DE4438083A1 - New aminoalkylphenyl substd. acyl-pyrrolidine or piperidine derivs. - Google Patents

Abstract

Aminoalkylphenyl-pyrrolidine or -piperidine derivs. of formula (I), their enantiomers, geometrical isomers and salts (partic. with (in)organic acids) are new: n = 1 or 2 and m = 1; or n = 1 and m = 2; R1 = H; 1-6C alkyl (opt. substd. by 1 or 2 OH or by one aminocarbonyl; the OH is not at 1 position and 2 OH cannot be on same Cl, or 3-6C alkenyl or alkynyl (with multiple bond isolated from the C-N bond); R2 is as R1 but not H, or R1 and R2 together complete a satd. 5-7 membered monocyclic gp.; R3 = up to 8C alkyl, alkenyl or alkynyl (all opt. substd. by phenyl, itself opt. substd. by 1-3 of halo, alkyl and/or CF3) or phenyl (opt. substd. as above); A = ethylene (in which CH2 bonded to phenyl can be replaced by O) or ethenylene; X = linear 1-3C alkylene; Z = CO or SO; halo = F, Cl or Br.

Description

The present invention relates to basic substituted Acylpyrrolidines and acylpiperidines, their salts with phy biologically compatible organic and inorganic acid ren, process for the preparation of these compounds, these Compounds containing drugs and their use.

The compounds of the invention are inhibitors of Cholesterol biosynthesis, in particular inhibitors of En zyms 2,3-epoxysqualene-lanosterol cyclase, a key enzyme of cholesterol biosynthesis. The Ver compounds are suitable for the treatment and prophylaxis of Hyperlipidemias, hypercholesterolemia and atherosclerosis rose. Further possible fields of application arise for the treatment of hyperproliferative skin and vascular illnesses, tumors, gallstones and mycoses.

Compounds that interfere with cholesterol biosynthesis are for the treatment of a number of conditions significant. Here are especially hypercholesterolemias and To name hyperlipidemias, the risk factors for the Ent stand atherosclerotic vascular changes and their Fol diseases such as coronary heart disease, cerebral ischemia, intermittent claudication and gangrene put.  

The importance of excessive serum cholesterol levels as the main Risk factor for the development of atherosclerotic vascular Ver Changes are generally accepted. Extensive clinical Studies have led to the realization that by Erniedri Serum cholesterol increases the risk of coronary heart disease illnesses can be reduced (Current Opinion in Lipi dology 2 (4), 234 [1991]). Because most of the cholesterol synthesized in the organism itself and only a small part taken with food, represents the inhibition of bio Synthesis a particularly attractive way, the increased To lower cholesterol levels.

In addition come as other possible applications of Cholesterol biosynthesis inhibitors the treatment hyperprolifera tive skin and vascular diseases as well as tumor treatments, the treatment and prophylaxis of gallstones and use in mycoses into consideration. In the latter case it is an intervention in the Ergosterolbiosyn in fungal organisms, which are largely analogous to Chole sterol biosynthesis in mammalian cells.

Cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, over a larger number of reac tion steps. This multistage process offers a number of possibilities of intervention, of which examples are given:
For the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase β-lactones and β-lactams with potential antihypercholesterolemic effect are mentioned (see J. Antibiotics 40, 1356 [1987], US-A 4,751,237, EP-A-0 462 667, US-A-4,983,597).

Inhibitors of the enzyme HMG-CoA reductase make 3,5-dihy is a statin-type droxycarboxylic acid and its δ-lactone, their representatives lovastatin, simvastatin and pravastatin in the therapy of hypercholesterolemia use find.  

Further possible fields of application of these compounds are Fungal infections (US-A-4,375,475, EP-A-0 113 881, US-A-5,106,992), skin diseases (EP-A-0 369 263) as well as Gallstones and tumors (US-A-5,106,992; Lancet 339, 1154-1156 [1992]). Another therapy possible It inhibits the proliferation of smooth muscle cells Lovastatin (Cardiovascular Drugs Ther 5, Suppl. 3, 354 [1991]).

Inhibitors of the enzyme squalene synthetase are e.g. B. Isopre noid- (phosphinylmethyl) phosphonates, their suitability for treatment hypercholesterolemia, gallstone disease and tumor Diseases described in EP-A-0 409 181 and J. Med. Chemistry 34, 1912 [1991], also the squalestatine with cho ester-lowering and antifungal activity (J. Antibotics A4, 639-647 [1992] and J. Biol. Chemistry 267, 11705-11708 [1992].

As inhibitors of the enzyme squalene epoxidase are known Allylamines such as naftifine and terbinafine, which are used as an antidote Fungal infections have found input into the therapy, so like the allylamine NB-598 with antihypercholesterolemic Effect (J. Biol. Chemistry 265, 18075-18078, [1990]) and Fluorosqualene derivatives having hypocholesterolemic activity (US-A-5,011,859). Furthermore, piperidines and azadecalines with potential hypocholesterolemic and / or antifunga ler effect, whose mechanism of action is not clear and which squalene epoxidase and / or 2,3-Ep oxisqualen-Lanostero 1-cyclase inhibitors (EP-A-0 420 116, EP-A-0 468 434, US-A-5,084,461 and EP-A-0 468 457).

Examples of inhibitors of the enzyme 2,3-Epoxisqualen-Lano Sterol cyclase are diphenyl derivatives (EP-A-0 464 465), amino alkyl derivatives (EP-A-0 401798), aminoalkoxybenzene derivatives (EP-A-0 410 359) and piperidine derivatives (J. Org. Chem. 57, 2794-2803, [1992]), which have an antifungal effect.  

Furthermore, this enzyme is expressed in mammalian cells by De calines, azadecalines and indan derivatives (WO 89/08450, J. Biol. Chemistry 254, 11258-11263 [1981], Biochem. Pharmacology 37, 1955-1964 [1988] and J 64 003 144), further by 2-aza-2,3- dihydrosqualene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 [1985]), by squalene epoxide vinyl ethers (J. Chem. Soc. Perkin Trans. I, 1988, 461) and 29-methylidene 2,3-oxidosqualene (J. Amer. Chem. Soc. 113, 9673-9674 [1991]) inhibited.

Finally, as inhibitors of the enzyme lanosterol-14α- Demethylase still steroid derivatives with potential antihyper To call lipemic effect, which is the enzyme HMG-CoA reductase influence (US-A-5,041,432, J. Biol. Chemistry 266, 20070-20078 [1991], US-A-5,034,548). also this enzyme is inhied by the azole-type antimycotics which represents N-substituted imidazoles and triazoles len. For example, this class includes on the Market Antifungals Ketoconazole and fluconazole.

The compounds of the following general formula I are New. It has surprisingly been found that they are very effective inhibitors of the enzyme 2,3-epoxysqualene-lanosterol- Cyclase (International Classification: EC5.4.99.7) put.

The enzyme catalyses 2,3-epoxysqualene-lanosterol cyclase a key step in cholesterol or ergosterol bio Synthesis, namely the conversion of 2,3-Epoxisqualens in the lanosterol, the first compound with steroid structure in the biosynthesis cascade. Inhibitors of this enzyme leave ge compared with inhibitors of previous biosynthesis steps, as in For example, HMG-CoA synthase and HMG-CoA reductase, the Vor part of the higher selectivity expect since the inhibition These early biosynthetic steps to decrease biosynthetically formed Mevalonsäure leads and thereby the Biosyn the mevalonic acid-dependent substances Dolichol, Ubichi  non and isopentenyl t-RNA can adversely affect (see. J. Biol. Chemistry 265, 18075-18078 [1990]).

Upon inhibition of biosynthetic steps after conversion of 2,3-Epoxisqualen in Lanosterol there is a risk of Accumulation of intermediates with steroid structure in the Organism and the triggering thereby caused toxic Effects. This is for example for Triparanol, a Des mosterol reductase inhibitor. This substance had to due to formation of cataracts, ichthyosis and alopecia withdrawn from the market (cited in J. Biol. Chemistry 265, 18075-18078 [1990]).

As already stated, inhibitors of 2,3-Ep oxisqualen-lanosterol cyclase isolated in the literature described. However, the structures of these compounds are completely different from the structure of the invention Compounds of the general formula I.

Further, piperidinylalkoxy and pyrrolidinylalkoxybenzoic acid derivatives (JP 92,112,868) and a heterocyclic Ring-containing phenylcarboxylic acid derivatives (EP 0 393 607) Known, the removed structural analogies to the compounds of the present application. These compounds be also have hypolipidemic properties, however not on inhibition of the enzyme 2,3-Epoxisqualen-Lano sterol cyclase are due.

The invention relates to the provision of antihypercho lesterolemic substances used for treatment and prophylaxis lax atherosclerosis are suitable and, in comparison to known active ingredients, by a better antihypercholeste rolemic effect with increased selectivity and thus he higher security are excellent. Since the erfindungsge Because of their high potency as In hibitors of the enzyme 2,3-epoxysqualene-lanosterol-cyclase also inhibit ergosterol biosynthesis in the fungal organism they are also suitable for the treatment of mycoses.  

The present invention has new basic substituted Acylpyrrolidines and acylpiperidines of the general formula I the subject,

in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may be substituted by one or two hydroxy groups or by an aminocarbonyl group, wherein a hydroxy group is not bonded in the 1-position and two hydroxy groups are not bonded to the same carbon atom, an alkenyl or alkynyl group having 3 to 6 carbon atoms, wherein the multiple bonds are isolated from the nitrogen-carbon bond, and
R₂ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may be substituted by one or two hydroxy groups or by an aminocarbonyl group, wherein a hydroxy group is not in the 1-position and two hydroxy groups are not attached to the same carbon atom, an alkenyl or alkynyl group with 3 to 6 Kohlenstoffato men, wherein the multiple bonds are isolated from the nitrogen-carbon bond, or
R₁ and R₂ together with the intermediate nitrogen atom have a saturated monocyclic 5-, 6- or 7-membered ring,
R₃ is a straight-chain or branched alkyl, alkenyl or alkynyl group each having up to 8 carbon atoms, each by a mono-, di- or tri-substituted phenyl group optionally substituted by a halogen atom, an alkyl or trifluoromethyl group, wherein the substituents are the same or ver may optionally be substituted by a halogen atom, an alkyl or trifluoromethyl group mono-, di- or trisubstituted phenyl group, where the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a straight-chain alkylene group having 1 to 3 carbon atoms and
Z is a carbonyl or sulfonyl group,
where an abovementioned halogen atom can denote a fluorine, chlorine or bromine atom,
their enantiomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or or ganic acids.

Preference is given to the compounds of the general formula Ia,

in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ is a hydrogen atom, a methyl group optionally substituted by an aminocarbonyl group, or a radic or branched alkyl group having 2 to 4 carbon atoms which may be terminally substituted by a hydroxy or amino carbonyl group, or an alkenyl group having 3 to 5 carbon atoms, said Doppelbin tion is isolated from the nitrogen-carbon bond, and
R₂ is an optionally substituted by an aminocarbonyl methyl group or a straight or branched te alkyl group having 2 to 4 carbon atoms, which may be terminal substituted by a hydroxy group or by an aminocarbonyl group, or an alkenyl group having 3 to 5 carbon atoms, wherein the double bond of the stick substance-carbon bond is isolated, or
R₁ and R₂, together with the intervening nitrogen atom, have a saturated monocyclic 5-, 6- or 7-membered ring,
R₃ is a straight-chain or branched alkyl or alkenyl group having in each case up to 5 carbon atoms, each terminal of which may be substituted by an optionally mono- or disubstituted by a fluorine or chlorine atom, a methyl or trifluoromethyl phenyl group, wherein the substituents same or different or a phenyl group optionally mono- or disubstituted by a fluorine or chlorine atom, a methyl or trifluoromethyl group, where the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a methylene or ethylene group and
Z is a carbonyl or sulfonyl group,
their enantiomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or or ganic acids.

Particular preference is given to the compounds of general formula Ia,
in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ represents a hydrogen atom, a methyl, ethyl, propyl, allyl, 3,3-dimethylallyl, 2-hydroxyethyl, 3-hydroxypropyl or aminocarbonylmethyl group,
R₂ is a methyl, ethyl, propyl, tert-butyl, allyl, 3,3-dimethylallyl, 2-hydroxyethyl, 3-hydroxypropyl or aminocarbonylmethyl group,
R₃ is an optionally terminally substituted by a phenyl group methyl, ethyl, n-propyl, n-butyl, n-Pen tyl-, ethenyl or propenyl group or a phenyl group, wherein the above-mentioned phenyl groups in each case by a chlorine atom, a methyl or trifluoromethyl group may be mono- or disubstituted and the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a methylene or ethylene group and
Z is a carbonyl or sulfonyl group,
their enantiomers and geometrical isomers and their salts, in particular for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids,
but especially the compounds
A = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] pyrrolidine,
B = 1- (4-chlorobenzenesulfonyl) -3- [2- (4- (N-methyl-allylaminomethyl) phenyl) ethyl] piperidine,
C = 1- (4-chloro-benzenesulfonyl) -3- [2- (4-diethylamino-methyl-phenyl) -ethyl] -piperidine,
D = 1- (4-chlorobenzoyl) -3- [4- [2- (N-methyl-allylamino) ethyl] phenoxymethyl] pyrrolidine,
E = 1- (4-chlorobenzoyl) -4- [4- (N-methyl-allylaminomethyl) phenoxymethyl] -piperidine,
F = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] -piperidine,
G = 1- (4-chlorobenzoyl) -4- [2- (4- (N-methyl-allylaminomethyl) phenyl) ethyl] piperidine,
H = 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] -piperidine,
I = 1- (4-chloro-benzenesulfonyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine,
J = 1- (4-chloro-phenylacetyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine
and their salts.

production method

The compounds of general formula I can be at For example, according to the following methods:

• a) By reacting an amine of the general formula II, in the
  R₁ and R₂ have the meanings mentioned above, with a compound of general formula III, in the
  n, m, R₃, A, X and Z are as defined above and W₁ is a reactive leaving group such as a halogen atom, for. Example, a chlorine, bromine or iodine atom, or an alkylsulfonyloxy- or arylsulfonyloxygruppe, for example, the p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethyl sulfonyloxy group represents.

The reaction is conveniently carried out in a suitable Lö such as ethanol, methylene chloride, acetone, acetone tril or dimethylformamide, optionally in the presence of a Base such as sodium carbonate, potassium carbonate or triethylamine, or in an excess of a compound of formula II, ge if appropriate in the presence of a reaction accelerator such as Potassium or sodium iodide, at a temperature between 0 and 120 ° C, but preferably at a temperature between 50 and 120 ° C, performed.

• b) by reductive alkylation of an amine of general formula II, in the
  R₁ and R₂ have the meanings mentioned above, with a compound of general formula IV, in the
  n, m, R₃, A, X and Z are as defined above and W₂ together with a vicinal methylene group of the radical X forms a formyl group.

The reductive alkylation is conveniently in a suitable alcoholic solvent, for example in Methanol, ethanol or propanol, optionally with addition an acid, for example acetic acid, using a suitable reducing agent, preferably a com metal hydrides such as sodium borohydride or sodium cyano borohydride, at a temperature between -80 and 100 ° C, before However, preferably carried out between 0 and 30 ° C.

• c) By reacting an amine of the general formula V, in the
  n, m, R₁, R₃, A, X and Z are as defined above, with a compound of general formula VI, R₂'-W₃ (VI) in the
  R₂ 'has the meanings mentioned above for R₂ or together with the radical R₁ of the formula V is an n-alkylene group having 4 to 6 carbon atoms and W₃ is a reactive leaving group, such as. Example, a halogen atom or an alkyl sulfonyloxy or Arylsulfonyloxygruppe, for example, the p-toluenesulfonyloxy, methanesulfonyloxy or Trifluorme thylsulfonyloxygruppe represents.

The reaction is conveniently carried out in a suitable Lö such as methylene chloride, chloroform, acetonitrile or dimethylformamide, optionally in the presence of a Base, such as sodium carbonate, potassium carbonate, triethylamine or Diisopropylethylamine, at a temperature between 20 and 120 ° C performed, for example, at the boiling point the reaction mixture.

In the implementation described above can in a Compound of formula V or VI optionally present reactive hydroxy groups protected by conventional protecting groups and the protective residues split off again after the reaction become.

For example, comes as a protective group for a hydroxy group the trimethylsilyl or tetrahydropyranyl group into consideration. The optional subsequent cleavage of such Protective remnant takes place for example hydrolytically in one aqueous solvent with the addition of an acid, for example hydrochloric acid or sulfuric acid, at a temperature between 25 and 50 ° C.

• d) For the preparation of compounds of the general formula I in which n, m, R₂, R₃ and Z are as defined above, R₁ except for the hydrogen atom and X except for a bound in the 4-position to the phenyl methylene group mentioned above Meanings and A is an ethylene group in which the methylene group bound to the phenyl radical is replaced by an oxygen atom, meaning:
  Alkylation of a phenyl of general formula VII, in the
  R₂ is defined as mentioned above, R₁ 'with the exception of the hydrogen atom mentioned at the outset R₁ and X' with the exception of one in the 4-position to the phenyl-bound methylene group have the meanings mentioned above for X, with a compound of general formula VIII, in the
  n, m, R₃ and Z have the meanings mentioned above and W₄ a hydroxy group or a reactive leaving group, such as. For example, a halogen atom or an alkylsulfonyloxy or Arylsulfonyloxygruppe, for example, the p-Toluolsul fonyloxy or Trifluormethylsulfonyloxygruppe represents.

The reaction of a phenol of formula VII with a verbin tion of the general formula VIII, in the W₄ a nucleo represents phile leaving group is suitably in  a suitable inert solvent such as acetone, acetone tril, dimethylformamide, methylene chloride or chloroform, ge if appropriate in the presence of a base such as potassium carbonate, Triethylamine or sodium hydride at a temperature between 20 and 120 ° C performed, for example, at you temperature of the reaction mixture.

The reaction of a phenol of formula VII with a verbin tion of the general formula VIII in which W₄ is a hydroxy is advantageously Mitsunobu Be conditions in the presence of triphenylphosphine and an azo dicarboxylic acid dialkyl ester in a suitable inert Lö Such as acetonitrile or tetrahydrofuran in a Temperature between 0 and 50 ° C, but preferably at room temperature performed. If the radicals R₁, and / or R₂ in a compound of formula VII free hydroxy groups be sit, it is advisable to implement this before implementation neter way and the protective groups after finished To split off again according to known methods.

For example, comes as a protective group for a hydroxy group the trimethylsilyl or tetrahydropyranyl group in Be costume. The optional subsequent cleavage of a such protective radical takes place for example hydrolytically in an aqueous solvent with the addition of an acid at For example, hydrochloric acid or sulfuric acid, at a tempera between 25 and 50 ° C.

The compounds prepared by the above methods gene of the general formula I, provided they are an asymmetric have carbon atoms as enantiomeric mixtures present, which separated according to methods known per se can be.

Thus, the compounds of formula I, which contain only one optically active center, according to Known methods (see Allinger N.L. and Eliel W.L. "Topics in Stereochemistry", Vol. 6, Wiley Interscience,  1971) in their optical antipodes, z. B. by Chromatography on optically active support materials, by Recrystallization from an optically active solvent or by reacting with one, with the racemic verb Salts forming optically active substance, in particular Acids, and separating the Salzgemi obtained in this way nice, z. Due to different solubilities, in the diastereomeric salts that make up the free antipodes by the action of suitable agents, e.g. B. by exposure excess bases can be released. Especially common, optically active acids are, for. B. the D and L-forms of tartaric acid, di-O-benzoyltartaric acid, malic acid, Mandelic acid, glutamic acid or quinic acid.

Further, the obtained compounds of the general If desired, formula I in their acid addition salts, ins special for the pharmaceutical application in their phy biologically compatible salts with inorganic or orga nical acids, are converted. As acids come here for example, hydrochloric acid, hydrobromic acid, sulfur acid, phosphoric acid, acetic acid, adipic acid, amber acid, lactic acid, citric acid, tartaric acid, fumaric acid or Maleic acid into consideration.

The compounds used as starting materials of the general Formulas II, VI and VII are known from the literature.

A starting compound of general formula III is obtained for example, from a corresponding alcohol of the formula IX,

in the
n, m, R₃, A, X and Z are as defined above, by halogenation z. B. with thionyl chloride, phosphorus tribromide or reaction with a corresponding sulfonyl chloride. The corresponding alcohol of the formula IX in turn is obtained by reduction of a corresponding aldehyde, a corresponding carboxylic acid or a corresponding ester, for example with a complex metal hydride such as sodium borohydride or lithium aluminum hydride or by acylation of a corresponding aminoalcohol of the general formula X,

in the
n, m, A and X are as defined above.

The compounds of general formula X can be, ana log for the preparation of the compounds of general formula IX, by reduction of a corresponding aldehyde, a ent speaking carboxylic acid or a corresponding ester, for example with a complex metal hydride.

Another way to make connections of the general formula X consists in the reduction of a Ver Compound of the general formula XI

in the
n, m and A are as defined above, X '' is a Bin tion, a methylene, ethylene or ethenylene group and R₄ represents an alkyl group having 1 to 10 carbon atoms, with a complex metal hydride and subsequent catalytic cal removal of the benzyl radical formed on N-terminal end, wherein one in the radicals A or X "optionally present before existing double bond is also hydrogenated.

The preparation of compounds of general formula XI as well as corresponding compounds of the general formula XII,

in the
n, m, A and X are as defined above, R₃ and Z 'are the meanings mentioned at the outset for R₃ and Z or together form a benzoyl group and W₅ together with an adjacent methylene group of the radical X is a formyl or alkoxycarbonyl group with 1 represents up to 10 carbon atoms in the alkoxy part, takes place in the case where A is an ethylene group in which the ge to the phenyl group bonded methylene group is replaced by an oxygen atom, by Mitsunobu reaction of a corresponding phenol of general formula XIII,

in the
X is defined as mentioned above and
W₅ together with an adjacent methylene group of the radical X is a formyl or alkoxycarbonyl group having 1 to 10 carbon atoms in the alkoxy part, with an alcohol of the general formula XIV,

in the
n and m have the meanings mentioned above, R₃ 'and Z' sit the meanings mentioned above for R₃ and Z be or together form a benzoyl group, or
by alkylating the phenol of general formula XIII with a derivative of a compound of general formula XIV in which the hydroxy group is replaced by a reactive leaving group, or in the event that A represents an ethylene or ethenylene group, by Wittig reaction of a corresponding Aldehydes of general formula XV,

in the
n and m have the meanings mentioned above, R₃ 'and Z' are the meanings mentioned at the outset for R₃ and Z or together form a benzoyl group, with a compound of the general formula XVI,

in the
X is defined as mentioned above, R₅ represents a Triarylphos phoniumrest or a phosphono group and W₆ a ge protected hydroxy group or together with an adjacent methylene group of the radical X is a protected formyl group or an alkoxycarbonyl group having 1 to 10 carbon atoms in the alkoxy, and optionally subsequent reduction of a Re thus formed ethenyl group to the ethylene group and subsequent removal of any protective residues present.

A starting compound of general formula IV is obtained by oxidation of an alcohol of the formula IX by the method from Swern, z. B. using dimethyl sulfoxide and an acylating agent or Jones by oxidation with Chromium (VI) oxide derivatives in the presence of pyridine.

However, a compound of general formula IV can also by careful reduction of a corresponding carboxylic acid esters with diisobutylaluminum hydride in tetrahydrofuran at Temperatures between -40 and + 25 ° C are obtained.

A compound of general formula V is obtained analogously the above-described method a) or b) from the Starting compounds III or IV by reaction with a Amine of general formula XVII,

R₁-NH₂ (XVII)

in the
R₁ has the meanings mentioned above.

A starting compound of general formula VIII is obtained by halogenation of a corresponding hydroxymethyl compound with thionyl chloride or phosphorus tribromide or by reaction with a corresponding sulfonyl chloride.

The compounds of general formula I have interes sante biological properties. They are inhibitors of Cholesterol biosynthesis, especially inhibitors of the enzyme 2,3-Epoxisqualen-Lanosterol-Cyclase. Due to their bio logical properties, they are particularly suitable for Be treatment and prophylaxis of hyperlipidemia, in particular  hypercholesterolemia, hyperlipoproteinemia and Hypertriglyceridemia and the resulting atheros sclerotic vascular changes with their sequelae such as coronary heart disease, cerebral ischemia, claudication intermittens, gangrene and others.

For the treatment of these diseases, the compounds the general formula I either alone to mono therapy or in combination with others cholesterol or lipid lowering substances for use the compounds, preferably as oral For optionally, in the form of suppositories as well rectal formulation can be administered. As Kombina For example:

• - bile acid binding resins such. Cholestyramine, Chole stipol and others,
• - Compounds that inhibit cholesterol absorption, such as z. For example, sitosterol and neomycin,
• - Compounds that enter into cholesterol biosynthesis fen, such as B. HMG-CoA reductase inhibitors such as lovastatin, Simvastatin, pravastatin and others,
• Squalene epoxidase inhibitors such as NB 598 and analogous connections as well
• - Squalene synthetase inhibitors such as representatives the class of isoprenoid (phosphinylmethyl) phosphonates and Squalestatin.

As another possible combination partners are still erwäh the class of fibrates, such as clofibrate, bezafibrate, gem fibrozil and others, nicotinic acid, its derivatives and analogues such as Acipimox and probucol.  

Furthermore, the compounds of the general formula I suitable for the treatment of diseases with excessive Cell proliferation related. Cholesterol is an essential cell component and must be for the cell prolix feration, d. H. Cell division, in sufficient quantity vorhan be his. The inhibition of cell proliferation by inhibition Cholesterol biosynthesis is exemplified by the glat muscle cells with the HMG-CoA reductase inhibitor of Sta tintyps lovastatin, as mentioned above.

As examples of diseases associated with excessive cell prol are related to life-cycle diseases call. In cell culture and in vivo experiments, ge shows that the lowering of serum cholesterol or Ein interfered with cholesterol biosynthesis by HMG-CoA reductase inhibits tumor growth (Lancet 339, 1154- 1156 [1992]). The compounds of the formula of the invention I are therefore because of their cholesterolbiosyntheseinhibi Toric effect potentially for the treatment of tumors suitable for illnesses. You can do it alone or to sub Use of known therapeutic principles find use.

Further examples are hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, plat tenepithelial carcinomas, keratosis and keratinization disorders to call. The term "psoriasis" as used herein denotes a hyperproliferative skin disorder that regulates changed the mechanism of skin mechanization. In particular, Lä formed the primary and secondary changes of the Proliferation in the epidermis, inflammatory reactions of the Skin and the expression of regulatory molecules such as lympho kine and inflammatory factors. Psoriatic skin is morphologically through increased sales of Epider miscellanous, thickened epidermis, abnormal keratinization inflammatory cell infiltrates into the dermis layer and poly morphonuclear leukocyte infiltration into the epidermis, the an increase in the basal cell cycle conditionally characterized.  

In addition, hyperkeratotic and parakeratotic cells are present. The term "keratosis", "basal cell carcinoma", "Squamous cell carcinoma" and "keratinization disorders" refers to hyperproliferative skin diseases which the regulatory mechanism for proliferation and Differentiation of skin cells is interrupted.

The compounds of formula I are effective as antagonists skin hyperproliferation, d. H. as a means that the hyper proliferation of human keratinocytes. as a result its compounds are hyper-treatment agents proliferative skin diseases such as psoriasis, basal cell carcinoma zinomata, keratinization disorders and keratosis. To treat these diseases, the compounds of formula I are administered either orally or topically, being either alone in the form of monotherapy or in Can be used in combination with known active ingredients NEN.

Further to call are by surgical measures such as PTCA (percutaneous transluminal coronary angioplasty) or Bypass surgeries triggered hyperproliferative vasculature Illnesses such as stenoses and vascular occlusions that are on the Proliferation of smooth muscle cells. As he at the beginning It is well known that this cell proliferation can be achieved Statin-type HMG-CoA reductase inhibitors, such as lovastatin, suppress. Due to their inhibitory effect on the Cholesterol biosynthesis are also the compounds of the general my formula I suitable for the treatment and prophylaxis These diseases, either alone or in combination nation with known active ingredients such. B. intravenous app Licensed heparin, preferably in oral administration Ver can find application.

Another possible use of Ver invention Compounds of general formula I is the prophylaxis and Treatment of gallstone disease. The gallstone formation is triggered by an unfavorable cholesterol-bile acid  Ratio in the bile, causing the solubility the cholesterol is exceeded and it precipitates of cholesterol in the form of gallstones. The Wirk the HMG-CoA reductase inhibitor lovastatin in the Dissolution of gallstones, especially in combination with Ursodeoxycholic acid, described in Gastroenterology 102, No. 4, Pt.2, A319 [1992]. Because of their mode of action the compounds of general formula I therefore also for the prophylaxis and treatment of gallstone disease of Be interpretation. You can do it either alone or in Kombina tion with known therapies such as the treatment treatment with ursodeoxycholic acid or the shock wave lithotrip they are preferably used in oral application.

Finally, the compounds of the general formula I suitable for the treatment of infections caused by pathogenic fungi such as Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and other. As already mentioned, the end product is sterol biosynthesis in the fungal organism not cholesterol but that eat for the integrity and function of the fungal cell membranes essential ergosterol. The inhibition of ergosterol biosynthesis therefore leads to growth disorders and possibly to Killing the fungal organisms.

For the treatment of mycoses, the compounds of all of general formula I administered either orally or topically who the. They can do it alone or in combination be used with known antifungal agents, especially with those in other stages of sterol intervene biosynthesis, such as the squalene-Epo xidas inhibit terbinafine and naftifine or the lanosterol Azole type 14α-demethylase inhibitors such as Ketoconazole and fluconazole.

Another use of the compounds of general formula I relates to the application in poultry  attitude. Lowering the cholesterol content of eggs Administration of the HMG CoA reductase inhibitor lovastatin Laying hens is described (FASEB Journal 4, A 533, Abstracts 1543 [1990]). The production of cholesterol eggs is from In interest, since the cholesterol load of the body by eggs with reduced cholesterol without any change in the er nutritional habits can be reduced. Because of your inhibitory effect on the cholesterol biosynthesis kön NEN the compounds of general formula I in the Ge Wing breeding for the production of cholesterol eggs use find, the substances preferably as an additive to Be given food.

The biological effect of compounds of the general Formula I was determined by the following methods:

I. Measurement of inhibition of ¹⁴C-acetate incorporation in the Digitonin precipitable steroids

Method:
Human hepatoma cells (HEP-G2) are stimulated after 3 days of cultivation for 16 hours in cholesterol-free medium. The substances to be tested (dissolved in dimethyl sulfoxide, final concentration 0.1%) are added during this stimulation phase. Subsequently, after addition of 200 .mu.mol / l 2-.sup.1 C acetate, incubation is continued for further two hours at 37.degree. C. in the incubator.

After detachment of the cells and saponification the sterol ester is added After extraction, digitonin was added and the precipitated Ste role isolated. The inserted into the digitoninfallable sterols built ¹⁴C-acetate is determined by scintillation.

The study of the inhibitory effect was carried out at test concentrations of 10 ^-7 and 10 ^-8 mol / l. It has been found that, for example, the following compounds A to J of the general formula I show a good inhibiting action at these test concentrations:
A = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] pyrrolidine,
B = 1- (4-chloro-benzenesulfonyl) -3- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine,
C = 1- (4-chlorobenzenesulfonyl) -3- [2- (4-diethylaminomethylphenyl) ethyl] piperidine,
D = 1- (4-chlorobenzoyl) -3- (4- [2- (N -methyl-allylamino) ethyl] phenoxymethyl] pyrrolidine,
E = 1- (4-chlorobenzoyl) -4- [4- (N-methyl-allylaminomethyl) phenoxymethyl] -piperidine,
F = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] -piperidine,
G = 1- (4-chlorobenzoyl) -4- [2- (4- (N-methyl-allylaminomethyl) phenyl) ethyl] piperidine,
H = 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] -piperidine,
I = 1- (4-chloro-benzenesulfonyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine and
J = 1- (4-chloro-phenylacetyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine.

The percentages by which the above compounds are ¹⁴C- Acetate incorporation are indicated in the following table ben:  

As mentioned above, in the literature isolated Inhi bitoren the enzyme 2,3-Epoxisqualen lanosterol cyclase be described, but structurally very different from the compounds of formula I according to the invention. The compounds structurally closest to the compounds of general formula I are described in EP 0 468 457. For comparison, therefore, Example 1 of this publication was tested according to the method of determination described above in test concentrations of 10 ^-5 mol / l and 10 ^-6 mol / l ge. The inhibition values of 41% and 13% found in this case show that these compounds are significantly inferior to the compounds of the general formula I according to the invention.

II. Measurement of the in vivo effect in the rat after oral gift

The inhibition of the enzyme 2,3-epoxysqualene-lanosterol cyclase causes an elevation of the 2,3-epoxysqualene levels in liver and plasma. The amount of formed 2,3-Epoxisqualen therefore serves as a direct measure of the potency of the whole animal. The determination is carried out according to the following method:
Male Wistar rats (160-190 g body weight), the suspended in 1.5% aqueous methyl cellulose Prüfsub punch via gavage applied. 5 hours after application, blood is recovered retro-orbitally from the venous plexus. Plasma is worked up by the method of Bligh and Dyer (Canad J. Biochem Physiol 37, 912, [1959]), purified by a precolumn and then analyzed by HPLC. The resulting peak of 2,3-epoxysqualene is quantified using an internal standard. The following table shows the plasma levels of 2,3-epoxysqualene in μg / ml determined after administration of 1 mg / kg of test substance.

The investigations were carried out with concentrations of 0.1 or 1.0 mg / kg. In the following table are at by way of example the results of the substances mentioned above A to I summarized:

2,3-Epoxysqual concentration (μg / ml) in plasma (rat)

In the control animals occur under the experimental conditions no measurable 2,3-epoxide squalane levels.

None of the inhibitors described in the literature of the enzyme 2,3-epoxysqualene-lanosterol-cyclase is so far  an inhibition of cholesterol biosynthesis in the whole animal be wrote.

The compounds of general formula I were found in the curative dosage as largely non-toxic. example Were the compounds A, B and I after oral Appli cation of 100 mg / kg, once daily for 4 days at the Mouse no toxic effects.

For pharmaceutical application, the compounds of the general formula I in a conventional manner in the conventional pharmaceutical preparations for oral, incorporate rectal and topical administration.

Formulations for oral administration include For example, tablets, dragees and capsules, for the rectal Preferably, suppositories are contemplated.

The daily dose is between 1 and 500 mg for a men with 60 kg body weight, but is preferably a Ta 5 to 100 mg dose for a person weighing 60 kg pergewicht. The daily dose is preferably in 1 to 3 A divided into portions.

For topical application, the compounds may be in the bait tions, which are about 1 to 1000 mg, in particular 10 to 300 mg Active ingredient per day, administered. The day dose is preferably divided into 1 to 3 single doses.

Topical formulations include gels, creams, lotions, Ointments, powders, aerosols and other conventional formulations for the application of remedies on the skin. The Wirk amount of substance for topical application is 1 to 50 mg per gram of formulation, but preferably 5 to 20 mg per Gram formulation. In addition to the application on the skin can the topical formulations of the present invention also be applied in the treatment of mucous membranes, the the topical treatment are accessible. For example  The topical formulations on the mucous membranes of the Mouth, lower colon, and others.

For use in poultry farming to produce choleste Rolar eggs become the active ingredients of the general formula I. the animals by the usual methods as an addition to approe animal feed. The concentration of the active in finished feed is normally 0.01 to 1%, but preferably 0.05 to 0.5%.

The active ingredients can be added to the feed as such the. Thus, the feeds of the invention for Le go next to the active substance and if necessary next to one usual vitamin-mineral mixture such as corn, soy bean meal, meat meal, feed fat and soybean oil. To this Food is one of the compounds mentioned above Formula I as active ingredient in a concentration of 0.01 to 1%, but preferably 0.05 to 0.5% mixed.  

The following examples serve for further explanation the invention.

Examples for the preparation of the starting materials:

example I 1-n-hexanoyl-3- (4-hydroxymethyl-phenoxymethyl) -piperidine

0.4 g (1.8 mmol) of 3- (4-hydroxymethyl-phenoxymethyl) -piperidine (prepared from 3-picolyl chloride by reaction with ethyl 4-hydroxypropoxybenzoate followed by catalytic hydrogenation of the resulting 4- (3-pyridylmethoxy) benzoic acid ethyl ester hydrochloride using platinum oxide as a catalyst and subsequent reduction with lithium aluminum hydride in ether) are dissolved in 40 ml of dioxane and after addition of 4 ml (4 mmol) of 1N sodium hydroxide solution with ice cooling, dropwise with a solution of 0.27 g (2 mmol) n Hexan acid chloride in 10 ml of dioxane. It is stirred for one hour, then diluted with water and extracted with ethyl acetate. The extracts are dried, concentrated and purified by column chromatography (silica gel; ethyl acetate).
Yield: 270 mg (47% of theory), oil.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
0.9 (m, 3H), 1.3 (m, 4H), 1.3-2.2 (m, 7H), 2.32 (t, 2H), 2.62 + 3.00 (t + m, 2H), 3.85 (m, 3H), 4.19 + 4.6 (s + 2m, 3H), 6.88 (d, 2H), 7.30 (d, 2H).

Analogously to Example I are obtained:

• a) 1-n-hexanoyl-3- [2- (4-hydroxymethylphenyl) ethyl] piperidine
  by reacting 3- [2- (4-hydroxymethyl-phenyl) -ethyl] -puridine (prepared by olefination of pyridine-3-aldehyde according to Wittig with 4-diethylphosphonomethyl-benzoic acid methyl ester, followed by catalytic hydrogenation using platinum oxide as catalyst and subsequent reduction with lithium aluminum hydride) with n-hexanoic acid chloride.
  Yield: 42% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.90 (t, 3H), 1.0-2.0 (m, 12H), 2.30 (m, 3H), 2.65 (t + m, 3H), 3.0 (t, 0, 5H), 3.75 (d, 1H), 4.45 (t, 1.5H), 4.67 (s, 2H), 7.18 (d, 2H), 7.28 (m, 2H).
• b) 3- [2- (4-Hydroxymethylphenyl) ethyl] -1- (4-methylbenzenesulphonyl) piperidine
  of 3- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-methyl-benzenesulfonyl chloride.
  Yield: 37% of theory.
  Melting point: 102-103 ° C.
• c) 1- (4-Chloro-benzenesulfonyl) -3- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine
  from 3- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-chlorobenzenesulfochloride.
  Yield: 39% of theory.
  Melting point: 133-135 ° C.
• d) 1- (4-Chlorobenzenesulfonyl) -4- [2- (4-hydroxymethylphenyl) ethyl] piperidine
  from 4- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-chlorobenzenesulfochloride.
  Yield: 41.6% of theory.
  Melting point: 128-129 ° C.
• e) 1- (4-Chlorobenzoyl) -4- [2- (4-hydroxymethylphenyl) ethyl] piperidine
  from 4- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-chloro benzoyl chloride.
  Yield: 33% of theory.
  Melting point: 114-116 ° C.
• f) 1- (4-Chloro-phenylacetyl) -4- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine
  from 4- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-chloro phenylacetyl chloride.
  Yield: 34% of theory,
  Melting point: 135-137 ° C.
• g) 4- [2- (4-Hydroxymethylphenyl) ethyl] -1- (4-phenylbutyryl) piperidine
  from 4- [2- (4-hydroxymethylphenyl) ethyl] piperidine and 4-phenyl-butyryl chloride.
  Yield: 34.6% of theory.
  Melting point: 96-97 ° C.

example II 4 - [[1- (4-methyl-benzenesulfonyl) pyrrolidinyl (3)] methyl oxy] benzaldehyde

2.8 g (8.4 mmol) of 3- (methanesulfonyloxymethyl) -1- (4-methylbenzenesulfonyl) pyrrolidine (prepared by reacting 3-hydroxymethyl-1- (4-methylbenzenesulfonyl) pyrrolidine with methanesulfonyl chloride) are dissolved in 30 ml of dimethylformamide and, after addition of 1.55 g (12.6 mmol) of 4-hydroxybenzaldehyde and 3.5 g (25 mmol) of potassium carbonate, stirred at 80 ° C. for 2.5 hours. Then it is poured into water and the ge formed crystals are filtered off with suction.
Yield: 96% of theory,
Melting point: 99-101 ° C.

Analogously to Example II are obtained:

• a) 4 - [[1- (4-Chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -3-methanesulfonyloxymethylpyrrolidine and 4-hydroxybenzaldehyde.
  Yield: 87% of theory, oil.
• b) 4 - [[1- (4-Chlorobenzoyl) piperidyl- (3)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -3-methanesulfonyloxy-piperidine and 4-hydroxybenzaldehyde.
  Yield: 64% of theory,
  Melting point: 99-102 ° C.
• c) 3 - [[1- (4-Chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -3-methanesulfonyloxymethylpyrrolidine and 3-hydroxybenzaldehyde.
  Yield: 62% of theory, oil.
• d) 3 - [[1- (4-Chlorobenzoyl) piperidyl- (4)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -4-methanesulfonyloxymethyl-piperidine and 3-hydroxybenzaldehyde.
  Yield: 77% of theory,
  Melting point: 80-82 ° C.
• e) 4 - [[1- (4-Chlorobenzoyl) piperidyl- (4)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -4-methanesulfonyloxymethyl-piperidine and 4-hydroxybenzaldehyde.
  Yield: 72% of theory,
  Melting point: 97-98 ° C.
• f) 3- [[1- (4-Chlorobenzoyl) piperidyl- (3)] methyloxy] benzaldehyde
  from 1- (4-chlorobenzoyl) -3-methanesulfonyloxymethyl-piperidine and 3-hydroxybenzaldehyde.
  Yield: 78% of theory, oil.
• g) 4 - [[1- (3-phenylpropionyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde
  from 3-Methanesulfonyloxymethyl-1- (3-phenylpropionyl) pyrrolinediamine and 4-hydroxybenzaldehyde.
  Yield: 69% of theory, oil.
• h) 4 - [[1- (4-Chloro-phenylacetyl) -pyrrolidinyl- (3)] methyl oxy] benzaldehyde
  from 1- (4-chloro-phenylacetyl) -3-methanesulfonyloxymethyl-pyrrolidine and 4-hydroxybenzaldehyde.
  Yield: 91% of theory, oil.

Example 1 3- (4-diethylaminomethyl-phenyoxymethyl) -1-n-hexanoyl- piperidine

220 mg (0.69 mmol) of 1-n-hexanoyl-3- (4-hydroxymethyl-phen oxymethyl) piperidine are dissolved in 20 ml of chloroform and after addition of 0.2 ml of thionyl chloride for 2 hours at room temperature and 1 hour at 60 ° C stirred. Then the reaction mixture is concentrated, the resulting Chlormethylver compound in 10 ml of dimethylformamide and added dropwise to the solution of 2 ml of diethylamine in 25 ml of dimethylformamide. At closing, one heats 2 hours at 50 ° C. Then it is added to ice-cold sodium bicarbonate solution and extracted with methylene chloride. The extracts are dried over magnesium sulfate, concentrated by evaporation and purified by column chromatography (aluminum oxide, petroleum ether / ethyl acetate = 2: 1).
Yield: 190 mg (73% of theory), oil.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
0.9 (m, 3H), 1.04 (t, 6H), 1.15-2.13 (m, 11H), 2.43 (t, 2H), 2.5 (q, 4H), 2 , 6-3.15 (dd + m, 2H), 3.5 (s, 2H), 3.82 (m, 3H), 4.21 + 4.60 (2d, 1H), 6.83 (i.e. , 2H), 7.23 (dd, 2H).

The following are produced analogously to Example 1:

• a) 3- [2- (4-diethylaminomethylphenyl) ethyl] -1-n-hexanoylpiperidine
  from 1-n-hexanoyl-3- [2- (4-hydroxymethyl-phenyl) -ethyl] -puridine by treatment with thionyl chloride and subsequent reaction with diethylamine.
  Yield: 77% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.9 (t, 3H), 1.05 (t, 6H), 1.05-2.05 (m, 13H), 2.3 (dt, 2H), 2.53 (q + m, 5H) , 2.65 + 3.0 (2t + m, 3H), 3.53 (s, 2H), 3.75 (d, 1H), 4.47 (dd, 1H), 7.1 (d, 2H ), 7.25 (dd, 2H).
• b) 3- [2- (4-diethylaminomethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine
  of 3- [2- (4-hydroxymethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine by treatment with thionyl chloride and subsequent reaction with diethylamine.
  Yield: 54% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.9 (m, 1H), 1.04 (t, 6H), 1.35-1.90 (m, 6H), 2.02 (t, 1H), 2.3 (t, 1H), 2 , 43 (s, 3H), 2.52 (q, 4H), 2.62 (t, 2H), 3.55 (s, 2H), 3.64 (t, 2H), 7409 (d, 2H) , 7.24 (d, 2H), 7.30 (d, 2H), 7.63 (d, 2H).
• c) 3- [2- (4-Methylaminomethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine
  from 3- [2- (4-hydroxymethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine by treatment with thionyl chloride and subsequent reaction with methylamine.
  Yield: 91% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.92 (m, 1H), 1.35-1.88 (m, 6H), 2.05 (t, 1H), 2.31 (t, 1H), 2.45 (2s, 6H), 2 , 62 (t, 2H), 3.6 (t, 2H), 3.75 (s, 2H), 7.11 (d, 2H), 7.25 (d, 2H), 7.31 (d, 2H), 7.64 (d, 2H).
• d) 3- [2- (4- (N -methyl-allylaminomethyl) -phenyl) -ethyl] -1- (4-methyl-benzenesulfonyl) -piperidine
  from 3- [2- (4-hydroxymethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 83% of theory,
  Melting point: 38 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.92 (m, 1H), 1.35-1.89 (m, 6H), 2.05 (t, 1H), 2.20 (s, 3H), 2.31 (t, 1H), 2 , 45 (s, 3H), 2.60 (t, 2H), 3.04 (d, 2H), 3.48 (s, 2H), 3.62 (t, 2H), 5.14 (d, 1H), 5.20 (d, 1H), 5.91 (2dt, 1H), 7.1 (d, 2H), 7.23 (d, 2H), 7.31 (d, 2H), 7, 63 (d, 2H).
• e) 1- (4-Chloro-benzenesulfonyl) -3- [2- (4-diethylamino-methyl-phenyl) -ethyl] -piperidine
  from 1- (4-chloro-benzenesulfonyl) -3- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine by treatment with thionyl chloride and subsequent reaction with diethylamine.
  Yield: 88% of theory,
  Melting point: 54 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.95 (m, 1H), 1.05 (t, 6H), 1.4-1.9 (m, 6H), 2.07 (t, 1H), 2.35 (t, 1H), 2 , 52 (q, 4H), 2.62 (t, 2H), 3.55 (s, 2H), 3.62 (t, 2H), 7.1 (d, 2H), 7.25 (d; 2H), 7.5 (d, 2H), 7.69 (d, 2H).
• f) 1- (4-Chloro-benzenesulfonyl) -3- [2- (4- (N-methyl-allylaminomethyl) -phenyl) -ethyl] -piperidine
  from 1- (4-chloro-benzenesulfonyl) -3- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 85% of theory,
  Melting point: 64-66 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.95 (m, 1H), 1.4-1.9 (m, 6H), 2.06 (t, 1H), 2.19 (s, 3H), 2.35 (t, 1H), 2 , 61 (t, 2H), 3.03 (d, 2H), 3.61 (t, 2H), 5.14 (d, 1H), 5.21 (d, 1H), 5.91 (2dt, 1H), 7.1 (d, 2H), 7.24 (d, 2H), 7.5 (d, 2H), 7.68 (d, 2H).
• g) 1- (4-Chloro-benzenesulfonyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine
  from 1- (4-chloro-benzenesulfonyl) -4- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 81.2% of theory,
  Melting point: 91-92 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.05-1.88 (m, 7H), 2,, 17 (s, 3H), 2.22 (t, 2H), 2.58 (t, 2H), 3.01 (d, 2H), 3.43 (s ,, 2H), 3.76 (d, 2H), 5.13 (d, 1H), 5.19 (d, 1H), 5.9 (2dt, 1H), 7.06 ( d, 2H), 7.19 (d, 2H), 7.5 (d, 2H), 7.69 (d, 2H).
• h) 1- (4-Chlorobenzoyl) -4- [2- (4- (N-methyl-allylaminomethyl) phenyl) ethyl] piperidine
  from 1- (4-chlorobenzoyl) -4- [2- (4-hydroxymethylphenyl) ethyl] piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 48.2% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.0-2.0 (m, 7H), 2.19 (s, 3H), 2.63 (t, 2H), 2.65-3.0 (bm, 2H), 3.02 (d, 2H), 3.45 (s, 2H), 3.7 (bs, 1H), 4.68 (bs, 1H), 5.13 (d, 1H), 5.21 (d, 1H), 5, 91 (2dt, 1H), 7.11 (d, 2H), 7.23 (d, 2H), 7.35 (2d, 4H).
• i) 4- [2- (4- (N -methyl-allylaminomethyl) phenyl) ethyl] -1- (4-phenylbutyryl) piperidine
  from 4- [2- (4-hydroxymethylphenyl) ethyl] -1- (4-phenylbutyl) piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 75% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.03 (m, 2H), 1.55 (m, 3H), 1.76 (d, 2H), 2.0 (m, 2H), 2.19 (s, 3H), 2.33 (t , 2H), 2.40-2.75 (m + t, 5H), 2.92 (t, 1H), 3.02 (d, 2H), 3.45 (s, 2H), 3.74 ( d, 1H), 4.61 (d, 1H), 5.13 (d, 1H), 5.2 (d, 1H), 5.91 (2dt, 1H), 7.04-7.35 (m , 9H).
• j) 1- (4-Chloro-phenylacetyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine
  from 1- (4-chloro-phenylacetyl) -4- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine by treatment with thionyl chloride and subsequent reaction with N-methyl-allylamine.
  Yield: 61% of theory,
  Melting point: 40-42 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  0.8-1.88 (m, 7H), 2.19 (s, 3H), 2.55 (t, 1H), 2.60 (t, 2H), 2.94 (t, 1H), 3 , 04 (d, 2H), 3.45 (s, 2H), 3.68 (s, 2H), 3.81 (d, 1H), 4.61 (d, 1H), 5.13 (d, 1H), 5.20 (d, 1H), 5.9 (2dt, 1H), 7.02-7.34 (m, 8H).
• k) 1- (4-Chlorobenzenesulfonyi) -4- [2- [4- (N- (2-hydroxyethyl) methylaminomethyl) phenyl] ethyl] piperidine
  from 1- (4-chloro-benzenesulfonyl) -4- [2- (4-hydroxymethyl-phenyl) -ethyl] -piperidine by treatment with thionyl chloride and after subsequent reaction with N- (2-hydroxyethyl) methylamine.
  Yield: 57.5% of theory,
  Melting point: 113-115 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.10-1.46 (m, 2H), 1.55 (m, 2H), 1.79 (d, 2H), 2.22 (s + t, 5H), 2.58 (2t, 4H) , 3.51 (s, 2H), 3.61 (t, 2H), 3.77 (bd, 2H), 7.08 (d, 2H), 7.18 (d, 2H), 7.50 ( d, 2H), 7.70 (d, 2H).

example 2 1- (4-chlorobenzoyl) -3- [4- (N-methyl-Allylaminomethyl) phenoxymethyl] piperidine

1.3 g (3.6 mmol) of 4 - [[1- (4-chlorobenzoyl) piperidyl- (3)] methyloxy] benzaldehyde are dissolved in 50 ml of methanol and, after addition of 0.81 g (11 mmol) of N- Methyl allylamine, 0.81 g (12.9 mmol) of glacial acetic acid and 0.46 g (7.6 mmol) of sodium cyanoborohydride stirred overnight at room temperature. Then 25 ml of 2N sodium hydroxide solution are added and it is stirred for 20 minutes to destroy the Borkomplexe formed. Subsequently ßend is diluted with water and extracted with ethyl acetate. After the extracts have been dried, the mixture is concentrated and purified by column chromatography (aluminum oxide, petroleum ether / ethyl acetate = 2: 1).
Yield: 1.34 g (90%, theory),
Melting point: 60-64 ° C.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
1.35-2.15 (m, 5H), 2.17 (s, 3H), 3.0 (d, 2H), 3.1 (m, 2H), 3.43 (s, 2H), 3 , 85 (bm, 3H), 4.35 + 4.70 (2bs, 1H), 5.10-5.25 (m, 2H), 5.91 (2dt, 1H), 6.78 (bd, 2H ), 7.20 (d, 2H), 7.32 (s, 4H).

Prepared analogously to Example 2:

• a) 3- (4-diethylaminomethyl-phenoxymethyl) -1- (4-methylbenzenesulfonyl) -pyrrolidine
  from 4 - [[1- (4-methyl-benzenesulfonyl) -pyrrolidinyl- (3)] -methyl oxy] -benzaldehyde and diethylamine.
  Yield: 66.7% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.04 (t, 6H), 1.7 (m, 1H), 2.0 (m, 1H), 2.41 (s, 3H), 2.5 (q, 4H), 2.55 (m , 1H), 3,12-3,78 (m + s, 8H), 6,68 (d, 2H), 7,2 (d, 2H), 7,27 (d, 2H), 7,71 ( d, 2H).
• b) 3- (4-Methylaminomethylphenoxymethyl) -1- (4-methylbenzenesulfonyl) pyrrolidine
  from 4 - [[1- (4-methyl-benzenesulfonyl) -pyrrolidinyl- (3)] -methyl oxy] -benzaldehyde and methylamine.
  Yield: 86.2% of theory,
  Melting point 100-102 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.7 (m, 1H), 2.0 (m, 1H), 2.43 (d, 6H), 2.58 (m, 1H), 3.12-3.8 (m + s, 8H) , 6.71 (d, 2H), 7.2 (d, 2H), 7.29 (d, 2H), 7.72 (d, 2H).
• c) 1- (4-Chlorobenzoyl) -3- (4-methylaminomethyl-phenoxymethyl) pyrrolidine
  from 4 - [[1- (4-chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and methylamine.
  Yield: 90% of theory,
  Melting point: 96-98 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.9 (m, 1H), 2.17 (m, 1H), 2.45 (s, 3H), 2.75 (m, 1H), 3.30-4.05 (s + m, 8H) , 6.82 (t, 2H), 7.22 (m, 2H), 7.38 (d, 2H), 7.48 (d, 2H).
• d) 1- (4-Chlorobenzoyl) -3- [4- [N- (2-hydroxyethyl) methylamino methyl] phenoxymethyl] pyrrolidine
  from 4 - [[1- (4-chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and N- (2-hydroxyethyl) methylamine.
  Yield: 62.8% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.88 (m, 1H), 2.2 (s + m, 4H), 2.57 (t, 2H), 2.75 (m, 1H), 3.30-4.05 (m + s + t, 10H), 6.82 (t, 2H), 7.18 (m, 2H), 7.37 (d, 2H), 7.48 (d, 2H).
• e) 1- (4-Chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] pyrrolidine
  from 4 - [(1- (4-chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and N-methyl-allylamine.
  Yield: 69% of theory,
  Melting point: 78-80 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.88 (m, 1H), 2.17 (s + m, 4H), 2.75 (m, 1H), 3.01 (d, 2H), 3.30-4.06 (s + m), 6H), 5.14 (d, 1H), 5.20 (d, 1H), 5.90 (2dt, 1H), 6.81 (t, 2H), 7.21 (m, 2H), 7, 38 (d, 2H), 7.48 (d, 2H).
• f) 1- (4-Chlorobenzoyl) -3- (3-diethylaminomethyl-phenoxymethyl) -pyrrolidine
  from 3 - [[1- (4-chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and diethylamine.
  Yield: 44% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.05 (t, 6H), 1.75-2.39 (2m, 2H) ₁ 2.52 (q, 4H), 2.73 (m, 1H), 3.30-4.05 (m, 8H), 6.74, (dd, 1H), 6.91 (m, 2H), 7.2 (m, 1H), 7.42 (2d, 4H).
• g) 1- (4-Chlorobenzoyl) -3- [3- (N-methyl-allylaminomethyl) phenoxymethyl] pyrrolidine
  from 3 - [[1- (4-chlorobenzoyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and N-methyl-allylamine.
  Yield: 56% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.99 (m, 1H), 2.20 (m + s, 4H), 2.73 (m, 1H), 3.01 (d, 2H), 3.30-4.10 (m, 7H) 5.15 (d, 1H), 5.21 (d, 1H), 5.89 (m, 1H), 6.75 (t, 1H), 6.88 (m, 2H), 7.2 (m , 1H), 7.38 (d, 2H), 7.47 (d, 2H).
• h) 1- (4-Chlorobenzoyl) -3- [3- (N-methyl-allylaminomethyl) phenoxymethyl] piperidine
  from 3 - [[1- (4-chlorobenzoyl) piperidyl- (3)] methyloxy] benzaldehyde and N-methyl-allylamine.
  Yield: 50% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.37-2.25 (5H), 2.20 (s, 3H), 3.02 (d + m, 4H) 3.46 (s, 2H), 3.86 (bs + m, 3H), 4.32 + 4.70 (2bs, 1H), 5.15 (d, 1H), 5.2 (d, 1H), 5.91 (m, 1H), 6.55-6.95 (d + m, 3H), 7.20 (t, 1H), 7.32 (s, 4H).
• i) 1- (4-chlorobenzoyl) -4- [4- (N-methyl-allylaminomethyl) phenoxymethyl] -piperidine
  from 4- [[1- (4-chlorobenzoyl) piperidyl- (4)] methyloxy] benzaldehyde and N-methyl-allylamine.
  Yield: 55% of theory,
  Melting point: 128-130 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.36 (m, 2H), 1.73-2.23 (2m, 3H), 2.17 (s, 3H), 3.01 (d + m, 4H), 3.42 (s, 2H) , 3.83 + 4.75 (2bm + d, 4H), 5.13 (d, 1H), 5.20 (d, 1H), 5.89 (2dt, 1H), 6.83 (d, 2H ), 7.22 (d, 2H), 7.37 (dd, 4H).
• j) 1- (4-Chlorobenzoyl) -4- [3- (N-methyl-allylaminomethyl) -phenoxymethyl] -piperidine
  from 3 - [[1- (4-chlorobenzoyl) piperidyl- (4)] methyloxy) benzaldehyde and N-methyl-allylamine.
  Yield: 46.5% of theory,
  Melting point: 52-54 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.38 (m, 2H), 1.89 (m, 2H), 2.07 (m, 1H), 2.20 (s, 3H), 3.03 (d + m, 4H), 3.48 (s, 2H), 3.85 (d + m, 3H), 4.75 (bs, 1H), 5.14 (d, 1H), 5.21 (d, 1H), 5.91 (2dt, 1H), 6.77 (d, 1H), 6.90 (m, 2H), 7.20 (d, 1H), 7.37 (dd, 4H).
• k) 3- (4-Diethanolaminomethyl-phenoxymethyl) -1- (3-phenyl-propionyl) -pyrrolidine
  from 4 - [[1- (3-phenylpropionyl) pyrrolidinyl] (3)] methyl oxy] benzaldehyde and diethanolamine.
  Yield: 23% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.62-2.22 (2m, 2H), 2.60 (t, 2H), 2.68 (t, 4H), 2.98 (t, 2H), 3.12-4.0 (m + t, 13H), 6.81 (d, 2H), 7.22 (m, 7H).
• l) 1- (4-Chloro-phenylacetyl) -3- (4-diethanolaminomethyl-phenoxymethyl) -pyrrolidine
  from 4 - [[1- (4-chloro-phenylacetyl) -pyrrolidinyl- (3)] methyl oxy] benzaldehyde and diethanolamine.
  Yield: 37.6% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.65-2.28 (2m, 2H), 2.39 (s, 2H), 2.7 (t + m, 5H), 3.30-4.0 (m, 14H), 6.80 ( d, 2H), 7.21 (m, 6H).
• m) 1- (3-Phenyl-propionyl) -3- [4- [piperidyl- (1) -methyl] -phenoxymethyl] -pyrrolidine
  from 4 - [[1- (3-phenylpropionyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and piperidine.
  Yield: 44% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.32-1.65 (2t, 6H), 1.65-2.23 (2m, 2H), 2.32 (t, 4H), 2.6 (t + m, 3H), 3.0 ( t, 2H), 3.13-4.0 (m, 8H), 6.8 (d, 2H), 7.22 (s + d, 7H).
• n) 1- (4-Chloro-phenylacetyl) -3- [4- [N- (2-hydroxyethyl) methylaminomethyl] phenoxymethyl] pyrrolidine
  from 4 - [[1- (4-chloro-phenylacetyl) pyrrolidinyl- (3)] methyloxy] benzaldehyde and N- (2-hydroxyethyl) methylamine.
  Yield: 37% of theory, oil.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.69-2.30 (m, 2H), 2.21 (d, 3H), 2.58 (t, 2H), 2.7 (m, 2H), 3.29-4.05 (2s + m, 10H), 6.8 (d, 2H), 7.12-7.35 (m, 6H).
• o) 1- (4-Chloro-phenylacetyl) -3- [4- [pyrrolidinyl- (1) methyl] phenoxymethyl] pyrrolidine
  from 4 - [[1- (4-chloro-phenylacetyl) -pyrrolidinyl- (3)] -methyloxy] -benzaldehyde and pyrrolidine.
  Yield: 38.6% of theory,
  Melting point: 74-77 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.53-2.30 (bs + 2m, 8H), 2.34-2.87 (bs + m, 5H), 3.27-4.05 (2s + m, 10H), 6.8 (i.e. , 2H), 7,13-7,37 (m, 6H).
• p) 1- (trans-4-chloro-cinnamoyl) -4- [4- (N- (2-hydroxyethyl) methylaminomethyl) phenoxymethyl] piperidine
  from 4 - [[1- (trans-4-chloro-cinnamoyl) piperidyl- (4)] methoxy] benzaldehyde and N- (2-hydroxyethyl) methylamine.
  Yield: 38% of theory,
  Melting point: 117-118 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.1-1.5 (m, 2H), 1.82-2.20 (m, 3H), 2.21 (s, 3H), 2.57 (t, 2H), 2.75 + 3, 17 (2bt, 2H), 3.49 (s, 2H), 3.60 (t, 2H), 3.65-3.90 (m, 2H), 4.12 + 4.78 (2bd, 2H) , 6.84 (d, 2H), 6.88 (d, 1H), 7.19 (d, 2H), 7.34 (d, 2H), 7.45 (d, 2H), 7.61 ( d, 1H).
• q) 1- (trans-4-chloro-cinnamoyl) -4- [4- [N- (3-hydroxypropyl) methylaminomethyl] phenoxymethyl] piperidine
  from 4 - [[1- (trans-4-chloro-cinnamoyl) piperidyl- (4)) methoxy] benzaldehyde and N- (3-hydroxypropyl) methylamine.
  Yield: 65% of theory,
  Melting point: 128-130 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.38 (m, 2H), 1.73 (m, 2H), 1.85-2.2 (m, 3H), 2.21 (s, 3H), 2.62 (t, 2H), 2 , 73 + 3.18 (2t, 2H), 3.45 (s, 2H), 3.80 (t + m, 4H), 4.16 + 4.79 (2bd, 2H), 6.83 (i.e. , 2H), 6.9 (d, 1H), 7.2 (d, 2H), 7.33 (d, 2H), 7.46 (d, 2H), 7.61 (d, 1H).

example 3 3- [2- [4- [N- (Aminocarbonylmethyl) methylaminomethyl] phenyl] ethyl] -1- (4-methyl-benzenesulfonyl) -piperidine

450 mg (1.16 mmol) of 3- [2- (4-methylaminomethylphenyl) ethyl] -1- (4-methylbenzenesulfonyl) piperidine are dissolved in 25 ml of acetonitrile and, after addition of 220 mg (2.3 mmol) of chloroacetamide and 500 mg of potassium carbonate refluxed for 4 hours. It is then concentrated, mixed with aqueous Natriumhy bicarbonate solution and hiert extra with methylene chloride. The extracts are dried, concentrated and purified by column chromatography (silica gel, methylene chloride / ethyl acetate / methanol 9: 1: 0.2).
Yield: 260 g (50.5% of theory),
Melting point: 150 ° C.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
0.93 (m, 1H), 1.38-1.89 (m, 6H), 2.05 (dd, 1H), 2.32 (s + m, 4H), 2.45 (s, 3H) , 2.63 (t, 2H), 3.04 (s, 2H), 3.56 (s, 2H), 3.62 (t, 2H), 5.5 (bs, 1H), 7.05 ( bs, 1H), 7.18 (dd, 4H), 7.32 (d, 2H), 7.63 (d, 2H).

Analogously to Example 3 are prepared:

• a) 3- [4- [N- (aminocarbonylmethyl) methylaminomethyl] phenoxy methyl] -1- (4-chlorobenzoyl) pyrrolidine
  from 1- (4-chlorobenzoyl-3- (4-methylaminomethyl-phenoxymethyl) pyrrolidine and chloroacetamide.
  Yield: 88.0% of theory,
  Melting point: 91-93 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.9 (m, 1H), 2.18 (m, 1H), 2.30 (s, 3H), 2.75 (m, 1H), 3.0 (s, 2H), 3.30-4 , 05 (s + m, 8H), 5.56 (bs, 1H), 6.83 (t, 2H), 7.02 (bs, 1H), 7.20 (m, 2H), 7.38 ( d, 2H), 7.49 (d, 2H).
• b) 3- [4- [N- (aminocarbonylmethyl) methylaminomethyl] phenoxy methyl] -1- (4-methylbenzenesulfonyl) pyrrolidine
  from 3- (4-methylaminomethylphenoxymethyl) -1- (4-methylbenzenesulfonyl) pyrrolidine and chloroacetamide.
  Yield: 96% of theory,
  Melting point 140-142 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.7 (m, 1H), 2.01 (m, 1H), 2.3 (s, 3H), 2.42 (s, 3H), 2.58 (m, 1H), 3.0 (s , 2H), 3.12-3.50 (m, 4H), 3.51 (s, 2H), 3.54-3.82 (m, 2H), 5.54 (bs, 1H), 6, 72 (d, 2H), 7.02 (bs, 1H), 7.17 (d, 2H), 7.29 (d, 2H), 7.72 (d, 2H).

example 4 1- (4-chlorobenzoyl) -3- [4- [2- (N-methyl-allylamino) ethyl] phenoxymethyl] pyrrolidine

0.5 g (1.3 mmol) of 1- (4-chlorobenzoyl) -3- [4- (2-chloroethyl) phenoxymethyl] pyrrolidine (prepared by Mitsunobu reaction of 1- (4-chlorobenzoyl) -3-hydroxymethyl -pyrrolidine and 4-hydroxyphenethyl chloride using diethyl azodicarbonate and triphenylphosphine (melting point: 96-98 ° C)) are dissolved in 25 ml of dimethylformamide and after addition of 106 mg (1.5 mmol) of N-methyl-allylamine, 3 g of potassium carbonate and a spatula tip of sodium iodide for 7 hours at 90 ° C stirred. Then the reaction mixture is poured into water and extracted with ethyl acetate. After drying and concentration of the extracts is säulenchromatogra phically purified (alumina, petroleum ether / ethyl acetate = 2: 1).
Yield: 160 mg (30% of theory),
Melting point: 81-85 ° C.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
1.87 (m, 1H), 2.15 (m, 1H), 2.28 (s, 3H), 2.56 (m, 2H), 2.71 (m, 3H), 3.05 (i.e. , 2H), 3.28-4.02 (m, 6H), 5.07-5.26 (m, 2H), 5.88 (2dt, 1H), 6.8 (dd, 2H), 7, 1 (m, 2H), 7.42 (2d, 4H).

Analogously to Example 4 were prepared:

• a) 1- (4-Chlorobenzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] -piperidine
  of 1- (4-chlorobenzoyl) -4- [4- (2-chloro-ethyl) phenoxymethyl] -piperidine (m.p .: 110-113 ° C) and N-methyl-allylamine.
  Yield: 13% of theory,
  Melting point: 64 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.10-2.22 (m, 5H), 2.28 (s, 3H), 2.58 (m, 2H), 2.72 (m, 2H), 2.7-3.05 (bm, 2H), 3.06, (d, 2H), 3.80 (d + m, 3H), 4.77 (bs, 1H), 5.1-5.25 (m, 2H), 5.87 ( 2dt, 1H), 6.8 (d, 2H), 7.11 (d, 2H), 7.38 (2d, 4H).
• b) 1- (4-Chlorobenzoyl) -3- [4- (2- (N-methyl-allylamino) ethylphenoxymethyl] -piperidine
  from 1- (4-chlorobenzoyl) -3- [4- (2-chloro-ethyl) phenoxymethyl] -piperidine and N-methyl-allylamine.
  Yield: 29% of theory,
  Melting point: 62-64 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.33-2.20 (m, 5H), 2.30 (s, 3H), 2.6 (m, 2H), 2.73 (m, 2H), 3.07 (d + m, 4H) , 3.83 (bs, 3H), 4.32 + 4.7 (2bs, 1H), 5.1-5.25 (m, 2H), 5.88 (2dt, 1H), 6.75 (b.p. , 2H), 7,10 (d, 2H), 7,31 (bs, 4H).

example 5 1- (4-chlorobenzoyl) -3- [4- (2-dimethylamino-ethyl) -phenoxy methyl] pyrrolidine

1.03 g (3.3 mmol) of 1- (4-chlorobenzoyl) -3-methanesulfonyloxy-methyl-pyrrolidine are dissolved in 50 ml of dimethylformamide and after addition of 1.0 g (3.3 mmol) of 4- (2-dimethylamino ethyl) phenol and 3.5 g (25 mmol) of potassium carbonate at 80 ° C for 6 hours. It is then poured into ice-water and extracted with ethyl acetate. The extracts are dried, concentrated by evaporation and the residue is purified by chromatography.
(Alumina, petroleum ether / ethyl acetate = 1: 2).
Yield: 280 mg (22% of theory),
Melting point: 90-92 ° C.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
1.75-2.25 (2m, 2H), 2.2.7 (s, 3H), 2.50 (m, 2H), 2.70 (m, 3H), 3.30-4.03 ( m, 6H), 6.8, (dd, 2H), 7.1 (m, 2H), 7.42 (dd, 4H).

Analogously to Example 5 was prepared:

• a) 1- (4-Chlorobenzoyl) -3- [4- (2-dimethylamino-ethyl) -phenoxy-methyl] -piperidine
  from 1- (4-chlorobenzoyl) -3-methanesulfonyloxymethyl-piperidine and 4- (2-dimethylamino-ethyl) -phenol.
  Yield: 29% of theory,
  Melting point 62-64 ° C.
  1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
  1.35-2.20 (3m, 5H), 2.28 (s, 6H), 2.5 (m, 2H), 2.7 (m, 2H), 3.05 (m, 2H), 3 , 83 (m, 3H), 4.35 + 4.68 (2m, 1H), 6.78 (bd, 2H), 7.1 (d, 2H), 7.31 (s, 4H).

In the following, the preparation of pharmaceutical Applic described using some examples:

example 6 Tablets containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (N-methyl-allyl aminomethyl) phenoxymethyl] piperidine composition

1 tablet contains:

Active ingredient | 5.0 mg lactose 148.0 mg potato starch 65.0 mg magnesium stearate  2.0 mg 220.0 mg

production method

Potato starch is used to produce a 10% slime by heating. The active substance, lactose and the remaining potato starch are mixed and granulated with the above mucus through a sieve of mesh size 1.5 mm. The granules are dried at 45 ° C, again by the above screen ben siege, mixed with magnesium stearate and pressed ver to tablets.
Tablet weight: 220 mg
Stamp: 9 mm

example 7 Dragèes with 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allyl amino) ethyl) phenoxymethyl] piperidine

The tablets prepared according to Example 6 are coated according to any known method with a shell which consists in wesent union of sugar and talc. The finished Dragèes are polished using beeswax.
Dragè weight: 300 mg

example 8 Suppositories containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl) allylamino) ethyl) phenoxymethyl] piperidine composition

1 suppository contains:

Active ingredient | 5.0 mg Suppository mass (eg Witepsol W 45®) 1695.0 mg 1700.0 mg

production method

The finely pulverized active substance is suspended in the molten suppository mass which has been cooled to 40.degree. Pour the mass at 37 ° C in slightly pre-cooled suppository forms.
Suppository weight: 1.7 g.

example 9 Capsules containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allyl amino) ethyl) phenoxymethyl] piperidine composition

1 capsule contains:

Active substance | 5.0 mg lactose 82.0 mg Strength 82.0 mg magnesium stearate  1.0 mg 170.0 mg

production method

The powder mixture is mixed thoroughly and on a cape Self-filling machine in size 3 hard gelatin capsule filled, with the final weight is checked continuously.

example 10 Tablets containing 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl) allylamino) ethyl) phenoxymethyl] piperidine composition

1 tablet contains:

Active ingredient | 5.0 mg lactose 148.0 mg potato starch 65.0 mg magnesium stearate  2.0 mg 220.0 mg

production method

Potato starch is used to produce a 10% slime by heating. The active substance, lactose and the remaining potato starch are mixed and granulated with the above mucus through a sieve of mesh size 1.5 mm. The granules are dried at 45 ° C, again by the above screen ben siege, mixed with magnesium stearate and pressed ver to tablets.
Tablet weight: 220 mg
Stamp: 9 mg

example 11 Cream for topical administration with 1 g of 1- (4-chloro benzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] piperidine

A formulation for the topical administration of the verbin The compounds of the formula I can have the following composition:

1. Active ingredient | 1.0 g 2. stearyl alcohol 4.0 g 3. Cetyl alcohol 4.0 g 4. mineral oil 3.0 g 5. Polysorbate 60 4.5 g 6. sorbitan stearate 4.5 g 7. Propylene glycol 10.0 g 8. Methylparaben 0.18 g 9. Propylparaben 0.02 g 10. Water, q.s. ad 100.00 g

The ingredients 2-6 are heated to 80 ° C until everything ge is melted. Thereafter, ingredient 1 is in the oily phase solved. Component 7 and 10 are heated to 90 ° C and the Ingredients 8 and 9 are in the resulting aqueous Phase solved. Thereafter, the aqueous phase is ge to the oil phase and stirred rapidly to give an emulsion. Then allowed to cool slowly to 50 ° C to the emulsion solidify. With further stirring, the preparation is on Room temperature cooled.  

The following example describes the production of a fut termittels for laying hens:

example 12

Feed for laying hens, containing as active ingredient 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] -piperidine Corn 633 g / kg soybean meal 260 g / kg meat meal 40 g / kg feed fat 25 g / kg soybean oil 17 g / kg dicalcium phosphate 12 g / kg calcium carbonate 6 g / kg Vitamin-mineral mixture 5 g / kg active substance 2 g / kg

These components in the stated amounts yield Carefully mix 1 kg of feed.

Claims (14)

1. Basically substituted acylpyrrolidines and acylpiperidines of the general formula I. in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may be substituted by one or two hydroxy groups or by an aminocarbonyl group, wherein a hydroxy group is not bonded in the 1-position and two hydroxy groups are not bonded to the same carbon atom, an alkenyl or alkynyl group having 3 to 6 carbon atoms, wherein the multiple bonds are isolated from the nitrogen-carbon bond, and
R₂ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms which may be substituted by one or two hydroxy groups or by an aminocarbonyl group, wherein a hydroxy group is not in the 1-position and two hydroxy groups are not attached to the same carbon atom, an alkenyl or alkynyl group with 3 to 6 carbon atoms, the multiple bonds being isolated from the nitrogen-carbon bond, or
R₁ and R₂ together with the intermediate nitrogen atom have a saturated monocyclic 5-, 6- or 7-membered ring,
R₃ is a straight-chain or branched alkyl, alkenyl or alkynyl group each having up to 8 carbon atoms, each by a mono-, di- or tri-substituted phenyl group optionally substituted by a halogen atom, an alkyl or trifluoromethyl group, wherein the substituents are the same or ver may optionally be substituted by a halogen atom, an alkyl or trifluoromethyl group mono-, di- or trisubstituted phenyl group, where the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a straight-chain alkylene group having 1 to 3 carbon atoms and
Z is a carbonyl or sulfonyl group,
where an abovementioned halogen atom can denote a fluorine, chlorine or bromine atom,
their enantiomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or or ganic acids. 2. Basically substituted acylpyrrolidines and acylpiperidines of the general formula Ia, in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ is a hydrogen atom, a methyl group optionally substituted by an aminocarbonyl group, or a radic or branched alkyl group having 2 to 4 carbon atoms which may be terminally substituted by a hydroxy or amino carbonyl group, or an alkenyl group having 3 to 5 carbon atoms, said Double bond is isolated from the nitrogen-carbon bond, and
R₂ is an optionally substituted by an aminocarbonyl methyl group or a straight or branched te alkyl group having 2 to 4 carbon atoms, which may be terminal substituted by a hydroxy group or by an aminocarbonyl group, or an alkenyl group having 3 to 5 carbon atoms, wherein the double bond of the stick substance-carbon bond is isolated, or
R₁ and R₂, together with the intervening nitrogen atom, form a saturated monocyclic 5-, 6- or 7-membered ring,
R₃ is a straight-chain or branched alkyl or alkenyl group having in each case up to 5 carbon atoms, each terminal of which may be substituted by an optionally mono- or disubstituted by a fluorine or chlorine atom, a methyl or trifluoromethyl phenyl group, wherein the substituents same or different or a phenyl group optionally mono- or disubstituted by a fluorine or chlorine atom, a methyl or trifluoromethyl group, where the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a methylene or ethylene group and
Z is a carbonyl or sulfonyl group,
their enantiomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or or ganic acids. 3. Basically substituted acylpyrrolidines and acylpiperidines of the general formula Ia,
in the
n the numbers 1 or 2 and
m is the number 1 or
n is the number 1 and
m is the number 2,
R₁ represents a hydrogen atom, a methyl, ethyl, propyl, allyl, 3,3-dimethylallyl, 2-hydroxyethyl, 3-hydroxypropyl or aminocarbonylmethyl group,
R₂ is a methyl, ethyl, propyl, tert-butyl, allyl, 3,3-dimethylallyl, 2-hydroxyethyl, 3-hydroxypropyl or aminocarbonylmethyl group,
R₃ is an optionally terminally substituted by a phenyl group methyl, ethyl, n-propyl, n-butyl, n-Pen tyl-, ethenyl or propenyl group or a phenyl group, wherein the above-mentioned phenyl groups in each case by a chlorine atom, a methyl or trifluoromethyl group may be mono- or disubstituted and the substituents may be the same or different,
A is an ethylene group in which the methylene group bound to the phenyl radical may be replaced by an oxygen atom, or an ethenylene group,
X is a methylene or ethylene group and
Z is a carbonyl or sulfonyl group,
their enantiomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or or ganic acids. 4. The following compounds of the general formula I
A = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) phenoxymethyl] pyrrolidine,
B = 1- (4-chloro-benzenesulfonyl) -3- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine,
C = 1- (4-chlorobenzenesulfonyl) -3- [2- (4-diethylaminomethylphenyl) ethyl] piperidine,
D = 1- (4-chlorobenzoyl) -3- [4- [2- (N-methyl-allylamino) ethyl] phenoxymethyl] pyrrolidine,
E = 1- (4-chlorobenzoyl) -4- [4- (N-methyl-allylaminomethyl) -phenoxymethyl] -piperidine,
F = 1- (4-chlorobenzoyl) -3- [4- (N-methyl-allylaminomethyl) -phenoxymethyl] -piperidine,
G = 1- (4-chlorobenzoyl) -4- [2- (4- (N-methyl-allylaminomethyl) phenyl) ethyl] piperidine,
H = 1- (4-chlorobenzoyl) -4- [4- (2- (N-methyl-allylamino) ethyl) phenoxymethyl] -piperidine,
I = 1- (4-chloro-benzenesulfonyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine,
J = 1- (4-chloro-phenylacetyl) -4- [2- (4- (N-methyl-allylamino-methyl) -phenyl) -ethyl] -piperidine
and their salts. 5. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids. 6. A pharmaceutical composition containing a compound after at least one of claims 1 to 4 or a physiologically acceptable Lich salt according to claim 5 besides optionally one or several inert carriers and / or diluents. 7. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for Inhi bition of cholesterol biosynthesis. 8. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for Be treatment or prophylaxis of hyperlipidemias. 9. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for Be Treatment of diseases with excessive cell prolifera tion.   10. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for Pro phylaxis and treatment of gallstone disease. 11. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for Be action of mycoses. 12. Use of a compound according to at least one of Claims 1 to 5 for the production of a feed for laying hens to produce cholesterol eggs. 13. A process for the preparation of a medicament according to An claim 6, characterized in that non-chemical Ways a connection according to at least one of claims 1 to 5 in one or more inert carriers and / or Diluent is incorporated. 14. A process for the preparation of the compounds according to minde least one of claims 1 to 5, characterized in that

• a) an amine of the general formula II, in the
  R₁ and R₂ are as defined in claims 1 to 4, with a compound of general formula III, in the
  n, m, R₃, A, X and Z are as defined in claims 1 to 4 defi ned
  and W₁ represents a reactive leaving group, is reacted or
• b) an amine of the general formula II, in the
  R₁ and R₂ are as defined in claims 1 to 4, with a compound of general formula IV, in the
  n, m, R₃, A, X and Z are as defined in claims 1 to 4 defi ned
  and W₂ together with a vicinal methylene group of the radical X forms a formyl group, is reductively alkylated or
• c) an amine of the general formula V, in the
  n, m, R₁, R₃, A, X and Z are as defined in claims 1 to 4, with a compound of general formula VI, R₂'-W₃ (VI) in the
  R₂ 'has the meanings mentioned in the claims 1 to 4 for R₂ or together with the radical R₁ of the For mel V is an n-alkylene group having 4 to 6 carbon atoms and W₃ represents a reactive leaving group is reacted and
  if necessary, in a compound of the formula V or VI optionally present reactive hydroxy groups are protected by a protecting group and the protective groups are split off again after the reaction, or
• d) for the preparation of compounds of general formula I in which n, m, R₂, R₃ and Z are as defined in claims 1 to 4, R₁ except the hydrogen atom and X except one in the 4-position to the phenyl radical gebun in which the methylene group has the meanings mentioned in claims 1 to 4 and A means an ethylene group in which the methylene group bound to the phenyl radical is replaced by an oxygen atom,
  a phenol of general formula VII, in the
  R₂ is as defined in claims 1 to 4, R₁ 'with the exception of the hydrogen atom, the meanings mentioned in claims 1 to 4 for R₁ and X' except for a 4-position bonded to the phenyl methylene group in the claims 1 to 4 sit for X mentioned meanings be, with a compound of general formula VIII, in the
  n, m, R₃ and Z are as defined in claims 1 to 4 and W₄ represents a hydroxy group or a reactive leaving group, is alkylated, and
  optionally present in a compound of general formula VII in the radicals R₁ 'and / or R₂ existing reactive hydroxy groups, if necessary protected by suitable Schutzgrup groups and the protective groups are split off again after the reaction and / or
  if desired, a compound of formula I thus obtained is resolved into its enantiomers or geometric isomers and / or
  a compound of the general formula I thus obtained ge, if desired, is converted into its acid addition salt.