DE3706585A1 - ARYL- AND ARYLOXY-SUBSTITUTED TERT.-ALKYLENAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE - Google Patents

Abstract

Aryl-substituted tert.-alkylenamines, have the formula (I), where R is an alkyl group with 1-6 C-atoms, or the total 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 is the carbonyl, hydroxymethylene, C2-C4-acyloxymethylene, methylene or oxygen residues, 2 is hydrogen, 2-fluor, 6-fluor, 2-chlor, 5-chlor, 2-methyl or 6-methyl, R1 is hydroxy or C2-C4 acyloxy, amino or NHR3, NH-CHO or NH-CO-NH2, R2 is hydroxy or C2-C4 acyloxy, when R1 is hydroxy, C2-C4 acyloxy, amino or NHR3, R3 is alkyl with 1-4 C-atoms, 4-methoxybenzyl, acetyl, methylsulphonyl or trifluormethylsulphonyl, or the residue (g) forms, by ring closure of R2 and Z, the bicyclic groups (h), (i), (j), (k) or (l), where R4 is hydrogen, methoxycarbonyl or ethoxycarbonyl. The invention also concerns the acid addition salts of these alkylenamines with biocompatible acids, the process for their manufacture and their use in pharmacy.

Description

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

Basically substituted butyrophenones of the structure below find wide therapeutic use as neuroleptics (M.E. Wolff [Ed.], Burger's Medicinal Chemistry, 4th Edition, Part III, J. Wiley, New York, 1981, p. 859).

e.g. B. X = 4-fluorine

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

Buflomedil  

In EP 29 707 similar compounds of the following are Structure with hypotensive effect claimed.

in which

(R ^I ) _m = OH, halogen, alkoxy etc. and Yspecific nitrogen-containing groups, such as. B. represent.

US 43 53 900 calls compounds

with an effect against hypertension and congestive heart Failure.  

EP 154 969 discloses piperazine compounds

With

R ^III = OH, OR etc. and R ^IV = SO₂NH₂, SO₂NHR etc.

known, which have an anti-hypertensive effect.

Recently, JP 61 27 963 compounds of formula

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

It has now been found that compounds with hydroxy groups in the 3- and 4-position of the left aromatic ring or with corresponding bioisosteric groups in the 3,4-position vasodilatory superior to the prior art Have effect.

The invention thus relates aryl- and aryloxy-substituted tert-alkylene amines Formula I.

wherein

Pure alkyl group with 1-6 carbon atoms or all of the rest the heterocyclic means, where R₅ is hydrogen, methyl, phenyl, 4-chlorophenol or 4-fluorobenzoyl, n = 2-4, Adie residues carbonyl, hydroxymethylene, C₂-C₄-acyloxymethylene, methylene or oxygen, hydrogen, 2-fluorine, 6-fluorine , 2-chlorine, 5-chlorine, 2-methyl or 6-methyl, R₁Hydroxy or C₂-C₄-acyloxy, if R₂ is hydroxy, C₂-C₄-acyloxy, amino or NHR₃, NH-CHO or NH-CO-NH₂, R₂Hydroxy or C₂-C₄-acyloxy, if R₁ represents hydroxy, C₂-C₄-acyloxy, amino or NHR₃, R₃alkyl with 1-4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluoromethylsulfonyl, or the rest by ring closure of R₂ and Z the bicyclic groups

R₄ as hydrogen, methoxycarbonyl or ethoxycarbonyl, as well as their acid addition salts with physiologically compatible Acids

mean.

R as an alkyl group with 1-6 C atoms means a saturated one straight chain or branched chain hydrocarbon residue such as B. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, etc. Residues with 1-4 C atoms are preferred. With R₃ as C₁-C₄-alkyl are the radicals already mentioned for R. meant. The C₂-C₄ acyloxy groups in A, R₁ and R₂ represent the Radicals acetyloxy, n-propionyloxy and n-butyryloxy. Inorganic acids come as physiologically acceptable acids or organic acids. Hydrogen halide in particular may be mentioned here HCl or HBr, as well as from organic acids Acetic acid and maleic acid. The new compounds are preferably used as salts used.  

The vasodilatory effect of the compounds according to the invention was measured in vitro. Isolated rings of the rabbit lienalis artery in a cancer Ringer's solution flushed with O₂ and CO₂ 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 / l. The dilatory effect caused by the test substances is measured by the decrease in the tension of the vascular rings.

Table 1 summarizes the test results of a representative Selection of the compounds of formula I according to the invention compared to the comparison substance buflomedil together (the numbers represent mean values from 4-8 measurements dar). The result is up to 5 times stronger relaxing effect for the new compounds.  

Table 1

The compounds can be therapeutic in all indications Find applications where vascular dilation is desired, such as. B. circulatory disorders, hypertension, Heart failure or coronary artery disease.

The compounds according to the invention are thus antihypertensive suitable.

For the use of the compounds according to the invention as a medicament these are according to known methods of Galenics in the form of a pharmaceutical preparation, which in addition to the active ingredient in particular for enteral application suitable organic or inorganic inert support materials, such as. B. water, gelatin, rubber arabicum, milk sugar, starch, magnesium stearate, talc, polyalkylene glycols etc. can contain. The pharmaceutical Preparations can be in solid form, e.g. B. as tablets, coated tablets, Suppositories, capsules or in liquid form, e.g. B. as Solutions, suspensions or emulsions are available. Possibly they also contain auxiliary substances such as preservatives, Stabilizers, wetting agents or emulsifiers, Salts to change the osmotic pressure or buffer.

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

The compounds of the formula I are prepared in a manner known per se, by one

• a) an aryl-substituted alkyl halide or tosylate of the formula II, wherein n = 2-4 and A'den carbonyl, dimethoxymethylene or oxygen, R₆die tosyloxy, chlorine or bromine and R'₁eine methoxy or benzyloxy group, R₂'eine methoxy, benzyloxy or methylsulfonamido group, Z'hydrogen and Z 'and R₂' together mean the group -CH₂-CO-NH- in the 2,3-position of the benzene ring, optionally after prior protection of the carbonyl group in A 'with an amine of formula III with the meanings already mentioned for R or all of the rest with a pyridine derivative of the formula IV, with the meanings already mentioned for R₅,
• b) a benzene derivative of the formula V, whereinR₁''Hydroxy or methoxy, R₂''CH₃CONH or R₂ '' and Z'' together the group with R₄ in the meaning given above, 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, in which n and R have the meanings already mentioned and R₇ represents a carboxyl radical or a cyano group, in the presence of polyphosphoric acid or AlCl₃,
• c) a benzene derivative of the formula VII, whereinR₁ ′ ′ ′ is hydrogen, methoxy or benzyloxy, R₂ ′ ′ ′ methoxy or benzyloxy, Z ′ ′ ′ is hydrogen, fluorine, chlorine or methyl and R₈ 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 with an amine of formula III and Implement formaldehyde and, if appropriate, that according to a) -d) Compounds I obtained an ether cleavage, reduction the carbonyl group in A, oxidation of the OH group in A, a LiAlH₄ reduction, an acylation or Umamidierung subjects or in the case of free NH₂ groups with potassium cyanate or reacted with alkylating agents.

The reactions according to a) are carried out either in polar solvents, such as B. butanol, methyl ethyl ketone, dimethylformamide, or without solvents at temperatures between 20 ° C and 200 ° C and reaction times of 0.5 to 48 hours.

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

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

Those for the preparation of the compounds according to the invention required starting compounds 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 added dropwise with 58.9 g of 4-methylpiperidine. It is boiled under reflux for 3 hours. That after refurbishment The product obtained is distilled in vacuo, 30.4 g the connection from the boiling point 89-92 ° C at 12-13 mm Hg be preserved.

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 × 10 ^-2 mbar and 75 ° C in a Kugelrohr. 58.4 g of ethyl 4- (4-methylpiperidino) butyrate are obtained as an oil.
• b) 5.0 g of the compound obtained under a) are with 50 ml of 18 percent hydrochloric acid at reflux for 20 hours heated. It is concentrated and boiled with acetone. It 4.8 g of 4- (4-methyl-1-piperidyl) butyric acid, hydrochloride obtained from the melting point 180 ° C.

4- (4-methyl-1-piperidyl) butyronitrile

22 ml of 4-bromobutyronitrile, 24 ml of 4-methylpiperidine and 27.6 g Potassium carbonate is 7 hours at 80 ° C and 16 hours Room temperature stirred in 400 ml of n-butanol, with 400 ml Ethyl acetate, once with saturated Washed sodium hydrogen carbonate solution, concentrated and the Residue distilled in vacuo. 30.3 g (4- (4- Methyl 1-piperidyl) butyronitrile with a boiling point of 91-93 ° C (0.01 bar).

3-chloro-4,5-dimethoxybenzonitrile

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

2-chloro-3,4-dimethoxybenzonitrile

1.34 g of 2-chloro-3,4-dimethoxybenzaldehyde (Ger. Offen. 27 51 258 from June 1, 78) with 0.63 g of hydroxylamine Hydrochloride and 8 ml of formic acid at reflux for one hour heated. The warm reaction mixture is on ice water given and neutralized with sodium hydroxide solution. The aqueous phase is extracted with dichloromethane. After drying over Sodium sulfate and concentration give 0.48 g of 2-chloro-3,4- dimethoxybenzonitrile with a melting point of 97-98 ° C.  

N- [5- (4-Chlorobutyryl) -2-methoxy] acetanilide

74.3 g of N- (2-methoxy) acetanilide in 700 ml of methylene chloride be at 0 ° C with 150 g of aluminum chloride and then 30 minutes with 59 ml of 4-chlorobutyryl chloride in 150 ml Methylene chloride added. After 90 minutes to 1 l poured concentrated hydrochloric acid and 3 l of ice water, once shaken out with ethyl acetate, the acetic acid ethyl ester fraction with saturated sodium chloride solution washed neutral, dried and concentrated. After crystallization from ethyl acetate / hexane, 105 g of N- [5- (4- Chlorobutyryl) -2-methoxy] acetanilide, melting point 111.5-112.5 ° C obtained.

3,4-dimethoxy-2-methyl-benzonitrile

4.5 g of 3,4-dimethoxy-2-methylbenzaldehyde and 2.98 g Hydroxylamine hydrochloride are in 100 ml of formic acid Boiled under reflux for 1.5 hours. It is poured on ice the solution is adjusted to pH 9 with 50 percent sodium hydroxide solution and shaken the product with methylene chloride. The product is chromatographed on silica gel with methylene chloride cleaned, 2.3 g of 3,4-dimethoxy-2-methylbenzonitrile can be obtained from the melting point 47-49 ° C.

4,5-dimethoxy-2-fluoro-benzaldehyde

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

4,5-dimethoxy-2-fluoro-benzonitrile

3.06 g of 4,5-dimethoxy-2-fluoro-benzaldehyde and 2.30 g Hydroxylamine hydrochloride are in 25 ml formic acid Boiled under reflux for 1 hour. It gets on ice water poured and the solid product filtered off. Chromatography on Silica gel with methylene chloride provides 1.19 g of 4,5-dimethoxy 2-fluoro-benzonitrile.

3- (3,4-dibenzyloxyphenoxy) propanol

4.8 g of 3,4-dibenzyloxy-phenol, 2.64 ml of 3-bromopropanol and 6.24 g of potassium carbonate in 180 ml of butanol for 5 hours cooked under reflux. The product is made on silica gel Acetone / methylene chloride 1: 1 chromatographed, 2.7 g of the compound can be obtained as an oil.

3- (3,4-dibenzyloxyphenoxy) 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, 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 with 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 dissolved in 100 ml of ethyl methyl ketone Boiled under reflux for 30 hours. It is from the solid product filtered off, the solution evaporated and the residue Chromatographic silica gel with methylene chloride / acetone 1: 1 cleaned, 9.8 g of 4- (4-methylpiperidino) -3 ', 4'-dimethoxy-butyrophenone be preserved.

b) 9.15 g of the compound prepared according to a) are stirred with 99 ml of a 1 molar 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 from the 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-thiomorpholinyl) -3'-4'-dihydroxy-butyrophenone, hydrobromide, melting point 245-255 ° C

Example 2 4-dimethylamino-3'-4'-dihydroxy-butyrophenone, hydrobromide

a) In 30 ml of ethyl methyl ketone with ice cooling Dimethylamine initiated for 0.5 hours, then 3.6 g of 4-chloro-3'-4'-dimethoxy-butyrophenone and 3.2 g Potassium carbonate added. It will be 2.5 hours at 50 ° C stirred, then 15 ml are saturated with dimethylamine Ethyl methyl ketone added and a further 24 hours at 50 ° C. touched. It is filtered, the solution evaporated and on Chromatograph silica gel with methanol / methylene chloride 2: 8, where 2.4 g of 4-dimethylamino-3 ', 4'-dimethoxy-butyrophenone be preserved.

b) 0.5 g of 4-dimethylamino-3'-4'-dimethoxy-butyrophenone are reacted as in Example 1b), 0.31 g 4-dimethylamino-3'-4'-dihydroxy-butyrophenone, hydrobromide, can be obtained from the melting point 170-186 ° C.

Example 3 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 Trimethyl orthoformate, 6.0 g ion exchanger Amberlyst 15 and 2 ml of methanol are 5 hours at room temperature touched. It is filtered, the solution is evaporated, the product dissolved twice in toluene and again evaporated, with crude 4-chloro-3 ', 4'-dimethoxy-butyro phenon-dimethylacetal is obtained.  

b) 11.7 g of the crude acetal are mixed with 10.3 g of 4- (4-chlorine phenyl) -4-hydroxy-piperidine and 6.9 g of potassium carbonate in 200 ml of ethyl methyl ketone boiled under reflux for 44 hours. It is filtered, the solution is evaporated down and on silica gel Chromatographed methylene chloride / methanol 9: 1, whereby 9.98 g 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 in 200 ml of 48 percent hydrobromic acid for 24 hours Heated 100 ° C, then the mixture obtained in 200 ml Poured in ethanol and recrystallized the solid product from methanol, where 1.2 g of 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′-dihydroxy butyrophenone, hydrochloride

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

b) 6.7 g of the compound prepared according to a) are in 60 ml of water dissolved and 4.5 g of sodium borohydride with ice cooling added in portions and stirred for 1 hour. 120 ml of 2N HCl are added dropwise with ice cooling, and that Recrystallized product from isopropanol, 3.0 g 4- (4-methyl-1,2,3,6-tetrahydro-1-pyridyl) -1- (3,4-dimethoxyphenyl) -bu-tanol from the melting point 88-90 ° C arise.  

c) 10.7 g of the compound prepared according to b) and 11.3 g Pyridinium chlorochromat in 140 ml 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 completely evaporated. The residue is recrystallized from ethanol where 4.3 g of 4- (4-methyl-1,2,3,6-tetrahydro- 1-pyridyl) -3 ′, 4′-dimethoxy-butyrophenone, hydrochloride from Melting point 183-189 ° C can be obtained.

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

Example 5 N- [4- (3,4-dihydroxyphenyl) -4-hydroxybutyl] -4-methylpiperidine, acetate

a) It is made from 1.46 g of magnesium and 10.5 g of 1- (3-chlorine propyl) -4-methyl-piperidine in 25 ml of tetrahydrofuran Grignard reagent is preparing. This solution is under Ice cooling a solution of 9.6 g of 3,4-dibenzyloxy-benzaldehyde added dropwise in 50 ml of tetrahydrofuran, then Cooked for 3 hours. With ice cooling, 75 ml of 2N hydrochloric acid added dropwise, the isolated material is recrystallized from water, where 12.6 g of N- [4- (3,3-dibenzyloxyphenyl) - 4-hydroxy-butyl] -4-methyl-piperidine, hydrochloride of Melting point 174-176 ° C can be obtained.  

b) 2.5 g of the compound prepared according to a) are with Sodium carbonate solution converted into the base, which is in Ethyl acetate in the presence of 200 mg palladium-carbon (10 percent) hydrogenated at normal pressure. After filtering of the catalyst with the equivalent amount of acetic acid added, evaporated and the residue from ethyl acetate recrystallized, whereby 0.67 g of N- [4- (3,4-dihydroxyphenyl) - 4-hydroxy-butyl] -4-methyl-piperidine, melting point acetate 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 Tetrahydrofuran is cooled to 0 ° C, then becomes 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 added dropwise. 3.7 g of N- [4- (3,4-dimethoxy phenyl) -4-hydroxy-butyl] -4-methyl-piperidine obtained as an oil, which when treated with petroleum ether becomes a solid product solidified from the melting point 72-75 ° C.

b) 0.9 g of the compound prepared according to a) are in 30 ml acetic acid and 3 ml concentrated hydrochloric acid in Presence of 200 mg palladium-carbon (10 percent) Normal pressure hydrogenated. The solution becomes after evaporation 0.7 g of crude N- [4- (3,4-dimethoxyphenyl) butyl] -4-methylpiperidine, Get hydrochloride.  

c) 0.43 g of the compound prepared according to b) are with 20 ml of 48 percent hydrobromic acid at 140 ° C for 1 hour heated. After evaporation and recrystallization from ethanol 0.15 g of N- [4- (3,4-dihydroxyphenyl) butyl] -4-methylpiperidine, Hydrobromide obtained from melting point 211-216 ° C.

Example 7 3 ′, 4′-dihydroxy-3-dipropylamino-propiophenone, hydrobromide

a) 18.0 g of 3,4-dimethoxy-acetophenone, 4.0 g of paraformaldehyde and 17.9 g dipropylamine hydrochloride in 30 ml ethanol in the presence of 1 ml of 1N HCl under reflux for 2 hours heated. 600 ml of acetone are added, precipitated Dipropylamine hydrochloride is separated off. From the solution 19.9 g of 3 ′, 4′-dimethoxy-3-dipropylamino-propiophenone, Obtained hydrochloride melting point 131-132 ° C.

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

Example 8 3- (4-methyl-piperidino) -3 ′, 4′-dihydroxy-propiophenone, Hydrobromide

a) 12.4 g of 3,4-dimethoxy-acetophenone are analogous to Example 7a) implemented. The hydrochloride obtained is with treated aqueous sodium bicarbonate solution, wherein 11.6 g of 3 ', 4'-dimethoxy-3- (4-methyl-piperidino) propiophenone can be obtained from the melting point 72-74 ° C.

b) 1.0 g of the compound prepared under a) are in 20 ml of 63 percent hydrobromic acid for 1 hour Reflux cooked. It is evaporated and made from ethanol recrystallized, 0.42 g of 3- (4-methyl-piperidino) - 3 ′, 4′-dihydroxy-propiophenone, hydrobromide from the melting point 194-195 ° C can be 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 July 7, 78) with a Grignard reagent from 2.11 g N- (3-chloropropyl) -4-methylpiperidine and 0.29 g magnesium in Tetrahydrofuran by refluxing for 3 hours implemented. The crude product is on silica gel with a Dichloromethane-methanol mixture 8: 2 chromatographed. It 0.62 g of 4- (4-methylpiperidino) -2′-fluoro-3 ′, 4′- Obtained dimethoxy-butyrophenone as an oil.  

b) 620 mg of the compound obtained under a) are with 5 ml of 63 percent hydrobromic acid for 2 hours on Heated to reflux. After concentrating, the residue is removed recrystallized from an ethanol-acetone mixture. It will 210 mg 4- (4-methylpiperidino) -2′-fluoro-3 ′, 4′-dihydroxybutyrophenone, Hydrobromide with a melting point of 231-235 ° C receive.

Example 10 4- (4-methylpiperidino) -2′-chloro-3 ′, 4′-dihydroxy-butyrophenone, Hydrobromide

a) 1.56 g of 2-chloro-3,4-dimethoxybenzonitrile with a Grignard reagent from 1.78 g of N- (3-chloropropyl) -4-methylpiperidine and 0.25 g magnesium as in Example 9a) implemented. The crude product is on silica gel with a Dichloromethane-methanol mixture 8: 2 chromatographed. It 1.0 g of 4- (4-methylpiperidino) -2'-chloro-3 ', 4'- Obtained dimethoxy-butyrophenone as an oil.

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

Example 11 4- (4-methylpiperidino) -3′-chloro-4 ′, 5′-dihydroxy-butyrophenone, Hydrobromide

a) 2.77 g of 3-chloro-4,5-dimethoxy-benzonitrile are with a Grignard reagent from 3.51 g of N- (3-chloropropyl) -4-methylpiperidine and 0.60 g magnesium analogous to Example 9a) implemented. The crude product is on silica gel with a Dichloromethane-methanol mixture 8: 2 chromatographed. It 1.50 g of 4- (4-methylpiperidino) -3'-chloro-4 ', 5'- Obtained dimethoxy-butyrophenone as an oil.

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

Example 12 4- (4-methyl-piperidino) -2′-methyl-4 ′, 5′-dihydroxy-butyrophenone, Hydrochloride

5.0 g of 4,5-dimethoxy-2-methyl-benzonitrile in 25 ml Dissolved tetrahydrofuran. This solution becomes a Grignard solution added dropwise from 1.36 g of magnesium and 9.9 g 1- (3-chloropropyl) -4-methyl-piperidine in tetrahydrofuran is prepared and boiled under reflux for 60 hours. The The reaction product is on silica gel with methylene chloride / methanol purified by chromatography, 1.0 g of 4 ', 5'-Di methoxy-4- (4-methyl-piperidino) -2'-methyl-butyrophenone be preserved.  

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′-dihydroxy-butyrophenone, Hydrochloride

a) From 0.13 g of magnesium and 0.93 g of 1- (3-chloropropyl) -4- methyl-piperidine becomes a Grignard solution in tetrahydrofuran produced. A solution of 0.50 g of 4,5-dimethoxy-2-fluoro-benzonitrile in tetrahydrofuran added dropwise and then under reflux for 2.5 hours cooked. The product is recrystallized from petroleum ether. 0.45 g of 4- (4-methyl-piperidino) -2'-fluoro-4 ', 5'- Obtained dimethoxy-butyrophenone.  

b) 0.24 g of the compound described under a) with Dimethyl sulfide and aluminum trichloride, as in Example 12b) described, reacted, 0.12 g of 4- (4-methylpiperidino) - 2'-fluoro-4 ', 5'-dihydroxy-butyrophenone, hydrochloride from 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 in 15.0 g Polyphosphoric acid heated to 100 ° C for 2 hours with ice water added and by adding solid sodium hydrogen carbonate alkalized. After recrystallization from diisopropyl ether 1.0 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) - butyryl]} - Acetanilide obtained from the melting point 97-99 ° C.

b) 81.0 g of N- [5- (4-chlorobutyryl) -2-methoxy] acetanilide, 108 ml of 4-methylpiperidine, 41.4 g of potassium carbonate and 10.0 g Potassium iodide in 1.2 l of ethyl methyl ketone are on for 24 hours Heated to 80 ° C. It is partly concentrated with water added, the reaction product with ethyl acetate shaken out and concentrated. The backlog is on Chromatograph silica gel with methylene chloride / methanol 4: 1 and recrystallized from ethyl acetate / hexane, 94.3 g N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} acetanilide of 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 in 100 ml of 65 percent hydrobromic acid Boiled for 18 hours, concentrated and from ethanol / diethyl ether crystallized, 8.0 g of 3'-amino-4'-hydroxy- 4- (4-methyl-1-piperidyl) -butrophenone, dihydrobromide from Decomposition point 155-157 ° C can be obtained.

Example 15 N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} formanilide, Hydrochloride

1.2 ml of pivaloyl chloride at 0 ° C with 240 mg of 18-Crown-6 and 820 mg sodium formate stirred for 6 hours, then with a Solution from 440 mg of 3'-amino-4'-hydroxy-4- (4-methyl-1- piperidyl) -butrophenone, dihydrobromide and 330 mg sodium acetate added in 12 ml of methanol. After 5 hours at 0 ° C and concentrated at room temperature for 16 hours, with saturated sodium bicarbonate solution and extracted 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 in Treated methanol with ethereal hydrochloric acid, 235 mg N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} formanilide, Obtained hydrochloride of melting point 195-196 ° C. will.  

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 sodium acetate and 0.15 ml Acetic anhydride are in 10 ml of acetic acid and 5 ml Methanol stirred for 2 hours at room temperature. That through Chromatography on silica gel with methanol / dichloromethane purified product is mixed with 100 mg of maleic acid and recrystallized from ethanol / diethyl ether, 305 mg N-2-hydroxy-5- [4-methyl-1-piperidinyl) butyryl] acetanilide, Get hydrogen maleate from melting point 87-89 ° C. will.

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 refluxed in 100 ml of ethyl methyl ketone for 20 hours cooked. The reaction product is on silica gel with methy Lenchlorid / methanol 7: 3 purified by chromatography, whereby 1.4 g of N- {2-methoxy-5- [4- (4-methyl-1-piperidyl) butyryl]} methanesulfonanilide be obtained as oil.  

b) 1.4 g of the compound described under a) are with 19 ml of a 1 molar solution of boron tribromide in 30 ml Methylene chloride stirred for 5.5 hours at room temperature with Methanol added, evaporated and the residue from ethanol recrystallized, whereby 0.47 g of N- {2-hydroxy-5- [4- (4- methyl-1-piperidyl) butyryl]} - methanesulfonanilide, hydrobromide can be obtained from the melting point 205-209 ° C.

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 are 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 3′-amino-4′-methoxy-4- (4-methyl-1-piperidyl) -butyrophenone, Dihydrochloride of melting point 199-201 ° C can be obtained. The dihydrochloride is dissolved in 300 ml of water and with saturated sodium bicarbonate solution added. The The precipitate is filtered off, dried and extracted from ethyl acetate recrystallized. 38.0 g of 3′-amino-4′- methoxy-4- (4-methyl-1-piperidyl) butyrophenone, melting point Get 100-102 ° C.

b) 1.3 g of 3'-amino-4'-methoxy-4- (4-methyl-1-piperidyl) -butyrophenone in 45 ml dichloromethane at 0 ° C for 16 hours stirred with 1.3 ml of trifluoromethanesulfonic anhydride, with saturated sodium bicarbonate solution added, suction filtered and the crystals with dichloromethane and water washed. 1.7 g of N- {2-methoxy-5- [4- (4-methyl-1- piperidyl) butyryl]} - trifluoromethanesulfonanilide of melting point 250 ° C.  

c) 840 mg of the compound described under b) 3.5 hours with 15 ml of 65 percent hydrobromic acid heated to 140 ° C and concentrated. The backlog is in Dissolved water, with saturated sodium bicarbonate solution added and the precipitate is suction filtered. To Crystallization from methanol 700 mg of N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide obtained from decomposition point 246-247 ° C.

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

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) -butyrophenone in 8 ml of acetic acid and 4 ml of water with 490 mg Potassium cyanate and 490 mg sodium acetate for 4 hours at room temperature touched. It is concentrated, the residue in Dissolved water, mixed with sodium hydrogen carbonate, the Aspirated precipitate and in methanol with maleic acid united. After adding diethyl ether, 400 mg are obtained N- {2-hydroxy-5- [4- (4-methyl-1-piperidyl) butyryl] phenyl} urea, Hydrogen maleate melting point 175.5-176 ° C.  

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 become 37% aqueous with 0.42 ml Formalin solution and 284 g sodium cyanoborohydride in 50 ml Methanol and 5 ml of 1.2 N ethereal hydrochloric acid reacted. Man receives 760 mg of 4'-methoxy-3'-methylamino-4- (4-methyl-1- piperidyl) -butrophenone with a melting point of 61 ° C.

b) 304 mg of 4'-methoxy-3'-methylamino-4- (4-methyl-1-piperidyl) -butyrophenone 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 4-anisaldehyde are with 32 mg sodium cyanoborohydride for 1 hour at 0 ° C and 15 hours stirred at room temperature. It is chromatographed on silica gel with methanol / dichloromethane 1: 1 and mixed with ethereal  Hydrochloric acid, with 75 mg of 4'-hydroxy-3 '- (4-methoxy benzylamino) -4- (4-methyl-1-piperidyl) butyrophenone, dihydrochloride can be obtained from the decomposition point 130-133 ° C.

Example 22 4'-amino-3'-hydroxy-4- (4-methyl-1-piperidyl) -butyrophenone, Dihydrobromide

a) 4.8 g of magnesium shavings and 150 ml of tetrahydrofuran in 30 minutes with 35 ml of 1- (3-chloropropyl) -4-methylpiperidine combined, refluxed for 1.5 hours and in 20 minutes at room temperature with 18.3 ml of 3-methoxybenzonitrile in 100 ml of tetrahydrofuran are added. It will reflux for 6 hours cooked, with ice cooling with 400 ml of 2N sulfuric acid combined and heated to 100 ° C for 1 hour. After adding Sodium bicarbonate is made three times with ethyl acetate shaken out, the ethyl acetate fraction combined, dried, concentrated and the residue in vacuo distilled. 34.6 g of 3′-methoxy-4- (4-methyl-1- piperidyl) -butyrophenone with a boiling point of 132-136 ° C (0.015 bar) receive. 29.0 g of this compound are added in methanol ethereal hydrochloric acid, with 34.0 g of 3'-methoxy-4- (4-methyl-1-piperidyl) -butrophenone, hydrochloride of Melting point 162-163 ° C can be obtained.

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 30.0 g of potassium nitrate were added for 30 minutes, for 30 minutes Stirred at 0 ° C and poured onto 1.5 l of ice water. You put up with 32 percent sodium hydroxide solution with ice cooling pH 10-11 and shakes 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) -butyrophenone obtained from the melting point 98-98.5 ° C (diisopropyl ether) will.

c) 1.6 g of 3'-methoxy-4'-nitro-4- (4-methyl-1-piperidyl) -butyrophenone are in 60 ml of tetrahydrofuran in the presence hydrogenated by 0.4 ml of Raney nickel. The product is made Recrystallized diisopropyl ether / hexane, 1.3 g 4'-amino-3'-methoxy-4- (4-methyl-1-piperidyl) -butyrophenone can be obtained from the melting point 99-100 ° C.

d) 1.45 g of 4'-amino-3'-methoxy-4- (4-methyl-1-piperidyl) -butyrophenone are, as described in Example 14c) with Hydrobromic acid reacted, 2.2 g of 4'-amino 3'-hydroxy-4- (4-methyl-1-piperidyl) butyrophenone, 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) -butyrophenone, Dihydrobromide in 10 ml of methanol and 15 ml of acetic acid with 330 mg of sodium acetate and 0.15 ml of acetic anhydride added, stirred at room temperature for 2 hours, with 0.15 ml of acetic anhydride and 10 ml of methanol combined and concentrated after 3 hours. 300 mg of N- {2-hydroxy 4- [4- (4-methyl-1-piperidyl) butyryl]} acetanilide, hydrobromide obtained from decomposition point 262-263 ° C (water).  

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 dichloromethane at 0 ° C with 700 mg methanesulfonic anhydride in 10 ml dichloromethane added, stirred for 48 hours at room temperature, with saturated Sodium bicarbonate solution added and the Concentrated dichloromethane fraction. After crystallization 500 mg of N- {2-methoxy-4- [4- (4-methyl-1-piperidyl) butyryl]} - methanesulfonanilide dated Melting point 118-119 ° C obtained.

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

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 mixed with trifluoromethanesulfonic anhydride, as described in Example 18b), wherein 272 mg N- {2-methoxy-4- [4- (4-methyl-1-piperidyl) butyryl]} - trifluoromethanesulfonanilide obtained from the decomposition point 256-257 ° C will.

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

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 implemented at 100 ° C. 7.0 g (7-methoxy-2-oxo-2,3- dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone obtained from melting point 174-175.5 ° C (methanol).  

b) 490 mg 7-methoxy-2-oxo-2,3-dihydroindole in 20 ml Dichloromethane are at 0 ° C with 975 mg aluminum trichloride Stirred for 10 minutes and in 30 minutes at 0 ° C with 0.42 ml 4-chlorobutyryl chloride combined in 5 ml dichloromethane. To 1.5 hours at 0 ° C with 200 ml of ice water and 5 ml concentrated hydrochloric acid and mixed with ethyl acetate shaken out. After trituration with diisopropyl ether 520 mg of (3-chloropropyl) - (7-methoxy-2-oxo-2,3-dihydro Obtained indol-4-yl) ketone with a melting point of 192-196 ° C.

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

d) 495 mg (7-methoxy-2-oxo-2,3-dihydroindol-4-yl) - [3- (4- methyl-1-piperidyl) propyl] ketone at 0 ° C with 30 ml 1m boron tribromide combined in dichloromethane and 24 hours stirred at room temperature. It is mixed with methanol concentrated, redistilled several times with methanol, the residue dissolved in water / ethanol, with sodium hydrogen carbonate moved and suctioned off. By treating with etheric Hydrochloric acid in methanol are 295 mg (7-hydroxy-2-oxo-2,3- dihydroindol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone, Get hydrochloride from decomposition point 286-288 ° C.  

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 Aluminum trichloride are suspended in 10 ml of dioxane and hydrogen chloride gas is introduced until solution with ice cooling. 300 mg of 7-hydroxy are obtained in 30 minutes at 0 ° C dropped in indole-2-carboxylic acid ethyl ester in 5 ml of dioxane and another 6 hours of hydrogen chloride gas under ice cooling initiated. After 16 hours at 0 ° C the reaction solution poured onto ice, the precipitate is sucked off with saturated sodium bicarbonate solution and then washed 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 be preserved.

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 3 hours with 300 g of polyphosphoric acid at 130-140 ° C. warmed, mixed with ice water and with cooling with 32 percent sodium hydroxide solution adjusted to pH 8.5. It will shaken four times with ethyl acetate, the aqueous Phase adjusted to pH 13 with 25 percent ammonia solution, shaken four times with n-butanol / ethyl acetate,  dried, concentrated and from ethanol / water recrystallized, whereby 2.6 g (7-hydroxy-1H-indazol-4-yl) - [3- (4-methyl-1-piperidyl) propyl] ketone, melting point 200-203 ° C can be obtained. 1.2 g of this compound with 510 mg of maleic acid dissolved in methanol and with diethyl ether transferred. 1.2 g (7-hydroxy-1H-indazol-4-yl) are obtained - [3- (4-methyl-1-piperidyl) propyl] ketone, hydrogen maleate from Decomposition product 176-177 ° C.

Example 29 4- [4- (4-methylpiperidino) butyryl] benzimidazol-7-ol, Dihydrobromide

a) 1.0 g of 4-methoxybenzimidazole (Ger. Offen. 19 21 911 vom 14. 6. 68) with 2.1 g of 4- (N-4-methylpiperidino) butyric acid, Hydrochloride in 20 ml of polyphosphoric acid for 2 hours 80 ° C stirred. After adding water, it is mixed with sodium carbonate neutralized and extracted with ethyl acetate. After this The residue is filtered off and concentrated from one Petroleum ether-ethanol mixture recrystallized. It will 1.5 g of 7-methoxy-4- [4- (4-methylpiperidino) butyryl] benzimidazole obtained from the melting point 109 ° C.

b) 500 mg of the compound obtained under a) are with 50 ml of 63 percent hydrobromic acid for 2 hours on Heated to reflux. After concentrating, the residue is removed recrystallized from a methanol-acetone mixture. It will 160 mg 4- [4- (4-methylpiperidino) butyryl] benzimidazol-7-ol, Obtained dihydrobromide melting point 140-145 ° C.  

Example 30 4- [4- (4-methylpiperidino) butyryl] -7-hydroxy-2,3-dihydrobenzimidazole - 2-one, Hydrobromide

a) 1.0 g of 4-methoxy-2,3-dihydrobenzimidazol-2-one (Ger. Open. 28 19 458 from May 3, 77) are mixed with 2.0 g of 4- (N-4-methyl- piperidino) butyric acid, hydrochloride in 20 ml polyphosphoric acid Stirred at 80 ° C for 2 hours. After adding water is neutralized with sodium carbonate and with an ethyl acetate-butanol mixture extracted. After filtering and The residue is recrystallized from methanol and concentrated. 0.69 g of 7-methoxy-4- [4- (4-methylpiperidino) - butyryl] -2,3-dihydrobenzimidazol-2-one from the melting point Obtained 160 ° C.

b) 300 mg of the compound obtained under a) are with 20 ml of 63 percent hydrobromic acid for 3 hours on Heated to reflux. After concentrating, the residue becomes with Acetone stirred. 180 mg of 4- [4- (4-methylpiperidino) - butyryl] -7-hydroxy-2,3-dihydrobenzimidazol-2-one, hydrobromide obtained from the melting point 259-261 ° C.

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 refluxed in 30 ml of butanol for 8 hours. The Product is on silica gel with methanol / methylene chloride 1: 1  purified chromatographically and with ethereal hydrochloric acid Treated ether, with 0.50 g of 1,2-dibenzyloxy-4- [3- (4- methyl-piperidino) propoxy] benzene, hydrochloride obtained will.

b) 0.24 g of the compound prepared under a) in 10 ml Methanol are in the presence of 100 mg of palladium-on-carbon (10 percent) hydrogenated. The product is made from ethanol / methanol recrystallized, 0.11 g of 1,2-dihydroxy-4- [3- (4-methyl-piperidino) propoxy] benzene, hydrochloride of Melting point 203-204 ° C can be obtained.

Example 32 3 ′, 4′-diacetoxy-4- (4-methyl-piperidino) -butyrophenone, 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-methyl-piperidino) -butyrophenone, hydrobromide (melting point 134-145 ° C).

Claims (3)

1. aryl-substituted tert-alkylene amines of the formula I, wherein Pure alkyl group with 1-6 C atoms or all of the rest the heterocyclic means, where R₅ represents hydrogen, methyl, phenyl, 4-chlorophenol or 4-fluorobenzoyl, n = 2-4, Adie residues carbonyl, hydroxymethylene, C₂-C₄-acyloxy-methylene, methylene or oxygen, Zhydrogen, 2-fluorine, 6 -Fluoro, 2-chloro, 5-chloro, 2-methyl or 6-methyl, R₁Hydroxy or C₂-C₄-acyloxy if R₂ hydroxy, C₂-C₄-acyloxy, amino or NHR₃, NH-CHO or NH-CO-NH₂ represents, R₂Hydroxy or C₂-C₄-acyloxy, if R₁ represents hydroxy, C₂-C₄-acyloxy, amino or NHR₃, R₃alkyl with 1-4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluoromethylsulfonyl, or
the rest by ring closure of R₂ and Z the bicyclic groups R₄ as hydrogen, methoxycarbonyl or ethoxycarbonyl, and their acid addition salts with physiologically acceptable acids mean. 2. A process for the preparation of compounds of formula I, characterized in that in a manner known per se

• a) an aryl-substituted alkyl halide or tosylate of the formula II, where n = 2-4 and A'den carbonyl, dimethoxymethylene or oxygen, R₆die tosyl, chlorine or bromine and R₁eine methoxy or benzyloxy group, R₂eine methoxy, benzyloxy or methylsulfonamido group, Z'hydrogen and Z 'and R₂ 'Together mean the group -CH₂-CO-NH- in the 2,3-position of the benzene ring, optionally after prior protection of the carbonyl group in A' with an amine of formula III with the meanings already mentioned for R or all of the rest or with a pyridine derivative of the formula IV, with the meanings already mentioned for R₅,
• b) a benzene derivative of the formula V, whereinR₁''Hydroxy or methoxy, R₂''CH₃CONH or R₂ '' and Z'' together the group with R₄ in the meaning given above, 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, in which n and R have the meanings already mentioned and R₇ represents a carboxyl radical or a cyano group, in the presence of polyphosphonic acid or AlCl₃,
• c) a benzene derivative of the formula VII, whereinR₁ ′ ′ ′ is hydrogen, methoxy or benzyloxy, R₂ ′ ′ ′ methoxy or benzyloxy, Z ′ ′ ′ is hydrogen, fluorine, chlorine or methyl and R₈ 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, or
• d) reacting 3,4-dimethoxyacetophenone with an amine of the formula III and formaldehyde and, if appropriate, the compounds I obtained according to a) -d) by ether cleavage, reduction of the carbonyl group in A, oxidation of the OH group in A, a LiAlH₄ reduction, subject to an acylation or Umamidierung or in the case of free NH₂ groups with potassium cyanate or with alkylating agents.

3. Medicines consisting of one or more compounds of formula I and usual auxiliary and Carriers.