FI80461B - Process for the preparation of therapeutically useful piperidine derivatives - Google Patents

Description

1 80461

A process for the preparation of therapeutically useful piperidine derivatives

Divided by application 822511 5

The invention relates to a process for the preparation of therapeutically useful piperidine derivatives of the formula I, their stereochemically isomeric forms and their pharmaceutically acceptable acid addition salts. 10 S .N R1 r3 Γ Ύ ύ / 2

A, JJ / \ / R

CH2-CH2-Nv_y \ Q (I), in which R1 is lower alkyl, R2 and R3 independently of one another are hydrogen or lower alkyl, A is a divalent radical of formula - (CH2) 2- or - (CH2) 3 -, and Q is a radical of formula -X-Ar (a) wherein X is> C = O,> CH-OH,> CH 2 or> C = N-OH and

Ar is halophenyl, or Q is a radical of formula 25 in S-30 JP 7,614-497 and

Ann. Rep. Sankyo Res. Lab. 29, 75-98 (1977) disclose certain 4H-pyrido [1,2-a] pyrimidin-4-one derivatives having an aminoalkyl substituent in the 3-position, the amino group of which may be morpholino, piperidino or part of piperazine-2 80461. These compounds have been reported to affect the cardiovascular and central nervous systems.

EP-A-37 265 discloses certain 3- (1-piperidinyl) -4H-pyrido [1,2-a] pyrimidin-4-one derivative-5 in which the piperidine ring is substituted by an aroyl radical or a reactive derivative thereof. These compounds are potent serotonin antagonists.

The compounds of formula I differ from the previously known compounds in that the 4H-pyrido [1,2-a] pyrid-10-midin-4-one group is replaced by 5H-thiazolo [3,2-a] pyrimidin-5-one or 3 With 4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one. These compounds are useful in the treatment of psychotropic disorders.

In defining a group of compounds of formula I, the term "halogen" means fluorine, chlorine, bromine or iodine. The term "lower alkyl" embraces straight and side chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like.

Preferred compounds of formula (I) are those wherein A is - (CH 2) 2 -, Q is a radical of formula (a) wherein X is> C = O, or a radical of formula (b) and R 3 is hydrogen.

A particularly preferred compound of formula (I) is 6- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] ] pyrimidin-5-one.

The piperidine derivatives of formula (I), their stereochemically isomeric forms and their pharmaceutically acceptable acid addition salts can be prepared by reacting a compound of formula c N R 1

/ JJC

0 3 80461 wherein R1 and A have the same meaning as above and W is halogen is reacted with a piperidine derivative of formula • V_A (III),

Q

wherein R 2, R 3 and Q are as defined above, in an inert solvent; and optionally converting the resulting compound of formula I wherein Q is Ar-CO- to a compound of formula I wherein Q is Ar-C- with hydroxylamine.

NOH

And / or the resulting compound is converted to a pharmaceutically acceptable acid addition salt or the resulting acid addition salt is converted to the free base, and / or the resulting compound is divided into its stereochemical isomers.

The present N-alkylation process is known per se. The reaction is carried out in a suitable reaction-inert solvent such as a lower alkanol, e.g. methanol, ethanol, propanol or butanol; in an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene; in an ether, e.g. 1,4-dioxane or 1,1'-oxybispropane; in a ketone, e.g. 4-methyl-2-pentanone; N, N-dimethylformamide; nitrobenzene; or in a similar solvent. A suitable base such as an alkali or alkaline earth metal carbonate or bicarbonate can be used to scavenge the acid released during the reaction. A small amount of a suitable metal iodine, for example sodium or potassium iodide, may be added to promote the reaction. Slightly higher than normal temperatures may be used to increase the reaction rate, and preferably the reaction is carried out at the boiling temperature of the reaction mixture.

4 80 461

Compounds of formula (I) in which X represents a radical of formula> C = NOH are readily obtained from the corresponding carbonyl compounds by reacting the latter with hydroxylamine hydrochloride in a manner known per se.

The compounds of formula (I) are basic and can therefore be converted into acid addition salts by treatment with suitable acids such as inorganic acids, for example hydrohalic acid, e.g. hydrochloric or hydrobromic acid or sulfuric acid, nitric acid or phosphoric acid; or organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, malonic acid, succinic acid, (Z) -2-maleic acid, (E) -2-maleic acid, 2-hydroxysuccinic acid, 2,3 -dihydroxysuccinic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-acrylic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylsulfonic acid, 4-methyl , 2-20 with hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid or the like.

The salt form can also be converted to the free base form by alkali treatment.

The compounds of formula (I) may exist in different stereochemical isomeric forms.

Compounds of formula (I) in which Q is a radical of formula (a), wherein X is> CH-OH, have at least one chiral center in their structure. This chiral center may be in the R or S configuration (see R. S. Chan, 30 C. Ingold and V. Prelog, Angew. Chem. Int. Ed. Engl., 5, 385 511 (1966)). Thus, the compounds of formula (I) may exist in two different enantiomeric forms, which may be separated, for example, by converting a mixture of enantiomers into their acid addition salt form with an optically active acid, separating the diastereomeric salts.

5 80 461 e.g. by selective crystallization, and release of pure enantiomers by treatment with alkali.

When R 3 is other than hydrogen, the piperidine ring has two asymmetric carbon atoms and each of these chiral centers may exist in the R and S configurations and the compounds of formula (I) may exist in different diastereochemical forms, resulting in substituents on the piperidine moiety. be in the cis and trans configuration, which can be separated by physical separation methods such as selective crystallization and chromatographic methods, e.g., countercurrent distribution method, column chromatography, and the like.

Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically or highly stereoselectively.

The starting materials of formula II may be prepared as described in Scheme 1 by stirring and, if desired, heating the reactants in a suitable solvent in the presence of a suitable halogenating agent, e.g. phosphoryl chloride, thionyl chloride, phosphorus pentabromide or the like. Alternatively, the cyclization and halogenation reaction can be performed in an acidic medium, e.g. in the presence of hydrochloric acid, 4-methylphenylsulfonic acid or the like.

6 80461

Scheme 1 R1 / S o = C; cyclization- '' \ j. CH-Alk-OH reaction A ^ tf n-r / - "7" 1

5 \ halogenation I

(IV) Substance L.

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25 (A w + Alk-OH halogenation- 'x substance (VIII-a) (XV) cyclization- R \ / W + (XV) reaction 30 H -9 halogenation- r5-C = 0 substance <VIII-b) cyclization- N w * (XXV) reaction, -1

H1 / w halogenating C / A substance 35 11 (X) 7 80461

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are potent antagonists of a series of neurotransmitters and therefore have useful pharmacological properties.

For example, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts have potent psychotropic activity, anti-histamine activity and anti-serotonin activity.

The effect of the target compounds as psychotropic substances 10 is evident from test values obtained from at least one of two different test methods, namely the method performed using rats in combined apomorphine, tryptamine and norepinephrine tests and the method in which the apomorphine test was performed in dogs. Experiments 15 have been performed following the methods described below, and the test results are summarized in Table 1.

Combined Apomorphine (APO), Tryptamine (TRY), and Norepinephrine (NOR) Experiments in Rats The experimental animals used in this experiment were full-grown male Wistar rats (weight 240 * 10 g). After overnight fasting, the animals were administered subcutaneously (1 ml / 100 g) an aqueous solution of the test compound (time = zero) and placed in isolated observation cages. Thirty minutes (time = 30 minutes), they were injected intramuscularly with 1.25 mg / kg apomorphine hydrochloride (APO) and the rats were observed for one hour for the presence or absence of the following apomorphine-induced phenomena: agitation and compulsive chewing. At the end of this hour period (time = 90 minutes), the same animals were injected intravenously with 40 mg / kg tryptamine (TRY) and the occurrence of typical tryptamine-induced bilateral seizures was noted. Two hours after pretreatment (time = 120 minutes), the same animals were finally given intravenous 1.25 mg / kg norepinephrine-35 (NOR) and the potential mortality was checked 60 minutes later.

8 80461

Table 1 gives the ED 2 values of several compounds under treatment. As used herein, the ED 2 Q value represents a dose that protects 50% of the animals from phenomena caused by apomorphine, tryptamine, or norepinephrine.

5 Apomorphine experiment in dogs (APO dog) The method used is described by P.A.J. Janssen and C.J.E. Niemegeers, Arzneim.-Forsch. (Drug Res.), 9, 765-767 (1959).

The compounds listed in Table 1 were administered subcutaneously to rabbits in different doses, and the animals were given a standard dose of 0.31 mg / kg apomorphine (subcutaneously) one hour later.

Table 1 shows the ED 2 values of the compounds.

As used herein, the ED 2 Q value represents a dose that protects 50% of 15 animals from vomiting.

9 80461

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10 80461

The efficacy of the target compounds as serotonin antagonists is clearly evident from the results obtained in the following experiments investigating the antagonistic activity of the target compounds against serotonin.

5 Effects in gastric injury experiments: injuries caused by compound 48/80

Compound 48/80 (a mixture of oligomers obtained by condensing 4-methoxy-N-methylbenzeneethanamine and formaldehyde) is an effective agent for releasing vasoactive amines such as histamine and serotonin from endogenous stores. In rats injected with 48/80, there are continuous changes in blood flow in various vascular media: bluish ears and limbs appear five minutes after injection of compound 15; rats die of shock within 30 minutes. Eukemia followed by death can be avoided if rats are pretreated with a classical H1 antagonist. However, the stimulatory effects on gastric secretion do not cease, so that rats treated with 48/80> / 2Q and protected against shock with an H1 antagonist may show all signs of intense gastric activity; a large opening reveals swollen stomachs with abnormal contents and jagged bright red spots throughout the mucosa, corresponding to 25 areas of disrupted glands. Many known serotonin antagonists such as, for example, methysergide, Cyproheptadine, cinanser, mianserin, pipamperone, spiperone, pizotifen, and metergoline, completely prevent blueing of the ears and limbs as well as damage to the gastric gland and abnormal bloating. Table 2 shows several compounds of formula (I) and doses (mg / kg body weight) at which no gastric bulging occurred at all in 50% of the experimental iEdj-Q values).

Antagonistic activity on the action of serotonin in the rat tail artery

Tail arteries taken from fasted male rats (210-235 g) were used in the experiment. Two helical strips 5-6 cm long and 2 mm wide were obtained from each artery and attached in a vertical position to a 100 ml organ bath containing oxidized Krebs-Henseleit solution. Arterial strip contractions were almost maximized by adding single doses of serotonin (40 ng / ml) to the bath over 2 minutes, each time at 10 minute intervals. The contraction amplitude was measured before and 5 minutes after drug addition. After rinsing, the active ingredient li-10 was adjusted again three times to see if the contraction had improved and normalized.

Table 2 shows the ED 2 values in ng / ml for several compounds of formula (I) and their pharmaceutically acceptable acid addition salts in the above 15 experiments. In this context, the ED 2 Q values are the minimum concentrations of the drugs in question which reduce the contraction amplitude to at least 50% of their normal value.

Inhibition of serotonin-induced guinea pig tracheal contraction 20 tracheal rings 5 mm long obtained from guinea pigs (400-500 g, fasted overnight) were suspended at 2 g in a 100 ml Tyrode bath gassed with a mixture of was 95% O 2 and 5% CO 2 (33 ° C). Contractions were recorded isometrically 25 (StathamUC2, JSI sensor amplifier, Kipp BD-9 pen plotter). A serotonin pill (0.31 mg / L, contact time 8 min.) Was added to the bath fluid every 30 minutes, before and 30 minutes after the incubation period, using a single concentration of antagonist. The reaction to the active ingredient in the presence of the antagonist was compared to the reaction before the addition of the antagonist. (The preparation did not appear to be suitable for time-activity studies). The ED 1 -Q values shown in Table 2 represent concentrations of antagonist that reduce the effect of the active ingredient by 50%.

The efficacy of the target compounds as histamine antagonists is demonstrated by the results obtained in the following experiment 80801, which examined the antagonistic activity of the target compounds against histamine.

Protection of rats against 48/80 mortality 5 48/80, a mixture of oligomers obtained by condensing 4-methoxy-N-methylphenethylamine and formaldehyde, has been described as an effective histamine releasing agent (Int. Arch. Allergy, 13, 336 (1958)). The protective effect against the lethal circulatory effect of compound 48/80 against tocollaps seems to be a simple way to quantify the anti-histamine effect of the test compounds. Congenital male Wistar-ro rats weighing 240-260 g were used in the experiment. After overnight fasting, the rats were transferred to air-conditioned laboratories (temperature = 21-1 ° C, relative humidity 65-5%).

Rats were administered the test compound or solvent (NaCl solution, 0.9%) subcutaneously or orally.

One hour after the dose, compound 48/80, freshly dissolved in water, was injected at a dose of 0.5 mg / kg (0.2 ml per 100 g body weight).

Based on control experiments in which a standard dose of 48/30 was injected into a 250-reel solvent-treated animal, after 4 hours the animals were not more than 2.8% alive, the administration of the drug can therefore be considered as a reliable criterion for the protective effect of the drug.

Table 2 shows the ED-g values (mg / kg) for several compounds of formula (I) and their pharmaceutically acceptable acid addition salts in the above experiment. In this context, the ED 2 values are the minimum doses of the compounds in question, administered subcutaneously, which protect 50% of the rats against the lethal effect of compound 48/80.

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i4 80461

In Table III, the compounds of formula I have been compared with the compounds described in FI patent publication 71737. The ED 50 values show that the compounds of the formula I are clearly more potent than the said known compounds.

Table III

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15 -SA- Q Gastric injury test ED ^ q mg / kg -S- (CH2) 2-CO-C6H4-4F 0.0005 -S- (CH2) 2H-indol-3-yl 0.004 -S- (CHO) , - CO-CcH.-4F 0.01 20 * J o 4 -S- (CH2) 1H-indol-3-yl 0.02 -CH = CH-CH = CH * CO-C6H4-4F 0.016 -CH = CH-CH = CH * 1H-indol-3-yl 0.08 25 * FI patent 71737 is 80461

Due to their pharmacological effects, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used for the treatment of psychotropic disorders and various anxiety conditions in which serotonin release is of primary importance, such as serotonin-induced bronchial and bronchial tissue venous contractions. The target compounds also have useful properties as sedatives, analgesics, antiseptics, anti-stress, muscle protectors and cardiovascular protectors, and therefore, are useful in the treatment of warm-blooded animals, e.g., during stress, e.g. In addition, the compounds are useful as protective agents against dispersal toxins and as anti-addictive agents.

The following examples illustrate the invention. Unless otherwise noted, all parts are by weight and all temperatures are in degrees Celsius.

2 0 Examples A. Preparation of starting materials

Example I

To a stirred, hot (40 ° C) mixture of 52 parts of 4,5-dihydro-2-thiazolamine, 76 parts of 3-acetyl-4,5-dihydro-2 (3H) -furanone and 450 parts of methylbenzene were added 340 parts of part of phosphoryl chloride. The whole mixture was heated to reflux and stirring was continued at this temperature for 3 hours. The reaction mixture was evaporated and the residue was poured into a mixture of crushed ice and ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methylbenzene and methanol (70:20:10, v / v) as eluent. The pure fractions were combined and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of 16 80461 2-propanol to give 7.5 parts of 6- (2-chloroethyl) -2,3-dihydro-7-methyl-5H-thiazolo / 3.2 -a7_pyrimidin-5-one (intermediate 2),

Example II

A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidiethanol, 25 parts of potassium carbonate, 270 parts of Ν, Ν-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added in one portion. : the temperature rises to 50 ° C. The entire mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and water was added to the residue. The solid product was washed with water and dried in vacuo at 100 ° C in a yield of 21 parts (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2,1b] 1,3 / thiat-15 sin-6-one: m.p. 155 ° C (interm. 8).

In a similar manner there was also prepared: 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one; mp. 148.7 ° C (interm. 9).

Example lii 20 A mixture of 20 parts of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2,1-b] 1,3] thiazin-6-one, 50 parts of acetic acid and 180 parts of a 67% acetic acid solution of hydrobromic acid were stirred and heated to boiling. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated to dryness and the solid residue was trituroid in 2-propanone. The product was filtered off and dried, yielding 24 parts (100%) of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazine. -6-one monohydrobromide; mp. 215 ° C (interm. 30 te 10).

In a similar manner there were also prepared: 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrobromide; mp. 237.2 ° C (interm. 11).

i7 8 0 461

Example IV

To a stirred mixture of 80 parts of 3-methylpyridine, 50.4 parts of 1H-indole and 360 parts of benzene was added dropwise at room temperature 57 parts of benzo-5-yl chloride (the reaction is exothermic, the temperature rose to 33 ° C. After stirring, stirring was continued. first for 2 hours at 50 [deg.] C. and then overnight at room temperature The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (9.8: 2 by volume) as eluent, the pure fractions were combined and the eluent was evaporated off. a few times with hexane, decanting the hexane after each wash, and the residue was taken up twice in methylbenzene, which was evaporated to give 108 parts (80%) of 1-benzoyl-1,4-dihydro-4- (1H-indole). 3-yl) -3-methylpyridine as an oily residue (intermediate 20).

Example V

A mixture of 108 parts of 1-benzoyl-1,4-dihydro-20-4- (1H-indol-3-yl) -3-methylpyridine and 560 parts of methanol was hydrogenated on a Parr apparatus using 5 parts of palladium-on-charcoal as catalyst. (10%). After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was collected. The filter cake was dissolved in N, N-25 in dimethylacetamide with heating. The solvent was evaporated and the residue was stirred into the previously recovered filtrate. The precipitated product was filtered off and purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were combined and the eluent was evaporated. The residue was boiled in 2-propanol. After cooling, the product was filtered and dried at 170 ° C to give 41.1 parts of cis-1-benzoyl-4- (1H-indol-3-yl) -3-methylpiperidine, m.p. 230.7 ° C (interm. 22).

i8 8 0 461

Example VI

A mixture of 21 parts of cis-1-benzoyl-4- (1H-indol-3-yl) -3-methylpiperidine, 60 parts of potassium hydroxide, 385 parts of 1,2-ethanediol and 80 parts of water was stirred. and boiled (about 130 ° C) overnight. After cooling for some time, about 200 parts of water were added, whereupon the product crystallized. The whole batch was further cooled and the solid product was filtered off, washed with a large amount of water and 2,2'-oxybispropane and dried to give 11.2 parts (80%) of cis-3- (3-methyl-4-piperidinyl) - 1H-indole (intermediate 23).

Example VII

A mixture of 60 parts of ethyl 4- (4-fluorobenzoyl) -4-methyl-1-piperidinecarboxylate and 675 parts of a solution of hydrobromic acid (48%) in water was stirred and refluxed for 1.5 hours. The reaction mixture was evaporated and the residue was dissolved in 2-propanol. The solution was filtered and the filtrate was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1-oxybisethane to give 43 parts of (4-fluoro-20-phenyl) (4-methyl-4-piperidinyl) -methanone hydrobromide.

B. Preparation of compounds of formula I.

Example VII

Mixture of 3.3 parts of 6- (2-chloroethyl) -2,3-25 dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, 3 parts (4-fluorophenyl) - (4-Piperidinyl) methanone hydrochloride, 8 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone, were stirred and boiled for 20 hours using a water separator. The reaction mixture was filtered through Mana-Hyflo and the filter cake was washed with trichloromethane. The filtrate was evaporated to dryness. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were combined and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-1980461 oxybispropane to give 2 parts of 6- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -2,3-dihydro -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one; mp. 165.6 ° C (comp. 1).

In a similar manner there were also prepared: 7- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one; mp. 165.2 ° C (comp. 2).

Example IX

A mixture of 3.5 parts of 6- (2-chloroethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, 2.6 parts of 3- ( 4-Piperidinyl) -1H-indole, 0.01 part of potassium iodide and 200 parts of 4-methyl-2-pentanone were stirred and boiled for 22 hours using a water separator. The reaction mixture was filtered hot through Hyflo and the filtrate was evaporated to dryness. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were combined and the eluent was evaporated.

The residue was crystallized from 2,2'-oxybisethane and 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.8 parts of 2,3-dihydro-6- [2- [4- (1H-indol-3-yl) -1-piperidinyl] ethyl] -7-methyl-5H-thiazolo [3 , 2-a] pyrimidin-5-one; mp.

238.2-241.7 ° C (decomp.) (Compound 15). In an analogous manner, cis-2,3-dihydro-6- [2- [4- (1H-indol-3-yl) -3-methyl-1-piperidinyl] ethyl] -7-methyl-5H-thiazolo was prepared. - [3,2-a] pyrimidin-5-one; mp. 234.0 ° C (compound 23) and 3,4-dihydro-7- (2- [4- (1H-indol-3-yl) -1-piperidinyl] -30 ethyl] -8-methyl-2H, 6H-pyrimido [2,1-b] thiazin-6-one, m.p.

227.1 ° C (comp. 3).

Example X

A mixture of 5.6 parts of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one monohydrobromide, 3.14 parts of α-3- (4-fluorophenyl) -4-piperidinium methanol, 8 parts of sodium carbonate, 0.1 part of potassium iodide, 1 part of sodium methoxide solution (30%) and 144 parts of 4-methyl-2- pentanone, stirred and refluxed overnight using a water separator. The reaction mixture was cooled, water was added and the layers were separated. The 4-methyl-2-pentanone phase was dried, filtered and concentrated to a volume of about 75 parts. The crystallized product was filtered off, dried and recrystallized from 120 parts of acetonitrile to give 3.3 parts (52%) after drying at 140 ° C.

7- [2- [4 - [(4-fluorophenyl) hydroxymethyl] -1-piperidinyl-yl] ethyl] -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] - [ 1,3] thiazin-6-one; mp. 174.1 ° C (comp. 27). Using (4-fluorophenyl) (4-methyl-4-piperidinyl-15-yl) methanone hydrobromide and ethyl 4- (4-fluorobenzoyl) -4-methyl-1-piperidinecarboxylate as starting materials, 6- [2- [4- (4-fluorobenzoyl) -4-methyl-1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one dihydrochloride, m.p. 257.1 ° C.

20 Example XI

A mixture of 6.8 parts of 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, 3.15 parts of α- (4 (fluorophenyl) -4-piperidinemethanol, 4.8 parts of sodium carbonate, 0.1 part of potassium iodide and 200 parts of 4-methyl-2-pentanone were stirred and boiled for 24 hours. The reaction mixture was cooled, washed with 50 parts of water, dried, filtered and evaporated to dryness. The residue was purified by column chromatography over silica gel using a trichloromethane / methanol mixture (90:10 by volume) as eluent. The pure fractions were combined and the eluent was evaporated. The residue became solid upon trituration in acetonitrile. The product was filtered off, washed twice with acetonitrile and dried to give 2.5 parts (42%) of 6- [2- [4 - [(4-fluorophenyl-3H) hydroxymethyl] -1-piperidinyl] ethyl] -2.3 -dihydro-2i 804617 7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one; mp. 204.3 ° C (comp. 33).

Example XII

A mixture of 4 parts of 6- [2- [4- (4-fluorobenzo-5-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, 0.7 parts of hydroxylamine hydrochloride, 1 part of N, N-diethylethanamine and 20 parts of ethanol were stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was stirred with water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was chromatographed on a column of silica gel using trichloroethane / methanol (95: 5 by volume) as eluent.

The first fraction [(E) -isomer] was collected and the eluent was evaporated. The residue was crystallized from 2-propano to give 1 part (24%) of (E) -6- [2- [4 - [(4-fluorophenyl) (hydroxyimino) methyl] -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, m.p. 214.1 ° C.

The second fraction [(Z) -isomer] was collected and the eluent was evaporated. The residue was crystallized from 2-propanol to give 0.2 parts (4.6%) of (Z) -6- [2- [4- [4- (4-fluorophenyl) (hydroxyimino) methyl] -1- piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, m.p. 220.8 ° C.

Example XIII

A mixture of 5.3 parts of 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one mono-hydrobromide, 5.45 parts 4 - [(4-fluorophenyl) methyl] piperidine 4-methylbenzenesulfonate (1: 1), 5.3 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone were stirred for 6 hours at reflux temperature. After cooling, water was added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over 22 8 G 461 silica gel using trichloromethane / methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the (E) -2-butenedioate salt in 2-propanol. The salt was filtered off and dried, yielding 2.5 parts (34%) of 6- [2- [4 - [(4-fluorophenyl) methyl] -1-piperidinyl] ethyl] -2,3-dihydro-7 -methyl 5H-thiazolo [3,2-a] pyrimidin-5-one (E) -2-butenedioate (1: 1) m.p. 197.9 ° C.

Claims (2)

23 8 0 4 61 A process for the preparation of therapeutically useful piperidine derivatives of the formula I, their stereochemically isomeric forms and their pharmaceutically acceptable acid addition salts, e / N 1 R 3 / Y JT r <? V .N. CHo-CHO-N X '; Wherein R 1 is lower alkyl, R 2 and R 3 are independently hydrogen or lower alkyl, A is a divalent radical of formula - (CH 2) 2 - or 15 - (CH 2) 3 - and Q is a radical of formula -X-Ar (a) if sa X is> C = O,> CH-OH,> CH2 or> C = N-OH and Ar is halophenyl, or Q is a radical of formula -O- is characterized in that a compound of formula „R1 ΐΎ YA CH 2 CH 2 ~ W wherein R 1 and A are as defined above and W is halogen , is reacted with a piperidine derivative 24 8 0 4 61 of the formula ™, A \ (III), 5. Q wherein R 2, R 3 and Q are as defined above, in an inert solvent; and optionally converting the resulting compound of formula I wherein Q is Ar-CO- with hydroxylamine to a compound of formula I wherein Q is Ar-C-NOH and / or converting the resulting compound to a pharmaceutically acceptable acid addition salt or converting the resulting acid addition salt to the free base and / or or the resulting compound is divided into its stereochemical isomers. Process according to claim 1 6- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidine For the preparation of -5-one or a pharmaceutically acceptable acid addition salt thereof, characterized in that 6- (2-chloroethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one is reacted with (4-fluorophenyl) - (4-piperidinyl) methanone, and if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt. 25 80 461