SK107393A3 - Aryliden-1-azacycloalkanes and arylalkyl-1-azacycloalkanes their salts, treatments compositions contained them compounds and their use and method of its production - Google Patents

Abstract

The invention relates to arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula <IMAGE> in which n, m, p, A, W<1>, W<2>, X, Y and R<1> to R<11> are defined as in Claim 1, their isomers and isomer mixtures and their salts, which have useful properties and in particular exert an inhibitory action on cholesterol biosynthesis.

Description

The importance of elevated serum cholesterol as a major risk factor for the development of atherosclerotic vascular changes is well known. Clinical studies have shown that by reducing serum cholesterol, the risk of coronary disease may be reduced (Current Opinion in Lipidology 2 (4), 234 (1991)). Since most of the cholesterol is synthesized in the body itself and only a minor part is consumed by food, reducing biosynthesis is a particularly attractive way to lower cholesterol.

In addition, other possible uses of cholesterol synthesis suppression for the treatment of hyperproliferative skin and vascular diseases as well as cancer, the treatment and prophylaxis of gallstones as well as mycosis are described as other possible applications. In the latter case, it is an intervention in ergosterol biosynthesis in fungal organisms, which is analogous to cholesterol biosynthesis in mammalian cells.

The synthesis of cholesterol or ergosterol proceeds starting from acetic acid and proceeding through a number of reaction steps. This multi-stage process provides a range of intervention options that include:

To inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) -synthesis, lactones and β-lactams with potential antihypercholesterolemic activity are selected (see J. Antibiotics 40, 1356 (1987), US-A-4751237 EP-A-0 462667

US-A-498,397).

The HMG-CoA reductase inhibitors are 3,5-dihydroxycarboxylic acids of the mevinolinic type and their δ-lactones, whose representatives of lovastatin, simvastatin and pravastatin are used in the treatment of hypercholesterolemia. Other possible areas of use for these compounds are fungal infections (US-A-4375475, EP-A-0113881, US-A-5106992), skin diseases (EP-A-0369263) as well as gallstone formation and cancer (US-A -5106992, Lancet 339, 1154-1156 (1992) Cardivasc Drugs Ther 5, Suppl 3, 354 (1991) discloses suppression of smooth muscle cell proliferation by lovastatin.

Squalene synthetase enzyme inhibitors are e.g. isoprenoid (phosphinylmethyl) phosphonates, their suitability for the treatment of hypercholesterolemia, bile stone formation and cancer are described in EP-A-0409181 as well as in J. Med. Chemistry 34, 1912 (1991), further described are squalestatins with cholesterol lowering activity and antifungal activity (J. Antibiotics, 45, 639-647 (1992) and J. Biol. Chemistry 267,

11705-11708 (1992).

Allylamines such as naphthifine and xerbinafine have been known as inhibitors of the squalene epoxidase enzyme, which have been used in the treatment of fungal diseases and allylamine NB-598 with antihypercholesterolemic activity (J. Biol. Chemistry 265, 18075-18078 (1990)) and fluorosqualene derivatives with hypocholesterolemic effect (US-A-5011859). Others are piperidines and azadecalins, where potential hypocholesterolemic and / or antifungal activity is described, their mechanism of action is not clearly elucidated and which are squalene epoxidase inhibitors and / or 2,3-epoxisqualene lanosterol cyclase inhibitors (EP-A-0420116, EP -A-0468434, US-A-5084461 and EP-A-0468457).

Examples of 2,3-epoxisqualene-lanosterol cyclase enzyme inhibitors are diphenyl derivatives (EP-A-0464465), aminoalkoxybenzole derivatives (EP-A-410359) as well as piperidine derivatives (J. Org. Chem. 57, 2794-2803, (1992) )) which exhibit antifungal activity. Furthermore, these enzymes in mammalian cells are inhibited by decalin, azadecalin, and indand derivatives (WO 89/084450, J. Biol. Chemistry 254, 11258-11263 (1981), Biochem. Pharmacology 37, 1955-1964 (1988) and J 64 003 144). 2-aza-2,3-dihydrogenqualene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 (1985)), squalenoid epoxide vinyl ether (J. Chem. Soc, Perkin Trans. I, 1988, 461) and 29-methylidene-2,3-oxidosqualene (J. Amer. Chem. Soc. 113, 9673-9674 (1991)).

Finally, steroid derivatives with potential antihyperlipemic activity, which at the same time affect the HMG-CoA reductase enzyme (US-A-5041432, J. Biol. Chemistry 266, 20070-20078 (1991), US) are also mentioned as inhibitors of the enzyme lanosterol-14-demethylase. -A-5,034,548). In addition, this enzyme is inhibited by azole-type antifungals which are N-substituted imidazoles and triazoles. This class includes, for example, the commercially available antimycotics ketoconazole and fluconazole.

The compounds of the following formula I are new. They were surprisingly found to be very potent inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase (international classification: EC5.4.99.7).

The enzyme 2,3-epoxysqualene-lanosterol cyclase catalyzes a key step in cholesterol or ergosterol biosynthesis in the biosynthesis cascade. Inhibitors of this enzyme over inhibitors of the earlier biosynthesis step, such as e.g. HMG-CoA synthase and HMG-CoA reductase have the advantage of higher selectivity, since inhibition of these previous steps leads to the removal of biosynthetically formed mevalonic acid, and thus also the biosynthesis of the mevalonic acid dependent substances of Dolichol, ubichone-isopentone and isopenyl can be negatively affected. RNA (cf. J. Biol. Chemistry 265, 18075-18078 (1990)).

Inhibition of the biosynthesis steps following the reaction of 2,3-epoxysqualene to lanosterol creates the risk of multiplication of intermediates with a stereogenic structure in the body and thus of toxic effects. This is described, for example, for triparanol, a desmosterol reductase inhibitor. This substance had to be withdrawn from the market due to cataract formation, ichtiosis and alopecia (cited in J. Biol. Chemistry 265, 18075-18078 (1990)).

As mentioned, 2,3-epoxysqualene-lanosterol cyclase inhibitors are described individually in the literature. However, the structures of these compounds are different from the structures of the compounds of the present invention having the general formula I below.

The invention encompasses the preparation of antihypercholesterolemic substances which are suitable for the treatment and prophylaxis of atherosclerosis and, in comparison with known active substances, exhibit improved antihypercholesterolemic activity with increased selectivity and thus higher safety. Since the compounds of the invention, because of their high potency as inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase, can also inhibit ergosterol biosynthesis in songs, they are also suitable for the treatment of mycoses.

The arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the present invention and their salts have the general formula

I. The compounds may optionally also be in the form of their enantiomers, diastereomers or mixtures thereof.

n number 0 or 1, m number 1 or 2, p number 0 or 1,

A is a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms, an alkylene group having 2 to 17 carbon atoms, or an alkynylene group having 2 to 4 carbon atoms,

V is a hydrogen atom or together form a carbon-carbon bond,

X is a carbonyl or sulfonyl group,

Y represents an oxygen or sulfur atom or a group> NRH; to R ** represents a hydrogen atom or one, two or three radicals to, which radicals may be the same or different, represent a straight or branched alkyl group having from 1 to 4 carbon atoms which may be substituted by hydroxy-, alkoxy-, alkylthio- or a dialkylamino group or optionally a halogen atom or an alkyl-substituted phenyl or alkoxycarbonyl group and the other radicals R @ 1; each of R 1, R 2 and R 2 may be an alkyl group or a halogen-substituted phenyl group,

R represents a hydrogen or halogen atom, an alkyl or alkoxy group;

R and R are each independently hydrogen or alkyl,

R ¹⁰ represents a hydrogen atom, a C 3 -C 6 cycloalkyl group or a halogen atom, a straight or branched C 1 -C 4 alkyl group, a trifluoromethyl-, alkoxy-, cyano-, nitro-, alkylsulfonyl- or a phenyl-substituted phenyl group , two trifluoromethyl groups, two to five halogen atoms or a halogen atom and an alkyl-substituted phenyl group, optionally a fluorine-substituted naphthyl or tetrahydronaphthyl group, a pyridyl group or optionally a halogen atom or an alkyl-substituted thienyl group,

R ¹¹ represents a hydrogen atom or an alkyl group, where A cannot be a single bond when X represents a sulfonyl group and a hydrogen atom and, unless otherwise stated, the alkyl, alkoxy, alkylthio and alkylsulfonyl radicals may each contain 1 to 3 atoms carbon and the said halogen atoms may in each case be a fluorine, chlorine or bromine atom.

Preferred are compounds of formula Ia

NXAR ( ^CH 2) / ^{2 P} (Ia) where n is 0 or 1, m is 1 or 2, p is 0 or 1,

A represents a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms, an alkylene group having 2 to 4 carbon atoms or an alkynylene group having 2 to 4 carbon atoms,

2

V and M are each hydrogen or together form a carbon-carbon bond,

X is a carbonyl or sulfonyl group,

Y represents an oxygen or sulfur atom or a group> NR ¹¹ , R ¹ to R ⁴ represent a hydrogen atom or one or two of the radicals R ¹ to R ⁴ independently represent a straight or branched alkyl group having 1 to 4 carbon atoms, which may be substituted with hydroxy, alkylthio or dialkylamino or optionally halogen substituted phenyl or phenyl and the other radicals R ¹ to R ⁴ represent a hydrogen atom,

R 6 and R 6, which may be the same or different, represent a hydrogen atom or a methyl group,

R? represents a hydrogen atom or a halogen atom, an alkyl or alkoxy group,

R @ 5 represents a hydrogen atom or an alkyl group,

R 6 represents a hydrogen atom,

R ¹⁰ is hydrogen, cycloalkyl having 3 to 6 carbon atoms, optionally with one or two halogen atoms, linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methoxy, cyano, nitro, methylsulfonyl or phenyl substituted phenyl, two trifluoromethyl or halogen and methyl substituted phenyl, three to five fluorine substituted phenyl, optionally fluorine substituted naphthyl, tetrahydronaphthyl or pyridyl, or optionally halogen substituted thienyl and thienyl;

R ¹¹ represents a hydrogen atom or an alkyl group, where A cannot be a single bond when X represents a sulfonyl group and R ¹⁰ represents a hydrogen atom, and unless otherwise stated the above alkyl radicals may each contain 1 to 3 carbon atoms and the above mentioned halogen aromatics can in each case mean fluorine, chlorine or bromine aromatics, their enantiomers, diastereomers and their salts.

Particularly preferred are compounds of formula Ia wherein n is 0 or 1, m is 1 or 2, p is 0 or 1,

A represents a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms or an alkylene group having 2 to 4 carbon atoms,

Ί

V and V are each hydrogen or together form a carbon-carbon bond,

X is a carbonyl or sulfonyl group,

Y represents an oxygen atom or a group> NR ⁴⁴ ,

R ³ to R ⁴ are each hydrogen or one or two radicals independently of each other are straight or branched (C 1 -C 4) alkyl and the other radicals R ³ to R ⁴ are each hydrogen, r 5a, which may be be the same or different, represent a hydrogen atom or a methyl group,

R 'represents a hydrogen or halogen atom, a methyl or methoxy group,

Q

R represents a hydrogen atom or a methyl group,

R 6 represents a hydrogen atom,

R ³ · ® represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, optionally one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl or halogen atoms and an alkyl substituted phenyl group, in the 4-position optionally a fluorine-substituted 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, pyridyl or 4-biphenyl group or an optionally halogen-substituted thienyl group and rH represents a hydrogen atom or a methyl group wherein A cannot be a single bond when X is a sulfonyl group and R ³ · ⁸ is a hydrogen atom and, unless otherwise stated, the above alkyl moieties may each contain 1 to 3 carbon atoms and the aforementioned halogen atoms may each a fluorine atom, a chlorine atom, their enantiomers, diastereomers and their salts.

The most convenient are compounds of formula Ia where - n means a number 0 or 1 m means a number First - P means a number 0 or 1 A means single bond,

9

V and V are each hydrogen or together form a carbon-carbon bond,

X is a carbonyl group,

Y is an oxygen atom,

R ¹ to R ** are each hydrogen,

R represents a hydrogen or halogen atom or a methyl group,

R (a) in each case represents a hydrogen atom, in the 4-position represents a fluorine, chlorine or bromine atom or a trifluoromethyl substituted phenyl, 4-chloro-3-methylphenyl, 5-chloro-2-thienyl or cyclohexyl group and their salts, in particular

1) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine;

2) 1- (4-chlorobenzoyl) -4- (4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine;

3) 4- [4- (2-oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine;

4) 1- (4-chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine;

5) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine;

6) 1- (5-chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine;

7) 1-cyclohexanecarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine;

8) 4- [4- (2-oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine;

(9) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine;

10) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine;

11) 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine;

12) 1- (4-chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine and salts thereof.

Production methods:

The compounds of formula (I) may be prepared by the following methods:

a) reaction of compounds of formula II

where

Q, m, p, A, V, V, X and R to R have the above meanings and 1

R is C 1 -C 10 alkyl with compounds of formula III

(III) wherein n, Y and R ¹ to R ⁶ are as previously defined.

The reaction is preferably carried out in a suitable solvent, e.g. an alcohol such as methanol, ethanol or propanol, in an ether such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane, in dimethylformamide, dimethylsulfoxide or in a mixture of the solvents mentioned, optionally in the presence of a hydrogen halide binding agent such as tertiary amines, carbonate sodium or calcium carbonate at a temperature between 0 to 100 ° C. Preferably, however, the reaction is carried out in an alcohol such as methanol or ethanol at a temperature between 20 to 80 ° C. Preferably, the compounds of formula II are used as salts, preferably hydrochloride, and the reaction is carried out in the presence of inorganic or organic bases, preferably tertiary organic amines or ethyldiisopropylamine, or in excess of compounds of formula III.

b) For the preparation of compounds of formula I wherein n, m, p. A, X, Y and R ¹ and R ¹⁰ have the above meanings and V ¹ and V ² together form a carbon-carbon bond:

by reacting phosphonoesters of formula IV

R

R

R

R

R

R

//

OR (IV) wherein n, Y and R ¹ to R ⁶ have the above meanings and

R is C 1 -C 10 alkyl with compounds of formula V

N - X - A - R (V) wherein m, p, A, X, R ⁹ and R ¹⁰ are as defined above.

The reactions are preferably carried out in a suitable solvent, e.g. in an ether such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane or in a hydrocarbon such as benzene, toluene, n-hexane or cyclohexane or in a mixture of the solvents mentioned, preferably in a mixture of tetrahydrofuran and n-hexane or tetrahydrofuran; cyclohexane. The compounds of formula (IV) are first converted into the corresponding phosphate anions at a temperature between -78 to 20 ° C by suitable bases such as n-butyllithium, phenyllithium, sodium amide, sodium hydride or lithium diisopropylamide and are then left at between -78 to 20 ° C. 100 ° C, preferably at a temperature between -15 to 50 ° C, react with compounds of formula V.

If the compound of formula (IV) contains a hydroxyl group, it is recommended to protect the compound with a suitable protecting group such as a silyl group and cleave the protecting group after the reaction is complete before carrying out the reaction. Suitable silylating agents are e.g. trimethylchlorosilane. The cleavage is carried out, for example, by acid hydrolysis or by treatment with fluoride ions, e.g. with cesium fluoride or tetrabutylammonium fluoride.

c) Reaction of compounds of formula VI

< ^CH 2> _p / (VI) where n, m, p, V · ·, V,, Y ar! to R ⁹ are as defined above, with compounds of formula VII

Z ¹ - X - A - R ¹⁰ (VII) where

A, X and R 6 are as defined above and

Z ¹ represents a reactive leaving group such as a halogen atom, preferably a chlorine atom or an imidazolide group.

When a halogen atom, the reactions are carried out in a suitable solvent such as diethyl ether, toluene, methylene chloride and the like, preferably at temperatures between -50 ° C and 50 ° C and in the presence of a hydrogen halide binding agent such as tertiary amines, sodium carbonate or calcium carbonate . Not only the free amines of the formula VI can be used, but also their salts, from which the amines can be liberated in situ by suitable bases, e.g. tertiary amines.

When Z is an imidazolide residue, the reactions are preferably carried out in an inert solvent such as xylene or tetrahydrofuran, at temperatures between room temperature and the boiling point of the reaction mixture.

If the compound of formula (VI) contains a hydroxy group, the reaction may be varied by using two equivalents of the compound of formula (VII) and, after the reaction, the ester group formed from the hydroxy group is saponified again.

The optional saponification of the thus formed ester group is preferably carried out by alkaline hydrolysis in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, optionally in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C.

d) For the preparation of compounds of formula I, wherein n, m, p,

7 * 9

X and R to R are as previously defined, A is a single bond or a straight or branched alkylene group having 1 to 17 carbon atoms, V and V ² 'are each a hydrogen atom and Y is an oxygen atom or a> NRH group, where R ¹¹ has as defined above, R ¹ to except alkylthio-substituted straight or branched (C 1 -C 4) alkyl and R ¹⁰ except optionally halogen-substituted thionyl groups have the previously defined meaning, where A can be a single bond when X is sulfonyl and R 1 ® represents a hydrogen atom:

^{! CH} 2> p /

N-X-A'-R (I) wherein

9 n, m, p, X and R to R 'are as defined above, A' represents a single bond or a straight or branched alkylene group having 1 to 17 carbon atoms, V and V together represent a carbon-carbon bond and Y 'represents an atom R @ 1 to R @ 6, with the exception of alkylthio substituted, straight or branched alkyl having 1 to 4 carbon atoms, and R ^{@ 1} , except for optionally halogen substituted thienyl groups, have the meanings given above, where A cannot be a single bond when X is a sulfonyl group and R ¹ is a hydrogen atom.

The hydrogenation is carried out in a suitable solvent such as an alcohol, for example methanol, ethanol or propanol, optionally in ethyl acetate, an ether, for example diethyl ether, tetrahydrofuran or dioxane, or mixtures thereof with catalytically released hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, rhodium, palladium, palladium on carbon, platinum or platinum on carbon and a hydrogen pressure of from 70 kPa to 3500 kPa, preferably 350 kPa to 700 kPa, at temperatures between 0 to 100 ° C but preferably at room temperature.

In the above hydrogenation may be mentioned a halogen atom in the radicals R ¹ to R @ optionally replace by hydrogen.

(e) For the preparation of compounds of the formula I wherein n, m, p, A, X, V ¹ , V ² and R ¹ to R ¹⁰ have the above meanings and Y represents an oxygen atom:

the compounds of formula VIII are cyclized

wherein n, m, p, A, X, V ¹ , V ² and R ¹ to R ¹⁰ are as defined above.

The cyclization is preferably carried out in a suitable solvent, e.g. in diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, methylene chloride, chloroform, benzene, toluene or n-hexane or in a mixture of these solvents in the presence of a water-withdrawing agent such as a combination of dialkyl azodicarbonate or triphenylphosphine triamide; (Burgess reagent) at a temperature between 0 to 150 ° C, preferably at a temperature between 0 to 100 ° C. The use of Burgess's reagent for the production of oxazoline is described in Tetrahedron Letters 33, 907-910 (1992). Another cyclization method is described in Tetrahedron Letters 33, 2807-2810 (1992).

The compounds of formula (I) prepared above can be purified by methods known per se, e.g. crystallization, distillation or chromatography and isolate. They can be converted into their inorganic or organic acid addition salts by known methods.

In the compounds of the present invention having the formula I, depending on the nature of the radicals R ¹ to R ⁶ , carbon atoms in optically active form can be associated therewith. The invention includes both pure isomers and mixtures of different isomers.

Starting materials:

The starting materials of formula II can be prepared from compounds of formula IX

(ix) where

7 10 m, p, A, W, M, X and R to R ^υ are as defined above and D is CN, reaction with alcohols of formula R ¹² OH wherein R ¹² is alkyl having 1 to 10 carbon atoms, in the presence of HCl.

Compounds of formula IX in which D represents a cyano or alkoxycarbonyl group are obtainable by reaction of phosphonoesters of formula X

(X) where

Q i 1

R and R are as defined above, R is C 1 -C 10 alkyl and D is cyano or 17 or alkoxycarbonyl, with ketones of formula V

X - A

R ¹⁰ (V) wherein m, p, A, X, and R 6 are as previously defined, in the presence of bases such as n-butyllithium, phenyllithium, sodium amide, sodium hydride or lithium diisopropylamide and optionally followed by hydrogenation of the olefinic bond thus obtained .

An alternative method for producing compounds of formula IX wherein m, p, A, V, X and R? ^^ and R are as defined above and D is alkoxycarbonyl or cyano, R 1 7 consists in that the phosphono ester of the formula X, wherein R, R and R @ ^J are as defined above, and D is cyano or alkoxycarbonyl, is reacted with a ketone of formula XI

- (CH

2'nT

- < ^CH 2>

N

(Ix)

R 1 wherein m, p and R 6 are as defined above.

The benzyl residue is then removed, for example by reaction with 1-chloroethyl chloroformate, by cleaving the formed urethane methanol and then reacting with compounds of formula VII

Z ¹ - X - A - R ¹⁰ (VII) where

A, X and R ¹ ® are defined as above, and EE represents a reactive leaving group such as e.g. a halogen atom, preferably a chlorine atom or an imidazolide group. The olefinic double bond may then, if desired, be hydrogenated.

Phosphonoesters of formula X may be prepared

Arbusow reaction from halides XII

CH

Hal (xii) where

R

R 1 and R 0 are as defined above, D represents a cyano- or alkoxycarbonyl group and Hal represents a halogen atom such as, for example, a chlorine or bromine atom and trialkylphosphites of the formula (Rj = O ^ P, where R ^XJ is as previously defined).

The Q variant of the reaction to produce compounds of formula X wherein R 0 is an alkyl group is that they are first prepared

Q compounds of formula X wherein R is hydrogen and these are then reacted with an alkylating agent of formula R-Z, where R 0 is a defined alkyl radical and Z is a halogen atom such as a chlorine, bromine or iodine atom or a sulfonyloxy group.

The starting compounds of the formulas III and XII are known from the literature or can be prepared by methods known per se.

The phosphonoesters of the formula IV can be obtained from the phosphonoesters of the formula XIII

(XIII) where

R 1, R c and R ^x are as defined above and

R ¹³ represents an alkyl group having 1 to 10 carbon atoms, by reaction with compounds of formula III.

Phosphonoesters of formula XIII are prepared from 2: phosphonoesters of formula X wherein D is cyano by reaction with alcohols of formula R OH, where R is as defined above, in the presence of hydrogen chloride.

Compounds of formula V are obtained by reacting compounds of formula XIV < ^CH 2> F (XIV) wherein m, p and R ⁹ are as defined above with compounds of formula VII.

The starting compounds of formula VI can be prepared from phosphonoesters of formula IV by reaction with compounds of formula XV (CH 2). ĺ m

^lCH 2 <

(XV) wherein m, R ⁹ PA are as hereinbefore defined and R ¹⁴ is triphenylmethyl or tert-butyloxycarbonyl group, in the presence of strong bases such as n-butyl lithium, phenyl lithium, sodium amide, sodium hydride or lithium diisopropylamide and optionally followed by catalytic hydrogenation of the formed olefinic20 as well as the cleavage of the radicals as defined above with trifluoroacetic acid, in the case of the triphenylmethyl compound, this protecting group can be simultaneously hydrolytically cleaved.

An alternative method of making compounds of the formula

ABOUT

VI, where p is 0, m is 1 and R 0 is hydrogen and n, V ¹ , V ² , Y, R ¹ to R ⁷ as well as R ⁹ are as defined above, is that the compound of the general formula of formula XVI

First

N I

COCH (xvi) wherein R ⁹ is as defined above with an aldehyde of formula XVII

(XVII) where

R &lt; 1 &gt; is as defined above while cleaving off the N-acetyl residue, then reacted with hydrogen chloride with an alcohol of formula R &lt; ¹² &gt; OH in which R &lt; ¹² &gt; is alkyl of 1 to 10 carbon atoms; of formula III

R>

NH (III) (C) -YH wherein n, Y and R1 to R ** have the same meanings as above.

Then, the amide group is reduced, for example, with lithium aluminum hydride and, if desired, the olefinic double bond is hydrogenated.

The starting compounds of formula (VIII) may be prepared from compounds of formula (IX) wherein m, p, M, V, X, A as well as R to R are as defined above and D represents an alkoxycarbonyl group, saponification of the alkoxycarbonyl group and reaction of the carboxylic acid formed. first with N, N'-carbonyldiimidazole and then with compounds of formula III, wherein R ⁴ to R 6 are as previously defined and Y represents an oxygen atom.

The compounds of formula I exhibit interesting biological properties. They are inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase. Due to their biological properties, they are particularly suitable for the treatment and prophylaxis of hyperlipidemia, in particular hypercholesterolaemia, hyperlipoproteinaemia and hypertriglyceridemia, and the resulting atherosclerotic vascular changes with their subsequent diseases such as coronary heart disease, cerebral ischemia, Claudicatio intermens, claudicatio intermens.

For the treatment of such diseases, the compounds of formula (I) may be used either alone as monotherapy or in combination with other substances that lower cholesterol or lipid content, whereby the compounds may preferably be formulated as oral preparations or optionally as suppositories as rectal preparations. As partners in such a combination, for example;

bile acid binding resins such as Cholestyramine, Cholestipol, and the like, compounds that inhibit cholesterol resorption, such as e.g. Sitosterol and Neomycin, compounds that interfere with cholesterol biosynthesis, such as e.g. HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin and the like; squalene epoxydase inhibitors such as e.g. NB 598 and analogous compounds as well as squalene synthetase inhibitors such as representatives of the isoprenoid (phosphinylmethyl) phosphonate and squalestitatin family.

Other possible combination partners include a group of fibrates such as clofibrate, bezafibrate, gemfibrozil and others, nicotinic acid, derivatives and analogs thereof such as acipimox as well as probucol.

Further, the compounds of formula I are useful in the treatment of diseases associated with excessive cell proliferation. Cholesterol is an essential cellular component and must be available in sufficient quantities for cell proliferation, i.e., cell division. For example, inhibition of cell proliferation by inhibiting cholesterol biosynthesis is exemplified by smooth muscle cells with the HMG-CoA reductase inhibitor lovastatin of the mevinoline type as previously described.

Examples of diseases associated with increased cell proliferation include cancer. In beech cultures and in vivo experiments, a decrease in serum cholesterol or intervention in cholesterol biosynthesis by HMG-CoA reductase inhibitors has been found to suppress tumor growth (Lancet 339, 1154-1156 (1992)). Therefore, the compounds of formula I are potentially useful for the treatment of cancer due to their inhibitory action on cholesterol biosynthesis. They can be used alone or in support of known therapeutic principles.

Other examples are hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, platelet epithelial carcinoma, keratosis, and keratinization disorders. The term psoriasis as used herein refers to hyperproliferative-inflammatory skin disease that alters the regulatory mechanism of the skin. In particular, lesions are formed which include primary and secondary changes in proliferation in the epidermis, inflammatory skin reactions, and expression of regulator molecules such as lymphokines and inflammatory factors. Psoriatic skin is morphologically marked by enhanced epidermal cell deposition, coarse epidermis, abnormal keratinization of the inflammatory cell infiltrate in the dermal layer, and polymorphonuclear infiltration of leukocytes into the epidermis that condition the basal cell cycle. Furthermore, hyperkeratotic and parakeratotic cells are present. The term keratosis, basal cell carcinoma, platelet epithelial carcinoma, and keratinization disorders refer to hyperproliferative skin diseases in which the regulatory mechanism of skin cell proliferation and differentiation is disrupted.

The compounds of formula I are effective as skin hyperproliferation antagonists, i. as agents that inhibit hyperproliferation of human keratinocytes. The compounds are useful as agents for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, keratinization disorders and keratosis. For the treatment of these diseases, the compounds of the formula I can be administered either orally or topically, and can be used either alone as monotherapy or in combination with known active compounds.

Surgical interventions such as PTCA (percutaneous transluminal coronary angioplasty) or bypass surgery to treat hyperproliferative vascular diseases such as stenosis and vascular occlusion caused by proliferation of smooth muscle cells may be mentioned. As mentioned above, this cell proliferation is known to be suppressed by HMG-CoA-reduction24 with mevinoline-type tase inhibitors such as lovastatin. Because of their inhibitory action on cholesterol biosynthesis, these compounds of formula I are also useful in the treatment and prophylaxis of these diseases, either alone or in combination with known active compounds such as e.g. intravenously administered heparin, preferably said compounds are administered orally.

Another possibility of using the compounds of the formula I according to the invention is the prophylaxis and treatment of gallstones. The formation of gallstones is explained by the fact that the concentration of cholesterol in the bile exceeds the maximum solubility of cholesterol in the gall bladder fluid, thereby excreting cholesterol in the form of gallstones. Lipid lowering agents from the fibrate family lead to increased secretion of neutral steroids by the bile and increase the tendency to form bile stones.

Nevertheless, cholesterol biosynthesis suppressants such as lovastatin or pravastatin do not lead to increased gallstone formation, but may cause a reduction in cholesterol concentration in the bile and thus reduce the so-called lithogenic index, a measure of the likelihood of gallstone formation. This is described in Gut 31, 348-350 (1990) as well as in Z. Gastroenterol. 29, 242-245 (1991).

In Gastroenterology 102, no. 4, no. 2, A 319 (1992) describes the efficacy of lovastatin for dissolving gallstones, particularly in combination with ursodeoxycholic acid. In view of their activity, the compounds of the formula I are therefore also suitable for the prophylaxis and treatment of gallstones. They can be used either alone or in combination with known therapies such as ursodeoxycholic acid or wave lithotripsy treatment, preferably by oral administration.

Finally, the compounds of formula I are suitable for the treatment of infections caused by pathogenic fungi such as e.g. Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp., And others. As mentioned above, the final product of sterol biosynthesis in fungal organism is not cholesterol, but ergosterol is essential for the integrity and function of fungal membranes. Inhibition of ergosterol biosynthesis therefore leads to growth disturbances and possibly to fungal death.

For the treatment of mycoses, the compounds of formula I may be administered either orally or topically. They can be used either alone or in combination with known antifungal agents, in particular those which interfere with other stages of sterol biosynthesis, such as, for example, squalene epoxidase-inhibiting agents - terbinafine and naphthifine or lanosterol-14a-demethylase-type azole inhibitors such as azole. for example, ketoconazole and fluconazole.

Another possibility of using the compounds of the formula I relates to the use in poultry farming. The decline in egg cholesterol using HMG-CoA reductase inhibitors of lovastatin on laying hens is described (FASEB Journal 4, A 533, Abstracts 1543 (1990)). The production of cholesterol-poor eggs is of particular interest, since the cholesterol load on the body by cholesterol-reduced eggs without altering nutrition can be reduced. In view of their inhibitory action on cholesterol biosynthesis, the compounds of formula (I) may also find use in raising poultry for the production of cholesterol-poor eggs, the substances being preferably used as an additive to feed.

The biological activity of the compounds of formula I was determined by the following methods:

I. Measurement of ¹⁴ C-acetate insertion into digitonin-precipitable steroids:

method:

Human liver cells (HEP-G2) are stimulated for 16 hours in cholesterol-free medium after three days of culture. Test substances (dissolved in dimethylsulfoxide, 0.1% final concentration) are added during this stimulation phase. Then, after addition of 200 g mol / l of 2- ¹⁴ C-acetate, incubation is carried out a further two hours at 37 ° C in a thermostat.

After cell separation and saponification of the sterol ester, sterol is precipitated by digitonin after extraction. ¹⁴ C-acetate incorporated into the digitonin precipitated sterol is determined by scintillation counting.

The measurement of the suppressive activity is carried out at the concentration concentrations of 10 mol / l and 10 ° mol / l. For example, test results of the following compounds A to AG of the formula I were obtained at the following tested concentrations:

A = 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,

B = 1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine,

C 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine,

D = 1- (4-chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,

E = 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,

F = 1- (5-chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,

G = 1-cyclohexanecarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine,

H = 4- [4- (2-oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine,

I = 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine

K = = 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine, L = = 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine, K = = 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine « L = = 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine M = = 1- (4-chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine N = = 1- (4-Chlorobenzoylsulfonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine 0 = = 1- (4-chlorobenzoylsulfonyl) -4- [4- (2-imidazolin-2-yl) benzylidene] piperidine P = = 1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzyl] - piperidine Q = = 1- (4-chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine R - = 1- (4-chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine with = 1- (4-Chlorobenzoyl) -4- [4- (5-phenyl-2-oxazolin-2-yl) benzylidene] piperidine T = = 1- (4-Chlorobenzoyl) -4- [4- (5-diexylaminomexyl-2-oxazolin-2-yl) benzylidene] piperidine

U = 1- (4-chlorobenzoyl) -4- [4- (4-hydroxymethyl-2'-oxazolin-2-yl) benzylidene] piperidine

V = 4- [4- (S-4-benzyl-2-oxazolin-2-yl) benzilidene] -1- (4-chlorobenzoyl) piperidine; V = 1- (4-chlorobenzoyl) -4- [4- ( 2-Oxazolin-2-yl) -α-methyl-benzylidene] piperidine f

X = 1- (5-chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

Y = 1- (4-cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

Z = 4- [4- (2-oxazolin-2-yl) benzilidene] -1- (pentafluorobenzoyl) piperidine

AA = 1-benzoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AB = 1- (4-tert-butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine AC = 1- (4-methoxybenzoyl) -4- [4- (2- oxazolin-2-yl) benzylidene] piperidine

AD = 1- (4-Bromobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AE = 1- (4-nitrobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AF = 1- (4-chlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

AG = 1- (1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

The percentages expressed as the higher compounds suppressing the incorporation of β-C-acetate are given in the following table:

listed above

M / 1 10 ' ⁷ 10 “ ⁸ A -81 -58 B -77 -51 C -90 -74 D -88 -55 E -81 -36 F -84 -55 G -80 -45 H -86 -62 I -89 -75 The -90 -56 L -83 -52 M -76 -32 N -86 -63 0 -45 -1 P -14 -5 Q -89 -44 R -88 -57 WITH -24 0 T -57 -29 U -60 -21 in -29 -15 in -77 -35 x -84 -35 Y -74 -51

FROM -45 -8 AA -70 -25 AB -18 -6 AC -25 -16 AD -85 -44 AE -71 -22 AF -63 -22 AG -67 -30

As mentioned above, individual 2,3-epoxysqualene-lanosterol cyclase enzyme inhibitors are described in the literature, but which differ greatly structurally from the compounds of formula I of the present invention. The compounds of the invention closest structurally similar to the compounds of formula I are described in EP 0468457 A1. For comparison, Example 1 of this publication was therefore tested by the above method at concentrations of 10mol / l and 10mol / l. A suppression value of 41% and 13%, respectively, was found, and these compounds were significantly worse than the compounds of the formula I.

II. Measurement of in vivo efficacy in rats after oral administration

Inhibition of the enzyme 2,3-epoxysqualene-lanosterol cyclase causes an increase in the level of 2,3-epoxisqualene in the liver and plasma. The amount of 2,3-epoxysqualene formed therefore serves as a direct measure of the effective force on the animal. The determination is carried out according to the following method:

Male Vistar rats (160-190 g body weight) received a test substance in 1.5% aqueous methylcellulose by gavage. Five hours after application, blood is collected retroorbitally from venenplexus. Plasma is treated according to the method of Bligh and Dyer (Canad. J. Biochem. Physiol. 37, 912 (1950)), purified by column and then analyzed by HPLC.

The peaks obtained are identified using standards and quantified. The internal standard serves to test the reproducibility of the results.

The experiments were carried out at concentrations of 0.1 and 1.0 mg / kg, respectively. The results of Substances A to M above are included in the following table:

Concentration of 2,3-epoxysqualene (gg / ml) in plasma (rats)

mg / kg 0.1 1.0 A 0.71 3.75 B 0.46 3.14 C 0.91 5.90 D 0.78 3.35 E 0.67 6.09 F 0.00 2.00 G 0.36 0.31 H 1.70 9.15 I 3.41 8.41 The 0.0 4.14 L 0.44 6.46 M 0.78 6.53

Controllable levels of 2,3-epoxysqualene were not achieved under experimental conditions.

None of the 2,3-epoxysysaldehyde-lanosterol cyclase enzyme inhibitors described in the literature have been reported to date to inhibit cholesterol biosynthesis.

III. Lipid Reduction in Normolipemic Golden Hamsters

Males of golden hamsters are fed ad lib. for 12 days with a cholesterol-free hamster diet. At the end of the experiment, total cholesterol, HDL fractions and VLDL + LDL fractions were determined by standard methods, and for comparison, the same experiment was performed with a control group fed without test substance.

The lipid lowering effect of the above substance A was tested. The result is shown in the following table.

concentration total cholesterol VLDL + LDL HDL 0.01% -19.8% -25.0% -12.4 % 0,03% -26.3% -31.2% -17.5 % 0,10% -25.8% -36.6% -13.9 %

IV. Determination of lithogenic index on normolipemic golden hamsters

The lithogenic index is a measure of the tendency to form bile stones and is defined as the ratio of the maximum equilibrium solubility of cholesterol at the indicated concentration of bile acid and phospholipids and the actual concentration of cholesterol in mol. %. It is determined according to the Carey and Small methods described in J. Clin. Investig. 61: 998-1026 (1978). The higher the lithogenic index, the greater the likelihood of gallstones. The determination of the lithogenic index was performed as follows:

Males of golden hamster are fed for 20 days ad. lib. a cholesterol-free hamster diet. The test substances are admixed to the food at a concentration of 0.01 to 0.1%. At the end of the experiment, total blood cholesterol, HDL fraction and VLDL + LDL fraction and bile acids, cholesterol and phospholipids are determined by standard methods.

Compound A above was tested. The percentage loss of lithogenic indices was determined by control. The result is shown in the following table.

Concentration of Litogenic Index

0.01% -24%

0.03% -10% (n.s.)

0.1% -28%

N.S. = insignificant

V. Suppression of Cell Proliferation

Normal human epidermal keratinocytes (NHEK) are cultured in keratinocyte growth medium (Gibco) in a humidified atmosphere containing 5% CO ₂ . The cells from the third passage are seeded at a density of 12,000 cells / ml.

After 24 hours, the test substance is added to the medium and the number of cells is determined after an additional 48 hours. The results are calculated relative to the control and are expressed as a percentage decrease in cell number.

The proliferation suppressing activity of the above compound A compared to simvastatin at concentrations of 106 to 101θ mol / l was tested.

The results are shown in the following table:

10 “ ⁶ IO ^-7 IO ^-8 IO ' ⁹ 10' ¹⁰

And simvastatin

-72% -68%

-73% -51%

-70% -20%

-48% -21%

-16% -7%

VI. Determination of fungistatic efficacy

The fungistatic efficacy is determined by the serial t test

Dilution (microtitertest). Sabouraudbujón serves as a nutrient medium. The inoculum contains about 10 to 10 $ KBE / ml (KBE = colony forming units), the propagation time is 2-4 days at 26 pri C.

The minimum suppressive concentration (MHK) is determined, i.e. the lowest concentration which will no longer allow growth, as well as the lowest concentration at which the growth of the test germs is reduced compared to the control.

The above compound I was tested. The results are summarized in the following table.

MHK growth inhibition gl / ml μΐ / ml

Candida albicans ATCC 10231 128 64 Rhodotorula rubra 49 128 32 Saco. carlsbergensis 128 64 ATCC 9080 Aspergillus niger > 1024 128 ATCC 16404 Trichophyton mentagrophytes ATCC 9129 512 Penicillium notatum 128 64 CBS 19746 Compounds A to I are show when curative dosage

as non-toxic. For example, compounds A, H and I do not show any toxic effects in mice after oral administration of 100 mg / kg once daily for 4 days.

For pharmaceutical use, the compounds of formula (I) may be formulated in conventional forms into conventional pharmaceutical formulations for oral, rectal and topical administration.

Formulations for oral administration include, for example, tablets, dragees, and capsules, and suppositories are suitable for rectal administration. The daily dose is between 1 and 1200 mg for a human having a body weight of 60 kg, but preferably the daily dose is between 5 and 100 mg for a human having a body weight of 60 kg. The daily dose is preferably divided into 1 to 3 individual doses.

For topical administration, the compounds may be formulated to contain about 1 to 1000 mg, in particular 10 to 300 mg, of active ingredient per day. The daily dose is preferably divided into 1 to 3 individual doses.

Topical preparations include gels, creams, lotions, ointments, powders, aerosols and other preparations used to treat the skin. An effective amount for topical use is 1 to 50 mg per gram of preparation, but preferably 5 to 20 mg per gram of preparation. In addition to use on the skin, the topical formulations of the present invention can also be used to treat mucous membranes that are accessible to topical treatment. For example, topical formulations may be applied to the mucous membranes of the mouth, lower column, and others.

For use in poultry for the production of cholesterol-poor eggs, the active compounds of the formula I are administered to animals by conventional methods as food additives. The concentration of active ingredient in the finished feed is usually 0.01 to 1%, but preferably 0.05 to 0.5%.

As such, the active ingredients may be added to the feed. This provides a feed according to the invention for laying hens containing, in addition to the active ingredient and, optionally, in addition to a conventional vitamin-mineral mixture, for example, corn meal, soy meal, meat meal, feed fat and soybean oil. Such a feed is admixed with one of the abovementioned compounds of the formula I as active ingredient in a concentration of 0.01 to 1%, preferably 0.05 to 0.5%.

The following examples serve to explain the invention in more detail. Said Rhodn values were determined on E. Merck, Darmstadt ready-to-use plates

a) aluminum oxide F-254 (type E)

b) silica gel 60 F-254.

DETAILED DESCRIPTION OF THE INVENTION

Examples of production of starting materials:

Example A

4-Cyanobenzylphosphonic acid diethyl ester g of 4- (bromomethyl) benzonitrile and 300 ml of triethylphosphite is heated to 140 ° C until the start of the reaction. It is then heated to reflux for a further two hours at a temperature of 150 to 160 ° C, and the ethyl bromide formed is distilled off. Heat for an additional hour at 150 CC and then triethyl phosphite is distilled off in vacuo. The residue is mixed with 250 ml of cyclohexane in an ice bath, the crystals formed are filtered off with suction and washed with 150 ml of cyclohexane. 125.6 g (99.2% of theory) of the title compound of melting point 41.5-43 ° C are obtained.

In the same way:

(a) 3-Cyanobenzylphosphonic acid diethyl ester from 3- (bromomethyl) benzonitrile and triethylphosphite.

Colorless oil.

b) 4-Methoxycarbonyl-3-methyl-benzylphosphonic acid diethyl ester from 4-methoxycarbonyl-3-methyl-benzyl bromide (J. Med. Chem. 33, 2437-2451 (1990)) and triethylphosphite.

Colorless oil.

(c) 2-Fluoro-4-methoxycarbonyl-benzylphosphonic acid diethyl ester from 2-fluoro-4-methoxycarbonyl-benzylbromide (made from 3-fluoro-4-methyl-benzoic acid methyl ester with bromine in the presence of benzoyl peroxide in carbon tetrachloride by irradiation with 1000 watts) ) and triethylphosphite.

Colorless oil.

d) 2-Bromo-4-methoxycarbonylbenzylphosphonic acid diethyl ester from 2-bromo-4-methoxycarbonylbenzylbromide (made from 3-bromo-4-methylbenzoic acid methyl ester and bromine in the presence of benzoyl peroxide in carbon tetrachloride and irradiated with 1000 watts) triethylphosphite.

Colorless oil.

e) 2-Methoxy-4-methoxycarbonylbenzylphosphonic acid diethyl ester from 2-methoxy-4-methylbenzylbromide (made from methyl 2-methoxy-4-methylbenzoate and bromo in the presence of benzoyl peroxide in carbon tetrachloride with irradiation with 1000 watt tungsten tungsten ) and triethylphosphite. Colorless oil.

Example B

1- (4-Cyanophenyl) ethylphosphonic acid diethyl ester

To a solution of 7.5 g of 4-cyanobenzylphosphonic acid diethyl ester in 60 ml of tetrahydrofuran is added dropwise at -50 ° C with stirring, 18.7 ml of a 1.6 M solution of n-butyllithium in n-hexane, then stirred for 25 minutes. 40 DEG C. and then 4.7 g of methyl iodide in 20 ml of tetrahydrofuran is added dropwise at -40 DEG. After stirring overnight at room temperature, the mixture was evaporated, taken up in ethyl acetate, washed with water, the organic phase dried and evaporated. Purification by silica gel column chromatography (petroleum ether / 2-propanol = 6: 1 to 2: 1, v / v) afforded 5.7 g of the title compound as a colorless oil.

Rf value: 0.52 (silica gel, petroleum ether / 2-propanol = 3: 1, v / v).

Example C

N- (4-chlorobenzoyl) -4-piperidone

To a suspension of 80.6 g of powdery 4-piperidone hydrochloride hydrate in 11 tetrahydrofuran was added successively 87.5 g of 4-chlorobenzoyl chloride and a cooled solution of 276 g of potassium carbonate in 552 ml of water was added to the 5 ° C. Stirring is continued for 45 minutes at room temperature. The organic phase is then separated, the aqueous phase is extracted twice more with ethyl acetate, the organic phases are combined, dried and evaporated. The residue was dissolved in ethyl acetate and treated with petroleum ether. 88.6 g of the title compound of melting point 61-63 ° C are obtained.

In the same way, the following shall be prepared:

a) N- (4-chlorobenzylsulfonyl) -4-piperidone from 4-piperidone hydrochloride hydrate and chlorobenzylsulfochloride.

Melting point: 158 to 160 ‘<3

b) N- (4-methylbenzoyl) -4-piperidone from 4-methylbenzoyl chloride and 4-piperidone hydrochloride hydrate.

Colorless resin.

c) N- (4-dihydrocinnamoyl) -4-piperidone from 4-dihydrocinnamic acid chloride and 4-piperidone hydrochloride hydrate.

Colorless crystals.

d) N- (4-chlorotinnamoyl) -4-piperidone from 4-chlorocinnamic acid chloride and 4-piperidone hydrochloride hydrate.

Colorless resin.

e) N-hexanoyl-4-piperidone from hexanoic acid chloride and 4-piperidone hydrochloride hydrate.

Colorless oil.

f) N-pivaloyl-4-piperidone from pivaloyl chloride and 4-piperidone hydrochloride hydrate. Colorless crystals.

g) N-cyclohexanecarbonyl-4-piperidone from cyclohexanecarboxylic acid chloride and 4-piperidone hydrochloride hydrate.

Colorless crystals.

Example D

1- (4-Chlorobenzoyl) -4- (4-cyanobenzylidene) piperidine

To a solution of lithium diisopropylamide made from 3.34 g of diisopropylamine in 20 ml of tetrahydrofuran and 19 ml of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise at -50 ° C.

7.6 g of 4-cyanobenzylphosphonic acid as diethyl ester in 50 ml of tetrahydrofuran. After stirring at this temperature for 20 minutes, a solution of 7.13 g of N- (4-chlorobenzoyl) -4-piperidone was added dropwise. Allow to warm to room temperature, pour an additional two hours on ice and extract with ethyl acetate. The organic phase is dried and evaporated. Recrystallization from ethyl acetate gave 7.6 g of the title compound of m.p. 134-135.5 C. C.

In the same way:

a) 1- (4-Chlorobenzoyl) -4- (3-cyanobenzylidene) piperidine from 3-cyanobenzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Colorless foam.

b) 1- (4-chlorobenzenesulfonyl) -4- (4-cyanobenzylidene) piperidine from 4-cyanobenzylphosphonic acid diethyl ester and N- (4-chlorobenzenesulfonyl) -4-piperidone.

Melting point: 129-130 ° C.

c) 1- (4-chlorobenzoyl) -4- (4-cyano-α-methylbenzylidene) piperidine from 1- (4-cyanophenyl) ethylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Melting point: 134 ’C.

d) 1-benzyl-3- (4-cyanobenzylidene) piperidine from 4-cyanobenzylphosphonic acid diethyl ester and N benzyl-3-piperidone.

Melting point: 113 C. C.

e) 1- (4-chlorobenzoyl) -4- (4-methoxycarbonyl-3-methylbenzylidene) piperidine from 4-methoxycarbonyl-3-methylbenzylphosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Melting point: 142-144 ° C.

f) 1- (4-chlorobenzoyl) -4- (2-fluoro-4-methoxycarbonyl) benzylidene) piperidine from 2-fluoro-4-methoxycarbonylbenzyl phosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Melting point: 110-112 ^e C.

g) 4- (2-bromo-4-methoxycarbonylbenzylidene) -1- (4-chlorobenzoyl) piperidine from 2-bromo-4-methoxycarbonylbenzyl phosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Melting point: 140-142 ° C.

h) 1- (4-chlorobenzoyl) -4- (2-methoxy-4-methoxycarbonylbenzylidene) piperidine from 2-methoxy-4-methoxycarbonylbenzyl phosphonic acid diethyl ester and N- (4-chlorobenzoyl) -4-piperidone.

Colorless oil.

Example E

1- (4-chlorobenzoyl) -3- (4-cyano-benzylidene) -piperidine

To 2.9 g of 1-benzyl-3- (4-cyanobenzylidene) piperidine in 20 ml of methylene chloride was added dropwise 1.8 g of 1-chloroethyl chloroformate in 5 ml of methylene chloride at 0 ° C and stirred at 0 'for 30 minutes. C. After 20 minutes at room temperature, it is evaporated, the residue is taken up in 20 ml of methanol and heated to reflux for 30 minutes. The reaction solution is evaporated, the residue is triturated with 100 ml of ethyl acetate and filtered off with suction. 1.9 g of 3- (4-cyanobenzylidene) piperidine hydrochloride are obtained as a colorless powder.

This product together with 2.1 g of triethylamine are dissolved in 15 ml of methylene chloride and 1.75 g of 4-chlorobenzoyl chloride in 5 ml of methylene chloride are added dropwise at room temperature. After 30 minutes, 100 mL of methylene chloride was added at room temperature, washed twice with water, dried over anhydrous magnesium sulfate, evaporated and purified by column chromatography (silica gel, ethyl acetate). 1.8 g of the title compound are obtained as colorless crystals, mp > 210 ^e C.

Example F

1- (4-chlorobenzoyl) -4- (4-cyanobenzyl) piperidine

8.4 g of 1- (4-chlorobenzoyl) -4- (4-cyanobenzylidene) piperidine were hydrogenated in 400 ml of toluene with the addition of 2 g of palladium-Mohr for 15 minutes at room temperature (0.5 MPa). After addition of 1 g of palladium-Mohr, it is hydrogenated for a further 2.5 hours, once more 1 g of catalyst is added and hydrogenated for a further 1 hour. 7.9 g (93.3% of theory) of the title compound are obtained as a colorless powder of m.p. 137-139 ^e C.

Example G

1- (4-Chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride

40.7 g of hydrogen chloride are introduced into a suspension of 10.8 g of 1- (4-chlorobenzoyl) -4- (4-cyanobenzylidene) piperidine in 70 ml of anhydrous ethanol. After stirring at room temperature for 16 hours, the solvent is evaporated at a bath temperature of 30 ° C, the residue is redissolved in 35 ml of ethanol and then evaporated again. The residue was triturated with ethyl acetate. It will be obtained

13.2 g of the title compound as a colorless powder.

In the same way:

a) 1- (4-Chlorobenzoyl) -4- (3-methoxyimidoyl-benzylidene) piperidine hydrochloride from 1- (4-chlorobenzoyl) -4- (3-cyanobenzylidene) piperidine and methanol.

Colorless resin.

b) 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoylbenzylidene) piperidine hydrochloride from 1- (4-chlorobenzenesulfonyl) -4- (4-cyanobenzylidene) piperidine and methanol.

Colorless resin.

c) 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-α-methylbenzylidene) piperidine hydrochloride from 1- (4-chlorobenzoyl) -4- (4-cyano-α-methylbenzylidene) piperidine; and ethanol.

Colorless foam.

d) 1- (4-chlorobenzoyl) -3- (4-ethoxyimidoyl-benzylidene) piperidine hydrochloride from 1- (4-chlorobenzoyl) -3- (4-cyanobenzylidene) piperidine Colorless crystals.

e) 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride from 1- (4-chlorobenzoyl) -4- (4-cyanobenzyl) piperidine. Melting point: 236 ’C.

Example H

4-Ethoxyimidoyl-benzylphosphonic acid diethyl ester

5.6 g of 4-cyanobenzylphosphonic acid diethyl ester and 24 g of hydrogen chloride in 35 ml of anhydrous ethanol are stirred at room temperature for 17 hours. The reaction mixture was then evaporated and the residue was evaporated to dryness twice after addition of ethanol. The obtained colorless crystals were used without further purification for further reactions.

Example 1

4- (2-Oxazolin-2-yl) benzylphosphonic acid diethyl ester

The product obtained in Example H is dissolved in 50 ml of ethanol. After addition of 1.8 g of ethanolamine and 4.1 g of triethylamine, the reaction solution is heated under reflux for two hours, then evaporated at 50 ° C and the residue is dissolved in 100 ml of ethyl acetate. The solution was washed three times with water, dried and evaporated. 4.2 g of the title compound of melting point 65 DEG C. are obtained.

Example K

4- [4- (2-Oxazolin-2-yl) benzylidene] -1-tritylpiperidine

To 2.97 g of diethyl 4- (2-oxazolin-2-yl) benzylphosphonic acid at 60 ^e C was added dropwise first 6.25 ml of 1.6 M n-butyllithium in hexane and after 20 min, 3.4 g of N- trityl-4-piperidone (made from 4-piperidone hydrochloride hydrate and trityl chloride) in 20 mL tetrahydrofuran. Stir 25 minutes at -60 ° C. The reaction solution was then allowed to warm to room temperature and stirred for an additional 1.5 hours at this temperature. The reaction solution is stirred into 150 ml of ice-water, extracted three times with 150 ml of ethyl acetate, the organic phase is dried and evaporated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 1, v / v):

vol.). 1.7 g of the title compound of melting point 110-115 C. ^E

The following are prepared analogously:

a) 4- (4- (2-oxazolin-2-yl) benzylidene] -1-trityl-hexahydroazepine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and 1-trityl-hexahydroazepin-4-one ( made from hexahydroazepin-4-one and trityl chloride).

Colorless foam.

Rf value: 0.40 (silica gel, petroleum ether / ethyl acetate =

1: 1, v: v)).

b) 1-tert-butyloxycarbonyl-4- (4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-tert-butyloxycarbonyl-4-piperidone (made from 4-piperidone hydrochloride hydrate and di-tert-butyl pyrocarbonate.

Melting point: 74 C. C.

Example L

1-tert-butyloxycarbonyl-4- [4- (2-oxazolin-2-yl)] piperidine

2.4 g (7 mmol) of 1-tert-butyloxycarbonyl-4- (4- (2-oxazolin-2-yl) benzylidene] piperidine, dissolved in 70 ml of anhydrous ethanol and 20 ml of ethyl acetate, in the presence of 2.5 g of palladium The catalyst was filtered off with suction, the filtrate was evaporated and the residue was used for the next reaction without purification.

exhaustive

4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

1.0 g of 4- [4- (2-oxazolin-2-yl) benzylidene] -1-tritylpiperidínu in 20 mL of methylene chloride at -10 ^much slowly treated with 2 mL of trifluoroacetic acid. After stirring at -10 ° C for one hour, the reaction mixture is poured into 150 ml of ice-water and immediately adjusted to pH 11.5 with 6 N sodium hydroxide. After stirring for 10 minutes, it is extracted twice with 150 ml of ether each time, the combined organic phases are washed, dried and evaporated. The residue was purified by alumina column chromatography (methylene chloride / methanol = 40: 1, v / v). It will be obtained

340 mg of the title compound, m.p. 126 ° C.

In the same way:

a) 4- [4- (2-oxazolin-2-yl) benzylidene] hexahydroazepine from 4- [4- (2-oxazolin-2-yl) benzylidene] -1-trityl-hexahydroazepine and trifluoroacetic acid.

Melting point: sintered from 46 ’C.

b) 4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 1-tert. butyloxycarbonyl-4- [4- (2-oxazolin-2-yl) benzyl] piperidine and trifluoroacetic acid.

Melting point: 110 ° C.

Example N

3- [4- (2-Oxazolin-2-yl) benzylidene] pyrrolidine

To a suspension of 5.36 g of sodium hydride (55% in oil) in 50 ml of tetrahydrofuran is added dropwise a solution of 5.0 g of N-acetyl-2-pyrrolidone and 5.17 g of 4-cyanobenzaldehyde in 50 ml of tetrahydrofuran at 5-10 g. ° C and then stirred at 0 ° C for one hour. Excess sodium hydride was quenched by the addition of a small amount of methanol, the reaction mixture was poured onto ice and neutralized with glacial acetic acid. The precipitate was filtered off with suction, dissolved in methylene chloride-methanol, dried and evaporated. The residue was triturated with ether and filtered off with suction. 1.4 g of 3- (4-cyano-benzylidene) -2-pyrrolidone are obtained as a colorless powder, m.p.

1.36 g of this product are suspended in 30 ml of methanol. About 10 g of hydrogen chloride were introduced under ice-cooling, then stirred at room temperature for 20 hours and allowed to stand at room temperature for two days. After evaporation, the residue is taken up in 40 ml of ethanol, 0.68 g of ethanolamine and 1.52 g of triethylamine are added, the mixture is heated under reflux for two hours and then evaporated. The residue was triturated with water / ethyl acetate and the precipitate was then filtered off with suction and dried. 1.5 g of (3- [4- (2-oxazolin-2-yl) benzylidene] -2-pyrrolidone, m.p. 258 DEG-262 DEG C. are obtained.

152 mg of lithium aluminum hydride are added to 0.49 g of this product in 10 ml of tetrahydrofuran and stirred at room temperature for 2 hours, and the precipitate is then filtered off with suction. The title compound obtained is reacted further in solution.

EXAMPLE O

1- (4-Chlorobenzoyl) -4- [2- (fluoro-4- (2-hydroxyethylaminocarbonyl) benzylidene] piperidine

9.0 g of 1- (4-chlorobenzoyl) -4- [2-fluoro-4-methoxycarbonylbenzylidene] piperidine in 150 ml of methanol are mixed with a solution of 4.0 g of 84% caustic liquor in 100 ml of water and stirred overnight at room temperature. The methanol is evaporated, the residue is mixed with water while cooling and acidified with dilute hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried under vacuum. 8.6 g (95% of theory) of 4- (4-carboxy-2-fluorobenzylidene) -1- (4-chlorobenzoyl) piperidine are obtained, m.p.

2.0 g of this product and 0.88 g of N, N'-carbonyldiimidazole in 50 ml of xylene were heated at 60 ° C for one hour, then 0.32 g of ethanolamine was added and stirred for three hours at a bath temperature of 160 ° C. . After evaporation of the solvent, the residue is mixed with water, extracted three times with methylene chloride, the organic extract is dried and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol = 10: 0.5, v: v).

obj). 0.4 g of the title compound is obtained as a colorless oil.

Rf value: 0.25 (silica gel, ethyl acetate / methanol = 10: 0.5, v / v)

In this way the following are prepared:

(a) 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -3-methylbenzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-methoxycarbonyl-3-methylbenzylidene) piperidine; and ethanolamine.

Colorless oil.

Rf value: 0.2 (silica gel, ethyl acetate / petroleum ether / methanol = 10: 5: 1, v / v: v / v).

The saponification of the starting ester is carried out at boiling point.

b) 4- [2-bromo-4- (2-hydroxyethylaminocarbonyl) benzylidene] -1 (4-chlorobenzoyl) piperidine from 4- (2-bromo-4-methoxycarbonylbenzylidene) -1- (4-chlorobenzoyl) piperidine and ethanolamine.

Melting point: 90-92 ° C.

c) 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl) -2-methoxybenzylidene] piperidine from 4- (2-methoxy-4-methoxycarbonylbenzylidene) -1- (4-chlorobenzoyl) piperidine; and ethanolamine.

Colorless oil.

Examples of production of finished products

Example 1

1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

13.2 g (0.315 mol) of 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) piperidine hydrochloride are suspended in 59 ml of anhydrous ethanol. After the addition of 2.64 g (0.042 mol) of ethanolamine and 6.5 g (0.063 mol) of triethylamine, the mixture is heated under reflux for 1.5 hours. After cooling in an ice bath, it is filtered off with suction and washed with ethanol. 10.4 g (88.6% of theory) of the title compound of melting point 181 DEG -183 DEG C. are obtained.

¹ H-NMR spectrum (200 MHz, CDCl 3), signals at ppm: 2.3-2.6 (m, 4H), 3.3-3.9 (m, 4H), 4.05 (t, 2H), 4.4 (t, 2H), 6.4 (s, 1H), 7.2 (d, 2H), 7.4 (s, 4H), 7.9 (d, 2H).

* 48

The hydrochloride of the title compound is formed by standing in ethanol with cold ethereal hydrochloric acid. It sintered at 69-71 ° C and at 80-81 ° C again becomes solid as gas evolves.

In the same way:

(a) 1- (4-chlorobenzenesulfonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride hydrochloride; and ethanolamine.

Melting point: 191.5-192.5 ° C.

b) 1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) piperidine hydrochloride and 3-aminopropanol.

Melting point: 159-160 ° C.

c) 1- (4-chlorobenzoyl) -4- [4- (4,4-dimethyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) hydrochloride piperidine and 2-amino-2-methylpropanol.

Melting point: 145-146 ° C.

d) 1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) piperidine hydrochloride and cysteamine.

Melting point: 162-163 ° C.

e) 1- (4-chlorobenzoyl) -4- [4- (R-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) ) piperidine hydrochloride and R1-amino-2-propanol.

Melting point: 104-106 ° C.

49 f) 1- (4-Chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4- ethoxyimidoylbenzylidene) piperidine and S1-amino-2-propanol.

Melting point: 107-108 ° C.

g) 1- (4-chlorobenzoyl) -4- [3- (2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (3-methoxyimidoylbenzylidene) piperidine hydrochloride and ethanolamine.

Melting point: 90-92 ° C.

h) 1- (4-chlorobenzoyl) -4- (4- (5,5-dimethyl-2-oxazolin-2-yl) benzylidene] piperidine from T- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) hydrochloride piperidine and 2-hydroxy-2-methylpropylamine, m.p. 145-146 ° C.

i) 1- (4-chlorobenzenesulfonyl) -4- [4- (2-imidazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride and ethylenediamine.

Melting point: 222-224 ° C.

j) 1- (4-chlorobenzenesulfonyl) -4- [4- (N-methyl-2-imidazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzenesulfonyl) -4- (4-methoxyimidoyl-benzylidene) piperidine hydrochloride; and N-methylethylenediamine. Colorless foam.

Rf value: 0.24 (alumina, ethyl acetate).

k) 1- (4-chlorobenzoyl) -4- [4- (S-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) hydrochloride piperidine and L-alaninol.

Melting point: 143 C. C.

- 5d 1) 1- (4-chlorobenzoyl) -4- [4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4- ethoxyimidoylbenzylidene) piperidine and D-alaninol.

Melting point: 143 C. C.

m) 1- (4-chlorobenzoyl) -4- [4- (5-phenyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) piperidine hydrochloride; and amino-2-phenylethanol.

Melting point: 147 C. C.

n) 1- (4-chlorobenzoyl) -4- [4- (5-diethylaminomethyl-2-oxazolin-2-yl) benzylidene] piperidine

- (4-chlorobenzoyl) -4- (4-ethoxyimidolylbenzylidene) piperidine and 1-amino-3-diethyl-2-propanol. Melting point: 91 ° C.

o) 1- (4-Chlorobenzoyl) -4- [4- (4-hydroxymethyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzylidene) piperidine hydrochloride and DL -serinolu.

Melting point: 137 C. C.

p) 1- (4-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) -α-methylbenzylene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-) hydrochloride amethylbenzylidene) piperidine and ethanolamine.

Melting point: 192 C. C.

q) 1- (4-chlorobenzoyl) -4- [4- (R-4-phenyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) of piperidine and R-2-amino-2-phenylethanol.

Melting point: 130 C. C.

r) 4- (4- (R-4-Benzyl-2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl- benzylidene) piperidine; and R-2-amino-3-phenyl-1-propanol.

Melting point: 142 C. C.

s) 4- [4- (S-4-Benzyl-2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) ) piperidine and S-2-amino-3-phenyl-1-propanol.

Melting point: 142-143 ° C.

t) 1- (4-chlorobenzoyl) -4- [4 - ((4-chlorobenzoyl)) - 2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzylidene) piperidine and 4-chlorophenylalanine.

Melting point: 127 C. C.

u) 1- (4-chlorobenzoyl) -4- [4- (4 - ((2-methylthioethyl)) - 2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- (4 (ethoxyimidoyl-benzylidene) piperidine and L-methioninol.

Melting point: 95-96 ° C.

v) 1- (4-chlorobenzoyl) -4- [4- (4 - ((1-methyl-5-propyl)) - 2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) - 4- (4-ethoxyimidoyl-benzylidene) piperidine and S-isoleucinol.

Melting point: 101 C. C.

w) 1- (4-chlorobenzoyl) -4- [4- (2-imidazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoyl-benzyl) piperidine hydrochloride and ethylenediamine.

Melting point: 155-157 ° C.

x) 1- (4-chlorobenzoyl) -4- [4- (S-4-methyl-2-oxazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzyl) hydrochloride ) piperidine and L-alaninol.

Melting point: 92-95 ° C.

y) 1- (4-chlorobenzoyl) -4- [4- (N-methyl-2-imidazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzyl) piperidine hydrochloride and N-methylethylenediamine.

Melting point: 163-167 ° C.

z) 1- (4-chlorobenzoyl) -4- [4- (S-5-methyl-2-oxazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzyl) hydrochloride of piperidine and S1-amino-2-propanol.

Melting point: 98-100 ° C.

aa) 1- (4-chlorobenzoyl) -4- [4- (R-5-methyl-2-oxazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzyl) hydrochloride of piperidine and R1-amino-2-propanol.

Melting point: 99-101 ° C.

ab) 1- (4-chlorobenzoyl) -4- [4- (2-thiazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbenzyl) piperidine hydrochloride and cysteamine.

Melting point: 106 to 108 ° C.

ac) 1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4-ethoxyimidoylbene) hydrochloride zyl) piperidine and 3-aminopropanol.

Melting point: 106 to 108 ° C.

ad) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -3- (4-ethoxyimidoylbenzyl) piperidine hydrochloride and ethanolamine.

Melting point: 151 ° C.

Example 2

1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

To 6 g (0.02 mol) of 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester in 80 ml of tetrahydrofuran was added dropwise at -50 ° C 12.5 ml (0.021 mol) of a 1.6 M solution of n-butyllithium in n. -hexane. The dark red solution was stirred at -55 ° C for 25 minutes and then 4.7 g (0.02 mol) of N- (4-chlorobenzoyl) 4-piperidone in 20 ml of tetrahydrofuran was added dropwise. After stirring at room temperature for 5 hours, the reaction mixture is stirred in 300 ml of water, the precipitate is filtered off with suction after a further 20 minutes and recrystallized from ethanol. 3.2 g (42% of theory) of the product identical to the title compound of Example 1 are obtained.

In the same way, the following shall be prepared:

a) 1- (4-Methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N- (4-methylbenzoyl) 4-piperidone.

Melting point: 169-171 ° C.

b) 1- (dihydrotinnamoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-dihydrotinnamoyl-4-piperidone.

Melting point: 98-100 ° C.

c) 1- (4-chlorotinnamoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N- (4-chlorotinnamoyl) 4-piperidone.

Rf value: 0.86 (alumina, ethyl acetate).

d) 1-hexanoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-hexanoyl-4-piperidone.

Melting point: 98-100 ° C.

e) 4- [4- (2-oxazolin-2-yl) benzylidene] -1-pivaloylpiperidine from 4- (2-oxazolin-2-yl) benzylphosphinic acid diethyl ester and N-pivaloyl-4-piperidone.

Melting point: 163-165 ° C.

f) 1-Cyclohexanecarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (2-oxazolin-2-yl) benzylphosphonic acid diethyl ester and N-cyclohexanecarbonyl-4-piperidone.

Melting point: 163-164 ° C.

Example 3

4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine

120 mg (0.5 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 75 mg (0.75 mmol) of triethylamine in 3 ml of ethyl acetate and 2 ml of methylene chloride are cooled to -5 to - 10 'C and added

104.3 mg (0.5 mmol) of 4-trifluoromethylbenzoyl chloride. Stirring

1.5 hours at room temperature, diluted with ethyl acetate, then washed sequentially with water, 2N sodium hydroxide and saturated aqueous sodium chloride solution, dried and evaporated. 115 mg (56% of theory) of the title compound of melting point 142 DEG C. are obtained.

1 H-NMR spectrum (200 MHz, CDCl 3), signals at ppm: 2.3-2.7 (m, 4H), 3.3-3.5 (m, 2H), 3.7-3.9 ( m, 2H), 4.05 (t, 3H), 4.4 (t, 3H), 6.4 (s, 1H), 7.2 (d, 2H), 7.55 (d, 2H), 7.7 (d, 2H); 7.9 (d, 2H).

In the same way:

a) 4- [4- (2-oxazolin-2-yl) benzylidene] -1-stearoylpiperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and stearic chloride.

Melting point: 72 ° C.

b) 1-cyclopropylcarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and cyclopropanecarboxylic acid chloride.

Melting point: 117 C. C.

c) 1- (4-chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; and 4-chloro-3-methylbenzoyl chloride.

Melting point: 145 ’C.

d) 1- (3,4-dichlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and chloride 3 4-dichlorophenylacetic acid.

Melting point: 132 C. C.

e) 1- (4-Fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-fluorobenzoic chloride acid.

Melting point: 146 C. C.

f) 1- (5-chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; and of 5-chlorothiophenecarboxylic acid.

Melting point: 145 ’C.

g) 1- (2-naphthylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and acid chloride 2 -naftalénoctovej.

Melting point: 133 ° C.

h) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] hexahydroazepine from 4- [4- (2-oxazolin-2-yl) benzylidene] hexahydroazepine and 4-chlorobenzoyl chloride.

Viscous oil.

Rf value: 0.42 (alumina, petroleum ether / ethyl acetate = 1: 1, v / v).

i) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-chlorobenzoyl chloride .

Melting point: 140 C. C.

j) 1- (1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and acid chloride 1 -naphthalenecarboxylic acid.

Melting point: 146-149 ° C.

k) 1- (3,4-difluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- (4- (2-oxazolin-2-yl) benzylidene] piperidine and 3, 4-Difluorobenzoyl chloride.

Melting point: 133-135 ° C.

l) 1- (3,5-bis-trifluoromethylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3, 5bis-trifluoromethylbenzoyl.

Melting point: 137 C. C.

m) 1- (4-cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-cyanobenzoyl chloride.

Melting point: 166 ’C.

n) 1- (2-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2- naphthalene.

Melting point: 167 ’C.

o) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (2-trifluoromethylbenzoyl) piperidine from 4- (4- (2-oxazolin-2-yl) benzylidene] piperidine and 2-trifluoromethylbenzoyl chloride.

Melting point: 128 ° C.

p) 1- (3,4-difluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3, 4-dichlorobenzoyl chloride.

Melting point: 159 C. C.

q) 1- (4-fluoro-1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-fluoronaphthalenecarboxylic acid hydrochloride.

Melting point: first at 132 ° C, then after temporary setting at 157 ° C.

r) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (pentafluorobenzoyl) piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and pentafluorobenzoyl chloride.

Melting point: 212 DEG C.

s) 1-benzoyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and benzoyl chloride.

Melting point: 136 C. C.

t) 1- (4-Methylsulfonylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-methylsulfonylbenzoyl chloride .

Melting point: 191 C. C.

u) 1- (4-tert-butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4terc. butylbenzoyl.

Melting point: 193 ° C.

v) 4- [4- (2-oxazolin-2-yl) benzylidene] -1- (3-trifluoromethylbenzoyl) piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3-trifluoromethylbenzoyl chloride .

Melting point: 99 ° C.

w) 1- (3-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 3-chlorobenzoyl chloride.

Melting point: 116 ° C.

x) 1- (4-methoxybenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-methoxybenzoyl chloride .

Melting point: 153 C.

y) 1- (2,5-difluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 2, Of 5-difluorobenzoyl chloride.

Melting point: 137 ° C.

z) 1- (4-Bromobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-bromo benzoyl chloride .

Melting point: 199 ^e C.

aa) 4- [4- (2-Oxazolin-2-yl) benzylidene] -1- (1,2,3,4-terafhydro)

2-naphthylcarbonyl) piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid chloride. Melting point: 151 C.

ab) 1- (4-nitrobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-nitrobenzoyl chloride.

Melting point: 192 C. C.

ac) 1- (4-chlorophenylacetyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine and 4-chlorophenylacetyl chloride.

Melting point: 107 C. C.

ad) 1-benzoyl-4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and benzoyl chloride.

Melting point: 78-80 ° C.

ae) 1- (2-Chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 2-chlorobenzoyl chloride .

Melting point: 105-108 ° C.

af) 1- (3-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 3-chlorobenzoyl chloride .

Resin.

Rf value: 0.6 (silica gel, ethyl acetate / petroleum ether = 10: 2, v / v).

ag) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-fluorobenzene benzoyl chloride.

Melting point: 111-113 ° C.

ah) 1- (4-tert-butylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4- terc.butylbenzoylchloridu.

Resin.

_Rf value: 0.3 (silica gel, ethyl acetate).

ai) 1- (4-biphenylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-biphenylcarbonyl chloride .

Melting point: 158-160 ° C.

aj) 1- (2-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 2- naphthalene.

Melting point: 100-105 ° C.

ak) 1- (1-naphthylcarbonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 1- naphthalene.

Melting point: 70-73 ° C.

a1) 1- (4-chlorophenylsulfonyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-chlorophenylsulfonyl chloride.

Melting point: 155-157 ° C.

am) 1- (4-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-methylbenzoyl chloride .

Melting point: 143-145 ° C.

an) 1- (4-cyanobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and 4-cyanobenzoyl chloride .

Melting point: 148-150 ° C.

ao) 4- [4- (2-oxazolin-2-yl) benzyl] -1- (4-pyridoyl) piperidine from 4- [4- (2-oxazolin-2-yl) benzyl] piperidine and isonicotinic acid chloride.

Melting point: 148-150 ° C.

ap) 1- (4-Chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine of 3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine and 4-chlorobenzoyl chloride.

Rf value: 0.36 (silica gel, methylene chloride / methanol = 24: 1, v / v).

Example 4

- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-pentinoyl) piperidine

356 mg (2.2 mmol) of N, N '-carbonyldiimidazole in 3 ml of tetrahydrofuran are mixed at room temperature with 200 mg (2 mmol) of 4-pentanoic acid in 2 ml of tetrahydrofuran. Stir for 1 hour at room temperature. 363 mg (1.5 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine are then added and the mixture is stirred at 40 ° C for 2 hours. Then the reaction mixture was evaporated and the residue was purified by column chromatography (silica gel, ethyl acetate). 320 mg (66% of theory) of the title compound of melting point 118 DEG C. are obtained.

¹ H-NMR spectrum (200 MHz, CDCl 3): signals at ppm: 2.0 (s,

1H), 2.3-2.7 (m, 8H), 3.4-3.8 (m, 4H), 4.05 (t, 2H), 4.4 (t, 2H), 6.4 (s, 1H), 7.2 (d, 2H), 2.9 (d, 2H).

In the same way:

(a) 4- [4- (2-oxazolin-2-yl) benzylidene] -1- (4-phenyl-3-butenoyl) piperidine from 4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 4-phenyl-3-butenoic acid and N, N'-carbonyldiimidazole.

Melting point: 139 C.

Example 5

- [4- (2-Oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine

441 mg (1 mmol) of 4- [4- (2-oxazolin-2-yl) benzylidene] -1 (4-trifluoromethylbenzoyl) piperidine was hydrogenated in 10 ml of anhydrous ethanol and 2.5 ml of ethyl acetate in the presence of 0.5 g of palladium on carbon (10%) (room temperature, 30 minutes, hydrogen pressure 350 kPa). The catalyst is filtered off with suction, the filtrate is evaporated under reduced pressure at a bath temperature of 50 ° C and the residue is purified by column chromatography (silica gel, ethyl acetate).

63 mg. (48% of theory) of the title compound of melting point 115 DEG C. were obtained.

1 H-NMR spectrum (200 MHz, CDCl 3): signals at ppm: 1.0-1.4 (m, 2H), 1.6-1.9 (m, 3H), 2.6 (d, 2H), 2.7-3.1 (m, 2H), 3.6 (m, 1H), 4.05 (t, 2H),

4.4 (t, 2H), 4.7 (m, 1H), 7.15 (d, 2H), 7.5 (d, 2H), 7.65 (d, 2H), 7.85 (d) , 2H).

In the same way:

a) 1- (4-chlorobenzoyl) -4- (4- (R-4-methyl-2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- [4- (R- 4-methyl-2-oxazolin-2-yl) benzylidene] piperidine.

Colorless resin.

Rf value: 0.37 (silica gel, ethyl acetate).

b) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -4- (4- (2-oxazolin-2-yl)) benzylidene] piperidine.

Melting point: 136-138 ° C.

c) 1- (4-chlorobenzoyl) -3- (4- (2-oxazolin-2-yl) benzyl] piperidine from 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl)] benzylidene] piperidine.

Colorless resin.

Rf value: 0.5 (silica gel, ethyl acetate).

Example 6

- (4-Chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzyl] piperidine

0.4 g (0.95 mol) of 1- (4-chlorobenzoyl) -4- (2-fluoro-4- (2-hydroxyethylaminocarbonyl) benzylidene] piperidine in 20 ml of tetrahydrofuran was added portionwise at 0 DEG C. over a period of 45 minutes with 0, 3 g (1.1 mmol) of methyl N- (triethylammoniosulfonyl) carbamate (Burgess reagent) is heated for a further 2 hours, evaporated and the residue is mixed with water, extracted three times with methylene chloride, dried over anhydrous sodium sulphate, evaporated and The residue was purified over a silica gel column (ethyl acetate / petroleum ether = 10: 4, v / v) to give 0.105 g (26% of theory) of the title compound, mp 158-160 ° C.

¹ H-NMR spectrum (200 MHz, DMSO-d 6): signals at ppm: 2.4 (m, 4H), 3.4-3.7 (m, 4H), 3.95 (t, 2H) 4.4 (t, 2H); 6.35 (s, 1H); 7.3-7.7 (m, 7H).

In the same way, the following shall be prepared:

a) 1- (4-chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl)] 3-methylbenzylidene] piperidine and Burgess reagent. Melting point: 88-90 ° C.

b) 4- [2-bromo-4- (2-oxazolin-2-yl) benzylidene] -1- (4-chlorobenzoyl) piperidine from 4- [2-bromo-4- (2-hydroxyethylaminocarbonyl) benzylidene] 1- (4-chlorobenzoyl) piperidine and Burgess reagent. Melting point: 185-187 ° C.

c) 1- (4-chlorobenzoyl) -4- [2-methoxy-4- (2-oxazolin-2-yl) benzylidene] piperidine from 1- (4-chlorobenzoyl) -4- [4- (2-hydroxyethylaminocarbonyl)] 2-methoxy-benzylidene] piperidine and Burgess reagent. Melting point: 150-152 ° C.

Further, the production of pharmaceutical dosage forms is described in each example:

Example I

5 mg tablets of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

Ingredients:

tablet contains:

active substance 5.0 mg milk sugar 148.0 mg Potato starch 65.0 mg magnesium stearate 2.0 mg

220.0 mg

Method of production:

10% slime is prepared from the potato starch by heating. The active substance, milk sugar and residual potato starch are mixed and granulated with the above slime through a 1.5 mm sieve. The granulate is dried at 45 ° C, sieved once again through the aforementioned sieve, mixed with magnesium stearate and compressed into tablets.

Tablet weight: 220 mg

Punch: 9 mm

EXAMPLE

Dragees with 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

The tablets prepared according to Example 1 are coated in a known manner with a coating consisting essentially of sugar and talc.

The finished dragees are polished with beeswax.

Dragee weight 300 mg.

Example III

Suppositories with 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

suppository contains:

active ingredient 5.0 mg lace mass (e.g. Vitepsol V 45 µ) 1695.0 mg

1700.0 mg

Method of preparation:

The finely powdered active ingredient is suspended in the molten lace mass at 40 ° C. The mass is poured at 37 ° C into easily pre-cooled lace molds.

Lace weight: 1.7 g.

Example IV

5 mg Capsules of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

capsule contains

effective: component 5.0 mg lactose 82.0 mg starch 82.0 mg stearate magnesium 1.0 mg

170.0 mg

Method of preparation:

The powder blend is vigorously mixed and filled on a capsule filling machine into hard gelatin push-fit capsules, and the final weight is continuously tested.

Example V

Tablets of 5 mg of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine

Ingredients:

tablet contains:

active substance 5.0 mg milk sugar 148.0 mg Potato starch 65.0 mg

Magnesium Sxearate 2.0 mg

220.0 mg

Method of production:

10% slime is prepared from the potato starch by heating. The active substance, milk sugar and residual potato starch are mixed and granulated with the above slime through a 1.5 mm sieve. The granulate is dried at 45 ° C, rubbed again with the aforementioned sieve and pressed into tablets. Tablet weight: 220 mg

Punch: 9 mm

Example VI

Topical application cream with 1 g of 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine

The composition for topical application of the compounds of formula I may have the following composition:

First active substance 1.0 g Second stearyl 4.0 g Third acetyl 4.0 g 4th mineral oil 3.0 g 5th Polysorbat 60 4.5 g 6th sorbitan 4.5 g 7th propylene glycol 10.0 g 8th methylparaben 0.18 g 9th propyl 0,02 g 10. water q.s. up to 100,00 g

Components 2 to 6 are heated to 80 ° C until they are all melted. Then component 1 is dissolved in the oil phase. The components 7 and 10 are heated to 90 ° C and the components 8 and 9 are dissolved in the aqueous phase thus obtained. The aqueous phase is then added to the oil phase and stirred rapidly to give an emulsion. It is then slowly cooled to 50 ° C to solidify the emulsion. With further stirring, the preparation was cooled to room temperature.

The following example describes the production of feed for laying hens:

Example VII

Feed for laying hens containing 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine as active substance

sweet corn 633 g / kg soya bean meal 260 g / kg fish meal 40 g / kg feed fat 25 g / kg soya oil 17 g / kg bikaleiumfosfát 12 g / kg calcium carbonate 6 g / kg a mixture of vitamins and minerals 5 g / kg active substance 2 g / kg

These ingredients, in the indicated amounts, will provide 1 kg of feed after intensive mixing.

Claims (12)

Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula I wherein n is 0 or 1, m is 1 or 2, p is 0 or 1, A is a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms, an alkylene group having 2 to 17 carbon atoms, or an alkynylene group having 2 to 4 carbon atoms, 1 * 2 ^A and V are each hydrogen or together form a carbon-carbon bond, X is a carbonyl or sulfonyl group, Y represents an oxygen or sulfur atom or a group>NRH; to r6 represent a hydrogen atom or one, two or three radicals R @ 1 to R @ 2, which may be the same or different, represent a straight or branched alkyl group having 1 to 4 carbon atoms which may be substituted by hydroxy-, alkoxy-, alkylthio- or a dialkylamino group or optionally a halogen atom or an alkyl-substituted phenyl group or an alkoxy70 carbonyl group and the other radicals R ¹ to R 6 are in each case a hydrogen atom, -i * 1 r wherein one, two or all three radicals R ^x , R ^j and R ^j may be optionally substituted by an alkoxy group or a halogen atom, R represents a hydrogen or halogen atom, an alkyl or alkoxy group, O Q R 0 and R ^y are each independently hydrogen or alkyl, R ( ¹⁾ is hydrogen, C 3 -C 6 cycloalkyl, optionally halogen, straight or branched (C 1 -C 4) alkyl, trifluoromethyl, alkoxy, cyano, nitro, alkylsulfonyl or phenyl substituted phenyl, phenyl substituted with two trifluoromethyl groups, two to five halogen atoms or halogen and alkyl or fluoro substituted naphthyl or tetrahydronaphthyl, pyridyl or optionally halogen or alkyl substituted thienyl, R ¹¹ is H or an alkyl group, wherein A can not represent a single bond when X is sulfonyl and ^R1 ^ is H and wherein, unless otherwise stated, may be mentioned alkyl, alkoxy, alkylthio and alkylsulfonyl radicals contain 1 to The 3 carbon atoms and the aforementioned halogen atoms may in each case be a fluorine, chlorine or bromine atom. their enantiomers, diastereomers and their salts. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes according to claim 1 of the general formula Ia (CH ₀ ) _m 2 m (CH) 2 p (1a) where n is a number m is a number p is a number 0 or 1, 1 or 2, 0 or 1, I A represents a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms, an alkylene group having 2 to 4 carbon atoms or an alkynylene group having 3 to 4 carbon atoms, T 7 V and V are in each case a hydrogen-carbon atom or together form a bond X is a carbonyl or sulfonyl group, Y represents an oxygen or sulfur atom or a group> NR, R @ ³ to R @ ⁴ represent a hydrogen atom or one or two radicals R ^{@ 1} to R @ ⁴ each independently represent a straight or branched alkyl group having from 1 to 4 carbon atoms which may be substituted by hydroxy, alkylthio or dialkylamino or optionally halogen substituted phenyl or phenyl and the other radicals R ³ to R ⁴ represent a hydrogen atom, r 5a, which may be the same or different, represent a hydrogen atom or a methyl group, R 'represents a hydrogen or halogen atom, an alkyl or alkoxy group, Q R represents a hydrogen atom or an alkyl group, R ⁹ represents a hydrogen atom, R ¹⁰ represents a hydrogen atom, a C 3 -C 6 cycloalkyl group, optionally one or two halogen atoms, a straight or branched C 1 -C 4 alkyl group, trifluoromethyl, methoxy, cyano, nitro, methylsulfonyl or phenyl substituted phenyl a group, two trifluoromethyl groups or a halogen atom and a methyl-substituted phenyl group, three to five fluorine-substituted phenyl groups, a fluorine-substituted naphthyl group, a tetrahydronaphthyl or pyridyl group, or an optionally halogen-substituted thienyl group, and R ¹¹ represents a hydrogen atom or an alkyl group, wherein A does not represent a single bond when X represents a sulfonyl group and R ¹⁰ represents a hydrogen atom and, unless otherwise stated, the above alkyl radicals may each contain 1 to 3 carbon atoms and the above atoms halogen may in each case be a fluorine, chlorine or bromine atom, their enantiomers, diastereomers and their salts. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of formula Ia according to claim 2, wherein: n means number 0 or First m means number 1 or 2 P means number 0 or 1 A represents a single bond, a straight or branched alkylene group having 1 to 17 carbon atoms or an alkenylene group having 2 to 4 carbon atoms, -jo ν ^Α and V ⁴ each represent a hydrogen atom or together form a carbon-carbon bond, X is a carbonyl or sulfonyl group, Y represents an oxygen atom or a group> NRH, R @ ³ to R @ ⁴ are each hydrogen or one or two radicals independently of one another are in each case straight or branched (C1 -C4) alkyl group and the other radicals R @ ³ - to R @ ⁴ are each hydrogen, R ⁵ and r 6, which may be the same or different, represent a hydrogen atom or a methyl group; R represents a hydrogen or halogen atom, a methyl or methoxy group, Q R represents a hydrogen atom or a methyl group, represents a hydrogen atom, R10 represents a hydrogen atom, a cycloalkyl group having 3 to 6 carbon atoms, optionally one or two halogen atoms, five fluorine atoms, an alkyl group, one or two trifluoromethyl groups, or - 74 halogen and alkyl-substituted phenyl, in the 4-position optionally fluorine-substituted 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, pyridyl or 4-biphenyl or optionally a halogen substituted thienyl group and rH represents a hydrogen atom or a methyl group, where A does not represent a single bond when X represents a sulfonyl group and R ^{@ 1} represents a hydrogen atom and, unless otherwise stated, the above alkyl portions may each contain 1; up to 3 carbon atoms and the aforementioned halogen atoms may in each case be a fluorine or chlorine atom, their enantiomers, diastereomers and their salts. Arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of formula Ia according to claim 2, wherein n is 0 or 1, m is 1, p is 0 or 1, And it means simple bond, M and V are each hydrogen or together form a carbon-carbon bond, X is a carbonyl group, Y represents an oxygen atom; to R ** are each hydrogen, * 7 R represents a hydrogen or halogen atom or a methyl group, 8 9 R and R a are each hydrogen, R &^lt; ¹⁰ &gt; is a fluorine, chlorine or bromine atom or a trifluoromethyl-substituted phenyl, 4-chloro-3-methyl, 5-chloro-2-thienyl or cyclohexyl group and their salts, Compounds of formula (I) according to claim 1 which are: 1) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 2) 1- (4-chlorobenzoyl) -4- [4- (4,5-dihydro-6H-oxazin-2-yl) benzylidene] piperidine; 3) 4- [4- (2-oxazolin-2-yl) benzylidene] -1- (4-trifluoromethylbenzoyl) piperidine; 4) 1- (4-chloro-3-methylbenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 5) 1- (4-fluorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 6) 1- (5-chloro-2-thienoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 7) 1-cyclohexanecarbonyl-4- [4- (2-oxazolin-2-yl) benzylidene] piperidine; 8) 4- [4- (2-oxazolin-2-yl) benzyl] -1- (4-trifluoromethylbenzoyl) piperidine; (9) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzyl] piperidine; 10) 1- (4-chlorobenzoyl) -3- [4- (2-oxazolin-2-yl) benzylidene] pyrrolidine; 11) 1- (4-chlorobenzoyl) -4- [2-fluoro-4- (2-oxazolin-2-yl) benzylidene] piperidine; 12) 1- (4-chlorobenzoyl) -4- [3-methyl-4- (2-oxazolin-2-yl) benzylidene] piperidine and salts thereof. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids. Medicament, characterized in that it comprises a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 in addition to one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the inhibition of cholesterol biosynthesis, for the treatment or prophylaxis of hyperlipidemia, for the treatment of diseases associated with excessive cell proliferation, for the treatment and prophylaxis of gallstones or mycoses. Use of a compound according to at least one of claims 1 to 6 for the manufacture of feed for laying hens for the production of cholesterol-poor eggs. A process for the manufacture of a medicament according to claim 7, characterized in that the compound according to at least one of claims 1 to 6 is processed in a non-chemical manner into one or more inert carriers and / or diluents. A process for the preparation of compounds according to at least one of claims 1 to 6, characterized in that (a) a compound of formula II N-X-A-R (II) where 19 7 1Ω m, p, A, V, V, X and R to R have the meanings given in claims 1 to 5 and 1 9 · R ^Z is alkyl of 1 to 10 carbon atoms, with a compound of formula III, n, Y and R ¹ to R ** are as defined in claims 1 to 5, or (b) for the preparation of compounds of formula I wherein n, m, p, A, X, Y and R ¹ to R ¹⁰ have the meanings set forth in claims 1 to 19 5 and V and V together represent a carbon-carbon bond, a phosphonoester of formula IV (IV) wherein 1A, Y and R to R have the meanings set forth in claims 1 to 5 and R represents an alkyl group having 1 to 10 carbon atoms, reacted with a compound of formula V (V) wherein m, p, A, X, R 6 and R 6 is as defined in claims 1 to 5 or c) the compound of the general formula VI (/ρ / (VI) n, m, p, V ^ ·, V ² , Y and R 1 to R ⁹ have the meanings given in wherein n, r of claims 1 to 5) is reacted with the compound of the general formula of formula VII (VII) Z ¹ - X - A - R ¹⁰ where A, X and are as defined in claims 1 to 5 and Z ¹ represents a reactive leaving group or d) for the preparation of compounds of the formula I in which n, m, p, X and R to R have the meanings indicated in claims 1 to 5, A represents a single bond or a straight or branched alkylene group having 1 to 17 carbon atoms, V ¹ and in each case represent a hydrogen atom and Y represents an oxygen atom or a group> NR ¹³ , wherein R ¹¹ is as defined in claims 1 to 5, R ¹ to except for alkylthio substituted straight or branched (C 1 -C 4) alkyl groups and R ¹ ® with the exception of optionally halogen-substituted thienyl groups, they have the meanings set forth in claims 1 to 5, wherein A is not a single bond when X is a sulfonyl group and R ¹ is hydrogen, hydrogenated compounds of formula I 'wherein 7 Q n, m, p, X and R to R ⁷ are as defined in claims 1 to 5, A * represents a single bond or a straight or branched alkylene group having 1 to 17 carbon atoms, V and V together represent a carbon-carbon bond and Y 'represents an oxygen atom or a group> NR, wherein R ¹ ·· ¹ · has the meanings set forth in claims 1 to 5, R ³ to R ® with the exception of alkylthio substituted straight or branched (C 1 -C 4) alkyl groups and R ¹ Except for optionally halogen-substituted thienyl groups, they have the meanings set forth in claims 1 to 5, wherein A is not a single bond when X is a sulfonyl group and R 1 -θ is a hydrogen atom, or e) for the preparation of compounds of the general formula I, wherein n, m, p, A, X, and R1 to R1 have the meanings given in claims 1 to 5 and Y represents an oxygen atom: to cyclize the compound of formula VIII N-X-A-R R (VIII) wherein n, m, p, A, X, V *, V ² and to have the meanings set forth in claims 1 to 5 and, if desired, the optionally present hydroxy group in the compound of formula VI is protected before carrying out reaction b) The protecting group and the protecting group are cleaved off again after the reaction is completed and / or optionally the hydroxy group present in the compound of formula VI is reacted with c) using two equivalents of formula VII and the corresponding ester group is saponified. of formula (I) is converted into its salt with an inorganic or organic acid.