FI83078B - Process for preparing novel therapeutically useful {[bis(aryl)methylene]-1-piperidinyl}alkyl-4H-pyrido[1,2 a]pyrimidin-4-one derivatives - Google Patents

Description

1 83078

Process for the preparation of novel therapeutically useful {[bis- (aryl) methylene] -1-piperidinyl} alkyl-4H-pyrido [1,2-a] pyrimidin-4-one derivatives 5 Separated from patent application 833,995

The invention relates to a process for the preparation of new therapeutically useful {[bis (aryl) methylene] -1-piperidinyl} alkyl-4H-pyrido [1,2-a] pyrimidin-4-one derivatives of formula (I) ryy * v 15 ^ Mk N \ _ / ^ Ar2 ®

O

wherein R is hydrogen, hydroxy or lower alkyloxy; A is a divalent group of formula (a) or (b) -CH 2 -CH 2 -CH 2 -CH 2 - (a) -CH = CR 3 -CR 4 = CR 5 - (b) wherein the carbon atom to which R 5 is attached is attached to the nitrogen atom of the pyrimidinone ring; R 3 is hydrogen or methyl; R 4 is hydrogen, methyl, halogen or amino; R 5 is hydrogen or methyl;

Alk is C 2-4 alkanediyl;

Ar 1 and Ar 2 are independently pyridinyl, thienyl or phenyl optionally substituted with halogen, hydroxy, lower alkyloxy, lower alkyl or trifluoromethyl; 2,83078 and their possible stereochemically isomeric and pharmaceutically acceptable acid addition salts.

U.S. Patent No. 4,342,870 describes 3- (1-5 piperidinylalkyl) -4H-pyrido [1,2-a] pyrimidin-4-ones having a piperidine ring substituted with an arylcarbonyl group or a functional derivative thereof.

U.S. Patent 4,443,451 discloses (1-piperidinyl) alkyl-5H-thiazolo [3,2-a] pyrimidin-5-ones, 10 -2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-ones and -5H-thiazolo [3,2] [1,3] pyrimidin-5-ones having a piperidine ring substituted with an arylcarbonyl group or a functional derivative thereof.

U.S. Patent 3,862,173 describes [[bis-15 (aryl) methylene] -1-piperidinyl] alkanol derivatives.

Compounds of the 1-piperinylethyl-4H-pyrido [1,2-a] pyrimidin-4-one type are described in FI patent application 810 956 and 1-piperinylethyl-5H-thiazolo [3,2-a] pyrimidin-5- oni-type compounds are described in FI patent-20 application 822 511.

FI patent publication 71,737 describes certain piperidine-substituted pyrido [1,2-a] pyrimidin-4-one derivatives.

The novel compounds of formula (I) differ from the above-mentioned compounds in that their [[bis (aryl) methylene] -1-piperidinyl] alkane moiety is substituted by a bicyclic pyrimidinone group and in that they are serotonin antagonists, which makes them useful in the treatment of diseases in which serotonin has 30 side effects, such as psychomatic illnesses.

In the above definitions, halogen means fluorine, chlorine or bromine; "lower alkyl" is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, 3,83078 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl. li, etc .; and C 2-4 alkanidinyl is a divalent straight or branched alkanediyl group having 2 to 4 carbon atoms.

Preferred compounds of formula (I) are those in which Alk is a 1,2-ethanediyl group.

The process according to the invention for the preparation of the compounds of the formula (I) is characterized in that the piperidine of the formula (III) is N-alkylated.

R

wherein R, Ar1 and Ar2 are as defined above, in a reaction-inert solvent with a compound of formula (II) CH3 ^ ^ N ^ 1-Alk-W ® 0 wherein A and Alk are as defined above and W is reactive leaving group; and, if desired, O-alkylating a compound of formula (I) wherein Ar 1 or Ar 2 is a hydroxy-substituted phenyl group with an alkyl halide in the presence of a base in a reaction-inert solvent to give a compound of formula (I) wherein Arx or Ar 2 is a lower alkyloxy-substituted phenyl group; and, if desired, converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt; and, if desired, preparing stereochemically isomeric forms of the compound of formula (1) thus obtained.

In the reactive ester of formula (II), W 5 has a reactive leaving group such as halogen, especially chlorine, bromine or iodine, or a sulfonyloxy group, e.g. methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like.

The reaction between an ester of formula (II) and a piperidine of formula (III) can be performed under standard conditions for N-alkylation methods. The reaction is preferably carried out in a suitable reaction-inert solvent such as a lower alkanol, for example methanol, ethanol, butanol and the like, an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene and the like; in ether, for example 1,4-dioxane, 1,1'-oxydispropane and the like; in a ketone, for example 4-methyl-2-pentanone; N, N-dimethyl-formamide; nitrobenzene and the like. A suitable base such as an alkali or alkaline earth metal carbonate or bicarbonate may be used in the reaction to scavenge the acid liberated in the reaction. A small amount of a suitable metal iodide, for example sodium or potassium iodide, may be added to promote the reaction. In order to improve the reaction rate, it is preferable to use a somewhat elevated temperature, preferably the reaction is carried out under reflux of the reaction mixture.

The compounds of formula (I) may also be converted into each other following art-known procedures for modifying functional groups.

For example, compounds of formula (I) wherein Ar 1 and / or Ar 2 is hydroxy-substituted phenyl may be converted to the corresponding compounds of formula (I) wherein Ar 1 and / or -35 or Ar 2 is lower alkyloxy-substituted phenyl by methods known in the art.

5,83078

For example, compounds of formula (I) wherein Ar 1 is hydroxy-substituted phenyl represented by formula (Ib) may be converted to compounds of formula (I) wherein Ar 1 is lower alkyloxy-substituted phenyl represented by formula (Ic) , by reacting the former with a suitable lower alkyl halide (XII).

lower alkyl halide (XII), r ch3 R.

This alkylation reaction can be carried out in a suitable solvent in the presence of a suitable base, e.g. sodium hydride or the like.

The compounds of formula (I) are basic in nature and can thus be converted into therapeutically active, non-toxic acid addition salts by treatment with suitable acids, e.g. inorganic acids such as hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid, nitric acid, nitric acid, nitric acid, .; or organic acids such as acetic, propane, hydroxyacetic, 2-hydroxypropane, 2-oxo-propane, propanedicarboxylic, butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) -2- butenedicarboxyl, 2-hydroxybutanedicarboxyl, 2,3-dihydroxybutanedicarboxyl, 2-hydroxy-1,2,3-propanetricarboxyl, methanesulfonic, ethanesulfonic, benzenesulfonic, 3,5-methylbenzenesulfonic, cyclohexane , 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acids and the like.

6 83078

Correspondingly, the salt can be converted to the free base by treating the salt with an alkali.

It will be apparent from formula (I) that such novel compounds in which Alk is an asymmetrically branched lower al-5anediyl group may exist in different stereochemical isomeric forms. The chiral center may be in the R or S configuration, with the R and S notation being used according to the rules set by R.C. Cahn, C. Ingold, and V. Prelog, Angew. Chem. Int. Ed. Engl., 5, 385, 511 (1966), 10. The compounds of formula (I) may thus exist in two different enantiomeric forms, which may be separated, for example, by converting a mixture of enantiomers into an acid addition salt with an optically active acid, separating diastereomeric salts, e.g. by selective crystallization, and liberating pure enantiomers.

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

Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

Many of the starting materials used in the process of the invention are known compounds, and others may be prepared by methods known in the art for the preparation of similar compounds; some of these synthetic methods are described below.

The starting materials of formula (II) may be prepared by converting the hydroxyl group of the corresponding alcohol (XIII) into a reactive cleavage group, e.g. with.

7 83078 / γγ · 1> JL-Alk-rm reactive ester oh -—- ^ (II) IL formation 5 (XIII)

The alcohols (XIII) used as starting materials above can be prepared by suitable cyclization methods. These 10 cyclization reactions using compounds (IV) and (XIV), (VI) and (XV) and (VIII) and (XV) as starting materials are described in Reaction Scheme 1.

Reaction scheme 1

15 / NH

f iT 2 0 = C

(\ c cyclization reaction N + ^ CH-Alk-ORb - (IV) o = c \ X2 \ 20 Ll, XIV) \ / 'V' + \ (l | 2 J fi cycle largest reaction> y ^ __ N (VI ) L "£ Alk-OR --- (XIII) iw ° (xv) y 25 ci + (XV) cycle ring reaction / * (VIII)

In Reaction Scheme 1, R 6 may be hydrogen and L 2 may represent a leaving group, in addition, R 6 and L 2 may together represent a direct bond.

Cyclization reactions can usually be carried out by mixing the reactants together, if desired in the presence of a suitable reaction-inert solvent such as an aliphatic, alicyclic or aromatic hydrocarbon, e.g. hexane, cyclohexane, benzene and the like, pyridine; In the presence of Ν, Ν-dimethyl-8 83078 formamide or the like. An elevated temperature may be suitably used to accelerate the reaction.

In some cases, it may also be advantageous to carry out the reaction at reflux temperature of the reaction mixture.

In some cases, it may be advantageous to carry out the cyclization reaction and the formation of the reactive ester at the same time.

Compounds of formula (II) wherein W is a halo gene represented by formula (II-a) 15 -RxYH3 A ^ N - ^ _ Aik "hai ° gene 0 (II-a) 20 can also be prepared directly from compounds (II-a) IV) and (XV) or (VI) and (XV) or (VIII) and (XV) 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 and the like. and the halogenation reaction may optionally be carried out in an acidic medium, for example, in the presence of hydrogen chloride, 4-methylphenylsulfonic acid and the like.

The starting materials of formula (III) can be prepared by reacting piperidine (XX) with a ketone (XXI) following a known Grignard reaction, followed by dehydration of the resulting tertiary alcohol (XXII) and deprotection of the resulting unsaturated intermediate 3b (XXIII).

9 83078

R 1 R

P-N \ -halogen + Mg + 0 = CGngnard- ρ_Ν ^ V — c-a,; 1 \ - '\ «r2 reaction> \ _ / · 2 ar Ar (χχ) (χχΙ) (χχΙΙ)

5 F

ΛΓ \ Ar1 dehydration- _ p_n \ = / P removal reaction> \ __ / \ r2> (1II) (XXIII) 10 The compounds of formula (1), their possible stereochemically isomeric forms and their pharmaceutically acceptable acid addition salts are potent serotonin antagonists, and at the same time, their effect is very specific to serotonin receptors compared to 15 receptors such as dopamine 1, norepinephrine and acetylcholine receptors. In addition, the compounds of the invention bind selectively to S2 receptors, the term S2 being used in the sense given, e.g., in Molecu-20ar Pharmacology 21, (1982) 301-314.

The compounds according to the invention are further characterized by their long-acting activity.

The S2 antagonist activity of the compounds of formula (I), their possible stereochemical isomeric forms and their pharmaceutically acceptable acid addition salts has been demonstrated in tail arterial experiments in rats.

Serotonin antagonist activity in rat tail experiments

The tail arteries of fasted male rats (210-235 g) were used in the experiment. A 5-6 cm long and 2 mm wide helical strip was cut from each artery and attached in an upright position to 100 ml of an organ bath containing 35 oxidized Krebs-Henseleit solution. Arterial strips were caused to submaximally shrink for 2 minutes by adding single doses of serotonin (40 ng / ml) to the organ bath at 10 minute intervals. The contractile amplitude was measured before and after drug administration. After washing the arterial-5 strips, the agonist was added again 3 times to determine if the contractions had returned and the arteries had returned to normal. Table 1 shows the ED50 values obtained in this experiment for several compounds of formula (I) and their pharmaceutically acceptable acid addition salts. In this context, the ED50 value is the minimum concentration of the compound in question at which the contraction amplitude decreases by at least 50% of its normal value.

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Due to their pharmacological activity, the compounds of formula (I), their possible stereochemically isomeric forms and their pharmaceutically acceptable acid addition salts can be used for the treatment of a wide variety of conditions caused by serotonin. In particular, the compounds of the invention may be used to treat patients with psychosomatic diseases.

The compounds of formula (I) are sedatives, analgesics, antiangressants and muscle protectants and can thus be used for the treatment of warm-blooded animals, for example in situations of stress.

In addition, the compounds of the invention can be used in many disease states in which serotonin has a significant effect, for example, in preventing serotonin-induced contractions of lung tissue and vasculature, both arteries and veins.

In addition, the compounds of the invention are suitable for the preparation of various pharmaceutical compositions suitable for administration due to their useful pharmacological properties. In preparing such pharmaceutical compositions, a pharmaceutically effective amount of the subject compound in base or acid addition salt form is mixed well with a pharmaceutically acceptable carrier, which may vary in form depending on the form of the preparation to be administered. These pharmaceutical compositions are preferably prepared in unit dosage form, which is preferably suitable for oral, reactive or parenteral injection.

The preferred dosage unit form contains 1 to 200 mg of active ingredient and particularly preferably 5 to 100 mg of active ingredient.

35 The following examples illustrate the invention. Unless otherwise stated is 83078, all parts are by weight and temperatures are in degrees Celsius.

eXAMPLES

A. Preparation of intermediates 5 Example I

A mixture of 5-nitro-2-pyridinamine (90 parts), 3-acetyl-4,5-dihydro-2- (3H) -furanone (90 parts) and methylbenzene (810 parts) was stirred at room temperature. 510 parts of phosphoryl chloride were added dropwise to the mixture over 1 hour, raising the temperature to 40 °. The reaction mixture was slowly heated to reflux where it was stirred for 5 hours. The solvent was evaporated. The hot residue was poured into a mixture of crushed ice and ammonium hydroxide. After stirring for 30 minutes, the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (97; 3 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane to give 54.8 parts of 3- (2-chloroethyl) -2-methyl-7-nitro-4H-pyrido [1,2-a] pyrimidin-4-one , sp. 170 ° (interm. 8).

A mixture of 3- (2-chloroethyl) -2-methyl-7-nitro-4H-pyrido [1,2-a] pyrimidin-4-one (40 parts) and methanol (240 parts) was hydrogenated under normal pressure at room temperature over a platinum oxide catalyst ( 0.5 parts) in the presence. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (95: 5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered and dissolved in water with heating. The solution was treated with activated carbon-35. The carbon was filtered using a hyflo filter, and the filter cake was washed with water. The filtrate was stirred in dilute ammonium hydroxide solution. The precipitated product was filtered off, washed with water and petroleum ether and dried to give 19.4 parts of 7-amino-3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimldin-4-one, m.p. 185 ° (interm. 9).

5 Example II

a) A solution of 4- (4-10 fluorobenzoyl) -1-piperidinecarboxylate (84 parts) was added dropwise with stirring to 112.2 parts of 1-bromo-4-methoxybenzene, 15 parts of magnesium and 540 parts of terahydrofuran under cooling to a heated Grignard complex. 360 parts of tetrahydrofuran. After the addition was complete, stirring was continued at reflux for 2 hours. The mixture was cooled to 10 ° and poured into a mixture of crushed ice (300 parts) and acetic acid (40 parts). The mixture was stirred for 5 minutes, then added to 360 parts of methylbenzene. The organic layer was separated, dried, filtered and evaporated, yielding 100 parts of ethyl 4- [4-fluorophenyl) hydroxy- (4-methoxyphenyl) methyl] -1-piperidinylcarboxylate as an oily residue (intermediate 10).

b) A mixture of ethyl 4 - [(4-fluorophenyl) hydroxy- (4-methoxyphenyl) methyl] -1-piperidinecarboxylate (100 parts), concentrated hydrochloric acid (1200 parts) and ethanol (160 parts) was stirred and refluxed for 24 hours. . HCl gas was bubbled into the mixture until the mixture was saturated and stirring and heating at reflux was continued for 64 hours. The reaction mixture was evaporated and the oily residue was dissolved by heating in 1000 parts of water. After cooling, the solution was washed twice with 210 parts of 1,1'-oxybisethane, and the solution was made alkaline with ammonium hydroxide. The precipitated product was filtered and suspended in 160 parts of acetonitrile. The product was filtered and suspended twice in 80 parts of methanol, the product was dried to give 44.4 parts (52%) of 4 - [(4-fluorophenyl) (4-piperidinylidene) methyl] phenol. mp. 260 ° (interm. 11).

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Example III

a) To a Grignard complex prepared from 70 parts of 1-bromo-4-fluorobenzene and 10 parts of magnesium in 270 parts of tetrahydrofuran was added dropwise at reflux temperature with stirring a solution of ethyl 1- (phenylmethyl) -4-piperidinecarboxylate (25 parts) in 90 parts of tetrahydrofuran. After the addition was complete, stirring at reflux was continued for 2 hours. The reaction mixture was cooled and poured into saturated ammonium chloride-10 solution. The organic phase was separated, filtered and evaporated, yielding 40 parts of α, α-bis (4-fluorophenyl) -1- (phenylmethyl) -4-piperidinylmethanol (interm. 12).

b) A mixture of α, o-bis (4-fluorophenyl) -1- (phenylmethyl) -4-15 piperidinemethanol (40 parts), hydrochloric acid (120 parts) and acetic acid (50 parts) was stirred and refluxed for 2 hours. The reaction mixture was cooled, and water and methylbenzene were added thereto to form 3 layers. The top two layers were separated and treated with ammonium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystallized, yielding 26 parts of 4- [bis- (4-fluorophenyl) methylene] -1- (phenylmethyl) piperidine (interm. 13).

C) A mixture of 4- [bis (4-fluorophenyl) methylene] -1- (phenylmethyl) piperidine (1.6 parts) and methanol (80 parts) was hydrogenated in the presence of 5% rhodium / carbon catalyst (1 part) at normal pressure and room temperature. After the calculated amount at room temperature. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated, yielding 1.2 parts of 4- [bis- (4-fluorophenyl) methylene] piperidine (interm. 14).

Example IV

To a warm (406) mixture of bromobenzene (600 parts) and aluminum chloride 35 (223 parts) was added 168.8 parts of 1-acetyl-4-piperidinecarbonyl chloride portionwise with stirring. After completion of the addition, stirring was continued for 1 hour at 50 ° and then overnight at room temperature. The reaction mixture was poured into a mixture of crushed ice (1500 parts) and hydrochloric acid. The mixture was stirred thoroughly, the precipitated product was filtered, washed with 2,2'-oxybispropane and dissolved in a mixture of trichloromethane (2250 parts) and water (200 parts). The layers were separated. The organic layer was dried, filtered and evaporated. The residue was suspended in 280 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 94 parts (34%) of 1-acetyl-4- (4-bromobenzoyl) piperidine, m.p. 1200 (interm. 15).

A solution of 1-acetyl-4- (4-bromobenzoyl) piperidine (94 parts) was added dropwise to a Grignard complex prepared from 52.5 parts of 1-bromo-4-fluorobenzene, 7.5 parts of 15 magnesium and 216 parts of tetrahydrofuran with stirring at reflux temperature. 450 parts of tetrahydrofuran. After the addition was complete, stirring at reflux was continued for 5 hours. The reaction mixture was cooled, poured into a mixture of crushed ice (300 parts) and acetic acid (40 parts), and the mixture was stirred for 15 minutes. 450 parts of methylbenzene were then added. The organic layer was separated, filtered and evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (90:10 by volume). The pure fractions were collected and the eluent was evaporated, yielding 75 parts of 1-acetyl-g- (4-bromophenyl) -g- (4-bromophenyl) -α- (4-fluorophenyl) -4-piperidinemethanol (intermediate 16).

A mixture of 1-acetyl-g- (4-bromophenyl) -g- (4-fluorophenyl) -4-piperidinemethanol (75 parts), concentrated hydrochloric acid (600 parts) and ethanol (80 parts) was stirred and refluxed for 18 hours. The reaction mixture 35 was evaporated and 500 parts of water were added to the residue.

«83078

The solution was treated with ammonium hydroxide. The product was extracted twice with 375 parts of trichloromethane. The combined organic layers were washed with 100 parts of water, dried and evaporated, the oily residue was purified by chromatography on a silica gel column eluting with a mixture of trichloromethane and methanol (90:10, v / v) saturated with ammonia. The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The mixture was evaporated and the residue was crystallized from 80 parts of acetonitrile. The product was filtered (filtrate 1 set aside) and crystallized from 160 parts of acetonitrile at 0 °. The product was filtered off and dried, yielding 36 parts of 4 - [(4-bromophenyl) (4-fluorophenyl) methylene] piperidine hydrochloride.

The collected filtrate 1 and filtrate 2 (see above) were evaporated to a volume of 40 parts. The concentrated solution was allowed to crystallize. The product was filtered off and dried, yielding 4 parts of 4 - [(4-bromophenyl) (4-fluorophenyl) methylene] piperidine hydrochloride.

Total yield: 40 parts (75%) of 4 - [(4-bromophenyl) - (4-fluorophenyl) methylene] piperidine hydrochloride (interm. 17).

Example V

To a cooled Grignard complex prepared from 134 parts of 4-chloro-1-methylpiperidine, 25 parts of 25 magnesium and 652.5 parts of tetrahydrofuran was added dropwise at 10-20 ° with stirring (4-fluorophenyl) - (3-pyridinyl) methanone ( 170 parts) solution in 405 parts of tetrahydrofuran. After the addition was complete, stirring was continued at room temperature for 30 hours and then at reflux for 30 minutes. The mixture was cooled and decomposed by pouring into a mixture of crushed ice and ammonium chloride. 270 parts of methylbenzene were added, the organic layer was separated, dried, filtered and evaporated. Residue 35 was boiled with activated carbon in acetonitrile, the carbon was filtered through a Hyflo filter and the filtrate was evaporated to give 240 parts (95%) of g- (4-fluorophenyl) -α- (1-methyl-4-piperidinyl) -3-pyridinemethanol ( intermediate 18).

A mixture of 5α- (4-fluorophenyl) -α- (1-methyl-4-piperidinyl) -3-pyridinemethanol (240 parts) and 48% aqueous hydrobromic acid (900 parts) was stirred under reflux for 1 hour. The mixture was evaporated to 1/3 volume, and the concentrated solution was treated with sodium hydroxide solution. The product was extracted into 4-methyl-2-pentanonine. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of trichloromethane and methanol (90:10 by volume) saturated with ammonia. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from petroleum ether containing a small amount of 2,2'-oxybispropane (10: 1, v / v). The product was filtered off and dried, yielding 112.5 parts (48%) of 3 - [(4-fluorophenyl) (1-methyl-4-piperidin-20-lidene) methyl] pyridine, m.p. 93.1 ° (interm. 19).

To a solution of ethyl carbonochloridate (180 parts) in 600 parts of trichloromethane was added dropwise with stirring a solution of 3 - [(4-fluorophenyl) -1-methyl-4-piperidinylidene) methyl] pyridine (110 parts) in 600 parts of tri-chloromethane. After the addition was complete, the mixture was heated to reflux with stirring for 16 hours. The reaction mixture was evaporated. The residue was mixed with water and basified with sodium hydroxide. The product was extracted with 4-methyl-2-petanone. The extract was dried, filtered and evaporated, yielding 100 parts (75%) of ethyl 4 - [(4-fluorophenyl) (3-pyridinyl) methylene] -1-piperidinecarboxylate (interm. 20).

A mixture of ethyl 4 - [(4-fluorophenyl) (3-pyridinyl) methylene] -1-piperidinecarboxylate (100 parts) and 48% hydrobromic acid (375 parts) was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was washed with 2,2'-oxybispropane. The oxybis-propane solution was decanted, and the residue was mixed with water, and the mixture was made alkaline with sodium hydroxide solution.

The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by chromatography on a silica gel column (2x) eluting with a mixture of trichloromethane and methanol saturated with ammonia (80:20, v / v). The main fraction was collected and the eluent was evaporated, yielding 30 parts (37%) of 3 - [(4-fluorophenyl) (4-piperidinylidene) methyl] pyridine (interm. 21).

By the same procedure and using the corresponding starting materials 4 - [(4-fluorophenyl) (2-thienyl) methyl] 15-piperidine (intermediate 22) was prepared.

Example VI

To a solution of α, α-bis (4-fluorophenyl) -1,2,3,6-tetrahydro-1- (phenylmethyl) -4-pyridinemethanol (50.9 parts) in 270 parts of tetrahydrofuran was added with stirring 750 parts of 1-m hydrochloric acid. The mixture was stirred at reflux for 7 hours and then at room temperature for 8 hours. The precipitated product was filtered and set aside. The filtrate was evaporated until all tetrahydrofuran was removed. After cooling, the precipitated product was filtered, suspended together with the precipitated product obtained above in 80 parts of acetonitrile. The product was filtered and stirred with heating to 40 parts of acetonitrile. The mixture was cooled to 10 °, the product was filtered off and dried, yielding 32.6 parts (58.7%) of 4 - [(bis (4-30 fluorophenyl) methylene] -1- (phenylmethyl) -3-piperidinol hydrochloride, mp 266 ° (interm. 23).

A mixture of 4- [bis (4-fluorophenyl) methylene] -1- (phenylmethyl) -3-piperidinol hydrochloride (27.8 parts) and methanol (200 parts) was hydrogenated on a 10% palladium on carbon catalyst (35 parts). 3 parts) in the presence of normal pressure and 22 83078 at room temperature. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 80 parts of acetonitrile. The product was filtered off and dried; to give 21.9 parts (100%) of 4- [bis (4-fluorophenyl) methylene] -3-piperidinol hydrochloride, m.p. > 260 ° (interm. 24).

Example VII

To a cooled (ice-10 bath) mixture of 4-pyridinecarbonyl chloride hydrochloride (141.5 parts) and fluorobenzene (400 parts) was added portionwise with stirring portionwise 399 parts of aluminum chloride. The reaction mixture was cooled, poured onto crushed ice and acidified with 15,240 parts of 10M hydrochloric acid. The layers were separated.

The aqueous phase was washed with methylbenzene (2 x 240 parts) and made strongly basic with 60% sodium hydroxide solution. The product was extracted 3 times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was dissolved in 900 parts of methylbenzene and the solution was treated with activated carbon. The carbon was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane to give 152 parts (75.5%) of (4-fluorophenyl) (4-pyridinyl) methanone, m.p. 85.5 ° (interm. 25 25).

A Grignard complex was prepared from 22.75 parts of 1-bromo-4-fluorobenzene, 3.2 parts of magnesium and 45 parts of anhydrous tetrahydrofuran. The reaction mixture was cooled in a 2-propanone / CO 2 bath to -20 to 25 °, and (4-fluorophenyl) (4-pyridinyl) methanone (20.1 parts) was added dropwise over 30 minutes at -20 °. solution in 45 parts of anhydrous methylbenzene. After the addition was complete, the mixture was stirred overnight at room temperature.

The mixture was cooled to 0 ° and quenched by the dropwise addition of 50 parts of acetic acid. After stirring for 1 hour at room temperature, the precipitated product was filtered off and set aside. The organic layer was separated from the filtrate, washed with 50 parts of water, dried, filtered and evaporated. The solid residue and the precipitated product obtained above were washed with water and azeotroped with methylbenzene (180 parts). The solid distillate was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 28 parts (94%) of g, o-bis (4-fluorophenyl) -4-pyridinemethanol (interm. 26).

To a mixture of 10 g of g-bis (4-fluorophenyl) -4-pyridinemethanol (89.2 parts) and acetonitrile (720 parts) was added dropwise at reflux with stirring 56.5 parts of (bromomethyl) benzene. After the addition was complete, stirring at reflux was continued for 22-15 hours. The reaction mixture was then allowed to stand at room temperature over the weekend. The product was filtered and set aside. The filtrate was evaporated to a volume of 50 parts. The product was allowed to crystallize. It was filtered and washed with the above batch of 2,2'-oxybispropane and dried to give 139.5 parts (99.2%) of 4- [bis (4-fluorophenyl) hydroxymethyl] -1- (phenylmethyl) pyridinium bromide (interm. 27) ♦ 4- [bis (4-fluorophenyl) hydroxymethyl] -1- (phenylmethyl) pyridinium bromide (140.5 parts) was added portionwise to methanol (2540 parts) with stirring over 2 hours at room temperature. (cooled with ice water if necessary) 15.1 parts of sodium borohydride. At the end of the addition, the mixture was stirred and refluxed for 30 minutes. The mixture was cooled to room temperature and 800 parts of water were added. The mixture was allowed to stand overnight. The reaction mixture was evaporated to completely remove methanol. 1040 parts of dichloromethane were added. The layers were separated, the organic layer was washed with 200 parts of water, dried, filtered and evaporated. Dry methylbenzene was added to the residue, and the mixture was evaporated to give 111 parts (94.5%) of α, α-bis (4-fluorophenyl) -1,2,3,6-tetrahydro-1- (phenylmethyl) - 4-Pyridinemethanol as an oily residue (intermediate 28).

5α, α-bis (4-fluorophenyl) -1,2,3-tetrahydro-1- (phenylmethyl) -4-pyridinemethanol (50.9 parts), methanol (320 parts) and 1-hydrochloric acid (800 parts). part) the mixture was stirred first for 3 hours at reflux temperature and then for 56 hours at room temperature. The methanol was completely removed from the mixture by evaporation. The free base was obtained by adding ammonium hydroxide. The product was extracted with 1040 parts of dichloromethane. The extract was washed with 100 parts of water, dried, filtered and evaporated. The residue was dissolved in 270 parts of N, N-dimethylformamide. The mixture was heated to 60 ° C. 2.5 parts of a 50% sodium hydride dispersion were added at 80 °. After stirring for 1 hour at 80 °, the mixture was cooled to room temperature. 9 parts of iodomethane were added dropwise to the mixture. After the addition was complete, the mixture was stirred and heated at 40 ° for 30 minutes. Mixture 20 was cooled and poured into 2000 parts of ice water. The product was filtered through methylbenzene (2 x 450 parts).

The combined extracts were dried, filtered and evaporated. The oily residue was purified by chromatography on a column of silica gel, eluting with a mixture of tri-chloromethane and methanol (98: 2 by volume). The pure fractions were collected and the eluent was evaporated, yielding 29.6 parts (57%) of 4- [bis (4-fluorophenyl) methylene] -3-methoxy-1- (phenylmethyl) piperidine (interm. 29).

A mixture of 4- [bis (4-fluorophenyl) methylene] -3-methoxy-1- (phenylmethyl) piperidine (29.6 parts) and methanol (200 parts) was hydrogenated under normal pressure and at room temperature to 10% palladium on carbon. in the presence of a catalyst (2 parts). After the calculated amount of hydrogen was bound, the kata-35 lysator was filtered and the filtrate was evaporated. Residue 83078 was purified by chromatography on a silica gel column eluting first with a mixture of trichloromethane and methanol (90:10, v / v) and then with a mixture of trichloromethane and methanol saturated with ammonia (80:20, 5 v / v). The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The mixture was evaporated. The oily residue became solid in 70 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 16.3 parts (63.4%) of 4- [10 [bis (4-fluorophenyl) methylene] -3-methoxypiperidine hydrochloride (interm. 30).

Example VIII

To 15 parts of magnesium, 112.2 parts of 1-bromo-4-methoxybenzene and 540 parts of tetrahydrofuran, the Grignard complex was added dropwise at reflux with stirring, stirring 80 parts of ethyl 4-benzoyl-1-piperidinecarboxylate in 360 parts. tetrahydro-furan. After the addition was complete, stirring at reflux was continued for 2 hours. The mixture was allowed to cool overnight and then poured into a mixture of crushed ice (300 parts) and acetic acid (40 parts) at 10 °. After stirring for 15 minutes, the layers were separated. The organic layer was dried, filtered and evaporated. Methylbenzene was added to the residue, it was evaporated. Residue 25 was suspended in 2,2'-oxybispropane, which was decanted, this was repeated 3 times. The residue was evaporated to dryness, yielding 106 parts of ethyl 4- [hydroxy (4-methoxyphenyl) phenylmethyl] -1-piperidinecarboxylate (interm. 31).

A mixture of ethyl 4- [hydroxy (4-methoxyphenyl) phenylmethyl] -1-piperidinecarboxylate (106 parts), concentrated hydrochloric acid (1200 parts) and ethanol (200 parts) was stirred and refluxed for 18 hours. Hydrogen chloride gas was bubbled into the mixture, and stirring was continued for 18 hours at reflux temperature. Mixture 26 8 3078 was evaporated. The residue was dissolved in a mixture of ethanol (200 parts) and 48% aqueous HBr (1950 parts). The mixture was stirred and refluxed overnight. The mixture was evaporated, the residue suspended in 1000 parts of water and the suspension treated with ammonium hydroxide. The oil was dissolved in 2100 parts of trichloromethane. The solution was washed with 500 parts of water, dried, filtered and evaporated. The residue was suspended in 70 parts of 2,2-oxybispropane, the solvent was evaporated, the same was repeated 3 times. The resulting residue 10 became solid in 40 parts of acetonitrile. The product was filtered off and dried, yielding 20 parts (25%) of 4- [phenyl (4-piperidinylidene) methyl] phenol, m.p. > 260 ° (interm. 32).

Example IX

To a mixture of 80.2 parts of 4-chloro-1-methylpiperidine, 14.6 parts of magnesium and 270 parts of tetrahydrofuran, 101 parts of (2-fluorophenyl) phenylmethanone dissolved in 450 parts of tetrahydrofuran were added dropwise with stirring at reflux temperature. At the end of the addition, the mixture was cooled in an ice bath and decomposed by adding 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product was filtered and washed with tetrahydrofuran. The filtrate was evaporated, methylbenzene was added to the residue, and the mixture was evaporated in a boiling water bath.

The residue was dissolved in 700 parts of 2,2'-oxybispropane. The cloudy solution was filtered and HCl gas was bubbled into the filtrate. The solid product was filtered and suspended in 1000 parts of water. Ammonium hydroxide was added to the suspension, and the mixture was extracted with 1,1'-oxybisethane (2 x 280 parts). The combined extracts were dried, filtered and evaporated. The oily residue was crystallized from 240 parts of acetonitrile. The mixture was cooled to 0 °, the product was filtered off and dried, yielding 66 parts (44%) of α- (2-fluorophenyl) -35 1-methyl-α-phenyl-4-piperidinemethanol (interm. 33).

273030 To a mixture of α- (2-fluorophenyl) -1-methyl-α-phenyl-4-piperidinemethanol (66.0 parts) and methylbenzene (450 parts) was added dropwise with stirring ethyl carbonochloridate (28.2 parts). After the addition was complete, the reaction mixture 5 was diluted with 630 parts of dimethylbenzene and the mixture was stirred at reflux overnight. The precipitate was filtered off and the filtrate was evaporated. The residue became solid upon stirring in 2,2'-oxybispropane (210 parts). The product was filtered off and dried, yielding 10 parts (34.5%) of ethylene 4 - [(2-fluorophenyl) hydroxyphenylmethyl] -1-piperidinecarboxylate (interm. 34).

A mixture of ethyl 4 - [(2-fluorophenyl) hydroxyphenylmethyl] -1-piperidinecarboxylate (26.0 parts) and 48% aqueous HBr (375 parts) was stirred and refluxed for 60 hours. The reaction mixture was evaporated and the residue was suspended in 250 parts of water. Ammonium hydroxide was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The product was extracted with trichloromethane (3 x 300 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by K-chromatography on a silica gel column eluting with a mixture of trichloromethane and methanol (90:10, v / v) saturated with ammonia. The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride-25 disalt in 2-propanol. The mixture was evaporated and the solid residue was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 14.3 parts (65%) of 4 - [(2-fluorophenyl) phenylmethylene] piperidine hydrochloride. mp. + 260 ° (interm. 35).

30 B. Manufacture of finished products

Example X

3- (2-Chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (4,5-parts), 4- [ (4-fluorophenyl) phenyl] ethylene] piperidine hydrochloride (4.6 parts), 30% sodium methoxide solution (2 parts), sodium carbonate (8 parts), potassium iodide (0.2 parts) and The mixture of 4-methyl-2-pentanone (240 parts) was stirred and refluxed for 22 hours. The reaction mixture was filtered hot and the filtrate was evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of trichloromethane and methanol (92: 8, v / v). The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in acetonitrile and 2-propanol. Salt 10 was filtered and dried, yielding 4.8 parts (60%) of 3- [2- [4-fluorophenyl) phenylmethylene] -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2- methyl 4H-pyrido [1,2-a] pyrimidin-4-one dihydrochloride, m.p. 264.6 ° (Compound 137) ♦ Using the same procedure using equivalent amounts of the appropriate starting materials, the following compounds were prepared: 3- [2- [4 - [(4-fluorophenyl) (3-methylphenyl) methylene] -1-piperidinyl] ethyl ] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 166.0 ° (comp. 138).

3- [2- [4 - [(4-fluorophenyl) 3- (trifluoromethyl) phenyl] methylene] -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl- 4H-pyrido [1,2-a] pyrimidin-4-one dihydrochloride, m.p. 254.0 ° (compound 140) and 7-amino-3- [2- [4- [bis (4-fluorophenyl) methylene] -1-25 piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2 -a] pyrimidin-4-one, m.p. 209.9 ° (comp. 141).

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Example XI

0.6 part of a 50% sodium hydride dispersion was rinsed with petroleum ether and the residue was suspended in 9 parts of Ν, Ν-dimethylformamide. The suspension was added in one portion to a stirred solution of 5.9 parts of 3- [2- [4 - [(4-fluorophenyl) (4-hydroxyphenyl) methylene] -1-piperidinyl] ethyl] -6.7, 8,9-Tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one in 36 parts of N, N-dimethylformamide at 40 °. Stirring was continued for one hour at 40 °. The mixture was cooled to 20 ° and then 1.8 parts of iodomethane were added in one portion (slightly exothermic reaction; the temperature rose to 25 °). The mixture thus obtained was stirred for one hour. The reaction mixture was poured into 400 parts of ice water. The product was extracted twice with 150 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. 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 collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol, evaporated and the solid residue suspended in 32 parts of acetonitrile. The product was filtered off and dried, yielding 4.7 parts (67%) of 3- [2- [4 - [(4-fluorophenyl) (4-methoxyphenyl) methylene] -1-piperidinyl] ethyl] -6.7, 8,9-Tetrahydro-2-methyl-2H-4H-pyrido [1,2-a] pyrimidin-4-one dihydrochloride m.p.

268.5 ° (comp. 146).

In a similar manner there were prepared 3- [2- [4 - [(4-fluorophenyl) (4-methoxyphenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4- onide dihydrochloride-30 dimonohydrate, m.p. 257.7 ° (compound 143).

Example XII

4.3 parts of 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one was converted to the sulfate salt in 48 parts of ethanol-35. The salt was filtered and crystallized from methanol. The product 35 83078 was filtered off and dried, yielding 2.5 parts (35%) of 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H- pyrido [1,2-a] pyrimidin-4-one sulfate (1: 2) dihydrate, m.p. 188.7 ° (compound 148).

The following compounds were also prepared by a similar salt-forming reaction: 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] ] pyrimidin-4-one (Z) -2-butenedicarboxylate, m.p. 201.8 ° (comp. 10149).

3- [2- [4- [Bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one 2-hydroxy- 1,2,3-pronan tricarboxylate (1: 1), m.p. 172.0 ° (compound 150).

15 Example XIII

5 parts of 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one dihydrochloride were dissolved in water. , and the base was liberated by the addition of ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in dilute ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.2 parts of 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] ] pyrimidin-4-one, m.p. 108.7 ° (comp. 156).

Claims (6)

A process for the preparation of new therapeutically useful {[bis (aryl) methylene] -1-piperidinyl} alkyl-4H-pyrido-5- [1,2-a] pyrimidin-4-one derivatives of formula (I) O YVk 10 ® O 15 wherein R is hydrogen, hydroxy or lower alkyloxy; A is a divalent group of formula (a) or (b) -CH 2 -CH 2 -CH 2 -CH 2 - (a) -CH = CR3-CR4 = CR5- (b) wherein the carbon atom to which R5 is attached is attached to the nitrogen atom of the pyrimidinone ring; R 3 is hydrogen or methyl; R 4 is hydrogen, methyl, halogen or amino; R 5 is hydrogen or methyl; Alk is C 2-4 alkanediyl; Ar 1 and Ar 2 are independently pyridinyl, thienyl or phenyl optionally substituted with halogen, hydroxy, lower alkyloxy, lower alkyl or trifluoromethyl; as well as for the preparation of their possible stereochemical isomers and pharmaceutically acceptable acid addition salts, characterized in that 35 N -alkylated piperidine of formula (III) 37 83078 RA ~ \ HN} = \ on) j- \ __ / Al2 o wherein R, Ar1 and Ar 2 is as defined above, in a reaction inert solvent with a compound of formula 10 (II) * -N 2 -N-Alk-W ® O 0 wherein A and Alk are as defined above and W is a reactive leaving group; and, if desired, O-alkylating a compound of formula (I) wherein Ar 1 or Ar 2 is a hydroxy-substituted phenyl group with an alkyl halide in the presence of a base in a reaction-inert solvent to give a compound of formula (I) wherein Ar 1 or Ar 2 is a lower alkyloxy substituted phenyl group; and, if desired, converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt; and further, if desired, stereochemically isomerized the compound of formula (I) thus obtained. 38 8 3 0 7 8 For the preparation of therapeutically active substances {[bis (aryl) methyl] -1-piperidinyl} alkyl-4H-5 pyrido [1,2-a] pyrimidin-4-one derivatives of formula (I) CH, R a Γ I) Γ Λ A v N ii-Alk-N / = \ CD 10. V _ / ^ A ^ O color R är väte, hydroxi eller lägre alkyloxi; A bivalent group of formula (a) or (b) 15 -CH2-CH2-CH2-CH2- (a) -CH = CR3-CR4 = CR5- (b) account kväveatomen i pyrimidinonringen; R3 is methyl or methyl; R 4 is methyl, halogen or amino; R5 is methyl or methyl; Alkyl C 2-4 alkanediyl; Ar1 and Ar2 are optionally substituted with pyridinyl, thienyl or optionally halogen, hydroxy, alkyloxy, alkyl or trifluoromethyl substituted phenyl; The same stereochemically isomeric and pharmaceutically acceptable compounds of the formula are selected from the group consisting of N-alkylers and piperidines of formula (III). 35 R / K_ IIN> = <(l * D \ _7 V 39 83078 color R, Ar1 and Ar2 betecnar samman soman, i and that reaction reactions with a solution of formula (II) CH3 5 ^^ N ® TO color A and the alkyl of the same group as the W-en reaction group of 10 groups and octyl groups, O-alkyler and compounds of formula (I), color Ar1 or Ar2 are hydroxyl-substituted phenyl groups, with in which the alkyl halides are present in the reaction and in the reaction process of formula 15 (I), the color Ar1 or Ar2 is not substituted by an alkyl substituent on the phenyl group, and in the case of the same, a further preferred form of the formula (I) account for a pharmaceutical product with a total of 20 stereochemical isomers, the stereochemical isomeric form of which is derived from the formulation (I) -