NO312244B1 - 1-azobicyclo (2.2.1) heptane derivatives, process for their preparation and pharmaceutical compositions - Google Patents

Description

The present invention relates to new substituted heterocyclic compounds, a method for their production and pharmaceutical preparations containing them as active ingredient.

More particularly, the present invention relates to a new class of substituted heterocyclic compounds for therapeutic use in pathological phenomena that implicate the tachykinin system, for example, but not exclusively: pain (D. Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (J.E. Morlay et al., Life Sciences, 1987,4_1, 527-544), circulatory failure (J. Losay et al., 1977, Substance P, Von Euler, I.S. and Pernow ed., 287-293 , Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sei., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders, neuropsychiatric disorders (CA. Maggi et al., J. Autonomic. Pharmacol., 1993, 13, 23-93).

In recent years, much research work has been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and in the peripheral nervous system. The receptors for tachykinins are known and are classified into three types: NK-i, NK2, NK3. Substance P (SP) is the endogenous ligand for the NK-i receptors, neurokinin A (NKa) is the one for the NK2 receptors and neurokinin B (NKg) is the one for the NK3 receptors.

The receptors NK-|, NK2, NK3 have been shown in different species. An overview of CA. Maggi et al. focuses on the receptors for tachykinins and their antagonists and describes pharmacological studies and therapeutic application in humans (J. Autonomic Pharmacol., 1993, 13, 23-93).

Among antagonists specific for the receptor NK-| mention may be made of the following non-peptide compounds: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proe. Nati. Acad. Sei. USA, 1991, 88, 10208-10212 ), SR 140333

(Curr. J. Pharmacol., 1993, 250, 403-413).

For the NK2 receptor, a selective non-peptide antagonist, SR 48968, has been described in detail (Life Sci., 1992, 50, PL101-PL106).

For the human receptor NK3 is a selective non-peptide antagonist, (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)-piperid-3-yl]propyl] -4-phenyl-piperid-4-yl]-N-methylacetamide hydrochloride or SR 142801 described (Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, July 31-August 3. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0. 9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterburry, 1995, April 6-8; Eur . J. Pharmacol., 1995, 278 (1), 17-25; 1st. Eur. Congress Pharmacol., Milan, 1995, June 16-19).

Patent application EP-A-336230 describes peptide derivatives which are antagonists for substance P and neurokinin A and useful for the treatment and prevention of asthma.

International patent applications WO 90/05525, WO 90/05729, WO 91/09844, WO 91/18899 and European applications EP-A-0436334, EP-A-0429466 and EP-A-0430771 describe antagonists for Substance P.

European Patent Applications EP-A-0428434, EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538, EP-A-591040, EP-A-0625509, EP-A-0630887 and international applications WO 94/10146, WO 94/29309, WO 94/26735, WO 95/05377, WO 95/12577, WO 95/16682, WO 95/28389, WO 96/06094, WO 96/05193 likewise relate to antagonists for receptors for neurokinins.

New substituted, heterocyclic compounds have now been found which are antagonists for receptors for neurokinins.

Thus, in one aspect, the present invention relates to compounds of the formula:

where:

- A represents a bivalent residue selected from:

- A<|)-0-CO-

- A3) -O-CH2-CO-

- m is 2 or 3;

- Ar-| represents phenyl substituted one or more times by halogen,

- T is a group CH2-Z,

- Z represents phenyl which is unsubstituted or mono- or polysubstituted with a halogen atom or a trifluoromethyl group,

- Am represents a group with the formula:

where:

Ar 2 represents phenyl;

n is zero or one;

X© represents a pharmaceutically acceptable anion and salts thereof,

where appropriate with mineral acids or organic acids.

The compounds of formula (I) according to the invention may comprise both racemic and optically pure isomers.

Besides the quaternary ammonium salts, salts can be formed with the compounds of formula (I). These salts include both those with mineral and organic acids which allow easy separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example mandelic acid or camphorsulfonic acid, as well as those which form pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, fumarate, 2-naphthalenesulfonate, benzenesulfonate, gluconate, citrate, isethionate and p-toluenesulfonate.

The anions Xe are those normally used to form quaternary ammonium ions and are preferably chloride, bromide, iodide, acetate, hydrogen sulfate, methanesulfonate, paratoluenesulfonate and benzenesulfonate ions.

It is preferred to use pharmaceutically acceptable anions, e.g. chloride, methanesulfonate or benzenesulfonate.

In the present description, the alkyl groups or alkoxy groups are linear or branched; and a halogen atom means either a chlorine, bromine, fluorine or iodine atom.

A group of preferred compounds according to the present invention are those with the formula:

where:

"<*>" means that the carbon atom thus marked has definite, absolute (+) or (-) configuration;

Am, m, Ar-|, A and T are as defined for the compounds of formula (I) in claim 1; as well as salts thereof with mineral acids or organic acids.

In another aspect, the present invention relates to a method for the preparation of compounds of formula (I) and salts thereof, characterized in that 1) a compound of the formula

where m, Ar<| and A is as defined for the compound of formula (I) in claim 1 and E represents hydrogen or an O-protecting group, is treated with a halogen derivative of formula: where Z is as defined in claim 1, and Hal represents halogen, giving a compound with the formula: where E, m, An, A and T are as defined above; 2) optionally, the O-protecting group is removed using an acid or a base, giving an alcohol with the formula:

where m, Ar-i, A and T are as defined above

3) the alcohol (VIII) is treated with a compound of the formula: where Y represents methyl, phenyl, tolyl or trifluoromethyl, which gives a compound of the formula: 4) the compound (X) is reacted with a cyclic tertiary amine of the formula:

where Ar2 and n are as defined for (I) in claim 1; and,

5) the thus obtained product is isolated in the form of a sulphonate and optionally a sulphonic acid salt or optionally the anion and optionally the acid salt in the thus obtained salt is replaced with another anion and optionally another salt of a mineral acid or pharmaceutically acceptable organic acid.

When E represents an O-protecting group, this is selected from classic O-protecting groups well known to those skilled in the art, for example tetrahydropyran-2-yl, benzoyl or (C-j-C^alkylcarbonyl.

If a halogenated derivative of formula (IV), (V) or (VI) is used, the reaction can be carried out in an inert solvent such as tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide, in the presence of a base such as potassium fert-butylate, sodium hydride or lithium diisopropylamide at temperatures between 0°C and 80°C.

The protecting groups in the resulting compound of formula (VII) in step 2) can be removed by methods known per se. If e.g. E is a tetrahydropyran-2-yl group, the removal of the protecting group can be carried out by acid hydrolysis using hydrochloric acid in a solvent such as ether or methanol, or in a mixture of these solvents, or by using pyridinium-p- toluenesulfonate in a solvent such as methanol, or by using an Amberlyst<®-> resin in a solvent such as methanol. The reaction is carried out at temperatures between room temperature and the boiling point of the solvent. If E is a benzoyl group or a (C 1 -C 4 )-alkylcarbonyl group, the deprotection can be carried out by hydrolysis in an alkaline medium using an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent such as water, methanol, ethanol or dioxane or a mixture of these solvents at temperatures between 0°C and the boiling point of the solvent.

In step 3) the reaction between the alcohol of formula (VIII) and the sulfonyl chloride of formula (IX) can be carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine or N-methylmorpholine in an inert solvent such as dichloromethane, benzene or toluene, at temperatures between -20°C and the boiling point of the solvent.

When in step 4) a compound of formula (X) is reacted with a compound of formula (XI), the reaction can be carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene or propan-2-ol and in presence or absence of a base. When a base is used, this is selected from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of a base, the reaction can be carried out using an excess of a compound of formula (XI) and in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. When -A- in the compound of formula (X) represents the bivalent residue -O-CO- or -CH2-O-CO-, the reaction can be carried out at a temperature between ambient temperature and 80°C. When -A- in the compound of formula (X) represents the bivalent radical -O-CH2-CO-, -O-CH2-CH2-, -N(R1)-CO-CO-, -N(R1)-CH2- CH2-, -N(R1)-CO- or -O-CH2-, the reaction can be carried out at a temperature between ambient temperature and 100°C.

The thus obtained products of formula (I) are isolated in the form of the sulfonate (YSO3<©>) or the sulfonate anion in the quaternary salt thus obtained is optionally exchanged with another pharmaceutically acceptable anion.

The sulfonate anion YSO3<©> resulting from the reaction between the compound of formula (XI) and the compound of formula (X) can be exchanged in situ or after isolation of the compound of formula (I) in which X<©> is the ion YSO3< ©>, with another anion X<©>, according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or with a solution of hydrochloric acid when X<©> represents chloride anion or exchange of anion by elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68<®> or Duolite A375<®>.

The compounds of formula (II) can be prepared according to different methods.

The compounds of formula (II) where -A- represents the bivalent residue bivalent -CH2-O-CO- and E represents hydrogen or an O-protecting group can be prepared according to SCHEME 1 below, where m and Ar-i are as defined for the compound of formula (I) and Pr means an O protecting group as defined above for E.

In step al in reaction scheme 1, a compound of formula (II) is reacted

with a compound of formula (XIII) by means of the method described in patent applications EP-A-0428434 and EP-A-0474561.

The resulting compound (XIV) is reacted in step bj. with an aqueous formaldehyde solution in the presence of a base such as 1,8-diazabicyclo[5,4,0]-undec-7-ene,

in a solvent such as 1,2-dimethoxyethane and at temperatures between room temperature and the boiling point of the solvent.

The nitrile derivative of formula (XV) is then reduced in step cl to give the primary amine of formula (XVI). This reduction can be carried out using hydrogen in the presence of a catalyst such as Raney<®>nickel, platinum oxide or palladium-on-charcoal, in an inert solvent such as an alcohol, e.g. ethanol, either as such or mixed with ammonia, or by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or borane in THF, in a solvent such as toluene, hexane, petroleum ether, xylene or tetrahydrofuran. The reaction is carried out at temperatures between 0°C and 70°C.

In step dj. the compound (XVI) is reacted with a reactive derivative of a carboxylic acid such as e.g. phosgene, in a solution of toluene, or 1,1'-carbonyldiimidazole in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine,

in a chlorinated solvent such as dichloromethane or 1,2-dichloroethane, or in an ether such as

tetrahydrofuran, at temperatures between -70°C and room temperature, giving a compound of the expected formula (II) where E is an O-protecting group.

Using the methods described above, the O-protecting group can be removed by hydrolysis (step 1), giving the compound of formula (II) where E is hydrogen.

The compounds of formula (II) where -A- is the bivalent radical -0-CH2-CO- and E is hydrogen or an O-protecting group, can be prepared as shown in reaction scheme 2 below, where m and An are as defined for a compound of formula (I). Pn and Pr2 are the O-protecting group Pr as defined above for E; more particularly, Pn is an O-protecting group that can be hydrolyzed in an acidic medium, and Pr2 is an O-protecting group that can be hydrolyzed in a basic medium.

In step a2 in reaction scheme 2, the synthesis of a cyanohydrin of formula (XVIII) from an aldehyde of formula (XVII) is carried out using methods which are known in themselves, e.g. as described in Organic Syntheses; Wiley, New York, 1932; Collect. Vol. 1, p. 336, or by adapting this method by using the action of sodium metabisulphite and potassium cyanide in aqueous brine.

In step b_2, the hydroxyl group in the compound of formula (XVIII) is protected by means of methods which are well known.

The resulting compound of formula (XIX) is then treated in step c2 with a strong base such as lithium diisopropylamide, potassium tefrbutylate or sodium hydride, giving a carbanion which is then reacted with a compound of the formula Hal-(CH2)m-0 -Pr 2 , where Hal is a halogen atom, preferably bromine or chlorine, which gives the compound of formula (XX). This reaction is carried out in an inert solvent such as an ether (e.g. tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane), an amide (e.g. N,N-dimethylformamide) or an aromatic hydrocarbon (e.g. toluene or xylene) at temperatures between -70°C and +60°C.

The nitrile derivative of formula (XX) is reduced in step d2 by methods described above, yielding the primary amine of formula (XXI).

In step e2, the compound of formula (XXI) is reacted with a compound of the formula Hal-CO-CH2-Hal, where Hal is a halogen atom, preferably chlorine or bromine, in the presence of a base such as a tertiary amine (e.g. triethylamine , N-methyl-morpholine or pyridine), giving a compound of formula (XXII). The reaction is carried out in an inert solvent such as e.g. in a chlorinated solvent (e.g. dichloromethane, dichloroethane or chloroform), an ether (e.g. tetrahydrofuran or dioxane) or an amide (e.g. N,N-dimethylformamide) at temperatures between -70°C and room temperature .

In step f_2, the O-protecting group is removed from the compound of formula (XXII) by means of acid hydrolysis by means of the methods described above.

Alternatively, the O-protecting group Ph can be removed from the compound of formula (XXI) by acid hydrolysis in step ]2, after which the resulting compound of formula (XXIV) is reacted in step k2 with a compound of the formula Hal-CO-CH2- Hal using methods described above in step e2.

The resulting compound of formula (XXIII) is cyclized in the presence of a base to give the expected compound of formula (II). If it is desired to prepare a compound of formula (II) where E is a protecting group Pr2, one can use a base such as an alkali metal carbonate (e.g. potassium carbonate), an alkali metal hydride (e.g. sodium hydride) or potassium -fetr-butylate in an inert solvent such as an aromatic hydrocarbon (e.g. xylene or toluene), an amide (e.g. N,N-dimethylformamide) or an ether (e.g. tetrahydrofuran) at temperatures between -30 °C and the boiling point of the solvent (step g2). If it is desired to prepare a compound of formula (II) where E is a hydrogen atom, one can use a base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) in a concentrated aqueous solution in a solvent, e.g. an alkanol

(e.g. propan-2-ol) or an amide (e.g. N.N-dimethylformamide) or a mixture of these solvents, at temperatures between room temperature and the boiling point of the solvent (step h2).

If it is desired, a compound of formula (II) can then be prepared where E is an O-protecting group Pri in step i2 by methods which are known in themselves.

The compounds of formula (II) where -A- is the bivalent radical -0-CH2-CH2- and E is hydrogen or an O-protecting group can be prepared using reaction scheme 3 below, where m and An are as defined for a compound of formula (I), and Pr-i and Pr2 are as defined in reaction scheme 2 above.

In step a3 in reaction scheme 3, a compound of formula (II) where -A- is the bivalent radical -0-CH2-CO- and E is a hydrogen atom or an O-protecting group, prepared as described in reaction scheme 2, is reduced. The reduction is carried out using a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or borane in THF, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at temperatures between room temperature and the boiling point of the solvent.

The compounds of formula (II) where -A- is the bivalent radical -O-CO- and E is a hydrogen atom or an O-protecting group can be prepared as shown in reaction scheme 4 below, where m and Ah are as defined for a compound with formula (I), and Pn and Pr2 are as defined in reaction scheme 2 above.

In step a4 of reaction scheme 4, the O-protecting group Pr-i in the compound of formula (XXI), prepared in step d2 of reaction scheme 2, is removed by acid hydrolysis using the methods described above.

The resulting compound of formula (XXIV) is reacted in step b_4 with a reactive derivative of a carboxylic acid, e.g. 1,1'-carbonyldiimidazole, phosgene in toluene or p-nitrophenylchloroformate, in the presence of a base such as triethylamine, N,N,-diisopropylethylamine or N-methylmorpholine, thereby obtaining a compound of the expected formula (II) where E is an O-protecting group. The reaction is carried out in an inert solvent such as a chlorinated solvent (e.g. 1,2-dichloroethane or dichloromethane), an ether such as tetrahydrofuran, an amide such as N,N-dimethylformamide or an aromatic solvent such as toluene, at temperatures between -60 °C and room temperature.

Using the methods described above, the O-protecting group Pr2 is removed by basic hydrolysis (step c4), giving the compound of formula (II) where E is hydrogen.

Compounds of formula (II) where -A- is the bivalent radical -N(Ri)-CO-CO- and E is hydrogen or an O-protecting group, can be prepared as shown in the subsequent reaction scheme 5, where m, An and Ri is as defined for a compound of formula (I), and P<p>i is as defined above.

In step a5 in reaction scheme 5, an α-aminonitrile compound of formula (XXV) is prepared from an aldehyde of formula (XVII) using the method described in Tetrahedron Letters, 1984, 25 (41), 4583-4586, by use an amine with the formula H2N-Ri.

The amino group in the compound of formula (XXV) is protected in step b_5 by means of an N-protecting group such as tert-butoxycarbonyl (Boe) or benzyloxycarbonyl, e.g. using methods known per se. The te/t-butoxycarbonyl group is shown in reaction scheme 5 above.

The resulting compound of formula (XXVI) is treated in step c5 with a strong base to form a carbanion, which is then reacted with a compound of formula Hal-(CH2)m-O-Pri to give a compound of formula (XXVII). The reaction is carried out using the method described in step c2 in reaction scheme 2.

The nitrile derivative of formula (XXVII) is reduced in step d5 by methods described above to give the primary amine of formula (XXVIII).

In step e_5, the O-protecting group and the N-protecting group are removed from the compound of formula (XXVIII) by acid hydrolysis using hydrochloric acid or trifluoroacetic acid, e.g. in a solvent such as an alcohol (eg methanol), an ether (eg diethyl ether, dioxane or tetrahydrofuran) or a chlorinated solvent at temperatures between 0°C and the reflux temperature of the reaction mixture.

In step f_5, the compound with the expected formula (II) is prepared by adapting the method described by R. Granger, H. Orzalesi and Y. Robbe in Trav. Soc. Pharm. Montpellier, 1965, 25, Phase. 4, 313-317, by reacting a compound of formula (XXIX) with diethyl oxalate in an alcoholic solvent such as ethanol, or an aromatic solvent such as toluene, or a mixture of these solvents, at a temperature between room temperature and the boiling point of the reaction mixture.

If desired, the compound of formula (II) where E is an O-protecting group Pr-i can be prepared in step g5 using methods which are known per se.

Compounds of formula (II) where -A- is the bivalent radical -N(R1)-CH2-CH2- and E is hydrogen or an O-protecting group can be prepared as shown in reaction scheme 6 below, where m, Ri and A ^ is as defined for a compound of formula (I), and Pri is an O-protecting group as defined above for E.

In step a6 in reaction scheme 6, a compound of formula (II) where -A- is the bivalent radical -N(R1)-CO-CO- and E is an O-protecting group is prepared as described in step g5 in reaction scheme 5, reduced. The reduction takes place using a reducing agent such as lithium aluminum hydride in an inert solvent such as an ether (e.g. tetrahydrofuran, 1,2-dimethoxyethane or diethyl ether) or an aromatic solvent such as toluene, at temperatures between room temperature and the boiling point of the solvent.

If desired, the O-protecting group can be removed in step b_6 by acid hydrolysis using the methods described above, which gives the compound of formula (II) where E is hydrogen.

The compounds of formula (II) where -A- is the bivalent radical -N(Ri)-CO- and E is hydrogen or an O-protecting group, can be prepared as shown in reaction scheme 7 below, where m, Ri and Ar-i is as defined for a compound of formula (I), and is as defined in reaction scheme 2 above.

In step a7, the hydroxyl group in the compound of formula (XXIX), prepared as described in step e_5 in reaction scheme 5, is protected using well-known methods.

In step b_7, the resulting compound of formula (XXX) is reacted with a reactive derivative of a carboxylic acid, e.g. 1,1'-carbonyldiimidazole, phosgene in toluene or p-nitrophenylchloroformate, in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, giving an expected compound of formula (II) wherein E is a O-protecting group. The reaction is carried out in an inert solvent such as a chlorinated solvent (e.g. 1,2-dichloroethane or dichloromethane), an ether (e.g. tetrahydrofuran), an amide (e.g. N,N-dimethylformamide) or a aromatic solvent (e.g. toluene) at temperatures between -60°C and +60°C.

If desired, a compound of formula (II) where E is hydrogen can be prepared in step c7 using well-known methods.

The compounds of formula (II) where -A- is the bivalent radical -0-CH2- and E is hydrogen or an O-protecting group are prepared as shown in reaction scheme 8 below, where m and Ar-i are as defined for a compound with formula (I), and Pr2 is as defined in reaction scheme 2 above.

In step a8 of reaction scheme 8, a compound of formula (XXIV) is reacted with an aqueous formaldehyde solution in an inert solvent such as tetrahydrofuran at temperatures between room temperature and the boiling point of the solvent, which gives a compound of the expected formula (II) where E is an O- protective group.

Using the methods described above, the O-protecting group Pr2 can be removed by basic hydrolysis (step b_8), giving the compound of formula (II) where E is hydrogen.

The compounds of formula (XI) are prepared according to known methods, such as those described in the following publications: - J. Chem. Soc, 1937,1523-1526;

- J. Chem. Soc, 1938, 400.

The compounds of formula (XI) can likewise be prepared according to SCHEME 9 below, where n and Ar 2 are as defined for a compound of formula (I) and Bz represents the residue benzyl.

In step a9 of FORM 9, the nitrogen atom in the piperidine of formula (XXXI) is protected with a benzyl group according to methods known to those skilled in the art.

The carboxy group in the 4-position in the thus obtained piperidine of formula (XXXII) is reduced in step bj^ which gives the compound of formula (XXXIII) substituted in the 4-position with a hydroxymethyl group. The reduction is carried out using a reducing agent such as borane in THF or the borane-dimethyl-sulfide complex, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or dichloromethane, at a temperature between ambient temperature and the reflux temperature of the solvent.

A compound of formula (XXXIII) can likewise be obtained from a compound of formula (XXXI) by reduction of the carboxy group (step c9), and then protection of the nitrogen in the obtained piperidine of formula (XXXIV) (step d9) according to methods indicated above.

In step §9, the compound (XXXIII) is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine, which gives the cyclized compound of formula (XXXV) in the form of quaternary ammonium. The reaction is carried out in an inert solvent such as dichloromethane or toluene, at a temperature between

-20°C and the reflux temperature of the solvent.

The compound (XXXV) is deprotected in step f_9 according to methods known to those skilled in the art. The expected compounds of formula (XI) are thus obtained.

The piperidines of formula (XXXI) are known or can be prepared according to known methods, such as those described in international application WO 94/26735.

In particular, a compound of formula (XXXI) where n = 1 can be prepared by acid hydrolysis of a corresponding piperidine substituted in the 4-position with a cyano group, which itself is obtained by reacting a 4-cyanopiperidine with a halide of the formula Ar2 -CH2-Hal in the presence of a base such as sodium diisopropylamide.

The 4-cyanopiperidine is obtained by reacting the isonipecotamide with phosphorus oxychloride.

The enantiomers of the compounds according to the invention with the formula:

is described above.

Cleavage of racemic mixtures of the compounds of formula (I) makes it possible to isolate the enantiomers of formula (I<*>).

However, it is preferred to cleave the racemic mixtures with a compound of formula (II) or an intermediate that can be used for the preparation of a compound of formula (II).

If it is thus desired to prepare the enantiomers (I<*>) of the compound of formula (1) where -A- is the bivalent radical -CH2-0-CO-, one can cleave the racemic mixture of an intermediate with the formula

where m and An are as defined for the compound of formula (I), obtained by removing the O-protecting group Pr from a compound of formula (XVI) using the methods described above. If it is desired to prepare the enantiomers (I<*>) of the compound of formula (I) where -A- is the bivalent radical -O-CO-, -0-CH2-CO-, -0-CH2-CH2-or -0-CH2, one can cleave the racemic mixture of an intermediate with the following formula where m and Ar-t are as defined for the compound of formula (I), and Pr2 is as defined in reaction scheme 2 above. If it is desired to prepare the enantiomers (I<*>) of the compound of formula (I) where -A- is the bivalent radical -0-CH2-CH2-, it is also possible to split the racemic mixture of a compound with the following formula where m and Ari are as defined for a compound of formula (I). If it is desired to prepare the enantiomers (I<*>) of the compound of formula (I) where -A- is the bivalent radical -N(Ri)-CO-, NCR^-CO-CO- or -N(Ri) -CH2-CH2-, one can split the racemic mixture of an intermediate product with the following formula

where m, Ar-i and Ri are as defined for a compound of formula (I).

If cleavage of the racemates is carried out using the intermediates of formulas (XXXVI), (XXIV), (XXIX) or (II) (-A- = -0-CH2-CH2- and E = H), this can be carried out using known methods which include the formation of a salt with optically active acids, e.g. with (+)- or (-)-tartaric acid. The diastereoisomers can then be separated in a commonly known manner, e.g. by crystallization or chromatography, after which the optically pure enantiomers can be prepared by hydrolysis.

In the compounds of formula (I) above, one or more hydrogen, carbon or iodine atoms may be replaced by their radioactive isotopes, e.g. tritium, carbon-14 or iodine-125. Such labeled compounds can be used in scientific studies, in metabolic or pharmacokinetic studies and in biochemical tests as receptor ligands.

The affinity of the compounds for the tachykinin receptors was investigated in vitro using several biochemical tests where radioligands are used: 1) Binding of [<125>I]BH-SP (substance P labeled with iodine-125 using

Bolton-Hunter's reagent) to the NK-i receptors in human lymphoblasts.

2) Binding of [<125>l]His-NKA to the NK2 receptors in the duodenum or bladder of rats. 3) Binding of [<125>l]His[MePhe<7>]NKB to the NK3 receptors in the cerebral cortex of rats, guinea pigs and gerbils, and to the human NK3 cloned receptor expressed using CHO cells (Buell et al., FEBS Letters, 1992, 299, 90-95).

All these tests were performed as described by X. Emonds-Alt et al., (Eur. J. Pharmacol., 1993, 250, 403-413).

The compounds according to the present invention generally have an affinity for the above-mentioned tachykinin receptors, preferably with an inhibition constant Ki below 10"<8>M.

More particularly, the compounds of the present invention are active principles in pharmaceutical preparations, and their toxicity is compatible with their use as medicines.

The compounds of the present invention will usually be administered in dosage units. These are preferably prepared as pharmaceutical preparations where the active principle is mixed with a pharmaceutical diluent.

The present invention thus also includes pharmaceutical preparations, characterized in that they contain as active ingredient, a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) above or their pharmaceutically acceptable salts can be used in daily doses from 0.01 to 100 mg per kg body weight for the patient being treated, preferably in daily doses of 0.1 to 50 mg per kg. For humans, the dose can vary from 0.5 to 4,000 mg per day, more particularly from 2.5 to 1,000 mg, depending on the age of the patient and the type of treatment, whether this is prophylactic or curative.

The pharmaceutical preparation according to the invention preferably contains 0.5 to 1000 mg of the active ingredient.

In pharmaceutical preparations according to the present invention for oral, sub-lingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, local or rectal use, the active principles can be administered to animals and humans in unit forms mixed with commonly known pharmaceutical carriers. Suitable unit forms for administration or use include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions that can be taken orally, sublingually or buccally, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration .

When preparing a solid preparation in the form of tablets, the active principle will be mixed with a pharmaceutical carrier such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablet can be coated with sucrose, various polymers or other suitable substances, or they can be treated so that they have a prolonged or delayed activity and optionally so that they release a predetermined amount of the active principle continuously.

A preparation in the form of gelatin capsules can be prepared by mixing the active principle with a diluent such as glycol or glycerol ester, and incorporating the mixture into soft or hard gelatin capsules.

A preparation in the form of a syrup or a juice may contain the active principle together with a sweetener which is preferably calorie-free, methyl paraben and propyl paraben as an antiseptic and a flavoring agent and suitable coloring agents.

Water-dispersing granules or powders may contain the active principle mixed with dispersing agents or wetting agents or suspending agents such as polyvinylpyrrolidone as well as sweetening agents and flavor correcting agents.

Rectal use is carried out by using suppositories which are made with binders that melt at normal body temperature, e.g. cocoa butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration is carried out using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/or wetting agents, e.g. propylene glycol or butylene glycol.

Delivery by inhalation is carried out using an aerosol such as e.g. contains sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or other biologically compatible propellants; besides that it is also possible to use a system containing the active principle in powder form, either as such or together with a diluent.

The active principle can also be processed as microcapsules with one or more carriers or additives as required.

In each individual dosage unit, the active principle of formula (I) will be present in a sufficient amount to provide the aforementioned daily doses. Generally, each dosage unit will be suitably adjusted depending on the dosage and the type of use of the preparation that is intended, e.g. tablets, gelatin capsules and the like, bags, ampoules, syrups and the like in addition to drops, so that the dosage unit contains from 0.5 to 1,000 mg of active principle, preferably 2.5 to 250 mg to be used one to four times per day.

The above preparations may also contain other active products, e.g. bronchodilators, antitussives, antihistamines, anti-inflammatory agents, antiemetics and chemotherapeutic agents.

Products of formula (I) can be used for the preparation of medicines to be used for the treatment of physiological disorders and diseases associated with an excess of tachykinins, in addition to all neurokinin-dependent pathological conditions in the respiratory tract, in the gastrointestinal tract, in the urinary tract, in addition in the immune system, the cardio-vascular or central nervous system in addition to pain and migraine.

Examples are as follows:

acute and chronic pain such as is associated with migraine, med pain in cancer and angina patients, and with chronic, inflammatory

processes, such as osteoarthritis and rheumatoid arthritis,

inflammations such as neurogenic inflammations, chronic inflammatory diseases such as congestion, chronic respiratory diseases, asthma, allergies, rhinitis, cough, bronchitis, hypersensitivity e.g. against pollen and mites, rheumatic arthritis, fibrositis, osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, inflammation in the digestive system (irritable colon), prostatitis, nervous bladder, incontinence, cystitis, urethritis and nephritis, eye diseases such as conjunctivitis and vitreoretinopathy, in addition to skin diseases such as contact dermatitis, atopic dermatitis, urticaria, eczema, pruritus and

burns, especially sunburns,

diseases of the immune system which are associated with a suppression or stimulation of the functions of the immune cells, e.g. rheumatic arthritis, psoriasis, Crohn's disease, diabetes, lupus and rejection reactions after

transplants,

small cell lung cancer and diseases where the myelin layer is destroyed, e.g.

multiple sclerosis and amyotrophic lateral sclerosis,

diseases of the central nervous system of the neuropsychiatric or neurological type, such as e.g. nervousness, insomnia, mood disorders, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's

disease, Alzheimer's disease, drug dependence, alcoholism, Down's syndrome and Huntington's chorea, as well as neurodegenerative

diseases and stress-related somatic disorders,

diseases of the digestive system, e.g. nausea, vomiting of any type,

irritated colon, ulcers in both the stomach and duodenum, ulcers in the oesophagus, diarrhoea

and hypersecretions,

diseases of the cardiovascular system, such as hypertension,

vascular aspects with regard to migraine, oedema, thrombosis, angina pectoris, vascular spasms, circulatory diseases resulting from

vasodilatation, Reynauld's disease, fibrosis and collagen diseases, and heart disorders both with regard to pulse and rhythm, especially those caused by pain and stress.

The following abbreviations are used in the presentations and in the examples:

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy

EtOH: ethanol

MeOH: methanol

Ether: diethyl ether

Isoether: diisopropyl ether

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

DCM: dichloromethane

THF: tetrahydrofuran

AcOEt: ethyl acetate

Na2C03: sodium carbonate

NaHCO3: sodium bicarbonate

NaCI: sodium chloride

Na2SC>4: sodium sulfate

MgSCv: magnesium sulfate

NaOH: sodium hydroxide

HCI: hydrochloric acid

TFA: trifluoroacetic acid

KCN: potassium cyanide

Na2S205: sodium metabisulphite

DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene

NH4CI: ammonium chloride

mp: melting point

RT: room temperature

Silica H: silica gel 60H, sold by Merck (DARMSTADT)

NMR: nuclear magnetic resonance

5: chemical shift

s: singlet

bs: wide singlet

d: duplicate

t: triplet

q: quad rough spot

mt: multiplet

m: massive.

MANUFACTURES

Production 1.1

5-(3,4-dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2/-/-1,3-oxazin-2-one

A) 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)-butanenitrile

A suspension of 17.75 g of sodium hydride (80% dispersion in oil) in 750 ml of THF was cooled in an ice bath and a solution of 100 g of 3,4-dichlorophenyl-acetonitrile in 250 ml of THF was added dropwise, after which the reaction mixture was stirred for 2 hours at RT. It was then cooled to -20°C and a solution of 112.36 g of 1-bromo-2r(tetrahydropyran-2-yloxy)ethane in 120 ml of THF was added dropwise, after which the mixture was again stirred for 2 hours at RT. It was then concentrated in vacuo, the residue was dissolved in water and extracted with ether, the organic phase was washed twice with a buffer solution of pH 4, then with a buffer solution of pH 7 and twice with a saturated NaCl solution and dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica using toluene and then toluene/ethyl acetate mixture (100/3; v/v) as eluent to give 113.5 g of the expected product which was used as such.

B) 2-(3,4-dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)butanenitrile

A mixture of 12.56 g of the compound from the previous step, 9.6 g of 37% aqueous formaldehyde solution and 0.3 g of DBU in 25 ml of 1,2-dimethoxyethane was refluxed for 1 hour. The reaction mixture was concentrated in vacuo, the residue was extracted with ether, the organic phase was then washed twice with water, twice with a buffer solution of pH 4, twice with water and then twice with a saturated NaCl solution, and then dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 17 g of the expected product which was used as such.

C) 2-(3,4-dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 17 g of the compound from the previous step and 6 g of Raney<®>nickel in 300 ml of ethanol and 40 ml of a 20% aqueous ammonia solution was hydrogenated for 5 hours at 40°C and atmospheric pressure. The catalyst was filtered off, and the filtrate concentrated in vacuo. The residue was dissolved in DCM, the organic phase was washed with water and then triturated with a saturated NaCl solution and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 16.5 g of the expected product as an oil which was used as such.

D) 5-(3,4-dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

24.6 g of a 20% solution of phosgene in toluene diluted in 150 ml of DCM was cooled to -70°C, and then a solution of 16.5 g of the compound from the previous step and 5.7 g of triethylamine in 100 ml DCM, after which the reaction mixture was stirred while the temperature slowly rose to RT. The mixture was concentrated in vacuo, the residue was dissolved in a water/ethyl acetate mixture, after which the product that crystallized on the interphase was filtered off, giving a first yield of the expected product. After decanting the filtrate, it became organic

the phase was washed with water, with a buffer solution of pH 4 and a saturated NaCl solution and then dried over magnesium sulfate, after which the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and the crystalline product was again filtered off, giving a second yield of product. A total of 4.5 g of the expected product was obtained.

Production 1.2

5-(3,4-dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

A) 2-(3,4-dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile

A solution of 50.8 g of 3,4-dichlorophenyl-acetonitrile in 250 ml of THF was added dropwise at a temperature below 20°C to a suspension of 12 g of sodium hydride (55% dispersion in oil) in 175 ml of THF, and the reaction mixture was stirred for 2 h at RT. It was then cooled to -20°C and a solution of 62.5 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 60 ml of THF was added dropwise, after which the mixture was stirred while the temperature rose to RT. The mixture was then poured into a solution of 31 g of ammonium chloride in 1.4 L of water, extracted with ether, the combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, after which the solvents were removed in vacuo. The residue was chromatographed on silica using toluene and then a toluene/ethyl acetate mixture (95/5; v/v) as eluent to give 64 g of the expected product which was used as such.

B) 2-(3,4-dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile

A mixture of 15 g of the compound from the previous step, 11.2 g of a 37% aqueous formaldehyde solution and 0.35 g of DBU in 30 ml of 1,2-dimethoxyethane was refluxed for 1 hour. The reaction mixture was concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water, twice with a buffer solution of pH 4, twice with water and twice with a saturated NaCl solution, and then dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica using toluene and then a toluene/ethyl acetate mixture (80/20; v/v) as eluent to give 15.5 g of the expected product which was used as such.

C) 2-(3,4-dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)pentylamine

A mixture of 15.5 g of the compound from the previous step and 5 g of Raney<®>nickel in 200 ml of ethanol and 40 ml of 20% aqueous ammonia solution was hydrogenated for 5 hours at 30°C and atmospheric pressure. The catalyst was filtered off, and the filtrate concentrated in vacuo. The residue was dissolved in DCM, the organic phase was washed with water and a saturated NaCl solution and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 14.9 g of the expected product as an oil which was used as such.

D) 5-(3,4-dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

21.4 g of a 20% solution of phosgene in toluene diluted in 120 ml of DCM was cooled to -70°C, and then a solution of 14.9 g of the compound from the previous step and 4.98 g of triethylamine in 80 ml DCM, after which the reaction mixture was stirred while the temperature slowly rose to RT. The mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ether, the organic phase was washed with water and with a saturated NaCl solution and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 12.5 g of the expected product used as such.

Production 1.3

6-(3,4-dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one

A) 2-(3,4-dichlorophenyl)-2-hydroxyacetonitrile

A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na2S205 in 300 ml of water was stirred overnight at RT: The reaction mixture was cooled to 0°C and then a solution of 52 g of KCN in 100 ml of water was added dropwise, after which the reaction mixture was stirred while the temperature rose to RT. The mixture was extracted with ether, the organic phase was washed with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 76 g of the expected product which was used as such.

B) 2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile

A solution of 76 g of the compound from the previous step and 0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM was cooled to 0°C, and then a solution of 39 g of 3,4-dihydro-2H-pyran in 50 mL of DCM, after which the mixture was stirred while the temperature rose to RT. It was then washed with saturated NaHCO 3 solution, then with water, after which the organic phase was dried over sodium sulfate and the solvent evaporated in vacuo to give 33 g of the expected product after a crystallization at 0°C from pentane. Temp. = 61 °C.

C) 4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile 56 ml of a 2M solution of lithium diisopropylamide in THF was cooled to -60°C and then added dropwise a solution of 32 g of the compound from the previous step in 50 ml of THF, after which the mixture was stirred for 1 hour at the mentioned temperature. A solution of 25.4 g of 2-bromomethylbenzoate in 50 ml of THF was then added dropwise at the same temperature, and the reaction mixture was stirred while the temperature slowly rose to RT. The mixture was concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water and then with a buffer solution of pH 4 and dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica using a toluene/ethyl acetate mixture (100/5; v/v) as eluent to give 34 g of the expected product which was used as such.

D) 4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine

A mixture of 34 g of the compound from the previous step and 10 g of Raney<®>nickel in 400 ml of ethanol and 40 ml of a concentrated ammonia solution was hydrogenated at RT and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in water and extracted with ether, after which the organic phase was washed with a saturated NaCl solution and then dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a gradient of DCM/methanol mixture (from 100/1; v/v to 100/3; v/v) as eluent to give 16 g of the expected product which was used as such.

E) N-(2-bromoacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine

A solution of 16 g of the compound from the previous step and 4.8 g of triethylamine

in 100 ml of DCM was cooled to -60°C, after which a solution of 5.68 g of bromoacetyl chloride in 20 ml of DCM was added dropwise, after which the reaction mixture was stirred for 30 minutes. It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water and then with a buffer solution of pH 4 and dried over sodium sulfate, after which the solvent was evaporated in vacuo. The product prepared was dissolved in a minimal amount of methanol and acidified to pH 1 by adding a saturated solution of gaseous HCl in ether, after which the solvents were evaporated in vacuo. The residue was dissolved in water and extracted with ethyl acetate, the organic phase was washed with saturated NaHCO 3 solution and then with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 16 g of the expected product which was used as such.

F) 6-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one

A mixture of 16 g of the compound from the previous step, 50 ml of propan-2-ol, 15 ml of 10 N sodium hydroxide solution and 10 ml of DMF was stirred for 4 hours. The reaction mixture was concentrated in vacuo, the residue was extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a gradient of DCM/methanol mixture (from 100/3; v/v to 100/5; v/v) as eluent to give 6.1 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

8: 2.05 ppm : mt: 2H

3.0 to 4.4 ppm : m : 6H

4.5 ppm : t: 1H

7.3 to 8.3 ppm : m : 4H

G) 6-(3,4-dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one

A solution of 1.7 g of the compound from the previous step and 0.003 g of p-toluenesulfonic acid monohydrate in 50 ml of DCM was cooled to 0°C, and then 0.588 g of 3,4-dihydro-2H-pyran in 10 ml of DCM was added dropwise , after which the reaction mixture was stirred for 1 h at RT. It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with saturated NaHCO 3 solution, water, dried over Na 2 SO 4 sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a DCM/methanol mixture (100/2; v/v) as eluent to give 1.8 g of the expected product which was used as such.

Production 1.4

6-[2-(benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A mixture of 4.8 g of the compound prepared as described under step E of Preparation 1.3 and 1.4 g of K 2 CO 3 in 100 ml of xylene was kept at 130°C overnight. After cooling to RT, the reaction mixture was filtered, and the filtrate concentrated in vacuo. The residue was extracted with ether, the organic phase was washed with a buffer solution of pH 2 and then with water, dried over magnesium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a DCM/methanol mixture (100/1; v/v) as eluent to give 1.4 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

6: 2.45 ppm : mt: 2H

3.75 ppm : AB system : 2H

3.9 to 4.5 ppm : m : 4H

7.4 to 7.9 ppm : m : 8H

8.25 ppm : bs : 1H

This compound can also be prepared using the following three steps in the method described below.

A') 4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride This compound is described in step A in preparation 1.7.

B') N-(2-chloroacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophrenyl)-2-hydro

A solution of 20 g of the compound from the previous step and 10.3 g of triethylamine in 100 ml of DCM was cooled to 0°C and 5.8 g of chloroacetyl chloride was added dropwise, after which the mixture was stirred for 30 minutes. It was then concentrated in vacuo, the residue was extracted with ethyl acetate, the organic phase was washed with water, then with a buffer solution of pH 2 and then with water, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give 22 g of the expected product which was used as such.

C) 6-[2-(benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A solution of 22 g of the compound from the previous step in 600 ml of THF was cooled to -10°C, then 11.42 g of potassium tefrbutylate was added, and the mixture was stirred until complete dissolution was obtained. It was then concentrated in vacuo, the residue was extracted with ethyl acetate, the organic phase was washed with a buffer solution of pH 2 and then with water and then dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 12.8 g of the expected product after crystallization from ether.

Production 1.5

2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)morpholine

A suspension of 1.6 g of lithium aluminum hydride in 25 ml of THF was heated to 60°C and then a solution of 4 g of the compound from step F of Preparation 1.3 in 20 ml of THF was added dropwise, after which the mixture was refluxed for 30 minutes . After cooling, 1.5 ml of water, 1.5 ml of 4 N NaOH and then 4.5 ml of water were added. The mineral salts were filtered off on Célite<®>, the filtrate was poured off and the organic phase was evaporated in vacuo. The residue was dissolved in ether and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 3.6 g of the expected product.

Production 1.6

2-(3,4-dichlorophenyl)-2-(3-hydroxypropyl)morpholine

A) 5-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentarinitrile

47 ml of a 1.5 M solution of lithium diisopropylamide in THF was cooled to -60°C, after which a solution of 19.3 g of the compound prepared as described in step B of Preparation 1.3 in 100 ml of THF was added dropwise, and the mixture was stirred for 30 minutes at -60°C. 17 g of 3-bromopropyl benzoate was then added dropwise at -60°C, and the reaction mixture was stirred as the temperature rose to RT. It was then concentrated in vacuo, the residue was extracted with ether, and the organic phase was washed with water and a saturated NaCl solution and then dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 21 g of the expected product after crystallization from hexane.

B) 5-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine

A mixture of 20 g of the compound from the previous step and 7 g of Raney<®>nickel in 300 ml of methanol was hydrogenated at RT and atmospheric pressure. The catalyst was filtered off, and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with ether, the organic phase was washed with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 20 g of the expected product which was used as such.

C) N-(2-chloroacetyl)-5-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yl-oxy)pentylamine

A solution of 9 g of the compound from the previous step and 2.4 g of triethylamine in 100 ml of DCM was cooled to 0°C and then a solution of 2.23 g of chloroacetyl chloride in 20 ml of DCM was added dropwise, and the reaction mixture was stirred for 30 minutes . It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 9.5 g of the expected product which was used as such.

D) N-(2-chloroacetyl)-5-(benzoyloxy

A saturated solution of gaseous HCl in ether was added to a solution of 9 g of the compound from the previous step in 50 mL of DCM and 50 mL of methanol until the pH was 1, and the mixture was stirred for 30 min at RT. It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water and saturated NaHCO 3 solution, then dried over sodium sulfate and the solvent was then removed in vacuo. The residue was chromatographed on silica H using a DCM/methanol mixture (100/3; v/v) as eluent to give 4.7 g of the expected product which was used as such.

E) 6-(3,4-dichlorophenyl)-6-(3-hydroxypropyl)morpholin-3-one

A mixture of 2.95 g of the compound from the previous step, 40 ml of propan-2-ol and 3 ml of 10 N NaOH solution was stirred for 2 hours at RT. The reaction mixture was then concentrated in vacuo, the residue was extracted with DCM, the organic phase was washed with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a gradient of DCM/methanol mixture (from 100/2; v/v to 100/5; v/v) as eluent, giving 0.5 g of the expected the product. Temp. = 130-132°C.

F) 2-(3,4-dichlorophenyl)-2-(3-hydroxypropyl)morpholine

A suspension of 0.82 g of lithium aluminum hydride in 10 ml of THF was heated to 60°C and then a solution of 2 g of the compound from the previous step in 20 ml of THF was added dropwise, after which the mixture was refluxed for 30 minutes. After cooling, 1 ml of water, 1 ml of a 4 N NaOH solution and 3 ml of water were added. The mineral salts were filtered off on Célite<®>, the filtrate was decanted, and the organic phase was evaporated in vacuo. The residue was dissolved in ether and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 2 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

5: 0.8 to 2.2 ppm : m : 4H

2.5 to 3.7 ppm : m : 8H

4.3 ppm:h: 1H

7.2 to 7.7 ppm : m : 3H

Production 1.7

5-[2-(benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one

A) 4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride

A saturated solution of gaseous HCl in ether was added to a solution of 12 g of the compound prepared as described in step D of Preparation 1.3 at RT in 50 ml of methanol until the pH was 1, after which the reaction mixture was stirred for 1 hour at RT. It was then concentrated in vacuo, the residue was dissolved in DCM, and the precipitate formed was filtered off and washed with ether to give 3.4 g of the expected product after recrystallization from propan-2-ol. Temp. = 200-204°C.

B) 5-[2-(benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one

1.4 g of 1,1'-carbonyldiimidazole was added at RT to a solution of 3 g of the compound from the previous step and 0.85 g of triethylamine in 30 ml of 1,2-dichloroethane, and the reaction mixture was stirred for 30 minutes at RT and then held at 50°C for 2 hours. It was then concentrated in vacuo, the residue was dissolved in water and extracted with DCM, after which the organic phase was washed with a buffer solution of pH 2 and then with water, then dried over sodium sulfate, after which the solvent was evaporated in vacuo, and this gave 3 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

5: 2.6 ppm : mt: 2H

3.75 ppm : AB system : 2H

4.35 ppm : mt: 2H

7.4 to 7.8 ppm : m : 8H

7.9 ppm : s : 1H

Production 1.8

6-(3,4-dichlorophenyl)-1-methyl-6-[2-tetrahydropyran-2-yloxy)ethyl]piperazine-2,3-dione

A) 2-(3,4-dichlorophenyl)-2-(methylamino)acetonitrile hydrochloride

A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyanotrimethylsilane was cooled in an ice bath and 10 mg of zinc iodide was added, after which the mixture was stirred for 30 minutes at RT. 20 ml of a 33% solution of methylamine in ethanol was then added, and the mixture was kept at 40°C for 2 hours. The solvent was concentrated in vacuo, the residue was extracted with ether, and the organic phase was dried over magnesium sulfate and filtered. A saturated solution of gaseous HCI in ether was added to the filtrate until the pH was 1, after which acetone was added until the precipitated product was obtained. This was filtered off, washed with ether and dried to give 12.8 g of the expected product. Temp. =172°C.

B) 2-(tert-butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)acetonitrile

Concentrated NaOH solution was added to an aqueous suspension of 12.8 g of the compound from the previous step until the pH was 13, after which the mixture was extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was dissolved in 20 ml of 1,4-dioxane, then 12.5 g of di-tert-butyl dicarbonate was added, and then kept at 60°C for 2 hours. It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with a buffer solution of pH 2, then with a saturated NaCl solution and 10% Na 2 CO 3 solution, dried over magnesium sulfate, after which the solvent was removed in vacuo. The residue was chromatographed on silica using heptane and then a heptane/ethyl acetate mixture (96/4; v/v) as eluent to give 12.7 g of the expected product which was used as such.

C) 2-(tert-butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetra-hydropyran-2-yloxy)butanenitrile

A solution of 11.1 g of the compound from the previous step in 60 ml of DMF was added dropwise to a suspension of 1.5 g of sodium hydride (60% dispersion in oil) in 50 ml of DMF while maintaining the temperature at 25°C, after which the mixture was stirred for 1 hour at RT. A solution of 8.1 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 20 ml of DMF was then added, and the reaction mixture was kept at 60°C for 4 hours. After cooling to RT, it was poured into a mixture of ice and a buffer of pH 2 and then extracted with ether, the organic phase was washed twice with water and dried over magnesium sulfate, after which the solvent was removed in vacuo. The residue was chromatographed on silica using heptane and then a heptane/ethyl acetate mixture (75/25; v/v) as eluent to give 13.2 g of the expected product which was used as such.

D) 2-(tert-butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydro-pyran-2-yloxy)butylamine

A mixture of 13.2 g of the compound from the previous step and 4 g of Raney<®>nickel in 150 ml of ethanol and 50 ml of 20% aqueous ammonia solution was hydrogenated at 30°C and atmospheric pressure. After 5 hours, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was extracted with ether, the organic phase was washed twice with water and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 12.6 g of the expected product which was used as such.

E) 2-(3,4-dichlorophenyl)-4-hydroxy-2-(methylamino)butylamine hydrochloride

A mixture of 4.6 g of the compound from the previous step and 10 ml of concentrated HCl solution in 40 ml of methanol was kept at 70°C for 1 hour. The solvent was then removed in vacuo, the residue was dissolved in acetone and the precipitate was filtered off, washed with ether and dried to give 2.79 g of the expected product. Temp. = 240°C (dec.).

F) 6-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-1-methyl-piperazine-2,3-dione

Concentrated NaOH solution was added to an aqueous suspension of 5.3 g of the compound from the previous step until the pH was 13, the mixture was then extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. 4 g of product was produced, which was dissolved in 50 ml of ethanol, 2.57 g of diethyl oxalate was added, and the mixture was stirred for 1 hour at RT. It was then concentrated in vacuo and the residue was dissolved in 60 ml of toluene and refluxed for 70 hours. It was then concentrated in vacuo to give 2.8 g of the expected product after crystallization from DCM. Temp. = 260°C.

G) 6-(3,4-dichlorophenyl)-1-methyl-6-[2-(tetrahydropyran-2-yloxy)ethydione

0.1 g of p-toluenesulfonic acid monohydrate and then 1.26 ml of 3,4-dihydro-2/-/- pyran was added to a suspension of 2.8 g of the compound from the previous step in 50 ml of DCM, and the reaction mixture was stirred overnight at RT. It was then washed with 10% Na 2 CO 3 solution and with water, the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica using ethyl acetate and then an ethyl acetate/methanol mixture (93/7; v/v) as eluent to give 3.1 g of the expected product which was used as such.

Production 1.9

2-(3,4-dichlorophenyl)-1-methyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine

A solution of 2 g of the compound from Preparation 1.8 in 20 ml of THF was added dropwise to a suspension of 1.2 g of lithium aluminum hydride in 20 ml of THF, and the mixture was refluxed for 1 hour. After cooling, 5 ml of water was added, the mineral salts were filtered off, the filtrate was concentrated in vacuo, the residue was dissolved in ether, the organic phase was dried over magnesium sulfate and the solvent was then removed in vacuo to give 1.9 g of the expected product in form of an oil.

Production 1.10

6-[2-(benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one

A) 2-(3,4-difluorophenyl)-2-hydroxyacetonitrile

A solution of 80.2 g of Na 2 S 2 O 5 in 250 ml of water was kept at 50°C and then 50 g of 3,4-difluorobenzaldehyde was added, and the reaction mixture was then stirred for 1 hour at 50°C and left overnight at RT. It was then cooled to 0°C and a solution of 77.7 g of KCN in 100 ml of water was added dropwise, after which the mixture was stirred while allowing the temperature to rise to RT, after which stirring was continued for 1 hour at RT. The reaction mixture was extracted with ether, the organic phase was then washed with water and dried over magnesium sulfate, after which the solvent was removed in vacuo. This gave 48 g of the expected product which was used as such.

B) 2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile

A solution of 48 g of the compound from the previous step and 0.2 g of p-toluenesulfonic acid monohydrate in 500 ml of DCM was cooled to 0°C, after which a solution of 28.6 g of 3,4-dihydro-2/ -/-pyran in 50 mL DCM, and the mixture was then stirred while allowing the temperature to rise to RT and stirring was continued at this temperature overnight. The reaction mixture was concentrated in vacuo, the residue was extracted with DCM, after which the organic phase was washed with 10% Na 2 CO 3 solution and then with water, dried over sodium sulfate after which the solvent was evaporated in vacuo. The residue was chromatographed on silica using toluene/ethyl acetate mixture (100/15; v/v) as eluent to give 43 g of the expected product which was used as such.

C) 4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile

133 ml of a 1.5 M solution of lithium diisopropylamine in THF was cooled to -60°C and then a solution of 43 g of the compound from the previous step in 250 ml of THF was added dropwise, after which the mixture was stirred for 30 minutes at said temperature. A solution of 45.8 g of 2-bromomethylbenzoate in 100 mL of THF was then added dropwise at -60°C, and the mixture was then stirred while allowing the temperature to rise to RT. The mixture was concentrated in vacuo, the residue was extracted with ether, and the organic phase was washed with water and with a buffer solution of pH 4 and then dried over sodium sulfate, after which the solvent was removed in vacuo. The residue was chromatographed on silica using toluene/ethyl acetate mixture (100/5; v/v) as eluent to give 47 g of the expected product which was used as such.

D) 4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine

A mixture of 47 g of the compound from the previous step and 10 g of Raney<®>nickel in 400 ml of ethanol was hydrogenated at RT and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in water, then extracted with ether, after which the organic phase was washed with water and dried over sodium sulfate. The solvent was then evaporated in vacuo to give 45 g of the expected product which was used as such.

E) 4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine hydrochloride

A saturated solution of gaseous HCl in ether was added at RT to a solution of 45 g of the compound from the previous step in 250 mL of methanol until the pH was 1, after which the mixture was stirred for 30 minutes at RT. It was then concentrated in vacuo, the residue was dissolved in ether, and the precipitate was filtered off and washed with ether, giving 15 g of the expected product after a recrystallization from propan-2-ol. Temp. = 202-204°C.

F) N-(2-chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine

A solution of 12.2 g of the compound from the previous step and 7.88 g of triethylamine in 100 ml of DCM was cooled to 0°C, after which a solution of 3.85 g of chloroacetyl chloride in 100 ml of DCM was added dropwise and the reaction mixture was allowed to stir in 30 minutes. It was then concentrated in vacuo, the residue was extracted with an ether/ethyl acetate mixture (50/50; v/v), after which the organic phase was washed with water, then with a buffer solution of pH 4 and then with water, then dried over sodium sulfate and the solvent was then removed in vacuo. This gave 13.5 g of the expected product which was used as such.

G) 6-[2-(benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one

A mixture of 13.5 g of the compound from the previous step and 20.7 g of K 2 CO 3 in 100 ml of toluene was refluxed overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in ether and the mixture was filtered. The filtrate was washed with water, with buffer solution of pH 2 and then with water, dried over magnesium sulfate, after which the solvent was evaporated in vacuo. The residue was chromatographed on silica H using a DCM/methanol mixture (100/1; v/v) as eluent to give 4.9 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

5: 2.35 ppm : mt: 2H

3.65 ppm : AB system : 2H

3.8 to 4.35 ppm : m : 4H

7.1 to 7.8 ppm : m : 8H

8.2 ppm: bs: 1H

Production 1.11

2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholine

A suspension of 1.8 g of lithium aluminum hydride in 20 ml of THF was added dropwise at RT to a solution of 2.8 g of the compound from Preparation 1.10 in 20 ml of THF, and the mixture was refluxed for 5 hours. After cooling, 2 ml of water, 2 ml of 4 N NaOH and then 6 ml of water were added. The mineral salts were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM, acidified to pH 1 by adding a saturated solution of gaseous HCl in ether and then extracted with water. The aqueous phase was washed with ether, made alkaline to pH 8 by adding a concentrated NaOH solution, then extracted with DCM, after which the organic phase was washed with water and dried over magnesium sulfate. The solvent was removed in vacuo to give 0.77 g of the expected product.

Production 1.12

5-[2-(benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidon-2-one

1 g of 1,1'-carbonyldiimidazole was added at RT to a solution of 21 g of the compound from step E in preparation 1.10 and 0.63 g of triethylamine in 50 ml of 1,2-dichloroethane, and the reaction mixture was stirred for 1 hour at RT and then held for 2 hours at 50°C. It was concentrated in vacuo, the residue was extracted with DCM, the organic phase was washed with water, then with a buffer solution of pH 2 and again with water, dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 1.5 g of the expected product.

Production 1.13

5-(3,4-dichlorophenyl)-1-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]-imidazolidin-2-one

A) 2-(3,4-dichlorophenyl)-2-(methylamino)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 3.4 g of the compound in step E of Preparation 1.8, 0.05 g of p-toluenesulfonic acid monohydrate and 2.1 ml of 3,4-dihydro-2/-/-pyran in 30 ml of DMF was kept at 60 °C for 45 minutes. The reaction mixture was poured onto ice, made alkaline by adding a concentrated NaOH solution, then extracted with ether, the organic phase was washed with water and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 4.3 g of the expected product used as such.

B) 5-(3,4-dichlorophenyl)-1-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]imidazolidin-2-one

1.6 g of 1,1'-carbonyldiimidazole was added to a solution of 3.2 g of the compound from the previous step in 100 ml of 1,2-dichloroethane, and the mixture was stirred for 30 minutes at RT. It was held at 60°C for 2 hours and then concentrated in vacuo. The residue was extracted with ethyl acetate, after which the organic phase was washed with a buffer solution of pH 2, then with a saturated NaCl solution and a 10% Na 2 CC> 3 solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica H using DCM and then a DCM/methanol mixture (98/2; v/v) as eluent to give 2.4 g of the expected product as of an oil.

Production 1.14

6-[3-(benzoyloxy)propyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A mixture of 7.5 g of the compound from step D of Preparation 1.6, 9.3 g of K 2 CO 3 and 3.75 g of sodium iodide in 100 ml of methyl ethyl ketone was refluxed overnight. After cooling, the reaction mixture was concentrated in vacuo, the residue was dissolved in ether, the mineral salts were filtered off and the filtrate was washed with a buffer solution of pH 2 and then with water. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica H using DCM and then a gradient of DCM/methanol mixture (from 99/1; v/v to 98/2; v/v) as eluent to give 1.3 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

5: 1.1 to 2.3 ppm : m : 4H

3.65 ppm : AB system : 2H

3.8 to 4.4 ppm : m : 4H

7.2 to 8.05 ppm : m : 8H

8.2 ppm : s : 1H

Production 1.15

6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-)-isomer

A) 4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (+)-isomer

A solution of 41 g of L-(+)-tartaric acid in 1200 ml of methanol was refluxed, after which a solution of 81.4 g of the compound in step E of Preparation 1.10 as the free base in 200 ml of methanol, and the mixture was set aside for crystallization for 48 hours while allowing the temperature to drop to RT. The crystals were filtered off and washed with ether, which gave 42.5 g of the tartaric acid salt.

The resulting salt was recrystallized from 1450 mL of 70° ethanol, yielding 35 g of the tartaric acid salt after the formed crystals were filtered off and washed with ether.

The resulting salt was dissolved in 2000 ml of ethyl acetate, 40 ml of 10% Na 2 CO 3 solution was added and after stirring and decanting, the organic phase was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 23.5 g of the expected product after crystallization from an isoether/pentane mixture. Temp. = 100.5-100.6°C.

B) N-(2-chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (+)-isomer

A solution of 23.5 g of the compound from the previous step and 8.1 g of triethylamine in 300 ml of DCM was cooled to 0°C, after which a solution of 8.3 g of chloroacetyl chloride in 50 ml of DCM was added dropwise, and the reaction mixture was stirred for 30 minutes at 0°C. It was then concentrated in vacuo, the residue was extracted with an ethyl acetate/ether mixture (50/50; v/v), after which the organic phase was washed with a pH 2 buffer solution and then dried over magnesium sulfate. The solvent was removed in vacuo to give 24.8 g of the expected product after crystallization from an isoether/pentane mixture.

C) 6-[2-(benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-)-isomer

A solution of 23.6 g of the compound from the previous step in 750 ml of THF was cooled to 0°C, 13.7 g of potassium tert-butylate was added, after which the reaction mixture was stirred for 15 minutes. It was then concentrated in vacuo, the residue was extracted with ethyl acetate, the organic phase was washed with a buffer solution of pH 2 and with water, after which it was dried over magnesium sulfate, after which the solvent was removed in vacuo. The residue was chromatographed on silica H using a DCM/methanol mixture (from 100/1; v/v to 100/1.5; v/v) as eluent to give 14.5 g of the expected product after crystallization from pentane.

Production 1.16

6-[2-(benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+)-isomer

A) 4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (-)-isomer

The filtration and washing liquids from the crystallization and then the recrystallization of the tartaric acid salt prepared in step A in preparation 1.15 were concentrated in vacuum. The residue was treated with 10% Na 2 CO 3 solution and then extracted with ethyl acetate, after which the organic phase was dried over magnesium sulfate. The solvent was evaporated in vacuo to give 49 g of the amino alcohol as a mixture of isomers. This was then dissolved in 120 ml of methanol, and the solution was added at once to a boiling solution of 24.1 g of D-(-)-tartaric acid in 730 ml of methanol. The mixture was set aside for crystallization for 48 hours while the temperature dropped to RT. The crystals formed were filtered off and washed with ether, yielding 40.7 g of the tartaric acid salt.

This salt was recrystallized from 1445 ml of 70° ethanol, which gave 35 g of the tartaric acid salt after the formed crystals were filtered off and washed with ether. The salt was then dissolved in 2000 ml of ethyl acetate, added 10% Na 2 CO 3 solution and then, after stirring and decanting, the organic phase was washed with water and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 27 g of the expected the product. Temp. = 102°C.

B) N-(2-chloroacetyl)-4-(benzoylote^ (-)-isomer A solution of 27 g of the compound from the previous step and 13 ml of triethylamine in 500 ml of DCM was cooled to -30°C and dropwise added 5, 8 g of chloroacetyl chloride, after which the reaction mixture was stirred for 15 minutes.It was then washed with water, with a 1 N HCl solution and 10% Na 2 CO 3 solution, after which the organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo, giving gave 28.6 g of the expected product after crystallization from an isoether/pentane mixture, mp = 63°C.

C) 6-[2-(benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+)-isomer

A solution of 28.5 g of the compound from the previous step in 250 ml of THF was cooled to -30°C, after which 18.5 g of potassium tert-butylate was added all at once, and the reaction mixture was then stirred for 45 minutes. It was then poured into 1 L of a pH 2 buffer solution and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 20.5 g of the expected product after crystallization from an ether/isoether mixture. Temp. = 92°C.

Production 1.17

2-[2-(benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (-)-isomer

A solution of 12 g of the compound in preparation 1.15 ((-)-isomer) in 75 ml of THF was added dropwise at RT to 100 ml of a 1 M solution of borane in THF, and the reaction mixture was stirred for 30 minutes at RT. It was then refluxed for 3 hours, 40 mL of a 1 M solution of borane in THF was added, after which refluxing was continued for 30 minutes. 80 mL of boiling methanol was added and refluxing was continued for a further 30 minutes. The mixture was then cooled in an ice bath, 30 mL of a saturated solution of gaseous HCl in ether was added, and the reaction mixture was stirred overnight at RT. It was then concentrated in vacuo, the residue was dissolved in 10% Na 2 CO 3 solution and extracted with ether, after which the organic phase was washed with water and with a saturated NaCl solution and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give 11.2 g of the expected product as an oil.

Production 1.18

2-[2-(benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (+)-isomer

A mixture of 19.9 g of the compound in preparation 1.16 ((+)-isomer) and 300 ml of a 1 M solution of borane in THF was kept at 60°C for 2 hours. 60 ml boiling methanol was added and refluxing continued for 30 minutes. The reaction mixture was then cooled to 10°C, 50 mL of a solution of gaseous HCl in ether was added, after which the reaction mixture was allowed to stand overnight at RT. It was then concentrated in vacuo, the residue was dissolved in 300 ml of 10% Na 2 CO* 3 solution, added with 300 ml of ether and then stirred for 30 minutes. After decantation, the organic phase was dried over magnesium sulfate and the solvent was then evaporated in vacuo to give 20 g of the expected product as an oil.

Production 1.19

2-[2-(Benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)morpholine

A solution of 6 g of the compound from preparation 1.4 in 30 ml of THF was added dropwise at RT to 76 ml of a 1 M solution of borane in THF, and the mixture was refluxed for 4 hours. 30 ml of methanol was added dropwise and refluxing was continued for 30 minutes. The reaction mixture was then cooled to 0°C, 30 mL of a saturated solution of gaseous HCl in ether was added, after which the reaction mixture was stirred overnight at RT. It was then concentrated in vacuo, the residue was dissolved in 10% Na 2 CO 3 solution and extracted with ether. The organic phase was then washed with 10% Na 2 CO 3 solution and with water and then dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give 5 g of the expected product.

Production 1.20

5-[2-(benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (-)-isomer

A mixture of 4 g of the compound in step A of Preparation 1.16 ((-)-isomer) and 2.2 g of 1,1'-carbonyldiimidazole in 40 mL of DCM was stirred for 30 min at RT and then refluxed for 1 h . After cooling to RT, the reaction mixture was washed twice with a 1 N HCl solution, the organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4.18 g of the expected product after crystallization from isoether. Temp. = 147°C.

Production 1.21

2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine

48 g of the compound in preparation 1.10 was added portionwise at RT to 700 ml of a 1 M solution of borane in THF, and the mixture was kept at 60°C for 2 hours. 150 ml of methanol was added dropwise and heating was continued for 30 minutes. The reaction mixture was cooled to 10°C, after which 120 ml of a saturated solution of hydrochloric acid in ether was added and the reaction mixture was left overnight at RT. It was then concentrated in vacuo, the residue was dissolved in 600 mL of a saturated Na 2 CO 3 solution and 500 mL of ether, after which the mixture was stirred for 1 hour at RT. After decantation, the organic phase was washed with water and dried over magnesium sulfate, after which the solvent was evaporated in vacuo. The residue was dissolved in 400 ml of propan-2-ol, 15 g of fumaric acid was added and the mixture was stirred for 30 minutes, after which the formed precipitate was filtered off. This was dissolved in 400 ml of 10% Na 2 CC* 3 solution and extracted with ether, after which the organic phase was dried over magnesium sulfate and the solvent then evaporated in vacuo to give 22 g of the expected product as an oil.

Production 1.22

5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidine

4 g of 37% aqueous formaldehyde solution was added to a solution of 9 g of the compound of step A of Preparation 1.7 (as the free base) in 100 mL of THF, after which the mixture was refluxed for 30 min and then overnight at RT . It was then concentrated in vacuo, the residue was extracted with ether, the organic phase was washed with water and dried over sodium sulfate, after which the solvent was evaporated in vacuo to give 9 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d6

8: 2.4 ppm : mt: 2H

3.2 ppm : mt: 2H

3.8 to 5.0 ppm : m : 4H

7.0 to 8.0 ppm : m : 8H

Production 1.23

5-[2-(benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (+)-isomer

This compound was prepared by the method described in Preparation 1.20 from the compound in step A of Preparation 1.15 ((+)-isomer).

Production 2.1

4-Phenyl-1-azabicyclo[2.2.1]heptane-methanesulfonate.

A) 1-benzyl-4-carboxy-4-phenylpiperidine.

To a suspension of 100 g of 4-carboxy-4-phenylpiperidine-p-toluenesulfonate in 600 ml of water was added 106 ml of a solution of 30% NaOH and then the obtained solution was cooled to 5°C, added dropwise a solution of 47.6 g of benzyl bromide in 100 ml of acetone and allowed to stand for 1 hour with stirring while the temperature was again allowed to rise to ambient temperature. The acetone is evaporated under vacuum and the pH of the remaining aqueous phase is adjusted to 9.5 by adding a concentrated solution of HCl, and then to pH = 8.5 by adding a 2N HCl solution. The precipitate formed is filtered off and washed with water and then acetone. You get 70 g of the desired product, Sm.p. = 286°C.

B) 1-benzyl-4-(hydroxymethyl)-4-phenylpiperidine

A suspension of 70 g of the compound obtained in the previous step in 150 ml of THF is cooled to 5°C, and quickly added with 237 ml of a 1M borane solution in THF and then heated to reflux for 1 hour. 474 mL of a 1M borane solution in THF is added and reflux continued for 3 hours. 100 ml of MeOH are added with heating over 30 minutes, and then with heating and over 30 minutes, 150 ml of a concentrated HCl solution. After cooling to ambient temperature, the reaction mixture is diluted with water, made basic by the addition of a 30% NaOH solution, extracted with a mixture of ether/THF, the organic phase is washed with water, dried over Na 2 SO 4 , and the solvents are evaporated under vacuum. 16 g of the desired product are obtained after two crystallizations in cyclohexane, mp. = 127°C.

This connection can also be achieved by following the two steps in the procedure described below.

A') 4-(hydroxymethyl)-4-phenylpiperidine hydrochloride.

A mixture of 10.25 g of 4-carboxy-4-phenylpiperidine-p-toluenesulfonate and 150 ml of a 1 M borane solution in THF is heated under reflux for 1 hour. 30 ml of MeOH are added with heating during 20 minutes and then, after cooling to ambient temperature, a saturated solution of HCI gas in ether is added to pH = 1 and the mixture is allowed to stand overnight with stirring at ambient temperature. The solvents are evaporated under vacuum, the residue is taken up in hot acetone for crystallization. The formed crystals are filtered off and washed with acetone and then ether. 11.1 g of the desired product is obtained,

Sm.p. = 263°C.

B') 1-benzyl-4-(hydroxymethyl)-4-phenylpiperidine.

A solution of 20.5 g of the compound obtained in the previous step in 100 ml of water and 200 ml of acetone is heated to 40°C, 27 ml of a 30% NaOH solution is added and then dropwise a solution of 17 g of benzyl bromide in 50 ml of acetone and the mixture is allowed to stand for 1 hour while stirring. The acetone is evaporated, the residue is diluted with water, the precipitate formed is filtered off, washed with water and dried. The precipitate is taken up in 800 ml of hot cyclohexane, insoluble material is filtered off and it is allowed to crystallize at ambient temperature. 19.3 g of the desired product is obtained.

C) 4-phenyl-1-benzyl-1-azoniabicyclo[2.2.1]heptane-methanesulfonate.

A mixture of 14.05 g of the compound obtained in step B and 5.55 g of triethylamine in 200 ml of DCM is cooled to 5°C, a solution of 6.01 g of methanesulfonyl chloride in 15 ml of DCM is added dropwise and the mixture is allowed to stand for 15 minutes with stirring at ambient temperature. The mixture is concentrated under vacuum at 30°C, the residue is extracted with 500 ml of AcOEt, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. 19.1 g of an oil are obtained which is dissolved in 180 ml of n-butanol. and heated under reflux for 2 hours. The mixture is concentrated under vacuum, the residue is taken up in 150 ml of hot acetone and allowed to stand under stirring at ambient temperature. The crystallized product obtained is filtered off and washed with ether. 16.85 g of the desired product is obtained, Sm.p. = 193°C.

D) 4-phenyl-1-azabicyclo[2.2.1]heptane-methanesulfonate.

A mixture of 15 g of the compound obtained in the previous step and 1.5 g of palladium on charcoal is hydrogenated for 4 hours at 40°C and atmospheric pressure to 10% in 150 ml of EtOH 95. The catalyst is filtered off on Celite®, washed with EtOH, and the filtrate is concentrated under vacuum. The residue is taken up in hot AcOEt and allowed to crystallize. 10.1 g of the desired product is obtained after centrifugation,

Sm.p. = 130°C.

EXAMPLE 1

5-(3,4-difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.1]hept-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl] oxazolidin-2-one hydrochloride monohydrate, (+)-isomer. A) 5-[2-(benzoyloxy)ethyl]-5-(3,4-difluorophenyl)-3-[3,5-bis(trifluoromethyl)benzyl]-oxazolidin-2-one, (+)-isomer.

To a solution of 3.5 g of the compound obtained in Preparation 1.23 ((+)-isomer) in a mixture of 50 ml of THF and 10 ml of DMF, 1.2 g of potassium fefr-butylate is added at ambient temperature and the mixture is allowed to stand for 30 minutes with stirring at ambient temperature. 2.7 g of 3,5-bis(trifluoromethyl)-benzyl chloride are then added and the mixture is heated at 60°C for 6 hours. The reaction mixture is poured into 200 ml of a buffer solution with pH = 2, extracted with ether, the organic phase is washed with water, dried over MgSO-4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H eluting with DCM. You get 3.6 g of the desired product. B) 5-(3,4-difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl] oxazolidin-2-one, (+)-isomer.

A mixture of 3.6 g of the compound obtained in the previous step, 0.32 g of lithium hydroxide monohydrate in 50 ml of MeOH and 5 ml of water is allowed to stand for 2 hours with stirring at ambient temperature. The reaction mixture is concentrated under vacuum, the residue is taken up in water, extracted with ether, the organic phase is washed with water, dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H eluting with DCM and then with a mixture of DCM/MeOH (98/2; v/v). 2.6 g of the desired product is obtained. C) 5-(3,4-difluorophenyl)-5-[2-methanesulfonyloxyethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one, (+)-isomer.

A solution of 2.6 g of the compound obtained in the previous step in 50 ml of DCM is cooled to 0°C, 1.14 ml of triethylamine and then 0.62 ml of methanesulfonyl chloride are added, and the mixture is allowed to stand for 10 minutes with stirring. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with water, dried over MgSC-4 and the solvent is evaporated under vacuum. You get 3 g of the desired product which is used as is. D) 5-(3,4-difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.1]hept-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl) benzyl]oxazolidin-2-one chloride monohydrate, (+)-isomer.

A mixture of 2.4 g of the compound obtained in the previous step, 1.6 g of 4-phenyl-1-azabicyclo[2.2.1]heptane-methanesulfonate and 1.7 g of K2CO3 in 2 ml of DMF is heated at 80°C for 5 hours. After cooling to ambient temperature, the reaction mixture is poured into water, extracted with DCM, the organic phase is washed with a solution of 10% HCl, with a saturated solution of NaCl, dried over Na 2 SO 4 and the solvent is evaporated in vacuo. The residue is chromatographed on silica H eluting with a mixture of DCM/MeOH (100/5; v/v). 1.46 g of the desired product is obtained.

+ 25.8° (c = 1; MeOH).

Proton NMR spectrum at 200 MHz in DMSO-dg

5: 2.0-2.4 ppm :m:4H

2.5 ppm : t: 2H

3.1-4.0 ppm : m : 10H

4.6 ppm : system AB : 2H

7.0 - 8.1 ppm : m : 11H

EXAMPLE 2

6-(3,4-dichlorophenyl)-6-[2-[4-phenyl-1-azonia-bicyclo[2.2.1]-hept-1-yl]ethyl]-4-[3,5-bis-( trifluoromethyl)benzyl]morpholin-3-one chloride. A) 6-[2-(benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzyl]-morpholin-3-one.

A mixture of 2.1 g of the compound obtained in Preparation 1.4, 0.616 g of potassium tert-butylate in 50 ml of THF is allowed to stand under stirring at ambient temperature for 30 minutes, 1.44 g of 3,5-bis(trifluoromethyl)benzyl chloride is added, and the mixture is heated under reflux for 1 hour. The reaction mixture is concentrated under vacuum, the residue is taken up in a buffer solution with pH = 4, extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica H eluting with a mixture of DCM/MeOH (100/0.5; volume/volume). 1.8 g of the desired product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-d6

5 : 2.4 ppm : mt: 2H

4.05 ppm : system AB : 2H

4.15 to 4.6 ppm : m : 4H

4.75 ppm : system AB : 2H

7.3 to 8.2 ppm : m : 11H B) 6-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one .

A mixture of 1.8 g of the compound obtained in the previous step, 4 ml of a concentrated solution of NaOH in 30 ml of MeOH is allowed to stand for 30 minutes under stirring at 0°C and stirring is then continued for 1 hour at ambient temperature. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 1.1 g of the desired product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-d6

5 : 2.0 ppm : t: 2H

2.9 - 3.45 ppm : mt: 2H

3.9 ppm : system AB : 2H

4.2 ppm : system AB : 2H

4.45 ppm :t: 1H

4.7 ppm : system AB : 2H

7.1 to 8.2 ppm : m : 6H

C) 6-(3,4-dichlorophenyl)-6-[2-(methanes-benzyl]morpholin-3-one.

To a solution of 1.1 g of the compound obtained in the previous step, 0.22 g of triethylamine in 30 ml of DCM, 0.25 g of methanesulfonyl chloride is added at ambient temperature and the mixture is allowed to stand for 1 hour with stirring. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. 1.2 g of the desired product is obtained, which is used as is. D) 6-(3,4-dichlorophenyl)-6-[2-[4-phenyl-1-azoniabicyclo[2.2.1]-hept-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl )benzyl]morpholin-3-one.

A mixture of 1.5 g of the compound obtained in the previous step, 0.67 g of 4-phenyl-1-azabicyclo[2.2.1] heptanemethanesulfonate and 1 g of K2CO3 in 2 ml of DMF is heated at 80-100°C for 3 hours. After cooling to ambient temperature, the reaction mixture is poured into water, extracted with DCM, the organic phase is washed with a solution of 10% HCl, with a saturated solution of NaCl, with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed over silica H eluting with a mixture of DCM/MeOH from (100/5; v/v) to (100/7.5; v/v). The product obtained is dissolved in hot DCM, poured into pentane and the precipitate formed is filtered off. 0.4 g of the desired product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-dg

8: 2.0-2.7 ppm : m : 6H

3.0-4.05 ppm : m : 10H

4.2 - 5.0 ppm : m : 4H

7.2-8.2 ppm : m : 11H

Claims (9)

1. Compound, characterized by the formula: where: - A represents a bivalent residue selected from: -Ai)-O-CO- - A3) -O-CH2-CO- - m is 2 or 3; - Ar<| represents phenyl which is substituted one or more times by halogen, - T is a group CH2-Z, - Z represents phenyl which is unsubstituted or mono- or polysubstituted with a halogen atom or a trifluoromethyl group, - Am represents a group with the formula: where: - Ar 2 represents phenyl; - n is zero or one; -X© represents a pharmaceutically acceptable anion and salts thereof, where appropriate with mineral acids or organic acids. 2. Optically pure compound according to claim 1, characterized by the formula: where: "<*>" means that the carbon atom thus marked has determined, absolutely (+)- or (-) configuration; Am, m, Ar-j, A and T are as defined for the compounds of formula (I) in claim 1; as well as salts thereof with mineral acids or organic acids. 3. Compound according to claim 1, characterized in that it is: 5-(3,4-difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.1]hept-1-yl]ethyl]- 3-[3,5-bis-(trifluoromethyl)-benzyl]oxazolidin-2-one. 4. Compound according to claim 1, characterized in that it is: 6-(3,4-dichlorophenyl)-6-[2-[4-phenyl-4-azonibicyclo[2.2.1]hept-1-yl-]ethyl]-4-[3,5-bis-(trifluoromethyl )-benzyl] morph ol in n-3-one. 5. Process for the preparation of the compounds of formula (I) according to claim 1 and salts thereof, characterized by 1) a compound with the formula where m, Ari and A are as defined for the compound of formula (I) in claim 1 and E represents hydrogen or an O-protecting group, is treated with a halogen derivative of formula: where Z is as defined in claim 1, and Hal represents halogen, giving a compound of the formula: where E, m, An, A and T are as defined above; 2) optionally, the O-protecting group is removed using an acid or a base, giving an alcohol with the formula: where m, An, A and T are as defined above 3) the alcohol (VIII) is treated with a compound of the formula: where Y represents methyl, phenyl, tolyl or trifluoromethyl, giving a compound of the formula: 4) the compound (X) is reacted with a cyclic tertiary amine with the formula: where Ar2 and n are as defined for (I) in claim 1; and, 5) the thus obtained product is isolated in the form of a sulphonate and optionally a sulphonic acid salt or optionally the anion and optionally the acid salt in the thus obtained salt is replaced with another anion and optionally another salt of a mineral acid or pharmaceutically acceptable organic acid. 6. Pharmaceutical preparation, characterized in that it contains as active ingredient, a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. 7. Pharmaceutical preparation according to claim 6 in the form of a unit dose, characterized in that the active ingredient is mixed with at least one pharmaceutical additive. 8. Pharmaceutical preparation according to claim 7, characterized in that it contains 0.5 to 1000 mg of the active ingredient. 9. Pharmaceutical preparation according to claim 8, characterized in that it contains 2.5 to 250 mg of the active ingredient.