EP0346367A1

EP0346367A1 - Aryl- and aryloxy-substituted tert.-alkylenamines, process for their manufacture and their use in pharmacy

Info

Publication number: EP0346367A1
Application number: EP88901794A
Authority: EP
Inventors: Rudolf Albrecht; Klaus Schöllkopf; Manfred Lehmann; Gertrud SCHRÖDER
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1987-02-25
Filing date: 1988-02-23
Publication date: 1989-12-20
Also published as: JPH02502376A; WO1988006580A1; DE3706585A1

Abstract

Des alkylénamines tert. à substitution aryle ont la formule (I), dans laquelle R est un groupe alkyle ayant entre 1 et 6 atomes de C, ou l'ensemble de résidu (a) représente les résidus hétérocycliques (b), (c), (d), (e) ou (f), où R5 est hydrogène, méthyle, phényle, 4 - chlorphénol ou 4-fluorbenzoyle, n = 2 - 4, A représente les résidus carbonyle, hydroxyméthylène, C2-C4-acyloxyméthylène, méthylène ou oxygène, Z représente hydrogène, 2-fluor, 6-fluor, 2-chlore, 5-chlore, 2-méthyle ou 6-méthyle, R1 représente hydroxy ou C2-C4-acyloxy, lorsque R2 est hydroxy, C2-C4-acyloxy, amino ou NHR3, NH-CHO ou NH-CHO-NH2, R2 est hydroxy ou C2-C4-acyloxy, lorsque R1 est hydroxy, C2-C4-acyloxy, amino ou NHR3, R3 est alkyle ayant entre 1 et 4 atomes de C, 4-méthoxybenzyle, acétyle, méthylsulfonyle ou trifluorméthylsulfonyle, ou le résidu (g) forme par cyclisation de R2 et de Z les groupes bicycliques (h), (i), (j), (k) ou (l), où R4 est hydrogène, méthoxycarbonyle ou éthoxycarbonyle. L'invention concerne également les sels d'addition d'acides de ces alkylénamines comportant des acides physiologiquement compatibles, leur procédé de production et leur utilisation en pharmacie.Tertiary alkylenamines. substituted aryl have the formula (I), in which R is an alkyl group having between 1 and 6 atoms of C, or the set of residue (a) represents the heterocyclic residues (b), (c), (d) , (e) or (f), where R5 is hydrogen, methyl, phenyl, 4 - chlorphenol or 4-fluorbenzoyl, n = 2 - 4, A represents carbonyl, hydroxymethylene, C2-C4-acyloxymethylene, methylene or oxygen residues, Z represents hydrogen, 2-fluorine, 6-fluorine, 2-chlorine, 5-chlorine, 2-methyl or 6-methyl, R1 represents hydroxy or C2-C4-acyloxy, when R2 is hydroxy, C2-C4-acyloxy, amino or NHR3, NH-CHO or NH-CHO-NH2, R2 is hydroxy or C2-C4-acyloxy, when R1 is hydroxy, C2-C4-acyloxy, amino or NHR3, R3 is alkyl having between 1 and 4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluormethylsulfonyl, or the residue (g) forms by cyclization of R2 and Z the bicyclic groups (h), (i), (j), (k) or (l), where R4 is hydrogen, methoxycarbonyl or ethoxycarbonyl. The invention also relates to the acid addition salts of these alkylenamines comprising physiologically compatible acids, their production process and their use in pharmacy.

Description

Aryl- and aryloxy-substituted tert-alkylene amines, processes for their preparation and their pharmaceutical use

The present invention relates to aryl-substituted tert-alkylene amines, processes for their preparation and their therapeutic use in cardiovascular diseases.

Basically substituted butyrophenones of the structure below have a broad therapeutic application as neuroleptics (M.E. Wolff (Ed.), Burger's Medicinal Chemistry, 4th Edition, Part III, J. Wiley, New York, 1981, p. 859).

However, some derivatives of this type of structure are characterized by cardiovascular effects. Buflomedil is used therapeutically for peripheral arterial circulatory disorders.

EP 29 707 claims similar compounds of the following structure with hypotensive activity,

where (R ^I ) _m = OH, halogen, alkoxy etc. and

Y special nitrogen-containing groups,

such as. represent.

US 43 53 900 calls compounds

with an effect against hypertension and congestive heart failure. EP 154 959 describes piperazine compounds

with R ^III = OH, OR etc. and R ^IV = SO ₂ NH ₂ , SO ₂ NHR etc. known, which have an antihypertensive effect.

Recently JP 61 27 963 compounds of the formula

with R ^V = called alkoxy, which have a calcium-antagonistic and hypotensive effect.

It has now been found that compounds with hydroxyl groups in the 3- and 4-position of the left aromatic ring or with corresponding bioisosteric groups in the 3.4-position have a superior vasodilatory effect compared to the prior art.

The invention thus relates

aryl- and aryloxy-substituted tert-alkylene amines of the formula I.

wherein R is an alkyl group with 1-6 carbon atoms or all of the rest are heterocyclic

or means, where R _{5 is} hydrogen,

Represents methyl, phenyl, 4-chlorophenol or 4-fluorobenzoyl, n = 2 - 4,

A the radicals carbonyl, hydroxymethylene, C ₂ -C ₄ -acyloxy-methylene,

Methylene or oxygen, Z is hydrogen, 2-fluorine, 6-fluorine, 2-chlorine, 5-chlorine, 2-methyl or

6-methyl,

R _{1 is} hydroxy or C ₂ -C ₄ -acyloxy if R _{2 is} hydroxy, C ₂ -C ₄ -acyloxy, amino or NHR ₃ , NH-CHO or NH-CO-NH ₂ ,

R _{2 is} hydroxy or C ₂ -C ₄ acyloxy when R _{1 is} hydroxy, C ₂ -C ₄ acyloxy, amino or NHR ₃ ,

R ₃ alkyl with 1-4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluoromethylsulfonyl, or

the rest by ring closure of R ₂ and Z the bicyclic groups

R ₄ as hydrogen, methoxycarbonyl or ethoxycarbonyl, and their acid addition salts with physiologically compatible acids.

R as an alkyl group with 1-6 C atoms means a saturated straight-chain or branched-chain hydrocarbon residue such as e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl etc. Preferred are residues with 1-4 C atoms.

R ₃ as C ₁ -C ₄ alkyl means the radicals already mentioned for R.

The C ₂ -C ₄ acyloxy groups in A, R ₁ and R ₂ represent the

Radicals acetyloxy, n-propionyloxy and n-butyryloxy.

Inorganic or organic acids are suitable as physiologically acceptable acids.

Particularly worth mentioning here are hydrogen halide, preferably HCl or HBr, and of the organic acids acetic acid and maleic acid.

The new compounds are preferably used as salts.

The vasodilatory effect of the compounds according to the invention was measured in vitro. Isolated rings of the rabbit lienalis artery in a Krebs-Ringer solution flushed with O ₂ and CO ₂ are contracted with noradrenaline before the start of the experiment. The test substances are added cumulatively in the concentration range from 10 -7 to 10 -5 mol / 1. It becomes the dilator effect caused by the test substances by the decrease of the

Tension of the vascular rings measured.

Table 1 summarizes the test results of a representative selection of the compounds of the formula I according to the invention in comparison with the comparison substance buflomedil (the numbers represent mean values from 4-8 measurements). This results in an up to 5 times stronger relaxing effect for the new compounds.

The compounds can find therapeutic uses in all indications in which vascular dilation is desired, such as circulatory disorders, hypertension, heart failure or coronary heart disease.

The compounds according to the invention are therefore suitable as antihypertensives.

For the use of the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation according to galenical methods known per se which, in addition to the active ingredient, are particularly suitable organic or inorganic inert carrier materials, such as e.g. May contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, polyalkylene glycols etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, Dragδes suppositories, capsules or in liquid form, e.g. present as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

For human use, the dosage is 50 to 1000 mg per day.

The compounds of the formula I are prepared in a manner known per se by a) an aryl-substituted alkyl halide or tosylate of the formula II,

where n = 2-4 and A 'is carbonyl, dimethoxymethylene or oxygen, R _{6 is} tosyloxy, chlorine or bromine and R' _{1 is} methoxy or benzyloxy, R ₂ ^'is methoxy, benzyloxy or methylsulfonamido, Z 'hydrogen and Z' and R ₂ together mean the group -CH ₂ -CO-NH- in 2,3-position of the benzene ring, optionally after prior protection of the carbonyl group in A 'with an amine of the formula III

with the meanings already mentioned for R or the entire rest of those with a pyridine derivative of the formula IV,

it implements the meanings already mentioned for R ₅ , a benzene derivative of the formula V,

wherein R ₁ "hydroxy or methoxy, R ₂ " CH ₃ CONH or

R ₂ "and Z" together form the group -NH

R ₄ in the meaning given above means the group -NH-N = CH-, the group -NH-CH = N- or the group in the 2,3 position of the benzene ring, with an amino acid derivative of the formula VI,

wherein n and R have the meanings already mentioned and R _{7 is} a carboxyl radical or a cyano group, in the presence of polyphosphoric acid or AlCl ₃ , c) a benzene derivative of the formula VII

wherein R ₁ '''is hydrogen, methoxy or benzyloxy, R ₂ ''' methoxy or benzyloxy, Z '''is hydrogen, fluorine, chlorine or methyl and R _{8 is} an aldehyde or cyano group, with a Grignard reagent of the formula VIII,

wherein n and R have the meanings already mentioned and X 'represents chlorine or bromine, or d) 3,4-dimethoxyacetophenone is reacted with an amine of the formula III and formaldehyde and, if appropriate, the compounds I obtained according to a) -d), an ether cleavage, reduction of the carbonyl group in A, oxidation of the OH group in A, a LiAlH ₄ reduction , subject to an acylation or Umamidierung or in the case of free NH ₂ groups with potassium cyanate or with alkylating agents.

The reactions according to a) are carried out either in polar solvents, e.g. Butanol, methyl ethyl ketone, dimethylformamide, or without solvent at temperatures between 20 ° C and

200 ° C and reaction times of 0.5 to 48 hours.

The reactions according to b) are carried out in pure polyphosphoric acid or in inert solvents such as methylene chloride, benzene, toluene at temperatures from 20 ° C. to 150 ° C. and reaction times from 0.5 to 48 hours.

The reactions according to c) are carried out in a solvent typical of the Grignard reaction, such as diethyl ether, tetrahydrofuran, at temperatures from 0 ° C. to the boiling point of the solvent with reaction times of 10 minutes to 48 hours.

The reactions according to d) are preferably carried out in an alcohol, e.g. Ethanol, in the presence of a mineral acid, e.g. Hydrochloric acid, at temperatures from 25 ° C to the boiling point of the solvent with reaction times of 0.25 to 48 hours.

The starting compounds required for the preparation of the compounds according to the invention are either known or can be synthesized as follows: Representation of the output connections

1- (3-chloropropyl) -4-methyl-piperidine

46.4 g of 1-bromo-3-chloropropane are dissolved in 120 ml of ether and 58.9 g of 4-methylpiperidine are added dropwise. It is boiled under reflux for 3 hours. The product obtained after working up is distilled in vacuo, giving 30.4 g of the compound having a boiling point of 89-92 ° C. at 12-13 mm Hg.

4- (4-methyl-1-piperidyl) butyric acid, hydrochloride

a) 100 g of 4-bromobutyric acid ethyl ester are dissolved in 200 ml of diethyl ether and mixed with 109 g of 4-methylpiperidine. After refluxing for 6 hours, water is added and the mixture is extracted with dilute hydrochloric acid. The aqueous phase is neutralized with sodium carbonate and extracted with diethyl ether. After drying over sodium sulfate and concentration, the residue is distilled at 3 x 10 ^-2 mbar and 75 ° C in a Kugelrohr. 58.4 g of ethyl 4- (4-methylpiperidino) butter are obtained as an oil.

b) 5.0 g of the compound obtained under a) are refluxed with 50 ml of 18 percent hydrochloric acid for 20 hours. It is concentrated and boiled with acetone. 4.8 g of 4- (4-methyl-1-piperidyl) butyric acid, hydrochloride with a melting point of 180 ° C. are obtained. 4- (4-methyl-1-piperidyl) butyronitrile

22 ml of 4-bromobutyronitrile, 24 ml of 4-methylpiperidine and 27.6 g of potassium carbonate are stirred for 7 hours at 80 ° C. and 16 hours at room temperature in 400 ml of n-butanol, mixed with 400 ml of ethyl acetate, once with saturated sodium bicarbonate solution washed, concentrated and the residue distilled in vacuo. 30.3 g of 4- (4-methyl-1-piperidyl) butyronitrile with a boiling point of 91-93 ° C. (0.01 bar) are obtained.

3-chloro-4,5-dimethoxybenzonitrile

10.0 g of 3-chloro-4,5-dimethoxybenzaldehyde (J. Org. Chem. 10, 527 (1945)) are refluxed with 6.0 g of hydroxylamine hydrochloride and 80 ml of formic acid for one hour. The warm reaction mixture is poured onto ice water and neutralized with sodium hydroxide solution. The aqueous phase is extracted with dichloromethane. After drying over sodium sulfate and concentration, 6.9 g of 3-chloro-4,5-dimethoxybenzonitrile with a melting point of 95-96 ° C. are obtained.

2-chloro-3, 4-dimethoxybenzonitri 1

1.34 g of 2-chloro-3,4-dimethoxybenzaldehyde (Ger. Offen. 27 51 258 from 1.6.78) are refluxed with 0.63 g of hydroxylamine hydrochloride and 8 ml of formic acid for one hour. The warm reaction mixture is poured onto ice water and neutralized with sodium hydroxide solution. The aqueous phase is extracted with dichloromethane. After drying over sodium sulfate and concentration, 0.48 g of 2-chloro-3,4-dimethoxybenzonitri 1 with a melting point of 97-98 ° C. is obtained. N- [5- (4-Chlorobutyryl) -2-methoxy] acetanilide

74.3 g of N- (2-methoxy) acetanilide in 700 ml of methylene chloride are mixed with 0 g of 150 g of aluminum chloride and then for 30 minutes with 59 ml of 4-chlorobutyryl chloride in 150 ml of methylene chloride. After 90 minutes, it is poured onto 1 liter of concentrated hydrochloric acid and 3 liters of ice water, shaken once with ethyl acetate, the ethyl acetate fraction is washed neutral with saturated sodium chloride solution, dried and concentrated. After crystallization from ethyl acetate / hexane, 105 g of N- [5- (4-chlorobutyryl) -2-methoxy] -acetane i l i d of melting point 111.5-112.5 ° C. are obtained.

-3,4-dimethoxy-2-methyl-benzonitrile

4.5 g of 3,4-dimethoxy-2-methylbenzaldehyde and 2.98 g of hydroxylamine hydrochloride are refluxed in 100 ml of formic acid for 1.5 hours. It is poured onto ice, the solution is adjusted to pH 9 with 50% sodium hydroxide solution and the product is shaken out with methylene chloride. The product is purified by chromatography on silica gel with methylene chloride, 2.3 g of 3,4-dimethoxy-2-methylbenzonitrile having a melting point of 47-49 ° C. being obtained.

4,5-dimethoxy-2-fluoro-benzaldehyde

1.51 g of 4-fluoroveratrol are dissolved in 15 ml of methylene chloride, cooled to 0 ° C. and 5.73 g of tin tetrachloride are added. 1.26 g of dichloromethyl methyl ether are added dropwise and the mixture is stirred at 0 ° C. for 1 hour. 1.63 g of 4,5-dimethoxy-2-fluoro-benzaldehyde with a melting point of 88-90 ° C. are obtained. 4,5-dimethoxy-2-fluoro-benzonitrile

3.06 g of 4,5-dimethoxy-2-fluoro-benzaldehyde and 2.30 g of hydroxylamine hydrochloride are refluxed in 25 ml of formic acid for 1 hour. It is poured onto ice water and the solid product is filtered off. Chromatography on silica gel with methylene chloride gives 1.19 g of 4,5-dimethoxy-2-fluoro-benzonitrile.

3- (3,4-dibenzyloxy-phenoxy) propanol

4.8 g of 3,4-dibenzyloxyphenol, 2.64 ml of 3-bromopropanol and 6.24 g of potassium carbonate are boiled under reflux in 180 ml of butanol for 5 hours. The product is chromatographed on silica gel with acetone / methylene chloride 1: 1, 2.7 g of the compound being obtained as an oil.

3- (3, 4-dibenzyloxy-pheπoxy) propyl-p-toluenesulfonate

The solutions of 2.8 g of 3- (3,4-dibenzyloxyphenoxy) propanol in 12 ml of pyridine and of 1.9 g of p-toluenesulfochloride in 12 ml of pyridine are cooled to 0 ° C., combined, for 6 hours at 0 ° C and stirred for 3 hours at room temperature. It is evaporated in vacuo and the residue is taken up in 2N hydrochloric acid and ethyl acetate. The product isolated from the ethyl acetate solution is chromatographed on silica gel using cyclohexane / ethyl acetate 1: 1, 0.86 g of the compound being obtained as an oil which solidifies on standing for a long time. example 1

4- (4-methylpiperidino) -3 ', 4'-dihydroxy-butyrophenone, hydrobromide

a) 12.1 g of 4-chloro-3 ', 4'-dimethoxy-butyrophenone

(Chem. Abstr. 55, 6428 (1961)), 11.8 ml of 4-methylpiperidine and 10.4 g of potassium carbonate are refluxed in 100 ml of ethyl methyl ketone for 30 hours. The solid product is filtered off, the solution is evaporated and the residue is purified chromatographically on silica gel with methylene chloride / acetone 1: 1, 9.8 g of 4- (4-methylpiperidino) -3 ', 4'-dimethoxy-butyrophenone being obtained.

b) 9.15 g of the compound prepared according to a) are stirred with 9-9 ml of an imolar solution of boron tribromide in methylene chloride for 0.5 hours at 0 ° C. and 2 hours at room temperature. While cooling with ice, 60 ml of methanol are added and the mixture is stirred for 1 hour, then the mixture is filtered and the solid product is recrystallized from ethanol, 6.5 g of 4- (4-methylpiperidino) -3 ', 4'-dihydroxy-butyrophenone, hydrobromide of melting point 217 -221 ° C can be obtained.

The following are represented in the same way:

4- (1-pyrrolidinyl) -3 ', 4'-dihydroxy-butyrophenone, hydrobromide, melting point 155-177 ° C

4- (1-piperidinyl) -3 ', 4'-dihydroxy-butyrophenone, hydrobromide, melting point 211-220 ° C

4- (4-Thiomorρholinyl) -3 ', 4'-dihydroxy-butyrophenone, hydrobromide, melting point 245-255 ° C Example 2

4-Dimethylarrιino-3 ', 4'-dihydroxy-butyrophenone, hydrobromide

a) Dimethylamine is introduced into 30 ml of ethyl methyl ketone with ice cooling for 0.5 hours, then 3.6 g of 4-chloro-3 ', 4'-dimethoxy-butyrophenone and 3.2 g of potassium carbonate are added. The mixture is stirred at 50 ° C. for 2.5 hours, then 15 ml of ethyl methyl ketone saturated with dimethylamine are added and the mixture is stirred at 50 ° C. for a further 24 hours. It is filtered, the solution is evaporated and chromatographed on silica gel with methanol / methylene chloride 2: 8, 2.4 g of 4-dimethylamino-3 ', 4'-dimethoxy-butyrophenone being obtained.

b) 0.5 g of 4-dimethylamino-3 ', 4'-dimethoxy-butyrophenone are reacted as in example 3b), 0.31 g of 4-dimethyiamino-3', 4'-dihydroxy-butyrophenone, hydrobromide, from the melting point 170-186 ° C can be obtained.

Example 3

4- [4- (4-chlorophenyl) -1,2,3,6-tetrahydro-1-pyridyl] -3 ', 4'-dihydroxy-butyrophenone, hydrobromide

a) 17.0 g of 4-chloro-3 ', 4'-dimethoxy-butyrophenone, 76 ml of trimethyl orthoformate, 6.0 g of Amberlyst 15 ion exchanger and 2 ml of methanol are stirred for 5 hours at room temperature. It is filtered, the solution evaporated, the product dissolved twice in toluene and evaporated again to give crude 4-chloro-3 ', 4'-dimethoxy-butyrophenone-dimethylacetal. b) 11.7 g of the crude acetal are boiled under reflux with 10.3 g of 4- (4-chlorophenyl) -4-hydroxy-piperidine and 6.9 g of potassium carbonate in 200 ml of ethyl methyl ketone for 44 hours. It is filtered, the solution is concentrated and chromatographed on silica gel with methylene chloride / methanol 9: 1, 9.98 g of 4- [4- (4-chlorophenyl) -4-hydroxy-piperidinyl] -3 ', 4'-dimethoxy- butyrophenone dimethyl acetal can be obtained as an oil.

c) 4.1 g of the compound shown in b) are heated in 200 ml of 48 percent hydrobromic acid at 100 ° C. for 24 hours, then the mixture obtained is poured into 200 ml of ethanol and the solid product is recrystallized from methanol, 1.2 g 4- [4- (4-chlorophenyl) -1,2,3,6-tetrahydro-1-pyridyl] -3 ', 4'-dihydroxy-butyrophenone, hydrobromide of melting point 245-257 ° C can be obtained.

Example 4

4- (4-methyl-1,2,3,6-tetrahydro-1-pyridyl) -3 ', 4'-dihydroxybutyrophenone, hydrochloride

a) 72.8 g of 4-chloro-3 ', 4'-dimethoxy-butyrophenone and 29.4 ml of γ-picoline are heated at 100 ° C for 20 hours, the residue with 250 ml of acetone at 40-50 for 2.5 hours ° C stirred. The solid product is filtered off and washed thoroughly with acetone to give 37.2 g of crude 1- [4- (3,4-dimethoxyphenyl) -4-oxobutyl] -4-methyl-pyridinium chloride.

b) 6.7 g of the compound prepared according to a) are dissolved in 60 ml of water and 4.5 g of sodium borohydride are added in portions with ice cooling and stirred for 1 hour. With ice cooling, 120 ml of 2N HCl are added dropwise and the product is recrystallized from isopropanol, 3.0 g of 4- (4-methyl-1,2,3,6-tetrahydro-1-pyridyl) -1- (3,4-dimethoxyphenyl ) -butanol with a melting point of 88-90 ° C. c) 10.7 g of the compound prepared according to b) and 11.3 g of pyridinium chlorochromate in 140 ml of methylene chloride

Stirred for 20 hours at room temperature, the solid product is mixed with 100 ml of ethanol and 10 ml of 2N HCl, then evaporated completely. The residue is recrystallized from ethanol, 4.3 g of 4- (4-methyl-1,2,3,6-tetrahydro-1-pyridyl) -3 ', 4'-dimethoxy-butyrophenone, hydrochloride of melting point 183-189 ° C can be obtained.

d) 3.6 g of the compound prepared according to c) are suspended in 120 ml of methylene chloride and cooled to 5 ° C., then 4.8 ml of dimethyl sulfide and 9.5 g of aluminum chloride are added. The mixture is stirred under ice-cooling for 75 minutes, then 6 ml of concentrated hydrochloric acid are added dropwise, 50 ml of ethanol are added, and the mixture is evaporated completely in vacuo. The residue is recrystallized from ethanol, 1.5 g of 4- (4-methyl-1,2,3,6-tetrahydro-1-pyridyl) -3 ', 4'-dihydroxybutyrophenone, hydrochloride of melting point 187-192 ° C. be preserved.

Example 5

N- [4- (3,4-Dihydroxyphenyl) -4-hydroxybutyl] -4-methylpiperidine, acetate

a) The Grignard reagent is prepared from 1.46 g of magnesium and 10.5 g of 1- (3-chloropropyl) -4-methyl-piperidine in 25 ml of tetrahydrofuran. A solution of 9.6 g of 3,4-dibenzyloxybenzaldehyde in 50 ml of tetrahydrofuran is added dropwise to this solution while cooling with ice, and the mixture is then boiled for 3 hours. 75 ml of 2N hydrochloric acid are added dropwise while cooling with ice, and the isolated material is recrystallized from water, 12.6 g of N- [4- (3,3-dibenzyloxyphenyl) -4-hydroxybutyl] -4-methylpiperidine, Hydrochloride of melting point 174-176 ° C can be obtained. b) 2.5 g of the compound prepared according to a) are converted into the base with sodium carbonate solution, this is hydrogenated in ethyl acetate in the presence of 200 mg of palladium-carbon (10 percent) at normal pressure. After filtering off the catalyst, the equivalent amount of acetic acid is added, the mixture is evaporated and the residue is recrystallized from ethyl acetate, 0.67 g of N- [4- (3,4-dihydroxyphenyl) -4-hydroxybutyl] -4-methyl -piperidine, acetate of melting point 121-125 ° C can be obtained.

Example 6

N- [4- (3,4-dihydroxyphenyl) butyl] -4-methylpiperidine, hydrobromide

a) A solution of 2.3 g of lithium aluminum hydride in 100 ml of tetrahydrofuran is cooled to 0 ° C., then a solution of 9.2 g of 4- (4-methylpiperidino) -3 ', 4'-dimethoxy-butyrophenone (Example 1a ) added dropwise in 100 ml of tetrahydrofuran. After stirring for 1.5 hours, 5 ml of a 50 percent NaOH solution are added dropwise. 3.7 g of N- [4- (3,4-dimethoxyphenyl) -4-hydroxy-butyl] -4-methyl-piperidine are obtained as an oil which, when treated with petroleum ether, turns into a solid product of melting point 72-75 ° C. stiffens.

b) 0.9 g of the compound prepared according to a) are hydrogenated in 30 ml of acetic acid and 3 ml of concentrated hydrochloric acid in the presence of 200 mg of palladium-carbon (10 percent) at normal pressure. After evaporation, 0.7 g of crude N- [4- (3,4-dimethoxyphenyl) butyl] -4-methylpiperidine, hydrochloride are obtained from the solution. c) 0.43 g of the compound prepared according to b) are heated to 140 ° C. for 1 hour with 20 ml of 48 percent hydrobromic acid. After evaporation and recrystallization from ethanol, 0.15 g of N- [4- (3,4-dihydroxyphenyl) butyl] -4-methylpiperidine, hydrobromide of melting point 211-216 ° C. is obtained.

Example 7

3 *, 4'-dihydroxy-3-dipropylamino-propiophenone, hydrobromide

a) 18.0 g of 3,4-dimethoxyacetophenone, 4.0 g of paraformaldehyde and 17.9 g of dipropylamine hydrochloride are refluxed in 30 ml of ethanol in the presence of 1 ml of 1N HCl for 2 hours. 600 ml of acetone are added, precipitated dipropylamine hydrochloride is separated off. 19.9 g of 3 ', 4'-dimethoxy-3-dipropylamino-propiophenone, hydrochloride of melting point 131-132 ° C. are obtained from the solution.

b) 1.5 g of the compound prepared under a) are heated in 10 ml of 48 percent hydrobromic acid at 140 ° C. for 3 hours. After evaporation in vacuo, the solid product obtained is washed out with isopropanol / ether, 0.45 g of 3 ', 4'-dihydroxy-3-dipropylamino-propiophenone, hydrobromide of melting point 111-114 ° C. being obtained.

Example 8

3- (4-methyl-piperidino) -3 ', 4'-dihydroxy-propiophenone, hydrobromide

a) 12.4 g of 3,4-dimethoxy-acetophenone are reacted analogously to Example 7a). The hydrochloride obtained is treated with aqueous sodium bicarbonate solution, 11.6 g of 3 ', 4'-dimethoxy-3- (4-methyl-piperidino) propiophenone of melting point 72-74 ° C. being obtained.

b) 1.0 g of the compound prepared under a) are refluxed in 20 ml of 63% hydrobromic acid for 1 hour. It is evaporated and recrystallized from ethanol, 0.42 g of 3- (4-methyl-iperiperidino) -3 ', 4'-dihydroxy-propiophenone, hydrobromide of melting point 194-195 ° C. being obtained.

Example 9

4- (4-methylpiperidino) -2'-fluoro-3 ', 4'-dihydroxy-butyrophenone, hydrobromide

a) 1.20 g of 2-fluoro-3,4-dimethoxy-benzonitrile (US 42 65 890 dated 7.7.78) are made with a Grignard reagent from 2.11 g of N- (3-chloropropyl) -4-methylpiperidine and 0.29 g of magnesium in tetrahydrofuran is reacted by refluxing for 3 hours. The crude product is chromatographed on silica gel with a dichloromethane-methanol mixture 8: 2. 0.62 g of 4- (4-methylpiperidino) -2'-fluoro-3 ', 4'-dimethoxy-butyrophenone are obtained as an oil. b) 620 mg of the compound obtained under a) are refluxed with 5 ml of 63% hydrobromic acid for 2 hours. After concentration, the residue is recrystallized from an ethanol-acetone mixture. 210 mg of 4- (4-methylpiperidino) -2'-fluoro-3 ', 4'-dihydroxybutyrophenone, hydrobromide of melting point 231-235 ° C. are obtained.

Example 10

4- (4-methylpiperidino) -2'-chloro-3 ', 4'-dihydroxy-butyrophenone, hydrobromide

a) 1.56 g of 2-chloroprop-3,4-dimethoxybenzonitri 1 are reacted with a Grignard reagent from 1.78 g of N- (3-chloropropyl) -4-methylpiperidine and 0.25 g of magnesium analogously to Example 9a). The crude product is chromatographed on silica gel with a dichloromethane-methanol mixture 8: 2. 1.0 g of 4- (4-methylpiperidino) -2'-chloro-3 ', 4'-dimethoxy-butyrophenone are obtained as an oil.

b) 500 mg of the compound obtained under a) are dissolved in 10 ml of dichloromethane. 4 ml of a one-molar boron tribromide solution in dichloromethane are added to this solution with cooling. After 6 hours, methanol is added and concentrated. The residue is recrystallized from ethanol. 220 mg of 4- (4-methylpiperidino) -2'-chloro-3 ', 4'-dihydroxy-butyrophenone, hydrobromide of melting point 203-208 ° C. are obtained. Example 11

4- (4-methylpiperidino) -3'-chloro-4 ', 5'-dihydroxybutyrophenone, hydrobromide

a) 2.77 g of 3-chloro-4,5-dimethoxy-benzonitrile are reacted with a Grignard reagent consisting of 3.51 g of N- (3-chloropropyl) -4-methylpiperidine and 0.60 g of magnesium as in Example 9a) . The crude product is chromatographed on silica gel with a dichloromethane-methanol mixture 8: 2. 1.50 g of 4- (4-methylpiperidino) -3'-chloro-4 ', 5'-dϊmethoxy-butyrophenone are obtained as an oil.

b) 870 mg of the compound obtained under a) are dissolved in 20 ml of dichloromethane. 10 ml of a one-molar boron tribromide solution in dichloromethane are added to this solution with cooling. After 12 hours, methanol is added and concentrated. The residue is extracted with acetone. 700 mg of 4- (4-methylpiperidino) -3'-chloro-4 ', 5'-dihydroxy-butyrophenone, hydrobromide of melting point 212-216 ° C. are obtained.

Example 12

4- (4-methyl-piperidino) -2'-methyl-4 ', 5'-dihydroxybutyrophenone, hydrochloride

5.0 g of 4,5-dimethoxy-2-methyl-benzonitrile are dissolved in 25 ml of tetrahydrofuran. A Grignard solution, which is prepared from 1.36 g of magnesium and 9.9 g of 1- (3-chloropropyl) -4-methyl-piperidine in tetrahydrofuran, is added dropwise to this solution and the mixture is boiled under reflux for 60 hours. The reaction product is purified by chromatography on silica gel with methylene chloride / methanol, whereby 1.0 g of 4 ', 5'-dimethoxy-4- (4-methyl-piperidino) -2'-methyl-butyrophenone are obtained. b) 0.6 ml of dimethyl sulfide are dissolved in 20 ml of methylene chloride and cooled to 0 ° C. 1.25 g of aluminum trichloride and 0.5 g of the compound prepared according to a) are added, the mixture is stirred at 0 ° C. for 1 hour and then heated to 10 ° C. within one hour. It is poured into water and acidified with hydrochloric acid. 0.25 g of 4- (4-methyl-piperidino) -2'-methyl-4 ', 5'-dihydroxy-butyrophenone, hydrochloride with a melting point of 199-200 ° C. are obtained.

The following are represented in the same way:

4- (4-methyl-piperidino) -2'-methyl-3 ', 4'-dihydroxy-butyrophenone, hydrochloride (from 3,4-dimethoxy-2-methyl-benzonitrile), melting point 239-241 ° C.

Example 13

4- (4-methyl-piperidino) -2'-fluoro-4 ', 5'-dihydroxybutyrophenone, hydrochloride

a) A Grignard solution is prepared in tetrahydrofuran from 0.13 g of magnesium and 0.93 g of 1- (3-chloropropyl) -4-methyl-piperidine. A solution of 0.50 g of 4,5-dimethoxy-2-fluoro-benzonitrile in tetrahydrofuran is added dropwise with cooling and the mixture is then boiled under reflux for 2.5 hours. The product is recrystallized from petroleum ether. 0.45 g of 4- (4-methyl-piperidino) -2'-fluoro-4 ', 5'-dimethoxy-butyrophenone are obtained. b) 0.24 g of the compound described under a) are reacted with dimethyl sulfide and aluminum trichloride, as described in Example 12b), 0.12 g of 4- (4-methylpiperidino) -2'-fluoro-4 ', 5'-dihydroxy-butyrophenone, hydrochloride of melting point 247-253 ° C can be obtained.

Example 14

3'-amino-4'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide

a) 660 mg of N- (2-methoxy) acetanilide and 1.3 g of 4- (4-methyl-1-piperidyl) butyric acid, hydrochloride are heated in 15.0 g of polyphosphoric acid at 100 ° C. for 2 hours, with ice water added and alkalized by adding solid sodium hydrogen carbonate. After recrystallization from diisopropyl ether, 1.0 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - acetanilide of melting point 97-99 ° C. is obtained.

b) 81.0 g of N- [5- (4-chlorobutyryl) -2-methoxyl-acetanilide,

108 ml of 4-methylpiperidine, 41.4 g of potassium carbonate and 10.0 g of potassium iodide in 1.2 l of ethyl methyl ketone are heated to 80 ° C. for 24 hours. It is partly concentrated, water is added, the reaction product is shaken out with ethyl acetate and concentrated. The residue is chromatographed on silica gel with methylene chloride / methanol 4: 1 and recrystallized from ethyl acetate / hexane, 94.3 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} Acetanilide melting point 98-89.5 ° C can be obtained. c) 6.6 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} acetanilide are boiled in 100 ml of 65% hydrobromic acid for 18 hours, concentrated and extracted from ethanol / Diethyl ether crystallized, whereby 8.0 g of 3'-amino-4'-hydroxy-4- (4-methyl-1-piperidyl) -butyrophenone, dihydrobromide were obtained from the decomposition point 155-157 ° C.

Example 15

N- {2-Hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} formanilide, hydrochloride

1.2 ml of pivaloyl chloride are stirred at 0 ° C. with 240 mg of 18-Crown-6 and 820 mg of sodium formate for 6 hours, then with a solution of 440 mg of 3'-amino-4'-hydroxy-4- (4-methyl- 1-piperidyl) -butyrophenone, dihydrobromide and 330 mg sodium acetate in 12 ml methanol. After 5 hours at 0 ° C. and 16 hours at room temperature, the mixture is concentrated, saturated sodium bicarbonate solution is added and the mixture is shaken out three times with 6: 1 ethyl acetate / n-butanol. The ethyl acetate solutions are concentrated and chromatographed on a silica gel column (system: methanol / dichloromethane 1: 1). the product is treated in methanol with ethereal hydrochloric acid, giving 235 mg of N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - formanilide, hydrochloride, melting point 195-196 ° C. become. Example 16

N- {2-Hydroxy-5- [4-methyl-1-piperidyl) butyryl]} acetanilide, hydrogen maleate

440 mg of 3'-amino-4'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide, 330 mg of sodium acetate and 0.15 ml of acetic anhydride are dissolved in 10 ml of acetic acid and 5 ml of methanol for 2 hours at room temperature touched. The product, purified by chromatography on silica gel with methanol / dichloromethane, is mixed with 100 mg of maleic acid and recrystallized from ethanol / diethyl ether, 305 mg of N- 2-hydroxy-5- [4-methyl-1-piperidinyl) butyryl] acetanilide, Hydrogen maleate can be obtained with a melting point of 87-89 ° C.

Example 17

N- {2-Hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide, hydrobromide

a) 3.1 g of N- [5- (4-chlorobutyryl) -2-methoxy] methanesulfonanilide, 2.95 ml of 4-methylpiperidine and 2.1 g of potassium carbonate are boiled under reflux in 100 ml of ethyl methyl ketone for 20 hours. The reaction product is purified chromatographically on silica gel with methylene chloride / methanol 7: 3, giving 1.4 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide as an oil become. b) 1.4 g of the compound described under a) are stirred for 5.5 hours at room temperature with 19 ml of an imolar solution of boron tribromide in 30 ml of methylene chloride, mixed with methanol, evaporated and the residue is recrystallized from ethanol, 0.47 g N- {2-Hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide, hydrobromide of melting point 205-209 ° C. can be obtained.

Example 18

N- {2-Hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide, hydrogen maleate

a) 50.0 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - acetanilide in 400 ml of ethanol, 400 ml of water and

400 ml of concentrated hydrochloric acid boiled for 5 hours, concentrated and recrystallized from methanol / diethyl ether, 55.0 g of 3'-amino-4'-methoxy-4- (4-methyl-1-piperidyl) -butrophenone, dihydrochloride melting at 199- 201 ° C can be obtained. The dihydrochloride is dissolved in 300 ml of water and saturated sodium hydrogen carbonate solution is added. The precipitate is filtered off, dried and recrystallized from ethyl acetate. 38.0 g of 3'-amino-4'-methoxy-4- (4-methyl-1-piperidyl) -butyrophenone with a melting point of 100-102 ° C. are obtained.

b) 1.3 g of 3'-amino-4'-methoxy-4- (4-methyl-1-piperidyl) -butrophenone in 45 ml of dichloromethane are stirred at 0 ° C. for 16 hours with 1.3 ml of trifluoromethanesulfonic anhydride, with saturated sodium bicarbonate solution added, suction filtered and the crystals are washed with dichloromethane and water. 1.7 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) -butyryl]} - trifluoromethane at su lfon an ilid from the melting point of 25 ° C. are obtained. c) 840 mg of the compound described under b) are heated for 3.5 hours with 15 ml of 65 percent hydrobromic acid to 140 ° C. and concentrated. The residue is dissolved in water, saturated sodium bicarbonate solution is added and the precipitate is filtered off with suction. After crystallization from methanol 700 mg of N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide are obtained from the decomposition point 246-247 ° C.

This compound is mixed with 230 mg of maleic acid in methanol and the solution obtained is concentrated. After recrystallization from methanol / diethyl ether, 600 mg of N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide, hydrogen maleate from the decomposition point 98-99 ° C. are obtained.

Example 19

N- {2-Hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl] phenyl} urea, hydrogen maleate

660 mg of 3'-amino-4'-hydroxy-4- (4-methyl-1-piperidyl) -butrophenone in 8 ml of acetic acid and 4 ml of water are stirred for 4 hours at room temperature with 490 mg of potassium cyanate and 490 mg of sodium acetate. It is concentrated, the residue is dissolved in water, sodium bicarbonate is added, the precipitate is filtered off with suction and combined in methanol with maleic acid. After addition of diethyl ether, 400 mg of N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl] phenyl} urea, hydrogen maleate with a melting point of 175.5-176 ° C. are obtained. Example 20

4'-Hydroxy-3'-methylamino-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide

a) 1.45 g of 3'-amino-4'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone are mixed with 0.42 ml of 37 percent aqueous formalin solution and 284 mg of sodium cyanoborohydride in 50 ml of methanol and 5 ml of 1, 2N ethereal hydrochloric acid. 760 mg of 4'-methoxy-3'-methylamino-4- (4-methyl-1-piperidyl) -butyrophenone of melting point 61 ° C. are obtained.

b) 304 mg of 4'-methoxy-3'-methylamino-4- (4-methyl-1-piperidyl) -butrophenone are reacted as described in Example 14c), 150 mg of 4'-hydroxy-3'-methylamino-4 - (4-methyl-1-piperidyl) -butrophenone, dihydrobromide can be obtained from the decomposition point 141-142 ° C.

The following is shown analogously:

3'-butylamino-4'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide, melting point 115-117 ° C.

Example 21

4'-Hydroxy-3 '- (4-methoxybenzylamino) -4- (4-methyl-1-piperidyl) butyrophenone, dihydrochloride

220 mg of 3'-amino-4'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide and 0.073 ml of 4-anisaldehyde are stirred with 32 mg of sodium cyanoborohydride for 1 hour at 0 ° C. and for 15 hours at room temperature . It is chromatographed on silica gel with methanol / dichloromethane 1: 1 and mixed with ethe hydrochloric acid, whereby 75 mg of 4'-hydroxy-3 '- (4-methoxybenzylamino) -4- (4-methyl-1-piperidyl) -butyrophenone, dihydrochloride are obtained from the decomposition point 130-133 ° C.

Example 22

4'-Amlno-3'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, dihydrobromide

a) 4.8 g of magnesium turnings and 150 ml of tetrahydrofuran are combined in 30 minutes with 35 ml of 1- (3-chloropropyl) -4-methylpiperidine, refluxed for 1.5 hours and in 20 minutes at room temperature with 18.3 ml of 3rd -Methoxybenzonitrile in

100 ml of tetrahydrofuran are added. The mixture is boiled under reflux for 6 hours, combined with 400 ml of 2N sulfuric acid with ice cooling and heated to 100 ° C. for 1 hour. After the addition of sodium hydrogen carbonate, the mixture is shaken three times with ethyl acetate, the ethyl acetate fraction is combined, dried, and concentrated, and the residue is distilled in vacuo. 34.6 g of 3'-methoxy-4- (4-methyl-1-piperidyl) -butrophenone with a boiling point of 132-136 ° C. (0.015 bar) are obtained. 29.0 g of this compound are mixed in methanol with ethereal hydrochloric acid, giving 34.0 g of 3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone, hydrochloride with a melting point of 162-163 ° C.

b) 31.0 g of 3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone, hydrochloride in 500 ml of sulfuric acid are in at 0 ° C in

10.0 g of potassium nitrate were added for 30 minutes, the mixture was stirred at 0 ° C. for 30 minutes and poured onto 1.5 l of ice water. The pH is adjusted to 10-11 with 32% sodium hydroxide solution while cooling with ice and the mixture is shaken out with ethyl acetate. It will be on one Alumina column (activity II, system: cyclohexane / ethyl acetate 1: 1) chromatographed, 6.4 g

3'-Methoxy-4'-nitro-4- (4-methyl-1-piperidyl) -butrophenone with a melting point of 98-98.5 ° C. (diisopropyl ether) can be obtained.

c) 1.6 g of 3'-methoxy-4'-nitro-4- (4-methyl-1-piperidyl) butyrophenone are hydrogenated in 60 ml of tetrahydrofuran in the presence of 0.4 ml of Raney nickel. The product is recrystallized from diisopropyl ether / hexane, 1.3 g

4'-Amino-3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone of melting point 99-100 ° C can be obtained.

d) 1.45 g of 4'-amino-3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone are reacted with hydrobromic acid as described in Example 14c), 2.2 g of 4'-amino 3'-Hydroxy-4- (4-methyl-1-piperidyl) -butrophenone, dihydrobromide can be obtained from the decomposition point 245-247 ° C.

Example 23

N- {2-Hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} acetanilide, hydrobromide

440 mg of 4'-amino-3'-hydroxy-4- (4-methyl-1-piperidyl) -butrophenone, dihydrobromide in 10 ml of methanol and 15 ml of acetic acid are mixed with 330 mg of sodium acetate and 0.15 ml of acetic anhydride for 2 hours stirred at room temperature, combined with 0.15 ml of acetic anhydride and 10 ml of methanol and concentrated after 3 hours. 300 mg of N- {2-hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} acetanilide, hydrobromide of decomposition point 262-263 ° C. (water) are obtained. Example 24

N- {2-Hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide, hydrogen maleate

a) 580 mg of 4'-amino-3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone in 15 ml of dichloromethane. 700 mg of methanesulfonic anhydride in 10 ml of dichloromethane are added at 0 ° C., the mixture is stirred at room temperature for 48 hours, saturated sodium bicarbonate solution is added and the dichloromethane fraction is concentrated. After crystallization from ethyl acetate / hexane, 500 mg of N- {2-methoxy-4- [4- (4-methyl-1-piperidyl) -butyryi]} - methanesulfonanilide of melting point 118-119 ° C. are obtained.

b) 370 mg of N- {2-methoxy-4- [4- (4-methyl-1-piperidyl) butyryl]} - methanesulfonanilide in 10 ml of dichloromethane are 2 hours at 0 ° C and 2 hours at room temperature with 5 ml 1m boron tribromide solution in dichloromethane and shaken with sodium bicarbonate solution. 200 mg of N- {2-hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide with a melting point of 159-162 ° C. are obtained. The compound is combined with maleic acid in methanol and diethyl ether is added, giving 215 mg of N- {2-hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl] 3-methanesulfonanilide, hydrogen maleate from decomposition point 179-180 ° C can be obtained.

Example 25

N- [2-Hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide, hydrobromide

a) 290 mg of 4'-amino-3'-methoxy-4- (4-methyl-1-piperidyl) butyrophenone are reacted with trifluoromethanesulfonic anhydride, as described in Example 18b), with 272 mg

N- {2-Methoxy-4- [4- (4-methy1-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide from decomposition point 256-257 ° C can be obtained.

b) 211 mg of the compound prepared according to a) are heated for 4 hours in 10 ml of 65 percent hydrobromic acid, concentrated and recrystallized from ethanol / diethyl ether. 220 mg of N- {2-hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide, hydrobromide with a melting point of 160-161 ° C. are obtained.

Example 26

(7-Hydroxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone, hydrochloride

a) 3.9 g of 7-methoxy-2-oxo-2,3-dihydroindole (Tetrahedron 1968, 24, 6106) and 8.0 g of 4- (4-methyl-1-piperidyl) butyric acid, hydrochloride with 80 , 0 g of polyphosphoric acid in 3 hours at 100 ° C, there are 7.0 g (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl ) -propyl] ketone melting point 174-175, 5 ° C (methanol) obtained. b) 490 mg of 7-methoxy-2-oxo-2,3-dihydroindole in 20 ml of dichloromethane are stirred at 0 ° C with 975 mg of aluminum trichloride for 10 minutes and in 30 minutes at 0 ° C with 0.42 ml of 4-chlorobutyryl chloride 5 ml of dichloromethane combined. After 1.5 hours at 0 ° C., 200 ml of ice water and 5 ml of concentrated hydrochloric acid are added and the mixture is shaken out with ethyl acetate. After trituration with diisopropyl ether, 520 mg (3-chloropropyl) - (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) ketone of melting point 192-196 ° C. are obtained.

c) 347 mg (3-chloropropyl) - (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) ketone are reacted with 4-methylpiperidine as described in Example 14b). 125 mg (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone of melting point 170-173 ° C. are obtained.

d) 495 mg (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone are at 0 ° C with 30 ml 1m Boron tribromide combined in dichloromethane and stirred for 24 hours at room temperature, methanol is added, the mixture is concentrated, the residue is repeatedly distilled with methanol, the residue is dissolved in water / ethanol, sodium bicarbonate is added and the mixture is filtered off with suction. By treatment with ethereal hydrochloric acid in methanol 295 mg (7-hydroxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone, hydrochloride from Decomposition point 286-288 ° C obtained.

Example 27

7-Hydroxy-4- [4- (4-methyl-1-piperidyl) butyryl] indole-2-carboxylic acid ethyl ester, hydrochloride

400 mg of 4- (4-methyl-1-piperidyl) butyronitrile and 800 mg of aluminum trichloride are suspended in 10 ml of dioxane and hydrogen chloride gas is introduced until the solution is dissolved while cooling with ice. 300 mg of 7-hydroxyindole-2-carboxylic acid ethyl ester in 5 ml of dioxane are added dropwise in 30 minutes at 0 ° C. and hydrogen chloride gas is introduced for a further 6 hours while cooling with ice. After 16 hours at 0 ° C., the reaction solution is poured onto ice, the precipitate is filtered off with suction, washed with saturated sodium hydrogen carbonate solution and then with ethyl acetate, 150 mg of 7-hydroxy- 4- [4- (4-methyl-1-piperidyl) -butyryl] -indole-2-carboxylic acid ethyl ester, hydrochloride from the decomposition point 235-236 ° C.

Example 28

(7-Hydroxy-1H-indazol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone, hydrogen maleate

5.4 g of 7-hydroxy-1H-indazole (J. Chem. Soc. 1955, 2418) and 26.0 g of 4- (4-methyl-1-piperidyl) butyric acid, hydrochloride, are mixed with 300 g of polyphosphoric acid for 3 hours Warmed 130-140 ° C, mixed with ice water and adjusted to pH 8.5 with cooling with 32 percent sodium hydroxide solution, it is shaken four times with ethyl acetate, the aqueous phase is adjusted to pH 13 with 25 percent ammonia solution, four times with n -Butanol / ethyl acetate shaken, dried, concentrated and recrystallized from ethanol / water, giving 2.6 g (7-hydroxy-1H-indazol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone of melting point 200-203 ° C can be obtained. 1.2 g of this compound are dissolved in methanol with 510 mg of maleic acid and diethyl ether is added. 1.2 g (7-hydroxy-1H-indazol-4-yl) [3- (4-methyl-1-piperidyl) propyl] ketone, hydrogen maleate with a decomposition point of 176-177 ° C. are obtained.

Example 29

4- [4- (4-methylpiperidino) butyryl] benzimidazol-7-ol, dihydrobromide

a) 1.0 g of 4-methoxybenzimidazole (Ger. Offen. 19 21 911 from 14.6.68) with 2.1 g of 4- (N-4-methylpiperidino) butyric acid, hydrochloride in 20 ml of polyphosphoric acid for 2 hours at 80 ° C stirred. After adding water, the mixture is neutralized with sodium carbonate and extracted with ethyl acetate. After filtering off and concentrating, the residue is recrystallized from a petroleum ether-ethanol mixture

1.5 g of 7-methoxy-4- [4- (4-methylpiperidino) butyryl] benzimidazole, melting point 109 ° C., were obtained.

b) 500 mg of the compound obtained under a) are refluxed with 50 ml of 63 percent hydrobromic acid for 2 hours. After concentration, the residue is recrystallized from a methanol-acetone mixture. 160 mg of 4- [4- (4-methylpiperidino) butyryl] benzimidazol-7-ol, dihydrobromide with a melting point of 140-145 ° C. are obtained. Example 30

4- [4- (4-Methylpiperidino) butyryl] -7-hydroxy-2,3-dihydrobenzimidazol-2-one, hydrobromide

a) 1.0 g of 4-methoxy-2,3-dihydrobenzimidazol-2-one (Ger. Offen. 28 19 458 from 3.5.77) are mixed with 2.0 g of 4- (N-4-methylpiperidino) butyric acid, Hydrochloride in 20 ml of polyphosphoric acid stirred at 80 ° C for 2 hours. After adding water, the mixture is neutralized with sodium carbonate and extracted with an ethyl acetate-butanol mixture. After filtering off and concentrating, the residue is recrystallized from methanol. 0.69 g of 7-methoxy-4- [4- (4-methylpiperidino) butyryl] -2,3-dihydrobenzimidazol-2-one are obtained with a melting point of 160 ° C.

b) 300 mg of the compound obtained under a) are refluxed for 3 hours with 20 ml of 63% hydrobromic acid. After concentration, the residue is extracted with acetone. 180 mg of 4- [4- (4-methylpiperidino) butyryl] -7-hydroxy-2,3-dihydrobenzimidazol-2-one, hydrobromide of melting point 259-261 ° C. are obtained.

Example 31

1,2-dihydroxy-4- [3- (4-methyl-piperidino) propoxy] benzene, hydrochloride

a) 0.78 g of 1,2-dibenzyloxy-4- (3-tosyloxypropoxy) benzene, 0.36 ml of 4-methyl-piperidine and 0.83 g of potassium carbonate are refluxed in 30 ml of butanol for 8 hours. The product is on silica gel with methanol / methylene chloride 1: 1 purified by chromatography and treated with ethereal hydrochloric acid in ether, giving 0.50 g of 1,2-dibenzyloxy-4- [3- (4-methyl-piperidino) propoxy] benzene, hydrochloride.

b) 0.24 g of the compound prepared under a) in 10 ml of methanol are hydrogenated in the presence of 100 mg of palladium-carbon (10 percent). The product is recrystallized from ethanol / methanol, giving 0.11 g of 1,2-dihydroxy-4- [3- (4-methylpiperidino) propoxy] benzene, hydrochloride with a melting point of 203-204 ° C.

Example 32

3 ', 4'-diacetoxy-4- (4-methyl-piperidino) -butrophenone, hydrobromide

0.72 g of 3 ', 4'-dihydroxy-4- (4-methyl-piperidino) -butrophenone, hydrobromide are stirred in 15 ml of acetic anhydride and 3 drops of 62% hydrobromic acid at 80 ° C. for 20 hours. It is evaporated in vacuo, the residue is dissolved in acetone and the product is precipitated with diisopropyl ether, giving 0.48 g of the compound having a melting point of 66-73 ° C.

The following is produced analogously:

3 ', 4'-Dibutyryloxy-4- (4-methy1-piperidino) -butrophenone, hydrobromide (melting point 134-145 ° C).

Claims

Aryl-substituted tert-alkylene amines of the formula I,

wherein R is an alkyl group with 1-6 carbon atoms or all

Rest -N the heterocyclic

Leftovers -

or means, where R _{5 is} hydrogen,

Represents methyl, phenyl, 4-chlorophenol or 4-fluorobenzoyl, n = 2 - 4,

A the radicals carbonyl, hydroxymethylene, C ₂ -C ₄ -acyloxy-methylene,

6-methyl,

R _{1 is} hydroxy or C ₂ -C ₄ -acyloxy, if R _{2 is} hydroxy, C ₂ -C ₄ -acyloxy, amino or NHR ₃ , NH-CHO or NH-C0-NH ₂ ,

R _{2 is} hydroxy or C ₂ -C ₄ acyloxy when R _{1 is} hydroxy, C ₂ -C ₄ acyloxy, amino or NHR,

R ₃ alkyl with 1-4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluoromethylsulfonyl, or the rest by ring closure of R ₂ and Z

the bicyclic groups

as hydrogen, methoxycarbonyl or ethoxycarbonyl, and their acid addition salts with physiologically acceptable acids.

2) Process for the preparation of compounds of the formula I, characterized in that a) an aryl-substituted alkyl halide or tosylate of the formula II, in a manner known per se,

where n = 2-4 and A 'the radical carbonyl, dimethoxymethylene or oxygen, R ₆ the radicals tosyl, chlorine or bromine and R ₁ a methoxy or benzyloxy group, R ₂ a methoxy, benzyloxy or methylsulfonamido group, Z' Hydrogen and Z 'and R ₂ together mean the group -CH ₂ -CO-NH- in 2,3-position of the benzene ring, optionally after prior protection of the carbonyl group in A' with an amine of the formula III

with the meanings already mentioned for R or the entire radical or with a pyridine derivative of the formula IV,

with the meanings already mentioned for R ₅ , a benzene derivative of the formula V,

wherein R ₁ "hydroxy or methoxy, R ₂ " CH ₃ CONH or R ₂ "and Z" together the group -NH - = CH - with R ₄ in the meaning given above means the group -NH-N = CH-, the group -NH-CH = N- or the group - in the 2,3 position of the benzene ring, with an amino acid derivative of the formula VI,

wherein n and R have the meanings already mentioned and R _{7 is} a carboxyl radical or a cyano group, in the presence of polyphosphonic acid or AlCl _3, c) a benzene derivative of the formula VII

wherein R ₁ '''is hydrogen, methoxy or benzyloxy, R ₂ ''' methoxy or benzyloxy, Z '''is hydrogen, fluorine, chlorine or methyl and R _{8 is} an aldehyde or cyano group, with a Griguard reagent of the formula VIII,

wherein n and R have the meanings already mentioned and X 'represents chlorine or bromine, implemented or d) 3,4-dimethoxyacetophenone is reacted with an amine of the formula III and formaldehyde and, if appropriate, the compounds I obtained according to a) -d), an ether cleavage, reduction of the carbonyl group in A, oxidation of the OH group in A, a LiAlH ₄ reduction , subject to an acylation or Umamidierung or in the case of free NH ₂ groups with potassium cyanate or with alkylating agents.

3) Medicaments consisting of one or more compounds of the formula I and customary auxiliaries and carriers.