LT3442B - Arylalkylamines, process for their preparation and pharmaceutical compositions containing the same - Google Patents

Abstract

Arylalkylamine of formula: <IMAGE> in which: - Y represents - either a group Cy-N in which Cy represents an optionally substituted phenyl; a C3-C7 cycloalkyl group; a pyrimidinyl group or a pyridyl group; - or a group <IMAGE> in which . Ar represents an optionally substituted phenyl; a pyridyl group; a thienyl group; . x is 0 or 1; . X represents a hydroxyl, a C1-C4 alkoxy; a C1-C4 acyloxy; a carboxyl; a C1-C4 carbalkoxy; a cyano; a group -N-(X1)2 in which the X1 groups independently represent hydrogen or a C1-C4 alkyl; a group -S-X2 in which X2 represents hydrogen or a C1-C4 alkyl group; or else X forms, with the carbon atom to which it is bonded and with the neighbouring carbon atom in the heterocycle, a double bond; - m is 2 or 3; - Ar' represents an optionally substituted phenyl; a thienyl; a benzothienyl, a naphthyl or an indolyl; - R represents hydrogen or a C1-C6 alkyl; - T represents a group chosen from -CO- and -CW-NH- being an oxygen or sulphur atom, and - Z represents either hydrogen, or M or OM when T represents the -CO- group, or M when T represents the -CW-NH- group; M represents a C1-C6 alkyl; a phenylalkyl, a pyridylalkyl, a naphthylalkyl; a pyridylthioalkyl; a styryl; an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group; or one of its salts with inorganic or organic acids. Application = antagonists of neurokinin receptors.

Description

The present invention relates to novel aromatic derivatives substituted by an amino group and different ester, anime or amide functional groups.

The invention also encompasses the use of compositions, compounds, for the preparation of a therapeutic use, namely, pathological events associated with the neurokinin system.

Endogenous ligands for neurokinin receptors have been previously described, for example, substance P (SP), neurokinin A (NKA) (SJ Bailey et al., Substance P, P. Skrabanck ed., 1617, Boole Press, Dublin, 1983) and neurokinin B (NKB). ) (SP Watson, Life Sciences, 25, 797-808 (1983)).

Neurokinin receptors are known to many formulations and are currently divided into 3 types: NK _x , NK ₂ and NK ₃ . While many of the preparations investigated until recently, such as the guinea pig colon, have multiple receptor types (NK _X , NK _2, and NK ₃ ), some have only one type, such as canine carotid artery (NK _X ), rabbit pulmonary artery without endothelium (NK ₂ ) and rat portal vein (NK ₃ ) (D. Regoli et al., Trends

Pharmacol Sci., 1988, 9, 290-295 and Pharmacology, 1989,

38, 1-15).

A more precise characterization of the different receptors has been made possible by the recent synthesis of selective antagonists. Thi, for example, [Sar ₉ , Met- (O ₂ ) _n ] -SP, [NIe ₁₀ ] -NKA _{4 -10} and [Me Phe ₇ ] -NKB are selective for NK _X , NK ₂ and NK ₃ receptors, respectively (supra). specified

D. Regoli et al. , Trends Pharmacol Sci., 1988, 9, 290295 and Pharmacology, 1989, 38, 1-15).

Currently, some differently substituted amine-containing aromatic derivatives have interesting pharmacological properties, such as those of the neurokinin A reLT 3442 B receptor antagonists, and are particularly useful in treating any pathology dependent on neurokinin A.

The NK ₂ receptor and neurokinin A receptor are described, for example, in neurogenic airway inflammation (PJ Barnes, Arch., Int. Pharmacodyn, 1990, 303, 67-82 and GF JOOS et al., Arch., Int. Pharmacodyn, 1990, 303). , 132-146).

Until recently, only peptide NK ₂ receptor antagonists have been described. In the published material, CA Maggi et al. , Br. J. Pharmacol. 1990, 100, 588-592 describes peptides which are selective antagonists of NK ₂ receptors.

In European patent no. No. 347802 discloses peptide antagonist derivatives of neurokinin A useful as immunosuppressants useful in the treatment of arthritis, asthma, inflammatory pain, gastrointestinal, hypermotoric disease, psychosis, hypertension, migraine, urticaria, Huntington's disease and other diseases.

In European patent no. O 336230 also describes peptide antagonist derivatives for substance P and neurokinin A useful in the prophylaxis and treatment of asthma.

Thus, in one aspect, the invention relates to various substituted aromatic amino compounds having the formula:

P

C N

I

A r '( ^CH o) _m Z m

- CH - N - T - Z in which

- Y is

- or the Cy-N group, where. Cy is a phenyl, unsubstituted or mono- or poly- substituted with one substituent selected from: hydrogen, a halogen atom, hydroxyl, C _x -C ₄ alkoxy, C _x -C ₄ alkyl, trifluoromethyl, furthermore, each of these substituents the same or different; cycloalkyl group C ₃ -C ₇ ; a pyrimidinyl group or a pyridyl group, - or a group Ar- (CH ₂ ) _X -C in which

I

.Is X is phenyl, unsubstituted or mono- or polysubstituted by one of the substituents selected from: hydrogen, a halogen atom, hydroxyl, C _x -C ₄ alkoxy, trifluoromethyl, C _x -C ₄ alkyl, in addition, said substituents are themselves or different; a pyridyl group; a thienyl group, • x is zero or a unit, • x is hydroxyl, C _x -C ₄ alkoxy; hydroxyalkyl wherein alkyl is C 1 -C 4; C _x -C ₄ acyloxy; phenacyloxy; carboxyl; C _x -C ₄ carbaloxy; cyano; aminoalkylene wherein alkylene is C ₁ -C ₃ ; A group -N- (X _x ) ₂ wherein X _y is independently hydrogen, C _y -C ₄ alkyl; -NH-C-Alk group,

II

wherein Alk is C _x -C ₆ alkyl; Al-NH-C-Alk Group,

II

wherein Alk _x is C _y -C ₃ alkylene and Alk _x is C _y -C ₃ alkyl; C _y -C ₄ acyl; A -SX ₂ group wherein X ₂ is hydrogen or a C 1 -C 4 alkyl group; or X, taken together with the carbon atom to which it is attached and the adjacent carbon atom to form a double bond in the heterocycle;

- m is 2 or 3;

- Ar 'is phenyl unsubstituted or mono- or poly-substituted with one of the substituents selected from hydrogen, halogen, preferably chlorine or fluorine, trifluoromethyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, in addition, the substitutions indicated are the same or different; thienyl; benzothienyl; naphthyl; indolyl; N-substituted C ₁ -C ₃ alkyl indolyl;

- R is hydrogen, C _x -C ₆ alkyl;

- T is a group selected from

-C- and -C-NHO W where W is an oxygen or sulfur atom; and

- Z is or denominator, or M or OM when T is -C- group, II 0 or M, when T is -C-NH II group; M is C 1 -C 8 alkyl; II w phenylalkyl, in which alkyl is C 1 -C ₃ group, pa-

optionally substituted in the aromatic ring by halogen, trifluoromethyl, alkyl, hydroxyl, C _; -C ₄ alkoxy; pyridylalkyl wherein alkyl is C _y -C ₃ , naphthylalkyl where alkyl is Οχ-Ο ₃ , optionally substituted naphthyl ring by halogen, trifluoromethyl, C 1 -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy; pyridylthioalkyl wherein alkyl is C ₁ -C ₃ ; styryl; optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic; or one of its salts with mineral or organic acids.

In this specification, alkyl or alkoxy groups are linear or branched.

Salts of compounds of formula (I) are salts with mineral or organic acids which provide separation and appropriate crystallization of compounds of formula (I), such as picric acid or oxalic acid, or an optically active acid such as almond or camphor sulfonic acid, as well as pharmaceutically acceptable salts. suitable salts such as chlorohydrate, bromohydrate, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, maleate, fumarate, 2-naphthalenesulfonate, glycolate, gluconate, citrate, isothionate.

In an individual case, in Formula (I), Z is an aromatic or heteroaromatic mono-, di- or tricyclic group which may be substituted with one or more substituents and in which the carbon atom of the aromatic carbocycle or aromatic heterocycle is directly linked to group T.

Alternatively, the radical Z may be a phenyl group which may be unsubstituted or optionally substituted by one or more substituents.

When Z is a phenyl group, the latter is preferably when mono or di-substituted, especially in the 2-, 4- position, but also, for example, in the 2, 3-, 4, 5-, 3, 4- or 3, 5- position; it may also be triple substituted, especially at positions 2, 4, 6, but also, for example, at positions 2, 3, 4, 4, 2, 3, 5 or 2, 4, 5, 3, 4, 5; tetra substituted, for example, in the 2, 3, 4, 5 positions; or penta-modified.

2-buten-2-yl, alkynyl, the phenyl substituent may be: F; Cl; Br; I; CN; OH; NH ₂ ; NH-CO-NH ₂ ; NO ₂ ; CONH ₂ ; CF ₃ ; C ₁ -C ₁₀ alkyl, preferably C _x -C ₄ alkyl, where methyl and ethyl are preferred, and also, for example, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl, decyl or n-decyl; alkenyl having 2-10, preferably 2-4 carbon atoms, for example vinyl, allyl,

1-propenyl, isopropenyl, butenyl or 1-buten-1-,

-2,3-ar-4-yl, 2-buten-1-yl, pentenyl, hexenyl or decenyl;

2-10, preferably 2-4 carbon atoms such as ethynyl, 1-propyn-1-yl, propargyl, butynyl or

2-butyn-1-yl, pentynyl, decinyl; cycloalkyl having 3-8, preferably 5 or 6 carbon atoms, more preferably cyclopentyl or cyclohexyl, and also, for example, cyclopropyl, cyclobutyl, 1-, 2- or

3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl, or cyclooctyl; bicycloalkyl having 4 to 11, preferably 7, carbon atoms, with exo or endo-2-norbornyl being preferred, as well as, for example, 2-isobornyl or 5-camphoyl; hydroxyalkyl having 1-5, preferably 1-2 carbon atoms, more preferably hydroxymethyl and 1- or 2-hydroxyethyl, as well as, for example, 1-hydroxyprop-1-yl,

2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 1-hydroxyprop-2-yl, 1-hydroxybut-1-yl, 1-hydroxypent-yl; alkoxy having 1 to 10, preferably 1 to 4 carbon atoms, more preferably methoxy or ethoxy, as well as, for example, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing

2-10, preferably 2-6 carbon atoms, for example alkoxymethyl or alkoxyethyl, namely methoxymethyl or

1- or 2-methoxyethyl, 1- or 2-n-butoxyethyl, 1-ar

2-n-octyloxyethyl; alkoxyalkoxyalkyl having up to 10, preferably 4-7 carbon atoms, for example alkoxyalkoxymethyl such as 2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxymethyl, alkoxyalkoxyethyl such as 2- (2-methoxyethoxy) -ethyl or 2- (2- ethoxyethoxy) ethyl; an alkoxyalkoxy group having 2 to 10, preferably 3 to 6 carbon atoms, for example 2-methoxyethoxy, 2-ethoxyethoxy or 2-n-butoxyethoxy; alkynyloxy having 2-10, preferably 2-4 carbon atoms, more preferably allyloxy, as well as vinyloxy, propenyloxy, isopropenyloxy, butenyloxy such as 1-buten-l-, -2-, - 3- or -4-yloxy, 2-buten-1-yloxy, 2-buten-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy, alkenyloxyalkyl having up to 10, preferably 3-6 carbon atoms, for example allyloxymethyl; alkynyloxy having 2-10, preferably 2-4 carbon atoms, moreover propargyloxy is preferred, as well as, for example, ethynyloxy, 1-propynyl-1-yloxy, butynyloxy or 2-butyn-1-yloxy, pentynyloxy - or a decynyloxy group; alkynyloxyalkyl having 3-10, preferably 3-6 carbon atoms, such as ethynyloxymethyl, propargyloxymethyl or 2- (2-butynyloxy) ethyl; cycloalkoxy having 3-8, preferably 5-6 carbon atoms, more preferably cyclopentyloxy or cyclohexyloxy, as well as, for example, cyclopropyloxy, eiclobutyloxy, 1-, 2 or 3-methylcyclopentyloxy, 1-, 2- , 3- or 4-methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy; an alkylthio group having 1-10 carbon atoms, preferably 1-4 carbon atoms, in addition, methylthio or ethylthio groups are preferred, as well as, for example, n-propylthio, isopropylthio, η-butylthio, isobutylthio, sec. butylthio, tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio or decylthio; alkylthioalkyl having 2-10, preferably 2-6 carbon atoms, such as methylthiomethyl, 2-methylthioethyl or 2-nLT 3442B-butyrylamino, caprolamino, isobuheptabenzothyrylamino, noylamino, cycloalkoxycarbonyl, carbon atoms, butylthioethyl; an acylamino group known as an alkanoylamino group having from 1 to 7, preferably from 1 to 4 carbon atoms, more preferably formylamino and acetylamino groups, as well as propionylamino, valerylamino and also aroylamino or ilamino groups; acylaminoalkyl, preferably alkanoylaminoalkyl having 2-8, preferably 3-6 carbon atoms, such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl, acetylaminopropyl, propionylaminopropyl, formylaminobutyl, acetylaminobutyl, and also propionylaminobutyl; acyloxy having 1-6, preferably 2-4 carbon atoms, in addition acetyloxy, propionyloxy or butyryloxy are preferred, as well as, for example, formyloxy, valeryloxy, capryloxy; alkoxycarbonyl having 2-5, preferably 2-3 carbon atoms, more preferably methoxycarbonyl and ethoxycarbonyl, as well as, for example, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl;

containing 4-8, preferably 6 or 7, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl is preferred, as well as cyclopropyloxycarbonyl, cyclobutyloxycarbonyl or cycloheptyloxycarbonyl; alkylaminocarbonylamino having from 2 to 4 carbon atoms, namely, methylaminocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino; dialkylaminocarbonylamino having 3-7, preferably 3-5 carbon atoms, preferably dimethylaminocarbonylamino, as well as di-n-propylaminocarbonylamino, diisopropylaminocarbonylamino; pyrrolidine-1-carbonylamino; (piperidino-1) carbonylamino; cycloalkylaminocarbonylamino having 4-8, preferably 6 or 7 carbon atoms, in addition, eiclopentylaminocarbonylamino, cyclohexylaminocarLT 3442 B are preferred, as well as cyclopropylaminocarbonylamino, eicobutylaminocarbonylamino, cycloheptylaminocarbonyl; alkylaminocarbonylaminoalkyl having 3-9, preferably

4-7 carbon atoms, in addition, methylaminocarbonylaminoethyl, ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl, ethylaminocarbonylaminobutyl are preferred, as well as, for example, methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl, n-butylaminocarbonylaminobutyl; dialkylaminocarbonylaminoalkyl containing 4 to 11 carbon atoms, such as dimethylaminocarbonylaminomethyl, diatylaminocarbonylaminoethyl, diethylaminocarbonylaminopropyl, diethylaminocarbonylaminobutyl, (pyrrolidino-1) carbonylaminoethyl, (piperidino-1) carbonylaminoethyl; cycloalkylaminocarbonylaminoalkyl containing

5-12, preferably 8-11 carbon atoms, in addition, cyclopentylaminocarbonylaminoethyl, cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarbonylaminobutyl, cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarbonylaminopropyl and cyclohexylaminocarbonylaminobutyl are preferred, as well as, for example, cyclohexylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl having 3-12, preferably 4-9 carbon atoms, in addition, methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, n-propoxycarbonylaminoethyl, n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl, sec-butoxycarbonylaminoethyl, n-butoxycarbonylaminoethyl, n-butoxycarbonylaminobutyl is preferred as well as, for example, n-propoxycarbonylaminopropyl, n-propoxycarbonylaminobutyl, isopropoxycarbonylaminobutyl; cycloalkoxycarbonylaminoalkyl having 5-12, preferably 8-11 carbon atoms, in addition to cyclopentyloxycarbonylaminoethyl, cyclopenyl 3442 B ethyl ethylaminocarnopropylamyloxycarbonylaminopropyl, cyclopentyloxycarbonylaminobutyl, cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonyl, carbamoylalkyl having 2-5, preferably 2 carbon atoms, preferably carbamoylmethyl, as well as carbamoylethyl, carbamoylpropyl, carbamoylbutyl; alkylaminocarbonylalkyl having 3-9, preferably 3-6 carbon atoms, in addition methylaminocarbonylethyl, ethylaminocarbonylmethyl, n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, n-butylaminocarbonylmethyl, isobutylaminocarbonylmethyl, t-butylaminocarbonylmethyl, tert-butylmethyl, tert-butylmethyl, tert-butylmethyl, bonylpropyl, ethylaminocarbonylbutyl, nocarbonylbutyl, n-butylaminocarbonylbutyl; dialkylaminocarbonylalkyl having 4-11 carbon atoms, preferably 4-8 carbon atoms, in addition dimethylaminocarbonylmethyl, diatylaminocarbonylmethyl, di-n-propylaminocarbonylmethyl, (pyrrolidino-1) carbonylmethyl, (piperidino1) carbonylmethyl are preferred, and, for example, diethylaminocarbonylmethyl, piperidino-1) carbonyl ethyl, diethylaminocarbonylpropyl, diethylaminocarbonyl butyl; cycloalkylaminocarbonylalkyl having 5-12, preferably 7-8 carbon atoms, more preferably cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl, and also, for example, cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl, cyclohexylaminocarbonylmethyl, cyclohexylaminocarbonylmethyl; alkylaminocarbonylalkoxy having from 3 to 10, preferably 3 to 5 carbon atoms, but preferably, and the methylethylamino carbonylmethoxy group is also, for example, methylaminocarbomethylaminocarbonylpropoxy; a dialkylLT 3442 B aminocarbonylalkoxy group having 4-10, preferably 4-7 carbon atoms, such as dimethylaminocarbonylmethoxy, diethylaminocarbonylethoxy, (piperidinyl-1) carbonylmethoxy; cycloalkylaminocarbonylalkoxy having 5-11, preferably 7 or 8 carbon atoms such as cyclopentylaminocarbonylmethoxy, cyclohexylaminocarbonylmethoxy.

The radical Z may also be an aromatic bicyclic group such as 1- or 2- naphthyl; 1-, 2-, 3-, 4-, 5-,

6-indenyl wherein one or more of the bonds may be hydrogenated, and the above groups may be unsubstituted or optionally substituted with one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups in which the alkyls are C 1 -C 4 groups.

The radical Z can also be pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzobenzothiazolyl, benzisothiazolyl, benzobenzoxazolyl, benzisoxazolyl, quinolyl, thienyl, quinolyl, quinolyl, thiazolyl, thienyl, chromenyl, pyrazolyl, pyrazinyl, isobenzofuranyl, pyrrolyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinozolinyl, acridinyl, isothiazolyl, isochromanyl, chromanyl, or one or more of the hydroxy groups which may be attached, the listed groups may be absent or optionally substituted with several substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups wherein the alkyls are C 1 -C 2.

The group Z is preferably a phenyl group optionally substituted with halogens such as chlorine or thienyl;

group T is preferably -C = O, and group R is preferably methyl.

One preferred group of compounds of the invention are compounds of formula (I) wherein Ar ', R, T, Z and m are as defined above and Y is a group of formula

X

II

Ar- (CH ₂ ) _x -C wherein Ar and x are as defined above and X is hydroxy or acetoxy

-NH-C-Alk,

II

And wherein Alk is C ₁ -C ₆ alkyl, and salts thereof with organic or mineral acids.

The group Ar 'is preferably a 3,4-dichlorophenyl group.

Particularly good is the racemic compound of N-methyl-N- [4- (4-phenyl-4-acetylaminopiperidine) -2- (3,4-dichlorophenyl) -butyl] -benzamide, or one of its enantiomers (+) or (-). and its salts with mineral or organic acids.

In another aspect, the invention relates to a process for the preparation of compounds of formula (I) and salts thereof, wherein: a) a free amine of formula:

H R

E- (CH ₂ ) _m -C-CH ₂ -NH (II),

Ar 'wherein m, Ar' and R are as defined above and E is a protecting group such as 2-tetrahydropyranyloxy or

Λ Λ

Y is a group wherein Y is denoted above, given that when Y is a group

Ar- (CH ₂ ) _x -C

X wherein X is hydroxyl may be protected;

running

-or a functional acid of the formula:

HO-CO-Z (III), a derivative wherein Z is as defined above to give a compound of formula (I) wherein T is -CO-,

-or or thio cyanate of the formula:

W = C = N-Z (III ') wherein W and Z are as defined above to give a compound of formula (I) wherein T is a -C (W) -NH- group to give a compound of formula:

H R I I

E- (CH ₂ ) _m -C-CH ₂ -NTZ (IV)

Ar '

-b) after E is a tetrahydropyranyloxy group, the acid is cleaved by tetrahydropyranyl,

-c) the N-substituted alkanolamine thus obtained having the formula:

H R t

HO - (CIU) - C - CH _O - N - T - ZZ m | Z

Does' work with methanesulfonyl chloride,

-d) the resulting mesylate having the formula:

H R

I I

CH ₃ SO ₂ -O- (CH ₂ ) _m -C-CH ₂ -NTZ I

Does' act on a secondary amine of the formula:

(VI)

(VII) wherein Y is as defined above; and

-e) removing the X-labeled hydroxyl protecting group, converting the resulting product, if necessary, into one of its salts.

The functional derivative of (III) acid is the acid itself, activated in a suitable manner, for example in the presence of cyclohexylcarbodiimide or benzotriazolyl-N-oxitris (dimethylamino) phosphonium hexafluorophosphate (BOF), or one of the functional derivatives which react with amines such as anhydride, mixed anhydride , chloro anhydride or activated ester. When Z is an OM group, the acid is carbonic acid and the functional derivative used is a monochloride, namely formate Cl-CO-OH.

When a compound of formula (II) wherein E is a group is used as a starting material, the process of the present invention can be illustrated and illustrated in detail in Scheme I:

I Scheme / ~~ Λ

N - (CH) - C - CH - - NU / 4: m | 2

Is '(11')

Cl - c - Z

II

(IITa)

N - (CH) - C - CH. z m i

Ar '(I, T = CO) (III') (CH_) - C - CH2 m to z

Ar '

C

II w

(I .T =

The reactive functional derivative of the formula (III) above in the formula (IIIa) above is an acid chloro anhydride. However, another functional derivative or free acid (III) may be used, the compound (II ') being treated with BOF (benzotriazolyl-N-oxitris (dimethylamino) phosphonium hexafluorophosphate) followed by addition of acid (III) at room temperature in the presence of an organic base such as triethylamine. in a solvent such as dichloromethane or dimethylformamide, the resulting compound (I) is then isolated and purified by conventional means such as chromatography or recrystallization from a.

The compounds of formula (I) may be reacted with W = C = NZ (III ') of compound (II') and iodo (thio) cyanate in an anhydrous inert solvent such as benzene at room temperature overnight followed by treatment of the reaction mixture. usual way.

Using the compound of formula (II) wherein E is a tetrahydropyranyloxy group as the parent compound, the process of the present invention can be illustrated and illustrated in Scheme 2.

Reactions of the compound (II '') with (IIa) and (III ') reactants are carried out according to Scheme I, adapted to the (IIa) acid anhydride, which can be replaced by another functional derivative or by a free acid such as activated BOF.

Schematic

V, ύ

Cj (CH.,) M

θ— ⁰ - ^(CI! 2> m - ^C Ar '

HO- (CH ") - C - CH _O Ar '

Ar '

ΓΗ

-3 SO _n Cl i ₃ so ₂ - o

CH.

N - T - Z (VI) (VII)

In order to obtain the free hydroxyl compound (V), the protecting group of the resulting intermediate (IV) is removed by gentle hydrolysis. The tetrahydropyranyloxy group of the compound (II '') can be directly removed by hydrolysis. In this way, the hydroxyl compound (II '' ') is obtained which is reacted directly with the reagents (IIIa) and (III') to give the compound (V) according to the procedure depicted in Scheme 2.

Compound (V) yields mesylate (VI) which is replaced by secondary amine (VII) to give compounds of formula (I).

The products of formula (I) thus obtained are isolated by classical methods in the form of the free base or of the salt.

When the compound of formula (I) is obtained in the form of the free base, the salt is formed by treatment of the selected acid in an organic solvent. When the free base is dissolved, for example in an alcohol such as isopropanol, the selected acid is dissolved in the same solvent to give the corresponding salt, which is isolated by classical methods. Chlorohydrate, bromohydrate, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methyl sulfonate, axalate, maleate, fumarate, 2-naphthalenesulfonate are thus obtained.

The compounds of formula (I) may be isolated in the form of their salts, for example, chlorohydrate or oxalate; in this case, if necessary, the free base can be obtained by neutralizing the desired salt with a mineral or organic alkali such as sodium hydroxide or triethylamine or an alkali metal carbonate such as sodium or potassium carbonate or bicarbonate.

The cleavage of racemic mixtures and, where appropriate, mixtures of diastereoisomers into enantiomers or diastereoisomers forms part of the invention.

One of the 2 compounds of Scheme (II '') and (II '' ') can be cleaved. No racemic compounds can be obtained according to the procedure described in this scheme. Preferably, the compound of formula (II '') wherein R is as above is preferably resolved, preferably when hydrogen is present. It is cleaved by methods known in the art to form a salt with an optically active acid such as D - (+) or D - (-) tartaric acid, cleavage of the diastereoisomeric salts and hydrolysis. A preferred compound of formula (II '' ') is that wherein R is hydrogen and Ar' is 2,4- or 3,4-dichlorophenyl.

The starting compounds of formula (II) are obtained by reduction of nitriles of the formula:

H

E- (CH ₂ ) _m -C-CN (VIII) i

Ar 'in which m, E and Ar' are noted above.

In the preparation of compounds of formula (II) wherein R is hydrogen, the starting nitriles (III) are hydrogenated in an alcohol such as ethanol in the presence of a catalyst such as Renee nickel, and the free primary amine can be isolated by classical methods.

In order to obtain (II) compounds of the formula wherein R is methyl, the free amine from the hydrogenation of the nitrile (VIII) as described above, is reacted with chloroformate, for example chloroformate of the formula Cl-CO-OR ^ wherein R _d group is as defined above receives carbamates, of the formula:

H

E- (CH ₂ ) _m -C-CH ₂ -NH-C-OR ₁

II

Ar 'are subsequently reduced in known ways, for example by treatment with a reducing agent such as a metal hydride such as sodium aluminum hydride, lithium aluminum hydride or boron hydride such as borane dimethyl sulfide. The reduction is carried out in a solvent such as ether, toluene or tetrahydrofuran at room temperature to 60 ° C. The resulting amine has the formula:

H R

I I

E- (CH ₂ ) _m -C-CH ₂ -NH (II, R = CH ₃ ),

I

Ar 'is isolated by conventional methods.

To obtain compound (IV) wherein R is other than H, a compound of formula:

H R

E- (CH ₂ ) _m -C-CH ₂ -NTZ (IV, R = H),

Ar 'wherein M, E, Ar', T and Z are as defined above, is reacted with an alkyl halide in the presence of a strong alkali such as a metal hydride such as sodium hydride in an inert solvent such as tetrahydrofuran heated to a temperature in the phlegm.

Nitriles of formula (VIII) are obtained from nitriles of formula:

Ar'-CH ₂ -CN (XI) which are alkylated with a compound of the formula:

E- (CH ₂ ) _m -G (XII) wherein M and E are as defined above and G is a halogen atom such as bromine or a protected hydroxyl group, affords compounds of (VIII).

Synthesis of nitriles (VIII), wherein E is tetrahydropyranyloxy, is carried out from the tetrahydropyranyloxy (THP-O-) obtained by reaction of an alkanol of formula Br- (CH ₂ ) m -OH where m is as above with a dihydropyran to give a compound of the formula:

Br- (CH ₂ ) _m -0

(XII, E = THP-O ~, G = Br) which is reacted in the presence of an alkali metal hydride with an acetonitrile derivative (XI) to form an intermediate

Synthesis of (VIII, E = THP-O-) Nitriles of Formula (VIII) wherein E is

The group Y N wherein Y is as defined above is carried out by known methods to a chlorine containing derivative of the formula:.

Y N- (CH ₂ ) _m -Cl 1 - (XIII), by attaching a derivative of the formula:

H-C-CN (XIV),

Ar 'in the presence of sodium amide in a solvent such as toluene at 30-80 ° C.

The chlorine-containing derivative (XIII) is obtained by reacting a hydroxylic derivative of a chlorinating reagent such as thionyl chloride with the formula:

Y N- (CH ₂ ) _m -OH (XV), which is obtained from an amino of formula (VII) in which, if X = OH, the hydroxyl group is protected by a selected O-protecting group in a conventional manner

Y

v / (VII), and the amine treated with ethylene oxide for m = 2 and 3 with halopropanol for m = 3.

The compounds of the invention have been investigated biochemically and pharmacologically. The antagonistic properties of the binding to NK ₂ receptors have been elucidated in tests on rat duodenal mucosa (Z. Bergstom et al. Mol. Pharmacol. 1987, 32, 764-771).

Experiments were also performed on rabbit pulmonary artery without endothelium containing NK ₂ receptors whose activation causes muscle contraction. Tests on different isolated organs were performed according to D. Regoli et al. , Trends Pharmacol. Sci, 1988, 9, 290-295 and Pharmacology, 1989, 38, 1-15.

Guinea pig bronchospasm induced by NK ₂ antagonist was tested according to H. Konzett et al., Arch. Exp. Path. Pharm., 1940, 195, 71-4.

The compounds of the invention remove [[2 L] histidyl] -neurokinin A from its receptor with K; 3 - 0.50 nM yesterday.

The pA ₂ of the same compounds in the rabbit pulmonary artery was 10.4-9.

Intravenous administration of the same compounds at a dose of 200 µg / kg and testing in guinea-pig bronchospasm showed neurokinin A antagonistic activity [NIe ¹⁰ ].

Given the antagonistic properties of the compounds of the invention to rteurokinin A, they may be useful in any pathology dependent on neurokinin A, namely, neurogenic airway inflammation, such as asthma or bronchial obstruction.

The compounds of the invention are of low toxicity; their low toxicity is well adapted to their use in the manufacture of a medicament for use in mammals. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered.

Generally, the compounds of the present invention are administered in dosage units. These dosage units are formulated into pharmaceutical compositions in which the active ingredient is mixed with pharmaceutical excipients.

Thus, in another aspect, the present invention relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I) or one of its pharmaceutically acceptable salts.

The pharmaceutical compositions of the present invention, wherein the active ingredient is in admixture with classical carriers for animals and humans, may be administered in a single oral, sublingual, subcutaneous, intramuscular, intravenous, transcutaneous, topical and rectal administration. Relevant single administration forms are oral administration forms such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, sublingual or oral administration, subcutaneous, intramuscular, intravenous, intranasal or subcutaneous administration, rectal administration. enteric formulations, and, for example, aerosol action of, for example, the nasal, throat or bronchial mucosa, containing the active component in solution or as a dry powder.

For the desired effect, the dosage of the active component may vary between 0.25-1000 mg / day, preferably 2-250 mg / day.

Each single dose in combination with a pharmaceutical carrier may contain from 0.25 to 250 mg, preferably from 1 to 125 mg, of the active component. This single dose may be administered 1 to 4 times daily.

In the manufacture of a solid tablet, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia and the like. The tablets may be coated with sucrose or other appropriate materials, or may be treated to provide extended or sustained release, and to provide a sustained release of the active ingredient.

Gelatin capsules are prepared by mixing the active ingredients with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

In syrup or elixir, the active component may be present in combination with a better non-caloric sweetener, an antiseptic such as methylparaben and propylparaben, and a flavoring agent and a suitable dye.

In water dispersible powders and granules, the active ingredient may be in admixture with a dispersing agent or wetting agent such as polyvinylpyrrolidone as well as a sweetening agent and a flavoring agent.

Suppositories that are made with a binder that melts at the temperature of the rectum, such as oil, cocoa or polyethylene glycols, are used for rectal administration.

For parenteral administration into the nasal cavity or under the eyelid, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersants and / or wetting agents such as propylene glycol or butylene glycol are used.

For inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane or any other biocompatible propellant is used.

Optionally, the active component can be formulated in microcapsules with one or more carriers or additives.

The above compositions may also contain other active compounds such as bronchodilators, antitussives or antihistamines.

The following examples further illustrate the invention.

The following abbreviations are used in the examples:

- Ac for acetyl,

- AcO is an acetoxy group,

- accompanying temp. - melting point in degrees Celsius.

NMR spectra recorded on deuterated dimethylsulfoxide at 200 MHz:

- m - array,

- s - singlet,

- is - extended singlet,

- t is the triplet,

- M - Multiplet.

An example

N- [2- (3,4-Dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -2,4-dichlorobenzonyl chlorohydrate.

a) α- (2-Tetrahydropyranyloxyethyl) -3,4-dichlorobenzoacetonitrile.

16.5 g of sodium hydride are suspended in 200 ml of dry tetrahydrofuran in 80% oil. 100 g of a solution of 3,4-dichlorobenzolacetonitrile in 500 ml of tetrahydrofuran are added dropwise over 30 minutes at 20 [deg.] C., followed by stirring at room temperature for 2 hours. The mixture is cooled to -20 ° C and 118 g of l-bromo-2-tetrahydropyranyloxyethane in 100 ml of tetrahydrofuran are added, the mixture is cooled to room temperature and 50 g of magnesium chloride in 3 liters of water are added after 2 hours. The mixture was extracted with 3 liters of ether, washed with saturated sodium chloride solution, separated, dried over MgSO ₄ and concentrated in vacuo.

The residue is chromatographed on silica gel eluting with dichloromethane followed by dichloromethane: ethyl acetate 95: 5.

b) β- (2-Tetrahydropyranyloxyethyl) -3,4-dichlorobenzolethanamine.

118 g of the nitrile obtained above are dissolved in 700 ml of absolute ethanol. 300 ml of concentrated ammonia are added, followed by the addition of Renee nickel (10% of the initial nitrile content) in the nitrogen stream. The mixture is then hydrogenated under a hydrogen atmosphere at room temperature under normal pressure.

Reacts with 16 liters of hydrogen in 4 hours. The catalyst is separated by filtration through celite, the filtrate is concentrated in vacuo and the residue is dissolved in a saturated sodium chloride solution. The mixture was then extracted with ether and dried over MgSO ₄ to give 112 g of a liquid oil.

c) N- [2- (3,4-Dichlorophenyl-4- (2-tetrahydropyranyloxy) butyl] -2,4-dichlorobenzamide.

of the amine obtained above is dissolved in 800 ml of dichloromethane. The solution was cooled to 0 ° C and 38.4 ml of triethylamine was added followed by 55 g of 2,4-dichlorobenzoic acid chloro anhydride. The reaction mixture was then stirred at room temperature for 1 hour and washed with water. The organic phase is decanted off, dried over MgSO ₄ and concentrated in vacuo to give 120 g of a liquid oil.

d) N- [2- (3,4-Dichlorophenyl) -4-hydroxybutyl] -2,4-dichlorobenzamide.

120 g of the product obtained above are dissolved in 1 liter of methanol in the presence of 12 g of para-toluenesulphuric acid. The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The residue is dissolved in dichloromethane and washed with 10% sodium carbonate solution. The organic phase was separated and dried over MgSO ₄ to give 106 g of a liquid oil.

e) N- [4-Methanesulfonyloxy-2- (3,4-dichlorophenyl) butyl] 2,4-dichlorobenzamide.

106 g of the alcohol obtained above are dissolved in 1 l of dichloromethane, after which the solution is cooled to 0 ° C, 44 ml of triethylamine and 24.2 ml of methanesulfonyl chloride are added. The reaction mixture was stirred at 0 ° C for 45 minutes, washed 3 times with ice-water, decanted, dried over MgSO _4, and concentrated in vacuo.

The residue is recrystallized from isopropyl ether.

m = 95 g of melt. temp = 93 ^ 0

f) A mixture of 1 g of the product obtained above, 0.8 g of 4-hydroxy-4-phenylpiperidine and 1 ml of dimethylformamide is heated at 60 ° C for 2 hours. The mixture is cooled, diluted with ether, washed with sodium hydroxide solution, then with water. Dry MgSO _4, the solvents evaporated and the residue chromatographed on 40 g of silica eluting with dichloromethane followed by dichloromethane / methanol 90:10. The pure fractions were concentrated to give 0.9 g of product, then HCl in ether solution was added until pH = 1 and the product was converted to the hydrochloride in dichloromethane. The residue is filtered off and then solidified in ether.

m = 0.95 g

NMR.

8.75 (t, 1H); 7.7-7 (m, 11H); 5.4 (s, 1H); 3.6-2.6 (m, 9H); 2, 6-1, 6 (m, 6H).

An example

N- [2- (3,4-Dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -acetamide chlorohydrate.

Cl n = 2; R = H; T-Z = -C-CH 3 H 0

N- [2- (3,4-Dichlorophenyl) -4-mesyloxybutyl] -acetamide is prepared according to the procedure described in Example 1 (a), (b), (c), (d) and (e), but substituting in step (a) 2 , 4-dichlorobenzoic acid, chloro anhydride with acetyl chloride.

The compound

A mixture of 6.5 g of the product obtained above, 6.8 g of 4-hydroxy-4-phenylpiperidine and 10 ml of dimethylformamide is heated at 60 ° C for 1 hour. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is separated off, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with methanol / dichloromethane 10:90. The pure product fractions were concentrated and the residue was treated with HCl in ether to give 6 g of chlorohydrate.

NMR

7.95 (t, 1H); 7.7-7.0 (m, 8H); 3.6-2.6 (m, 9H); 2.6-1.3 (m, 9H).

An example

N- [ethyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -2-thiophenecarboxamide chlorohydrate.

a) N- [ethyl- [4-hydroxy-4-phenylpiperidinyl] -ethyl-3,4-dichlorobenzolethanamine chlorohydrate.

To a suspension of 0.96 g of lithium aluminum hydride in 10 ml of tetrahydrofuran is added 5.5 g of a solution of Compound 2, previously obtained, in 20 ml of tetrahydrofuran, and the reaction mixture is then heated at reflux for 2 hours. The mixture was cooled and hydrolyzed with 4 ml of 4N sodium hydroxide solution, filtered through brine, washed with tetrahydrofuran and evaporated. The salt is formed with a solution of HCl in ether and the hydrochloride is triturated with isopropanol / isopropyl ether; 4.7 g of product are obtained.

b) Compound 3

To a solution of 2.45 g of the product obtained in dichloromethane at 0 ° C is added 2.75 ml of triethylamine, followed by 0.8 g of 2-tenoyl chloride. The reaction mixture is hydrolyzed with 0.1 N sodium hydroxide solution and extracted with dichloromethane, and the product is purified by chromatography over silica H; eluent: methanol / dichloromethane - 2.5: 97.5. The crude product is treated with a solution of HCl in ether to give 1.0 g of chlorohydrate.

NMR

7.75-6.9 (m, 11H); 5.35 (s, 1H); 3.9-2.55 (m, 11H);

2.55-1.5 (m, 6H); 0.95 (t, 3H).

An example

N-Ethyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -4-methoxybenzamide chlorohydrate.

Prepared according to the procedure described in Example 3 b), starting from the compound obtained in a) and

By replacing 2-tenoyl chloride with 4-methoxybenzoic acid by chloro-anhydride.

Lyd. mp = 165 ° C.

An example

N- {4- [4-Hydroxy-4- (2-pyridinylmethyl) -piperidinyl] -2 (3,4-dichlorophenyl) -butyl} -2,4-dichlorobenzamide dichlorohydrate.

a) N- [2- (3,4-Dichlorophenyl) -4- (4,4-ethylenedioxypiperidinyl) butyl] -2,4-dichlorobenzamide.

A mixture of 12.1 g of mesylate obtained in Example 1 e) and 8.6 g of 4,4-ethylenedioxypiperidine is heated at 100 ° C for 15 minutes. The mixture is cooled and washed with water. The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is chromatographed on silica gel; eluent: methane 1is / dichloromethane - 2:98.

The pure fractions were concentrated to give 12.15 g of product.

b) N- [2- (3,4-Dichlorophenyl) -4- (4-oxopiperidinyl) butyl] 2,4-dichlorobenzamide.

The product obtained above is dissolved in 100 ml of acetone, followed by the addition of 100 ml of 6N HCl. After 2 hours, 1 L of water, 1 L of ether are added and the aqueous phase is removed. The aqueous phase is brought to pH = 10 with sodium hydroxide and then extracted with 1 L of ether. The organic phase is dried and evaporated to give 9.7 g of pure product.

c) Compound 5

To 1 g of the product obtained above in 5 ml of tetrahydrofuran at 25 ° C under nitrogen is added

2.15 M solution of 2-picollit in tetrahydrofuran. The solution turns a stable red color (see Synthesis, 43, 1974). The solution is hydrolysed and extracted with ether and the residue is chromatographed on silica gel; eluent: methanol / dichloromethane - 15:85. The pure fractions were evaporated and the residue was treated with HCl in ether to give 400 mg of a white foam.

NMR 8.8-7.15 (m, 11H); 5.3 (broad s, 1H); 4-2.55 (m, 11H); 2.35-1.4 (m, 6H).

example

N- [4- (4-Benzyl-4-hydroxypiperidinyl) -2- (3,4-dichlorophenyl) -butyl] -N'-naphth-1-yl urea chlorohydrate.

a) N- [4- (2-Tetrahydropyranyloxy) -2- (3,4-dichlorophenyl) butyl] -N-naphth-1-yl urea.

To a solution of 7.6 g of naphth-1-yl isocyanate in 50 ml of toluene was added 12 g of - (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzolethanamine in 50 ml of toluene. The reaction mixture was stirred for 10 minutes, methanol (50 mL) was added and concentrated in vacuo.

b) N- [4-Hydroxy-2- (3,4-dichlorophenyl) -butyl] -N'-naphth-yl-urea.

To the solution of the product obtained above was added 2 g of p-toluic acid and the mixture was stirred for 10 min. heated at phlegm temperature. The solution is washed with sodium bicarbonate and concentrated to dryness. The residue was purified by chromatography on silica gel eluting with ethyl acetate. We obtain 13.1 g of a colorless liquid oil.

c) N- [2- (3,4-Dichlorophenyl) -4-mesyloxybutyl-N'-naphth-1-ylcarbamide.

To a solution of 13.1 g of the product obtained above in 100 ml of dichloromethane at 0 ° C is added 5.37 ml of triethylamine, followed by 2.77 ml of mesyl chloride. The solution is washed 3 times with 100 ml of ice-water, then the organic phase is dried and evaporated. The residue is then recrystallized from isopropanol, filtered and washed with isopropyl ether.

m = 8 g

Lyd. mp = 120 ° C

d) Compound 6 A mixture of g of the above compound, 4 g of 4-hydroxy-4-benzylpiperidine and 4 ml of dimethylformamide is heated at 100 ° C for 20 minutes. All this is poured into water and extracted with dichloromethane. The residue is then purified by chromatography on silica gel eluting with methanol / dichloromethane 4:96. The pure compound is treated with a solution of HCl in ether to give 1.0 g of the pure hydrochloride salt.

NMR

8.7 (s, 1H); 8.2-6.8 (m, 16H); 3.5-2.5 (m, 11H); 2.3-1.3 (m, 6H).

The compounds listed in Tables 1, 2 and 3 were synthesized according to the procedure described in Examples 1-5. All of these compounds are chlorohydrates.

Table

Example # With x

NMR spectrum 8.54 (t, 2H) ; 7.7-7 (m, 11H); 4.8 (wide s, 1H); 3, 8 -2.55 (m, 11H); 2, 4-1.25 (m, 6H). 8, 6 (t, 1H); 7.8-7.2 (m, 10H); 4.9 (s, 1H); 3.7-2.6 (m, 11H); 2.2- 1.4 (m, 6H). 8.55 (t, 1H); 7.8-7.2 (m, 10H); 5.70 (s, 1H); 3.6-2.6 (m, 9H); 2, 6- 1.6 (m, 6H). 8.7 (d, 2H) ; 8.45 (t, 1H); 7.85 (d, 2H) ; 7.6-7 (M, 6H); 5, 3 (wide s, 1H); 4, 0-2, 3

(m, 11H); 2.3-0.6 (m, 6H).

Example No.

r \ 7

NMR spectrum

8.8 (m, 3H); 7.2-7.8 6H); 6, 8 (t, 1H); 4.7 2H); 2.6- 3.8 (m, 11H); (M, 2H).

Table

Example No. R ₇ R \ x NMR spectrum

H, H 7.8-6.8 (m, 11H); 4.75 (s, 1H);

4.0-2.5 (m, 14H); 2.3-1.3 (m, 6H).

4-OCH ₃ H 0 6.9-7.4 (m, 5H); 3.9-4.9 (m,

1H); 0.6-2.6 (m, 11H).

An example

N-Methyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -benzamide chlorohydrate.

a) N- [2- (3,4-Dichlorophenyl) -4- (2-tetrahydropyranyloxy) butyl] ethylcarbamate.

To a solution of 80 g of amine obtained in Example 1 (b) and 39 ml of triethylamine in 800 ml of dichloromethane solution is cooled to -20 ° C, 26.4 ml of ethyl chloroformate. After 30 minutes, the reaction mixture was washed twice with water, then with pH = 2 buffer. The organic phase was separated and dried over MgSO ₄ , then concentrated in vacuo to give 98 g of a liquid oil.

b) N-Methyl- (2-tetrahydropyranyloxy) -3-ethyl-3,4-dichlorobenzenethanamine.

Introduce, under a stream of nitrogen, 20 g of a suspension of lithium aluminum hydride in 200 ml of tetrahydrofuran into a 2 liter flask. A solution of 98 g of the previously obtained carbamate in 800 ml of tetrahydrofuran is then added at 20 ° C.

The reaction mixture is carefully heated to reflux temperature and refluxed for 18 hours.

The reaction mixture was cooled to 0 ° C and hydrolysed with 35 ml of water followed by 17 ml of a concentrated sodium hydroxide solution and 150 ml of water. The solids are filtered off and the residue is concentrated to give 80.5 liquid oil.

c) N-Methyl-p-hydroxyethyl-3,4-dichlorobenzenetanamine chlorohydrate.

To 50 g of the above protected amino alcohol dissolved in 500 ml of ethanol are added 20 ml of concentrated HCl. After 2 hours and 30 minutes, the mixture was concentrated in vacuo, the residue was dissolved in 200 mL of acetonitrile, then 350 mL of ether was added slowly. The reaction mixture is stirred for 1 hour and the resulting crystals are filtered off and rinsed with ether.

m = 32.8 g

Lyd. mp = 152 ° C

d) N-Methyl-N- [2-3, 4-dichlorophenyl) -4-hydroxybutyl] tert-butyl carbonate.

To 32.8 g of the previously obtained chlorohydrate dissolved in 300 ml of dioxane and 30 ml of water are added 20 ml of triethylamine. 27 g of BOC ₂ O (di-tert-butyl dicarbonate) are then added and the mixture is stirred at room temperature for 15 minutes. The reaction mixture was heated at 60 ° C for 30 minutes. It is then concentrated to dryness and extracted with ether, washed with water, then with pH = 2 buffer and again with water. The resulting product was dried over MgSO ₄ , concentrated in vacuo to give 40 g of a liquid oil.

e) N-Methyl-N- [2- (3,4-dichlorophenyl) -4-methanesulfonyloxybutyl] tert-butyl carbamate.

To 40 g of the previously obtained alcohol dissolved in 400 ml of dichloromethane are added 17 ml of triethylamine. The reaction mixture was cooled to 0 ° C and treated with 9.3 ml of mesyl chloride. After 15 minutes, it is washed twice with water, dried over MgSO ₄ and concentrated to dryness to give 40 g of a liquid oil.

f) N-Methyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) butyl] tert-butyl carbamate chlorohydrate.

A mixture of 1 g of the product obtained above and 18 g of 4-hydroxy-4-phenylpiperidine in 40 ml of dimethylformamide is heated at 70 ° C for 1 hour and 30 minutes. The solution is then poured into 300 ml of ice-water, the precipitate is filtered off and washed with water. The solid is extracted with ether, dried over MgSO ₄ and evaporated. The crude product is purified by chromatography on silica gel eluting with a methanol mixture (up to 5%) in dichloromethane. 22 g of pure product are obtained.

g) N-Methyl- [4-hydroxy-4-phenylpiperidinyl] - p -ethyl-3,4-dichlorobenzenemethanamine dichlorohydrate.

To 22 g of the resulting derivative, add 100 ml of concentrated HCl and 20 ml of water to a solution of 100 ml of methanol. The reaction is carried out for 1 hour, after which the reaction mixture is concentrated in vacuo. A foamy material is obtained which is powdered in ether and dried.

m = 2 0.7 g

h) Compound 14

To a solution of 2 g of the product obtained above and 2 ml of triethylamine in 20 ml of dichloromethane are added nitrogen atm. and - 0.51 ml of benzoyl chloride are added to the slurry at 78 ° C at 3442 B and stirred for 10 minutes. The reaction mixture was hydrolyzed with 0.1 N sodium hydroxide solution, extracted with dichloromethane, and the resulting product was purified by chromatography eluting with a methanol / dichloromethane mixture (10:90).

1.37 g of pure product are obtained, followed by addition of a solution of RCl in ether to pH = 1 to give the hydrochloride. 1.40 g of foam are obtained.

NMR

7.7-6.6 (m, 13H); 5.35 (s, 1H); 3.8-2.5 (m, 12H); 2.51.5 (m, 6H).

An example

N-Methyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -N-benzylurea chlorohydrate.

To 2 g of the product obtained according to the procedure of 14 g) and 1.2 ml of triethylamine in 20 ml of dichloromethane solution in nitrogen atm. and 0.60 ml of benzyl isocyanate are added at 0 [deg.] C. and the mixture is stirred for 1 hour. The mixture is then washed with 0.1N sodium hydroxide solution and the product is purified by chromatography on silica gel; eluent methanol / dichloromethane 6:94. The HCl solution in ether was then added to give 34 g of chlorohydrate.

NMR

7.7-6.9 (m, 13H); 6.75 (t, 1H); 5.4 (broad s, 1H); 4.1 (m. 2H); 3.7-2.5 (m, 12H); 2.5-1.4 (m, 6H).

An example

N-Methyl-N- [2- (3,4-dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -ethylcarbamate chlorohydrate.

HO

To a solution of 2 g of the product obtained according to the procedure described in step 14 g) and 2 ml of triethylamine in 20 ml of dichloromethane at -78 ° C under nitrogen atm. 0.44 ml of ethyl chloroformate is added. The reaction is carried out for 5 minutes, after which the mixture is hydrolyzed with 0.1 N sodium hydroxide solution and extracted with dichloromethane. The product is then purified by chromatography on silica gel; eluent methanol / dichloromethane - 8:92. The pure fractions were concentrated in vacuo, added with ethereal HCl solution to give 1.1 g of white effervescent chlorohydrate.

NMR

7.7-7.1 (m, 8H); 5.45 (s, 1H); 4.1-2.6 (m, 14H); 2.61, 6 (m, 6H); 1.1 (t, 3H).

and Tables 5 and 5 are synthesized according to the procedure described in Examples 14-16. These compounds are chlorohydrates.

Table 4

Example # M R _y m NMR spectrum or melt. temp. ° C 1 2 3 4 5

-CH ₃ H 2

-CH ₂ -CH ₂ -CH ₃ H

7.8-7.1 (m, 8H); 3.7- 2.65 (m, 12H); 2.65-1.6 (m, 9H). 7.7-7.0 (m, 8H); 3.7- 2.55 (m, 12H); 2.55-0.5 (m, 13H) • 7.8-7.1 (m, 8H); 5.5 (wide s, 1H); 3.9- 2.65 (m, 13H); 2.65-0.5 (m, 12H) • 7.7-6, 8 (m, 13H); 5.35 (c, 1H); 3.7-2.5 (m, 14H); 2.5-1.5 (m, 6H). 7, 8-6, 9 (m, 12H); 5, 6 (s, 1H); 3.9-2.6 (m, 12H); 2.6-1.6 (m, 6H).

203

198-200

180 (decomposition)

7.9-7.0 (m, 10H); 5.40 (m, 1H); 3.9-2.6 (m, 12H); 2.6-1.6 (m, 9H). 7, 9-6.5 (m, 11H); 5, 45 (s, 1H); 3.9-2.6 (m, 12H); 2.6-1.6 (m, 6H). 7, 8-6, 4 (m, 11H); 5, 3 (s, 1H); 3, 9-2, 6 (m, 12H); 2, 4-1.6 (m, 6H). 7.6-7.2 (m, 8H); 6, 8 (s, 1H) ; 6.4 (s, 1H); 6.05 (s, 1H); 5.4 (s, , 1H); 3.7 (m, , 2H); 3, 4-2, 6 (m, 7H) ; 3.0 (s, 3H); 2.4 (m, 2H); 2.1 (m, 2H); 1.7 (m, 2H).

Table

7.7-7.0 (m, 11H); 6.85 (d,

J = 8 Hz, 1H); 6.75 (d, J = 8

Hz, 1H); 5.35 (s, 1H); 3.82,6 (m, 12H); 2.4 (m. 2H);

2.1 (m, 2H); 1.7 (m, 2H).

An example

N- [2- (3,4-Dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -N-methyl-2-thiophenecarboxamide chlorohydrate.

a) N- [2- (3,4-Dichlorophenyl) -4- (2-tetrahydropyranyloxy) butyl] -2-thiophenecarboxamide.

A mixture of 4.77 g of the amine obtained according to the procedure described in Example 1 b) and 1.7 g of triethylamine in 50 ml of dichloromethane is stirred at room temperature. Then 2.19 g of 2-tenoyl chloride in 20 ml of dichloromethane are added dropwise at room temperature and the reaction mixture is left at room temperature overnight.

The solvent is concentrated in vacuo and the residue is washed with water, extracted with ether, washed with 5% sodium bicarbonate solution, then with a saturated sodium chloride solution; the organic phase is separated off, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is chromatographed on silica gel eluting with methanol / dichloromethane 98: 2. The pure fractions are collected and concentrated in vacuo. The residue is washed with 5% sodium hydroxide solution, extracted with ether and dried. 4,6 g of a colorless liquid oil are obtained.

b) N- [2- (3,4-Dichlorophenyl) -4- (2-tetrahydropyranyloxy) butyl] -N-methyl-2-thiophenecarboxamide.

A mixture of 3.4 g of the amide obtained above and 0.45 g of sodium hydride (55% in 10 ml of tetrahydrofuran) is stirred at room temperature. Thereafter, 1.23 g of iodomethane in 10 ml of tetrahydrofuran are added thereto, the mixture is stirred at room temperature for 1 hour and the reaction mixture is heated for 1 hour. Concentrate the tetrahydrofuran, extract the residue with water, extract with ether, wash again with aqueous sodium chloride solution and concentrate in vacuo.

m = 3.4 g

c) N- [2- (3,4-Dichlorophenyl) -4-hydroxybutyl] -N-methyl-2-thiophenecarboxamide.

3.5 g of the product obtained above are dissolved in 30 ml of methanol in 0.35 g of resin (Amberlyst H-15, Aldrich, dry acid sulpho-resin) and the mixture is heated at phlegm for 1 hour and 30 minutes.

The mixture is filtered through celite, the filtrate is concentrated in vacuo, the residue is washed with hexane then extracted with ether / hexane. 2.6 g of white crystals are obtained.

Lyd. mp = 107-109 ° C

d) N- [2- (3,4-Dichlorophenyl) -4-methanesulfonyloxybutyl] -N-methyl-2-thiophenecarboxamide.

of the previously obtained alcohol and 0.65 g of triethylamine in 30 ml of dichloromethane are stirred at room temperature. A solution of 0.69 g of mesyl chloride in 10 ml of dichloromethane is then added dropwise. The mixture was then heated at phlegm temperature for 30 minutes. The dichloromethane is evaporated in vacuo, the residue is taken up in water, extracted with ethyl acetate, washed with 5% sodium bicarbonate solution, then with saturated sodium chloride solution, dried over Na ₂ SO ₄ and the solvent is evaporated.

m = 1.2 g

e) 33 g of compound obtained in the previous solution, 1 g of 4-hydroxy-4-phenylpiperidine and 2 ml of dimethylformamide was stirred for 2 hours at 6O ^J C.

The reaction mixture was cooled, diluted with ether, washed with water and then diluted with sodium hydroxide solution. MgSO ₄ was dried and the solvents evaporated. The residue is chromatographed on silica gel; Elution with chloromethane / dichloromethane / 2.5% methanol gave 0.7 g of product which was dissolved in dichloroethane, added HCl solution in ether to pH = 1 and concentrated in vacuo. The resulting chlorohydrate is solidified with ether.

m = 0.74 g

NMR

7.8-6.8 (m, 11H); 5.3 (s, 1H); 3.8-2.5 (m, 12H); 2.51.4 (m, 6H).

The examples in the table are obtained according to the method described in Example 33. All of these compounds are chlorohydrates.

An example

N-Methyl-N- {2- (3,4-dichlorophenyl) -4- [4-hydroxy-4- (4-hydroxyphenyl) -piperidinyl] -butyl} -2-thiophenecarboxamide chlorohydrate.

a) Preparation of the amine: 4-hydroxy-4- (4-hydroxyphenyl) -piperidine.

Stage

- (Benzyloxy) bromobenzene.

A mixture of 32.6 g of 4-bromophenol, 34.2 g of benzyl bromide and 42 g of potassium carbonate in 150 ml of dimethylformamide was stirred at 40 ° for 2 hours.

The solution is concentrated in vacuo, the residue is taken up in water, then extracted with ether, washed with water, decanted, dried over MgSO ₄ and concentrated in vacuo.

The residue is recrystallized from isopropanol.

m = 30 0 g

Lyd. mp = 61 ° C.

Stage l-benzyl-4- (4-benzyloxyphenyl) -4-hydroxypiperidine g of the product obtained previously is dissolved in 100 ml of tetrahydrofuran and 60 ^u C was added 1.2 g of magnesium in 20 ml of tetrahydrofuran. The temperature of the reaction mixture was maintained at 60 ° C for 2 hours, followed by stirring

The 4-benzylpipe10 is cooled to -10 C. The solution of the ridine is added dropwise and the mixture is allowed to warm to room temperature. The mixture was poured into a saturated solution of amino chloride, extracted with ether, washed with water, decanted, dried over MgSO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel; eluent: dichloromethane / methanol 97.5: 2.5. The pure fractions were concentrated to give 9 g of product.

Lyd. temp = 104-107 ^v C.

stage

4-Hydroxy-4- (4-hydroxyphenyl) -piperidine.

g of the product obtained above, dissolved in 200 ml of ethanol at room temperature and hydrogenated at atmospheric pressure, with 10% Pd / C. After the theoretical volume of hydrogen has been reacted, the catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is extracted with ether and the resulting crystals are filtered off.

m = 1.1 g

Lyd. temp. = 232-235 ° C.

b) Compound 34

2.1 g of the product of 33 d) The procedure described in Example, 1 g of the 3 phases of a amine and 1.1 g of triethylamine in 5 ml of dimethylformamide and 2 hours at 80 C ^u. The mixture was concentrated in vacuo and the residue was acidified with a retractable water and 6 N HCl to pH 3 and extracted with ethyl acetate and decanted, and dried over MgSO ₄ and concentrated in vacuo.

The residue is taken up in acetone and concentrated with ether.

m = 0.7 g

NMR

9.3 (s, 1H); 6.6-8 (m, 10H); 5.2 (s, 1H); 2.6-4 (m, 12H); 1.6-2.4 (m, 6H).

no. \ y

Ό · HO Δ 7.8-6.8 (m, 10H); 5.5 (s, 1H); V / "4.0-2.6 (m, 12H); 2.6-1.5 (m, 6H). • n HO _ Λ 8-7 (m, 10H); 5.8 (s, 1H); << 4-2.7 (m, 12H); 2.7-1.7 (m, 6H). οΛ HO \ / 7.85 (s, · 1H); 7.75-7.2 (m, -λ , ^N = 7H); 7.05 (s, 1H); 5, 8 z v - (s, 1H); 3.8-2.6 (m, 12H); Ct'3 2, 6-1.6 (m, 6H).

6.8-7.8 (m, 6H); 2.6-4 (m, 17H); 0.8-2.2 (m, 12H).

8.2 (s, 2H); 6.7-7.8 (m, 11H);

2-4 (m, 18H).

6.7-7.8 (m, 10H); 1.8-4 (m, 10H).

7-8 (m, 10H); 6.35 (s, 1H);

2-4.2 (m, 16H).

EXAMPLE

N- [4- (4-Benzyl-4-acetyloxypiperidinyl) -2- (3,4-dichlorophenyl) -butyl] -2,4-dichlorobenzamide chlorohydrate.

n-;

0.4 g of N- [4- (4-benzyl-4-hydroxypiperidinyl) -2- (3,4-dichlorophenyl) -butyl] -2,4-dichlorobenzamide chlorohydrate of Compound 7, prepared according to the procedure of Example 1 and dissolved in 10 0.12 g of acetyl chloride are added in 2 ml of dichloromethane in two equivalents of triethylamine.

The reaction mixture was stirred for 1 hour at room temperature, washed with water, the organic phase was separated, dried over MgSO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel; eluent: dichloromethane followed by dichloromethane / methanol 95: 5. The pure product fractions are concentrated in vacuo, then HCl in ether solution is added to pH = 1 and the ether is concentrated in vacuo.

Chlorohydrate is solidified with ether m = 0.26 g

NMR

8.5 (t, 1H); 7.7-6.98

1.8 (m, 9H).

(m, 11H); 3.6-2.6 (m, 11H); 2.47 In Table 5 methods.

1-4 Examples provided

Table

An example No. R; X NMR spectrum 43 H -O-C-CH, 0 7.9-6.9 (m, 11H); 4.0-2.65 (m, 12H); 2.65-1.8 (m, 9H). 44 4-C1 -O-C-CH, II 0 7.7-6.9 (m, 10H); 3.8-2.5 (m, 12H); 2.5-2.1 (m, 6H); 2.0 (s, 3H). 45 H -CN 7-7.9 (m, 11H); 2-4.1 (m, 18H). 46th H v®, 0 7-7.8 (m, 11H); 1.8-4 (m, 21H). 47 H -C-CCH 3 CH 3 0 7-7.9 (m, 11H); 2-4.3 (m, 20H); 1.15 (T, 3h).

Table

N- (CH _{2) 2} CH 2'CH-

Z2

Example No.

With ¹

NMR spectrum or -RZ _r Z ₂ melts. m.p.

CH-, H

H, 186

H H H 148-152

CH,

144-146

OCH,

OCH,

8.4 (d, J = 8Hz, 1H) 8, Ο- 7.7 (m, 4H); ν, 7- 7.2 (m, 8H); 6, 6 (m, 2H); 5.4 (s, 1H) , 4.1-2.8 (m, 9H) ; 3.8 (s, 3H); 3, 6 (s, 3H); 2, 5- 2.2 (m, 4H); 1.8 (m, 2H).

ch ₃ och ₃

140-145 (decomposition)

H 118

CH ₃ H

7.7-6.7 (m, 15H);

5.4 (m, 1H); 4.0-2.6 (m, 15H);

2.4-1.6 (m, 6H).

Table

Example No.

/ “Λ Y NBMR spectrum or melt. tem , ° C

CH3

7, 8-6, 9 (m, 12H); 3.9-2.7 (m, 12H); 2.7-1.8 (m, 9H).

ooKO

200

7.8-6.8 (m, 13H); 4.6 (m, 1H), r 3.8-1.8 (m, 20H).

u «3

CH2-CH3

NCH2-NH2

7, 8-6, 9 3.8-2.6 2.5-1.9 1.1 (t,

140

163 (m, 13H); (m, 14H); (m, 6H); J = 6Hz, 3H).

CO-CH3

OCH ₃

V /

188-190

134

114-116

Table 128-130

Example No.

Ar- (CH ₂ ) _X n.

v

Z Lyd. temperature, ° C or NMR

ch ₃ -CH ₂ % // \\ 7.7-6, 8 (m, 12H); v 4.7 (s, 1H); C1 3.6-2.4 (m, 16H); 2.2-1.4 (m, 6H). CH, ^CH2A O 7, 7-6, 8 (m, 22H): y 3, 7-2.5 (m, 14H); Cl 2.6-2.0 (m, 6H).

An example

N-Methyl-N- [4- (4-phenyl-4-acetaminopiperidinyl) -2- (3,4-dichlorophenyl)] -benzamide chlorohydrate.

A) Amine preparation:

4-Acetamido-4-phenylpiperidine Chlorohydrate.

a) 4-Acetamido-4-phenyl-1-benzylpiperidine chlorohydrate.

To a suspension of 69 g of 1-benzyl-4-hydroxy-4-phenylpiperidine in 300 ml of acetonitrile is added dropwise 260 ml of 95% sulfuric acid at 25-30 ° C. The reaction mixture is stirred at room temperature for 4 hours, then ice is added gradually and the mixture is neutralized with 30% sodium hydroxide solution.

The precipitate is filtered off, washed with water and dried with acetone.

m = 58 g

Lyd. temp. = 180.6-182 ° C

b) 4-Acetamido-4-phenylpiperidine Chlorohydrate.

58 g of the product obtained above, dissolved in 600 ml of methanol, are made up in ether saturated with HCl to pH = 1. The mixture was hydrogenated at room temperature and atmospheric pressure at 10% Pd / C. After reacting with a theoretical volume of hydrogen, the catalyst is filtered off, the filtrate is concentrated in vacuo and the residue is recrystallized from ethanol.

m = 45 g

Lyd. temp. = 286, 5-288 ° C

B) 71 Preparation of compound

a) N- [4-Methanesulfonyloxy-2- (3,4-dichlorophenyl) -butyl] -N-methyl-benzamide.

This compound is prepared according to Method 1 (e). Lyd. temp. = 100-102 ° C For example described (b) Compound 71 1.4 g of 4-acetamido-4-phenylpiperidine and 1.4 g before it of the resulting mesylate in 3 mL of DMFA for 2 hours heated 80 ° C tem-

in the literature. Ice was added to the mixture and extracted with dichloromethane. The organic phase is separated off and washed with water, then with saturated NaCl solution and dried over MgSO4. The organic phase is concentrated in vacuo and the residue is chromatographed on silica gel; eluent: dichloromethane / methanol - 97: 3.

The pure product fractions were concentrated and the resulting residue was extracted with methanol. Saturated HCl ether is then added to give the chiorhydrate.

m = 0.8 g

NMR: 3H at 2 (s, CH ₃ - C -); 18H 2.10-3.90 (m, N-CH ₃ ,

II

O all CH ₂ , CH - C ₆ H ₅ ); 13H 7.00-7.8 (m, H aromatic);

1H at 8.20 (s, NH - C -).

II

Example (-) - N-Methyl-N- [4- (4-phenyl-4-acetylaminopiperidinyl) -2 (3,4-dichlorophenyl) -butyl] -benzamide chlorohydrate.

Step a- (2-Tetrahydropyranyloxyethyl) -3,4-dichlorobenzolacetonitrile.

Obtained according to the procedure described in Example 1 a).

Step β- (2-Tetrahydropyranyloxyethyl) 3,4-dichlorobenzolethanamine.

Obtained according to the procedure described in Example 1 (b).

stage β-hydroxyethyl-3,4-dichlorobenzolethanamine.

g of the product obtained in Step 2 above is dissolved in 38 ml of methanol.

80 ml of saturated HCl ether solution are added at 20-25 ° C. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated to dryness. The residue was dissolved in 250 ml of water, washed twice with ether, basified with NaOH solution and extracted with dichloromethane. It is then dried over MgSO ₄ , concentrated to dryness over celite, the filtrate concentrated in vacuo, the amino alcohol crystallized and stirred overnight. It is then filtered, washed with isopropyl alcohol and pentane. 30.2 g of product are obtained.

Lyd. temp. = 90-91 ° C.

Step (+) -? - hydroxyethyl-3,4-dichlorobenzolethanamine.

To a boiling solution of 29 g of D - (-) tartaric acid in 800 ml of methanol is added 44.7 g of a solution of the product obtained in Step 3 in 300 ml of methanol.

The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. It is then filtered, washed with ethanol and ether. 34.1 g of tartrate are obtained.

The product was recrystallized from 1.75 g of methanol to give 26.6 g of tartar.

ta]% = -4.2 (c = 1, H ₂ O)

Dissolve the tartrate in 120 ml of water. The mixture was basified with NaOH and concentrated to dryness. The resulting product was dissolved in a small amount of isopropyl ether, pentane added and filtered to give 15.4 g of product.

Lyd. temp. = 79-80 ° C.

[α] ²⁵ d = + 9.4 (c = 1, MeOH) step

For N- [4-hydroxy-2- (3,4-dichlorophenyl) -butyl] -ethyl carbamate: as.

Dissolve g of the product of Step 4 in 200 ml of dichloromethane and add 9.0 ml of triethylamine.

Cool the mixture to 0 ° C and add 6.3 ml of ethyl chloroformate in 30 ml of dichloromethane solution at that temperature. After 15 minutes, rinse with aqueous NaHOC ₃ . Dry dry MgSO ₄ and concentrated to give 20 g of product (liquid oil).

Step (+) - N-Methyl-p-hydroxyethyl-3,4-dichlorobenzolethanamine chlorohydrate.

To a suspension of 5.1 g of lithium aluminum hydride in 60 ml of anhydrous THF is added a solution of 20 g of the product obtained in Step 5 in 150 ml of anhydrous THF. The mixture is heated for 1 hour before the phlegm is formed. It is then hydrolysed with 20 ml of water, the solid is filtered off and the filtrate is concentrated to dryness. The resulting liquid oil was dissolved in 100 ml of acetone. Add ether saturated with HCl to pH = 1, then ether again until cloudy. The mixture is stirred for 1 hour and the precipitated crystals are filtered off, rinsed with a little acetone and then with ether to give 11 g of product.

Lyd. temp. = 12 9 ° C [α] ²⁵ D = + 8.4 (c = 1, MeOH).

Step (-) - N- [4-Hydroxy-2- (3,4-dichlorophenyl) -butyl] -N-methylbenzamine.

To a suspension of 8.1 g of the product obtained in Step 6, 120 ml of dichloromethane are added 8.4 ml of triethylamine. The mixture is cooled to 0 ° C and a solution of 3.4 ml of benzoyl chloride in 35 ml of dichloromethane is added dropwise. After 15 minutes, the mixture is rinsed with vending fluid and then diluted

HCl followed by a solution of NaHCO _{3 in} vernal. It is dried over MgSO ₄ and concentrated to dryness. A solid is obtained which is extracted with ether and filtered.

m = 9.0 g

Lyd. temp. = 129 ° C [α] ²⁵ D = -19 (c = 1, MeOH).

Step (-) - N- [4-Methanesulfonyloxy-2- (3,4-dichlorophenyl) -butyl] -N-methyl-benzamide.

10.5 g of the product obtained according to the procedure described in step 7 and dissolved in 120 ml of dichloromethane are added.

4.8 mL of triethylamine. The mixture is cooled to 0 ° C and 2.7 ml of methanesulfonyl chloride are added dropwise. After 15 minutes, it is washed twice with water and then with a saturated aqueous solution. It is dried over MgSO ₄ and concentrated to dryness to afford a foam.

[α] ²⁵ D = -2.3 (s = 1, CHCl ₃ ).

stage

The compound

Dissolve 22.7 g of 4-phenyl-4-acetylaminopiperidine in 20 ml of water. Add 10 ml of concentrated sodium hydroxide solution. The mixture was extracted twice with dichloromethane and dried over MgSO ₄ . The product obtained in Step 8 is added to the resulting solution. Concentrate the mixture to dryness, add 30 mL of DMFA and heat at 70 ° C for 1 h 30 min. The solution is poured very slowly into a mixture of 30 ml of water and ice. The precipitate is filtered off, extracted several times with water and dried. Purify by chromatography over SiO ₂ , eluting with pure dichloromethane followed by dichloromethane with 10% methanol.

Chlorohydrate: The base is dissolved in acetone. Ether saturated with HCl to pH = 1 is added. The solution is poured into isopropyl ether, filtered and dried.

m = 11 g [α] ²⁵ D = -29.5 (c = 1, MeOH).

NMR: 3H at 1.05 (s, CH ₃ - C - O); 18H 2.00-3.75

II

O (m, N - CH ₃ , all CH ₂ , CH - C ₆ H ₅ ); 13H 6.80-7, 70 (m, H aromatic), 1H at 8.10 (s, NH - C -).

O

Example (+) - N-Methyl-N- [4-phenyl-4-acetylaminopiperidinyl) -2 (3,4-dichlorophenyl) -butyl] -benzamide chlorohydrate.

The (+) enantiomer is prepared according to the procedure described in Example 41 by substituting the (-) enatiomer in step 4 for D - (-) tartaric acid with L - (+) tartaric acid.

[α] ²⁵ D = +30.6 (c = 1, MeOH).

NMR: 3H at 1.85 (s, CH ₃ -C-O); 18H 2.00-3.75 (m, N)

II

O

- CH ₃ , all CH ₂ , CH - C ₆ H ₅ ); 13H 6.80-7.70 (m, H aromatic), 1H at 8.10 (s, NH - C -).

Example (-) - N- [2- (2,4-Dichlorophenyl) -4- (4-hydroxy-4-phenyl-piperidinyl) -butyl] -N-methyl-2-thiophenecarboxamide chlorohydrate.

Obtained according to the procedure described in Example 72.

[α] ²⁵ D = -51.0 (c = 1, MeOH).

Example (+) -N- [2- (2,4-Dichlorophenyl) -4- (4-hydroxy-4-phenylpiperidinyl) -butyl] -N-methyl-2-thiophenecarboxamide chlorohydrate.

Obtained according to the procedure described in Examples 72 and 73.

[α] ²⁵ D = +52.7 (c = 1, MeOH).

For the preparation of the compounds of formula (1), the intermediates are alcohols synthesized according to 1 d)

(c) the methodology described in the example.

Table A shows the different alcohols which are suitable for the preparation of compounds (1).

Table A. Synthesis intermediates

HO-CH2-C1 -M

R

I

Product no.

R NMR spectrum

CH ₃ 6.8-7.8 (m, 8H);

4.5 (se, 1H);

2.6-4 (m, 8H);

1.3-2.1 (m, 2H).

CH ₃ 6.8-7.6 (m, 6H);

3-4.2 (m, 5H);

2.4 (s, 3H);

1.4-2.2 (m, 8H).

CH ₃ 6.8-7.8 (m, 6H);

4.4 (t, 1H);

2.6-4 (m, 8H);

1.4-1.9 (se, 2H).

CH ₃ 1.3 (m, 2H);

2.6-5 (m, 9H);

8.2-6.2 (m, 10H);

5-2.6 (m, 9H);

1.3 (m, 2H).

Claims (12)

DEFINITION OF INVENTION 1. Arylalkylamines having the formula: (CH ₂ ) _m -CH-CH ₂ -NTZ Is' where Y is a Cy - N group in which - Cy is phenyl unsubstituted or mono- or poly-substituted with one of the substituents selected from hydrogen, halogen, hydroxy, C ₁ -C ₄ alkoxy, C ₆ -C ₄ alkyl, trifluoromethyl, all of which are the same or different; A C ₃ -C ₄ cycloalkyl group; a pyrimidinyl group or a pyridyl group; or Y is a group Ar - (CH ₂ ) _X - C wherein X - is phenyl unsubstituted or mono- or poly-substituted with one of the substituents selected from: hydrogen, halogen, hydroxyl, C ₁ -C ₄ alkoxy, trifluoromethyl, C ₁ -C ₄ alkyl, in addition to all of these the substituents are the same or different; a pyridyl group; thienyl group; - x is zero or a unit; - X is hydroxyl, Ο ₇ -Ο ₄ alkoxy; hydroxyalkyl wherein the alkyl residue is a C 1 -C 3 group; C ₃ -C ₄ acyloxy; phenacyloxy; carboxyl; C _r -C _THE carbalkoxy; cyano; aminoalkylene wherein alkylene lieLT 3442 in channel B has a C ₁ -C ₃ group; A group -N- (X _x ) ₂ wherein X _x is independently hydrogen, C _x -C ₄ alkyl; -NH-C-Alk group, II wherein Alk is C _x -C ₆ alkyl; Alk _x -NH-C-Alk 'group, II wherein Alk _x is C ₁ -C ₃ alkylene and Alk 'is C _x -C ₃ alkyl; C _x -C ₄ acyl; A -SX ₂ group wherein X ₂ is hydrogen or a C _x -C ₄ alkyl group; or X, together with the carbon atom to which it is attached and the adjacent carbon atom in the heterocycle, form a double bond; - m is 2 or 3; - Ar 'is phenyl, unsubstituted or mono- or poly- substituted with one substituent selected from: hydrogen, a halogen atom, preferably a chlorine or fluorine atom, trifluoromethyl, C _x -C ₄ alkoxy, C _x -C ₄ alkyl, in all these substituents being the same or different; thienyl; benzothienyl; naphthyl; indolyl; indolyl, N-substituted with C _x -C ₃ alkyl; - R is hydrogen, C _x -C ₄ alkyl; - T is a group selected from O W II II -C- and -C-NH-, wherein W is an oxygen or sulfur atom, and - Z is either hydrogen or M or OM when T is -CII o or M when T is -C-NH; M is a C _x -C ₆ alkyl; phenylalkyl wherein the alkyl is C ₁ -C ₃ group, substituted, if necessary, on the aromatic ring by halogen, Trif luormet yl, alkyl, hydroxy, C _x -C ₄ alkoxy; pyridylalkyl wherein the alkyl moiety contains a C _x -C ₃ group; naphthylalkyl in which the alkyl moiety is C ^ Cu-group, substituted naphthyl ring by halogen, trifluoromethyl, C! -C ₄ alkyl, hydroxy, C _r -C ₄ alkoxy; piridiltioalkilas in which the alkyl moiety is a Ci ^- C ₃ group; styryl; optionally substituted aromatic or heteroaromatic mono-, di- or tricyclic; or one of its salts with mineral or organic acids. 2. A compound according to claim 1 wherein Ar 'is a 3,4-dichlorophenyl group or one of its salts with mineral or organic acids. 3. A compound according to any one of claims 1 or 2 wherein X is hydroxy, acetyloxy or -NH-C-Alk where Alk is II C ^ Cg alkyl or one of its salts with mineral and organic acids. 4. A compound according to claims 1-3, wherein R is methyl or one of its mineral or organic salts. 5. A compound according to claims 1-4, wherein T is -C = O or one of its mineral or organic salts. 6. A compound according to claims 1-5, wherein T is a -C = O group and Z is a thienyl group or one of its mineral or organic salts. 7. A compound according to claims 1-5 wherein T is -C = O and Z is phenyl optionally substituted with halogens such as chlorine or one of its mineral or organic salts. 8. A compound according to any one of claims 1 to 7, which is in the racemic or enantiomeric form of N-methyl- [4- (4-phenyl-4-acetylaminopiperidinyl) -2- (3,4-dichlorophenyl) butyl] -benzamide. (+) or (-) form, or its salts with mineral and organic acids. 9. (-) - N-Methyl-N- [4- (4-phenyl-4-acetylaminopiperidinyl) 2- (3,4-dichlorophenyl) -butyl] -benzamide and its salts with mineral and organic acids. 10. (+) - N-Methyl-N- [4- (4-phenyl-4-acetylaminopiperidine) -2- (3,4-dichlorophenyl) butyl] -benzamide and its salts with mineral and organic acids. Process for the preparation of compounds according to any one of claims 1 to 10, characterized in that (a) the free amine of the formula H R E- (CH ₂ ) _n -C-CH 2 -NH Ar '(II) wherein m, Ar' and R are as defined in claim 1 and E is an O-protecting group such as, for example, 2-tetrahydropyranyloxy or the group wherein Y is as defined in claim 1, provided that when Y is a group Ar- (CH ₂ ) _X -C where X is hydroxy, X is the hydroxyl which may be protected, or an amine of formula: H R HO- (CH ₂ ) _m -C-CH ₂ -NH (II '''), I Ar 'in which m, Ar' and R are as noted above and the amine of formula (II '' ') is optically pure, - a functional acid derivative of the formula HO-CO-Z (III) wherein the Z group is as defined in claim 1 to give a compound of formula (1) wherein T is -CO-, - or cationic (thio) cyanate of the formula W = C = N-Z (III '), wherein W and Z are as defined in claim 1, to give a compound of formula (1) wherein T is -C (W) -NH- to give a compound of formula: H R E- (CH ₂ ) _m -C-CH ₂ -NTZ Ar '(IV) b) thereafter, if E is a tetrahydropyranyloxy group, acts on an acid and cleaves the tetrahydropyranyl group, directly removing the protecting group of compound (II) to give a compound of formula (II '' ') and then reacting it with (III) or (III) ') a compound of the formula; - (c) the resulting N-substituted alkanolamine of the formula: HO- (CH ₂ ) _m -C-CH ₂ -NTZ I Is' acting on methanesulfonyl chloride, - (d) the resulting mesylate having the formula H R CH ₃ SO ₂ -O- (CH ₂ ) _m -C-CH ₂ -NTZ I Ar 'acts on a secondary amine of formula Y> JH \ V (V) (VI) (VII) wherein Y is designated in claim 1; and - (e) removing the protecting group from the hydroxyl labeled X to give a product which converts to one of its salts. 12. A pharmaceutical composition comprising the compounds of formula (I) according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient.