DD290186A5 - PROCESS FOR PREPARING PIPERIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of piperidine derivatives of the formula wherein X, Y, R 1, R 2 and R 3 have the meanings given in the description. The compounds according to the invention have valuable pharmaceutical properties and are especially active against tumors. They are produced in a manner known per se. Formula (I) {Piperidine Derivatives Preparation; Pharmaceuticals, tumor inhibiting}

Description

Field of application of the invention

The invention relates to processes for the preparation of piperidine derivatives. which are used as pharmaceuticals.

DESCRIPTION OF THE PRIOR ART Publications which underlie the present invention as a prior art are currently unknown.

Object of the invention

By the method according to the invention pharmacologically extremely valuable piperidine derivatives are provided.

Explanation of the essence of the invention

The present invention has for its object to produce novel compounds which have tumor-inhibiting, immunomodulating, anti-inflammatory, antibacterial and antiparasitic activity. The invention relates to processes for the preparation of compounds of the formula I.

R - CH - CH - CH ₉ - N »J (D,

^{1 2} / \

wherein R _{1 is} Ci-C ₃₀ -AlkVl means; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N ₁ N-di-lower alkylcarbarr.oyl, cyano or lower alkyl substituted by hydroxy, lower alkoxy, acyl, amino, lower alkylamino, di-lower alkylamino or acylamino; R _{3 is} hydrogen, lower alkyl or aryl; wherein one of the radicals X and Y is hydroxy, lower alkoxy or acyloxy and the other of the radicals X and Y is hydrogen; or in which both radicals X and Y can also be hydrogen, if R _{2 is} cyano or substituted by amino or acylamino-substituted lower alkyl and R _{1 is} C ₂ -C ₃ O-AIkYl means; and their salts, processes for the preparation of these compounds, pharmaceutical preparations containing these compounds, the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical preparations.

Pie used above and below general terms have the following meanings in the context of the present application:

The prefix "lower" denotes a radical having 1 to 7 and especially having 1 to 4 carbon atoms.

Lower alkyl - as such and in compound terms such. B. lower alkoxycarbonyl, N-lower alkylcarbamoyl, Ν, Ν-Diniederalkylcarbamoyl, lower alkoxy, lower alkylamino or di-lower alkylamino - is

z. For example, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and especially methyl.

Ci-Cjo-alkyl is preferably linear Ci-C ₃₀ alkyl, but may also be branched, and is z. B. for Niederalkv I as defined above, or z. For example, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, n-pentadecyl, or z. B. 2,7-dimethyloctyl. C ₁ -C ₃₀ -alkyl is in particular C ₁ -C ₁₉ -alkyl, especially C _t -C _1B -alkyl and in particular C ₇ -C ₁₅ -alkyl.

C ₂ -C ₃₀ -alkyl corresponds to C ₁ -C ₃₀ -alkyl with the exception of methyl and is in particular C ₂ -C ₁₉ -alkyl and primarily C ₇ -C ₁₆ -alkyl.

An acyloxy radical X or Y is z. Arylcarbonyloxy, aryl-loweralkanoyloxy, halo-loweralkanoyloxy, C ₁ -C ₃₀ -alkylkynyloxy, carbamoyloxy, N-loweralkylcarbamoyloxy, N-aryl-lower alkylcarbamoyloxy or N-arylcarbamoyloxy, especially C ₁ -C ₁₈ alkanoyloxy or N-phenyl-lower alkylcarbamoyloxy, and the first Line C ^ C ^ alkanoyloxy.

Acyloxy in general is z. Arylcarbonyloxy, aryl-lower alkanoyloxy, halo-lower alkanoyloxy or lower alkanoyloxy.

and preferably lower alkanoyloxy.

Acylamino is e.g. Arylcarbonylamino, aryl-lower alkanoylamino, halo-lower alkanoylamino or lower alkanoylamino, and especially lower alkanoylamino.

Aryl - as such and in compound terms such. B. arylcarbonyloxy, aryl-lower alkanoyloxy, Arylcarbonylamino or Arylniederalkanoylamino - is z. Phenyl or naphthyl, such as 1- or 2-naphthyl, or substituted phenyl or naphthyl, e.g. Phenyl or naphthyl which are substituted by lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen and / or nitro. Aryl is preferably unsubstituted or substituted as indicated above phenyl, and in particular phenyl.

Arylcarbonyloxy {£ Aroy loxy) is z. B. Benzoyloxy or Naphthoy lo \ y.

Aryl lower alkanoyloxy is e.g. Phenyl-lower alkanoyloxy, such as phenylacetyloxy or phenylpropionyloxy.

Halo-lower alkanoyloxy is z. B. trifluoroacetyloxy.

C _t -C 30 -alkanoyloxy is, for example, palmitoyloxy, stearoyloxy or lower alkanoyloxy.

Lower alkanoyloxy is e.g. As acetyloxy, propionyloxy or pivaloyloxy, also also z. B. formyloxy.

Arylcarbonylamino \ = aroylamino) is z. B. benzoylamino or naphthoylamino.

Aryl lower alkanoylamino is e.g. Phenyl-lower alkanoylamino such as phenylacetylamino or phenylpropionylamino.

Halo-lower alkanoylamino is z. B. trifluoroacetylamino.

Niederalkanoylamino is z. As acetylamino, propionylamino or pivaloylamino, also also z. B. formylamino.

Halogen is z. As fluorine or iodine, especially bromine and especially chlorine.

Halo-lower alkyl is z. B. trifluoromethyl.

Salts of compounds of the invention are primarily pharmaceutically acceptable, non-toxic salts.

For example, compounds of formula I with basic groups acid addition salts, for. As with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, eg. B.

Acetic, fumaric or methanesulfonic acid, or z. B. with amino acids such as arginine or lysine form. In presence

mono- or polysalts can be formed from several basic groups. Compounds of the formula I with an acidic

Group, e.g. Carboxy, and a basic group, e.g. B. amino, z. In the form of internal salts, d. H. in zwitterionic Form, or there may be a part of the molecule as i,: noros salt, and another part as a normal salt. For isolation or Reiniguno also pharmaceutically unsuitable salts, eg. As picrates or perchlorates, use

Find. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

Depending on the structural conditions, the compounds of the present invention may be in the form of Isomer mixtures or pure isomers. The compounds of the formula I according to the invention have valuable, in particular pharmacologically usable, Properties on. In particular, they show a strong inhibitory effect on the protein kinase C. Those of phospholipids

and calcium dependent protein kinase C occurs in several forms within the cell and participates in various fundamental processes such as signal transduction, proliferation and differentiation as well as the secretion of

Hormones and neurotransmitters. The activation of these enzymes is known to be either by a via receptors

mediated hydrolysis of phospholipids of the cell membrane or by a direct interaction with certain tumor-promoting

Agents. Receptor - mediated signal transduction via degradation of inositol phospholipids can be achieved by modulating the Activity of protein kinase C is affected. Substance! t capable of selectively activating the activity of protein kinase C.

to modify, as the compounds of formula I - may find use as tumor-inhibiting, immunomodulating, anti-inflammatory, antibacterial and antiparasitic, such as antitrypanocidal or antimalarial agents.

The compounds of the invention are also antivirally active and can be used e.g. to treat by HIV virus

induced diseases such as ARC or AIDS.

The valuable pharmacological properties of the compounds of the invention can be, for. With the following

standard biological tests: 1. modulation of the effect of protein kinase C (from rat brain); 2. Antiproliferative

Action against e.g. the human T24 bladder carcinoma in vitro; 3. Antitumor effect in vivo z. B. in human T24 bladder

and MBA 9812 lung xenografts at the nude mouse; 4. Inhibition of HIV Reverse Transcriptase and DNA Polymerase.

The effective concentrations of the compounds of the invention leading to a 50% inhibition in the in vitro tests

lead (IC50 values), are minimal at about 1OnM, the effective doses in in vivo experiments correspond to a maximum of one

One-fifth of the dose tolerata maxima and are between about 0.5 and 50mg / kg. Therefore, the compounds of formula I are z. B. suitable for the treatment of benign and malignant tumors. You can Tumor regressions cause and further the proliferation of tumor cells and the growth of micrometastases

prevent.

Furthermore, the compounds of the formula I in which R _{2 is} cyano are also valuable intermediates for the preparation

other compounds of the formula I, for. B. those in which R _{2 is} aminomethyl. The latter can be obtained from the former

Reduction, such as with lithium aluminum hydride and aluminum trichloride produce. Bevoizugt are the compounds of formula I, wherein R _{1 is} C ₁ -Ci ₉ -AlkyI; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, Ν, Ν-di-lower alkylcarbamoyl, cyano or lower alkyl which is protected by hydroxy, lower alkoxy, Lower alkanoylpoxy, amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino substituted means; R ₃ for Is hydrogen, lower alkyl or phenyl; in which one of the radicals X and Y is hydroxy, lower alkoxy, C, -C, _8- alkanoyloxy, Carbamoyloxy, N-lower alkylcarbamoyloxy, N-phenyl-lower alkylcarbamoyloxy or N-phenylcarbamoyloxy means and the

others of the radicals X and Y is hydrogen, or in which both radicals X and Y can also be hydrogen, if R _{2 is}

Cyano or lower alkyl substituted by amino or lower alkanoylamino and R _{1 is} C ₂ -C ₁₉ alkyl; in which Phenyl radicals unsubstituted or by lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, Niedertlkanoyloxy, halogen

and / or nitro are substituted; and their salts.

Particular preference is given to the compounds of the formula I in which R _{1 is} C ₁ -C ₁₅ -alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, Carbamoyl, cyano or lower alkyl substituted by hydroxy, amino or lower alkanoylamino; R ₃ for Is hydrogen, lower alkyl or phenyl; in which one of the radicals X and Y is hydroxyl, Ci-Cu-alkanoyloxy or N- Phenylniederalky lcarbamoy loxy and the other of the radicals X and Y is hydrogen, or wherein both radicals X and Y can also be hydrogen if R _{2 is} aminomethyl and R _{1 is} C ₂ -C ₁₅ -alkyl; and their salts. Most preferred are the compounds of formula I wherein R _{t is} C ₇ -C ₁₅ alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, Carbamoyl, hydroxymethyl, aminomethyl or lower alkanoylaminomethyl; R _{3 is} hydrogen, methyl or phenyl

stands; wherein one of X and Y is hydroxy and the other of X and Y is hydrogen, or both

Radicals X and Y can also be hydrogen if R _{2 is} aminomethyl; and their salts. Preferred above all the compounds df ι formula I wherein R ₁ is C ₇ -C ₁₆ -alkyl, R ₂ stands for Aminomcthyl, R ₃ is Phenyl, and (a) X is hydroxy and Y is hydrogen, or (b) X is hydrogen and Y is hydroxy

or (c) X and Y are hydrogen; and their salts.

The invention relates in particular to the specific compounds described in the Examples and pharmaceutically

applicable salts thereof.

The compounds of formula I can be prepared in a conventional manner by z. B.

(a) a precursor of the formula II

wherein R ₁ , R ₃ , X and Y have the meaning given under formula I, R ₂ 'is a group which is convertible by reduction into a radical R ₂ , or, if W and W together are oxo, also for a Rest R ₂ , as defined under formula I, "and W and W together represent an oxo group or represent two hydrogen atoms, is reduced, or (b) a compound of formula III

H <. (Ill),

· - · R ₃

wherein R ₂ and R _{3 have} the meaning given under formula I, with a compound of formula IV

(IV)

Y X '

wherein R ₁ , X and Y have the meaning given in Formsl I and Z is a nucleofugic leaving group and wherein X and Z may together also denote an epoxy group, alkylated, or

(C) for the preparation of compounds of formula I ₁ wherein X or Y is hydroxy, in a compound of formula V

.-. R ₂

R 1 -CH-CH-CH ₂ -n () · ((V)

YX - R ₃

s s

wherein R ₁ , R ₂ and R ₃ are as defined for formula I, one of X ₅ and Y _{1 is} a protected by a protective hydroxy group and the other of X, and Y, is hydrogen, the hydroxy protecting group splits; and / or, if desired, converting a compound of formula I obtained into another compound of formula I, and / or, if desired, converting a salt obtained into the free compound or into another salt, and / or, if desired, converting a resulting free compound of the formula I into a salt, and / or separating a mixture of isomeric compounds of the formula I obtained into the individual isomers.

In the following detailed description of the processes a) -c), the symbols R ₁ , R ₂ , R ₃ , X and Y each have the meaning given under formula I, unless stated otherwise.

Process (a): As groups R ₂ ', which can be converted by reduction into a radical R ₂ , z. Cyano and carbamoyl, which are normally converted to aminomethyl under the chosen reductive conditions, or lower alkoxycarbonyl and carboxy which are converted to hydroxymethyl under the selected reductive conditions.

The reduction according to process (a), when R ₂ 'in the compound of formula II is cyano, z. B. with a mixture of lithium aluminum hydride (LiAIH ₄ ) and aluminum trichloride.

Compounds of the formula Ii in which R ₂ 'repudiates carbamoyl, lower alkoxycarbonyl or carboxy are reduced, for example, with LiAlH ₄ alone.

The starting compounds of the formula II, wherein W and W 'together are oxo (= O), z. B. dadurcch that a compound analogous to formula III, which contains a group R ₂ 'as defined under formula II instead of the radical R ₂ , with an acid of the formula R ₁ -CHY-CHX-COOH, or a reactive derivative thereof, such as an acid halide or anhydride, acylated. The starting compounds of the formula II in which W and W 'represent two hydrogen atoms generally correspond to compounds of the formula I and are described, for example, in US Pat. B. according to method (b) or (c).

Process (b): The reaction according to process (b) proceeds in the sense of a conventional nucleophilic substitution reaction. In this case, the secondary nitrogen atom is alkylated in a compound of the formula III. Optionally, the reaction in the presence of inorganic or organic acid-binding agents, for. As tertiary amines, such as triethylamine, or potassium carbonate performed.

In a compound of formula IV is a nucleofugic leaving group Z z. Example, for halogen, in particular Chbr, bromine or iodine, or aliphatic- or aromatic-substituted sulfonyloxy, z. Methylsulfonyloxy or 4-methylphenylsulfonyloxy.

When X and Z together in a compound of the formula IV are an epoxy group (O), then when carrying out the process (b) compounds of the formula I are obtained in which H is hydroxyl.

The starting compounds of the formula III and IV are known per se or can be prepared analogously to known compounds.

Process (c): A protected by a protecting group hydroxy group X ₉ or Y, for example, is organic silyloxy, in particular tri-lower alkylsilyloxy, z. B. trimethylsilyloxy, dimethyl-tert-butylsilyl and especially dimethyl-thexylsilyloxy (thexyl A 2,3-dimethyl-2-butyl), or acyloxy, in particular lower alkanoyloxy, for example formyloxy, acetyloxy or pivaloyloxy; Halo-lower alkanoyloxy, for example chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy-ortrifluoroacetyloxy; lower alkoxy

lower alkanoyloxy, ζ. Methoxyacetyloxy; Aryl-lower alkoxy-lower alkanoyloxy, ζ. B. triphenylmethoxyacetyloxy; Aryloxyniederalkanoyloxy.z.B. Phenoxyacetyloxy; Benzoylolxy; Lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbolnyloxy; or aryl-lower alkoxycarbonyloxy, e.g. B. in each case unsubstituted or substituted by nitro Benzyloxycarbonyloxy or Diphenylmethoxycarbonyloxy.

The cleavage of the hydroxy protective group according to process (c) is carried out in a manner known per se by solvolysis, in particular hydrolysis, or else alcoholysis. Organic SiIyI is z. B. cleaved by treatment with W'.sser, hydrochloric acid or methanol. Preferred systems for the elimination of organic SiIyI z. (A) acetic acid / tetrahydrofuran / water, (b) 1% conc. Hydrochloric acid in ethanol, (c) hydrogen fluoride-urea complex in cyclohexane, (d) tetrabutylammonium fluoride in tetrahydrofuran and (e) trifluoroacetic acid / acetonitrile / water. Acyl groups are particularly produced by alcoholysis, but also hydrolysis, in the presence of a base, e.g. Sodium or potassium ethoxide or sodium or potassium hydroxide cleaved.

The starting compounds of formula V are z. Example, in that nan of one of the processes (a) and (b) for the preparation of compounds of formula I or a conversion of a compound of formula I in a second compound of formula I with gescnützter hydroxy group X or Y is carried out.

Compounds of the formula I can be converted into other compounds of the formula I.

For example, compounds of formula I in which R _{2 is} cyano can be converted as described in process (a) by reduction with, for example, a mixture of LiAlH ₄ and AICI ₃ in compounds of formula I in which R _{2 is} aminomethyl.

Furthermore, compounds of the formula I in which R _{2 is} carbamoyl or lower alkoxycarbonyl or carboxy, as described in the process (a) by reduction, for. B. with LiAlH ₄ , in compounds of formula I, wherein R _{2 is} aminomethyl or hydroxymethyl, are transferred.

Compounds of formula I in which R _{2 is} lower alkoxycarbonyl may be obtained by hydrolysis, e.g. B. in the basic medium, such as with NaOH or KOH in lower alkanols, in compounds of formula I, wherein R _{2 is} carboxy, are transferred.

Compounds of the formula I in which X or Y are hydroxyl can be converted by reaction with lower alkylating or acylating agents into compounds of the formula I in which X or Y is lower alkoxy or acyloxy.

Suitable lower alkylating agents are, for. Lower alkyl halides, mesylates or tosylates, preferably in the presence of strong bases, e.g. For example, sodium hydride, are applied. As acylating z. As alkanecarboxylic acids, in particular reactive derivatives thereof, such as acid chlorides or anhydrides, in question, which are preferably used in the presence of inorganic ou'er organic acid-binding agents. If the acylation of the OH group X or Y is carried out with z. As lower alkyl, Phenylniederalkyl- or phenyl isocyanates, we obtain compounds of formula I, wherein X or Y is N-lower alkylcarbamoyloxy, N-Phenylniederalkylcarbamoyloxy or N-phenylcarbamoyloxy.

Conversely, the compounds of formula I wherein X and Y are carbamoyloxy, N-lower alkylcarbamoyloxy, N-phenyl-lower alkylcarbamoyloxy or N-phenylcarbamoyloxy, e.g. B. by hydrolysis by means of sodium hydroxide solution or by reduction with LiAIH ₄ again into the analogous compounds of formula I, wherein X or Y is hydroxy.

Acylated the OH group X or Y in a compound of formula I with an optically active isocyanate, for. B. (-) - 1 phenylethyl isocyanate, we obtain a diastereomeric mixture of urethanes. The individual diastereomers can be separated and z. B. by hydrolysis with sodium hydroxide solution or by reduction with LiAIH ₄ in the pure enantiomers of the compounds of formula I, wherein X or Y is hydroxy, transfer.

The free compounds of the formula I obtainable by the process according to the invention with salt-forming properties can be converted into their salts in a manner known per se. Compounds with basic properties by treatment with acids or suitable derivatives thereof. Compounds with acidic properties by treatment with bases or suitable derivatives thereof.

According to the invention available mixtures of Isom jren can be separated in a conventional manner in the individual isomers, racemates z. B. by forming salts with optically pure salt-forming reagents and separating the thus obtainable diastereomer mixture, for. B. by fractional crystallization.

If in process (a), (b) and (c) for the preparation of compounds of formula I optically active starting compounds, in particular optically active epoxides of the formula IV in the process (b), the individual isomers are obtained directly in the Carrying out the corresponding procedures.

The reactions cited can be carried out under reaction conditions known per se, in the absence or usually in the presence of solvents or diluents, preferably those which are inert towards and dissolve the reagents used, in the absence or presence of catalysts, condensing agents or neutralizing agents, depending on the nature of the reaction and / or the reactants at reduced, normal or elevated temperature, eg. B. in the temperature range of about -70 ° C to about 19O ⁰ C, preferably from about -2O ⁰ C to about 150 ⁰ C, z. At the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, if appropriate under pressure, and / or in an inert atmosphere, e.g. B. under a nitrogen atmosphere.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable.

The invention also relates to those embodiments of the process starting from a compound obtainable as an intermediate at any process stage and carrying out the missing process steps, or in which a starting material is formed under the reaction conditions or in the form of a derivative, e.g. As a salt thereof is used.

The present invention also relates to pharmaceutical preparations containing as active ingredient one of the pharmacologically active compounds of the formula I. Particularly preferred are preparations for enteral, in particular oral, as well as for parenteral administration. The preparations contain the active ingredient alone or preferably zus immen with a pharmaceutically acceptable carrier material. The dosage of the active substance depends on the disease to be treated, as well as on species, their age, weight and individual condition, as well as on the mode of administration.

The pharmaceutical preparations contain from about 5% to about 95% of the active ingredient, with single-dose forms of administration preferably from about 20% to about 90% and non-single-dose forms of administration preferably from about 5% to about 20% active ingredient. Dose patency forms such as dragées, tablets or capsules contain from about 0.01 g to about 1.0 g of the active ingredient.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, for. Example by means of conventional roller mixing, granulating, coating, solution or Lyophilisierungsverfahron produced. Thus, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with one or more feston excipients, optionally granulating a resulting mixture, and optionally admixing the mixture or granules, if desired, with additional adjuvant clay, into tablets or granules DrageO-Kernon verarboitet. Suitable carriers are in particular K'Hstoffe, wio sugar, z. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, eg. Tricalcium phosphate or calcium hydrogen phosphate, also binders, wio starches, e.g. Corn, wheat, rice or potato starch, Mothylcollulose, Hydroxypropylmethylcolluloso, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, non-crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional aids are primarily Fließregulior- and lubricants, z. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol, or derivatives thereof. Dragoe cores can be provided with suitable, optionally gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose precursors, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance. Orally applicable pharmaceutical compositions are also gelatin capsules, as well as soft, closed gelatin gobs and a plasticizer such as glycerine or sorbitol. The capsules can be the active ingredient in the form of granules, eg. B. in admixture with fillers, such as corn starch, binders and / or lubricants, such as talc or magnesium stearate, and optionally of stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added.

Other oral forms of administration are for. B. in the usual way prepared syrups containing the active ingredient z. B. in suspended form and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration, the z. B. in the measurement of 5 or 10mI a suitable single dose results included. Furthermore, z. B. also powdered or liquid concentrates for the preparation of shakes, ζ. As in milk, into consideration. Such concentrates may also be packaged in single dose amounts. As rectally applicable pharmaceutical preparations come z. As suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base are z. As natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkenols.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, or aqueous injection suspensions containing viscosity-increasing substances, e.g. As sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers. In this case, the active ingredient, optionally together with auxiliary stiffeners, also be present in the form of a lyophilisate and be brought into solution prior to parenteral administration by adding suitable solvents.

Solutions, such as B. used for parenteral administration, can also be used as infusion solutions.

The invention also relates to a method for the treatment of the above-mentioned disease states. The compounds of the present invention may be administered prophylactically or therapeutically, preferably in the form of pharmaceutical preparations. At a body weight of about 70 kg, a daily dose of about 0.05 g to about 5 g, preferably from about 0.1 g to about 1 g of a compound of the present invention is administered.

embodiments

The following examples illustrate the present invention; Temperatures are given in degrees Celsius. The following abbreviations are used: THF A tetrahydrofuran; Ethyl acetate A ethyl acetate; Ether: diethyl ether; Section. & Absolute, en, em); conc. & concentrated, en, em).

Example 1: (a) 4-Cyano-1- (2'-hydroxy-1'-decyl) -4-phonyl-piperidine

18.72 g (0.12 mol) of 1,2-epoxydecane (Aldrich) are dissolved in 180 ml of ethanol, with 26.72 g (0.12 mol) of 4-cyano-4-phenylpiperidine hydrochloride (Aldrich) and 16.56 g '0, 12 mol) of potassium carbonate and heated under reflux for 6 h. The inorganic salts are filtered off after cooling, the filtrate is evaporated, the residue dissolved in 100 ml of methylene chloride and washed with saturated sodium bicarbonate and saturated sodium chloride solution. Thereafter, the organic phase is dried over magnesium sulfate and evaporated. The resulting oil is triturated with petroleum ether and the crystallizing product is filtered off, washed with cold petroleum ether and dried; . Mp 77-79 ⁰ C. Analogously to Example 1 a be produced the following compounds:

(b) 4-Cyano-1- (2'-hydroxy-1'-hexyl) -4-phenylpiperidine, m.p. 55-58 ° C.

(c) 4-Cyano-1- (2'-hydroxy-1'-octyl) -4-phenylpiperidine, m.p. 61-63 ° C.

(d) 4-Cyano-1- (2'-hydroxy-1'-dodecyl) -4-phenylpiperidine, m.p. 54-56 ° C.

(e) 4-Cyano-1- (2'-hydroxy-1'-tetradecyl) -4-phenyl-piperidine.

50.4 g (0.24 mol) of 1,2-epoxytetradecane (Aldrich) are dissolved in 300 ml of ethanol, with 54.4 g (0.24 mol) of 4-cyano-4-phenylpiperidine hydrochloride (Aldrich) and 33.2 g (0, 24 mol) of potassium carbonate and heated for 5 hours under reflux. After cooling, the inorganic salts are filtered off, the filtrate is evaporated, the residue is dissolved in 300 ml of ether and washed with 100 ml of water and 50 ml of saturated sodium chloride solution. Thereafter, the organic phase is dried over potassium carbonate and concentrated to half the volume. After addition of 100 ml of petroleum ether is allowed to stand at ^{0 0} C. The title compound crystallizes out, is filtered off, washed with cold petroleum ether and dried under high vacuum. Mp 68-9 ° C.

(f) R - (- M -cyano-1- (2'-hvdroxv-V-tGtradecv!) - 4-phenylene), m.p. 69-7O ⁰ C.

(g) S - (+) - 4-cyano-1- (2'-hydroxyV-totradocyl) -'-t-phonylpip (jrldln, IR (KBr): 2940,2870,224 / (weak), 1550, 1468cnr \ (h) 4-cyano-1- (2'-hydroxy-1'-hexadecyl) -4-phenylplperldin, mp. 67-69 ⁰ C.

(i) 4-Cyano-1- (2'-hydroxy-V-octadecyl) -4-phenylpiperidine, m.p. 88-90 "C

(j) 4-Cyano-1- (2'-hydroxy-1'-bulyl) -4-phonyl piperol, Snip. 73 ⁰ C.

Example 2: (a) 4-Amnomethyl-1- (2'-hydroxy-1 ^l -docyl) -4-phenylplperlene-1-diol (hydrochloride

A solution of 23.8 g (0.179 mol) of aluminum trichloride in 360 ml abs. THF is under nitrogen and at room temperature in oino suspension of 6.83 g (0.179 mol) of lithium aluminum hydride in 450ml abs. THFgetropft. It is stirred for 15 minutes and then heated to 35 ° C. To this mixture is added dropwise a solution of 26.1 g (0.179 mol) of 4-cyano-1- (2'-hydroxy-1'-decyl) -4-phenylpiperidine ( s. example 1 a) in 450 ml of THF abs. to. the reaction mixture is then stirred for 2.5 h boi 40 to 5O ⁰ C. After cooling to room temperature, dom carefully place approximately 250 ml of concentrated sodium hydroxide solution until the mixture alkaline roaglert The emulsion is filtered through kieselguhr (Hyflo Super CeI, Fluka), the filtrate is extracted with ether and the organic phase is dried over sodium sulfate and evaporated The rosultiorendo residue is dissolved in a little ethanol and treated with 51 ml of a 10% ethanolic hydrochloric acid solution. The title compound crystallizes out in needles, mp 259-261 ° C. Analogously to Example 2a, the following compounds are prepared:

254-256 ⁰ (2'-hydroxy-1 '-hexylM-phenylpiperidine dihydrochloride, mp C. - (b) 4-Aminomethyl -1.

(c) 4-Aminomethvl-1- (2'-hydroxy-1'-octyl) -4-phenylpiperidine dihydrochloride, mp. 243-245 ⁰ C.

(d) 4-aminomethyl-1- (2'-hydroxy-1'-dodecyl) -4-phenylpiperidine dihydrochloride, mp. 250-253 ⁰ C.

(e) 4-Aminomethyl- (2'-hydroxy-V-tetradecyl) -4-phenyl-substituted dihydrochloride.

A solution of 10.6 g (0.08 mol) of aluminum trichloride in 160 mL of absolute tetrahydrofuran is added under nitrogen and at room temperature to a suspension of 3.0 g (0.08 mol) of 4-cyano-1- (2'-hydroxy-1 ' -totradecyl) -4-ph9nylpiporidine (Example 1e) in 160 ml abs. Dropped tetrahydrofuran. The reaction mixture is then stirred for 3 hours at about 50 ° C. After cooling (O ⁰ C) is carefully added 120 ml of conc. Sodium hydroxide solution until the mixture reacts alkaline. The emulsion is filtered through diatomaceous earth (Hyflo Super CeI, Fluka), the filtrate extracted with ether, the organic phase dried over sodium sulfate and evaporated. The residue is dissolved in a little ethanol and treated with a small excess of ethanolic hydrochloric acid. The title compound crystallizes out. It is filtered off and dried. Mp 238-243 ⁰ C; free base mp. 71-72 ⁰ C.

(f) R - (-) - 4-Aminomethyl-1- (2'-hydroxy-V-tetradecyl) -4-phenyl-p-diidine dihydrochloride, m.p. 240-243 ⁰ C (brown discoloration); free base, mp. 65-66 ⁰ C.

(g) 4-Aminomethyl-1- (2'-hydroxy-1'-hexadecyl) -4-phenylpiperidine dihydrochloride, mp 243 -245 ⁰ C. free base, mp. 76-77 ⁰ C (h) 4-aminomethyl-1- (2'-hydroxy-1'-octadecyl) -4-phenylpiperidine dihydrochloride, Smp./!52-254 ⁰ C.

(i) 4-Aminomethyl-1- (2'-hydroxy-1'-butyl) -4-phenylpiperidine dihydrochloride, mp. 265-267 ⁰ C.

Example 3: (Two diastereomers of) 4-Cyano-1-I2 '- (1 "-phenylethylamino-carbonyloxy) -V-tetradecyl] -4-phenylplatinum 2.0g (0.005 mol) of 4-cyano-1- (2'-hydroxy 1'-tetradecyl) -4-phenylpiperidine (Example 1 e) are dissolved in 5 ml of methylene chloride and admixed at room temperature with 1.0 ml (0.0071 mol) of (-M-phenylethyl isocyanate (Fluka).) After the reaction has ended (about 16 h By recrystallizing twice from methanol, a (-) - rotating 4-cyano-1- (2 '- (1 "-phenylethylaminocarbonyloxyj-i-tetradecyl) -phenylpiperidine (isomer A) can be obtained pure, m.p. 59-63 ⁰ C, [a \ l ° = -46.3 ° ± 0.9 ° (c = 'in ethanol) By chromatography of the mother liquors on silica gel 60th (eluent: petroleum ether / Essigester 4: 1) can also be the second (-) - rotating 4-cyano-1- | 2 '- (1 "-phenylethylaminocarbonyloxy) -1'-tetradecyl) -4-.beta.-phenylpiperidine (isomer B) is obtained as an oil, [a 1 = -21 , 1 "(c = 1 in ethanol) elute under the chromatographic conditions indicated First, the diastereomer A.

Example 4: (a) S - (+) - 4-Aminomothyl-1- (2'-hydroxy-1'-tetradecyl) -4-phenyl-substituted-dihydrochloride

A solution of 19.1 g (0.143 mol) of aluminum trichloride in 300 ml of absolute THF is added dropwise at room temperature and under nitrogen to a suspension of 5.67 g (0.143 mol) of lithium aluminum hydride in 390 ml of absolute THF 20.3 g (0.0372 mol) of 4-cyano-1- [2 '- (1 "-phenylethylaminocarbonyloxy) -1'-tetradecyl] -4-phenylpiperidine (isomer B, see example 3) in 390 ml abs. THF dropwise. The reaction mixture is stirred for 3.5 h at 40 to 50 ° C, cooled and hydrolyzed by the addition of 400 ml of a 30% sodium hydroxide solution (cool in an ice bath). It is then diluted with 800 ml of ether and 200 ml of water and shaken well in a separating funnel. The aqueous phase is extracted with ether, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is dissolved in 20 ml of ethanol and mixed with 50 ml of a saturated ethanolic hydrochloric acid solution. Upon cooling, the product crystallizes out. It is filtered, washed with cold ethanol and dried under high vacuum; Mp 234-238 "C (under browning), (alJ ⁰ = + 13.0" + 0.9 ° (c = 1 in methanol).

(b) In an analogous manner, isomer A (see Example 3) is used to prepare R - (-) - 4-aminomethyl-1- (2'-hydroxy-1'-tetradecyl) -4-phenylpiperidine dihydrochloride, m.p.236-239 ⁰ C (under browning), [α) έ ° = -13.6 "± 0.9 ° (c = 1.1 in methanol).

Example 5: 4-Cyano-4-phenyl-1-tetradecylplperidin

11 g (0.05 mol) of 4-cyano-4-phenylpiperidine hydrochloride (Aldrich), 41 g (0.3 mol) of potassium carbonate (ground, anhydrous) and 13 ml (0.05 mol) of tetradecyl bromide are dissolved in 150 ml of acetonitrile for 5 h heated to reflux. After cooling, the filtrate is filtered off from the insoluble inorganic salts, the filtrate is evaporated, the residue is taken up in methylene chloride and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, evaporated and the residue is recrystallized from methanol; Mp 46-48 ° C.

Example 6: 5-Amnomethyl-4-phenyl-1-tetradecylpiperidine

A solution of 11.9 g (0.089 mol) of aluminum trichloride in 175 ml abs. THF is placed under nitrogen and at room temperature in a suspension of 3.4g (0.089 mol) of lithium aluminum hyarid in 220ml abs. THF dripped. It is stirred for 15 min and then heated to 35 ⁰ C. To this mixture is added dropwise a solution of 14.5 g (0.089 mol) of 4-cyano-4-phenyl-1-tetradecylpip'jridin (see examples).

In IVBmI abs. THF too. The Reaktlonsgomlsch is then 3h bol 40-60'C goruhrt. After cooling to room temperature, carefully sotze about 130ml concentrated. Sodium hydroxide solution until the mixture reacts alkaline. The emulsion is filtered through kieselguhr (llytlo Super CeI, Fluke), the filtrate is extracted with ether, the organic phase is dried over sodium sulphate and evaporated. The resulting residue is converted to 95% lgom Molhanoi Snip. ΊΊ-46'C.

Example 7: VTotrcdocyl -plporidinylcarbonamide

2.6 g (0.02 mol) of 4-piperidinecarboxylic acid (Jansen) are dissolved in COmI acetonitrile and after addition of 8.2 g (0.00 mol) of potassium carbonate (gomahlone, wnsaorfr oi) and 5.4 ml (0, 02 mol) Totrodocylbromid gochocht 22 hours under reflux, obgokuhlt and filtered. The solid is extracted with a mixture of Mothylon chloride / ethanol (9: 1); Then the filtrate and the extracts are evaporated and crystallized from ethanol. M.p. 120-125'C.

Example 8: 4-Amnnomothyl-1-tetradecylplperlenediol hydrochloride

To a suspension of 1.7 g (0.045 mol) of lithium hydanthene hydride in 50 ml abs. THF is added dropwise under nitrogen and boi Raumtemporatur a warm, saturated solution of 3.2 g (0.01 mol) of i-Totradecyl ^ -plperldincarbonsäureamid (see Boisplol 7) in 350ml abs. THF too. Thereafter, the reaction mixture is heated for 7 h under reflux, cooled and vorsotzt cautious with 1.1 ml of Wassor, 1.1 ml 15% liger sodium hydroxide solution and 3.3 ml Wassor. After filtration, the inorganic salts are washed well with ether, the organic phase is dried over sodium sulphate and evaporated. Dissolve the rosultiorondo oil in ethanol and prepare with 2 equivalents of 10% ethanolic acid hydrochloric acid solution. The product fails. It is filtered off and dried; M.p. 240 ° C (decomposition).

Example 9: i-U'-hydroxy-V-tetradecylM-plperldlcarbonsiureamid

2.56 g (0.02 mol) of 1,2-epoxytetradocane (Aldrich), 4.24 g (0.02 mol) of 4-piporidinecarboxylic acid (Jansen) and 25 ml of ethanol are refluxed for 2 hours. Thereafter, it is cooled, added to 10 ml of Ethor and filtered from the product; M.p. 135-137'C.

Example 10: 4-Amnomothyl-1- (2'-hydroxy-1'-tetradocyl) -plperldine-dlhydrochloride

To a suspension of 1.1 (i (0.029 mol) lithium aluminum hydride in 50 ml abs THF is added dropwise under nitrogen and boi room temperature, a solution of 3.4 g (0.01 mol) of 1- (2'-hydroxy> 1'-totradocyl 4-piperidinecarboxamide (Example 9) in 80 ml of absolute THF, then the reaction mixture is heated under reflux for 4 hours, cooled, treated cautiously with 1.1 ml of water, 1.1 ml of 15% sodium hydroxide solution and 3.3 ml Water and filtrate Dio inorganic salts are well dried with Ethor gowaschon, the pre-treated organic phases are dried over sodium sulphate and evaporated.The resulting oil is dissolved in ethanol and mixed with 2 equivalents of a 10% ethanolic hydrochloric acid solution. It is filtered off and dried, mp 280 ° C.

Example 11: 1- (2'-Hydroxy-1'-tetradecyl) -plperlene-4-carboxylic acid ethyl ester

4.2 g (0.02 mole) of 1,2-epoxytetradecane and 3.1 g (0.02 mole) of piperidine-4-carbon & 1-retaryl ester were refluxed together in 20 ml of ethanol for 5.5 hours. The reaction solution is then cooled, evaporated and the residue recrystallized from aqueous ethanol; Mp. 33-34 ° C.

Example 12: 1- (2'-Hydroxy-1'-tetradecyl) -plastylenic-4-carboxylic acid

1, 5g (0.05 mol) of 1- (2'-hydroxy-V-tetradecyl) piperidine-4-carboxylic acid ethyl ester (Example 11) are dissolved in 100 ml of ethanol and, after addition of 50 ml of 2N sodium hydroxide solution, heated to reflux for 2 hours. The reaction solution is then neutralized at 0 ° C using 2 N hydrochloric acid (50 ml ώ 0.1 mol) and eingoongt as far as possible. Dor residue is stirred with 400 ml of methylene chloride, dried over sodium sulfate and evaporated. The crystalline residue is triturated with ether / petroleum ether (1: 1), filtered and dried; Mp. 140-145 "C.

Example 13: 4-Aminoethyl- (2'-hydroxy-V-tetradecyl) -4-methyl-p-lip-dinedione hydrochloride

0.99 g (0.002 mol) of 4-aminomothyl-1- (2'-thylthyldimethylsilyloxy-1'-tetradocyl) -1'-mothylpiporidine hydrochloride are added to my 3% solution of conc. Dissolved hydrochloric acid in ethanol and heated to reflux for 7h. The cooled reaction solution is evaporated, the residue is taken up in 50 ml of methylene chloride, washed with saturated sodium carbonate solution, dried over sodium sulfate and evaporated again. The oil thus obtained is dissolved in ethanol, combined with 1.5 ml of a 10% strength ethanolic hydrochloric acid solution, concentrated a little and crystallized by adding a little ether. The title compound decomposes at about 260 ° C.

The Ausyang compound is prepared as follows:

(a) 1- (2'-Thexyldimethylsilyloxy-1'-tetradocyl) -piperidine-4-carboxylic acid ethyl ester: 1.84 g (0.005 mol) of 1- (2'-hydroxy-V-tetradecyl-piperidinyl) -carboxylate (Example 11 ) and 0.34 g (0.005 mol) of imidazole are dissolved in 10 ml of dimethylformamide and treated at room temperature with 0.89 ml (0.005 mol) of Thexyldimethylchlorsilan (Fluka) (Thoxyl 4 2,3-dimethyl-2-butyl) and stirred for 24 h at room temperature It is evaporated, the residue is extracted with a mixture of ether / petroleum ether 1: 1, washed with saturated sodium bicarbonate solution (NaOH), dried over sodium sulfate and evaporated. The residue is chromatographed (silica gel 60, ethyl acetate / petroleum ether 2: 1). The title compound elutes with the first fractions (Rf value = 0.88); IR 1709 cm ^-1 (c = 0), analysis: found: C 69.9% H 12.2% N 2.5%, calculated: C 70.4% H 11.9% N 2.7%.

(b) Ethyl 1- (2'-Thexyldimethylsilyloxy-1'-tetradecyl) -4-methylpiperidine-4-carboxylate: A solution of 18.2 g (0.035 mol) of 1- (2'-thexyldimethylsilyloxy-1'-tetradecyl) -piperidine -4-carboxylic acid ethyl ester in 50ml abs. THF is added at -78 ° C and under nitrogen to a solution of Li'.hiumdiisopropylamid in 60ml abs. THF (prepared from 7.3 ml (0.052 mol) of diisopropylamine and 32.4 ml [0.052 mol] of a 1.6 molar butyllithium solution in hexane) was added dropwise. After 1 h at -78 ° C, 2.2 ml (0.035 mol) of methyl iodide are added dropwise. The mixture is stirred for ² h at -78 ⁰ C, the mixture is allowed to warm slowly to room temperature and stirred overnight. By dropwise addition of 5.5 ml of 50% acetic acid at 0 ° C, the reaction mixture is hydrolyzed.

It is then precut with ether, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and the solvent is distilled off in a rotary evaporator. Chromatography on silica gel 60 (Esslgester / Potrolothor 1, 9) provides the title compound as an oil (Rf word »0.44 in the above system).

(c) 1 - (2'-Thoxyldimethylsilyloxy-1'-tetradocylM-mothylplorporolcarboxylic acid p: 15.6g (0.03 mol) of 1 (2'-thoxydimethylsilyloxy-tetradecylM-motnylplperldincarboxylic acid ethylstyrene are dissolved in 180 ml of ethanol The mixture is heated for 5 hours under reflux, cooled and neutralized with 30 ml of 2N hydrochloric acid, the alcohol is distilled off, the residue is partitioned between methyl chloride and water, the organic phase is dried over sodium sulphate, evaporated and concentrated dried in a high vacuum, and the title precursor thus obtained reaches the next stage of the synthesis without further purification.

(d) 4-Mothyl-1- (2'-thexyldimethyl-8-hydroxy-V-tetradecyl) -piporidine-4-carboxylic acid amide: 21 g (0.042 mol) of 1- (2'-thexyldimethylsilyloxy-1 '· totradocylM-mothylpiporiclin-1-carboxylic acid was dissolved in 690 ml of abs. TMF, cooled to ⁰ ° C. and admixed with 43.7 ml (0.355 mol) of ethyl chloroformate with 43.7 ml of pyridine and then immediately 135 ml of concentrated ammonia solution were added dropwise and the mixture was diluted with 680 ml of water extracted with Essigostor, the organic phase is washed with saturated Notriumbicarbonatlösung (NaHCOj), dried over sodium sulfate and evaporated .. For purification is chromatographed on Kieselgel 60 (methylene chloride / ethanol 1: 1) (Rf value in this system = 0.52). The title compound is used as oil orhalton and without further Roinigung in the next stage.

(o) 9.69g (0.0195 mole) of 4-Mothyl-1- (2'-thexyldimethylsilyloxy-1'-totradecyl) -piperidine-4-carboxylic acid amide are dissolved in 115ml abs. Dissolved THF and at room temperature and under nitrogen to a suspension of 1.5 g (0.0388 mol) of lithium aluminum hydride in 115 ml abs. THF dripped. The mixture is then heated under reflux for 2 h, then cooled to ⁰ ° C. and hydrolyzed by the addition of 1.5 ml of water, 1.5 ml of a 15% strength sodium hydroxide solution and 4.5 ml of water. The mixture is diluted with 200ml Ethorr, filtered, the filtrate was washed with water, trcknct os over sodium sulfate and. ^{1 it} evaporates. The product is purified by chromatography on Kiosolgel 60 (chloroform / methanol / concentrated ammonia solution 150: 50: 1) and converted to the dihydrochloride by treatment with a 10% ethanolic hydrochloric acid solution. This gives 4-aminomethyl-1- (2'-thexykimethylsilyloxy-1'-tetradecyl) -4-methylpiperidine dihydrochloride, which is acidic and melts at 80 ° C.

Example 14: Ethyl 1- (2'-hydroxy-1'-tetradecyl) -4-methyl-p-beadyl-4-carboxylate

8.3 g (0.015 mol) of 1- (2'-Thexyldimethylsilyloxy-1'-tetradocyl) -4-mothylpiperidin-4-carbonyl-thylester (Example 13b) are dissolved in 120 ml of 1% conc. Hydrochloric acid dissolved in ethanol and heated to reflux for 12 h. After cooling, the mixture is evaporated, the residue is taken up in methylene chloride, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated again. The resulting oil is chromatographed on silica gel 60 (ethyl acetate / petroleum ether 8: 2). The pure fractions give the title compound as an oil; Mass spectrum: 383.184.

Example 15: i-U'-hydroxy-V-tetraHcylM-methylplperlene-1-carboxylic acid

2 g (0.005 mol) of ethyl 1 - (2'-hydroxy-1'-tetradecylM-methylpiperidine) -carboxylate (Example 14) are dissolved in 30 ml of ethanol and heated to reflux for 4 hours after the addition of 5 ml (0.01 mol) of 2 N sodium hydroxide solution. For workup, the mixture is cooled to ⁰ ° C., neutralized with 5 ml (0.01 mol) of 2 N hydrochloric acid and the alcohol is distilled off on a rotary evaporator The aqueous residue is extracted with methylene chloride, the organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. The solid residue is recrystallized from methanol and the title compound melts at 198-200 * C, mass spectrum: 355.156.

Example 16: 4-Hydroxymethyl- (2'-hydroxy-1'-tetradecyl) -4-methyl-plperldlene hydrochloride

0.15 g (0.004 mol) of lithium aluminum hydride under nitrogen in 15 ml abs. Ether submitted. A solution of 0.8 g (0.002 mol) is added dropwise ¹ - (2'-hydroxy-1'-tetrac'6cyl) -4-methylpiperidin-4-carboxylate (Example 14) is added and stirred 12 h. The reaction mixture is added sequentially with 0.15 ml of water, 0.15 ml of 15% sodium hydroxide solution and 0.45 ml of water, diluted a little with ether and filtered. The filtrate is dried over sodium sulfate and evaporated. The residue is converted by means of 10% ethanolic hydrochloric acid into the hydrochloride; Mp. 100 ⁰ C (waxy compound).

Example 17: 4-Hydroxymethyl-1- (2'-hydroxy-1'-tetradecyl-piparinediamine hydrochloride

0.76 g (0.02 mol) of lithium aluminum hydride under nitrogen in 50ml abs. Ether submitted. A solution of 3.69 g (0.01 mol) of ethyl 1- (2'-hydroxy-1'-tetradecyl) -piperidine-4-carboxylate (60 ml of ether) (Example 11) is added dropwise, and the mixture is stirred for a further 1.5 hours. The reaction mixture is added in turn with 0.75 ml of water, 0.75 ml of 15% sodium hydroxide solution and 2.28 ml of water, diluted a little with ether and filtered. The filtrate is dried over sodium sulfate and evaporated. The residue is recrystallized from petroleum ether (mp of the free base 40-42 ⁰ C). The hydrochloride is obtained by dissolving the free base in a little ethanol, adding 10% ethanolic hydrochloric acid solution and concentrating; M.p. 11O ⁰ C.

Example 18: 4-Cyano-1- (2'-deoanoyloxy-1'-tetradecyl) -4-phenylplperlene hydrochloride

15.92p i0.04 mol) 4-cyano-1- (2'-hydroxy-1'-tetradecyl) -4-phenylpiperidine (Example 1 e) are dissolved in 40 ml of methylene chloride and treated dropwise at room temperature with 11.4 g (0, 06 moles) decanoyl chloride. The reaction mixture is stirred for 15 min at room temperature, then heated at reflux for 30 min. After cooling, it is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel 60 (ethyl acetate / petroleum ether 3: 7). The hydrochloride is obtained by treating the pure fractions with ethanolic hydrochloric acid; Mp. 63-65 ⁰ C.

Example 19: 4-Amnomethyl-1- (2'-decanoyloxy-1'-tetradecyl) -4-phenylpiperidine-dlhydrochloride

33.6 g (0.06 mol) of 4-cyano-1- (2'-decanoyloxy-1'-tetradecyl) -4-phenylpiperidine (Example 18) are hydrogenated in 500 ml of acetic acid and 3.6 g of platinum oxide at atmospheric pressure. After 14 h, the reaction comes to a standstill, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylene chloride, with saturated sodium bicarbonate solution

washed, dried over sodium sulfate and evaporated again. Chromatography on Klosolgol 60 by means of methylene chloride / methanol (7: 3) gives the free structure of the riveted compound (oil), which is dissolved in ethanol and converted into the hydrochloride by addition of 10% ethanol-hard saline; M.p. 85-87 ⁰ C.

Example 20: 4-HydroxymethvM - (a'-hydroxy-i'-tntradecy !! - piperidine

iuu under exclusion of moisture gorührt suspension of 0.25 g (6.6 mmol) of lithium aluminum hydride in 10 ml abs. 1HF at 50 ⁰ C was added dropwise a solution of 1.2 g (3.1 mmol) of i-O'-HydroxymyrlstoyD-prlperidin ^ -carbonsäureethylestor ÄOrnl in abs. THF added. One stirs for 16h, no-body temperature. After cooling, carefully add 5 ml of 5N sodium hydroxide solution to ¹⁰ ml of water, and heat twice with 50 ml of ether. The ether solution is washed with water, Na. '.msulfat dried and evaporated. This gives the title precursor as a yellowish oil, Rf value - 0.4 (Kioselgeldünnschichtplatten, Mothylonchlorid: Mothanol: Vonz. Ammonia 40: 20: 1 ,.

The starting compound is prepared as follows:

A solution of 2.4 g (10 μmol) 3-hydroxymyristic acid in 100 ml dimethylformamide is treated with 1.57 g (10 μmol) piperidine-4-carboxylic acid aryl ester and 5.0 g (20 μmol) 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ ) and 30h at 50 ° C. The reaction mixture is evaporated and the residue with methylene chloride / ethyl acetate 1: 1 on silica gel chromatographies. This gives the 1O'-hydroxyrnyristoyl-plperidine M-carboxylic acid ethyl ester as a yellowish oil, R f = 0.32 (silica gel thin layer platelet, methylene chloride.Essigoster 1: 1).

Example 21: 4-Amnomethyl-1- (3'-hydroxy-1'-tetradecyl) -4-phenyl-pearyl oxalate A suspension of 0.17Sg (4.6mMol) lithium aluminum hydride in 5 mL THF, stirred under exclusion of moisture, is treated with a solution of 0.613 g (4.6 mmol) of aluminum trichloride in 5 ml THF and heated to 5O ⁰ C warmed. To this mixture, a solution of 0.76 g (1.84 mmol) of 4-cyano-1- (3'-hydroxymyristoyl) -4-phenylpiperidine in 10 mL of THF is added dropwise and the mixture is stirred for 16 h. The crude mixture is worked up analogously to Example 20 and dus orhalteno product crystallized as oxalate from methanol; Mp. 190-192 ⁰ C.

The starting compound is prepared as follows:

A solution of 2.4 g (10 mmol) of 3-hydroxymyristic acid in 100 ml of dimethylformamide is added successively with 1.38 ml (10 μmol) triethylamine, 2.3 μl (10 μmol) 4-cyano-4-phenylpiperidine hydrochloride and 5.0 g (20 μmol) 2 -Ethoxy-1-ethoxycdrbonyl-1,2-dihydroquinoline (EEDQ) and stirred at 50 ° C for 30h. The reaction mixture is evaporated and the residue over 250 g of silica gel with methylene chloride / ethyl acetate (1: 1) chromatography ^. This gives the 4-Cya.io-1- (3'-hydroxymyristoyl) -4-phenylpiperidine as gulbes oil.

Example 22: 4- (N-Acetylamnomethyl) -1-U'-h'-droxy-1'-dodecyl) -4-phenyl-2-chloro-2-ol hydrochloride (0.0053 mol) 4-aminomethyl-1- (2'-hydroxy) 1'-dodecyl) -4-phenylpiperidine (Example 2d), 10 ml of pyridine and 10 ml of acetic anhydride are stirred for 16 h at room temperature. After cooling, diluted with 150 ml of ice water and allowed to stand for 45 min. After extraction with ethyl acetate, the organic phase is washed with 2 N hydrochloric acid, 2N sodium hydroxide solution, as saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel 60 (gradient: To'uol-Essigestar 80:20 to 40:60). The Diacetylverbindung entl old fractions are evaporated, the residue dissolved in 32 ml of methanol and treated with 1.21 g (0.00875 mol) of potassium carbonate in 8 ml of water. After stirring for 17 h at room temperature, the yellow solution is mixed with 100 ml of a saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is washed int saturated sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel 60 (gradient: pure chloroform to chloroform-methanol 95: 5) and recrystallization of the pure fractions from methylene chloride / ether / petroleum ether gives the title compound as the free base (mp 68-7O ⁰ C). The hydrochloride is obtained by addition of ethanolic hydrochloric acid and crystallization from ether; Mp. 70-75 ° C.

Example 23: Capsules containing 0.25 g of active ingredient, e.g. B. nine of the compounds of Examples 1-22 can be prepared as follows:

Composition (for 5000 capsules)

active substance 1250 g talc 180g wheat starch 120g magnesium stearate 80 g lactose 20 g

The powdery substances are forced through a sieve with a mesh size of 0.6 mm and mixed. Portions of 0.33 g each of the mixture are filled into gelatin capsules by means of a capsule filling machine.

Claims (21)

-.- i.90186 Claims: 1. A process for the preparation of Fiperldlnderivaten of formula I. R, - CH - CH - CH ₉ - N). ' .. 'β-tf K (lh Y X wherein Ri is C ₁ -C ₃₀ alkylalkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbarnoyl, N-lower alkylcarbamoyl, N, N-dinledloroalkyl, arbamoyl, cyano or lower alkyl which is substituted by hydroxy, lower alkoxy, acyloxy, amino, lower alkylamino, diniodoalkylamino or acylamino; R _{3 is} hydrogen, lower alkyl or aryl; wherein one of X and Y is hydroxy, Nioderalkoxy or acyloxy and the other of X and Y is hydrogen; or in which boide radicals X and Y can also be hydrogen, if R _{2 is} cyano or substituted by amino or acylamino lower alkyl and! means; and their salts, characterized in that (a) a precursor of the formula II W V / '* R _± - GH - CH - C - N "... (II), wherein R ₁ , R ₃ . X and Y have the meaning given under formula I, R ₂ 'is a group which is convertible by reduction into a radical R ₂ , or, if W together W' together oxo, also for a radical R ₂ as under formula I can be defined, and W and W 'together denote an oxo group or stand for two hydrogen atoms, reduced, or b) a compound of formula III HN V (HD. wherein R ₂ and R _{3 have} the meaning given under formula I, with a compound of formula IV R _{1 is} -CH-CH-CH ₂ -Z (IV), Y X in which R ₁ , X and Y have the meaning given under formula I and Z is a nucleofuge leaving group and in which X and Z may together also denote an epoxy group, alkylated, or c) for the preparation of compounds of formula I, wherein X or Y is hydroxy, in a compound of formula V \ _Λ - CH - CH - CH ₀ - N Y X 8 p wherein Ri, R ₂ and R3 have the meaning described in formula I, one of the radicals X, and Y _{s is} a protected by a protective hydroxyl group and the other of X ₉ and Y, is hydrogen, the hydroxy-protecting group cleaved; and / or, if desired, converting a compound of formula I obtained into another compound of formula I, and / or, if desired, converting a salt obtained into the free compound or into another salt, and / or, if desired, converting a resulting free compound of the formula I into a salt, and / or separating a mixture of isomeric compounds of the formula I obtained into the individual isomers. 2. The method according to claim 1, characterized in that a compound of formula I is prepared wherein R _{1 is} Ci-Cig-alkyl; R2 is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, NN-di-lower alkylcarbamoyl, cyano or lower alkyl substituted by hydroxy lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino; R _{3 is} hydrogen, lower alkyl or phenyl; wherein one of X and Y is hydroxy, lower alkoxy, C, -C ₁₈ alkanoyloxy, carbamoyloxy, N-lower alkylcarbamoyloxy, N-phenyl-lower alkylcarbamoyloxy or N-phenylcarbamoyloxy and the other of X and Y is hydrogen, or both X is X. and Y can also be hydrogen if R _{2 is} cyano or lower-alkyl substituted by amino or lower alkanoylamino and R _{1 is} C ₂ -C ₁₉ -alkyl, where phenyl radicals are unsubstituted or lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, Halogen and / or nitro are substituted; and their salts. 3. Process according to Claim 1, characterized in that a compound of the formula I is prepared in which R _{1 is} C ₁ -C ₁₅ -alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, cyano or lower alkyl which is substituted by hydroxy, amino or lower alkanoylamino; R _{3 is} hydrogen, lower alkyl is phenyl; in which one of the radicals X and Y is hydroxyl, CVC ^ alkanoyloxy or N-phenyl-lower alkylcarbamoyloxy and the other of the radicals X and Y is hydrogen, or in which both radicals X and Y can also be hydrogen, if R _{2 is} aminomethyl and R _{1 is} C ₂ -C ₁₆ -alkyl; and their salt. " 4. The method according to claim 1, characterized in that a compound of formula I is prepared wherein R _{1 is} C ₇ -C ₁₅ -Alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, hydroxymethyl, aminomethyl or lower alkanoylaminomethyl; R _{3 is} hydrogen, methyl or phenyl; wherein one of X and Y is hydroxy and the other of X and Y is hydrogen, or wherein both of R and X can also be hydrogen when R _{2 is} aminomethyl; and their salts. Process according to claim 1, characterized in that a compound of formula I is prepared, wherein R _{1 is} C ₇ -C ₁₆ -alkyl; R _{2 is} aminothenyl; R _{3 is} phenyl and (a) X is hydroxy and Y is hydrogen, or (b * X is hydrogen and Y is hydroxyl, or (c) X and Y are hydrogen, and their salts. 6. The method according to claim 1, characterized in that 4-aminomethyl-1- (2'-hydroxy-1'-tetradecyO-piparidine and pharmaceutically acceptable salts thereof are prepared. A process according to claim 1, characterized in that 4-aminomethyl-4-phenyl-1-tetradecylpiporidine and pharmaceutically acceptable salts thereof are prepared. 8. The method according to claim 1, characterized in that 4-Aminometiiy-1- (2'-hydroxy-1'-tetradecyl) -4-phenylpiprididine and pharmaceutically acceptable salts thereof have been prepared. 9. The method according to claim 1, characterized in that 4-Aminomothy! - 'l-tetradecylpiperidine and pharmaceutically acceptable salts thereof are prepared. 10. Compounds of the formula I _ _R j "_ _{(!. Ll} _, _{v (l) 1} wherein R _{1 is} Cy-C ,; _C , -Alky! means; R ₂ carboxy .. Niederaii.o.vycarbonyl, Carbamoy !, N-lower alkylcaiLiarnoyl, NN-Diniedefalkvk.arbar.-ioyt .. Cyano oc * he Nieueralkyl, which by Hydroxy, lower alkoxy, acyl oxy, amino, lower alkylamino, di-lower alkylamino or acylamino; R _{3 is} hydrogen, lower alkyl or aryl; wherein one of X and Y is hydroxy, lower alkoxy or acyloxy and the other of X and Y is hydrogen; or wherein both radicals other radicals X and Y is hydrogen; or in which both radicals X and Y can also be hydrogen, if R _{2 is} cyano or is lower alkyl substituted by amino or acylamino and R 1 is C ₂ -C ₃₀ -alkyl; and their salts. 11. Compounds of formula I according to claim 10, wherein Ri Ci-C ₁₉ alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano or lower alkyl substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino; R _{3 is} hydrogen, lower alkyl or phenyl; wherein one of X and Y is hydroxy, lower alkoxy, Cr-Ci8-alkanoyloxy, carbamoyloxy, N-lower alkylcarbarnoyloxy, N-phenyl-lower alkylcarbamoyloxy or N-phenylcarbamoyloxy and the other d9r radicals X and Y is hydrogen, or both X and Y are both may also be hydrogen when R _{2 is} cyano or lower alkyl substituted by amino or lower alkanoylamino and R 1 is C ₂ -C ₁₉ alkyl, where phenyl is unsubstituted or lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen and / or nitro are substituted; and their salts. 12. Compounds of formula I according to claim 10, wherein R _{1 is} C, -C _1B alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, cyano or lower alkyl substituted by hydroxy, amino or lower alkanoylamino; R _{3 is} hydrogen, lower alkyl or phenyl; in which one of the radicals X and Y is hydroxy, C, -C ₁₂ alkanoyloxy or N-phenyl-nichloro-carbamoyloxy and the other of the radicals X and Y is hydrogen, or in which both radicals X and Y can also be hydrogen, when R _{2 is} aminomethyl and R _{1 is} C ₂ -C ₁₅ alkyl; and their salts. 13. Connections of the forms! I according to claim 10, wherein R _{1 is} C ₇ -C ₁₆ -alkyl; R _{2 is} carboxy, lower alkoxycarbonyl, carbamoyl, hydroxymethyl, aminomethyl or lower alkanoylaminomethyl; R _{3 is} hydrogen, methyl or phenyl; wherein one of X and Y is hydroxy and the other of X and Y is hydrogen, or wherein both X and Y may also be hydrogen when R _{2 is} aminomethyl; and their salts. 14. Compounds of the formula I according to claim 10, in which R _{1 is} C ₇ -C ₁₅ -alkyl, R _{2 is} aminomethyl, R _{3 is} phenyl, and (a) X is hydroxyl and Y is hydrogen, or (b) X Is hydrogen and Y is hydroxy, or (c) X and Y are hydrogen; and their salts. 1b. 4-Aminomethyl-1- (2'-hydroxy-1'-tetradecyl) -piperidine and pharmaceutically acceptable salts thereof according to claim 10. 16. ^ Aminomethyl ^ -phenyl-i-tetradecylpiperidine and pharmaceutically acceptable salts thereof according to claim 10. 17. 4-Aminomethyl-1- (2'-hydroxy-1'-tetradecyl) -4-phenylpiperidine and pharmaceutically acceptable salts thereof according to claim 10. 18. 4-Aminomethyl-1-tetradecylpiperidine and pharmaceutically acceptable salts thereof according to claim 10. 19. A pharmaceutical preparation containing a compound according to any one of claims 10 to 18 and at least one pharmaceutically acceptable carrier material. 20. A compound according to any one of claims 10 to 18 for use in a method for the therapeutic treatment of the animal or human body. 21. A compound according to any one of claims 10 to 18 for use as an antitumor agent. 22. Use of a compound according to any one of claims 10 to 18 for the preparation of pharmaceutical preparations.