DE4407135A1 - New heterocyclyl substd. aryl-cycloalkyl:amine derivs. - Google Patents

Abstract

Heterocyclyl-substd. aryl-cycloalkylamine derivs. of formula (I) and their salts are new: A = 1-17C alkylene, 2-17C alkenylene, 2-4C alkynylene, or a single bond; X = CO or SO2; Y = O, S, or N(R<11>); R<1>-R<6> = H; or 1-3 of R<1>-R<6> = alkoxycarbonyl and/or opt. substd. 1-4C alkyl; or 1-3 of R<1>, R<3> and R<5> = opt. substd. Ph; R<7> = H, halo, alkyl, or alkoxy; R<8>, R<11> = H or alkyl; R<9> = H, 1-6C alkyl, 3-6C cycloalkyl, allyl, or propargyl, or opt. substd. Bz; R<10> = H, 3-6C cycloalkyl, naphthyl, pyridyl, or opt. substd. Ph, tetrahydronaphthyl, or thienyl; n, p = 0 or 1; m = 1 or 2; cpds. where A is a single bond, X = SO2 and R<10> = H are excluded.

Description

The present invention relates to arylcycloalkylamines, their Salts with physiologically acceptable organic and anorga niche acids, process for the preparation of these compounds 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-4,751,237, EP-A-0 462 667, US-A-4,983,597).

Inhibitors of the enzyme HMG-CoA reductase make 3,5-dihy Mevinoline-type droxycarboxylic acids and their δ-lactones are their representatives lovastatin, simvastatin and pravastatin in the therapy of hypercholesterolemia use find. Further possible fields of application of these compounds are Fungal infections (US-A-4,375,475, EP-A-0 113 881, US-A-5,106,992), skin diseases (EP-A-0 369 263) as well as  Gallstones and tumors (US-A-5,106,992; Lancet 339, 1154-1156 [1992]). Inhibition of proliferation smooth muscle cells 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-0 409 181 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, 18075-18078, [1990]) and Fluorosqualene derivatives having hypocholesterolemic activity (US-A-5,011,859). 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-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-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 89/08450, J. Biol. Chemistry 254, 11258-11263  [1981], Biochem. Pharmacology 37, 1955-1964 [1988] and J 64 003 144), further by 2-aza-2,3-dihydrosqualene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 [1985]), by squalene epoxide vinyl ethers (J. Chem. Soc. Perkin Trans. I, 1988, 461) and 29-methylidene-2,3-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 Pat. No. 5,041,432, J. Biol. Chemistry 266, 20070-20078 [1991], US-A-5,034,548). 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, 18075-18078 [1990]).  

Upon inhibition of biosynthetic steps after conversion of 2,3-Epoxisqualen in Lanosterol there is a risk of Accumulation of intermediates with steroid structure in the Organism and the triggering 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, 18075-18078 [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 arylcycloalkylamines of the present invention and their Salts have the general formula I. The compounds kön optionally also in the form of enantiomers, diastereo or mixtures thereof.  

In the general formula I mean
n are the numbers 0 or 1,
m the numbers 1 or 2,
p 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,
X is a carbonyl or sulfonyl group,
Y is an oxygen or sulfur atom or a <NR¹¹ group,
R¹ to R⁶ each represent a hydrogen atom or
one, two or three of the radicals R¹ to R⁶, where the radicals may be identical or different, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, by a hydroxy, alkoxy, alkylthio or dialkylamino group or by an optionally a halogen atom or an alkyl group substituted phenyl group may be substituted, or an alkoxycarbonyl group and the remaining of the radicals R¹ to R⁶ each represents a hydrogen atom, wherein one, two or all three of R¹, R³ and R⁵ is also an optionally by an alkyl group or a halogen atom substituted phenyl group may mean
R⁷ is a hydrogen or halogen atom, an alkyl or alkoxy group,
R⁸ is a hydrogen atom or an alkyl group,
R⁹ is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an allyl, propargyl or a benzyl group optionally substituted by a halogen atom,
R¹⁰ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by a halogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl, alkoxy, cyano, nitro, alkylsulfonyl or phenyl group, a phenyl group substituted by two trifluoromethyl groups, two to five halogen atoms or by a halogen atom and an alkyl group, a naphthyl or tetrahydronaph group optionally substituted by a fluorine atom, a pyridyl group or a thienyl group optionally substituted by a halogen atom or an alkyl group,
R¹¹ represents a hydrogen atom or an alkyl group,
wherein A can not be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
wherein, unless mentioned otherwise, the above-mentioned alkyl, alkoxy, alkylthio and alkylsulfonyl radicals may each contain 1 to 3 carbon atoms and the aforementioned halogen atoms may each mean a fluorine, chlorine or bromine atom.

Preference is given to the compounds of general formula I in which
n are the numbers 0 or 1,
m the numbers 1 or 2,
p is the number O or 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,
X is a carbonyl or sulfonyl group,
Y is an oxygen atom or a <NR¹¹ group,
R¹ to R⁴ each represent a hydrogen atom or
one or two of R¹ to R⁴ independently of each other each of a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and the remaining of the radicals R¹ to R⁴ each represents a hydrogen atom,
R⁵ and R⁶, which may be the same or different, represent a hydrogen atom or a methyl group,
R⁷ is a hydrogen or halogen atom, a methyl or methoxy group,
R⁸ is a hydrogen atom or a methyl group,
R⁹ is a hydrogen atom or an alkyl group,
R¹⁰ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl groups or by a halogen atom and an alkyl group, optionally in the 4-position by a fluorine atom substituted 1-naphthyl group, a 2-naphthyl group, a 1,2,3,4-tetrahydro-2-naphthyl group, a pyridyl or 4-biphenyl group or an optionally substituted by a halogen atom Thie nylgruppe and
R¹¹ represents a hydrogen atom or a methyl group,
wherein A can not be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
wherein, unless otherwise stated, the above-mentioned alkyl moieties can each contain 1 to 3 carbon atoms ent and the above-mentioned halogen atoms may each mean a fluorine or chlorine atom whose enantiomers, diastereomers and their salts.

Particularly preferred are the compounds of the general For mel I, in the
n is the number 0
in the number 1,
p is the number 1,
A is a single bond,
X is a carbonyl group,
Y is an oxygen atom,
R¹ to R⁴ each represent a hydrogen atom,
R⁷ and R⁸ each represent a hydrogen atom,
R⁹ is a methyl group,
R¹⁰ represents a phenyl group optionally substituted by a fluorine, chlorine or bromine atom in position 4,
and their salts,
but especially the connection

• (1) trans -N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazoline) 2-yl) phenyl] cyclohexylamine.

production methods

The compounds of general formula I can be manufactured len by reacting a compound of the general formula II

in the
m, p, A, X and R⁷ to R¹⁰ are as defined above and R¹² is an alkyl radical having 1 to 10 carbon atoms, with a compound of general formula III,

in which n, Y and R¹ to R⁶ are as defined above.

The reactions are conveniently carried out in a suitable Solvent, for. In an alcohol such as methanol, ethanol or propanol, in an ether such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane, in di methylformamide, dimethyl sulfoxide or in a mixture of aforementioned solvent, optionally in Anwe senheit of a hydrogen halide-binding agent such ter tiary amines, sodium carbonate or calcium carbonate in one Temperature between 0 and 100 ° C performed. Preferably However, the reaction is in an alcohol such as methanol or Ethanol at a temperature between 20 and 80 ° C Runaway leads. Advantageously, the compounds of the general my formula II as salts, preferably as hydrochlorides, used and the reaction in the presence of inorganic or organic bases, preferably tertiary organic Amines such as triethylamine or ethyldiisopropylamine or a Excess of the compounds of the general formula III guided.

The compounds prepared by the above process 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,  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.

In the compounds of the formula I according to the invention the aryl radical bound to the cycloalkyl ring and the stick atom atom either equatorial or axial arrangement einneh men. The invention includes both the pure isomers and the mixtures of the different isomers.

Preparation of the starting compounds

The starting compounds of general formula II can be as follows:

First, a compound of general formula IV,

in the m, p, R⁷ and R⁸ are as defined above, with an amine the formula R⁹NH₂ reductively aminated and then with a Acylating agent of the formula V,

R¹⁰-A-X-Z (V)

in the R¹⁰, A and X are as defined above and Z is a reactive Leaving group such as a halogen atom, converted to a corresponding compound of formula VI,  

The compounds of the formula VI can be prepared according to known Me Methods (Chem. Ber. 9388 (1960) and Chem. Ber. 107, 1221-1227 (1974)) into the corresponding cyano compounds of the all common formula VII,

Transform by treating with an alcohol of For mel R¹²OH in the presence of hydrogen chloride in the Verbindun can be converted gene of formula II.

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 HMG-CoA reductase inhibitors such as Lovasta tin, 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 339, 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 For mel 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 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. After addition of 200 μmol / l of 2-¹⁴C- Acetate for another two hours at 37 ° C in the incubator on 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.

The connection

• (1) = trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazoline) 2-yl) phenyl] cyclohexylamine

has at these concentrations an inhibitory effect of -88.19% and -70.51% respectively.

As mentioned above, in the literature isolated Inhi bitoren the enzyme 2,3-Epoxisqualen lanosterol cyclase be described, but structurally very different from the compounds of formula I according to the invention. The compounds structurally closest to the compounds of general formula I are described in EP 0 468 457 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 gift

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.

The compound showed thereby a 2,3-Epoxisqualen Konzentra tion of 0.52 and 2.75 μg / ml in the plasma of the 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 materials:

Example A cis- and trans-N-methyl-4-phenylcyclohexylamine

22.4 g of 4-phenylcyclohexanone and 150 ml of a 9% solution of methylamine in toluene are reacted with 10 g of molecular sieve 4 Å and stirred for three days at room temperature. It is aspirated from the molecular sieve and the toluene evaporated. The residue was dissolved in 100 ml of methanol and at 0 ° C., 4.5 g of sodium borohydride were added in portions. The mixture is stirred for two more hours at room temperature, the methanol is evaporated, the residue triturated with water, coated with ethyl acetate over, acidified with 2N hydrochloric acid and then adjusted to pH 12 with 6N sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried with magnesium sulfate and concentrated. The residue is purified by column chromatography on aluminum oxide (petroleum ether / ethyl acetate = 1: 1, v: v). This gives first 4.5 g of the cis compound of R _f value 0.52 and then 9.7 g of the trans-Ver bond of R _f value 0.27.

Example B trans-N- (4-chlorobenzoyl) -N-methyl-4-phenylcyclohexylamine

9.7 g of trans-N-methyl-4-phenylcyclohexylamine and 5.7 g Triethylamine are presented in 300 ml of ethyl acetate  and, at room temperature, it becomes 9.9 g of 4-chlorobenzoyl chloride dropwise. After one hour, one after the other with water, Sodium hydroxide solution, water and finally with saturated sodium chloride washed solution, dried with magnesium sulfate and turned evaporated. The residue is recrystallized from ethyl acetate lisiert. This gives 13.2 g of colorless crystals with a Melting point of 146 ° C.

Example C trans-N- (4-chlorobenzoyl) -N-methyl-4- (4-formylphenyl) cyclo hexylamine

To 8.5 g of trans -N- (4-chlorobenzoyl) -N-methyl-4-phenylcyclo hexylamine in 80 ml of methylene chloride at -5 ° C 14.9 g of Ti tantetrachlorid added. Become the orange solution without external cooling 12.0 g of dichloromethyl methyl ether to quickly dripped. Upon heating to 30-35 ° C, hydrogen chloride sets winding and it forms a dark precipitate. To About 4 hours is poured onto 200 ml of ice water and 25 minutes stirred. It is extracted three times with 100 ml of ether, the organic extract with water, sodium bicarbonate solution and washed with saturated brine. After drying over Magnesium sulfate is evaporated. This gives 8.93 g of a gel ben solid.

Example D trans-N- (4-chlorobenzoyl) -N-methyl-4- (4-cyanophenyl) cyclohexylamine

To 8.37 g of trans -N- (4-chlorobenzoyl) -N-methyl-4- (4-formyl phenyl) cyclohexylamine in 30 ml of pyridine are first 1.72 g Hydroxylamine hydrochloride in 6 ml of water and then 5 g of triethyl given amine. After 45 minutes, 50 ml of methylene chloride diluted and there are 1.175 g of copper (II) sulfate (pentahydrate) added. After 30 minutes, 5.8 g of N, N'-dicyclohexyl  carbodiimide in 15 ml of methylene chloride and after one hour 2 g Copper II sulfate (pentahydrate) added. After two hours at 40 ° C is added some formic acid, diluted with ether, filtered off, the filtrate with 2N hydrochloric acid, water, Natriumbicar carbonate and once more shaken out with water, with magnesium sulphate dried and evaporated. After column chromatography (Kie selgel, petroleum ether / ethyl acetate = 1: 1) gives 4 g the title compound as a colorless foam.

Example E trans-N- (4-chlorobenzoyl) -N-methyl-4- (4-methoxyimidoyl phenyl) cyclohexylamine hydrochloride

In a solution of 4 g of trans -N- (4-chlorobenzoyl) -N-methyl-4- (4- cyanophenyl) cyclohexylamine in 85 g of methanol become 70 g of chlorine hydrogen gas introduced. After stirring overnight at room temperature is evaporated, dissolved in methanol and again evaporated. 5 g of the title compound are obtained as colorless Crystals.  

Example for the production of the final products:

example 1 trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazolin-2-yl) phenyl] cyclohexylamine

5 g (11.9 mmol) of trans -N- (4-chlorobenzoyl) -N-methyl-4- (4- methoxyimidoylphenyl) cyclohexylamine hydrochloride, 3 g (23.8 mmol) ethyldiisopropylamine, 0.943 g (15.4 mmol) of ethane nolamin are dissolved in 30 ml of ethanol and allowed to stand for two hours Reflux heated. It is evaporated, ver with 50 ml of water rubbed and sucked off. After column chromatography on silica gel (Methylene chloride / methanol = 40: 1, v: v) gives 2.3 g (48.9% of theory) colorless crystals of melting point 200 ° C.

¹H-NMR spectrum (200 MHz, CDCl₃), signals at ppm: 1.3-1.5 (m, 1H); 1.6-2.1 (m, 7H); 2.4-2.6 (m, 1H); 2.8-3.1 (M, 3H); 3.6 and 4.6 (2m, 1H); 4.0 (t, 2H); 4.4 (t, 2H); 7.1-7.4 (m, 6H) 7.75 (d, 2H).  

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

Example I Tablets containing 5 mg of trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazolin-2-yl) phenyl] cyclohexylamine

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

Example II Drag'es with 5 mg of trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazolin-2-yl) propenyl] cyclohexylamine

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.
Drag'e weight: 300 mg.

Example III Suppositories containing 5 mg trans-N- (4-chlorobenzoyl) -N-methyl- 4- [4- (2-oxazolin-2-yl) propenyl] cyclohexylamine

composition 1 suppository contains: active substance 5.0 mg Suppository mass (eg Witepsol W 45®) 1 695.0 mg 1 700.0 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 containing 5 mg of trans-N- (4-chlorobenzoyl) -N-methyl- 4- [4- (2-oxazolin-2-yl) propenyl] cyclohexylamine

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 trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazolin-2-yl) propenyl] cyclohexylamine

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 cooled temperature.  

The following example describes the production of a feed by means of laying hens:

Example VI Feed for laying hens, containing as active ingredient trans-N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazoline 2-yl) propenyl] cyclohexylamine

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. Arylcycloalkylamines of the general formula I, in the
n are the numbers 0 or 1,
m the numbers 1 or 2,
p is the numbers 0 or 1,
A is 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,
X is a carbonyl or sulfonyl group,
Y is an oxygen or sulfur atom or a <NR¹¹ group,
R¹ to R⁶ each represent a hydrogen atom or
one, two or three of the radicals R¹ to R⁶, where the radicals may be identical or different, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, by a hydroxy, alkoxy, alkylthio or dialkylamino group or by an optionally a halogen atom or an alkyl group-substituted phenyl group may be substituted, or an alkoxycarbonyl group and the remaining of the radicals R¹ to R⁶ each represents a hydrogen atom,
where one, two or all three of the radicals R¹, R³ and R⁵ can also be a phenyl group optionally substituted by an alkyl group or a halogen atom,
R⁷ is a hydrogen or halogen atom, an alkyl or alkoxy group,
R⁸ is a hydrogen atom or an alkyl group,
R⁹ is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an allyl, propargyl or a benzyl group optionally substituted by a halogen atom,
R¹⁰ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by a halogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl, alkoxy, cyano, nitro, alkylsulfonyl or phenyl group, a phenyl group substituted by two trifluoromethyl groups, two to five halogen atoms or by a halogen atom and an alkyl group, a naphthyl or tetrahydronaph group optionally substituted by a fluorine atom, a pyridyl group or a thienyl group optionally substituted by a halogen atom or an alkyl group,
R¹¹ represents a hydrogen atom or an alkyl group,
wherein A can not be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
Unless otherwise stated, the abovementioned alkyl, alkoxy, alkylthio and alkylsulfonyl radicals may each contain 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. Arylcycloalkylamine of the general formula I according to claim 1,
in the
n are the numbers 0 or 1,
m the numbers 1 or 2,
p is the number O or 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,
X is a carbonyl or sulfonyl group,
Y is an oxygen atom or a <NR¹¹ group,
R¹ to R⁴ each represent a hydrogen atom or
one or two of the radicals R¹ to R⁴ are each independently a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and the remaining radicals R¹ to R⁴ are each a hydrogen atom,
R⁵ and R⁶, which may be the same or different, are a hydrogen atom or a methyl group,
R⁷ is a hydrogen or halogen atom, a methyl or methoxy group,
R⁸ is a hydrogen atom or a methyl group,
R⁹ is a hydrogen atom or an alkyl group,
R¹⁰ represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl groups or by a halogen atom and an alkyl group, optionally in the 4-position by a fluorine atom substituted 1-naphthyl group, a 2-naphthyl group, a 1,2,3,4-tetrahydro-2-naphthyl group, a pyridyl or 4-biphenyl group or an optionally substituted by a halogen atom Thie nylgruppe and
R¹¹ represents a hydrogen atom or a methyl group,
wherein A can not be a single bond when X is the sulfonyl group and R¹⁰ is a hydrogen atom, and
wherein, unless stated otherwise, the abovementioned alkyl moieties can each contain 1 to 3 carbon atoms and the abovementioned halogen atoms may each represent a fluorine or chlorine atom,
their enantiomers, diastereomers and their salts. 3. Arylcycloalkylamine of the general formula I according to claim 1,
in the
n is the number 0
m is the number 1,
p is the number 1,
A is a single bond,
X is a carbonyl group,
Y is an oxygen atom,
R¹ to R⁴ each represent a hydrogen atom,
R⁷ and R⁸ each represent a hydrogen atom,
R⁹ is a methyl group,
R¹⁰ represents a phenyl group optionally substituted by a fluorine, chlorine or bromine atom in position 4,
and their salts. 4. The following compound of general formula 1 according to claim 1:

• (1) trans -N- (4-chlorobenzoyl) -N-methyl-4- [4- (2-oxazolin-2-yl) phenyl] cyclohexylamine

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 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 at least one of claims 1 to 5, characterized in that
a compound of general formula II, in which m, p, A, X and R⁷ to R¹⁰ as defined in claims 1 to 4 defi ned and R¹² represents an alkyl group having 1 to 10 carbon atoms, with a compound of general formula III, in which n, Y and R¹ to R⁶ are as defined in claims 1 to 4, is reacted and
if desired, a compound of general formula I thus obtained is converted into its salt with an inorganic or organic acid.