DE4407139A1 - New amino-alkylene(oxy) substd. aryl-aza:cycloalkane derivs. - Google Patents

Abstract

Aminoalkylene- and aminoalkyleneoxy-substd. aryl-azacycloalkane derivs. (I) and their salts are new. A=1-17C alkylene; 2-17C alkenylene; 2-4C alkynylene; or a single bond; B = methylene; ethylene; or ethyleneoxy linked to the Ph ring via the O atom; X=CO or SO2; R<1>=1-5C alkyl; and R<2>=1-5C alkyl opt. mono-substd. by aminocarbonyl (opt. mono- or disubstd. by 1-3C alkyl) or CN, or opt. mono- substd. (other than in the 1-position) by 1-3C alkoxy, (1-3C alkyl)carbonyloxy or OH or disubstd. (other than in the 1-position and not on the same C atom) by OH; or NR<1>R<2>=5-7-membered satd. heterocyclic ring opt. contg. O or S in place of CH2 in the 4-position when the ring is 6- or 7-membered; R<3>,R<4>=H or 1-3C alkyl; R<5>=H; 3-6C cycloalkyl; Ph opt. mono-substd. by 1-3C alkyl or CF3 or mono- or disubstd. by F, Cl or Br; naphthyl; tetrahydronaphthyl; pyridyl; or thienyl opt. mono-substd. by F, Cl, Br or 1-3C alkyl; n=1 or 2; m=0 or 1; cpds. where A is a single bond, X=SO2 and R<5>=H are excluded.

Description

The present invention relates to aryl-1-azacycloalkanes, their salts with physiologically acceptable organic and inorganic acids, process for making this verbin and medicines containing them.

The compounds of the invention are inhibitors of Cholesterol biosynthesis, in particular inhibitors of En zyms 2,3-epoxysqualene-lanosterol cyclase, a key zyms of cholesterol biosynthesis. The Ver compounds are suitable for the treatment and prophylaxis of Hyperlipidemias, hypercholesterolemia and atherosclerosis se. Other possible applications arise for the Treatment of hyperproliferative skin and vascular diseases conditions, 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 Secondary diseases such as coronary heart disease, cerebral ischemia, intermittent claudication and gangrene represent.

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 Lipidology 2 (4), 234 [1991]). Because the biggest part of cholesterol in the organism itself synthesized and only a small part of the food is consumed the inhibition of biosynthesis is a particularly attractive route to lower the elevated cholesterol level.

In addition, as further possible applications of Cholesterol biosynthesis inhibitors the treatment hyperprolifera tive skin and vascular diseases as well as of tumor patients conditions, the treatment and prophylaxis of gallstones as the use described in mycoses. This is it in the latter case an intervention in the Ergosterolbio synthesis in fungal organisms, which are largely analogous to Cholesterol biosynthesis proceeds in mammalian cells.

Cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, over a greater number of reac tion steps. This multistage process offers a range of intervention options, of which are given as examples are:

For the inhibition of the enzyme 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) synthase becomes β-lactones and β-lactams with potential antihypercholesterolemic effect mentions (see J. Antibiotics 40, 1356 [1987], US-A-47 51 237, EP-A-04 62 667, US-A-49 83 597).

Inhibitors of the enzyme HMG-CoA reductase make 3,5-dihy Mevinoline-type droxycarboxylic acids and their 8-lactones are their representatives lovastatin, simvastatin and pravastatin in the Therapy of hypercholesterolemias use. Further potential applications of these compounds are fungal infections (US-A-43 75 475, EP-A-01 13 881, US-A-51 06 992), skin  diseases (EP-A-03 69 263) and gallstones and Tumor diseases (US-A-51 06 992; Lancet 112, 1154-1156 [1992]). The inhibition of smooth muscle cell proliferation by lovastatin is described in Car diovasc. 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-04 09 181 and J. Med. Chemistry 34, 1912 [1991], also the squalestatine with cho ester-lowering and antifungal activity (J. Antibotics 45, 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, 18 075-18 078, [1990]) and Fluorosqualene derivatives having hypocholesterolemic activity (US-A-50 11 859). Furthermore, piperidines and Azadeca line with potential hypocholesterolemic and / or anti fungal action, their mechanism of action is not described is clearly clarified and which squalene epoxidase and / or Represent 2,3-epoxysqualene-lanosterol cyclase inhibitors (EP-A-04 20 116, EP-A-04 68 434, US-A-50 84 461 and EP-A-04 68 457).

Examples of inhibitors of the enzyme 2,3-Epoxisqualen-Lano Sterol cyclase are diphenyl derivatives (EP-A-04 64 465), amino alkoxybenzene derivatives (EP-A-04 10 359) and piperidine-Deri vate (J. Org. Chem. 57, 2794-2803, [1992]), which has an anti possess fungal effect. Furthermore, this enzyme is in Mammalian cells by Decaline, Azadecaline and Indanderi (WO 89/08 450, J. Biol. Chemistry 254, 11 258-11 263  [1981], Biochem. Pharmacology 11, 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-oxidosqua len (J.Amer.Chem. Soc. 113, 9673-9674 [1991]).

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-50 41 432, J. Biol. Chemistry 266, 20 070-20 078 [1991], US-A-50 34 548). except this enzyme is made by the azole-type antimycotics which is N-substituted imidazoles and triazoles put. 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, Ubi quinone and isopentenyl t-RNA can adversely affect (see. J. Biol. Chemistry 265, 18 075-18 078 [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 of toxic Ef fect. This is for example for Triparanol, a Desmo sterol reductase inhibitor. This substance had to due to formation of cataracts, ichthyosis and alopecia of Market (cited in J. Biol. Chemistry 265, 18 075-18 078 [1990]).

As already stated at the outset are inhibitors of 2,3-epoxysqualene-lanosterol cyclase isolated in the lite described. The structures of these compounds are but completely different from the structure of the erfindungsge Compounds of the general Formula I.

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, through a better antihyperchole sterolemic effect with increased selectivity and thus Increased 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 aryl-1-azacycloalkanes of the present invention and their Salts have the general formula I. The compounds kön optionally also in the form of enantiomers, diastereomers or mixtures thereof.

In the general formula I mean
n the numbers 1 or 2,
m is the numbers 0 or 1,
A represents a single bond, a straight-chain or branched alkylene group having 1 to 17 carbon atoms, an alkenylene group having 2 to 17 carbon atoms or an alkynylene group having 2 to 4 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl ring via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
R² represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms, optionally substituted by one or two hydroxyl groups, an alkoxy or by an alkylcarbonyloxy group having 1 to 5 carbon atoms in the alkyl moiety, which alkyl moiety may be straight-chain or branched, by an alkoxycarbonyloxy group, wherein the abovementioned substituents can not be bonded in position 1 of the alkyl group and two of these radicals can not be bonded to the same carbon atom, and can be substituted by an aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or cyano group, or
R¹ and R² together with the nitrogen atom, a 5- to 7-membered, saturated heterocyclic ring, wherein in a 6- or 7-membered ring, a methylene group in the 4-position may be replaced by an oxygen or sulfur atom,
R³ and R⁴, which may be the same or different, each represent a hydrogen atom or an alkyl group,
R⁵ is a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, an optionally substituted by an alkyl group, by one or two halogen atoms or a Trifluormethylgrup pe substituted phenyl group, a naphthyl, Tetrahydronaph thyl or optionally substituted by a halogen atom or an alkyl thienyl group .
wherein A can not be a single bond when X is the sulfonyl group and R⁵ is a hydrogen atom, and
wherein, unless stated otherwise, the above-mentioned he alkyl and alkoxy moieties may each contain 1 to 3 Kohlenstoffa atoms and the above-mentioned halogen atoms Kgs each mean a fluorine, chlorine or bromine NEN Kings.

Preference is given to the compounds of the general formula I
in the
n is the number 1,
m is the number 1,
A is a single bond, a straight-chain or branched alkylene group having 1 to 17 carbon atoms or an alkenyl group having 2 to 4 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl group via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
R² is a straight-chain or branched alkyl group having 1 to 5 carbon atoms and represented by one or two hydroxy groups, an alkoxy or an alkylcarbonyloxy group having 1 to 5 carbon atoms in the alkyl moiety, which alkyl moiety may be straight or branched, through an alkoxycarbonyloxy group the abovementioned substituents can not be bonded to position 1 of the alkyl group and two of the water residues can not be bonded to the same carbon atom, substituted by an aminocarbonyl or cyano group, or
R¹ and R² together with the nitrogen atom represent a pyrrolidino, piperidino, morpholino or thiomorpholino group,
R³ is a hydrogen atom or an alkyl group,
R⁴ is a hydrogen atom,
R⁵ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group optionally substituted by a 1 or 2 halogen atoms or a trifluoromethyl group,
wherein A can not be a single bond when X is the sulfonyl group and R⁵ is a hydrogen atom, and
wherein, unless otherwise stated, the abovementioned alkyl and alkoxy moieties each may contain from 1 to 3 carbon atoms and the aforementioned halogen atoms may each represent a fluorine, chlorine or bromine atom, their enantiomers, diastereomers and their salts ,

Particularly preferred are the compounds of the general For mel I, in the
n is the number 1,
m is the number 1,
A is a single bond, a straight-chain or branched alkylene group having 1 to 5 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl group via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ is the methyl or ethyl group,
R 2 is a straight-chain or branched alkyl group having 1 to 3 carbon atoms which may be substituted by a hydroxyl group or an aminocarbonyl group, where the hydroxy group may not be bonded to position 1 of the alkyl group,
R³ and R⁴ each represent a hydrogen atom,
R⁵ represents a hydrogen atom or a phenyl group optionally substituted in the 4-position by a chlorine atom or a trifluoromethyl group,
where A can not be a single bond, if X is the sulfonyl group and R⁵ is a hydrogen atom, and their salts,
but especially the compounds

(1) = 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) piperidine,
(2) = 1- (4-chlorobenzoyl) -4- [4- (3-hydroxypropyl) methylamino methylphenyl] piperidine,
(3) = 4- (4-aminocarbonylmethyl-methylaminomethylphenyl) -1- (4-chlorobenzoyl) piperidine,
(4) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((2-hydroxyethyl)) methylaminoethyl) phenyl] piperidine,
(5) = 4- [4- (2-aminocarbonylmethyl-methylaminoethyl) phenyl] -1- (4-chlorobenzoyl) piperidine,
(6) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((3-hydroxypropyl)) methylaminoethyl) phenyl] piperidine,
(7) = 1- (4-chlorobenzoyl) -4- [4- (2-diethylaminoethoxy) phenyl] piperidine,
(8) = 1- (4-chlorobenzoyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine,
(9) = 1- (4-chlorobenzenesulfonyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine

and their salts.

production methods

The compounds of general formula I can be after create the following methods:

• a) Compounds of the general formula I in which R¹ and R², which may be identical or different, each represent a straight-chain or branched alkyl group having 1 to 5 carbon atoms or together with the nitrogen atom is a 5- to 7-membered ring, wherein in a 6- or 7-membered ring, a methylene group in the 4-position may be replaced by an oxygen or sulfur atom,
  B is an ethylene or ethyleneoxy group, the latter being bonded via the oxygen atom to the phenyl ring, means:
  By reacting compounds of general formula II, in the
  R¹ and R², which may be the same or different, each represent a straight-chain or branched alkyl group having 1 to 5 carbon atoms or, together with the nitrogen atom, a 5- to 7-membered ring in which, in the case of a 6- or 7-membered ring a methylene group in the 4-position may be replaced by an oxygen or sulfur atom,
  B is an ethylene or ethyleneoxy group, the latter being bonded to the phenyl ring via the oxygen atom, and
  n, m, R³ and R⁴ are defined as mentioned above,
  with a compound of general formula IIIR⁵-AX-Z¹ (III) in the
  A, X and R⁵ have the meanings mentioned above and
  Z¹ is a reactive leaving group such as. As a halogen atom, preferably a chlorine atom, or imidazolide group means.
  When Z¹ is a halogen atom, the reactions are carried out in a suitable inert solvent such as diethyl ether, toluene, methylene chloride and the like, preferably at temperatures between -50 ° C and 50 ° C and in the presence of a halogen-hydrogen bonding agent, e.g. As a tertiary amine, sodium carbonate or calcium carbonate performed. Not only the free amines of the general formula II can be set, but also their salts, from which in situ the amines by suitable bases, for. As tertiary organic amines can be released.
  If Z¹ represents the imidazolide radical, the reactions are preferably carried out in an inert solvent such as xylene or Te trahydrofuran at temperatures between room temperature and the boiling point of the reaction mixture.
• b) Compounds of the general formula I, in which B denotes the methylene or ethylene group:
  By reacting a compound of general formula IV, in the
  n, m, A, X and R³ to R⁵ are defined as mentioned above,
  B represents the methylene or ethylene group and
  Z 2 represents a reactive leaving group such as a halogen atom, for example a chlorine or bromine atom, or a sulphonyloxy group,
  with an amine of the general formula V in the
  R¹ and R² are defined as mentioned above.
  The reaction is conveniently carried out in a suitable solvent such as ethanol, tert-butanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide or in a mixture of the abovementioned solvents, optionally in the presence of a base such as potassium carbonate, sodium carbonate or a difficult-to-alkylate tertiary amine, such as B. N-ethyldiisoproylamine, at temperatures between 0 ° C and 100 ° C, but preferably at a temperature between 0 and 40 ° C, carried out.
• c) Compounds of the general formula I, in which B denotes the ethyleneoxy group:
  By reacting compounds of general formula VI, in the
  n, m, A, X and R³ to R⁵ are as defined above,
  with an alkylating agent of general formula VII, in the
  R¹ and R² are as defined above and
  Z 2 represents a reactive leaving group such as a halogen atom, for example a chlorine or bromine atom, or a sulphonyloxy group.
  The reaction is conveniently carried out in a suitable solvent such as ethanol, tert-butanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide or in a mixture of the abovementioned solvents, optionally in the presence of a base such as potassium carbonate, sodium carbonate or a difficult-to-alkylate tertiary amine, such as B. N-ethyldiisoproylamine, at temperatures between 0 ° C and 100 ° C, but preferably at a temperature between 0 and 40 ° C, carried out.

The compounds prepared by the above methods gene of the general formula I can be according to known Me methods, eg As crystallization, distillation or chromato clean and insulate graph.

Furthermore, the obtained compounds of the general if desired, into its acid addition salts, especially 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, sw hydrochloric acid, phosphoric acid, fumaric acid, succinic acid, milk acid, citric acid, tartaric acid or maleic acid into consideration.  

Starting materials:

The starting compounds of general formula II can be represent, by first a connection of the general Formula VIII,

in which B and R¹ to R³ are defined as mentioned above,
is converted into the corresponding organolithium compound, this then with a compound of formula IX,

in which n, m and R⁴ are defined as mentioned above,
is converted to a corresponding compound of formula X.

By dehydration and subsequent treatment with water In the presence of noble metal catalysts Ver obtained compounds of formula II.  

Compounds of the formula IV in which B is the methylene group and Z² represents a chlorine atom can be obtained by first a compound of formula XI,

in the
n, m, R³ and R⁴ are defined as mentioned above,
by reaction with a compound of formula V in which R⁵, A, X and Z¹ are as defined above, in a corre sponding compound of formula XII

is transferred and this of the chloromethylation under to throw.

Compounds of formula IV in which B is the ethylene group and Z² represents a sulfonyloxy group can be obtained by first a compound of formula XIII

converted into the corresponding organolithium compound and this with a compound of the above defined  Formula IX is converted to the corresponding compound of Formula XIV,

these subsequently by dehydration and hydrogenolyti removal of the benzyl radical with simultaneous hydrie tion of the double bond formed in the corresponding verbin of formula XV,

is transferred, which in turn with a compound of standing defined formula III N-acylated and finally by treating with a sulfonyl halide in the compound the formula IV is converted.

The starting compounds of the formula VI are obtained on analogous Way by reacting a compound of formula XVI,

in the
R³ is defined as mentioned above,
with a compound of the formula IX defined above, followed by dehydration, catalytic hydrogenation and N-acylation with a compound of the formula III as defined above.

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 Monothe or used in combination with other cho lesterol- or lipid-lowering substances for use ge long, the compounds preferably as oral Formu lierungs, possibly also in the form of suppositories as 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 Inhi The synthesis of cholesterol biosynthesis is exemplified by the glat muscle cells with the HMG-CoA reductase inhibitor of Me vinoline type lovastatin, as mentioned at the beginning.

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 112, 1154-1156 [1992]). The compounds of the invention Formula I are therefore due to their cholesterol biosynthesis inhibitory effect potentially for the treatment of Suitable for tumor diseases. You can do it alone or to support known therapeutic principles use Find.

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 net a hyperproliferative-inflammatory skin disease, the  changed the regulatory mechanism of the skin. In particular Lesions are formed, the primary and secondary changes proliferation in the epidermis, inflammatory re actions of the skin and the expression of regulatory moles such as lymphokines and inflammatory factors. Pso riyan skin is morphologically enhanced by a um Epidermal cells, thickened epidermis, abnormal Ke Ratinization of inflammatory cell infiltrates into the dermis layer and polymorphonuclear leukocyte infiltration into the Epidermis, which causes an increase in the basal cell cycle, ge features. In addition, hyperkeratotic and parake ratotic cells present. The term "keratosis", "Ba saline carcinomas, squamous cell carcinomas and keratini sierungsstörungen "refers to hyperproliferative skin diseases, where the regulatory mechanism for the Proliferation and differentiation of skin cells interrupted is.

The compounds of formula I are effective as antagonists skin hyperproliferation, d. H. as a means that the hyper proliferation of human keratinocytes. The verbin As a result, treatments are hyper-medications 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 HMV CoA reductase inhibitors of the mevinolin type, such as Lovasta  tin, suppress. Due to their inhibitory effect on cholesterol biosynthesis are also the compounds of general formula I suitable for treatment and prophylaxis lax of these diseases, either alone or in Combination with known agents, such. B. intravenously applied 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 the fact that the cholesterol concentration in bile the maximum solubility of cholesterol in the Bile exceeds, causing it to precipitate of cholesterol in the form of gallstones. lipid-lowering agents from the class of fibrates lead to increased excretion Neutral Steroids via the bile and increase the Nei for gallstone formation.

In contrast, cholesterol biosynthesis inhibitors such as Lovastatin or pravastatin did not increase gallstones on the contrary, a reduction of Cho lesterol concentration in the bile effect and thus the so called lithogenic index, a measure of the probability reduce gallstone formation. This is described ben in Gut 31, 348-350 [1990] and in Z. Gastroenterol. 29 242-245 [1991]

In addition, in Gastroenterology 102, No. 4, Pt. 2, A 319 [1992] the efficacy of lovastatin in the dissolution of gallstones, in particular in combination with Ur Sodeoxycholic acid described. Because of their mode of action Therefore, the compounds of general formula I are also for the prophylaxis and treatment of gallstone disease Meaning. You can do it either alone or in Kombina tion with known therapies such as the treatment with ursodeoxycholic acid or shock wave lithotripsy  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 on more complete. As already mentioned, the end product of Sterol biosynthesis in the fungal organism not cholesterol, son this is important for the integrity and function of the fungus cell membrane essential ergosterol. The inhibition of ergosterol biosynthesis therefore leads to growth disorders and give if necessary to kill 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 biosynthesis, such as the squalene Epoxidase inhibitors terbinafine and naftifine or the Lanoste azol-type rol-14α-demethylase inhibitors such as, for example, wise 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 Interest, because the cholesterol load of the body through Eggs with reduced cholesterol content without a change the nutritional habits can be reduced. by virtue of their inhibitory effect on cholesterol biosynthesis the compounds of general formula I can also be found in the Poultry 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 dosed after 3 days pork for 16 hours in cholesterol-free medium. The substances to be tested (dissolved in dimethyl sulfoxide, End concentration 0.1%) during this stimulation phase added. Subsequently, after addition of 200 .mu.mol / l 2-¹⁴C-acetate for another two hours at 37 ° C in the brood cabinet further incubated.

After detachment of the cells and saponification of the sterol esters after extraction sterols with digitonin for precipitation introduced. The ¹⁴C-Ace incorporated into digitonable sterols tat is determined by scintillation measurement.

The investigation of the inhibitory effect was carried out at test concentrations of 10 ^-7 mol / l and 10 ^-8 mol / l. By way of example, the test results of the following compounds (1) to (9) of the general formula I are stated at these test concentrations:

(1) = 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) piperidine,
(2) = 1- (4-chlorobenzoyl) -4- [4- (3-hydroxypropyl) methylamino methylphenyl] piperidine,
(3) = 4- (4-aminocarbonylmethyl-methylaminomethylphenyl) -1- (4-chlorobenzoyl) piperidine,
(4) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((2-hydroxyethyl)) methylaminoethyl) phenyl] piperidine,
(5) = 4- [4- (2-aminocarbonylmethyl-methylaminoethyl) phenyl] -1- (4-chlorobenzoyl) piperidine,
(6) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((3-hydroxypropyl)) methylaminoethyl) phenyl] piperidine,
(7) = 1- (4-chlorobenzoyl) -4- [4- (2-diethylaminoethoxy) phenyl] piperidine,
(8) = 1- (4-chlorobenzoyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine,
(9) = 1- (4-chlorobenzenesulfonyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine.

The percentages by which the above compounds are ¹⁴C-Ace inhibit tat incorporation are given in the following table:

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 04 68 457 A1. 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. The inhibition values of 41% and 13% found in this case show that these compounds are clearly inferior to the compounds of general formula I according to the invention.

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

The inhibition of the enzyme 2,3-epoxysqualene-lanosterol-Cyc lase causes an increase in the 2,3-epoxyqualene levels in Liver and plasma. The amount of 2,3-epoxysqualene formed 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) will be the Test Subd suspended in 1.5% aqueous methylcellulose applied via gavage. 5 hours after application Blood is recovered retro orbitally from the venous plexus. Plasma is prepared by the method of Bligh and Dyer (Canad. Biochem. Physiol. 37, 912, [1959]), on a Pre column cleaned and then analyzed by HPLC. The obtained peaks are identified by calibration substances and quantified. An internal standard is used for checking testing the reproducibility of the results.

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 for the abovementioned sub (1), (2) and (5) to (9).  

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.

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 1200 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 to illustrate the invention. The R _f values given were determined on ready-made panels from E. Merck, Darmstadt, namely:

• a) alumina F-254 (type E)
• b) Silica gel 60 F-254.

Examples for the preparation of the starting compounds Example A 4- (4-hydroxyphenyl) piperidine

21.4 g of 4-benzyloxy-bromobenzene (prepared from benzyl bromide and 4-bromophenol in the presence of aqueous ethanolic Na Tronlauge, melting point: 62-64 ° C) in 200 ml Tetrahy Dissolved drofuran and at -75 ° C to -65 ° C 51 ml to a 1.6 M Added solution of n-butyllithium in hexane. After 30 minutes stirring at -75 ° C, 15.4 g of 1-benzyl-4-piperidone in 50 ml of tetrahydrofuran was added dropwise. After heating to room temp stirring is continued for 4 hours, stirred into water and washed with Extracted ethyl acetate. The organic phase is with Washed water and brine, dried and evaporated. The residue is converted from diisopropyl ether crystallized. 16.8 g of N-benzyl-4- (4-benzyloxy phenyl) -4-hydroxypiperidine of melting point 103-105 ° C.

This product is combined with 8.6 g of p-toluenesulfonic acid in 200 ml of toluene for 3 hours on a water to reflux it hitzt. After cooling, it is diluted with ethyl acetate, with saturated sodium carbonate solution until the alkaline reaction ver sets and separates the organic phase. After washing with Water and saturated saline are dried and poured steamed. The residue (15.3 g) is dissolved in 300 ml of acetic acid ethyl ester / methanol (1: 1, v: v) and suspended in the presence of 2.5 g of 10% palladium carbon hydrogenated (50 ° C, 5 bar, 3.5 hours the). Then the catalyst is sucked off, evaporated and the  The residue was boiled with ethyl acetate, filtered off with suction and washed with ethyl acetate and ether. This gives 7.4 g colorless crystals of melting point 224-226 ° C.

In an analogous manner was obtained:

• a) 4- [4- (2-hydroxyethyl) phenyl] piperidine
  from 4- (2-benzyloxyethyl) bromobenzene and 1-benzyl-4-piperidone.
  Colorless resin.
  R _f value: 0.19 (silica gel, toluene / ethanol / concentrated ammonia = 15: 15: 0.4, v: v: v)
• b) 4- [4- (2-dimethylaminoethyl) phenyl] piperidine.
  from 4- (2-dimethylaminoethyl) bromobenzene and 1-benzyl-4-piperidone.
  Colorless resin.
  R _f value: 0.26 (alumina, ethyl acetate / methanol = 1: 1, v: v)

Example B 1- (4-chlorobenzoyl) -4- (4-hydroxyphenyl) piperidine

531 mg of 4- (4-hydroxyphenyl) piperidine and 1.1 ml of ethyldiisopro pylamine are dissolved in 15 ml of dimethylformamide and it will be while cooling with ice, 525 mg of 4-chlorobenzoyl chloride were added dropwise. To Stirring overnight is poured onto water and treated with acetic acid extracted ethyl ester. The organic phase is mixed with water and saturated brine, and evaporated. The Residue is boiled with ethyl acetate and after sucked off the cooling. 520 mg (54.9% of theory) are obtained. the title link.  

In an analogous manner were obtained:

• a) 1- (4-Chlorobenzoyl) -4- [4- (2-hydroxyethyl) phenyl] piperidine
  from 4- [4- (2-hydroxyethyl) phenyl] piperidine and 4-chlorobenzoyl chloride.
  Melting point: 97-98 ° C.
• b) 1- (4-chlorobenzoyl) -4-phenylpiperidine
  from 4-phenylpiperidine and 4-chlorobenzoyl chloride.
  Colorless crystals.

Example C 1- (4-chlorobenzoyl) -4- (4-chloromethylphenyl) piperidine

In a suspension of 18 g of 1- (4-chlorobenzoyl) -4-phenylpiperi din, 14 g paraformaldehyde and 14 g zinc chloride in 700 ml Me Methylene chloride is allowed at room temperature for 30 minutes Hydrogen chloride introduced. The clear solution will be overnight stirred, stirred into 800 ml of ice water, the methylene chloride separated phase and the water phase with 200 ml of methylene chloride rid extracted. The combined organic phases are with Dried magnesium sulfate and evaporated. The remaining one Oil is purified by column chromatography (silica gel, Pe trolether / isopropanol = 15: 1 to 4: 1, v: v) and from Diisopro pyl ether / petroleum ether crystallized. This gives 12 g of colorless Crystals of melting point 94 ° C.

Example D 1- (4-chlorobenzoyl-4- [4- (2-methylsulphonyloxyethyl) phenyl] piperidine

653 mg of 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethyl) phenyl] piperi din in 10 ml of methylene chloride with ice cooling with  Added 294 mg of methanesulfonyl chloride. After dropping from 385 mg of triethylamine is stirred for one hour. It is with Diluted with methylene chloride, washed with ice water, the organi dried phase with magnesium sulfate and evaporated. The yellow resin obtained is further reacted without further purification puts.

Examples of the preparation of the end products example 1 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethyl) phenyl) piperidine

2 g (5.7 mmol) of 1- (4-chlorobenzoyl) -4- (4-chloromethylphenyl) piperidine in 10 ml of ethanol are mixed with 5 ml of a 40% added aqueous dimethylamine and at four hours Stirred 50 ° C. The reaction solution is poured into 100 ml of water stirred, extracted twice with ethyl acetate, the organic extracts washed with saturated brine, dried over sodium sulfate and concentrated. After säulenchro matographic cleaning (alumina, petroleum ether / vinegar acid ethyl ester = 1: 1, v: v) gives 1.6 g (79% of theory Colorless crystals of melting point 91 ° C. ¹H-NMR spectrum (200 MHz, CDCl₃), signals at ppm: 1.6-2.0 (m, 4H); 2.2 (s, 6H); 2.7-3.1 (m, 3H); 3,4 (s, 2H); 3.85 and 4.85 (2m, 2H); 7.1-7.3 (m4, H); 7.4 (s, 4H).

In an analogous manner were obtained:

• a) 1- (4-Chlorobenzoyl) -4- [4- (3-hydroxypropyl) methylaminomethylphenyl] piperidine
  from 1- (4-chlorobenzoyl) -4- (4-chloromethylphenyl) piperidine and N-methylpropanolamine.
  Colorless oil.
  R _f value: 0.5 (alumina, ethyl acetate)
• b) 4- (4-aminocarbonylmethyl-methylaminomethylphenyl) -1- (4-chlorobenzoyl) piperidine
  from 1- (4-chlorobenzoyl) -4- (4-chloromethylphenyl) piperidine and sarcosine amide.
  Melting point: 107 ° C.
• c) 1- (4-Chlorobenzoyl) -4- [4- (2 - ((2-hydroxyethyl)) methylaminoethyl) phenyl] piperidine.
  from 1- (4-chlorobenzoyl) -4- [4- (2-methylsulfonyloxyethyl) phenyl] piperidine and N-methylethanolamine.
  Colorless resin.
  R _f value: 0.14 (silica gel, ethyl acetate / methanol = 3: 1, v: v).
• d) 4- [4- (2-aminocarbonylmethyl-methylaminoethyl) phenyl] -1- (4-chlorobenzoyl) piperidine
  from 1- (4-chlorobenzoyl) -4- [4- (2-methylsulfonyloxyethyl) phenyl] piperidine and sarcosinamide.
  Melting point: 122-124 ° C.
• e) 1- (4-Chlorobenzoyl) -4- [4- (2 - ((3-hydroxypropyl)) methylaminoethyl) phenyl] piperidine.
  of 1- (4-chlorobenzoyl) -4- [4- (2-methylsulfonyloxyethyl) phenyl] piperidine and N-methyl-3-aminopropan-1-ol.
  Colorless resin.
  R _f value: 0.15 (silica gel, ethyl acetate / methanol = 1: 1, v: v).

Example 2 1- (4-Chorbenzoyl) -4- [4- (2-diethylaminoethoxy) phenyl] piperidine

520 mg (1.65 mmol) of 1- (4-chlorobenzoyl) -4- (4-hydroxyphenyl) pyridine, 312 mg (2.66 mmol) of diethylaminoethyl chloride hydrochloride and 456 mg (3.3 mmol) of potassium carbonate are dissolved in 5 ml of dimethylformamide stirred at room temperature overnight. At closing the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water and saturated brine, dried and evaporated. After purification by column chromatography (alumina, petroleum ether / ethyl acetate = 5: 1, v: v), 340 mg (70.8% of theory) of colorless crystals of melting point 53-55 ° C.
1 H-NMR spectrum (200 MHz, DMSO-d₆), signals at ppm:
0.95 (t, 6H); 1.4-1.7 (m, 4H); 2.5 (q, 4H); 2.7 (t, 3H); 2.8-3.1 (m, 2H); 3.6 and 4.6 (2m, 2H); 3.95 (t, 2H); 6.8 (d, 2H); 7.15 (d, 2H); 7.5 (q, 4H).

Example 3 1- (4-chlorobenzoyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine

1.51 g (6.5 mmol) of 4- [4- (2-dimethylaminoethyl) phenyl] piperidine and 1.32 g (13 mmol) of triethylamine in 100 ml of ether are added Ice cooling with 1.25 g (7.15 mmol) of 4-chlorobenzoyl chloride ver and stir at room temperature for one hour. To Dilute with ether to 20% sodium carbonate solution is added Etherphase separated and the water phase with acetic acid extracted ethyl ester. The combined organic phases are dried over magnesium sulfate and evaporated. To Purification by column chromatography (silica gel, acetic acid ethyl ester / methanol = 3: 2, v: v) gives 2.4 g (99.5% of Theory) crystals of melting point 68-71 ° C.

In an analogous manner were obtained:

• a) 1- (4-Chlorobenzenesulfonyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine
  from 4- [4- (2-dimethylaminoethyl) phenyl] piperidine and 4-chlorobenzenesulfochloride.
  Melting point: 117-120 ° C.

The following is the preparation of pharmaceutical application described using a few examples:

Example I Tablets containing 5 mg of 1- (4-chlorobenzoyl) -4- (4-dimethylamino) methylphenyl) 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 becomes a 10% mucus by heating manufactured. The active substance, lactose and the rest Potato starch is mixed with the above mucus through Granulated a sieve of mesh size 1.5 mm. The granules is dried at 45 ° C, again by the above sieve ben, mixed with magnesium stearate and pressed into tablets.

Tablet weight: 220 mg
Stamp: 9 mm.

Example II Dragees with 5 mg of 1- (4-chlorobenzoyl) -4- (4-dimethylamino methylphenyl) piperidine

The tablets prepared according to Example I are after be Known method coated with a shell, which in essence consists of sugar and talc. The finished dragees are polished using beeswax.

Dragee weight: 300 mg.

Example III Suppositories containing 5 mg of 1- (4-chlorobenzoyl) -4- (4-dimethylamino) methylphenyl) 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 powdered active substance is melted in the and suspended at 40 ° C suppository mass suspended. You pour the mass at 37 ° C in slightly pre-cooled suppository forms.

Suppository weight: 1.7 g.  

Example IV Capsules with 5 mg of 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethyl phenyl) 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 V Cream for topical administration with 1 g of 1- (4-chloro benzoyl) -4- (4-dimethylaminomethylphenyl) 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 feed by means of laying hens:

Example VI Feed for laying hens, containing as active ingredient 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) 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 specified amounts give after sorg Mix thoroughly 1 kg of feed.

Claims (10)

1. Aryl-1-azacycloalkanes of the general formula I, in the
n the numbers 1 or 2,
m is the numbers 0 or 1,
A represents a single bond, a straight-chain or branched alkylene group having 1 to 17 carbon atoms, an alkenylene group having 2 to 17 carbon atoms or an alkynylene group having 2 to 4 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl ring via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
R² is a straight-chain or branched alkyl group having 1 to 5 carbon atoms optionally substituted by one or two hydroxy groups, an alkoxy or an alkylcarbonyloxy group having 1 to 5 carbon atoms in the alkyl moiety, wherein the alkyl moiety may be straight-chain or branched, by an alkoxycarbonyloxy group wherein the abovementioned substituents can not be bonded in position 1 of the alkyl group and two of these radicals can not be bonded to the same carbon atom, and can be substituted by an aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or cyano group, or
R¹ and R² together with the nitrogen atom, a 5- to 7-membered, saturated heterocyclic ring, wherein in a 6- or 7-membered ring, a methylene group in the 4-position may be replaced by an oxygen or sulfur atom,
R³ and R⁴, which may be the same or different, each represent a hydrogen atom or an alkyl group,
R⁵ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by an alkyl group, one or two halogen atoms or a trifluoromethyl group, a naphthyl or tetrahydronaphthyl group or a thienyl group optionally substituted by a halo atom or an alkyl group interpret,
wherein A can not be a single bond when X is the sulfonyl group and R⁵ is a hydrogen atom, and
Unless otherwise stated, the abovementioned alkyl and alkoxy moieties may each contain from 1 to 3 carbon atoms and the abovementioned halogen atoms may each be a fluorine, chlorine or bromine atom,
their enantiomers, diastereomers and their salts. 2. aryl-1-azacycloalkane of the general formula I according to claim 1,
in the
n is the number 1,
m is the number 1,
A is a single bond, a straight-chain or branched alkylene group having 1 to 17 carbon atoms or an alkenyl group having 2 to 4 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl group via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms
R² is a straight-chain or branched alkyl group having 1 to 5 carbon atoms which is represented by one or two hydroxy groups, an alkoxy or an alkylcarbonyloxy group having 1 to 5 carbon atoms in the alkyl moiety, which alkyl moiety may be straight or branched, through an alkoxycarbonyl oxy group the abovementioned substituents can not be bonded to position 1 of the alkyl group and two of these radicals can not be bonded to the same carbon atom, and can be substituted by an aminocarbonyl or cyano group, or
R¹ and R² together with the nitrogen atom represent a pyrrolidino, piperidino, morpholino or thiomorpholino group,
R³ is a hydrogen atom or an alkyl group,
R⁴ is a hydrogen atom,
R⁵ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group optionally substituted by a 1 or 2 halogen atoms or a trifluoromethyl group,
wherein A can not be a single bond when x is the sulfonyl group and R⁵ is a hydrogen atom, and
Unless otherwise stated, the abovementioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms and the abovementioned halogen atoms may each denote a fluorine, chlorine or bromine atom,
their enantiomers, diastereomers and their salts. 3. aryl-1-azacycloalkane of the general formula I according to claim 1,
in the
n is the number 1,
m is the number 1,
A is a single bond, a straight-chain or branched alkylene group having 1 to 5 carbon atoms,
B is a methylene, ethylene or ethyleneoxy group, the latter being bonded to the phenyl group via the oxygen atom,
X is a carbonyl or sulfonyl group,
R¹ is the methyl or ethyl group,
R 2 is a straight-chain or branched alkyl group having 1 to 3 carbon atoms which may be substituted by a hydroxyl group or an aminocarbonyl group, where the hydroxy group may not be bonded to position 1 of the alkyl group,
R³ and R⁴ each represent a hydrogen atom,
R⁵ represents a hydrogen atom or a phenyl group optionally substituted in the 4-position by a chlorine atom or a trifluoromethyl group,
where A can not be a single bond, if X is the sulfonyl group and R⁵ is a hydrogen atom,
and their salts. 4. The following compounds of general formula I according to claim 1: (1) = 1- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) piperidine,
(2) = 1- (4-chlorobenzoyl) -4- [4- (3-hydroxypropyl) methylamino methylphenyl] piperidine,
(3) = 4- (4-aminocarbonylmethyl-methylaminomethylphenyl) -1- (4-chlorobenzoyl) piperidine,
(4) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((2-hydroxyethyl)) methylaminoethyl) phenyl] piperidine,
(5) = 4- [4- (2-aminocarbonylmethyl-methylaminoethyl) phenyl] -1- (4-chlorobenzoyl) piperidine,
(6) = 1- (4-chlorobenzoyl) -4- [4- (2 - ((3-hydroxypropyl)) methylaminoethyl) phenyl] piperidine,
(7) = 1- (4-chlorobenzoyl) -4- [4- (2-diethylaminoethoxy) phenyl] piperidine,
(8) = 1- (4-chlorobenzoyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine,
(9) = 1- (4-chlorobenzenesulfonyl) -4- [4- (2-dimethylaminoethyl) phenyl] piperidine and salts thereof. 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 In hibition of cholesterol biosynthesis, treatment or Prophylaxis of hyperlipidemia, for the treatment of Erkran related to excessive cell proliferation stand for the prophylaxis and treatment of gallstone disease or for the treatment of mycoses. 8. 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. 9. 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. 10. A process for the preparation of the compounds according to minde least one of claims 1 to 5, characterized in that

• a) for the preparation of compounds of the general formula I in which
  R¹ and R², which may be the same or different, each represent a straight-chain or branched alkyl group having 1 to 5 carbon atoms or, together with the nitrogen atom, a 5- to 7-membered ring, wherein in the case of a 6- or 7-membered ring Methylene group in the 4-position can be replaced by an oxygen or sulfur atom, represent and
  B is an ethylene or ethyleneoxy group, the latter being bonded to the phenyl ring via the oxygen atom,
  a compound of general formula II, in the
  R¹ and R², which may be the same or different, each represent a straight-chain or branched alkyl group having 1 to 5 carbon atoms or, together with the nitrogen atom, a 5- to 7-membered ring, wherein in the case of a 6- or 7-membered ring Methylene group in the 4-position may be replaced by an oxygen or sulfur atom,
  B is an ethylene or ethyleneoxy group, the latter being bonded to the phenyl ring via the oxygen atom, and
  n, m, R³ and R⁴ as defined in claims 1 to 4 are defi ned,
  with a compound of general formula III, R⁵-AX-Z¹ (III) in the
  A, X and R⁵ are defined as mentioned in claims 1 to 4 and
  Z¹ represents a reactive leaving group, is reacted or
• b) for the preparation of compounds of the general formula I, in which B denotes the methylene or ethylene group,
  a compound of general formula IV, in the
  n, m, A, X and R³ to R⁵ are defined as mentioned in claims 1 to 4,
  B represents the methylene or ethylene group and
  Z 2 represents a reactive leaving group,
  with an amine of the general formula V in the
  R¹ and R² are defined as defined in claims 1 to 4, or is reacted
• c) for the preparation of compounds of the general formula I in which B denotes the ethyleneoxy group,
  a compound of general formula VI, in the
  n, m, A, X and R³ to R⁵ are defined as mentioned in claims 1 to 4,
  with an alkylating agent of general formula VII, in the
  R¹ and R² are defined as defined in claims 1 to 4 are reacted, and
  if desired, a compound of general formula I thus obtained is converted into its salt with an inorganic or organic acid.