DE4421582A1 - New 4-(4-aminoalkylphenyl)cyclohexyl phenyl ketone derivs. - Google Patents

Abstract

4-(4-Aminoalkylphenyl)cyclohexyl phenyl ketone derivs. of formula (I) and their isomers and salts are new. X = H and Y+Z = O, or X+Y = a bond and Z = 1-6C alkoxy; m = 1-4; R1, R2 = 1-5C alkyl opt. substd. by OH, CONH2 or mono- or di(1-3C alkyl)carbamoyl (but not alpha-substd. by OH), or 3-5C non-alpha alkenyl or alkynyl; R3, R4 = H, F, Cl, Br or CF3.

Description

The present invention relates to basic substituted Phe nylcyclohexylketones and their enol ethers, their salts with phy biologically compatible organic and inorganic acids, Process for the preparation of these compounds, this verbin containing medicinal products and their use.

The compounds of the invention are inhibitors of Cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase, a key enzyme of the Cholesterol biosynthesis. The compounds of the invention are suitable for the treatment and prophylaxis of hyperlipidemia, Hy percholesterolemias and atherosclerosis. Other possible Areas of application arise for the treatment of hyperpro liferative skin and vascular diseases, tumors, gallstones suffer as well as from mycoses.

Compounds that interfere with cholesterol biosynthesis are used to treat a number of conditions Meaning. Here are especially hypercholesterolemias and hyper to name lipidemias, the risk factors for the emergence atherosclerotic vascular changes and their sequelae diseases such as coronary heart disease, cerebral Ischemia, intermittent claudication and gangrene.

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 humiliation  of serum cholesterol the risk of coronary heart disease to fall ill, can be reduced (Current Opinion in bi pidology 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 Cho lower lesterol levels.

In addition, as further possible applications of Cholesterol biosynthesis inhibitors the treatment hyperprolifera tive skin and vascular diseases as well as tumors, the treatment and prophylaxis of gallstone disease and the Use in mycoses described. These are in the In the last case an intervention in the Ergosterolbiosynthese in Fungal organisms, which are largely analogous to the Cholesterolbio synthesis in mammalian cells.

Cholesterol or ergosterol biosynthesis proceeds going from acetic acid, over a larger number of reaction reached. This multi-stage process offers a number of inputs possibilities of access, of which are given as examples:

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 No. 4,751,237, EP-A-0 462 667, US-A-4,983,597)
Inhibitors of the enzyme HMG-CoA reductase represent 3,5-dihydroxy carboxylic acids of the mevinolin type and their δ-lactones, their representatives lovastatin, simvastatin and pravastatin in the Thera pie of hypercholesterolemias use.

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) and Gal  pelvic and tumor diseases (US-A-5,106,992; Lancet 339, 1154-1156 [1992]). The inhibition of proliferation smoother Lovastatin muscle is described in Cardiovasc. 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 of hypercholesterolemia, gallstone disease and tumor is described in EP-A-0 409 181 and J. Med. Chemi stry 34, 1912 [1991], and the squalestatine with cholesterol lowering and antifungal activity (J. Antibiotics 45, 639-647 [1992] and J. Biol. Chemistry 267, 11705-11708 [1992].

As inhibitors of the enzyme squalene epoxidase are known Al lylamines such as naftifine and terbinafine, which are used as an antidote Fungal infections have found input into therapy, as well the allylamine NB-598 with antihypercholesterolemic action (J. Biol. Chemistry 265, 18075-18078, [1990]) and fluorosqua len derivatives with hypocholesterolemic action (US-A-5,011,859). Furthermore, piperidines and azadecalines with potential hypocholesterolemic and / or antifungal Effect described, the mechanism of action is not clearly ge is clarified and which squalene epoxidase and / or Represent 2,3-epoxysqualene-lanosterol 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 alkoxybenzene derivatives (EP-A-0 410 359) and piperidine derivatives (J. Org. Chem. 57, 2794-2803, [1992]), which is an antifungal Own effect.

Furthermore, this enzyme is expressed in mammalian cells by Deca line, azadecalines and indan derivatives (WO 89/08450, J. Biol. Che mistry 254, 11258-11263 [1981], Biochem. Pharmacology 37,  1955-1964 [1988] and J 64 003 144), further by 2-aza-2,3-di hydrosqualenes 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 antihyperli To call pamic effect, which is the enzyme HMG-CoA reductase influence (US Pat. No. 5,041,432, J. Biol. Chem stry 266, 20070-20078 [1991], US-A-5,034,548). In addition, will this enzyme is inhibited by the azole-type antimycotics, which are N-substituted imidazoles and triazoles. To This class includes, for example, those 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 same inhibitors of the enzyme 2,3-epoxysqualene-lanosterol-Cy clase (International Classification: EC5.4.99.7).

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, 18075-18078 [1990]).  

Upon inhibition of biosynthetic steps after conversion There is a risk of 2,3-epoxysqualene in lanosterol accumulation of intermediates with steroid structure in the organ nism and the triggering of toxic effects caused thereby. This is for example for Triparanol, a Desmosterol-Re ductase inhibitor. This substance had to be because of Bil cataracts, ichthyosis and alopecia have been withdrawn from the market (cited in J. Biol. Chemistry 265, 18075-18078 [1990]).

As stated above, inhibitors of the 2,3-epoxy are squalene-lanosterol cyclase isolated in the literature be wrote. The structures of these compounds are, however, completely different from the structure of the compounds of the invention compounds of the general formula I.

The invention relates to the provision of antihyperchols sterolemic substances necessary for treatment and prophylaxis Atherosclerosis are suitable and, in comparison to known Active ingredients, through better antihypercholesterolemic Effect with increased selectivity and thus increased safety are excellent. Since the compounds of the invention Reason for their high activity as inhibitors of the enzyme 2,3-Epoxisqualen-Lanosterol-Cyclase also the Ergosterol-Bio They are also able to inhibit the synthesis in the fungal organism Treatment of mycoses suitable.

The present invention has new basic substituted Phe nylcyclohexylketone and their enol ethers of the general formula I the subject,

in the
X is a hydrogen atom and
Y and Z together represent an oxygen atom or
X and Y together are a bond and
Z is an alkoxy group having 1 to 6 carbon atoms,
m is the numbers 1 to 4,
R¹ and R², which may be the same or different, each ei ne straight-chain or branched alkyl group having 1 to 5 Koh lenstoffatomen, which may be substituted by a hydroxy, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, wherein the hydroxy group is not in the 1-position an alkenyl or alkynyl group having 3 to 5 carbon atoms, wherein the multiple bond is not in 1-Stel ment,
R³ and R⁴ independently of one another each represent a hydrogen or halogen atom or a trifluoromethyl group,
Unless otherwise stated, the abovementioned alkyl moieties may each contain from 1 to 3 carbon atoms and the abovementioned halogen atoms may in each case denote a fluorine, chlorine or bromine atom,
their enantiomers, diastereomers and geometric isomers and their salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or organic acids.

Preference is given to the compounds of the general formula I
in the
X is a hydrogen atom,
Y and Z together represent an oxygen atom,
m is the numbers 1 to 3,
R¹ and R², which may be the same or different, each represents a straight-chain alkyl group having 1 to 4 carbon atoms which may be terminally substituted by an aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group, or a straight-chain alkyl group having 2 to 4 carbon atoms terminated by a terminal Substituted hydroxy group,
R³ and R⁴ independently of one another each represent a hydrogen, fluorine or chlorine atom or a trifluoromethyl group,
their geometric isomers and their salts, in particular for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids,
Particular preference is given to the compounds of general formula I,
in the
X is a hydrogen atom,
Y and Z together represent an oxygen atom,
m is the numbers 1 to 3,
R¹ is a methyl group optionally substituted by a methylaminocarbonyl group, the ethyl, 2-hydroxyethyl or 3-hydroxypropyl group,
R² is the methyl or ethyl group,
R³ is a hydrogen or chlorine atom or a trifluoromethyl group and
R⁴ represents a hydrogen or chlorine atom,
their geometric isomers and their salts, in particular for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids,
but especially the compounds

• (1) 4-Chlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclo hexyl] ketone
• (2) 4-Chlorophenyl- [4- (4- (N- (2-hydroxyethyl) -N-methyl-amino methyl) phenyl) cyclohexyl] ketone
• (3) 3,4-dichlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclo hexyl] ketone

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 is as defined above and R² is a hydrogen atom or has the meanings mentioned above for R², with a compound of general formula III,
  in the X, Y, Z, m, R³ and R⁴ are as defined above and W¹ is a reactive leaving group, such as. As a chlorine, bromine or iodine atom, an alkylsulfonyloxy or Arylsulfonyloxygruppe such. B., the methanesulfonyloxy or toluenesulfonyloxy be indicated, and optionally subsequent reaction of a compound of the general formula IV so he held, in the
  X, Y, Z, m, R¹, R³ and R⁴ are as defined above, with a compound of general formula V, R² - W¹ (V) in the
  R² has the meanings mentioned above and W¹ is defined as mentioned above.
• The reactions are conveniently carried out in a suitable Solvents such as ethanol, methylene chloride, acetone, acetonitrile 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, optionally 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, carried out.
• b) compounds of the general formula I in which x and Y together are a bond and Z is an alkoxy group having 1 to 6 carbon atoms:
  By Wittig-Horner reaction of a phenylcyclohexanone of the general formula VI, in the
  m, R¹ and R² are as defined above, with a phosphonic ester of the general formula VII, in the
  R³ and R⁴ have the meanings mentioned above, R⁵ represents an alkyl radical having 1 to 3 carbon atoms and Z represents an alkoxy group having 1 to 6 carbon atoms.
• If the radicals R¹ and / or R² in a compound of the general my formula VI free hydroxy groups or aminocarbonyl groups it is recommended that they are suitable for use before implementation neter way to protect, for. B. by silylation with trialkyl silyl chlorides, and the protecting groups after completion of the reaction to split off again according to known methods.
• The Wittig-Horner reaction is carried out in an inert solvent such as tetrahydrofuran or diethyl ether in the presence of a star ken base such as n-butyl lithium or lithium diisopropylamide at Temperatures between -100 ° C and + 20 ° C, preferably at Tem temperatures between -70 ° C and 0 ° C.
• c) compounds of general formula I in which X is a hydrogen atom and Y and Z together represent an oxygen atom:
  By hydrolytic cleavage of an enol ether of the general formula VIII, in the
  m and R¹ to R⁴ have the meanings mentioned above and Z represents an alkoxy group having 1 to 6 carbon atoms.

The hydrolytic cleavage of the enol ethers takes place, for example by treatment with aqueous hydrochloric or sulfuric acid at Tem temperatures between 20 ° C and 50 ° C, where appropriate dene Silylschutzgruppen are also eliminated. in this connection the ketones of general formula I are obtained as mixtures their geometric isomers.

The compounds prepared by the above methods of the general formula can be determined by known methods, z. B. by crystallization or chromatography, and isolate. So can be by crystallization or by Chromatography from the mixtures of geometric isomers the ketones of general formula I the pure equatorial equatorial (e, e) or equatorial-axial (e, a) substituted Phenylcyclohexylketone obtained.

Furthermore, the obtained compounds of the general If desired, formula I in their acid addition salts, esp especially for pharmaceutical use in their physiological compatible salts with inorganic or organic acids, be transferred. As acids come for example for this Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Fumaric acid, adipic acid, succinic acid, lactic acid, lemons acid, tartaric acid or maleic acid into consideration.

The compounds used as starting materials of the general Formulas II, III, V, VI and VII are known, or are after obtained known methods. The enol ethers of the general Formula VIII are prepared according to process b).

The compounds of general formula I have interesting biological properties. They are inhibitors of choles Sterolbiosynthese, in particular inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase. Due to their biolo gical properties, they are particularly suitable for the treatment treatment and prophylaxis of hyperlipidemia, in particular Hy  percholesterolemias and hypertriglyceridemias and the resulting resulting atherosclerotic vascular changes with their Consequences such as coronary heart disease, cerebral ischa intermittent claudication, gangrene and others.

For the treatment of these diseases, the compounds of the general formula I either alone for monotherapy used or in combination with other cholesterol or lipid-lowering substances are used, wherein the compounds preferably as an oral formulation given However, if necessary, in the form of suppositories administered you can. As combination partners come here for example in question:

• - 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 interfere with cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as lovastatin, Sim vastatin, 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 further possible combination partners are still to be mentioned the class of fibrates, such as clofibrate, bezafibrate, gemfibrozil and others, nicotinic acid, its derivatives and analogs as in For example, Acipimox and probucol.  

Furthermore, the compounds of general formula I ge is used to treat disorders that are excessive Cell proliferation related. Cholesterol is a essential cell component and must be used for cell proliferation, d. H. Cell division, be present in sufficient quantity. The Inhibition of cell proliferation by inhibition of cholesterol Sterol biosynthesis is exemplified by smooth muscle cells the HMG-CoA reductase inhibitor of the statin type lovastatin, such as mentioned at the beginning, described.

As examples of diseases with excessive cell proliferation are related to tumor diseases NEN. In cell culture and in vivo experiments it was shown that lowering of serum cholesterol or intervention in Cho lesterol biosynthesis by HMG-CoA reductase inhibitors the Tu reduced growth (Lancet 339, 1154-1156 [1992]). He inventive compounds of formula I are therefore due their cholesterol biosyntheseinhibitorischen effect potentially suitable for the treatment of tumor diseases. You can alone or in support of known therapy prinzi find use.

The compounds of formula I are also effective as antago of skin hyperproliferation, d. H. as a means that the Inhibit hyperproliferation of human keratinocytes. The Ver As a result, compounds are considered hyper-treatment agents proliferative skin diseases such as psoriasis, basal cell carcinoma nomen, keratinization disorders and keratosis. to Treatment of these diseases may be the compounds of the For mel I are administered either orally or topically, where they either alone in the form of nonotherapy or in combination can be used with known active ingredients.

Further to call are by surgical measures such as PTCA (Percutaneous Transluminal Coronary Angioplasty) or By  pass surgery triggered hyperproliferative vascular disease conditions such as strictures and occlusions on the proliferator tion of smooth muscle cells. As mentioned above leaves This cell proliferation is known to be due to HMG-CoA reduct inhibitors of mevinoline type such as lovastatin. Due to their inhibitory effect on cholesterol bio Synthesis are also the compounds of general formula I. suitable for the treatment and prophylaxis of these diseases where either alone or in combination with known ones Active ingredients, such as. As intravenously administered heparin, before can be used preferably in oral application.

Another possible use of the invention verbin The compounds of general formula I is the prophylaxis and treatment treatment of gallstone disease. The gallstone is thereby triggered that the cholesterol concentration in the bile maximum solubility of cholesterol in the bile which causes it to precipitate cholesterol in Form of gallstones comes. Lipid lowering agent from the class of Fibrates lead to increased elimination of neutral substances roil over the bile and increase the propensity for gallstone education.

In contrast, cholesterol biosynthesis inhibitors such as Lova statin or pravastatin to no increased gallstone formation, but on the contrary can reduce cholesterol effect concentration in the bile and thus the so-called li Thogen index, a measure of the probability of bile stone formation, diminish. This is described in Good 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, especially in combination with ursodeoxychol acid. Because of their mode of action, the Ver compounds of the general formula I therefore also for the Prophy  Lax and treatment of gallstone disease of importance. you can be either alone or in combination with known Therapies such as treatment with ursodeoxychol acid or the Schockwellenlithotripsie preferably in oral Application find use.

Finally, the compounds of general formula I ge suitable for the treatment of infections caused by pathogenic fungi such as z. Candida albicans, Aspergillus niger, Trichophyton menta grophytes, Penicillium sp., Cladosporium sp. and other. As already mentioned is the end product of Sterolbiosyn in the fungal organism not cholesterol, but that for the Integrity and function of fungal cell membranes essential Ergo sterol. The inhibition of ergosterol biosynthesis therefore leads to stunted growth and possibly to kill the fungus organisms.

For the treatment of mycoses, the compounds of the general my formula I can be administered either orally or topically. They can either alone or in combination with be knew antifungal agents are used, esp especially with those involved in other stages of sterol biosynthesis intervene, such as the squalene epoxidase inhibitors Ter binafin and naftifine or the lanosterol-14α-demethylaseinhi azole-type bacteria such as ketoconazole and flucon azole.

Another use of the compounds of the general my formula I concerns the application in poultry farming. Lowering the cholesterol content of eggs by administration hGG-CoA reductase inhibitor lovastatin to laying hens is described (FASEB Journal 4, A 533, abstracts 1543 [1990]). The production of cholesterol eggs is of interest as the cholesterol load of the body is reduced by eggs with redu Cholesterol content without a change in the nutritional content habits can be reduced. Because of their inhibitori  effect on the cholesterol biosynthesis, the verbin of the general formula I in poultry breeding Generation of cholesterol eggs find use, the Substances preferably administered as an additive to the feed who the.

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 with Digi tonin precipitable steroids method

Human hepatoma cells (HEP-G2) are grown after 3 days of culture stimulated for 16 hours in cholesterol-free medium. The too testing substances (dissolved in dimethylsulfoxide, final concentration 0.1%) are added during this stimulation phase. Subsequently, after the addition of 200 .mu.mol / l 2-1⁴C acetate for incubated for a further two hours at 37 ° C in the incubator.

After detaching the cells and saponifying the sterol esters after extraction, the sterols are precipitated with digitonin. The ¹⁴C-acetate incorporated in digitoninfallable sterols becomes determined by scintillation measurement.

The study 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 (3) of the general formula I are stated at these test concentrations:

• (1) 4-Chlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclo hexyl] ketone
• (2) 4-Chlorophenyl- [4- (4- (N- (2-hydroxyethyl) -N-methyl-amino methyl) phenyl) cyclohexyl] ketone  
• (3) 3,4-dichlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclo hexyl] ketone.

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

As mentioned above, isolated in the literature inhibitors of the enzyme 2,3-Epoxisqualen-lanosterol cyclase ben described ben, but structurally very different from the compounds of formula I according to the Invention. The compounds structurally next to the compounds of the general formula I are described in EP 0 468 457 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 ge found inhibitory values of 41% and 13% show that these connec tions are clearly inferior to the compounds of the general For mel I 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 2,3-epoxis in liver and liver 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) will be the in 1.5% aqueous methylcellulose suspended test substance applied via gavage. 5 hours after application Blood recovered retroorbital from the venous plexus. Plasma becomes according to the method of Bligh and Dyer (Canad J. Biochem Phy siol. 12, 912, [1959]) worked over a precolumn gerei then analyzed by HPbC. The obtained peaks are identified and quantified by means of calibration substances. On internal standard is used to check the reproducibility the Results.

The tests were carried out at concentrations of 0.1 and 1.0 mg / kg. In the following table, the results for the aforementioned substances (1) to (3) are summarized by way of example:
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 Enzymes 2,3-Epoxisqualen-Lanosterol-Cyclase is an In Hibierung the cholesterol biosynthesis described in the whole animal.

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

Formulations for oral administration include, for example wise tablets, dragees and capsules, for rectal administration preferably suppositories are considered.

The daily dose is between 0.1 and 200 mg for a men 60 kg body weight, but one day is preferred dose of 0.5 to 10 mg for a human with 60 kg Körperge weight. The daily dose is preferably in 1 to 3 single doses divided up.

When used topically, the compounds can be used in preparations gene, about 1 to 200 mg, in particular 10 to 100 mg of active be administered per day. The daily dose is preferably divided into 1 to 3 individual doses.

Topical formulations include gels, creams, lotions, sal for example, powders, aerosols and other conventional formulations Application of remedies on the skin. The amount of active ingredient for topical application is 1 to 50 mg per gram of formulation tion, but preferably 5 to 20 mg per gram of formulation. In addition to the application on the skin, the topical Formulie ments of the present invention are also applied in the Treatment of mucous membranes, topical treatment too are accessible. For example, the topical formulations may on the mucous membranes of the mouth, the lower colon, and on be applied.

For use in poultry farming for the production of cholesterol eggs are the active ingredients of the general formula I den Animals according to the usual methods as an addition to suitable Fut administered. The concentration of active ingredients in the Ready-made feed is normally 0.01 to 1%, preferably however 0.05 to 0.5%.

The active compounds can be added as such to the feed. Thus, the feed according to the invention for laying hens  in addition to the active ingredient and optionally in addition to a conventional Vitamin-mineral mixture such as corn, soybean meal, Meat meal, feed fat and soybean oil. To this food is a the compounds of formula I mentioned above as the active ingredient in a concentration of 0.01 to 1%, but preferably 0.05 to 0.5% mixed.  

The following examples serve to explain the Invention.

Examples for the preparation of the starting materials: Example A 4- [4- (tetrahydro-2H-pyran-2-yl) oxymethyl-phenyl] cyclohexanone

50 g (0.267 mol) of 4-bromobenzyl alcohol are dissolved in 250 ml Tetrahy drofuran and after addition of 80 ml (0.88 mol) of 3,4-dihy dro-2H-pyran and 1.0 g of p-toluenesulfonic acid for 16 hours at room temperature stirred. Then it is concentrated in a vacuum, gives aqueous sodium bicarbonate solution and extracted with Ether. The extracts are dried and concentrated. The out 1-bromo-4- (tetrahydro-2H-pyran-2-yl) oxymethyl-benzene existing The residue will be further processed uncleaned.

73.0 g (0.267 mol) of the residue are dissolved in 300 ml of absolute tetrahydrofuran and added dropwise at -70 ° C under nitrogen with 166 ml of a 1.6 M solution of n-butyllithium (0.266 mol) in hexane. The mixture is stirred for 30 minutes, then added dropwise to a solution of 41.6 g (0.267 mol) of cyclohexane-1,4-dione mono ethylene ketal in 100 ml of absolute tetrahydrofuran and allowed to come to room temperature within 16 hours. Then ice-water is added and extracted with ethyl acetate. The extracts are dried and concentrated, the residue was digested with 50 ml of ice-cold ether and the resulting crystalline precipitate of 4-hydroxy-4- [4- (tetrahydro-2H-pyran-2-yl) oxymethyl-phenyl] cyclohexanone ethylene ketal aspirated.
Yield: 52 g (56% of theory);
Melting point: 99 ° C.

52 g (0.149 mol) of this intermediate are abso in 250 ml Nitrous pyridine and dissolved under nitrogen and cooled to -12 ° C. added dropwise with 56.7 g (0.476 mol) of thionyl chloride.  

After 2 hours at 0 ° C, add to ice-water, adjust with 2N Sodium hydroxide to pH 8-9 and extracted with methylene chloride. The Extracts are dried, concentrated in vacuo and the reverse after dissolving in a mixture of 500 ml of ethyl acetate ester and 250 ml of methanol using 10 g of palladium on calcium carbonate as a catalyst for 48 hours at room temperature hydrogenated and 5 bar hydrogen pressure. Then the catalyst filtered off, concentrated and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1: 1, v: v) This gives 30.1 g of 4- [4- (tetrahydro-2H-pyran-2-yl) oxymethyl phenyl] cyclohexanone ethylene ketal (61% of theory; point: 49 ° C).

14 g (42 mmol) of this intermediate are dissolved in 50 ml of acetone and stirred for 4 hours at room temperature after addition of 50 ml of half-concentrated hydrochloric acid. It is then diluted with water and extracted with ether. The extracts are dried, concentrated and the residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1: 1, v: v). This gives 5.8 g (48% of theory) of the title compound as an oily product.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
1.35-2.17 (m, 12H); 2.27 (bd, 2H); 2.61 (dd, 2H); 3.06 (m, 1H) 3.48 (m, 1H); 3.8 (m, 1H); 4.4 (d, 1H); 4.64 (d, 1H); 4.68 (s, 1H) 7.28 (s, 4H).

Example B 4- [4- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) phenyl] cyclohexanone

18 g (90 mmol) of 4-bromo-phenylethanol are dissolved in 150 ml Tetrahy drofuran and after addition of 25 g (0.3 mol) of 3,4-dihydro-2H-pyran and 0.5 g of p-toluenesulfonic acid at 18 hours Room temperature stirred. It is then concentrated, made alkaline with Natriumhydrogencarbo natlösung and extracted with ether. After drying the extracts is concentrated again and Kugelrohr distillation performed. (Bp approx. 120 ° C / 0.3 mm Hg).
Yield: 20 g (78% of theory).

28.5 g (0.1 mol) of the thus obtained 1-bromo 4- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] benzene are dissolved in 100 ml of absolute Tetrahy drofuran and under nitrogen, at -70 ° C, added dropwise to 69 ml of a 1.6 M solution of n-butyllithium (0.11 mol) in hexane. After 30 minutes, added dropwise to a solution of 15.6 g (0.1 mol) of cyclohexane-1,4-dione monoethylenketal in 50 ml of absolute tetrahydrofuran and then allowed slowly to room temperature erwär men. Then it is poured into ice-water and extracted with ether. The extracts are dried over magnesium sulfate, concentrated and the residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1: 1, v: v). This gives 26 g (72% of theory) of oily 4-hydroxy-4- [4- (2- (tetra-hydro-2H-pyran-2-yloxy) ethyl) phenyl] cyclohexanone ethylene ketal.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
1.3-1.8 (m, 10H); 1.8-2.05 (m, 4H); 2.79 (t, 2H); 3.3-3.45 (m, 1H) 3.46-3.7 (m, 2H); 3.7-3.95 (m, 1H); 3.87 (s, 4H); 4.57 (bs, 1H) 4.84 (s, 1H); 7.16 (d, 2H); 7.36 (d, 2H)

1.5 g (4 mmol) thereof are dissolved in 50 ml of toluene and after addition of 5 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid heated for 6 hours on a water. After cooling, it is mixed with 20 ml of 2M sodium hydroxide solution and extracted with toluene. After the extracts have been dried, the mixture is concentrated and the residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2: 1, v: v). This gives 0.6 g (57.6%) of 4- [4- (2-hydroxyethyl) phenyl] -3-cyclohexen-1-one ethylene ketal.
Melting point: 98-100 ° C.

The subsequent catalytic hydrogenation in the presence of palladium (10% on carbon) in methanol at room temperature and a pressure of 5 bar provides 4- [4- (2-hydroxyethyl) phenyl] cyclohexanone ethylene ketal.
Melting point: 88 ° C.

For cleavage of the ketal protecting group is stirred with a mixture of half-concentrated hydrochloric acid and acetone (1: 2, v: v) at room temperature for 2 hours. After extraction with ether, it is concentrated by evaporation and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2: 1, v: v). 4- [4- (2-hydroxyethyl) phenyl] cyclohexanone is obtained.
Melting point: 60 ° C.

3.5 g (0.016 mol) of 4- [4- (2-hydroxyethyl) phenyl] cyclohexanone who dissolved in 50 ml of tetrahydrofuran and after addition of 4.2 g (0.05 mol) of 3,4-dihydro-2H- pyran and 0.5 g of p-toluenesulfonic acid for 24 hours at room temperature. It is then concentrated, made alkaline with sodium bicarbonate solution and extracted with ether. The extracts are dried and concentrated. The residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 8: 1, v: v). This gives 4.0 g (83% of theory) of the title compound of oily consistency.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
1.3-2.18 (m, 10H); 2.27 (bd, 2H); 2.56 (dt, 2H); 2.80 (t, 2H); 3.04 (bt, 1H); 3.30-3.46 (m, 1H); 3.47-3.90 (m, 3H); 4.57 (bs, 1H); 7:19 (2d, 4H).

Example C 1- (4-chloro-α-ethoxy-benzylidene) -4- [4- (tetrahydro-2H-pyran 2-yl) oxymethyl-phenyl] cyclohexane

2.4 g (24 mmol) of diisopropylamine are dissolved in 25 ml of absolute Te submitted trahydrofuran and at -15 ° C under nitrogen with 13.8 ml (22 mmol) of a 1.6 M solution of n-butyllithium in hexane added. Then added dropwise at -15 ° C, a solution of 6.75 g (22 mmol) of 4-chloro-α-ethoxy-benzylphosphonic acid diethyl ester (prepared analogously to Liebigs, Ann. Chem. (1977), 88-100; Boiling point: 125-128 ° C / 0.25 mmHg) in 10 ml of tetrahydrofuran.  

The solution is stirred for 30 minutes and then treated dropwise with a solution of 5.1 g (17.7 mmol) of 4- [4- (tetrahydro-2H-pyran-2-yl) oxymethyl-phenyl] cyclohexanone in 10 ml of tetrahydrofuran , After stirring for 2 hours at room temperature, it is poured onto ice / ammonium chloride solution and extracted with ether. The extracts are washed with sodium bicarbonate solution, dried and concentrated. The concentration residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 9: 1, v: v). This gives 4.4 g (56% of theory) of the title compound as an oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
1.10 (t, 3H); 1.35-2.14 (m, 12H); 2.40 (bd, 1H); 2.71 (bt, 1H); 3.15 (bd, 1H); 3.35-3.55 (m, 3H); 3.8 (m, 1H); 4.38 (d, 1H); 4.63 (d, 1H); 4.67 (s, 1H); 7.22 (2d, 4H); 7.34 (d, 2H); 7.47 (d, 2H).

Analogously to Example C is obtained:
1- (4-Chloro-α-ethoxy-benzylidene) -4- [4- (2- (tetrahydro-2H-pyran-2-yloxy) -ethyl) -phenyl] -cyclohexane
from 4- [4- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) phenyl] cyclohexanone and 4-chloro-α-ethoxy-benzylphosphonic acid diethyl ester.
Yield: 37% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
1.10 (t, 3H); 1.30-2.12 (m, 12H); 2.39 (bd, 1H); 2.67 (bt, 1H); 2.78 (t, 2H); 3.12 (bd, 1H); 3.30-3.87 (m, 6H); 4.56 (bs, 1H); 7.15 (s, 4H); 7.33 (d, 2H); 7.44 (d, 2H).

Example D 4-chlorophenyl [4- (4-hydroxymethylphenyl) cyclohexyl] ketone (100% e, e)

2.8 g (6.3 mmol) of 1- (4-chloro-α-ethoxy-benzylidene) -4- [4- (tetrahydro-2H-pyran-2-yl) oxymethyl-phenyl] -cyclohexane are dissolved in 25 ml Dissolved acetone and stirred for 2 hours at 40 ° C after addition of 25 ml of half-concentrated hydrochloric acid. Then the acetone is removed in vacuo, diluted with water and extracted with Essigsäureethyl ester. After the extracts have been dried, the mixture is concentrated and the residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3: 1, v: v). This gives 24% of 4-chlorophenyl [4- (4-tetrahydro-2H-pyran-2-yl) oxy methyl-phenyl) cyclohexyl] ketone (melting point: 97-99 ° C, 100% e, e-isomer) and 48% chlorophenyl- [4- (4-hydroxymethylphenyl) cyclohexyl] ketone (m.p. 143-144 ° C; 100% e, e-isomer)
Analogously to Example D is obtained:
4-Chlorophenyl- [4- (2-hydroxyethyl) phenyl] cyclohexyl ketone (78% e, e and 22% e, a)
from 1- (4-chloro-α-ethoxy-benzylidene) -4- [4- (2- (tetrahydro-2H-pyran-2-yloxy) -ethyl) -phenyl] -cyclohexane and semi-concentrated hydrochloric acid.
Yield: 1.0 g (62% of theory).
Melting point: 84 ° C.

Example E 4- [4- (2-diethylaminoethyl) phenyl] cyclohexanone

To 18.8 ml (0.03 mol) of a 1.6 M solution of n-butyllithium in Hexane is added dropwise under nitrogen at -70 ° C, a solution of 6.4 g (0.025 mol) of 4-bromo-1- (2-diethylaminoethyl) benzene in 20 ml absolute tetrahydrofuran. It is stirred for 30 minutes, dripping then a solution of 4.1 g (0.026 mol) of cyclohexane-1,4-dione-mo Rioethylenketal in 25 ml of absolute tetrahydrofuran and allowed come to room temperature within 16 hours. subsequently, ßend is mixed with ice water and ethyl acetate extracted. After drying the extracts is concentrated and the residue was purified by column chromatography (alumina,  Activity level III; Petroleum ether / ethyl acetate = 4: 1, v: v).

This gives 4.3 g (49% of theory) of oily 4- [4- (2-diethyl aminoethyl) phenyl] -4-hydroxy-cyclohexanone ethylene ketal.

Subsequent dehydration and catalytic hydrogenation analogue Example 4- to 4- [4- (2-diethylaminoethyl) phenyl] cyclohexanone ethylene ketal affords the title compound as a colorless oil after deketalization.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.95 (t, 6H); 1.72-2.34 (m, 6H); 2.42-2.70 (m, 10H); 3.02 (bt, 1H) 7.07-7.26 (2d, 4H).

Analogously to Example E is obtained:
4- [4- (3-diethylaminopropyl) phenyl] cyclohexanone
from cyclohexane-1,4-dione monoethylene ketal and N, N-diethyl-3- (4-bromophenyl) allylamine, then catalytic hydrogenation to 4- [4- (3-diethylaminopropyl) phenyl] -4-hydroxycyclohexanone ethylene ketal , subsequent dehydration, as well as renewed catalytic Hy drierung and Deketalisierung. Colorless oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.92 (t, 6H); 1.55-2.15 (m, 6H); 2.16-2.70 (m, 12H); 3.02 (bt, 1H) 7.07-7.25 (2d, 4H).

Examples of the preparation of the end products example 1 1- (4-chloro-α-ethoxy-benzylidene) -4- (4-dimethylaminomethyl phenyl) cyclohexane

12.3 g (40 mmol) of 4-chloro-α-ethoxy-benzylphosphonic acid diethyl ester (prepared analogously to Lieb, Ann. Chem. (1977), 88-100, they depunkt: 125-128 ° C / 0.25 mmHg) dissolved in 10 ml of absolute Te trahydrofuran and treated at -78 ° C under nitrogen with 25 ml of a 1.6 M solution of n-butyllithium in hexane. The solution is stirred for 20 minutes and then added dropwise with a solution of 6.9 g (30 mmol) of 4- (4-dimethylaminomethylphenyl) cyclohexanone (J. Med. Chem. (1989) 32, 351-357) in 15 ml absolute tetrahydrofuran was added. After 3 hours at -78 ° C allowed to come to room temperature, decomposed with water and extracted with ether. After the ether extracts have been dried, the mixture is concentrated and the residue is purified by column chromatography (aluminum oxide activity grade III, petroleum ether / ethyl acetate = 20: 1, v: v).
Yield: 7.8 g (66% of theory), oil.
1 H-NMR spectrum (200 MHz, CDCl₃-CD₃OD); Signals at ppm:
1,2 (t, 3H); 1.34-1.68 (m, 2H); 1.83-2.13 (m, 4H); 2.24 (s, 6H) 2.52 (bd, 1H); 2.71 (bt, 1H); 3.25 (bd, 1H); 3.43 (s, 2H); 3.50 (q, 2H); 7.2 (s, 4H); 7.31 (2d, 4H).

Analogously to Example 1 are obtained:

(1) 1- (4-Dimethylaminomethyl-phenyl) -4- (α-ethoxy-4-trifluoro-methyl-benzylidene) -cyclohexane
from 4- (4-dimethylaminomethylphenyl) cyclohexanone and diethyl α-ethoxy-4-trifluoromethylbenzylphosphonate (boiling point: 109-117 ° C / 0.4 mmHg).
Yield: 58% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.15 (t, 3H); 1.35-1.65 (m, 2H); 1.80-2.10 (m4H); 2.14 (s, 6H); 2.45 (bd, 1H); 2.73 (bt, 1H); 3.20 (bd, 1H); 3.35 s, 2H); 3.45 (q, 2H); 7.19 (s, 4H); 7.54 (d, 2H), 7.73 (d, 2H).

(2) 1- (3,4-Dichloro-α-ethoxy-benzylidene) -4- (4-dimethylamino-methyl-phenyl) -cyclohexane
from 4- (4-dimethylaminomethyl-phenyl) -cyclohexanone and 3,4-di-chloro-α-ethoxy-benzylphosphonic acid diethyl ester (boiling point: 140-150 ° C / 0.5 mmHg).
Yield: 61% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppmm:
1.15 (t, 3H); 1.30-1.62 (m, 2H); 1.75-2.10 (m, 4H); 2.15 (s, 6H) 2.40 (d, 1H); 2.71 (bt, 1H); 3.14 (bd, 1H); 3.35 (s, 2H); 3.46 (q, 2H); 7.19 (s, 4H); 7.30 (d, 1H); 7.50 (s, 1H); 7.62 (d, 1H).

(3) 1- (4-Chloro-α-ethoxybenzylidene) -4- [4- (2-diethylaminoethyl) phenyl] cyclohexane
from 4- [4- (2-diethylaminoethyl) phenyl] cyclohexanone and diethyl 4-chloro-ethoxy-benzylphosphonate.
Yield: 55.2% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.95 (t, 6H); 1.10 (t, 3H); 1.30-1.70 (m, 2H); 1.70-2.20 (m, 4H) 2.30-2.78 (m, 10H); 3.13 (bd, 1H); 3.41 (q, 2H); 7.12 (s, 4H); 7.33 (d, 2H); 7.45 (d, 2H).

(4) 1- (4-Chloro-α-ethoxybenzylidene) -4- [4- (3-diethylaminopyryl) phenyl] cyclohexanone
from 4- [4- (3-diethylaminopropyl) phenyl] cyclohexanone and diethyl 4-chloro-ethoxy-benzylphosphonate.
Yield: 64.9% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.92 (t, 6H); 1.10 (t, 3H); 1.30-2.10 (m, 6H); 2.30-2.58 (m, 11H) 2.67 (bt, 1H); 3.13 (bd, 1H); 3.42 (q, 2H); 7.04-7.20 (2d, 4H); 7.32 (d, 2H); 7.46 (d, 2H)

Example 2 4-chlorophenyl [4- (4-dimethylaminomethyl-phenyl) cyclohexyl] ketone

7.0 g (18 mmol) of 1- (4-chloro-α-ethoxybenzylidene) -4- (4-dimethylaminomethylphenyl) cyclohexane are dissolved in a mixture of 15 ml of 2N hydrochloric acid and 15 ml of ethanol and left to stand for 1 hour stirred at 60 ° C ge. It is then made alkaline with 2N sodium hydroxide solution, extracted with ether, the extracts are dried and concentrated. The residue is purified by column chromatography (silica gel, methylene chloride / methanol = 10: 1, v: v).
Yield: 5.9 g (92% of theory, mixture of isomers: 50% e, e + 50% e, a).
Melting point: 110-119 ° C.
1 H-NMR spectrum (200 MHz, CDCl₃); Signals at ppm:
1.5-2.21 (m, 8H); 2.23 (d, 6H); 2.6 (m, 1H); 3.3 + 3.55 (2m, 1H); 3,4 (d, 2H); 7.13-7.3 (m, 4H); 7.38-7.5 (m, 2H); 7.8-7.98 (m, 2H).

By adding a little ethanol and ethereal hydrochloric acid, the hydrochloride of a 2: 1 mixture of the e, e and e, a isomers is obtained.
Melting point: 239-240 ° C.
1 H-NMR spectrum (200 MHz, CD₃OD); Signals at ppm:
1.5-2.2 (m, 8H); 2.65 (m, 1H); 2.83 (d, 6H); 3.38-3.75 (m, 1H); 4.28 (s, 2H); 7.3-7.6 (m, 6H); 7.87-8.08 (m, 2H).

The following are produced analogously to Example 1:

(1) 4- (4-Dimethylaminomethyl-phenyl) -cyclohexyl] - (4-trifluoro-methyl-phenyl) -ketone (100% e, e)
from 1- (4-dimethylaminomethylphenyl) -4- (α-ethoxy-4-trifluoromethylbenzylidene) cyclohexane.
Yield: 90% of theory, melting point: 101-102 ° C.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.4-2.07 (2m, 8H); 2.15 (s, 6H); 2.55 (m, 1H); 3.35 (s, 2H); 3.54 (bt, 1H); 7.21 (s, 4H); 7.89 (d, 2H); 8.20 (d, 2H).

(2) 3, 4-dichlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclohexyl] ketone (100% e, e)
from 1- (3,4-dichloro-α-ethoxybenzylidene) -4- (4-dimethylaminomethylphenyl) cyclohexane.
Yield: 39% of theory, melting point: 114-116 ° C.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.4-1.8 (m, 4H); 1.82-2.03 (m, 4H); 2.04 (s, 6H); 2.55 (bt, 1H) 3.34 (s, 2H); 3.50 (bt, 1H); 7.2 (s, 4H); 7.79 (d, 1H); 7.97 (dd, 1H); 8.17 (d, 1H).

(3) 4-Chlorophenyl- [4- (4- (2-diethylaminoethyl) phenyl] cyclohexyl] ketone (mixture of isomers 66% e, e + 33% e, a);
from 1- (4-chloro-α-ethoxybenzylidene) -4- [4- (2-diethylaminoethyl) phenyl] cyclohexane.
Yield: 90% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.95 (dt, 6H); 1.40-2.08 (m, 8H); 2.40-2.72 (m, 9H); 3.48 + 3.71 (2m, 1H); 7,12 (d, 4H); 7.54-7.68 (m, 2H; 7.90-8.10 (m, 2H).

(4) 4-chlorophenyl- [4- (4- (3-diethylaminopropyl) phenyl] cyclohexyl] ketone; (Isomer mixture 50% e, e + 50% e, a).
from 1- (4-chloro-α-ethoxybenzylidene) -4- [4- (3-diethylaminopyryl) phenyl] cyclohexane.
Yield: 58% of theory, oil, partially solid.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.93 (dt, 6H); 1.40-2.10 (m, 10H); 2.30-2.70 (m, 9H); 3.48 + 3.71 (2m, 1H); 7,12 (d, 4H); 7.54-7.68 (m, 2H); 7.90-8.08 (m, 2H).

Example 3 4-chlorophenyl [4- (4- (N- (2-hydroxyethyl) -N-methyl-amino methyl) phenyl) cyclohexyl] ketone (100% e, e)

450 mg (1.4 mmol) 4-chlorophenyl- [4- (4-hydroxymethyl-phenyl) cyclohexyl] ketone (100% e, e, Example D) are dissolved in 10 ml of Me dissolved and after addition of 500 mg (4.2 mmol) Thionyl chloride heated for 1 hour at reflux. Subsequently, will concentrated in vacuo, the residue in 20 ml of acetonitrile and after addition of 600 mg (8 mmol) of 2-methylaminoethanol and 400 mg (3 mmol) of potassium carbonate at 50-60 ° C for 6 hours touched. Then allowed to cool, mixed with water and extracted with ethyl acetate.

The extracts are dried, concentrated by evaporation and the residue is purified by column chromatography (alumina activity grade III, petroleum ether / ethyl acetate = 1: 1, v: v).
Yield: 150 mg (28% of theory),
Melting point: 110 ° C.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.4-1.8 (m, 4H); 1.83-2.04 (m, 4H); 2.17 (s, 3H); 2.45 (t, 2H); 2.55 (m, 1H); 3.48 (s, 2H); 3.52 (t + m, 3H); 7.21 (d, 4H); 7.60 (d, 2H); 8.01 (d, 2H).

Analogously to Example 3 are obtained:

(1) 4-Chlorophenyl- [4- (4- (N- (3-hydroxypropyl) -N-methyl-amino-methyl) -phenyl-cyclohexyl] -ketone (100% e, e)
from 4-chlorophenyl- [4- (4-hydroxymethylphenyl) cyclohexyl] ketone (100% e, e, Example D), thionyl chloride and 3- (methylamino) propanol.
Yield: 35% of theory; waxy firm.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.4-1.8 (m, 6H); 1.84-2.03 (m, 4H); 2.1 (s, 3H); 2.42 (t, 2H); 2.53 (m, 1H); 3.42 (s, 2H), 3.46 (t + m, 3H); 7.2 (s, 4H); 7.6 (d, 2H); 8.02 (d, 2H).

(2) 4-Chlorophenyl- [4- (4- (2-diethylaminoethyl) phenyl] cyclohexyl] ketone (60% e, e + 40% e, a)
from 4-chlorophenyl [4- (4- (2-hydroxyethyl) phenyl) cyclohexyl] ketone (Example D (1)) by bromination with triphenylphosphine / carbon tetrabromide and subsequent reaction with diethylamine.
Yield: 15% of theory, oil.
1 H-NMR spectrum (200 MHz, DMSO-d₆); Signals at ppm:
0.95 (dt, 6H); 1.40-2.08 (m, 8H), 2.40-2.72 (m, 9H); 3.48 + 3.71 (2m, 1H); 7.12 (d, 4H), 7.54-7.68 (m, 2H), 7.90-8.10 (m, 2H)

Example 4 4-chlorophenyl [4- (4- (N- (methylaminocarbonylmethyl) -N-methyl aminomethyl) phenyl) cyclohexyl] ketone (100% e, e)

1.0 g (3 mmol) of 4-chlorophenyl- [4- (4-hydroxymethylphenyl) cyclohexyl] ketone (100% e, e) are dissolved in 10 ml of chloroform and, after addition of 0.5 ml (7 mmol) of thionyl chloride Heated under reflux for 1 hour. It is then concentrated, the residue taken up in 20 ml of acetonitrile and poured into 10 ml of 40% aqueous Me methylamine solution. After standing overnight, concentrated, digested with water / petroleum ether and filtered off with suction from the crystalline precipitate. The crude 4-chlorophenyl [4- (4- (N-methyl-aminomethyl) phenyl] cyclohexyl] ketone is suspended in 15 ml of acetonitrile and, after addition of 260 mg (2.4 mmol) of N-methyl- chloroacetamide and 2.0 ml of N-ethyl-diisopropylamine for 2 days at room temperature. It is then concentrated and the residue was purified by column chromatography (aluminum oxide activity grade III, petroleum ether / ethyl acetate = 1: 1, v: v).
Yield: 0.6 g (60% of theory),
Melting point: 100 ° C.
1 H-NMR spectrum (200 MHz, DMSO-d₆ / CD₃OD); Signals at ppm:
1.4-1.8 (m, 4H); 1.85-2.02 (m, 4H); 2.18 (s, 3H); 2.45-2.66 (m, 1H; s, 3H); 2.92 (s, 2H); 3.38-3.6 (t, 1H; s, 2H); 7.27 (2d, 4H); 7.59 (d, 2H); 8.0 (d, 2H).

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

Example I Tablets containing 5 mg of 4-chlorophenyl- [4- (4-dimethylaminomethyl phenyl) cyclohexyl] ketone

composition 1 tablet contains: active substance 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 ver to tablets ver presses.

Tablet weight: 220 mg
Stamp: 9 mm.

Example II Drag'es with 5 mg of 4-chlorophenyl [4- (4-dimethylaminomethyl -phenyl) cyclohexyl] ketone

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

Example III Suppositories with 5 mg of 4-chlorophenyl- [4- (4-dimethylaminomethyl phenyl) cyclohexyl] ketone

composition 1 suppository contains: active substance 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 IV Capsules with 5 mg of 4-chlorophenyl- [4- (4-dimethylaminomethyl -phenyl) cyclohexyl] ketone

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 placed on a capsule filling machine in hard gelatine capsules size 3 abge fills, whereby the final weight is constantly checked.  

Example V Cream for topical administration with 1 g of 4-chlorophenyl [4- (4-dimethylaminomethyl-phenyl) cyclohexyl] ketone

A formulation for the topical administration of the compounds of formula I may 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 4-Chorphenyl- [4- (4-dimethylaminomethyl-phenyl) cyclohexyl] ketone

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 (11)

1. phenylcyclohexyl ketones and their enol ethers of the general formula I, in the
X is a hydrogen atom and
Y and Z together represent an oxygen atom or
X and Y together are a bond and
Z is an alkoxy group having 1 to 6 carbon atoms,
in the numbers 1 to 4,
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, which may be substituted by a hydroxy, aminocarbonyl, al kylaminocarbonyl or dialkylaminocarbonyl group, wherein the hydroxy group is not in the 1-position an alkenyl or alkynyl group having 3 to 5 carbon atoms, wherein the multiple bond is not in 1-Stel ment,
R³ and R⁴ each independently represent a hydrogen or halogen atom or a trifluoromethyl group, and unless mentioned otherwise, the above-mentioned alkyl moieties may each contain 1 to 3 carbon atoms and the above-mentioned halogen atoms are each fluorine, chlorine or bromine can mean
their enantiomers, diastereomers and geometric isomers as well as their salts. 2. Phenylcyclohexylketone and their enol ether of the general formula I according to claim 1,
in the
X is a hydrogen atom,
Y and Z together represent an oxygen atom,
in the numbers 1 to 3,
R¹ and R², which may be the same or different, each represents a straight-chain alkyl group having 1 to 4 carbon atoms which may be terminally substituted by an aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group, or a straight-chain alkyl group having 2 to 4 carbon atoms terminated by a terminal Substituted hydroxy group,
R³ and R⁴ independently of one another each represent a hydrogen, fluorine or chlorine atom or a trifluoromethyl group,
their geometric isomers and their salts. 3. phenylcyclohexyl ketones and their enol ethers of the general formula I according to claim 1,
in the
X is a hydrogen atom,
Y and Z together represent an oxygen atom,
in the numbers 1 to 3,
R¹ is a methyl group optionally substituted by a methylaminocarbonyl group, the ethyl, 2-hydroxyethyl or 3-hydroxypropyl group,
R² is the methyl or ethyl group,
R³ is a hydrogen or chlorine atom or a trifluoromethyl group and
R⁴ represents a hydrogen or chlorine atom,
their geometric isomers and their salts. 4. The following compounds of general formula I according to claim 1:

• (1) 4-Chlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclohexyl] ketone
• (2) 4-Chlorophenyl- [4- (4- (N- (2-hydroxyethyl) -N-methylaminoethyl) phenyl) cyclohexyl] ketone
• (3) 3,4-dichlorophenyl- [4- (4-dimethylaminomethylphenyl) cyclohexyl] ketone

and their salts. 5. Physiologically acceptable salts of the compounds after min at least one of claims 1 to 4 with inorganic or or ganic 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 Inhibi tion of cholesterol biosynthesis, for treatment or prophylaxis of hyperlipidemias, for the treatment of disorders associated with excessive cell proliferation are related to Pro phylaxis and treatment of gallstone disease or treatment development 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 claim 6, characterized in that non-chemically A compound according to any one of claims 1 to 5 in a or more inert carriers and / or diluents is incorporated. 10. A process for the preparation of the compounds according to at least one of claims 1 to 5, characterized in that

• a) an amine of the general formula II, in the
  R¹ is as defined in claims 1 to 4 and R² 'is a hydrogen atom or has the meanings mentioned in claims 1 to 4 for R², with a compound of general formula III, in the
  X, Y, Z, in, R³ and R⁴ are as defined in claims 1 to 4 and W¹ is a reactive leaving group, is reacted and optionally subsequently a compound of the general formula IV thus obtained, in the
  X, Y, Z, m, R¹, R³ and R⁴ are as defined in claims 1 to 4 defi ned, with a compound of general formula V, R² - W¹ (V) in the
  R² has the meanings mentioned in claims 1 to 4 and W¹ is defined as mentioned above, or
• b) for the preparation of compounds of the general formula I in which X and Y together form a bond and Z an alkoxy group having 1 to 6 carbon atoms, a phenylcyclohexanone of the general formula VI, in the
  m, R¹ and R² are as defined in claims 1 to 4, with a phosphonic ester of the formula VII, in the
  R³ and R⁴ have the meanings mentioned in claims 1 to 4, R⁵ is an alkyl radical having 1 to 3 carbon atoms and Z is an alkoxy group having 1 to 6 carbon atoms, is reacted or
• c) for the preparation of compounds of general formula I in which X represents a hydrogen atom and Y and Z together represent an oxygen atom, an enol ether of general formula VIII, in the
  m and R¹ to R⁴ have the meanings mentioned in claims 1 to 4 and Z represents an alkoxy group with I to 6 carbon atoms, is split hydrolytically and
  optionally present in the radicals R¹ and / or R² of a compound of general formula VI existing free hydroxyl groups or aminocarbonyl groups before carrying out the reaction b) ge and the protective groups after completion of the reaction are split off again and
  if desired, a mixture of the geometric isomers of a compound of the general formula I thus obtained is separated into the pure equatorial-equatorial (e, e) or equatorial-axial (e, a) sub-substituted phenylcyclohexyl ketones, or
  a compound of general formula I thus obtained is converted into its salt with an inorganic or organic acid.