylthio group, e.g. ethylthio, ethylthio, propylthio and butylthio, in particular methylthio. A C -C alkenyl group is preferably allyl. A C -C alkynyl group is preferably propargyl. A C -C alkanoyl group is e.g. a C -C 4 alkanoyl group, in particular acetyl and propionyl. Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, with inorganic e.g- nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids, or organic e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, fumaric, mandelic and salicylic acids. Preferred compounds of the invention are the compounds of formula (I) wherein each of R, R and R , which may be the same or different, is hydrogen, halogen, cyano, CF ό_, C X-C A. alkylthio, C 1-C,, alkoxy or -N(R A„ R.D) in which each of R. and R independently is hydrogen, C -C alkyl, formyl or C -C alkanoyl; R 3 is which n is 1 or 2 and R„ is C -C alkyl; and the pharmaceuti¬ cally acceptable salts thereof. Examples of preferred compounds according to the invention are the following, which, if appropriate, may be either in the endo- or exo-configuration or mixtures thereof: 2,3,3a,4-tetrahydro-2-(l-azabicyclo [2.2.2]oct-3-yl) -lH-imidazo[5,l-cJ Cl,4]benzoxazin-l-one; 2,3,3a,4-tetrahydro-2- ( 1-azabicyclo[2.2.2_Joct-3-yi)- -8-chloro-lH-imidazo[5,1-c] [1,4]benzoxazin-1-one; 2,3,3a,4-tetrahydro-8-chloro-2-(8-methyl-8- -azabicycloC3.2.l]oct-3-yl)-lH-imidazoC5,l-c] fl. ] benzoxazin-1-one; 2,3,3a,4-tetrahydro-2-(8-methyl-8-azabicyclo [3.2.lloct-3-y1)-lH-imidazo[5,1-cJ[l,4jbenzoxazin- -1-one; 2,3,3a,4-tetrahydro-2-(9-methyl-9-azabicyclo [3.3.l]non-3-yl)-lH-imidazo[5,1-c] [l,4jbenzoxazin-1- -one; 2,3,3a,4-tetrahydro-8-chloro-2-(9-methy1-9- -azabicyclo[3.3.llnon-3-yl)-lH-imidazo[5,1-cJ [1,4j benzoxazin-1-one; and the pharmaceutically acceptable salts thereof, in particular the hydrochloride. The compounds of the invention and the salts thereof can be obtained by a process comprising reacting a compound of formula (II) wherein R, R , R and R are as defined above, with a carbonyl containing cyclizing agent and, if desired, converting a compound of formula (I) into another compound of •formula (I), and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof, -id/or, if desired converting a salt into a free-compound, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers. A carbonyl containing cyclizing agent, according to the invention, is e.g. an alkyl-haloformiate, typical¬ ly a C -C alkyl-haloformiate, in particular methyl chloroformiate, N.N-carbonyldiimidazole, the latter being the pref red. The cyclizing reaction can be carried out in an aprotic organic solvent chosen for instance from tetrahydrofuran, benzene, toluene and xylene, at reaction temperatures ranging from about 50°C to reflux temperature and if need be under an inert, e.g. nitrogen, atmosphere. A compound of formula (I) can be converted, if desired into another compound of formula (I). Thus for instance a compound of formula (I) wherein one or more of R, R and is a ino can be converted into another compound of formula (I) wherein one or more of R, R and R is C -C alkanoylamino or formylamino. A compound of formula (I) in which one or more of R, R. and R is carboxy can be converted into another compound of formula (I) wherein one or more of R, R and R_ is C -C, alkoxycarbonyl, and vice versa. These 2 1 6 optional conversionscan be carried out by methods known in themselves. The optional salification of a compound of formula (I) as well as the conversion of a salt into the free com¬ pound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods. For example the separation of a mixture of geometric isomers, e.g. endo- and exo-isomers, may be carried out by fractional crystallization from a suitable solvent or by chromatography, either column chromato- graphy or high pressure liquid chromatography. If desired, the separation of a mixture of isomers into che single isomers may carried out also on the inter¬ mediate products e.g. by following the above described methods and in general according to techniques well known in the art. The compounds of formula (II) which are new an d are a further object of this invention can be obtained by reacting a compound of formula (III) (III) wnerein R, R and R are as defined above, either with , a compound of formula (IV) or of formula (V), or a salt thereof in particular the hydrochloride. wherein R and n are as defined above, thus obtaining a compound of formula (II) wherein R is as defined above. The reaction of a compound of formula (III) with a com¬ pound of formula (IV) or (V) can be carried out accord- ing to known methods in the art. According to a prefer¬ red embodiment of the invention, if the reaction provi¬ des a mixture of isomers of a compound of formula (II), before submitting them to the above cyclizing reaction such mixture of isomers can be separated into the single isomers, e.g. endo- and exo-isomers, by methods well known in the art, e.g. by silica gel flash-chro- atography. The compounds of formula (III) are known or may be obtained according to known procedures as described in J. Heterocyclic Chem., 20, 259 (1983). The compounds of formula (IV) and (V) are well known compounds or may be obtained from known compounds and by known methods. When in the compounds described above groups are present which need to be protected during the reactions described above, such groups can be protected in a conventional way before the reaction takes place and then deprotected. Examples of protecting groups are those employed usually in the chemistry of peptides. The compounds of the invention are active on the serotoninergic system, in particular as 5HT 3 receptor antagonists, as proven for example by the fact that they have been found to be active in antagonizing the von Bezold-Jarisch che oreflex evoked by 5-HT in the anesthetised rat according to the method described by Fozard J.R. , Naunyn-Schmiederberg's Arch.Pharmacol. 326, 36- 44 (1984). -._ The following Table I reports the in vivo 5HT 3 antagonist activity data obtained in this test for the representative compounds of the invention 2,3,3a,4-tetrahydro-2-(l-azabicyclo [2.2.2]oct-3-γl)-8-chloro-lH-imidazo[5,1-c][1,4]benzoxazin-l- -one hydrochloride (internal code FCE 26781); 2,3,3a,4-tetrahydro-2-(l-azabicyclo[2.2.2]oct-3-yl)-lH-imidazo [5,1-c][l,4]benzoxazin-l-one hydrochloride (internal code FCE 26962); (endo)-2,3,3a,4-tetrahydro-8-chloro-2-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-lH-imidazo[5,l-c][l,4]benzoxazin-l-one hydrochloride (internal code FCE 26783); (endo)-2,3,3a,4-tetrahydro-2-(8-methyl-8-azabicyclo[3.2.1]oct- -3-yl)-lH-imidazo[5,1-c] [1,4]benxozazin-l-one hydrochloride (internal code FCE 26878) , and ( endo ) -2,3,3a,4-tetrahydro-2-(9-methyl-9-azabicyclo[3.3.1]non- -3-yl)-lH-imidazo[5,1-c] [1, ]benzoxazin-l-one hydrochloride ( internal code FCE 26963). Table I Inhibition of the Bezold-Jarisch reflex elicited by 5-HT (20 ug/kg i.v.) by i.v. FCE compounds in the anesthetized rat. Values are mean + S.E.M. from N animals * p <0.01 vs controls (Dunnett's test) N = number of animals N.C. = not calculated. The compounds of the invention have also been found to be potent and selective inhibitors of the binding of 3 H-GR65630 (a selective 5-HT 3 receptor antagonist) according to the method described by Kilpatrick G.J. et al.. Nature, 330, 746-748 (1987). The following Table II reports the data obtained in this in vitro test for a representative group of compounds of the invention in comparison with the known reference compounds MDL 72222 and Metoelopramide. MDL 72222 is the compound of formula GR 65630 is the compound of formula For MDL 72222 see Nature, 330, 746-748 (1987) and for Metoclopramide see Merck Index 10th Edition 6019, page 880. FCE 26785 is (endo)-2,3,3a,4-tetrahydro-8-chloro-2- (9-methγl-9-azabicyclo[3.3.1]non-3-yl)-lH-imidazo[5,1-c] [1, ]benzoxazin-l-one hydrochloride. Table II 5-HT 3 binding affinity < * > for rat entorhinal cortex Ki (juM) low 1.9 14.0 72 0.6 <m, [ 3 H]-GR 65630 labelled 5-HT 3 sites. The tested compounds were able to interact with 5-HT 3 -serotonin receptors labelled in the entorhinal cortex of the rat brain with 3 H-GR 65630. Of these FCE 26781, FCE 26963 and FCE 26875 interacted according to a two site non-linear fitting model, while MDL 72222, Metoclopramide, FCE 26783 and FCE 26878 displaced 3 H-GR 65630 according to one site non-linear fitting: this is the reason why only one (rather than two) Ki value is reported in Table II for the latter four compounds. The affinity for serotonin 5-HT 3 receptor was also assessed for instance in rat entorhinal cortex using the selective radioligand 3 H-BRL 43649 as described by Nelson and Thomas (1989). Nelson D.R. and Thomas D.R. , [ 3 H]-BRL 43694 (Granisetron) . a specific ligand for 5-HT 3 binding sites in rat brain cortical membranes Biochem. Pharmac. 38, 1693-1695, 1989. The following Table III summarizes the data obtained in this in vitro test for a representative group of compounds of the invention in comparison with the known reference compounds MDL 72222 and Metoelopramide. Table III 5-HT 3 binding affinity to) for rat entorhinal cortex. Compound Ki (nM) FCE 26781 13 FCE 26962 0.4 FCE 26783 30 FCE 26878 9 FCE 26963 170 FCE 26785 310 MDL 72222 23 Metoelopramide 490 ■ *~ - 3 H-BRL 43964 labelled 5-HT 3 sites The above data clearly show a superior activity of the compounds of the invention over the references. In view of the said activities, the compounds of the present invention can be useful, for example, in the treatment of CNS disorders such as, e.g. anxiety and psychosis, and/or in the treatment of gut motility disorders, and/or emesis. In view of the above activities the compounds of the invention can be also useful as, for example, anti-migraine, anti-drug addiction agents, as cognition activators, or as analgesics. The dosage levels suitable for administration to adult humans of the compounds of the invention, either for prophylaxis or therapeutic treatment, may range from about 0.010 to about 20 mg/kg of body weight, depending on the chosen route of administration, on the particular compound chosen, on the particular patient under treatment and also on the nature and severity of the disorder. For instance for the compound of the invention 2,3,3a,4- -tetrahydro-2-(l-azabicyclo[2.2.2]oct-3-yl)-8-chloro-lH-imidazo [5,1-c][l,4]benzoxazin-l-one is suitable administered orally at a dosage in this range. Preferably the compounds may be, e.g., administered in single or divided doses such that the total daily dosage falls within the range of about 0.020 to about 10 mg/kg per day. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response. The compounds of the invention can be administered in a variety of αosage forms, e.g. orally, in tne form o tablets, capsules, sugar, or film coated tablets, liquid solutions or suspensions. The invention includes pharmaceutical compositions co prising a compound of the invention in association wi a pharmaceutically acceptable excipient (which can be a carrier or diluent). The nature of the pharmaceutical compositions containin the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administra¬ tion. The compositions may be formulated in the conventiona manner with tne usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions, or suspensions tablets, pills, gelatine capsules, syrups, drops or su positories. Thus, for oral administration, the pharmaceutical co position containing the compounds of this invention are preferably tablets, pills or gelatine capsules wic contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbito cellulose; lubrificants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or tney may also contain binders, such as sta ches, gelatine, methylcellulose, carboxymethylcellulose gum-arabic, tragacanth, polyvinylpyrrolidone; disaggre¬ gating agents, such as starches, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuff sweeteners; wetting agents, such as lecithin, polysorb tes, laurylsulphates; and in general, non-toxic and pharmacologically inactive substances used in pharma¬ ceutical formulations. Said pharmaceutical preparation may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coatin or film-coating processes, the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccna- rose or saccharose with glicerine and/or mannitol and/ or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a pharma¬ ceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. prolylene glycol, and if desired, a suitable amount of lidocaine nydro- chloride. The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions. The suppositories may contain together with the activ compound a pharmaceutically acceptable carrier e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit th present invention. Example 1 3, -dihydro-3- 1(1-azabicycloC2.2.2]oct-3-yl)aminomethylJ- 2H-6-chloro-l,4 benzoxazine. To a stirred solution of 2H-3,4-dihydro-3-aminomethyl- -6-chloro-l,4-benzoxazine (2.6 g; 0.0131 moles) in 50 ml of anhydrous methanol kept under nitrogen atmosphere, 3-quinuclidinone hydrochoride (2.3 g; 0.0142 moles) is added. Tne pH is adjusted to pH 6 by addition of glacial acetic acid. Sodium cyanoborohydride (1.8 g; 0.0286 moles) is added in two portions. The reaction mixture is refluxed for 12 hours, cooled and then filtered. After evaporation to dryness the residue is taken up with water, basified with 20% sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by silica gel flash-chro atography (ethyl ace- tate-methanol-30 ammonium/hydroxide, 130:70:6 as eluant) to give the captioned product as a clear oil (2.6 g). C1, £ 6H_...C1 N,0 required = C:62.43;H:7.21;N:13.65;C1:11.52 found = C:62.80;H:7.52;N:13.32;C1:11.18 By proceeding analogously the following compound can be prepared as a clear oil. 3, -dihydro-3-C(1-azabicyclo[2.2.2]oct-3-yl)aminomethyl 2H-1 , -benzoxazine. C, e H ( -._N_0 required = C:70.30;H:8.48;N:15.37 lb 2 found = C:70.63;H:8.80;N * :14.98. Example 2 3,4-dihydro-3-[(endo-8-methyl-8-azabicyclo[3.2.13oct- -3-yl)aminomethyl]-2H-6-chloro-l,4-benzoxazine;3,4- dihydro-3- (exo-8-methyl-8-azabicyclo[3.2.0 oct-3-yl) aminomethylJ-2H-6-chloro-l,4-benzoxazine. To a stirred solution of 2H-3,4-dihydro-3-aminomethyl- -6-chloro-l,4 benzoxazine (5 g; 0.0252 moles) in -70 ml of anhydrous methanol kept under nitrogen atmosphere, tropinone (3.8 g; 0.0273 moles) is added. The pH was adjusted to pH 6 by addition of glacial acetic acid. Sodium cyanoborohydride (3,4 g; 0.0541 moles) is added in three portions. The reactionmixture is refluxed 8 hours, cooled and then filtered. After evaporation the residue is taken up with water, basified with 20% sodium hydroxide solution and extracted tnree times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by silica gel flash-chromatography (ethyl acetate-methanol- 30% ammonium hydroxide, 130:70:5 as eluant) to give a mixture of captioned endo and exo productsas an oil (5.3 g). C._H Cl N O required= C:63.44; H:7.52; N:13.06; Cl:11.02 found =C:63.25; H:7.74; N:12.87; Cl:10.83 By proceeding analogously the following mixture of end and exo products can be prepared as an oil. 3,4-dihydro-3- endo-8-methyl-8-azabicyclo[3.2.lloct-3 yl)aminomethyl]-2H-l,4-benzoxazine; 3,4-dihydro-3-[(exo-8-methy1-8-azabicyclo[3.2.lloct-3- aminomethy1]-2H-1,4-benzoxazine. C H N 0 required = C:71.04;H:8.77;N:14.62 found = C:70.82;H:9.02;N:14.33. By proceeding analogousl;. starting from 2H-3,4-dihydro 3-aminomethyl-6-chloro-l,4-benzoxazine and 9-methyl-9- azabicyclo[3.3.l]nonan-3-one hydrochloride the compoun 3,4-dihydro-3-[(9-methy1-9-azabicyclo[3.3.1}non-3-yl) aminomethyl]-2H-6-chloro-l,4-benzoxazine can be obtain as a mixture of endo and exo products as an oil. C, β H C1N.-.0 required = C:64.36;H:7.80;N:12.51;C1:10. 18 26 found = C:64.20;H:8.03;N:12.24;C1:10. Analogously the following compound as a mixture of end and exo products can be prepared as an oil: 3,4-dihy ro-3-[(9-methy1-9-azabicyclo[3.3.1 Jnon-3-yl) aminomethyl]-2H-1,4-benzoxazine. C H N 0 required = C:71.72;H:9.03;N:13.94 found = C:71.49;H:9.40;N:13.59 Example 3 2,3,3a,4-tetrahydro-2-(l-azabicyclo[2.2.2]oct-3-yl)- -8-chloro-lH-imidazo[5,1-c][1,4]benzoxazin-l-one hydro¬ chloride. To a stirred solution of 3,4-dihydro-3-[(l-azabicyclo[2.2.2] oct-3-yl)aminomethyl]-2H-6-chloro-l,4-benzoxazine (2 g; 0.0065 moles) in anhydrous tetrahydrofuran (10 ml), N,N-car- bonyldiimidazole (2.1 g; 0.13 moles) is added. The reaction mixture is refluxed for 10 hours under nitrogen atmosphere. After evaporation, the residue is taken up in ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After filtration and evaporation to dryness, the product is purified by silica gel flash-chromatography (ethyl acetate: methanol: 30% ammonium hydroxide, 100:50:5 as eluant), followed by treatment with an excess of a solution of hydrochloric acid in ethanol. The crude salt is collected by filtration and recrystallized from absolute ethanol to yield 1.2 g of the desired product as a diastereoisomeric mixture (about 50:50); .p. 316-323 β C dec. By proceeding analogously the following compound can be prepared 2,3,3a,4-tetrahydro-2-(l-azabicyclo[2.2.2]oct-3-yl)-1H- -imidazo[5,l-c][l,4]benzoxazin-l-one hydrochloride, m.p. 288-295 β C dec. Example 4 (endo )-2 ,3,3a, - tetrahydro-8-chloro-2-(8-me thy 1-8- azabicyclo[3.2.lloct-3-yl)-lH-imidazo[5,1-c][l,4j benzoxazin-1-one hydrochloride ; (exo)-2,3,3a,4- 5 tetrahydro-8-chloro-2-(8-methyl-8-azabicyclo[3.2.lJ oct-3-yl)-lH-imidazo[5,l-c] [l,4]benzoxazin-l-one hydr chloride. To a stirred solution of a mixture of 3,4-dihydro-3- [ ( endo-8-me thy 1-8-azabicyclo [3.2.l3oc -3-yl)amino- 10 methy -2H-6-chloro-l,4-benzoxazine and 3,4-dihydro-3- [(exo-8-methyl-8-azabicyclo[3.2.l oct-3-yl) ami-ncraethyl} -2H-6-chloro-l,4-benzoxazine (4.8 g; 0.0149 moles) in 30 ml of anhydrous tetrahydrofuran, N,N-carbonyldiimi dazole (4.8 g; 0.0296 moles) is added. 15 The reaction mixture is refluxed for 8 hours under nitrogen atmosph re. After evaporation, the residue i taken up in methylene chloride, washed with water and dri over anhydrous sodium sulfate. After filtration and evaporation to dryness, the mixture is purified by 20 silica gel flash-chromatography (ethyl acetate: methan triethylamine, 80:15:5 as eluant) to obtain the CendoT and the C exo 3 product. By treatment of the [endo] product with an excess of hydrochloric acid in ethanol a crude salt is obtained 25 After filtration and recrystallization from absolute ethanol the desired product is obtained (2.1 g); m.p. 260-283 β C dec. Analogously the [exol product was obtained (1.5) as hydrochloride; m.p. 290-310 β C dec. By proceeding analogously the following compounds can be prepared either as a free product or as hydrochloride salt thereof. ( endo ) -2 , 3 , 3a , 4- te trahydro-2- ( 8-me thyl-8-azabicyclo [3.2. l] oc t-3-yl )-lH-imidazo [5 , 1-c] [l , 4 " )benzoxazin-l- one, hydrochloride m.p. 300 β C dec; ( exo ) -2 , 3 , 3a , 4-te trahydro-2- ( 8-me thyl-8-azabicyclo [3.2. l]oct-3-yl)-lH-imidazo[5,l-c] [l,4] benzoxazin-1- one, hydrochloride m.p. 290-3.00°C dec; (endo)-2,3,3a,4-tetrahydro-8-chloro-2-(9-methyl-9- azabicyclo [3.3. l]non-3-yl )-lH-imidazo [5, 1-c] [l ,4} benzoxazin-1-one hydrochloride m.p. 270-280°C dec; (exo)-2,3,3a,4-tetrahydro-8-chloro-2-(9-methyl-9- azabicyclo [3.3. l]non-3-yl)-lH-imidazo[5, 1-c] [l,4] benzoxazin-1-one hydrochloride m.p. 150 β C; ( endo)-2,3,3a,4-tetrahydro-2-(9-methyl-9-azabicyclo [3.3. l] non-3-y 1 ) - lH-imidazo [5 , l-c3 [l , 4j benzoxazin-1- one hydrochloride m.p. 247-251°C; and ( exo ) -2,3,3a,4-tetrahydro-2-(9-methyl-9-azabicyclo [3.3.l]non-3-yl ) -lH-imidazo [5,1-c] [l,4]benz xazin-l- one m.p. 206-210°C. Example 5 Tablets each weighing 150 mg and containing 60 mg of the active substance can be manufactured by blending and compressing the following ingredients: 2,3,3a,4-tetrahydro-2-(1-azabicyclo[2.2.2]oct-3-yl) 8-chloro-lH-imidazo[5,1-c}[l 14 benzoxazin-1-one Hydrochloride Starch Cellulose microcrystalline Polyvinylpyrrolidone Sodium carboxymethyl starch Magnesium stearate Example 6 Capsules, each dosed at 200 mg and containing 80 mg of the active substance can be prepared as follows. 2,3,3a,4-tetrahydro-2-(l-azabicyclo chloro-lH-imidazo[5,l-c £l, ]benzoxazin-1-one Hydrochloride 80 mg Corn starch 60 mg Cellulose microcrystalline 59 mg Magnesium stearate 1 m g Th i s formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 200 mg for each capsule.

Claims: C L A I M S 1. A compound of formula (I) wherein each of R, R and R , which may be the same or dif¬ ferent, is hydrogen, halogen, hydroxy, cyano, C -C c alkyl, CF,., C -C, alkoxy, C -C, alkylthio, 1 6 3 1 6 D formyl, C2-Co., alkanoyl, carboxy, C,-Cb, alkoxy-car- bonyl, nitro, -N(R A.R,D) in which each of R A. and R,b independently is hydrogen, C -C, alkyl, formyl or 1 6 C -C,, alkanoyl; or a (R,R_)N-S0. group, in which 2 6 b i d each of R, and R_ independently is hydrogen or 6 7 C 1 -C 6 alkyl; wherein n is an integer of 1 or 2 and R is hydrogen, c -C o 1 6 alkyl unsubstituted or substituted by phenyl, C 2~ C 4 alken yl. C 2 ~ C alkynyl, formyl or C 2 -C 6 alkanoyl; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I), according to claim 1, wherein each of R, R and R , which may be the same or different, is hydrogen, halogen, cyano, CF3_, C,1-C,, alkylthio, C1-C4. alkoxy or -N(R A.R I-)) in which each of R. and R, independently is hydrogen, 4 5 C -C alkyl, formyl or C -C alkanoyl; 2 in which n is 1 or 2 and R g is C,-C 4 alkyl; or a pharmaceutically acceptable salt thereof. 3. A compound selected from the group consisting of: 2,3,3a,4-tetrahydro-2-(l-azabicyclo[2.2.2]oct-3-yl) -lH-imidazo[5,l-c] [l,4]benzoxazin-l-one; 2, 3, 3a, -tetrahydro-2-( l-azabicyclo [2.2.2]oct-3-yl ) -8-chloro-lH-imidazo[5,l-c] [l,4]benzoxazin-l-one; 2 , 3, 3a, 4-tetrahydro-8-chloro-2-( 8-me thy 1-8- -azabicyclo[3.2.lloct-3-yl)-lH-imidazo[5,l-c] [l,4] benzoxazin-1-one; 2 , 3 , 3 a , 4- te trahy dro- 2- ( 8-me thyl- 8- azabicyclo ' [3. 2 . 1 ] oct-3-yl )-lH-imidazo [5 , 1-c] l , 4] benzoxazin- 1-one ; 2 , 3, 3a, 4 - tetrahy d ro- 2 -( 9-me thy 1-9- azabicyclo [ 3 .3. l Jnon-3-yl )-lH-imidazo [5, l-c] [l , 4] benzoxazin- 1-one ; 2,3,3a,4-tetrahydro-8-chloro-2-(9-methy1-9- aza b icyclo[3.3.l " |non 3-yl)-lH-imidazo[5,l-c] [l,4] benzoxazin-1-one which, if appropriate, may be 10 either in the endo- or exo- configuration or mixtures thereof, and the pharmaceutically accept ble salts thereof. A process for the preparation of a compound of formula (I), as defined in claim 1, or a pharma¬ 15 ceutically acceptable salt thereof, the process comprising reacting a compound of formula (II) wherein R, R,, R ^ an R,. are as defined in claim 1, with a 1 2 « 3 20 carbonyl containing cyclizing agent and, ifdesired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, con ¬ verting a compound of formula (I) into a pharma ¬ ceutically acceptable salt thereof, and/or, if 25 desired, converting a salt into a free-compound, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers , SUBSTITUTESHEET A pharmaceutical composition comprising a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) or a pharmaceutically acceptabl salt thereof as defined in claim 1, 2 or 3. 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in the treatment of CNS disorders. 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use as an anti-anxiety agent. 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use as an anti-emesis agent. 9. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, in the preparation of a medicament for use in treating CNS disorders, gut motility disorders, emesis or migraine, or as a cognition activator, an anti-drug addiction agent or an analgesic. 10. A compound of formula ( II ) wherein eac h of R, R and R , which may be the same or dif ¬ ferent, is hydrogen, halogen, hydroxy, cyano, alkyl, CF„, C -C, alkoxy, C,-C, alkylthio, formyl, 3 1 b 1 o C -C, alkanoyl, carboxy, C -C alkoxy-carbonyl, 2 6 1 o nitro, -N(R.R , ) in which each of R. and R_ indepen 4 5 4 b dently is hydrogen, C 1-C, alkyl, formyl or C2-C6, alkanoyl; or a (R,R_)N-S0,- group, in which each of 6 7 2 R, and R_ independently is hydrogen or C -C , alkyl 6 7 1 6 wherein n is integer of 1 or 2 and R g is hydrogen, C -C,alky 1 6 unsu b stituted or su b stituted by phenyl, C 2 -C 4 alken C -C 4 alkynyl, formyl or C,,-C 6 alkanoyl.

Inventors: ARRIGONI CLAUDIO, CACCIA CARLA, HEIDEMPERGHER FRANCO, VARASI MARIO, ARRIGONI, CLAUDIO, CACCIA, CARLA, HEIDEMPERGHER, FRANCO, VARASI, MARIO
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1993
Main classification: C07D491
IPC codes: A61K31, A61P25, C07D498, C07D519