MXPA99005277A - Substituted 4-(6-fluoro-(1h)-indol-3-yl)-1,2,3,6-tetrahydropyridine for the treatment of cns-disorders - Google Patents

Abstract

A pharmaceutical compound of formula (I), in which R1 is hydrogen, C1-4 alkyl, C1-4 alkoxy or halo, and R2 is hydrogen, C1-4 alkyl or C1-4 alkoxy;or a salt thereof. The compounds of the invention and their pharmaceutically acceptable salts are indicated for use in the treatment of disorders of the central nervous system.

Description

4- (6-FLUORO- (1H) -INDOL-3-IL) -1,2,3,6- TETRAHYDROPYRIDINE SUBSTITUTED FOR TREATMENT OF CNS DISORDERS Field of Invention This invention relates to pharmaceutical compounds and their use in the treatment of disorders of the central nervous system.

Background of the Invention It is known that changes occur in certain neuronal serotonin (5-HT) receptors, such as, for example, the 5-HT2A receptor, in the central nervous system disorders such as, for example, depression. One purpose for better medications is to provide compounds that bind to specific receptors, such as the 5-HT2A receptor, and that also have beneficial activity with other receptors to give. a desirable profile of activity without, or even minimized, collateral effects not required. For example, it is desired for a drug to combine the affinity for the serotonin receptor and also to inhibit Ref .: 30225 the inhibition of the resumed serotonin, passing from a low bond to the α-adrenergic receptors and dopamine D2. A high affinity for the ai and D2 receptors is associated with unwanted cardiovascular and motor side effects.

Certain compounds have serotonin antagonist properties as described in EP-A 0 433 149.

Description of the invention.

The present invention provides compounds of the formula: (0 wherein R1 is hydrogen, C? _4alkyl, C? ~4alkoxy or halo, and R is hydrogen, C alquilo _alkyl or C? _alkoxy; and you leave it.

The compounds of the invention and their pharmaceutically acceptable salts are indicated for use in the treatment of disorders of the central nervous system. These are active in in vitro and in vi ve tests that indicate serotonergic modulation and, in particular, binding activity to the 5-HT2A receptor, as described below. In this it is appreciated that the compounds of the invention are surprisingly superior to the prior art. These also strongly inhibit the serotonin reuptake and have very low affinity with the a. and D2.

In the above formula (I), a C ?4 alkyl group may be branched or unbranched, for example, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl, and is preferably methyl or ethyl, and especially methyl. A C 1 -4 alkoxy group is an alkyl group such linked to the ring through an oxygen atom, and is preferably methoxy or ethoxy, and especially methoxy. A halo group is preferably chloro or fluoro, and especially fluoro.

A preferred group of compounds is one of formula (I) above, wherein both R1 and R2 are hydrogen, or either R1 or R2 is hydrogen; and you leave it. Preferably R1 is hydrogen, methyl, methoxy or fluoro, and R2 is preferably hydrogen or methyl.

A more preferred compound is l-. { 2- [4- (6-fluoro-lH-indol-3-yl) -1,2,3,6-tetrahydro-l-pyridinyl] -l-ethyl} 5,6-dihydro-1H, 4H-1, 2, 5-thiadiazole [4, 3, 2-ji] quinoline-2, 2-dioxide, and its salts, having the structure of formula (I) above, in that both R1 and R2 are hydrogen.

As indicated above, it is, of course, possible to prepare salts of the compounds of the invention and such salts are included in the invention. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with appropriate acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, or with organic acids, such as organic carboxylic acids, for example glycolic, maleic, hydroxymelic, fumaric, melic, tartaric, citric, salicylic, o-acetoxybenzoic, or organic sulfonic, 2-hydroxyethane sulfonic, toluene-p-sulphonic, naphthalene-2-sulphonic or bisetane sulfonic acids. Phosphate is the most preferred salt.

In addition to the pharmaceutically acceptable salts, other salts are included in the invention. These can serve as intermediates in the purification of compounds or in the preparation of compounds or in the preparation of others, for example pharmaceutically acceptable acid addition salts, or are useful for identification, characterization or purification.

It will be appreciated that the compounds of the invention may contain one or more asymmetric carbon atoms that give rise to the isomers. The compounds are usually prepared as racemic mixtures, but individual isomers can be isolated by conventional techniques if desired. Such racemic mixtures and individual optical isomers form part of the present invention, the compounds are employed as racemates or in enantiomerically pure forms.

The invention includes processes for producing the compounds of the invention. The compounds can be prepared, for example, by the reaction of an indolyl piperidinyl compound of the formula: (») with a thiadiazole dioxide quinoline of the formula (Hl) where X is a leaving group such as halo, especially chloro. The reaction is preferably carried out in a polar solvent such as, for example, acetonitrile, or water, in the presence of a base such as, for example, sodium carbonate, and at a temperature from 50 ° C to 150 ° C.

The compound of formula (II) can be prepared by methods known in the art, for example, by reacting 4-piperidone with 6-fluoroindole in the presence of a base such as potassium hydroxide, and employing as solvent an alcohol such as methanol. Similarly, methods for preparing the compounds of formula (III) are known in the art as, for example, by reaction of thiadiazole quinoline dioxide in salt formed with 1,2-dihaloethane, in. presence of sodium hydride and an appropriate solvent such as dimethyl formamido.

As mentioned above, the compounds of the invention are active, at the serotonin, 5-HT2A receptors. This binding activity is demonstrated in the test described by Nelson, D.L. et al., J. Pharmacol. Exp. Ther., 265, 1272-1279, in which the affinity of the compound for the human 2A receptor is measured by its ability to displace the ketanserin linkage [3H]. In this test, the compounds of the invention in the following Examples had Ki 's measurements less than 6 nM. These were at least four times more active in this test than the structurally-related compound referred to specifically described in EP-A 0 433 149, called 1-. { 3 - [4 - (5-Fluoro-lH-indol-3-yl) -1,273,6-tetrahydro-l-pyridinyl] -l-propyl} -5,6-dihydro-lH, H-1, 2,5-thiadiazole [4, 3, 2-ij] quinoline-2,2-dioxide. Indeed, the most active compound of the invention, the compound in which both R and R2 are hydrogen, is about twenty-eight times more active.

The affinity of the compounds of the invention for the 5-HT2A receptor and above is confirmed in a guinea pig model by a modified version of the test described by Skingle, M. et al., J. Psychopharmacol. , 8, 14-21, in which the effect of the compound 2,5-dime toxi- -iodo-amphetamine (DOI) that induces hypermia is observed.

In addition, the compounds of the invention are inhibitors of serotonin reuptake, and possess excellent activity as, for example, in the test described by Carrol et al., J. Med. Chem. (1993), 36, 2886-2890, in which the intrinsic activity of the compound is measured to completely inhibit the binding of the selective serotonin reuptake inhibitors transported. These results are also confirmed by in vitro tests in which the effect of the compound on behavioral syndrome in a mouse dosed with 5-HTP and a monoamine oxidase inhibitor (MAOI) such as parglin, is measured, see Christensen, AV, et al., Eur. J. Pharmacol. 41, 153-162 (1977).

As stated above, the compounds of the invention have an excellent receptor binding profile that not only combines exceptionally high with the 2A linkage and excellent retakes inhibition, but also has the required low affinity for the receptors? and D2. The measure of the trainer is described in Greengrass P. et al., Eur. J. Pharmcol. 55: 323-326, and the second in Hall H. et al., Prog. Neuro-Psycopharmcol. Biol. Psychiat. 12: 559-568. This characteristic profile of activity distinguishes the compound of the invention from the structural compound reported in the prior art, referred to above. Other prior art compounds such as those described in J. Med. Chem. 1991, 34, 2477-2483 and J. Med. Chem., 1993, 36, 1194-1202, have additional structural differences or lack effectiveness in vi .

In view of the selective affinity of the compounds of the invention for serotonin receptors, these are indicated for use in the treatment of a variety of conditions such as depression, bipolar disorder, anxiety, obesity, eating disorders such as anorexia and bulimia, alcoholism, pain, hypertension, aging, memory loss, sexual dysfunction, psychotic disorders, schizophrenia, gastrointestinal disorders, headache, cessation of smoking, epilepsy, drug abuse and addiction, emesis, Alzheimer's disorder and disorders of the dream. The compounds of the invention are primarily planned for the treatment of depression and anxiety, or disorders with depressive or anxiety symptoms.

The compounds of the invention are effective over a wide range of doses, the current dose to be administered will depend on such factors as the particular compound to be used, the condition to be treated and the type and size of the animal to be treated. However, the required dose will normally fall within the range of 0.001 to 20, such as 0.01 to 20 mg / kg per day, for example in the treatment of adult humans, doses of 0.5 to 100 or 200 mg per day may be used.

The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usually be used in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

Accordingly, the invention includes a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof, associated with a pharmaceutically acceptable diluent or carrier. To make the compositions of the invention, the active ingredient may usually be mixed with a carrier, or diluent for a carrier, or enclosed within a carrier which may be in the form of a capsule, pad, paper or other container. More than one active ingredient or excipient can be used, of course. The excipient may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate or oil . The compositions of the invention can, if desired, be formulated to be rapidly delivered, sustained or delayed release of an active ingredient after administration to the patient.

Depending on the route of administration, the aforementioned compositions can be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories. Preferably the compositions are formulated in a unit dose form, each dose contains from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.

The following examples illustrate the preparation of the compounds of the invention.

EXAMPLE 1 1 - . 1-dimethylamino-2 - (4-fluoro-2-njtro) phenylethyl.

A mixture of 4-fluoro-2-ni trotoluene (50 g, 0.32 mol), dimethylformamide dimethylacetyl (76.77 g) and dimethylformamide (910 ml) was heated to reflux under nitrogen with stirring for 7 hours, cooled, allowed it was for 16 hours, it was emptied in ice-water (2000 ml), stirred for 15 minutes, the resulting precipitate was isolated by filtration, washed with water (500 ml) and dried to give a red solid. 6-fluoroindole An A 0 liter Cook hydrogenator was charged under a nitrogen atmosphere with 10% palladium in mineral carbon (9 g) suspended in toluene (400 ml). To this suspension was added 1-di e-tilamino-2 - (4-fluoro-2-nitro) phenylethane (137.2 g., 0.653 mol) in toluene (1400 ml) and the mixture was hydrogenated at 5.44 atm (80 psi) for 3.5 hours. The suspension was then filtered through a pad of celite, which was washed through with toluene (2 x 200 ml) and the filtrate and washing was evaporated under reduced pressure to give a brown oil which was crystallized in fixed for a brown solid. yellow 93.65 g. This solid was dissolved in ethyl acetate-hexane (7: 3) and filtered through a flash silica pad. The required fractions were collected and evaporated under reduced pressure to give a pale brown solid. 4- (6-fluoro- [1 H] -indol-3-yl) -l, 2,3,6-tetrahydropyridine Powdered potassium hydroxide (144.4 g) was carefully added to a mechanical stirrer with a mixture of 6-fluoroindole (49.23 g, 0.364 mol) and piperidone hydrochloride monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml). The mixture was then heated to reflux under nitrogen for 18 hours and then more potassium hydroxide (40 g) was added and the rean mixture was heated to reflux for an additional 4 hours. The rean mixture was allowed to cool to room temperature, emptied in ice-water (3000 ml) and stirred for 1 hour. The precipitated solid was isolated by filtration and dried at 50 ° C in vacuo to give a solid product. 8-amino-1, 2, 3, 4-tetrahydroquinoline. 8-n-troquinoline (25 g, 0.143 mol) was dissolved in acetic acid (300 mL) and catalytically hydrogenated with Pt02 (0.75 g) at 4.42 atm (65 psi) overnight at room temperature. The catalyst was removed by filtration through a pad of celite and the solvent was removed by evaporation. The residue was dissolved in CH2C12 and saturated aqueous sodium hydrogen carbonate was added. The organics were extracted with CH2C12 and the extracts were washed with water (3 x 100 mL) and brine (3 x 100 mL). The extracts were then dried over anhydrous magnesium sulfate, filtered and evaporated to leave the crude product as a brown oil. This was immediately dissolved in CH2C12 and filtered through a short pad of silica eluting with ethyl acetate to leave the title compound.

Potassium salt of 5,6-dihydro-lH-4H-1, 2,5-thiadiazole- [4, 3, 2-ij] -quinoline-2,2-dioxide. 8-Aminot etrahydroquinoline (6.60 g, 0.045 mol) in dry diglyme (25 mL) was added to a stirred solution of sulfamide (4.93 g, 0.051 mol) in dry diglyme (40 mL) at 155-160 ° C. The rean was then heated for 2 hours. After this time, the rean was cooled to room temperature, water was added and the mixture was acidified with 1N hydrochloric acid. The solution was extracted with t-butyl ether (4 x 100 mL). The extracts were washed with water (2 x 100 mL) and then mineral carbon is added and filtered thoroughly to leave a clear red solution. 8N potassium hydroxide is added dropwise to the solution by precipitating a white solid. This is then filtered completely and washed with ether to give the required product. 2-Chloroethyl-5,6-dihydro-lH, 4H-l, 2,5-thiadiazole [4, 3, 2-ij] quinoline-2, 2-dioxide Dissolve 5,6-dihydro-lH-4H, 1,2,5-thiadiazole- [4,3,2-ij] -quinoline-2,2-dioxide (1.92 g, 0.009 mol) in dry DMF (80 mL ) and sodium hydride (0.48 g, 0.010 mol) is added in portions under nitrogen to the mixture at room temperature. Bromochloroene (1.44 g, 0.010 mol) is added in one portion and the solution is stirred overnight at room temperature. The rean is quenched with water, extracted with ethyl acetate, the combined extracts are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a brown oil. The material is purified by flash silica chromatography eluting with 20% ethyl acetate / hexane. The product is obtained as a clear oil with fixed crystallization. l-. { 2- [4- (6-fluoro- [lH] -indol-3-yl) -1,2,3,6-tetrahydro-1-pyridinyl] -l-ethyl} -5,6-dihydro-lH, H-1, 2,5-thiadiazole [4, 3, 2-ij] quinoline-2, 2-dioxide.

Refluxed for 18 hours 2-chloroethyl-5,6-dihydro-1H, 4H-1, 2,5-thiadiazole [4,3,2-ij [quinoline-2, 2-dioxide (3.75 g, 0.0137 mol ) and 4- (6-fluoro- [lH] -indol-3-yl) -l, 2,3,6-te-trahydropyridine (2.97 g, 0.0137 mol) in water (120 mL) containing sodium carbonate (7.26 g) , 0.0085 mol) with a catalytic amount of sodium iodide (0.08 g). After cooling, the material was extracted with dichloromethane, the extracts were dried with anhydrous magnesium sulfate, filtered and evaporated to leave an orange foam. This material was purified by chromatography eluting with dichloromethane, followed by 5% methanol / dichloromethane giving the product as a pale yellow solid. The product was recrystallized from ethyl acetate, m.p. 183-185 ° C.

The free base was dissolved in methanol, orthophosphoric acid was added and the white precipitate was filtered and dried to produce the phosphate salt, m.p. 156-158 ° C.

EXAMPLE 2 Preparation of intermediaries 6-fluoro-8-nitroquinoline.

Sulfuric acid (75% by weight) (116 g) was added to a mixture of sodium 3-nitrobenzene sulfonate (46.4 g, 0.206 mol), 2-nitro-4-fluoroaniline (25 g, 0.156 mol) and glycerol (29 g, 0.315 mol) and slowly warmed to 13.0-135 ° C and maintained at this temperature for 8 hours. This was cooled and allowed to stand for, 11 hours, diluting with water (100 ml), basifying with ammonia (d = 0.88 g / ml) and filtering the solid precipitate. The filtrate was washed with sodium hydroxide (2M, 2 x 50 mL) and water (3 x 50 mL), dried with air and then dried in va cu or at 60 ° C for 4 'hours to give 6-fluoro -8-nitroquinoline as a solid. 8-amino-6-fluoro-l, 2, 3, 4-tetrahydroquinoline.

Platinum oxide (0.475 g) was added to a solution of 6-fluoro-8-n-troquinoline (14.0 g, 72.9 mmol) in acetic acid (195 ml) and hydrogenated at 4.08 atm (60 psi) for 24 hours. The acetic acid solution was filtered through celite to remove the catalyst and then evaporated in vacuo and the residue was treated with toluene (150 ml). The toluene was stirred in vacuo and more toluene was added. The resulting solution was filtered and then evaporated in vacuo. The crude product, a dark liquid, was used immediately in the next step. 8-fluoro-5,6-dihydro-lH, 4H-l, 2,5-thiadiazol- [4,3,2-ij] -quinoline-2, 2-dioxide.

Crude 8-amino-6-fluoro-1,2,3-tetrahydroquinoline (10.34 g, 62.29 mmol) in dry pyridine (60 mL) was added to hot sulfamide (7.026 g, 74.75 mmol) in dry pyridine (60 mL). ) and the mixture was heated and stirred under reflux for 4 hours. This cooled down and he was allowed to stay all night. The pyridine was evaporated in vacuo to give a black residue which was partitioned between ethyl acetate (300 ml) and 2M hydrochloric acid (195 ml). The mixture was stirred, separated and washed with more 2M hydrochloric acid (100 ml), water (100 ml) and then separated again. The solid was dried with magnesium sulfate, the magnesium sulfate was removed by filtration, and the filtrate was treated with mineral carbon. The mineral coal was then removed by filtration, the filtrate was evaporated and then evaporated in vacuo to give a slightly pink solid, m.p. 174-176 ° C. 3-methyl-8-nitroquinoline Sulfuric acid (34 ml, 63.2 g, 645.2 mmol) in water (12 ml) was added a. a mixture of arsenic pentoxide (22.26 g, 96.8 mmol) and 2-nitroaniline (22.28 g, 161.3 mmol) and the solids were dissolved. The resulting solution was then heated to 100 ° C and 2-methyl-2-propene-1,1-diol diacetate (50 g, 290.3 mmol) was added, causing an exothermic reaction which was controlled not to exceed 130 ° C. After the addition of 2-methyl-2-propene-1,1-diol diacetate, the mixture was heated and stirred at 130 ° C for 2 hours. The reaction mixture was then cooled and drained in ice-water. The resulting mixture was basified with aqueous sodium hydroxide solution (50%) and then toluene was added and the mixture was heated to 90 ° C for 1 hour. The toluene layer was then fully decanted and replaced with more toluene (400 ml). The mixture was then heated and stirred overnight and the toluene was decanted. More toluene (400 ml) was then added and the mixture was heated and stirred for 2 hours before decanting and combining with the two previous toluene extracts. The combined toluene extracts were dried (MgSO 4), filtered and the filtrate was evaporated in vacuo to give a dark brown solid. This solid was triturated with diethyl ether, the solid was isolated by filtration, pulverized, washed with ether and dried in vacuo at 50 ° C for 2 hours to give the solid product. 8 -. 8-amino-3-methyl-l, 2,3-tetrahydroquinoline.

Platinum oxide (0.375 g) was added to a solution of 3-methyl-8-nitroquinoline (12.47 g), 66.3 mmol) in acetic acid (150 ml) and hydrogenated at 4.08 atm (60 psi) for 24 hours. The acetic acid solution was filtered through celite to remove the catalyst and then evaporated in vacuo and the residue treated with toluene (150 ml). The toluene was stirred in va cuo. More toluene was added and the resulting solution was filtered and then evaporated in vacuo. The crude product was then dissolved in ethyl acetate and purified by chromatography on a silica pad. The ethyl acetate fractions containing the product were collected and combined, then washed with a solution of aqueous sodium hydrogen carbonate (75 ml), dried (MgSO 4) and filtered. The filtrate was evaporated in vacuo to give a dark brown oil.

Potassium salt of 5-methyl-5,6-dihydro-lH, H-1, 2, 5 • thiadiazol- [, 3, 2-ij] -quinoline-2, 2-dioxide. 8-amino-3-methyl-1,2,3,4-tetrahydroquinoline (7.56 g, 46.66 mmol) in dry pyridine (50 mL) was added to hot sulfamide (5.38 g, 56 mmol) in dry pyridine (50 mL) and the mixture was heated and mechanically stirred under reflux for 2 hours. The pyridine was evaporated in vacuo to give a black residue which was partitioned between ethyl acetate and 2.5M hydrochloric acid. The acid layer was separated and the organic layer was washed with brine. The aqueous acid layer was then extracted with ethyl acetate (3x), combined with the original ethyl acetate layer, treated with charcoal, dried with magnesium sulfate, filtered and the filtrate evaporated in vacuo to give an orange solid. This solid was dissolved in the minimum of tert-butyl methyl ether and the resulting solution was treated with an 8M potassium hydroxide solution. The solid chlorine cream precipitate was collected by filtration and dried in vacuo at 50 ° C to give the potassium salt as a solid m.p. > 250 ° C.

The following compounds of the invention were prepared as in Example 1, using intermediates prepared in the manner described above.

R, S l- (2- (4- (6-fluoroindol-3-yl) -l, 2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-4-methyl-1H, 4H-1, 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 196-197 ° C.

R, S l- (2- (4- (6-fluoroindol-3-yl) -l, 2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-5-methyl-lH, 4H-1, 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 197-200 ° C.

R, S l- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-6-methyl-1H, 4H-1, 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 156-158 ° C. 1- (2- (4- (6-fluoroindol-3-yl) -1,22,3,6-tetrahydro-idyridin-1-yl) ethyl) -5,6-dihydro-7-methyl-1H , 4H-1, 2,5-thiadiazole- [4,3,2-i, 'j] -quinoline-2,2-dioxide, mp 187.8-189.7 ° C. 1- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6- 'tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-8-methyl'lH, 4H- l, 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 169.4-174 ° C. 1- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-9-methyl-1H, 4H-1 , 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 189.2-190.3 ° C. 7-Fluoro-l- (2- (4- (6-fluoroindol-3-yl) -l, 2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-lH, 4H-1 2, 5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 178-178.4 ° C. 8-fluoro-l- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-1H, H-1 2, 5-thiadiazole- [4, 3, 2-i, j] -quinoline-2, 2-dioxide, mp 173-175 ° C. 9-Fluoro-l- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-lH, 4H-1 2, 5-thiadiazole- [4, 3, 2-i, j] -quinoline-2, 2-dioxide, mp 188-190 ° C. l- (2- (4- (6-fluoroindol-3-yl) -l, 2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-9-ethyl-lH, 4H-l , 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, mp 166.4-168 ° C. 1- (2- (4- (6-fluoroindol-3-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -5,6-dihydro-9-methoxy-1H, 4H-1 , 2,5-thiadiazole- [4,3,2-i, j] -quinoline-2,2-dioxide, 187-189 ° C.

The following Examples illustrate typical formulations containing the compound of the invention.

EXAMPLE 3 Each tablet is made containing 10 mg of the active ingredient as follows: Active ingredient 10 mg Starch 160 mg 100 mg microcrystalline cellulose Polyvinylpyrrolidone (as 10% of 13 mg solution in water) Sodium carboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, starch and cellulose are mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders and passed through a sieve. The granules thus produced are dried and passed through the sieve. The sodium carboxymethyl starch and the magnesium stearate are then added to the granules which, after mixing, are compressed in a tablet machine to produce tablets weighing 300 mg each.

EXAMPLE 4 Capsules are prepared each containing 20 mg of the active ingredient as follows: Active ingredient 20 mg Dry starch 178 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, starch and magnesium stearate are passed through a sieve and filled with hard gelatin capsules in amounts of 200 mg.

EXAMPLE 5 Capsules are prepared each containing 20 mg of the medicine as follows: Active ingredient 20 mg Lactose 171 mg Sodium lauryl sulfate 2 mg Sodium starch glycolate 6 mg Magnesium stearate 1 mg Total 200 mg The active ingredient, lactose, sodium lauryl sulfate and sodium starch glycolate are thoroughly mixed. The grinding is mixed with the magnesium stearate and filled with hard gelatin capsules in amounts of 200 mg.

EXAMPLE 6 Each tablet containing 20 mg and medications are made as follows: Active ingredient 20 mg Lactose 103 mg Microcrystalline cellulose 150 mg Hydroxypropylmethyl cellulose 15mg Sodium starch glycolate 9 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, lactose, microcrystalline cellulose, sodium starch glycolate and hydroxypropylmethylcellulose is passed through a sieve and milled together. HE . add water to the ground powders to form a moist mass. The wet mass is passed through a thick screen, dries, is reviewed by the screen. The dry granules are mixed with the magnesium stearate and compressed into 300 mg tablets.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (14)

Claims

1. A compound of the formula (0 characterized in that R1 is hydrogen, C4_4alkyl, C4_4alkoxy or halo, and R2 is hydrogen, C4_4alkyl or C4_4alkoxy, or a salt thereof.

2. The compound according to claim 1, characterized in that both of R1 and R2 are hydrogen, or either R1 or R2 is hydrogen.

3. The compound according to either claims 1 and 2, characterized in that R1 is hydrogen, methyl, methoxy fluoro and R 'is hydrogen or methyl.

4. l-. { 2- [4- (6-fluoro-l-indol-3-yl) -1,2,3,6-tetrahydro-l-pyridinyl] -l-ethyl} 5,6-dihydro-1H, 4H-1, 2, 5-thiadiazole [4, 3, 2-i j] quinoline-2, 2-dioxide, a salt thereof.

5. l-. { 2- [4- (6-fluoro-l-indol-3-yl) -1,2,3,6-tetrahydro-1-pyridinyl] -l-ethyl} -5,6-dihydro-lH, 4H-1, 2,5-thiadiazole [4, 3, 2-ij] quinoline-2, 2-dioxide.

6. Phosphate salt of 1-. { 2 - [4 - (6-fluoro-) -! - [_ indol-3-yl) -1,2,3,6-tetrahydro-l-pyridinyl] -1-ethyl} -5,6-dihydro-lH, 4H-l, 2,5-thiadiazole [4,3,2 - /; / - ij] quinoline-2, 2-dioxide

7. A pharmaceutical formulation comprising a compound according to any of the rei indications 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that it is associated with a pharmaceutically acceptable diluent or carrier thereof.

8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a compound according to either claim 5 and 6, characterized in that it is to be used as a pharmaceutical.

9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for the treatment of depression or anxiety, having a high binding activity to the 5-HT2A receptor.

10. The use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a compound according to either claim 5 and 6, for the manufacture of a medicament for the treatment of a disorder of the Central Nervous System.

11. A process for producing a compound according to claim 1, characterized in that it comprises reacting a compound of the formula: (") with a compound of the formula (II!) where X is a starting group.

12. A compound, characterized in that it is produced in accordance with claim 11.

13. A process for producing a pharmaceutical formulation, characterized in that it comprises mixing a compound according to any of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a compound according to either claim 5 and 6, with a diluent or pharmaceutically acceptable carrier thereof.

14. A unit dosage form containing from 0.5 to 100 mg of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, as an active ingredient.