SI9300513A - Basic quaternary amids, procedure for their preparation and pharmaceutical compositions comprising them - Google Patents

Abstract

The invention relates to basic quaternary amides of formula <IMAGE> in which - Ar represents an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group; - T represents a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is C1-C4 or a C1-C5 alkylene group; - Ar' represents a phenyl which is unsubstituted or substituted one or a number of times, a thienyl, a benzothienyl, a naphthyl or an indolyl; - R represents hydrogen, a C1-C4 alkyl, an omega -(C1-C4)alkoxy(C2-C4)alkyl or an omega -(C1-C4)alkanoyloxy(C2-C 4)alkyl, - Q represents hydrogen; - or else Q and R, together, form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; - Am<(+)> represents the radical <IMAGE> in which X1, X2 and X3, together and with the nitrogen atom to which they are bonded, form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; - A<(-)> is a pharmaceutically acceptable anion. These compounds are useful in the preparation of medicaments intended for the treatment of pathologies involving the tachykinin system.

Description

ELF SANOFI

Quaternary basic amides, the process for preparing them and the pharmaceutical compositions in which they are present

The present invention relates to novel quaternary basic amides, to a process for their preparation and to pharmaceutical compositions in which they are present as active substances.

More specifically, the present invention relates to a new class of quaternary basic amides for therapeutic use in pathological phenomena comprising the tachykinin system, such as pain (D. Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation ( J. E. Morlay et al., Life Sciences, 1987, 41, 527-544), Circulatory insufficiency (J. Losay et al., 1977, Substance P, Von Euler, US and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484) and respiratory disorders (J. Mizrahi et al., Pharmacology, 1982,25,39-50), at these cases being neither restrictive nor exclusive.

Ligands endogenous to tachykinin receptors have been described, such as substance P (SP), neurokinin A (NK _A ) (SJ Bailey et al., 1983, Substance P, P. Skrabanck ed., 16.17 Boole Press, Dublin) and neurokinin B (NK ₀ ) (SP Watson, Life Sciences, 1983, 25, 797-808).

Thus, in accordance with one aspect, the present invention relates to quaternary basic amides of the formula wherein

Ar is optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;

T is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is a C 1 -C ₄ , or a C 1 -C 6 alkylene group;

Ar 'phenyl which is unsubstituted or mono- or polysubstituted by a substituent selected from a halogen atom, preferably a chlorine or fluorine atom, trifluoromethyl, C 1 -C ₄ -alkoxy or C 1 -C ₄ -alkyl, wherein these substituents are the same or different , thienyl, benzothienyl, naphthyl or indolyl;

R is hydrogen or C ₁ -C ₄ alkyl or C ₁ -C ₁ alkyl - (o-alkoxy (C ₂ -C ₄ ) alkyl or C ₂ -C ₄ ) o-alkanoyloxy (C ₁ -C ₄ ) alkyl;

Q is hydrogen;

or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;

Am® is the residue <Q

Ar-T-CO -N- € H ₂ -C-CH ₂ -CH ₂ -Am ®. Α ^{θ (1}} ) j

Ar 'wherein X _{p 2} and X ₃ together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; and is

A pharmaceutically acceptable anion.

Pharmaceutically acceptable anions are those commonly used for the salification of quaternary ammonium ions of products for pharmaceutical use, preferably chloride, bromide, iodide, hydrogen sulphate, methanesulfonate, paratoluenesulfonate acetate and benzenesulfonate ions.

In particular, in formula (I), Ar is a mono-, di- or tricyclic aromatic or heteroaromatic group which may carry one or more substituents and wherein the carbon atom of the aromatic carbocycle or aromatic heterocycle is directly attached to T.

Specifically, the Ar residue may be a phenyl group which may be unsubstituted or may optionally contain one or more substituents.

If Ar is a phenyl group, it may preferably be mono- or di-substituted, especially in position 2,4, but also e.g. in position 2,3, 4,5, 3,4 or 3,5; it may also be trisubstituted, especially in the 2,4,6 position, as well as e.g. in position 2,3,4, 2,3,5, 2,4,5 or 3,4,5, tetrasubstituted e.g. in position 2,3,4,5 or pentasubstituted. The phenyl group substituents may be: F; Cl; Br; I; CN; OH; NH ₂ ; NH-CONH ₂ ; NO ₂ ; CONH ₂ ; CF ₃ ; C _f C ₁₀ -alkyl, preferably C _f C ₄ -alkyl, wherein methyl or ethyl as well as e.g. n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, octyl or n-octyl, nonyl or n-nonyl or decyl or n-decyl ; alkenyl containing 2 to 10 carbon atoms, preferably 2-4 carbon atoms, e.g. vinyl, allyl, prop-1-enyl, isopropenyl, butenyl or but-1-en-1-, -2-, -3 or -4-yl, but-2-en-1-yl, but-2-en- 2-yl, pentenyl, hexenyl or decenyl; alkynyl containing 2 to 10 carbon atoms, preferably 2-4 carbon atoms, e.g. ethynyl, prop-1-yn-1-yl, propargyl, butynyl or but-2-yn-1-yl, pentynyl or decinyl; cycloalkyl containing 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, with cyclopentyl or cyclohexyl being preferred, as well as e.g. cyclopropyl, cyclobutyl, 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl or cyclooctyl; bicycloalkyl containing 4 to 11 carbon atoms, preferably 7 carbon atoms, with exo or endo-2-norbornyl being preferred, as well as e.g. 2-isoboril or 5-camphil; hydroxyalkyl containing 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, hydroxymethyl and 1- or 2-hydroxyethyl as well as e.g. 1-hydroxyprop-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 1-hydroxyprop-2-yl, 1-hydroxybut-1-yl or 1-hydroxypent-1-yl, alkoxy, containing 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, preferably isopropoxy or ethoxy as well as e.g. n-propoxy, methoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, e.g. alkoxymethyl or alkoxyethyl, such as methoxymethyl or

1- or 2-methoxyethyl, 1- or 2-n-butoxyethyl or 1- or 2-n-octyloxyethyl; alkoxyalkyloxyalkyl containing up to 10 carbon atoms, preferably 4 to 7 carbon atoms, e.g. alkoxyalkoxymethyl, such as 2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or

2- isopropoxyethoxymethyl or alkoxyalkoxyethyl such as 2- (2-methoxyethoxy) ethyl or 2- (2ethoxyethoxy) ethyl; alkoxyalkoxy containing from 2 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, e.g. 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms, preferably allyloxy as well as e.g. vinyloxy, propenyloxy, isopropenyloxy, butenyloxy, such as but-1-en-1-, -2-, -3- or -4-yloxy, but-2-en-1-yloxy or but-2-en-2-yloxy , pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkyl, with up to 10 carbon atoms, preferably 3 to 6 carbon atoms, e.g. allyloxymethyl; alkynyloxy containing from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms, with propargyloxy as well as e.g. ethynyloxy, prop-1-and-1-yloxy, butynyloxy or but-2-yn-1-yloxy, pentinyloxy or decinyloxy; alkynyloxyalkyl containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, e.g. ethinyloxymethyl, propargyloxymethyl or 2- (but-2in-1-yloxy) -ethyl; cycloalkoxy containing from 3 to 8 carbon atoms, preferably from 5 or carbon atoms, preferably cyclopentoxy or cyclohexyloxy as well as e.g. cyclopropoxy, cyclobutoxy, 1-, 2- or 3-methylcyclopentoxy, 1-, 2-, 3- or 4-methylcyclohexyloxy, cycloheptyloxy or cyclooxyloxy; alkylthio containing from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, preferably methylthio or ethylthio as well as e.g. n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentyl-thio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl containing from 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, e.g. methylthiomethyl, 2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylamino containing from 1 to carbon atoms, preferably 1 to 4 carbon atoms, with formylamino and acetylamino as well as propionylamino, butyrylamino, isobutyrylamino, valerylamino, caproylamino or heptanoylamino or aroylamino or benzylamino; acylaminoalkyl, preferably alkanoylaminoalkyl containing from 2 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylobutylobutylobutylobutylobutylobutylobutylobutylobutylbutyl acyloxy containing from 1 to 6 carbon atoms, preferably 2 to 4 carbon atoms, preferably acetoxy, propionyloxy or butyryloxy as well as e.g. formyloxy, valeryloxy or caproloxy; alkoxycarbonyl containing from 2 to 5 carbon atoms, preferably 2 or 3 carbon atoms, preferably methoxycarbonyl and ethoxycarbonyl as well as e.g. n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; cycloalkoxycarbonyl containing from 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms, preferably cyclopentoxycarbonyl and cyclohexyloxycarbonyl, as well as cyclopropoxycarbonyl, cyclobutoxycarbonyl or cycloheptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4 carbon atoms such as methylaminocarbonylamino, ethylaminocarbonylamino or propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3 to 7 carbon atoms, preferably 3 to 5 carbon atoms, preferably dimethylaminocarbonylamino as well as di-n-propylaminocarbonylamino or diisopropylaminocarbonylamino; (pyrrolidin-1-yl) carbonylamino; cycloalkylaminocarbonylamino; containing from 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms, preferably cyclopentylaminocarbonylamino and cyclohexylaminocarbonylamino as well as cyc5 lopropylaminocarbonylamino, cyclobutylaminocarbonylamino or cycloheptylaminocarbonylamino; alkylaminocarbonylaminoalkyl containing from 3 to 9 carbon atoms, preferably 4 to 7 carbon atoms, preferably methylaminocarbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl and ethylaminocarbonylaminobutyl as well as e.g. methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl and n-butylaminocarbonylaminobutyl; nalkylaminocarbonylaminoalkyl containing from 4 to 11 carbon atoms, e.g. dimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl, diethylaminocarbonylaminopropyl and diethylaminocarbonylaminobutyl; (pyrrolidin-1-yl) carbonylaminoethyl; (piperidin-1-yl) carbonylaminoethyl; cycloalkylaminocarbonylaminoalkyl containing from 5 to 12 carbon atoms, preferably 8 to 11 carbon atoms, with cyclopentylaminocarbonylaminoethyl, cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarbonylaminobutyl, cyclohexylaminocarbonylaminoethylcarbonylaminoethylcarbonylcarbonylaminoethylcarbonylaminoethylcarbonylaminoethanol; cyclopropylaminocarbonylaminoethyl or cycloheptylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl containing from 3 to 12 carbon atoms, preferably 4 to 9 carbon atoms, being preferred metoksikarbonilaminoetil, etoksikarbonilaminoetil, n-propoksikarbonilaminoetil, izopropoksikarbonilaminoetil, n-butoxycarbonylaminoethyl, izobutoksikarbonilaminoetil, sek.butoksikarbonilaminoetil, tert-butoxycarbonylaminoethyl, etoksikarbonilaminopropil n -butoxycarbonylaminopropyl, ethoxycarbonylaminobutyl and n-butoxycarbonylaminobutyl as well as e.g. n-propoxycarbonylaminopropyl, n-propoxycarbonylaminobutyl or isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl containing from 5 to 12 carbon atoms, preferably 8 to 11 carbon atoms, preferred are cyclopentoxycarbonylaminoethyl, cyclopentoxycarbonylaminopropyl, cyclopentoxycarbonylaminobutyl, cyclohexyloxycarbonylaminoethyl, cyclohexylcarbonyloxycarbonylcarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylaminoethyl cyclopropoxycarbonylamiomethyl or cycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5 carbon atoms, preferably 2 carbon atoms, preferably carbamoylmethyl as well as carbamoylethyl, carbamoylpropyl or carbamoylbutyl; alkylaminocarbonylalkyl containing from 3 to 9 carbon atoms, preferably 3 to 6 carbon atoms, preferably methylaminocarbonylethyl, ethylaminocarbonylmethyl, n-propylaminocarbonylmethyl, isopropylaminocarbonylmethylcarbonylaminocarbonylmethyl, isobutylmethylaminocarbonylmethyl, isobutylmethylaminocarbonylmethyl, isobutylmethylaminocarbonylmethyl, isobutylmethylaminocarbonylmethyl; . ethylaminocarbonylethyl, ethylaminocarbonylpropyl, ethylaminocarbonylbutyl, propylaminocarbonylbutyl or n-butylaminocarbonylbutyl; dialkylaminocarbonylalkyl containing from 4 to 11 carbon atoms, preferably 4 to 8 carbon atoms, preferably dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and di-propylaminocarbonylmethyl as well as e.g. diethylaminocarbonylethyl, diethylaminocarbonylpropyl or diethylaminocarbonylbutyl; (pyrrolidin-1-yl) carbonylmethyl; (piperidin-1yl) carbonylmethyl; (piperidin-1-yl) carbonylethyl; cycloalkylaminocarbonylalkyl containing from 5 to 12 carbon atoms, preferably 7 or 8 carbon atoms, with cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl as well as e.g. cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl or cyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3 to 10 carbon atoms, preferably 3 to 5 carbon atoms, preferably methylaminocarbonylmethoxy, as well as e.g. methylaminocarbonylethoxy or methylaminocarbonylpropoxy; dialkylaminocarbonylalkoxy containing from 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy or diethylaminocarbonylethoxy; (piperidin-1-yl) carbonylmethoxy; and cycloalkylaminocarbonylalkoxy containing from 5 to 11 carbon atoms, preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxy or cyclohexylaminocarbonylmethoxy.

The residue Ar may also be a bicyclic aromatic group, such as 1- or 2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, where one or more bonds may be hydrogenated, at these groups being optionally unsubstituted or optionally containing one or more substituents such as: halogen, more specifically fluorine atom, and alkyl, phenyl, cyano, hydroxylalkyl, hydroxy, C1-C6-alkoxy, oxo, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups in which alkyl is C 1 -C ₄ .

The residue Ar can also be pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, isoquinolyl, benzoxazolyl, benzoxazinyl, benzopyrazolinyl, benzoxazolyl, benzoxazolyl, benzopyrazolinyl , isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl or chromanyl groups, where one or more double bonds may be hydrogenated, leaving or unstable for these groups optionally containing one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups wherein alkyl is C 1 -C 4.

Advantageously, the residue Ar is phenyl which is unsubstituted or mono- or polysubstituted by a halogen atom, more specifically a chlorine or fluorine atom, trifluoromethyl, C 1 -C 6 alkyl, hydroxy or C 1 -C 6 -alkoxy, unsubstituted, mono- or polysubstituted by halogen, trifluoromethyl, C ^ -C ^ alkyl, hydroxy or _Cj-C4 alkoxy, pyridyl, thienyl, indolyl, quinolyl, benzothienyl or imidazolyl.

Particularly preferred compounds are those of formula (I) wherein Ar is a phenyl group substituted with an isopropoxy group, preferably in position 3.

In formula (I), T is preferably a methylene group.

The substituents R and Q are preferably methyl and. hydrogen; 2-methoxyethyl and hydrogen; 2-acetoxyethyl and hydrogen; or R and Q together form a 1,3-propylene group.

The Ar 'substituent is preferably a phenyl group conveniently substituted by two chlorine atoms, more specifically at positions 3 and 4.

The residue represented by Am® preferably contains from 5 to 9 carbon atoms in the azabicyclic or azatricyclic system.

The residue ^X 2 ~ N 20 ^x 3 represented by the substituent Am® in formula (I) is preferably the residue of an azabicyclic or azatricyclic system selected from the following, such as:

(a) l-azoniabicyclo [2.2.0] hexane (b) l-azoniabicyclo [3.1.0] hexane (c) l-azoniabicyclo [2.2.1] heptane (d) l-azoniabicyclo [2.2.2] octane (e) ) l-azoniabicyclo [3.2.1] octane (f) l-azoniabicyclo [3.2.2] nonane (g) l-azoniabicyclo [3.3.1] nonane (h) hexahydro-1H-pyrrolizinium-4 (i) octahydroindolizinium-4 (j) octahydro-2H-quinolizinium-5 (k) l-azoniatricyclo [3.3.1.1 ^3,7 ] decane (l) 4-phenyl-l-azoniabicyclo [2.2.2] octane, with particular preference being given to (d) ) and (1).

Particularly preferred quaternary basic amides of the present invention are those of formula (I) in which

- Ar 3-isopropoxyphenyl group;

- T methylene group;

- R and Q are methyl and hydrogen; 2-acetoxyethyl and hydrogen; or R and Q together form a 1,3-propylene group;

- Ar 'is 3,4-dichlorophenyl; 1 ^X 2-N ^X 3

Am® is a residue of (d) or (1) as defined above; and is

- A 'is a pharmaceutically acceptable anion, preferably chloride, methanesulfonate and benzenesulfonate.

These formula products

R 'Q'

R. A® a

(Γ) in which iPr is isopropyl, R ′ and Q ′ are methyl and hydrogen; oz. 2-acetoxyethyl and hydrogen; or R 'and Q together form a 1,3-propylene group, R' is hydrogen or a phenyl group and A ', as defined above, in particular a methanesulfonate or chloride ion, are potent antagonists of substance P.

Compounds of formula (Γ), wherein R ′ and Q ′ together form a 1,3-propylene group, are extremely effective and exhibit a greater affinity for the neurokinin-1 receptor than substance P. Therefore, they represent a preferred feature of the present invention.

Of these compounds, the most valuable are those of the formula (! ”):

wherein A 'is a pharmaceutically acceptable anion, in particular methanesulfonate, chloride and benzenesulfonate.

According to a further feature, the present invention relates to the preparation of compounds of formula (I) above, characterized in that a derivative of formula is treated

R Q

Ar-T-CO-N-CH2-C-CH2-CH ₂ -OY (II)

Ar 'where Y is any removable group, preferably methanesulfonyl or benzenesulfonyl, with a cyclic tertiary amine of formula ^X 1

I ^x 2 y (m)

X ₃ where X _p X ^ and X ^ together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system, optionally substituted by a phenyl group, in an organic solvent at a temperature between room temperature and 120 ° C and isolate the product obtained or, if appropriate, exchange the methanesulfonate anion of the resulting quaternary salt with another pharmaceutically acceptable anion.

The organic solvent used is preferably a polar aprotic solvent, e.g. acetonitrile, Ν, Ν-dimethylformamide or Ν, Ν-dimethylphenylacetamide, but it is also possible to use ether, e.g. tetrahydrofuran, dioxane or methyl t-butyl ether, or ketone, e.g. methyl ethyl ketone, acetonitrile being particularly preferred.

In the above temperature range, a temperature of 70-90 ° C is preferred. If acetonitrile is used as the solvent, the reaction is advantageously carried out at reflux of the reaction mixture.

The product thus obtained is isolated by conventional techniques, e.g. by concentrating the solvents, then rinsing the residue with water and then cleaning with conventional techniques, e.g. by chromatography or recrystallization.

The methanesulfonate anion resulting from the reaction between a tertiary amine of formula (III) and a methanesulfonyloxy derivative of formula (II) can be exchanged in situ or after isolation of a compound of formula (I) wherein A is a 'methanesulfonate ion, with another anion A' by conventional methods, e.g. by exchange in solution, such as hydrochloric acid solution in the case where A 'is a chloride anion, or by exchanging the anion with another anion by eluting compound (I) on an ion exchange resin, e.g. Amberlite IRA68® or Duolite Α375®.

The derivatives of formula (II) used as starting compounds for the process of the present invention can be prepared according to Scheme 1 below, wherein in the formulas indicated:

Q = H; R = H, C ₁ -C ₄ -alkyl

R + Q = - (CH ₂ ) _n - where n = 2, 3, 4

In Scheme 1, the reactions in various stages are shown representatively by showing the type of these reactions without specifying the known agents.

So e.g. in mode A, step 2 and mode B, step 6, H ₂ means that the nitrile output is reduced, e.g. is catalytically hydrogenated (Raneyev Ni in ethanol, in the presence of ammonia to give primary amine IV).

In the same step 2 of mode A, the term alkylation means that, after reduction, the primary amine is alkylated, either directly with alkyl halide or sulfate or indirectly by acylation and reduction of the carbonyl group. Thus, e.g. the reaction of the primary amine (IV) with ethyl chloroformate and the reduction of the ethoxycarbonyl group is a product of formula (IV) wherein R is methyl as described in EP-0 428 434 and EP-0 474 561. A compound of formula (IV) wherein RC ₂ -C ₄ -alkyl is prepared by replacing ethyl chloroformate with chloride (or other functional derivative) of C ₂ -C ₄ -alkanoic acid and reducing the carbonyl group of the resulting N-acylated derivative. Ethyl chloroformate can be replaced by di-t-butyl carbonate (Boc-O-Boc) to prepare the product of formula IV (R = methyl).

By replacing ethyl chloroformate with e.g. ethyl N-acyl derivatives are obtained with ethyl ethyloxalyl, ethyl hemimalonate or ethyl hemisuccinate. The carbonyl groups are then reduced by the usual methods to give α> -hydroxy (C ₂ -C ₄ ) alkyl derivatives which are O-acylated or O-alkylated to give ω-alkanoyloxyalkyl derivatives or ω-alkoxyalkyl derivatives of formula IV, where R (n- (C ₂ -C ₄ -) alkanoyloxy (C ₂ -C ₄ -) alkyl or - (C ₁ -C ₄ -) alkoxy (C ₂ -C ₄ -) alkyl is similar to replacing alkyl chloroformates by chloride of o- (C ₁ -C ₄ -) alkoxy (C ₂ -C ₄ -) carboxylic acid, followed by reduction as described above, directly yields the ω-alkoxyalkyl derivatives of formula IV, where R (N - (C C 1-6 alkoxy-C 1-6 alkyl.

Also e.g. in step 4 of the AH ⁺ mode, it means that the tetrahydropyranyloxy group is acid hydrolyzed under conditions known from the literature.

mode A

Scheme 1 way B n'— o

OCH ₂ -CH ₂ -Br + Ar'-CH ₂ -CN

-o wrestler.

ch ₂ -ch ₂ - ch-cn '—O

1) H ₂

2) alkylation as required ch ₂ -ch ₂ -ch-ch ₂ -nh

Ar '(IV)

HO-CO-T-Ar

O-CH ₂ -CH ₂ -CH-CH ₂ -N-CO-T-Ar

Ar '

4 \ H ⁺

Ar '

Br- (CH ₂ ) _nr co ₂ Ei where m = 1,2 lda or 3

CV '- o (CH ₂ ) _m -CO ₂ Et ch ₂ -ch ₂ -c-cn

Ar '

v / o-ch ₂ -ch ₂ - ((CH ₂ ) m \ ^ .NH

Ar '

LiAlH ₄ ch ₂ -ch ₂ -

Ar

N-H (V)

H0-C0-T-Ar I) H ⁺ 2).

HO-CH ₂ -CH ₂ -C-CH ₂ -N-CO-T-At (where * are Q and R, as ¹ is defined for (I))

Ar '

Y Cl *? I

CH ₃ SO ₂ -O-CH ₂ -CH ₂ -C -CH ₂ -N-C0-T-At (Π)

Ar '(with Y - removable group) vi

The importance of the Ar substituent depends on the choice of HO-CO-T-Ar acid used in steps 3 and 8 as one of its functional derivatives. All these acids are known in the literature or readily prepared according to the literature or are commercially available.

The importance of the substituent Ar 'depends on the choice of the nitrile Ar'-CH ₂ -CN which, after reaction with 2-tetrahydropyranyloxy-1-bromoethane, hydrogenation of the product obtained and N-alkylation, if appropriate (step 2), yields an amine.

Mode A of Scheme 1 wherein R = H, alkyl and Q = H is described in the literature and in patent applications EP-A-0 428 434 and EP-A-0 474 561.

Scheme 1 mode B covers a series of reactions known to those skilled in the art, such as alkylation of nitrile with a brominated derivative in the presence of lithium diisopropylamide (LDA) (step 5), followed by reduction of nitrile in the presence of a catalyst to give the corresponding amine after reduction of the intermediate amide (step 7) obtained by cyclization (step 6), e.g. по А.В. El'tsov et al., Biol, Soedin., Acad. Doctrine of the USSR, 1965, 109-12 (CA, 1965, 63, 16299).

In both Scheme 1 modes, the reaction conditions for the same steps are the same. Thus, the reduction of level 2 (mode A) and level 6 (mode B) is carried out under the same conditions. Similarly, step 7 (mode B) and reduction of the N-acylated derivative or ethoxycarbonyl in the indirect alkylation reaction of stage 2 (mode B) are carried out under the same conditions. Finally, acylation in step 3 (mode A) and step 8 (mode B) is performed under the same conditions.

The process for the preparation of compounds (I) according to the invention consists of the reaction of a derivative (II) prepared by the reaction of an alcohol (IV) with a YC1 derivative, e.g. mesyl chloride or benzenesulfonyl chloride (step 9), with a tertiary amine of formula (III) according to Scheme 2 below.

SCHEME 2

Q R

CH ₃ -5O ₂ -O-CH ₂ -CH ₂ -C-CH ₂ ^ iT-CO-Ar '(II)

Ar ' ^X 1

(I)

Separation of racemic mixtures (I) enables the enantiomers (I *) to be isolated, which also form part of the invention.

However, it is preferable to separate racemates at the rate of intermediate amino alcohols capable of administering salts with optically active acids. The amino alcohols correspond to the compounds (IV) and (V) obtained according to step 2 (mode A) and according to step 7 (mode B) of scheme 1 after deprotection of the compounds by hydrolysis in an acid medium:

θ- ° '—o

CH ₂ -CH ₂ -CH-CH ₂ -NH and Ar '(IV)

v / (CH ₂ ) _m \ / o-ch ₂ -ch ₂ -9 J7 _h ^h

(V) where Ar 'and R are as defined for (I) and m is 1, 2 or 3.

The enantiomers are then separated by conventional methods such as crystallization or chiral preparative high pressure chromatography.

The preparation of optically pure compounds is illustrated in Scheme 3 below, where the carbon atom identified by this symbol is defined to have a (+) or (-) configuration.

Scheme 3 states in the last step that it is carried out with free acid but can be carried out with its functional derivative which could affect the molecule on both the hydroxy group and the amino group. In this case, it is desirable to again protect the hydroxy group, e.g. with dihydropyran to form tetrahydropyranyl ether.

The preparation of compounds of formula (VI *) according to Scheme 3, wherein R is hydrogen or a C 1 -C 6 alkyl group and Q is hydrogen, is described in EP-A-0 428 434 and EP-A-0 474 561.

Scheme 3 / O-CH ₂ -CH ₂ -CH-CH ₂ -NH ° ' ^CH 2' ^CH 2'y ⁱⁿ ° L in ^{0 A} (IV)

H ί Γ ho-ch ₂ -ch ₂ -c-ch ₂ -nh

Ar '(VII)

Refining enantiomers? I

HO-CH ₂ -CH ₂ -CiCH ₂ -NH

Ar '(VH *) HO-CO-T-Ar (VI *)

Optically Pure compounds of formula (VI *), wherein Q and R are linked together to form 1,2 ethylene, 1,3-propylene or 1,4-butylene, are prepared in the same manner.

In particular, compound (VII *) obtained after separation of the enantiomers (VII) is coupled with an acid of formula Ar-T-COOH in the presence of a coupling agent according to the usual procedures. As noted above, it is possible to use a functional derivative of this acid such as the acid itself, suitably activated e.g. with cyclohexylcarbodiimide or benzotriazolyl-Noxitrisdimethylaminophosphonium hexafluorophosphate (BOP), or one of the functional derivatives that react with amines, e.g. anhydride, mixed anhydride, acid chloride or activated ester, such as paranitrophenyl ester.

The resulting compound of formula

Q

HO-CH ₂ -CH ₂ -C * -CH ₂ -N-CO-T-Ar ^(vi * ^}

Ar 'is then reacted with YC1 derivative according to step 9 of Scheme 1 to obtain an optically pure derivative (II).

The products of formula (I) wherein T is hydroxymethylene, C ₁ -C ₄ alkoxymethylene or C ₂ C ₅ -alkylidene have two centers of asymmetry. In this case, diastereoisomers and pure isomers can be prepared by the reaction of an optically pure amino alcohol and either optically pure or racemic acid HO-CO-T-Ar; in the latter case diastereoisomers can be separated e.g. by chromatography.

Reaction with the tertiary amine (III) allows the preparation of product (I) of the invention in optically pure form.

The amines of formula (III) are those described in the literature.

Of these amines, the preferred are 5 to 9 carbon atoms in the ring system and a nitrogen atom, examples of which are given below:

(a ') l-Azabicyclo [2.2.0] hexane prepared in accordance with C.A. Grob et al., Helv. Chim. Acta, 1964, (47), 8, 2145-55.

(b ') l-azabicyclo [3.1.0] hexane prepared in accordance with A.L. Logothetis, J. Am. Chem. Soc., 1965, (87), 4, 749-754.

(c ') l-azabicyclo [2.2.1] heptane prepared according to Gassman et al, J. Am. Chem. Soc., 1968, (90), 5.1355-6.

N (d ') l-azabicyclo [2.2.2] octane or quinuclidine.

(e ') l-azabicyclo [3.2.1] octane prepared according to B. Thill et al, J. Org. Chem.,

1968, (33), 12, 4376-80. 25 (f) l-azabicyclo [3.2.2] nonane prepared according to C. Ruggles et al, J. Am. Chem. Soc., 1988, (110), 17, 5692-8.

iV / N (g ') l-azabicyclo [3.3.1] nonane prepared according to S. Miyano et al, J. Chem. Soc., Perkin Trans. 1,1988, 5,1057-63.

(h ') hexahydro-1H-pyrrolizine-4 prepared according to P. Edwards et al., Tetrahedron Letters, 1984, (25), 9, 939-42.

i- _N -1 (i ') octahydroindolizin-4 prepared according to J. Chastanet et al., J. Org. Chem., 1985, (50), 16, 2910-14.

(j ') octahydro-2H-quinolysin-5 prepared according to P. Edwards et al., Tetrahedron Letters, 1984, (25), 9,939-42.

(k ') l-azatricyclo [3.3.1.1 ^3,7 ] decane or 1-azaadamantane prepared according to Y. Bubnov et al., J. Organomet. Chem., 1991,412, (1-2), 1-8.

(Γ) 4-Phenyl-1-azabicyclo [2.2.2] octane or 4-phenylquinuclidine prepared according to T. Perrine, J. Org. Chem., 1957, 22, 1484-1489.

The compounds of formula (I) above also include those in which one or more carbon or hydrogen atoms have been replaced by their radioactive isotope, e.g. tritium or carbon-14. Such labeled compounds are useful in research, metabolic or pharmacokinetic activities and in biochemical assays as receptor ligands.

The compounds of the invention are subjected to biochemical tests.

Compounds (I) exhibit antagonistic anti-binding properties of substance P in assays performed on rat cortex membranes and IM9 lymphoblastic cells according to M.A. Cascieri et al., J. Biol. Chem., 1983, 258, 5158-5164, and D.D. Paya et al., J. Immunol, 1984, 133, 3260-3265.

Among the tested compounds, (+) - 1- [2- [3- (3,4-dichlorophenyl) -1 - [(3isopropoxyphenyl) acetyl] piperidin-3-yl] ethyl] -4-phenyl-1- azoniabicyclo [2.2.2] octanchloride (compound 4) potent NK1 receptor antagonist of substance P: inhibits binding of substance P to its receptor by an inhibition constant (Ki) of 10-20 pM in various biochemical tests performed.

In particular, the compounds of the present invention are effective substances of pharmaceutical compositions whose toxicity is compatible with their use as drugs.

The compounds of formula (I) above may be used at daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. In humans, the dosage may advantageously vary from 0.5 to 4000 mg per day, more specifically from 2.5 to 1000 mg per day, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

For use as medicaments, the compounds of formula (I) are generally administered in dosage units. These dosage units are preferably formulated as pharmaceutical compositions in which the active substance is mixed with the pharmaceutical carrier.

Thus, in accordance with another feature, the present invention relates to pharmaceutical compositions wherein the compound of formula (I) is present as an active substance.

In the pharmaceutical compositions of the present invention for oral, sublingual, sub19-cutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, the active substances may be administered to animals or humans in unit dosage forms mixed with conventional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingually and buccally, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and rectal administration. .

When preparing a solid tablet formulation, the main active substance is mixed with a pharmaceutical solvent such as gelatin, starch, lactose, magnesium stearate, talc, arabic gum or the like. The tablets may be coated with sucrose or other suitable substances, or they may be treated in such a way as to have prolonged or sustained activity and to continuously release a predetermined amount of the active substance.

The gelatin capsule formulation is prepared by mixing the active substance with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The syrup or elixir preparation may contain the active substance together with a calorie-free sweetener, methylparaben and propylparaben as antiseptics, flavoring and suitable color.

Water-dispersible granules or powders may contain the active substance mixed with dispersing or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as sweeteners or flavors.

Rectal administration is performed using suppositories prepared with binders melting at rectal temperature, e.g. cocoa butter or polyethylene glycols.

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

Inhalation administration is performed using an aerosol containing e.g. sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biocompatible propellant.

The active substance may also be formulated as microcapsules, optionally with one or more carriers or additives.

In each dosage unit, the active substance of formula (I) is present in amounts suitable for the intended daily doses. In general, each dosage unit is appropriately adjusted according to the dosage and intended type of administration, e.g. tablets, gelatin capsules, etc., bags, ampoules, syrups, etc., and drops such that such dosage unit contains from 0.5 to 1000 mg of active substance, preferably from 2.5 to 250 mg, for administration once to four times daily.

According to another feature, the present invention relates to the use of products of formula (I) for the preparation of medicaments intended for the treatment of physiological disorders associated with excess tachykinins, in particular substance P, and all tachykinin-dependent pathologies of respiratory, gastrointestinal, urinary, immune or cardiovascular system and central nervous system as well as pain and migraines.

E.g. without limitation:

- acute and chronic pain caused by e.g. migraine, cancer patient with angina, chronic inflammatory processes such as osteoarthritis and rheumatoid arthritis,

- inflammation, such as obstructive chronic respiratory diseases, asthma, allergies, rhinitis, hypersensitivity, such as pollen or dust mites, rheumatoid arthritis, osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, inflammation of the intestine (irritable bowel), prostatitis, bladder, prostatitis , cystitis, urethritis, nephritis,

- diseases of the immune system caused by destruction or stimulation of immune cell functions, e.g. rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus,

- central nervous system diseases such as anxiety, depression, psychotic conditions, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drug addiction, Down syndrome and Huntington's chorea, as well as neurodegenerative diseases,

- gastrointestinal diseases, such as nausea, irritable colon, stomach and duodenal ulcer, diarrhea, hypersecretion,

- cardiovascular diseases such as vascular aspects of migraine, edema, thrombosis, angina and vascular spasms. The present invention also includes a method for treating these diseases at the above doses.

The following examples illustrate, but are not limited to, the invention.

Product melts, m.p., are measured on a Koffler heated table.

PREPARATIONS

A. AMINO ALCOHOLS (VII) and (VII *)

PREPARATION I: Scheme 1 - Method A (a) α- (2-Tetrahydropyranyloxyethyl) -3,4-dichlorobenzenacetonitrile

Suspend 16.5 g of 80% sodium hydride dispersion in oil in 200 ml of dry tetrahydrofuran. A solution of 100 g of 3,4 g of dichlorophenylacetonitrile in 500 ml of tetrahydrofuran was added dropwise over 30 minutes and the reaction mixture was then stirred for 2 hours at room temperature. The mixture was cooled to -20 DEG C., a solution of 118 g of 1-bromo-2-tetrahydropyranyloxyethane in 100 ml of tetrahydrofuran was added, the mixture was allowed to warm to room temperature and a solution of 50 g of ammonium chloride in 3 L of water was added after 2 hours. It was extracted with 1.5 L of ether and the extract was washed with saturated NaCl solution, decanted, dried over MgSO ₄ and concentrated in vacuo.

The residue was chromatographed on silica gel using CH ₂ Cl ₂ and then ethyl acetate (95/5 v / v) as eluent. The pure product fractions were concentrated in vacuo to give 118 g of oil.

(b) 2- (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzenetamine:

Dissolve 118 g of the nitrile obtained above in 700 ml abs. ethanol. 300 ml of concentrated aqueous ammonia was added, followed by the addition of Raney nickel (10% of the amount of starting nitrile), rinsing with nitrogen. It is then hydrogenated under an atmosphere of hydrogen at room temperature and normal pressure.

16 catalysts are absorbed within 4 hours. The catalyst is filtered off on celite, the filtrate is concentrated in vacuo and the residue is taken up in saturated NaCl solution. Extraction with ether and drying over MgSO ₄ gave 112 g of an oil.

(c) 2- (2-hydroxyethyl) -3,4-dichlorobenzenethanamine:

g of the product obtained above (b) is dissolved in 38 ml of methanol.

80 ml of a saturated solution of hydrogen chloride in ether are added while maintaining the temperature between 20 and 25 ° C. The mixture was stirred for 30 minutes at room temperature and then concentrated to dryness. The residue was dissolved in 250 ml of water, washed twice with ethyl ether, basified with NaOH solution and extracted with CH ₂ Cl ₂ . After drying over MgSO _{4, the} extract is concentrated to dryness, the residue is taken up in 800 ml of isopropyl ether, the insoluble material is filtered off on celite, the filtrate is concentrated in vacuo to about 300 ml and the crystals are separated with amino alcohol and the mixture is stirred overnight.

The crystals were filtered off and washed with isopropyl ether and then with n-pentane to give 30.2 g of the expected product. Tal. = 90-91 ° C.

(d) 2- (2) -hydroxyethyl) -3,4-dichlorobenzenethanamine (+):

A solution of 44.7 g of the product obtained in accordance with step (c) above is added to boiling solution of 29 g of D (-) tartaric acid in 800 ml of methanol in 300 ml of methanol.

The mixture was allowed to cool to room temperature and stirred for 4 hours. The product was filtered off, washed with ethanol and then with ether to give 34.1 g of tartrate.

This was recrystallized from 1.75 l methanol to give 26.6 g of tartrate.

[ _a ] »= -4.2 ° (c = 1, vH ₂ O)

The tartrate was taken up in 120 ml of water, basified with NaOH solution, extracted twice with CH ₂ Cl ₂ , the extract dried over MgSO ₄ and concentrated to dryness. The residue is taken up in a small amount of isopropyl ether, n-pentane is added and the mixture is filtered to give 15.4 g of product. Tal. = 79-80 ° C.

[ _a ] 2 ⁵ = + 9,4 ° (c = 1, vCH ₃ OH) (e) N-methyl-2- (2-hydroxyethyl) -3,4-dichlorobenzenethanamine (+) hydrochloride:

(el) Ethyl-N- [4- (2-hydroxyethyl) -2- (3,4-dichlorophenyl) butyl] carbamate g of the product obtained according to step (d) above is dissolved in 200 ml of CH ₂ C1 ₂ Add 9.9 ml of triethylamine.

The mixture was cooled to 0 ° C and a solution of 6.3 ml ethyl chloroformate in 30 ml CH ₂ Cl _{2 was} added dropwise at this temperature. After 15 minutes, the mixture was washed with water, then with dilute HCl solution and then with saturated aqueous NaHCO ₃ solution. After drying over MgSO _4, it was concentrated to dryness to give 20 g of the product as an oil.

(e2) Reduction of ethoxycarbonyl group to methyl group.

A solution of 20 g of the product obtained in step (d) above in 150 ml of anhydrous THF is added to 5.1 g of a suspension of lithium aluminum hydride in 60 ml of anhydrous THF. The mixture was refluxed for 1 hour. It is hydrolyzed with 20 ml of water, the inorganic material is filtered off and the filtrate is concentrated to dryness. The resulting oil was dissolved in 100 ml of acetone. A saturated solution of hydrogen chloride in ether was added to pH 1 and then ether was added until turbidity appeared. The mixture was stirred for 1 hour, the crystals were filtered off, washed with a small amount of acetone and then with ether to give 11 g of N-methyl-2- (2-hydroxyethyl) -3,4-dichlorobenzenethanamine hydrochloride. Tal. = 129 ° C.

^{+ 8} ' ⁴ ° ( ^{c =} 1' ^{v CH} 3 ^OH ) (f) N-methyl-2- (2-hydroxyethyl) -3,4-dichlorobenzenethanamine (-) hydrochloride:

The (-) enantiomer is obtained by the above procedure from L (+) - tartaric acid. Tal. = 129 ° C. [a] ²⁵ = -8.4 ° (c = 1, vCH ₃ OH)

PREPARATION II: Scheme 1 - Method B, m = 1 (a) 3,4-Dichloro-α- (2-tetrahydropyranyloxyethyl) benzenacetonitrile 55-60% dispersion of sodium hydride in oil was suspended in 200 ml of dry tetrahydrofuran. A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran was added dropwise at 20 ° C for 30 minutes and the reaction mixture was then stirred for 2 hours at room temperature. To this mixture, cooled to -20 ° C, was added a solution of 98 g of 2-bromoethoxytetrahydropyran in 100 ml of tetrahydrofuran, the mixture was allowed to warm to room temperature and a solution of 50 g of ammonium chloride in 3 L of water was added after 2 hours. The extraction was carried out with 1.5 L of ethyl ether and the extract was washed with saturated sodium chloride solution, decanted, dried over MgSO ₄ and concentrated in vacuo.

The residue is chromatographed on silica gel using dichloromethane as eluent. The pure product fractions were concentrated in vacuo to give 83.6 g of oil.

(b) Ethyl- (3-tetrahydropyranyloxyethyl) -3-cyano- [3- (3,4-dichlorophenyl) propionate g nitrile prepared above (a) is dissolved in 100 ml of tetrahydrofuran and then a solution is added dropwise at room temperature. 0.067 moles of dilithium diisopropylamine in 100 ml of tetrahydrofuran and the reaction mixture was stirred for 1 hour at room temperature. Then, 12 g of ethyl bromoacetate are added and the mixture is heated at 50 ° C for 2 hours. The mixture was cooled, poured into saturated ammonium chloride solution and extracted with ethyl ether, the extract was washed with water and the ether phase separated by decantation, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel using dichloromethane / ethyl acetate (100/1 v / v) as eluent. Concentration of the pure fractions gave 13 g of the expected compound.

(c) 4- (2-Tetrahydropyranyloxyethyl) -4- (3,4-dichlorophenyl) -2-pyrrolidone g of the above compound is dissolved in 250 ml of ethanol and 40 ml of aqueous ammonia and hydrogenated at room temperature and atmospheric pressure in the presence of Raney nickel . When the theoretical volume of hydrogen is absorbed, the mixture is filtered on celite and the filtrate is concentrated in vacuo. The residue was taken up in water and extracted with ethyl ether and the ether phase was then washed with water, dried over MgSO ₄ and concentrated in vacuo, m = 8.6 g.

(d) 3- (2-tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) pyrrolidine

3.9 g of the 4- (2-tetrahydropyranyloxyethyl) -4- (3,4-dichlorophenyl) -2pyrrolidone prepared above was dissolved in 250 ml of tetrahydrofuran and 0.9 g of lithium aluminum hydride, heated to 60 ° C, was added to the solution. The reaction mixture was heated at 60 ° C for 1 hour and then cooled. Add 1 ml of water, 1 ml of 4 N sodium hydroxide and 3 ml of water. The inorganic material was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in ethyl ether, dried over MgSO ₄ and concentrated in vacuo to give 3.4 g of the expected product.

(e) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) pyrrolidine

A solution of hydrogen chloride in ether was added to a solution of 3.4 g of 3-tetrahydropyranyloxyethyl 3- (3,4-dichlorophenyl) pyrrolidine in 20 ml of methanol to pH 1. The mixture was stirred for half an hour at room temperature and concentrated to dryness, the residue taken up in water, basified with sodium hydroxide solution, extracted with dichloromethane, the extract was washed with saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated to dryness to give an oil.

This oil was taken up in 20 ml of isopropyl mixture of isopropyl ether / ether mixture (50/50 v / v). After stirring and filtration, the product was washed with ethyl ether and dried in vacuo over P ₂ O ₅ , m = 2.6 g.

PREPARATION III: Scheme 1 - Method B, m = 2 (a) Ethyl-γ- (2-tetrahydropyranyloxyethyl) -7-cyano (7-3,4-dichlorophenyl) butanoate g nitrile prepared according to step (a) above, dissolved in 100 ml of tetrahydrofuran, then a solution of 0.067 mol of lithium diisopropylamide in 100 ml of tetrahydrofuran was added dropwise at room temperature and the reaction mixture was stirred for 1 hour at room temperature. Then, 12 g of ethyl bromopropionate are added and the mixture is heated at 50 ° C for 2 hours. The mixture was cooled, poured into saturated ammonium chloride solution and extracted with ether, the extract was washed with water and the ether phase was decanted, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel using dichloromethane / ethyl acetate (100/1 v / v) as eluent. Concentration of pure fractions gave 13 g of the expected compound.

(b) 5- (2-Tetrahydropyranyloxyethyl) -5- (3,4-dichlorophenyl) -2-piperidinone g of the above compound is dissolved in 250 ml of ethanol and 40 ml of aqueous ammonia and hydrogenated at room temperature and atmospheric pressure in the presence of Raney nickel . When the theoretical amount of hydrogen is absorbed, the mixture is filtered on celite and the filtrate is concentrated in vacuo. The residue was taken up in water and extracted with ether and the ether phase then washed with water, dried over MgSO ₄ and concentrated in vacuo, m = 9 g.

(c) 3- (2-tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) piperidine

3.9 g of the 5- (2-tetrahydropyranyloxyethyl) -5- (3,4 dichlorophenyl) piperidinone prepared above was dissolved in 50 ml of tetrahydrofuran and the solution was added to a suspension of 0.9 g of lithium aluminum hydride heated to 60 ° C. The reaction mixture was heated at 60 ° C for 1 hour and then cooled. Add 1 ml of water, 1 ml of 4 N sodium hydroxide and 3 ml of water. The inorganic material was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in ethyl ether, dried over MgSO ₄ and concentrated in vacuo to give 3.4 g of the expected product.

(d) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) piperidine: (compound (V)

A saturated solution of hydrogen chloride in ether was added to a solution of 55 g of 3- (2-tetrahydropyranyloxyethyl-3- (3,4-dichlorophenyl) piperidine in 200 ml of methanol to pH 1. The mixture was stirred for half an hour at room temperature and concentrated to dryness, the residue taken up in water. basified with sodium hydroxide solution, extracted with dichloromethane, the extract was washed with saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated to dryness to give an oil.

This oil was taken up in a mixture of isopropyl ether / ether (50/50 v / v). After stirring and filtration, the product was washed with ethyl ether and dried under vacuum over P ₂ O ₅ to give 45 g of the expected product, m.p. = 122 ° C.

(e) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -piperidine (+) - (compound (V *)

A solution of 23.54 g of L (+) - tartaric acid in 750 ml of 100 ° ethanol was added to a refluxing solution of 43 g of the above product in 250 ml of 100 ° ethanol. The reaction mixture was refluxed for half an hour and allowed to cool to room temperature, the crystals obtained were filtered off, washed with 100 ° ethanol and dried in vacuo at 50 ° C above P ₂ O ₅ to give 31 g of tartrate.

After recrystallization from 540 ml of 100 ° ethanol and filtration, the tartrate was washed with ethyl ether and dried in vacuo over P ₂ O ₅ to give 25 g of tartrate.

[a] “(c = l, vH ₂ O)

The tartrate is then taken up in water, neutralized with NaOH solution and extracted with CH ₂ Cl ₂ , the extract is washed with water, dried over MgSO ₄ and evaporated to dryness. The oil was taken up in a mixture of ethyl ether / isopropyl ether and the crystals were filtered off, washed with ethyl ether, dried in vacuo at 50 ° C to give 13.5 g of base. Tal. = 138 ° C.

[a] ^ ⁵ = + 8.4 ° (c = 1, in CH ₃ OH) (f) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -piperidine (-) (-) enantiomer obtained by the above procedure, starting with D (-) - tartaric acid. Tal. = 139 ° C.

[α] θ ° = −8.4 ° (c = 1, vCH ₃ 0H)

PREPARATION IV: Scheme 1 - Method B, m = 3 (a) Ethyl 5- (2-tetrahydropyranyloxyethyl) -5-cyano-5- (3,4-dichlorophenyl) pentanoate

4.6 g of 60% NaH was added in small portions to a solution of 36 g of the above 3,4 dichloro-α - [(2-tetrahydropyranyloxy) ethyl] benzenacetonitrile (prepared after preparation of II (a)) in 100 ml of dimethylformamide. The reaction mixture was stirred for 3 hours at room temperature, cooled to 100 ° C and then 22.4 g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide were added. The reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with ether, and the extract was washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel using toluene as eluant to afford 24 g of the expected product.

(b) 6- (2-tetrahydropyranyloxyethyl) -6- (3,4-dichlorophenyl) perihydro-2-azepinone g of the above product, dissolved in 120 ml of ethanol, is hydrogenated at room temperature and atmospheric pressure in the presence of Raney nickel.

When the theoretical amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is concentrated in vacuo.

The resulting oil was then taken up in 20 ml of xylene and the reaction mixture was refluxed for 48 hours. It was evaporated and the resulting residue was purified by chromatography on silica gel using dichloromethane / methanol (100/1 v / v) as the eluent to give 4 g of the expected product as an oil.

(c) 3- (2-tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) perihydroazepine

1.7 g of the expected product are obtained in the form of an oil after previous preparation, step (d), starting from 2 g of the product obtained above and 0.49 g of lithium aluminum hydride.

(d) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) azepine

1.3 g of the expected product is obtained from the previous preparation, step (e) starting from 1.7 g of the product obtained above.

B - SUBSTITUTED PHENYL ACETIC ACIDS

B. 3-ISOPROPOXYPHENYL ACETIC ACID

PREPARATION V.l

3-Isopropoxyphenylacetic acid is not known in the literature, but can be prepared by known processes for the preparation of alkoxyphenylacetic acids.

(a) Ethyl 3-hydroxyphenyl acetate

A solution of 55 g of 3-hydroxyphenylacetic acid in 400 ml of 100 ° ethanol was refluxed overnight in the presence of a few drops of concentrated H ₂ SO ₄ . Evaporate to dryness, take up the residue in ethyl ether and wash with water and then with saturated aqueous NaHCO ₃ solution. After drying over MgSO ₄ followed by evaporation, 58 g of oil were obtained.

(b) Ethyl 3-isopropoxyphenyl acetate

A solution of 58 g of the product obtained above, 88 gf CO 2 and 108 g 2-iodopropane in 300 ml DMF was heated at 80-100 ° C for 8 hours. The DMF was evaporated in vacuo, the residue was taken up in ethyl acetate and washed with 10% aqueous K2 COg. After drying over MgSO ₄ followed by evaporation, the residue was purified by chromatography on silica gel using CH ₂ Cl ₂ as eluent to give 61 g of oil.

(c) 3-Isopropoxyphenylacetic acid

A solution of 31 g of the product obtained above and 20 g of NaOH in 400 ml of ethanol was refluxed for 2 hours. Evaporate to dryness, take up the residue in water and acidify with concentrated HCl. The extraction was carried out with ether, the extract was washed with water, dried over MgSO ₄ and concentrated to dryness to give 27 g of the expected acid. Tal. - 3335 ° C.

B2.2-iodo-5-isopropoxyphenylacetic acid

PREPARATION V.2

2. Iodo-5-isopropoxyphenylacetic acid is not known in the literature, but can be prepared by known methods, e.g. by R.E. Counsel et al., J. Med. Chem., 1973, 16, 6, 684-687, replacing benzyl chloride with 2-iodopropane.

g of the 2-iodo-5-isopropoxyphenylacetonitrile thus prepared is dissolved in 160 ml of ethanol in the presence of 18 g of KOH and then the mixture is refluxed for 2 hours. It is concentrated in vacuo, the residue is taken up in water and washed successively with ethyl ether, the aqueous phase is acidified by the addition of HCl to pH 1, extracted with ethyl ether, the extract is washed with water, dried over Na ₂ SO ₄ and filtered. It is concentrated in vacuo and the residue is purified by chromatography on silica gel using CH ₂ Cl ₂ -CH ₃ OH (100-2 v / v) as the eluent to give, after concentration of pure fractions, 8 g of the expected acid as an oil. NMR spectrum (200 MHz): 1.2 ppm - 2CH ₃ ; 3.5 ppm - 1CH ₂ ; 4.6 ppm 1CH; 6.6 ppm - 1H aromatic; 6.9 ppm - 1H aromatic; 7.6 ppm - 1H aromatic.

C. ACYL DERIVATIVES (VI) AND SULPHONYLOX DERIVATIVES (II)

PREPARATION VI: Scheme 1 - Method B, m = 1 (a) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylpyrrolidine

2.25 ml of triethylamine and then 2.6 g of the 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) pyrrolidine prepared above are added to a solution of 1.9 g of 3-isopropoxyphenylacetic acid in 50 ml of CH ₂ Cl ₂ . The mixture was cooled to 0 [deg.] C., then 4.42 g of BOP was added and the reaction mixture was pushed to room temperature. After 30 minutes the mixture was concentrated in vacuo, the residue taken up in ethyl ether and washed successively with water, dilute NaOH solution, saturated NaCl solution, dilute HCI solution, saturated NaCl solution and NaHCO ₃ solution. The ether phase was dried over MgSO ₄ , filtered and concentrated in vacuo to give 3.6 g of the expected product.

(b) 3- (2-methanesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylpyrrolidine

Dissolve 2.2 g of the above product in 50 ml of CH ₂ Cl ₂ and cool the solution to 0 ° C. 1.5 g of triethylamine are added followed by 0.57 g of methanesulfonyl chloride dropwise. The reaction mixture was allowed to stand at 0 ° C for 15 minutes and then concentrated in vacuo, the residue taken up in ether and washed with water, the ether phase dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate (50/50 v / v) to pure ethyl acetate as eluent.

The pure product fractions were concentrated in vacuo and the residue was then solidified in an ethyl ether / isopropyl ether mixture to give 2.5 g of the expected product.

PREPARATION VII: Scheme 1 - Method B, m = 2 (a) Optically pure 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -1- (3isopropoxyphenyl) acetyl] piperidine

22.5 ml of triethylamine and then 22 g of 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) piperidine (-) prepared above after preparation III (f) are added to a solution of 16 g of 3-isopropoxyphenylacetic acid in 500 ml CH ₂ C1 ₂ . The mixture was cooled to 0 ° C, then 42.6 g of BOP was added and the reaction was allowed to warm to room temperature. After 30 minutes the mixture was concentrated in vacuo, the residue taken up in ether and washed successively with water, dilute NaOH solution, saturated NaCl solution, dilute HCI solution, saturated NaCl solution and NaHCO ₃ solution. The ether phase was dried over MgSO ₄ , filtered and concentrated in vacuo to give 36 g of optically pure product.

(b) 3- (2-Methanesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylpiperidine (+) g of the above product was dissolved in 500 ml CH ₂ C1 ₂ and cooled to 0 ° C. Add 11.5 ml of triethylamine and then 6.3 ml of methanesulfonyl chloride dropwise. The reaction mixture was allowed to stand at 0 ° C for 15 minutes and then concentrated in vacuo, the residue taken up in ether and washed with water, the ether phase dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate (50/50 v / v) to pure ethyl acetate as eluent.

The pure product fractions were concentrated in vacuo and the residue was then solidified in an ethyl ether / isopropyl ether mixture to give 37.5 g. Tal. = 72 ° C.

[ _a ] ™ (c = 1, vCHCl ₃ ) (c) 3- (2-benzenesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] piperidine

4.6 ml of triethylamine are added and then 4.3 ml of benzenesulfonyl chloride are added dropwise to 11.3 g of the product prepared above after preparation VII (a) in 160 ml of CH ₂ Cl ₂ and the solution is cooled to 0 ° C. The reaction mixture was allowed to stand at room temperature for 18 hours and then sequentially treated with 100 ml of HCl, 100 ml of 10% Na ₂ SO ₄ and 100 ml of water. The organic phase was filtered off, dried over Na ₂ SO ₄ and then concentrated in vacuo. The residue was chromatographed on silica gel using cyclohexane (AcOEt 80/20 v / v) as eluent. The pure product fractions were concentrated to give 8.5 g of the expected product.

PREPARATION VIII: Scheme 1 - Method B, m = 3 (a) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetyl] perihydroazepine

1.2 g of triethylamine and then 1.15 of the 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) azepine prepared above were added to a solution of 0.76 g of 3-isopropoxyphenylacetic acid in 50 ml of CH ₂ Cl ₂ . The mixture was cooled to 0 ° C, then 1.77 g of BOP was added and the reaction was allowed to warm to room temperature. After 30 minutes the mixture was concentrated in vacuo, the residue taken up in ethyl ether and washed successively with water, dilute NaOH solution, saturated NaCl solution, dilute HCl solution, saturated NaCl solution and NaHCO _r solution _{. The} ether phase was dried over MgSO ₄ , filtered and concentrated in vacuo. vacuum to obtain 1.8 g.

(b) 3- (2-methanesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylperihydro azepine

Dissolve 1.8 g of the above preparation in 50 ml of CH ₂ Cl ₂ and cool the solution to 0 ° C. 0.38 g of triethylamine are added and then 0.44 g of methanesulfonyl chloride are added dropwise. The reaction mixture was allowed to stand at 0 ° C for 15 minutes, then concentrated in vacuo, the residue taken up in ethyl ether and washed with water, the ether phase dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate (50/50 v / v) to pure ethyl acetate as eluent.

The pure product fractions were concentrated in vacuo and the residue was then solidified in an ethyl ether / isopropyl ether mixture to give 2 g of the expected product.

EXAMPLE 1 <i> A: A, = VQ; T = -CH ₂ -; R = -CH ₃ ; Q = H;

'O- iPr

a

0.75 g of 4-phenylquinuclidine synthesized by T. Perrine, J. Org. Chem., 1957, 22, 1484-1489, and 1 g of N- [2- (3,4-dichlorophenyl) -4-methanesulfonyloxybutyl] -N-methyl- (3-isopropoxyphenyl) carboxamide prepared according to EP-A-0 428 434, dissolved in 5 ml of acetonitrile. The reaction mixture was refluxed for 4 hours and then concentrated in vacuo. The residue was taken up in CH ₂ Cl ₂ , then washed sequentially with 2 N HCl solution and saturated NaCl solution, and the organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was solidified in ethyl ether to give 0.39 g of 1- (3- (3,4-dichlorophenyl) -4- (N-methyl-3-isopropoxyphenylacetylamino) butyl] -4-phenyl-1-azonia-bicyclo [2.2 .2] octane chloride (Compound 1), mp = 98-100 ° C.

EXAMPLE 2 ^(, > ^{: αγ} = λΟ,; T = -CH ₂ -; R = -CH ₃ ; Q = H;

0— iPr

Optically pure (-) - 1- (3- (3,4-dichlorophenyl) -4- (N-methyl-3-isopropoxyphenyl acetylamino) butyl] -4-phenyl-1-azoniabicyclo [2.2.2] octane chloride derivative ( compound 2), mp 97-99 ° C, was obtained according to the procedure of Example 1 using an optically pure (-) - N- [2- (3,4-dichlorophenyl) -4-methanesulfonyloxybutyl] -N-methyl- (3 -isopropoxyphenyl) carboxamide prepared according to EP-A-0 428 434 as starting material.

[α] θ ° = −47.2 ° (c = 1, vCH ₃ OH)

EXAMPLE 3

1- [3- (3,4-Dichlorophenyl) -4- (N-methyl-3-isopropoxyphenylacetylamino) butyl] -1-azonia bicyclo [2.2.2] octane chloride (compound 3), m.p. = 68-70 ° C, is obtained according to the procedure of Example 1 using quinuclidine as tert.amine.

EXAMPLE 4

Cl

2.25 g of 4-phenylquinuclidine and 3.17 g of mesylate prepared after preparation VII (b) were dissolved in 30 ml of acetonitrile and the reaction mixture was refluxed for 10 hours. The mixture was concentrated in vacuo, the residue was taken up in CH ₂ Cl ₂ and washed sequentially with 3 N HCl solution and then saturated NaCl solution. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was precipitated from a mixture of acetone / ether to give 2.8 g of optically pure (+) - 1- [2- [3- (3,4-dichlorophenyl) -1 - [(3isopropoxyphenylacetyl] piperidin-3-yl] ethyl) ] -4-Phenyl-1-azoniabicyclo [2.2.2] octanchloride (Compound 4), mp = 132 ° C.

[α] θ ° = + 16.3 ° (c = 1, in CH ₃ OH)

EXAMPLE 5 (I): Ar; T = <H ₂ -; R + Q = - (CH ₂ ) ₃ 0- iPr

Cl

2.65 g of 4-phenylquinuclidine in 8.3 g of benzenesulfonate prepared according to PREPARATION VII (c) are dissolved in 40 ml of acetonitrile and the reaction mixture is refluxed for 6 hours. The mixture was concentrated in vacuo, the residue taken up in CH ₂ Cl ₂ and washed successively with a 1% aqueous solution of benzenesulfonic acid and then with water. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was precipitated from isopropyl ether to give 8 g of optically pure (+) - 1- [2- [3- (3,4-dichlorophenyl) -1 - [(3isopropoxyphenyl) acetyl] piperidin-3-yl] ethyl] -4 -phenyl-1-azoniabicyclo [2.2.2] octane-benzenesulfonate (compound 5). Tal. = 195.5 ° C.

[α] ^2θ = -50.7 (c = l, vCH ₃ OH)

Compounds 6 to 12 described in Tables I and II below are prepared according to the following Examples 1 to 5.

- 36 TABLE I

CIO

R

- (C H 2) 2-C H-C H 2-N-C 0-T-Ar Ar '

Example no. Ar ' R T Ar Tal. ; v 'C and / or ['] _D. 6 ό A ci a ch ₃ - F 150 -57.9 · 7 0. ^F F ch ₃ - F I 178 8 0. ^F F ch ₃ -ch ₂ - Cl OiPr 97 9 ίύο H - _By OCH, T 104-106 och ₃

[ ^α 1ϋ 'is measured at 20 ° C, c = 1 * Dryness, in CH3OH.

R = -CHO-CHg-O CO CH3. Ar '=

Cl

Cl

Am + =; A® = CP ©

8.2 g of ethyloxalyl chloride were added dropwise to a solution of 19 g of 2- (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzenethanamine (obtained according to PREPARATION (I) - step (b)) and 7 g of triethylamine. The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo. The residue was taken up in ethyl ether, washed successively with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel using CH ₂ Cl ₂ / CH ₃ OH (100/1 v / v) as the eluent to give 16 g of N-ethyloxy-2- (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzenethanamine as an oil.

Step 2 g of the product obtained above was dissolved in 40 ml of THF and 1.7 g of LiAlH ₄ in 5 ml of THF at 50 ° C was added dropwise. The reaction mixture was refluxed for 4 hours, cooled, hydrolyzed, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using CH ₂ Cl ₂ / CH ₃ OH (100/5 v / v) as eluant to give 14 g of N- (2-hydroxyethyl) -2- (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzenethanamine in the form oils.

Tier 3

3.55 g of BOP was added at 0 ° C to a solution of 2.4 g of the above product, 1.1 g of triethylamine and 1.3 g of 3-isopropoxyphenylacetic acid in 60 ml of CH ₂ Cl ₂ . The reaction mixture was stirred for 1 hour at 0 ° C and then sequentially concentrated in vacuo, taken up in AcOEt, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel using CH ₂ Cl ₂ / CH ₃ OH (100/3 v / v) as eluent to give 2.2 g of N- (2-hydroxyethyl) -N-3-isopropoxyphenylacetyl-2- (2- tetrahydropyranyloxyethyl) -3,4-dichlorobenzenethanamine as an oil.

Tier 4

0.41 g of acetyl chloride is added to a solution of 2.2 g of the above product in 10 ml of CH ₂ Cl ₂ in the presence of 0.56 g of triethylamine in CH ₂ Cl ₂ . The reaction mixture was stirred for 1 hour and then concentrated in vacuo, washed with ethyl ether, water, dried over Na ₂ SO ₄ and concentrated in vacuo to give 2 g of N- (2-acetoxyethyl) -N-3-isopropoxyphenylacetyl-2 - (2-Tetrahydropyranyloxyethyl) -3,4-dichlorobenzenethanamine as an oil.

A step of 5 g of the oil obtained above was dissolved in 20 ml of methanol saturated with HCl and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, the residue taken up in AcOET, washed with water, dried over Na ₂ SO ₄ and chromatographed on silica gel using CH ₂ Cl ₂ / CH ₃ OH (100/3 v / v) as eluent to give 1. 2 g of N- (2-acetoxyethyl) -N-3-isopropoxyphenylacetyl-2-hydroxyethyl) -3,4 dichlorobenzenethanamine as an oil.

Level 6

Dissolve 0,5 g of the above product in 10 ml of CH ₂ Cl ₂ in the presence of 0.11 g of triethylamine. 0.125 g of mesyl chloride is added and the reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo and then the residue was sequentially taken up in AcOET, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo to give 0.5 g of N- (2-acetoxyethyl) -N-3-isopropoxyphenylacyl til-2 - Mesyloxyethyl-3,4-dichlorobenzenetamine as an oil.

Level 7

0.5 g of the above product and 0.25 g of 4-phenylquinuclidine are dissolved in 1 ml of dimethylformamide and the reaction mixture is heated at 80 ° C for 2 hours. The reaction mixture was poured into water and then sequentially extracted with AcOET, washed with water, saturated NaCl solution, concentrated in vacuo and the residue chromatographed on silica gel using CH ₂ Cl ₂ / CH ₃ OH (100/5 v / v) as eluent. The pure fractions were concentrated in vacuo, the residue was taken up in CH ₂ Cl ₂ and precipitated by addition of ethyl ether to give 0.45 g of 1- [3,4- (3-dichlorophenyl) -4- (N- (2-acetoxyethyl) - 3-Isopropoxyphenyl acetylamino) butyl] -1-azoniabicyclo [2.2.2] octane chloride (Compound 13). Tal. = 9092 ° C.

EXAMPLE 14

Tablet containing:

compound 4 250 mg lactose 80 mg crosslinked polyvidone 20 mg methylhydroxypropylcellulose 10 mg hydrogenated castor oil 40 mg EXAMPLE 15 Enteric tablet containing: Tablet: compound 4 250 mg hydroxypropylcellulose 6 mg lactose 62 mg microcrystalline cellulose 60 mg carboxymethyl starch 12 mg polyethylene glycol 6000 10 mg coating: Endraget L100 lmg dibutylphthalate lmg isopropyl alcohol (evaporated) 28 mg

EXAMPLE 16 Oral solution containing: compound 4 100 mg ethyl alcohol 100 mg propylene glycol 50 mg a polyvidone carrier 20 mg glycerol 50 mg artificial aroma 2.5 mg purified water qsp 1.0 mg

EXAMPLE 17

Injectable suspension containing:

compound 4 50 mg Polysorbate 80 In mg polyoxyethylene glycol 20 mg methyl- and propyl-para- hydroxybenzoate 1.5 mg sorbitol 30 mg a polyvidone carrier 10 mg water for injection preparations of qsp 1 mg

EXAMPLE 18

Herbal capsule containing:

compound 4 from 2.5 to 250 mg modified corn starch 50 mg talc 25 mg anhydrous colloidal silica lmg stearic acid 10 mg lactose qsp 100 mg gelatin capsule

EXAMPLE 19

Suppository containing compound 4 150 mg solid semi-synthetic glycerides qsp

Claims (15)

PATENT APPLICATIONS 1. Quaternary basic amide of formula R Q Ar-T-CO -N-CH ₂ -C-CH ₂ -CH ₂ -Am °. A ° ^(I) Ar 'in which it is Ar is optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is C _x -C ₄ , or a C 1 -C 6 alkylene group; Ar 'is phenyl, which is unsubstituted or mono- or polysubstituted by a substituent selected from a halogen atom, preferably a chlorine or fluorine atom, trifluoromethyl, Cj-C ^ -alkoxy or C _x -C ₄ alkyl, wherein said substituents are the same or various, thienyl, benzothienyl, naphthyl or indolyl; R is hydrogen or Cj-C ^ alkyl or C _x -C ₄ alkyl - (o-alkoxy (C ₂ -C ₄₎ alkyl or C ₂ -C ₄₎ ω-Η ^ ηοΐΙοΙίκΐζϋ -CJalkil; Q is hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am® is the residue of ^X 1 I® X ₂ - N where Χ _χ , and X ₃ together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system, optionally substituted by a phenyl group; and is A 'a pharmaceutically acceptable anion. Quaternary basic amide of formula (I), characterized in that the residue represented by Am® contains from 5 to 9 carbon atoms in its azabicyclic or azatricyclic system. (I) The quaternary basic amide of claim 1 or 2 of formula I Ar-T-CO-N-CH ₂ -C-CH ₂ -CH ₂ -Am®. Α ^θ Ar 'in which Ar, T, Ar', R and Q as defined in claim 1, characterized in that Am® residue I® x ₂ -n- in formula (I) and is a residue of an azabicyclic or azatricyclic system selected from the following, such as: (a) l-azoniabicyclo [2.2.0] hexane (b) l-azoniabicyclo [3.1.0] hexane (c) l-azoniabicyclo [2.2.1] heptane (d) l-azoniabicyclo [2.2.2] octane (e) ) l-azoniabicyclo [3.2.1] octane (f) l-azoniabicyclo [3.2.2] nonane (g) l-azoniabicyclo [3.3.1] nonane (h) hexahydro-1H-pyrrolizinium-4 (i) octahydroindolizinium-4 0) octahydro-2H-quinolizinium-5 (k) 1-azoniatricyclo [3.3.1.1 ^3,7 ] decane (1) 4-phenyl-1-azoniabicyclo [2.2.2] octane, and A 'is a pharmaceutically acceptable anion. Quaternary basic amide of formula I according to any one of claims 1 to 3, characterized in that T, R, Ar 'and Q are as defined for (I), Am® is l-azoniabicyclo [2.2.2] octane or 4-phenyl-1-azoniabicyclo [2.2.2] octane residue, Ar is phenyl substituted with C 1 -C 4 -alkoxy, and A 'is a pharmaceutically acceptable anion. 5. Quaternary basic amide of formula R 'Q' iPr-O Ω ch ₂ -co-n-ch ₂ -c-ch ₂ -ch ₂ -n (Γ 'where R' and Q 'are methyl and hydrogen or 2-acetoxyethyl and hydrogen; or R' and Q together form 1, The 3-propylene group, R 'is hydrogen or a phenyl group and A' is a pharmaceutically acceptable anion. A quaternary basic amide of the formula wherein A 'is a pharmaceutically acceptable anion. Quaternary basic amide according to any one of claims 1 to 6, characterized in that A 'is selected from chloride, bromide, iodide, hydrogen sulfate, methanesulfonate, paratoluenesulfonate and acetate. 8. (+) - 1- [2- [3- (3,4-Dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] piperidin-3yl] ethyl] -4-phenyl-1-azoniabicyclo [2.2.2 ] octane chloride. Process for the preparation of compounds of formula (I), characterized in that the derivative of the formula Ar-T-CO-N-CH ₂ -C-CH ₂ -CH ₂ -OY (II) Ar 'where Y is any removable group, preferably methanesulfonyl or benzenesulfonyl, is treated with a cyclic tertiary amine of formula ^X 1 X ₂ “N (III) 20 X ₃ where X _p X ^ and Xg together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system, optionally substituted by a phenyl group, in a polar aprotic solvent at a temperature between room temperature and 120 ° C and then after if necessary, exchange the anion of the quaternary salt obtained with another pharmaceutically acceptable anion. A process according to claim 9, characterized in that the cyclic tertiary amine (III) contains from 5 to 9 carbon atoms in its azabicyclic or azatricyclic system. Process according to claim 9 or 10, characterized in that the cyclic tertiary amine (III) is selected from: N Pharmaceutical composition, characterized in that the compound of formula (I) according to claim 1 is present as an active substance. Pharmaceutical composition according to claim 12 in the form of a dosage unit, characterized in that the active substance is mixed with at least one pharmaceutical carrier. Composition according to claim 13, characterized in that it contains 0.5 to 1000 mg of active substance. Composition according to claim 14, characterized in that it contains from 2.5 to 250 mg of active substance.