CH633009A5 - Process for the preparation of new phenylpiperazine derivatives - Google Patents

Abstract

Phenylpiperazine derivatives of formula (I) <IMAGE> and their pharmaceutically acceptable salts are prepared. R<1> represents benzyl, C1-6 alkyl or an optionally substituted phenyl; R<2> represents an optionally substituted phenyl, R<3> represents hydrogen or C1-4 alkyl, Q represents furan, thiophene, oxazole or thiazole, m is an integer from 1 to 3 and n is 0 or 1. When m is 2 and n is 0, R<1> cannot represent a methyl group when Q is the 5-thiazolyl group. The preparation is carried out by reducing a compound of formula: <IMAGE> in which X represents -CH2-CR<3>=, to form a compound in which n is 0 or 1. The compounds thus obtained are useful in the prophylactic and therapeutic treatment of diseases of immediate hypersensitivity, especially asthma in mammals. These compounds have a low toxicity.

Description

The present invention relates to a process for the preparation of a new class of phenylpiperazine derivatives which exhibit interesting pharmacological activity.

The process of the invention relates more particularly to a phenylpiperazine derivative of formula (I):

60

wherein R1 represents C1-4 alkyl or phenyl optionally substituted with C1-4 alkyl, C1-4 alkoxy, nitro or C1-6 haloalkyl and R2 is phenyl optionally substituted with 65 C1-6 haloalkyl.

5. Method according to claim 1, characterized in that a furan of formula (II) is prepared

R1-Q- (CHJ - (CKR3) -N dm n

/ ~ \

R

\ / (I)

in which R1 represents benzyl, C1-6 alkyl or an optionally substituted phenyl, R2 represents a possible phenyl-

3

633009

Lement substituted, R3 represents hydrogen or Ci-4 alkyl, Q represents furan, thiophene, oxazole or thiazoie, m represents a number from 1 to 3 and n represents 0 or 1; as are the pharmaceutically acceptable salts of these compounds, with the proviso that when m is 2 and n is 0, R1 cannot represent a methyl group when Q is the thiazol-5-yl group.

Preferably, R2 and also R1 when it represents phenyl, is optionally substituted by one or two radicals chosen from halogen, C1-4 alkyl, C1-4 haloalkyl, amino, C2-4 alkanoylamino, hydroxyl, C1-4 alkoxy, nitro and C1-4 alkylsulfonamido.

The expression “C1-4 alkyl” as used in the present description relates to a straight or branched chain alkyl group which contains from 1 to 4 carbon atoms, for example methyl, ethyl, isopropyl, n-butyl, s-butyl, iso-butyl and t-butyl. The term "Cm haloalkyl" refers to a C1-4 alkyl group as defined above substituted by one or more fluorine, chlorine, bromine or iodine atoms and includes groups such as trifluoromethyl and pen- tachloromethyl. Similarly, the expression "Ci-4 alkoxy" refers to the aforementioned C1-4 group attached to the intervention of an oxygen atom to the phenyl group.

Preferred classes of compounds of formula (I) are those which have one or more of the following characteristics:

(a) m is 1 and n is 0;

(b) Qestthiazoie;

(c) Q is oxazole;

(d) Q is thiophene;

(e) Q is furan;

(0 R1 is C1-3 alkyl such as methyl or isopropyl;

(g) R1 is phenyl;

(h) R1 is benzyl;

(I) R2 is phenyl substituted with one or two methyl radicals.

A particularly active class of phenylpiperazine derivatives of formula (I) consists of:

10 furans of formula (II)

(II)

(CH> 2 m

/

-N N

w

R '

In which R1 is phenyl optionally substituted by one or two radicals chosen from halogen, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl, R2 is phenyl optionally substituted by C1-4 alkyl, amino, Ci-4 alkylsulfonamido and C1-4 alkoxy and m represents 1 or 3, except the compounds in which R1 is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl;

or in which R1 is methyl, m is 1 and R2 is phenyl optionally substituted by a single radical chosen from halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or is substituted twice by two C1 radicals -4 alkyl;

thiophenes of formula (III):

(CH) 2 m

(CHS5) N

/

not

W

(III)

in which R ′ is phenyl, R2 is phenyl, phenyl substituted only once by C1-4alkyl or C1-4 haloalkyl or substituted twice by two radicals chosen from the group formed by halogen, C1-4 haloalkyl and C1-4 alkyl, and wherein m is 1 or 2 and n is 0;

or wherein m is 1, n is 1 and R3 is ethyl; oxazoles of formula (IV):

Wherein R1 is benzyl, R2 is phenyl or p-halophenyl;

or thiazoles of formula (VI)

1

(IV)

(C3J

2 m

/

i

\

\ /

(VI)

NOT

NOT

\ /

in which R1 represents C1-4 alkyl or phenyl optionally substituted by Ci-4alkyl, Ci-4alkoxy, nitro or in which R1 is phenyl optionally substituted by 55 Ci-4haloalkyle and R2 is phenyl optionally substituted by Ci-4alkoxy or halogen, R2 is optionally subs- C1-4haloalkyl phenyl;

titrated by Ci-4alkyle, Ci-4haloalkyle, halogen, amino or as well as the pharmaceutically acceptable salts of these

C2-4alkanoylamino and m is 1 or 2; thiazoles of formula (V)

//

/ \ at

—CH N N - R

r * w

(v)

compounds.

Preferably, in the abovementioned derivatives, and where 60 is applicable, m represents 1.

Particularly preferred compounds of formula (I) are the following:

1- [2- (5-phenylthiophene-2-yl) ethyl] -4-phenylpiperazine; 65 1 - (5-methylfuran-2-ylmethyl) -4- (3-chlorophenyl) piperazine;

1- [5- (4-methoxyphenyl) -furan-2-ylmethyl] -4-phenylpipe-razine;

633009

1- [5- (3,4-dimethylphenyl) -furan-2-ylmethyl] -4-phenylpi-perazine;

1 - (3- [5- (3,4-dichlorophenyl) -furan-2-yl] prop-1 -yl} -4- (4-methylphenyl) piperazine; 1 - [2- (5-phenylthiophen-2- yl) but-1-yl] -4-phenylpiperazine; 1- (5-phenylthiophen-2-ylmethyl) -4- (3,4-dimethyl-phenyl) piperazine;

1- [3- (5-phenylfuran-2-yl) prop-1-yl] -4- (4-methyl-phenyl) piperazine;

1- [5- (4-methoxyphenyl) -furan-2-ylmethyl] -4- (4-methyl-phenyl) piperazine;

1- (5-phenyloxazol-2-ylmethyl) -4- (4-methylphenyl) -piperazine;

1- (2-benzylthiazol-4-ylmethyl) -4-phenylpiperazine;

and the addition salts with acids which are pharmaceutically acceptable of these compounds.

Other illustrative examples of the new compounds of the invention are:

1- (5-phenylthiophen-2-ylmethyl) -4- (3-chlorophenyl) piperazine:

1- (5-phenylthiophene-2-ylmethyl) -4- (4-methoxy-phenyl) piperazine;

1- [5- (3-trifluoromethyl-4-chlorophenyl) -furan-2-ylmé-thyl] -4- (4-fluorophenyl) piperazine;

1- [3- (5-phenylfuran-2-yl) prop-1-yl] -4- (3-trifluoromethyl-phenyl) piperazine;

1- (2-methylthiazol-4-ylmethyl) -4- (3-chlorophenyl) piperazine;

1- [2- (4-phenylthiazol-2-yl) ethyl] -4- (4-aminophenyl) piperazine;

1- [2- (4-phenylthiazol-2-yl) ethyl] -4- (4-nitrophenyl) piperazine;

1- (5-phenyloxazol-2-ylmethyl) -4-phenylpiperazine;

l- [4- (3-trifluoromethylphenyl) -thiazol-2-ylmethyl] -4-phenyl-

piperazine;

1- (4-phenylthiazol-2-ylmethyl) -4-phenylpiperazine;

l - {2- [5- (4-chlorophenyl) oxazol-2-yl] -ethyl} -4-phenylpiperera-

Zine;

1- [2- (5-phenyloxazol-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine;

1- [2- (5-phenyloxazol-2-yl) ethyl] -4- (4-methoxyphenyl) -pipe-razine;

1 - [1 - (5-phenyloxazol-2-yl) prop-2-yl] -4- (4-methyl phenyl) -piperazine;

1 - [1 - (5-phenyloxazol-2-yl) ethyl] -4- (4-methylphenyl) -piperazine;

1- (5-phenyloxazol-2-ylmethyl) -3-methyl-4- (4-methyl-phenyl) -piperazine;

1- (5-phenyloxazol-2-ylmethyl) -2,3-dimethyl-4- (4-methyl-phenyl) -piperazine;

1- {2- [4- (chlorophenyl) -thiazol-2-yI] ethyl} -4-phenylpiperazine;

1- [2- (4-phenylthiazoI-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine;

1- [2- (4-phenylthiazol-2-yl) ethyl] -4- (4-methoxyphenyl) -pipe-razine;

1 - [1 - (4-phenylthiazol-2-yl) prop-2-yl] -4- (4-methyl phenyl) -piperazine;

1 - [1 - (4-phenylthiazol-2-yl) ethyl] -4- (4-methylphenyl) -piperazine;

1- (4-phenylthiazol-2-yImethyl) -4- (4-methanesulfonamido-phenyl) -piperazine;

l - {2- [5- (4-chlorophenyl) -furan-2-yl] ethyl} -4-phenylpipe-razine;

1- [2- (5-phenylfuran-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine;

1- [2- (5-phenylfuran-2-yl) ethyl] -4- (4-methoxyphenyl) -pipe-razine;

1 - [1 - (5-phenylfuran-2-yl) prop-2-yl] -4- (4-methylphenyl-piperazine;

s 1 - [1 - (5-phenylfuran-2-yl) ethyl] -4- (4-methylphenyl) -pipe-razine;

1- (5-phenylfuran-2-ylmethyl) -4- (4-methylphenyl) -piperazine;

1- (5-phenylfuran-2-ylmethyl) -4- (4-methanesulfonamido-10 phenyl) -piperazine;

1 - [4-phenylthiazol-2-yl) but-1-yl] -4-phenylpiperazine;

l- (5-phenylthiophen-2-ylmethyl) -4- (4-methylphenyl) -pipe-

razine;

1- (5-phenylthiophen-2-ylmethyl) -4-phenylpiperazine; is 1 - (5-methyloxazoI-2-ylmethyl) -4-phenylpiperazine;

1- (4-methyloxazol-2-ylmethyl) -4- (4-methylphenyl) -piperazine;

1- [2- (5-methyloxazol-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine;

1 - [2- (4-methyloxazol-2-yl) ethyl] -4- (3-methylphenyl) -piperazine;

1 - [3- (5-methyloxazol-2-yl) prop-1 -yl] -4- (2-chloro-phenyl) piperazine;

1- (5-benzyloxazol-2-ylmethyl) -4- (4-nitrophenyl) piperazine; 1 - (4-benzyloxazol-2-ylmethyl) -4- (4-acetylaminopheny 1) pipé-razine;

1- [2- (5-benzyloxazol-2-yl) ethyl] -4- (4-nitrophenyl) piperazine; 1- [2- (5-benzyloxazol-2-yl) ethyl] -4- (4-ethylphenyl) piperazine; 1 - [3- (5benzyloxazol-2-yl) prop-1 -yl] -4- (4-ethoxyphenyl) pipé-30 razine;

1- (5-methylthiazol-2-ylmethyl) -4-phenylpiperazine;

l- (4-methylthiazol-2-ylmethyl) -4- (4-methylphenyl) pipera-

Zine;

1- [2- (5-methylthiazol-2-yl) ethyl] -4- (4-chlorophenyl) pipera-zine;

1- [2- (4-methylthiazol-2-yl) ethyl]) - 4- (3-methylphenyl) piperazine;

1 - [3- (5-methylthiazol-2-yl) prop-1 -yl] -4- (2-chloro-phenyl) piperazine; 40 1 - (5-benzylthiazol-2-ylmethyl) -4- (4-nitrophenyl) piperazine; 1- (4-benzylthiazol-2-ylmethyl) -4- (3-acetylamino-phenyl) piperazine;

1- [2- (5-benzylthiazol-2-yl) ethyl] -4- (4-aminophenyl) piperazine;

45 1- [2- (5-benzylthiazol-2-yl) ethyl] -4- (4-ethylphenyl) piperazine; 1 -t3- (5-benzylthiazol-2-yl) prop-1 -yl] (4-ethoxyphenyl) piperazine;

1- (5-methylfuran-2-ylmethyl) -4-phenylpiperazine; 1- (4-methylfuran-2-ylmethyl) -4- (4-methylphenyl) pipera-50 zine;

1- [2- (5-methylfuran-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine;

1- [2- (4-methylfuran-2-yl) ethyl] -4- (3-methylphenyl) -pipe-razine;

55 1- [3- (5-methylfuran-2-yl) prop-1-yl] -4- (2-chloro-phenyl) piperazine;

1- (5-benzylfuran-2-ylmethyl) -4- (4-nitrophenyl) piperazine; 1- (4-benzylfuran-2-ylmethyl) -4- (3-acetylamino-phenyl) piperazine;

60 1 - [2- (5-benzylfuran-2-yl) ethyl] -4- (4-ethylphenyl) piperazine;

1 - [3- (5-benzylfuran-2-yl) prop-1 -yl] -4- (4-ethoxy-phenyl) piperazine;

1- (5-methylthiophen-2-ylmethyl) -4-phenylpiperazine; 65 1 - (4-methylthiophen-2-ylmethyl) -4- (4-methylpheny 1) -pipe-razine;

1- [2- (5-methylthiophen-2-yl) ethyl] -4- (4-chlorophenyl) piperazine;

5

633009

1- [2- (4-methylthiophen-2-yl) ethyl] -4- (3-methylPhényIpipérazine;

1 - [3- (5-methylthiophen-2-yl) prop-1 -yl] -4- (2-chloro-phenyl) piperazine;

1- (5-benzylthiophen-2-ylmethyl) -4- (4-nitrophenyl) piperazine;

1- (4-benzylthiophen-2-ylmethyl) -4- (3-acetylamino-phenyl) piperazine;

1- [2- (5-benzyIthiophen-2-yI) ethyl] -4- (4-nitrophenyl) piperazine;

1- [2- (5-benzylthiophen-2-yl) ethyl] -4- (4-ethylphenyl) piperazine;

1 - [3- (5-benzylthiophen-2-yl) prop-1 -yl-4- (4-ethoxy-pheny!) Piperazine;

and the addition salts with acids which are pharmaceutically acceptable of these compounds.

The process according to the invention for the preparation of piperazine derivatives of formula (I), or addition salts with the acids thereof, comprises:

reduction of a compound of formula aVccivVi— x— N N- * 2

\ / (IX)

in which X represents -CH2-CR3 = to form a compound in which n is 0 or 1.

The reduction of the compounds of formula in which X represents -CH2-CR3 can be carried out using reaction conditions described in J.A.C.S. 93,2897-2904 (1971) or in Synthesis 135-146 (1975). The reduction is preferably carried out using sodium cyanoborohydride but other forms of reduction, for example catalytic hydrogenation or the use of other suitable chemical reducing agents is possible. As indicated above, the reaction preferably takes place in a temperature range from 0 to 80 ° C.

The compounds of formula (I) obtained by the aforementioned processes can be isolated as such or in the form of an addition salt with an acid.

The addition salts with an acid are preferably non-toxic addition salts, pharmaceutically acceptable, with suitable acids such as those obtained with inorganic acids such as for example hydrochloric, hydrobromic, nitric, sulfuric acid. or phos-phoric or with organic acids such as organic carboxylic acids, for example glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotonic acid, and organic sulfonic acids for example methane sulfonic acid, ethane sulfonic, 2-hydroxyethane sulfonic, p-toluene-sulfonic, or naphthalene-2-sulfonic. In addition to the addition salts with pharmaceutically acceptable acids, other salts also fall within the scope of the invention, namely acid addition salts such as those obtained for example with picric or oxalic acid; the latter can be used as intermediates in the purification of the compounds or for the production of other addition salts with acids, for example the pharmaceutically admissible addition salts or can also be useful for the identification, characterization or purification of bases.

An addition salt with an acid obtained can be converted into the free compound by known methods, for example by treating with a base such as a hydroxide or a metal alkoxide, for example an alkali metal hydroxide or of an alkaline earth metal, namely lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate such as an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, with ammonia or with a hydroxyl ion exchange preparation or with any other suitable reagent.

An addition salt with an acid obtained can be transit) formed into another addition salt with an acid by known methods; for example, a salt of an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt of an acid in a suitable diluent, in which the inorganic salt obtained is insoluble. fad thus allowing it to be removed from the reaction medium. An acid addition salt can be converted to another acid addition salt by treatment with an anion exchange preparation.

The compounds of formula (I) and their pharmaceutically acceptable salts have shown properties useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases, including mammalian asthma. The compounds have low toxicity.

The compounds obtained by the process of the present invention can be administered by different routes and for this purpose can be presented in the form of compositions of different forms. Thus, the compounds or compositions can be administered orally, rectally, topically or parenterally (for example by injection or by continuous or discontinuous intravenous infusion) in the form, for example, of tablets, diamonds, sucking tablets, cachets, sachets , elixirs, suspensions, suppositories, aerosols, ointments or ointments (containing for example from 1 to 10% by weight of an active compound in a suitable base) of soft or hard gelatin capsules, solutions or suspensions of injection into physiologically acceptable media or of powders in sterile packaging adsorbed on a material support making it possible to prepare injection solutions.

Advantageously for this purpose, the compositions can be provided in unit dosage form which preferably each contain from 5 to 500 mg (from 5.0 to 50 mg in the case of parenteral administration, from 5.0 to 50 mg in in the case of inhalation and from 25 to 500 mg in the case of oral or rectal administration) of a compound of formula I. Doses 45 varying from 0.5 to 300 mg / kg per day, preferably from 0 , 5 to 20 mg / kg of active component can be applied although it will be understood that the amount of compound or compounds of formula (I) which will actually be administered will be determined by the attending physician, taking into account the circumstances. Particular, including the state to be treated, the choice of the compound administered and the choice of the route of administration and therefore, the aforementioned dosage area and dosage, in no way limit the scope of the present invention.

The compositions will normally consist of at least one compound of formula I with a support or diluted with a support or else coated or encapsulated in an ingestible support in the form of a capsule, a sachet, a cachet, paper packaging or other packaging or in disposable packaging such as an ampoule. The carrier or diluent can be a solid, semi-solid or liquid material, which serves as a vehicle, excipient or medium for the therapeutically active substance.

Some examples of diluents or carriers which can be used in the pharmaceutical compositions of the present invention are: lactose, dextrose, sucrose, sor-bitol, mannitol, propylene glycol, liquid paraffin, tender paraffin white, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate,

633009

6

silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, acacia gum, calcium phosphate, cocoa butter, ethoxylated esters, theobromine oil, d oil peanut, alginates, tragacanth, gelatin, BP syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trio-leate, sorbitan sesquioleate and oleyl alcohol as well as propellants such as trichloromono-fluoromethane, dichlorodifluoromethane and dichloroté-trafluoroethane. In the case of tablets, a lubricant can be incorporated to prevent sticking and adhesion of the powdered ingredients to the dies and punches of the presses. For this purpose, it is possible to use, for example, aluminum, magnesium or calcium stearates, talc or mineral oil.

The invention will be illustrated in more detail in the following examples:

Example 1

l- [5- (3,4-dimethylphenyl) -furan-2-ylmethyl] -4-phenyl-piperazine

4.0 g (0.02 mole) of 5- (3,4-dimethylphenyl) -furan-2-car-boxaldehyde prepared by the method of C. S. Davis and G.S. Lougheed J.Het.Chem. 4153, (1967), are quickly added to a stirred solution of 3.2 g (0.02 mole) of N-phe-nylpiperazine in 30 ml of methanol brought to pH 7 (using MeOH / HCl). After 30 minutes, a solution of 0.48 g (0.0075 mol) of sodium cyanoborohydride in 10 ml of methanol is added dropwise and the mixture is stirred at room temperature for 2 hours. After removing the methanol by evaporation, the solid obtained is purified by chromatography on silica gel. The fractions containing the desired compound are combined, evaporated and the crystalline solid which forms is recrystallized from petroleum ether at 60/80 ° C to give the title compound, mp 110 ° C.

Similarly, the following compounds were prepared:

Example 2

1- [5- (3-trifluoromethyl-4-chlorophenyl) -furan-2-ylmé-îo thyl] -4- (4-fluorophenyl) piperazine

Mp 94 ° C.

Example 3

l- [5- (4-chlorophenyl) -furan-2-ylmethyl] -4- (4-nitro-phenylpiperazine)

Mp 149 ° C.

Example 4

1- [5- (4-methoxyphenyl) furan-2-ylmethyl] -4- (4-methyl-20 phenylpiperazine)

Mp 138 ° C.

Example 5

1- [5- (3,4-Dichlorophenyl) furan-2-ylmethyl] -4- (3-trifluoromethylphenyl) piperazine monohydrochloride

Mp 210 ° C.

Example 6

1- (5-phenylthiophene-2-ylmethyl) -4- (3,4-dichloro-30 phenylpiperazine)

Mp 140 ° C.

B

Claims (7)

633009 2 CLAIMS 1. Process for the preparation of a phenylpiperazine derivative of formula (I) R'-Q-CCH) - (CHR3) d ni / \ ) - N N - \ / (CH.) -2 □ (II) 2 R (I) " N N— R V_ / wherein R1 represents benzyl, C1-6 alkyl or optionally substituted phenyl; R2 represents an optionally substituted phenyl, R3 represents hydrogen or C1-4 alkyl, Q represents furan, thiophene, oxazole or thiazoie, m represents a number from 1 to 3 and n represents 0 or 1, as well as the pharmaceutically acceptable salts of these compounds, provided that when m is 2 and n is 0, R1 cannot represent a methyl group when Q is the thiazol-5-yl group, characterized in that it comprises: reduction of a compound of formula: /AT —X — N N w R S (V) wherein R1 is benzyl, R2 is phenyl or p-halophenyl. 4. Method according to claim 1, characterized in that a thiazoie of formula (VI) is prepared in which R1 is phenyl optionally substituted by one or two radicals chosen from halogen, Ci-4alkyl, io Ci-4alkoxy and Ci-4haloalkyle, R2 is phenyl optionally substituted by Ci-4alkyl, amino, Ci-4 alkyl-sulfonamido and Ci- 4alköxy and m represents 1 or 3, with the exception of the compounds in which R 'is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl; Or in which R1 is methyl, m is 1 and R2 is phenyl optionally substituted by a single radical chosen from halogen, CMalkyl, C1-4 alkoxy, C1-4haloalkyl or is twice substituted by two C1-4 alkyl radicals. 6. Method according to claim 1, characterized in that an oxazole of formula (IV) is prepared: (IX) 25 R (CH I ' 2 m in which X represents -CH2-CR3 = to form a compound in which n is 0 or 1. 2. Method according to claim 1, characterized in that R1 and R2 independently represent phenyl optionally substituted by one or two radicals chosen from halogen, Ci-4alkyl, Ci-4hyloalkyle, amino, C2-4alkanoylamino, hydroxyl, Ci-talkoxy, nitro and Ci-4aIkylsulfonamido. 3. Method according to claim 1 characterized in that a thiazoie of formula (V) is prepared (IV) s2 wherein R1 is phenyl optionally substituted with C1-4alkoxy or halogen, R2 is phenyl optionally substituted with C1-4alkyl, CMhaloalkyl, halogen, amino or C2-4alkanoylamino and m is 1 or 2. 7. Method according to claim 1, characterized in that a thiophene of formula (III) is prepared. 35 * (III) R (GHJ; 2 m / -NOT Y v_y R " in which R1 is phenyl, R2 is phenyl, phenyl substituted only once by C1-4 alkyl or C1-4 haloalkyl or subs-45 twice substituted by two radicals chosen from the group formed by halogen, C1-4 haloalkyl and C1- 4 alkyl, and in which m is 1 or 2. 8. Method according to claim 3, characterized in that one prepares the l- (2-benzylthiazol-4-ylmethyl) -4-phenylpipera-50 zine. (VI) N N W R 55