CA2251016C - .alpha.1-adrenergic receptor antagonists - Google Patents

Abstract

Phenylpiperazine derivatives having a high affinity for the alpha 1-adrenergic receptor and pharmaceutical compositions containing same are disclosed. A method for the use of such derivatives to treat benign prostatic hyperplasia is also described.

Description

ANTAGONISTS OF THE AL-ADRENERGIOUE RECEPTOR

Neuroreceptors are considered dynamic entities that constitute a means accessible clinical manipulation. The sympathetic neurotransmitter norepinephrine and the adrenal hormone epinephrine regulate many activities physiological through interactions with α- and α-adrenergic receptors.
adrenergic are mediators of many of the physiological effects of catecholamines, especially the glycogenolysis, contraction of vascular and genitourinary smooth muscle, hyperpolarization intestinal smooth muscle, contractile force and cardiac arrhythmia.

In one of its aspects, the invention relates to a compound of formula I:
Ri R2 R5-N% - (CH2) 3-NC- u-R3 (I) in which :

R1 represents hydrogen, lower alkyl, or aryl-lower alkyl;

R2 is hydrogen, lower alkyl, OR6, S (O) II, R6 (wherein m is is 0, 1, or

2), NHS (O) õR6 (wherein n is 1 or 2), OC (O) R6, CONR6R7, NR6R7, or N (R7) C (O) R6;

R3 and R4, independently of one another, represent hydrogen, or one of the following compounds substituted (i.e., one to four times on the atoms carbon or nitrogen) or unsubstituted: lower alkyl, cyanoalkyl, aryl, arylalkyl lower, a heterocycle, or a heterocycle-lower alkyl, wherein said substituent is a lower alkyl, halogen, OR6, SR6, NR6R7, CN, NO2, CF3, a heterocycle, or an aryl, or R3 and R4 together with the carbon atom to which they are jointly related, an aryl or substituted heterocycle (i.e. one to four locations) or unsubstituted, wherein said substituent is lower alkyl, OH, or hydroxyl-lower alkyl;

R5 is substituted aryl (i.e., on one to four carbon atoms) or unsubstituted, wherein said substituent is lower alkyl, cycloalkyl, hydroxy-alkyl hydroxyl-cycloalkyl, an alkoxy-lower alkyl, an alkoxy-cycloalkyl, a halogen, OR6, SR6, NR6R7, or CN; and R6 and R7, independently of one another, represent a hydrogen or one of the following compounds substituted (i.e., one to four carbon atoms) or not-substituted: lower alkyl, aryl or aryl-lower alkyl, wherein said substituent is a lower alkyl, halogen, or lower alkoxy; in which if R3 or R4 represents a hydrogen, R2 is not OH unless the compound of formula I is hydroxy-N- [3-{4- (2-methoxyphenyl) -1-pypérazinyl} -propyl] benzeneacetamide; or one of his salts pharmaceutically acceptable.

In another of its aspects, the invention relates to a compound of formula I
~ - ~ Ri R2 R5-N N- (CH2) 3-N-C-C-R3 in which RI represents hydrogen or lower alkyl R2 represents a hydrogen, a lower alkyl, OR6, S (O) n, R6 in which m is 0, 1 or 2, NHS (O) õR6 wherein n is 1 or 2, C (O) NR6R7, NR6R7 or N (R7) C (O) R6;

each of R3 and R4, independently of one another, represents one groupings following substituted with one or more substituents or unsubstituted:
lower alkyl, cyclohexyl, phenyl, naphthyl or benzyl wherein said substituent is a alkyl lower, halogen, OR6, SR6, NR6R7, CN, NO2, CF3 or phenyl, or R3 and R4, together with the carbon atom to which they are jointly bound, form the radical 9-xanthenyl or 9-fluorenyl;

R5 represents a phenyl substituted with one or more substituents chosen among alkyl lower, CN, halogen, hydroxy-lower alkyl, cyclopropylhydroxymethyl, a lower alkoxy-lower alkyl, or OR6 in which R6 is alkyl inferior ; and each of R6 and R7, independently of one another, represents a hydrogen or one following groups substituted with one or more substituents or substituted: a lower alkyl, phenyl or benzyl wherein said substituent is a lower alkyl, one halogen, or lower alkoxy;

Being heard that if R2 represents OR6 and R6 represents lower alkyl, then R4 does not does not represent the radical halophenyl or lower alkoxy-phenyl and 2a) RZ, R3 and R4 can not simultaneously represent lower alkyl "and if R2 represents OR6 and R6 represents hydrogen, then R3 and R4, so independent one on the other, do not represent one of the substituted or non-substituted following substitutions phenyl, naphthyl or benzyl;

is in one of the following formulas:
a-hydroxy-N- [3- {4- (3-methylphenyl) -1-piperazinyl} -propyl] -a-phenyl-benzeneacetamide;
a-hydroxy-N- [3- {4- (2-methylphenyl) -1-piperazinyl} -propyl] -a-phenyl-benzeneacetamide;
a-hydroxy-N- [3- {4- (4-methylphenyl) -1-piperazinyl} -propyl] -a-phenyl-benzeneacetamide;
N- [3- {4- (2,3-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;

N- [3- {4- (2,4-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;

N- [3- {4- (2,6-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;

N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;

N- [3- {4- (2-ethoxyphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;
N- [3- {4- (2-chlorophenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;
N- [3- {4- (2-cyanophenyl) -1-piperazinyl} -propyl] -α-hydroxy-a-phenyl-benzeneacetamide, hydrochloride;

α-hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] -α-phenyl-benzeneacetamide;

2-chloro-α- (2-chlorophenyl) -α-hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] -benzeneacetamide;

α-hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] -benzeneacetamide ;
N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-4-methoxy-a- (4-methoxyphenyl) benzeneacetamide;

2b) α-amino-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] benzeneacetamide;
N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α- (methylsulfonylamino) -benzeneacetamide;

N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-benzylaminocarbonyl benzeneacetamide;

N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α- (4-methylphenyl) -sulfonylamino-benzeneacetamide;

N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-benzylcarbonylamino benzeneacetamide (f) -N- [3- {4- (2- (propyl) -phenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide;

or a pharmaceutically acceptable salt thereof.

In one embodiment, R1 represents hydrogen or an alkyl lower, R2 represents a hydrogen, a lower allcyl, OR6 (wherein R6 represents a hydrogen or aryl-lower alkyl), SR6 (wherein R6 is lower alkyl), NH2, NHSO2R6 (in R6 is lower alkyl or aryl-lower alkyl), OC (O) R6 (in which which R6 is a aryl-lower alkyl) or CONR6R7 or N (R7) C (O) R6 (wherein R7 represents a hydrogen and R6 is aryl-lower alkyl); R5 represents a phenyl substituted or unsubstituted, wherein said substituent is lower alkyl, CN, halogen, hydroxy-alkyl lower, hydroxy-cycloalkyl, lower alkoxy-lower alkyl, or OR6 (wherein Rb is lower alkyl); and R3 and R4, independently of one another, represent a hydrogen or one of the following substituted or unsubstituted compounds:
lower alkyl, one cycloalkyl, or aryl, wherein said substituent is a halogen, OR6 (in which R6 is lower allcyl), or aryl.

In another embodiment, R 1 represents. a hydrogen and R5 represents the 2,5-dimethylphenyl; R2 represents OR6 (wherein R6 represents a hydrogen, alkyl lower, or aryl-lower alkyl); and R3 represents a lower alkyl and R4 represents a phenyl.

2c) In another embodiment, R3 and Rq, together with the carbon atom which they are together, constitute an aryl or heterocycle; Ri represents a hydrogen and R5 represents 2-methoxy-phenyl or 2,5-dimethyl-phenyl; and R2 represents OR6 (dam wherein R6 is hydrogen, lower alkyl, or arylalkyl inferior).

In yet another embodiment, R3 and R4, together with the atom of carbon they are jointly bound, constitute 9-xanthenyl or 9-fluorenyl.

The following examples are examples of compounds according to the present invention.
invention:

WO 97/3798

3 PCT / FR97 / 00615 Compound n ~
Q
NN

h {3C ~ ~ .N
~~
eo cl ~~
~ N ~ 3 HN / ~, NJ

H, C
HO ' ~
~ 'O

~~~
bone HsCQ
rHO N 6 ~
t O
.

e ' o 0 N /, NJ CH3 O

HõC..O
N NJ '' 8 . ~ / ~.

p eo

-4-NOT
HO ~~ N 10 Ni ~ .N

CHs NOT
o ~ 11 N. ~~ NJ CI-s O

c> ~

CN ~ N ,! C1 ~ 13 O

.IN '13 N. ~ .N
~ O

I Hi ~ t 0 N .... N / N '14 yv- Nv ~ N1 15 O ',, N ~
FI
= t 3Co = I
HO

',OR
~~.
e Ci O
NN
HO 'CI ~ N ~ 17 t ~ H3 ~ 'i O
N ~ N1 18 ',NOT
I ~ c-0

-5-Hi C 0 OH ~ N

N. ~~ .N ..%

~
.
II
rN 20 . N ~ / ~ .N / CH3 aH, O NN J ~

HO N ,,. ,, - ~ NJ Ci- ~
~ O

HC N .., - ~ N / CH3 23 cF ~

} {~ C ~ SN ~ tiNJ CH ~ 24 O ~ CH, HO N, -., J CK, 25 cr ~, s NN ~
Fi3C

-6-CHI.

N / ~ .N.JN CH3 27 H3C O, HO N, ~ NJ cH, 28 cH, = ~
a N 29 Mo N ~~~~ NJ CH, M, CO

q ~
at ~ r'N 31 HO N ~~~ NJ CH.

O

cx, o ~ lyo NH N ~ ~ N ~ 33 YO &

CH, HO N ~, NJ CH ~

-7-CH, 35 N, ~ - (V i (~
~

OH
HIC

O

~ N. ~ .N..i . O

H3C ~ N ~ a . 38 N. ~ .NJ

~
s ~ NJ c & l, 39 O

Hi CH

HO N ~~ NJ CHI

HO N ,,,, NJ CH3 41 n N ,, -, N, i Cii ~

-8-HO N ~~~ NJ CH

.
.
-i HO N ~~ N ~ i Ct11 44 CH ~
i ~~
H3C ~ N CH ~ 45 HO Q

.
H0. N ~ N ~ s ~ 46 ~ C o "t ~ 2 C * 4 CH ~
i O.Ç.O, ~ 48 NH
NOT

O

4 CO ~ 49 NOT
O

~

-9 ch'i HC '~ N S1 CH, CH ~

M ~
Ni O ZN,. ,, N / CH3 52 Ci CI ~

HO N / Ciis CO ~

rN 54 e No ~ N., = ~, N ~ i ~ +, N .... NJ
o rj 56 ~
~ eO

or a pharmaceutically acceptable salt thereof.

-10-In another aspect, the present invention relates to the application as a drugs of products of the general formula I as described above, as well as a composition pharmaceutical composition comprising a compound of formula I:
R1 Rz R5-N- (CH2) 3-N-Cl CI - R3 (n I
at in which :
R1 represents hydrogen, lower alkyl, or aryl-lower alkyl;

R2 is hydrogen, lower alkyl, OR6, S (O), õR6 (wherein m is worth 0, 1, or 2), NHS (O) õR6 (wherein n is 1 or 2), CONR6R7, NR6R7, or N (R7) C (O) R6;

R3 and R4, independently of one another, represent hydrogen or one of the compounds substituted or unsubstituted: lower alkyl, cyanoalkyl, aryl, an aryl-alkyl lower, a heterocycle, or a heterocycle-lower alkyl, wherein said substituent is a lower alkyl, halogen, OR6, SR6, NR6R7, CN, NO2, CF3, a heterocycle, or an aryl, or R3 and R4 together with the carbon atom to which they are jointly related, a heterocycle such as the 9-xanthenyl or 9-fluorenyl radical; or one of his salts pharmaceutically acceptable.

R5 is a substituted or unsubstituted aryl, wherein said substituent is a lower alkyl, a hydroxyl-lower alkyl, lower alkoxyalkyl, halogen, OR6, SR6, NR6R7 or CN; and R6 and R7, independently of each other, represent hydrogen or one of the compounds following substituted or unsubstituted: lower alkyl, aryl or aryl-alkyl lower, in which said substituent is lower alkyl, halogen, or lower alkoxy ; or one of its salts pharmaceutically acceptable.

According to one embodiment, R1 represents a hydrogen, R5 represents 2,5-dimethylphenyl;
R2 represents OR6 (wherein R6 represents hydrogen, alkyl lower, or an aryl-alkyl inferior) ; R3 represents lower alkyl; and R4 represents phenyl.

As used herein, "lower alkyl" includes hydrocarbon groups saturated aliphatic at a time linear, branched, or straight chain, having 1 to 6 carbon atoms. of the examples of groups lower alkyls include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and Similar.

As used herein, a "cycloalkyl" includes any hydrocarbon moiety cyclic non-aromatic having from 3 to 10 carbon atoms in which from 3 to 8 carbon atoms constitute a

-11-cycle. Examples of such fragments include, but are not limited to, the cyclopropyl, the methyl-cyclopropyl, ethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the cyclopropyl-methyl, cyclopropyl-ethyl, and cyclohexyl-ethyl.

As used herein, "aryl" includes any stable ring (s) or carbon ring (s) monocyclic, bicyclic, or tricyclic, up to 7 members in each cycle, in which least one cycle is aromatic. Examples of such aryl groups include phenyl, the naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl, and Similar.

As used herein, "lower alkoxy" includes hydrocarbon groups saturated aliphatic to linear, branched, and straight chain, having from 1 to 6 carbon atoms carbon and an atom oxygen. Examples of lower alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

The term heterocycle, as used herein, represents a ring or ring heterocyclic a stable unicycle of 5 to 7 limbs or a stable bicycle of 8 to 11 limbs or a tricycle 11 to 15 members, which is either saturated or unsaturated, and consists of in atoms of carbon and 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any one of the rings defined heterocyclic above is linked to a benzene ring. The heterocyclic ring can be linked to any heteroatom or carbon atom which results in the creation of a stable structure.
Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, the benzisoxazolyl, bensofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, the dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, the piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl, the tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, the thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, the thienyl, 9-xanthenyl, and the like.

As used herein, a halogen represents a chlorine, fluoro, brominyl, or iodo.

The compounds of the present invention may comprise an asymmetric center and introduce yourself as racemates, racemic mixtures, or diastereomers individual, with all possible isomers, including optical isomers, all being included in the

- 12 -present invention. For simplicity, when no specific configuration is not described in structural formulas, we understand that all enantiomeric forms and their mixtures are represented. In one embodiment, the carbon atom bonded to R2, R3, and R4 is in the configuration "S".

The compounds of this invention may be provided in the form of salts acceptable pharmaceutically. Acceptable salts include, but are not limited to, acidic salts addition of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide, and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluene sulfonate, the pamoate, salicylate, oxalate, and stearate. Also included in the present invention, where possible, salts formed from bases such as hydroxide sodium or potassium. For other examples of pharmaceutically acceptable salts, see "Pharmaceutical Salts", J. Pharm. Sci. 66: 1 (1977).

In one embodiment, the invention relates to a compound according to the formula I, wherein said compound has the formula:

(I

HO N ~ / N CHs O
or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating disorders whose α1-adrenergic receptor is a mediator. Examples of such troubles include hypertension, disorders of the lower urinary tract (eg benign hyperplasia of the prostate), arrhythmia, myocardial ischemia, lipid serum levels, glaucoma, motility disorders of the gastrointestinal tract, cholesterol synthesis, the erectile dysfunction, Raynaud's disease, congestive pathologies heart, portal hypertension, and multi-drug resistance, cirrhosis.

The invention also relates to a pharmaceutical composition comprising a composed of general formula I as described above, in combination with a carrier pharmaceutically acceptable.

12a) The invention also relates to the use of the products of general formula I as described above above, for the preparation of a medicament for treating hyperplasia benign prostate, portal hypertension and cirrhosis.

Another aspect of this invention relates to the use of a formula I ' R ' R ' R'5 N N- (CH2) 3 NR ~ 3 Ra OI ~
in which R ', represents hydrogen or lower alkyl R'2 is hydrogen, lower alkyl, OR6, S (O) n, R6 wherein m is 0, 1 or 2, NHS (O) õR6 wherein n is 1 or 2, C (O) NR6R7, NR6R7 or N (R7) C (O) R6;

each of R'3 and R'4, independently of each other, represents one groupings following substituted with one or more substituents or unsubstituted:
lower alkyl, cyclohexyl, phenyl, naphthyl or benzyl wherein said substituent is a alkyl lower, halogen, OR6, SR6, NR6R7, CN, NO2, CF3 or phenyl, or R'3 and R'4 together with the carbon atom to which they are jointly bound, form the radical 9-xanthenyl or 9-fluorenyl;

R'5 represents a phenyl substituted with one or more substituents chosen among alkyl lower, CN, halogen, hydroxy-lower alkyl, cyclopropylhydroxymethyl, a lower alkoxy-lower alkyl, or OR6 in which R6 is alkyl inferior ; and each of R6 and R7, independently of one another, represents a hydrogen or one following groups substituted with one or more substituents or substituted: a lower alkyl, phenyl or benzyl wherein said substituent is a lower alkyl, one halogen, or lower alkoxy;
with the proviso that if R'2 is OR6 and R6 is lower alkyl, so R'4 does not does not represent the halophenyl or lower alkoxy-phenyl radical; or one of its salts pharmaceutically acceptable preparations for the preparation of a medicament for treat portal hypertension or cirrhosis.

12 b) In another embodiment, the invention relates to a method of Treatment of portal hypertension, the method comprising the administration of a quantity therapeutic effective of a compound having a Kb of contraction inhibition of the vein rat portal that is at minus five times (for example, at least ten or twenty times) less than Kb said compound for inhibiting the contraction of the rat aorta, wherein said compound binds to the receiver ai-adrenergic with a Ki of at least 1 M (for example, at least 10 nM or 1 nM), that is to say as described in the tests described herein. In another embodiment, said compound has a Kb inhibition of rabbit portal vein contraction which is at least five times (for example, at less than ten or twenty times) less than the Kb of said compound for the inhibition of contraction of rabbit aorta, i.e., as described in the assay described herein. In yet another mode of realization, said compound has a Kb of contraction inhibition of the vein rabbit portals that is at least twice (for example, at least five or

-13 nine times) less than the Kb of said compound for inhibition of contraction saphenous vein rabbit, that is to say as described in the tests described here.

The subject of the invention is also the use of compounds having a Kb inhibition of contraction of the rat portal vein which is at least five times (by example, at least ten or twenty times) less than the Kb of said compound for inhibition of contraction from the rat aorta, wherein said compound binds to the ocl-adrenergic receptor with a Ki at least 1 M
(for example, at least 10 nM or 1 nM), for the preparation of a medicament intended to treat portal hypertension or cirrhosis.

The invention also relates to a method of treating hypertension portale, said method comprising administering a therapeutically effective amount of a compound of formula IM:

Rio R'2 ) -V_ (CH2) P_N_c_c_R3 R's R11 q R1 X R'4 IM
in which W represents a nitrogen or carbon atom;

R 1 represents hydrogen, lower alkyl, aryl-lower alkyl, CN, CO2R9, CON (R9) 2, cycloalkyl or (CH2) pCO2R9;

R'2 is hydrogen, lower alkyl, OR6, S (O) mR6 wherein m is 0, 1 or 2, NHS (O) nR6 wherein n is 1 or 2, OC (O) R6, C (O) NR6R7, NR6R7, N (R7) C (O) R6, C02R10, (CH2) p-CO2R10, OR12, N-R12-R13, (CH2) pCN (R10) 2 or CR'2 forms a ring cyclopropyl and one of R'3 and R'4 does not exist.

each of R'3 and R'4, independently of one another, represents a hydrogen or one substituted or unsubstituted compounds: alkyl or alkoxy lower one cycloalkyl, aryl, aryl-lower alkyl, heterocycle, heterocycle-lower alkyl or NR'IOR "10, wherein said substituent is lower alkyl possibly substituted by one or more halogen atoms, a halogen, OR6, SR6, NR6R7, CN, NO2, a heterocycle, aryl or methylenedioxy on two adjacent carbons, or R'3 and R'4, together with the carbon atom to which they are jointly bound, form an aryl or a substituted or unsubstituted heterocycle, wherein said substituent is a lower alkyl, OH, or hydroxy-lower alkyl;

WO 97/37983 PCT / P1t97 / 00615

-14-R'S is a substituted or unsubstituted lower alkyl, aryl or heterocycle substituted, in which said substituent is lower alkyl, optionally substituted with one or several atoms halogen, cycloalkyl, hydroxy-lower alkyl, hydroxy-cycloalkyl, an alkoxy lower alkyl, alkoxy-cycloalkyl, halogen, methylenedioxy on two carbons adjacent, OR6, SR6, NR6R7, CN, CO2R10, (CH2) pCON (R10) 2 or (CH2) pCO2R1;

each of R6 and R7, independently of one another, represents a hydrogen or one substituted or unsubstituted compounds: a lower alkyl, a aryl or a aryl-lower alkyl, wherein said substituent is lower alkyl, a halogen, or a lower alkoxy;

R8 is selected from hydrogen, cyano, CO2R9, CON (R9) 2 or aryl, being heard that when W is a nitrogen atom, R8 does not exist;

each of R 9, R 10, R 10, R 10 and R 11, independently of one another, is a hydrogen, lower alkyl or cycloalkyl, alkyl and cycloalkyl radicals possibly being substituted by one or more halogens;

each of R12 and R13, independently of one another, represents hydrogen, a radical lower alkyl or substituted or unsubstituted cycloalkyl, CHO, COR10-CONR10R1 i or (CH2) pOR10;

V is selected from -CH2- CHORIO, CHF, CHR, CR1oRit, CF, ~ ~
~ 2 ~ CH-CHF2, / C = CF2 or CO;

q is an integer of 0 to 3 p is an integer of 0 to 3;

X is selected from oxygen, sulfur or NR14, wherein R14 is hydrogen, cyano or SO2R10;

RI $ is hydrogen or hydroxy;

it being understood that when n = p = 0, V does not represent CH20R10 =
or a pharmaceutically acceptable salt thereof.

The subject of the invention is also the use of products of formula IM
For the preparation a drug to treat portal hypertension or cirrhosis.

-15-The products of formula IM whose preparation is not described in the this application,.
can be prepared by the method described in WO 96J40136.
The invention also relates to the use of the compounds as described in the application WO 96/40136, for the preparation a drug to treat portal hypertension or cirrhosis.

The invention also relates to a method of treating hypertension portal or the cirrhosis, said method comprising administering a quantity therapeutically effective a compound of formula IN:

R17 J_z R'S -RX IN

where R'5, R9 and RIO have the meaning indicated in claim 38;
Z represents a CHRg1 or NHR9 radical;

Rx is chosen from the radicals O

- (CHZ) 3-N or II T
O.-Sp O
wherein R19 represents a hydrogen atom or a chlorine atom;

T is -NH- (CH2) 3 or -N;

R16, R17 and R18 are selected from hydrogen and cyano, aryl, heterocycle CONR9R10 = CO2R9 or SO2R9, as well as the use of products of formula IN
for the preparation of a medicament for treating portal hypertension or cirrhosis.

The products of formula IN can be prepared by the process described in WO 96140135.

-16-The subject of the invention is also the use of the compounds as described in the request WO 96/40135 for the preparation of a medicament for treating portal hypertension or cirrhosis.

The invention also relates to a method of treating hypertension portale, said method comprising administering a therapeutically effective amount of a compound of formula IR:

~ ~ ~ --- ~ R22 N N-CH 2 - i - CH 2 - R 24 in which :

R20 represents acetylamino, amino, cyano, trifluoroacetylamino, halogen, a hydrogen, hydroxy, nitro, methylsulfonylamino, 2-propynyloxy or any of the radicals substituted one to three times by the following halogen or non-substituted atoms: alkyl lower one cycloalkyl, cycloalkyl-lower alkyl, lower alkoxy, cycloalkyloxy, a cycloalkyl-lower alkoxy or lower alkylthio; or one of following radicals: a aryl, an aryl-alkyl, a heterocycle, a heterocyclo-lower alkyl, a aryloxy, a aryl-lower alkoxy, a heterocycle-oxy or a heterocycle-lower alkoxy, in which the aryl radical or heterocycle are optionally substituted by one or two radicals independent selected from a halogen atom and the cyano radical;

R21 represents CN, halogen, hydrogen, hydroxy or one of the radicals following optionally substituted with one to three halogen atoms: an alkyl lower or alkoxy inferior ;

R22 and R23 are, independently, hydrogen or methyl or, together, ethylene;

R24 represents one of the compounds of formula IRa, IRb. IRc and IRd:

O, R25O, R25O, R25O; Z25 ~ _N ~ -N ~ -N ~ _N
-N ~ Zl -NO -NX 1 -NO
R Z1 R Yt R27 IRa IRb IRc IRd

-17-in which :

X1 represents C (O), CH2 or CH (OH);
Y1 is CH2 or CH (OH);

Z1 is N or C (R29), wherein R29 is hydrogen, alkyl lower or hydroxy;

R25 represents hydrogen, one of the following radicals optionally substituted by one to three halogen atoms: lower alkyl, cycloalkyl, cycloalkyl lower alkyl;
or one of the following radicals: aryl, heterocycle, arylalkyl lower or one heterocycle-lower alkyl, in which the aryl radical or the heterocycle are eventually lo substituted with one to three radicals selected from the halogen atom, cyano, lower alkoxy, lower alkyl or aryl;

R26 represents R30C (O) -, carbamoyl, cyano, di (lower alkyl) amino, a halogen, a hydrogen, hydroxy, hydroxyiminomethyl, R30S, R30SO2; one of the radicals substituted by one to three radicals selected from halogen, hydroxy or lower alkoxy, or unsubstituted compounds: lower alkyl, cycloalkyl, alkoxy lower or alkoxy lower-lower alkyl; or one of the following radicals:. .aryle, a -heterocycle, an aryl lower alkyl or a heterocycle-lower alkyl, in which the radical aryl or heterocycle.
are optionally substituted with one to three radicals selected from halogen cyano a lower alkoxy, lower alkyl or aryl; or R26 and R29 form together the radical -CH 2 - (CH 2) 2 -CH 2 -;

R27 and R28 are independently hydrogen, hydroxy, methyl or ethyl;
R 30 represents lower alkyl;

or a pharmaceutically acceptable salt or an N-oxide thereof; and more particularly, in the case where the IR compound represents 3- [3- [4- [4-fluorophenyl]

2- (2,2,2-trifluoroethoxy) phenyl] -1-piperazinyl] propyl] -dihydro-2,4- (1H, 3H) pyrimidine dione.

The subject of the invention is also the use of a product of IR formula as defined above, for the preparation of a medicament for treating portal hypertension or cirrhosis.

The products of formula IR can be prepared by the process described in EP 748 800, application.

WO 97/37983

-18 - PGT / FR97 / b0615 The subject of the invention is also the use of the compounds as described in the application.
EP 748 800, for the preparation of a medicament for treating portal hypertension or cirrhosis.

An effective therapeutic amount of a compound of said invention and a support substance pharmaceutically acceptable (for example, magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle) together a pharmaceutical composition (for example, a pill, a tablet, a capsule, or a liquid) for administration (for example, orally, intravenously, transdermal, or subcutaneous) to a subject in need of the compound. The pill, the tablet, or the capsule can be covered with a substance capable of protecting the composition of the acids gastric or intestinal enzymes in the subject's stomach for a period of time sufficient for allow the composition to pass to the undigested state in the small intestine from subject The dose of a compound of the present invention for the treatment of diseases or troubles mentioned above varies according to the mode of administration, the age and body weight the subject, and the condition of the subject to be treated, and ultimately it will be decided by the doctor or Veterinary attending. Such a quantity of the compound as determined by the doctor or the attending veterinarian will be referred to here as an "effective therapeutic amount".

Also considered as part of the invention is a method of preparation of compound of formula (I) or formula (II) and chemical intermediates new used in these syntheses as described herein.

Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.

It is considered that one skilled in the art can, based on the description given here, use the present invention in all its extent. The embodiments following specific are thus mentioned merely as an illustration and do not limit the scope of the disclosure in any way.

Unless otherwise defined, all technical terms and scientists used here have the same meaning as that commonly understood by those skilled in the art ordinary this invention applies. - -Synthesis As shown in Scheme I, the compounds of the invention can usually be prepared by condensation of 3-amino-1-propanol derivatives of the formula general (II)

-19-(Kim, JK et al., J. Org Chem 54: 1714 (1989) and Koepke, SR et al., J.
Org. Chem.
44: 2718 (1979)) with the appropriate acid derivatives of general formula (III).

Scheme I

(II ~ O- (CHZ) 3-NH + i ~ -R3 (III) Ij1 R2 HO- (CH2) 3-N- ~ - ~ R3 (IV) 0 Ra R1 R2 ~ - ~ Ri X- (CH2) 3-NC ~ R3 (V) R5-N% - (CH2) 3 -NH (VII) R

(VI) R5 - N1H - R3 (III) RI R
R5-N N- (CH2) 3-N- ~ - ~ - R3 (I) ~ - / O Ra In Scheme I, R1-R5 are defined above and X is a grouping Eliminable, by methanesulfonyloxy, p-toluenesulphonyloxy, chlorine, bromine or iodine. of the derivatives of benzyl acid (III), in which R3 and R4 represent aromatic and R2 represents OH, are obtained either by heating at 80 C benzyl derivatives and a hydroxide of alkali metal (e.g., KOH) in the solid state (Toda, F. et al., Chem.
Letts. pp. 373-376, The Chemistry Society of Japan (1990), as illustrated by Example 25, by heating to WO 97/37983 PCT / FTt97 / 00615

-20-95 C in aqueous organic solvents (Rzeszotarski, WJ et al., J. Med.
Chem. 27: 156 (1984)).

Acid derivatives (III), in which R3 represents an alkyl chain, R4 represents a aromatic, and R2 represents OH, can be obtained from other methods. A
method involves the reaction of acetophenone derivatives with the trimethylsilyl cyanide presence of a catalytic amount of Zn12 at room temperature for get some cyanohydrins after acid hydrolysis (Gassman, PG et al., Tetrahedron Lett.
40: 3773 (1978)). These cyanohydrins are then converted to α-hydroxy acids in making them reflux in concentrated HCl (Org Synth Synth Coll Vol 1: 289 (1941)). A
other method involves the alkylation of trianions of α-hydroxycarboxylic acids at -78 C
with some alkyl chlorides (Newcomb M., et al., J. Org Chem 43: 3963 (1978)) which pipe also to the desired alkylated acids as exemplified by Example 28.
Another one method is the synthesis of α-aryl-alkanoic esters from? -ketoesters, for example ethyl-pyruvate, and aryl nucleophiles such as aryl bromides magnesium (Solomon, RG et al., J. Org. Chem. 47: 4692 (1982)). The aryl magnesium derivatives are in a way prepared by refluxing aryl bromide and magnesium in THF or diethyl ether dry or anhydrous ("dry"). The condensation step takes place doing pass through tubing ("cannulating") the cold derivative magnesium aryl on a-ketoester previously cooled (-78 C) as illustrated by the example 40. Saponification is easily effected by stirring these esters in the presence of KOH in methanol during many hours. Chiral α-aryl-α-hydroxyalkanoic esters are accessible mainly through the addition of organometallic reagents on the chiral α-ketoesters (Basavaiah, D. and Bharathi, TK, Tetrahedron Lett.
32: 3417 (1991)) in using, for example, trans-2-phenylcyclohexanol as a chiral auxiliary.

The acid derivatives (III) in which R3 represents a hydrogen or a alkyl chain, R4 represents an aromatic, and R2 represents an aminocarbonyl are prepared from practical way to from phenylmalonic diesters. The optional alkylation step takes place, In the conditions anhydrous, in the presence of a strong base such as NaH and an agent alkylation R6-X, as defined above, in a dry polar solvent, for example DMF or THF.
Saponification with an equivalent of ethanolic KOH at room temperature allows access to drifts mono-acids which are easily converted into carboxamide derivatives by reaction with a amine NR6R7, as defined above, under peptide conditions classics. This condensation step takes place in the presence of dicyclohexylcarbodiimide and of hydroxybenzotriazole as coupling reagents in an inert solvent of preferably the dichloromethane or DMF (Bodanszky, M. and Bodanszky, A., The Practice of peptide Synthesis, 145 (Springer-Verlag, 1984)). Alternatively, these derivatives carboxamides are accessible by the direct condensation of an amine NR6R7, as described above, with

-21-phenylmalonic diesters by heating them in a mixture of solvents such as than THF / Toluene in the presence of sodium diethyl dihydroaluminate (Sim, TB and Yoon, NM
Synlett 827 (1994)). The deprotection of the second acid function is performed exactly such as previously described.

The peptide coupling reaction of compounds of general formulas (II) and (III) is good known in the prior art (Bodanszky, M. and Bodanszky, A., The Practice of peptide Synthesis, 145 (Springer-Verlag, 1984)). The primary hydroxyl group of composed of general formula (IV) can easily be converted into an eliminable group, for example a sulfonyloxy group, by reaction with a methanesulfonyl chloride in presence of triethylamine in dichloromethane or p-toluenesulfonyl chloride in the pyridine. When R2 represents OH, the selective activation of the primary alcohol will be performed only by means of halogenation-type reactions, for example with formula iodides (V), wherein X is I, which are prepared so practice by reaction with iodine, triphenylphosphine, and imidazole (Garegg, PJ et al., J. Chem.
Soc. Perkin 1, 681 (1982)) as illustrated by the intermediate synthesized in Example 1.2. The reaction of condensation of a compound of general formula (V) with a compound of formula General (VI) (see diagram I) can be carried out by heating the mixture to 80 C in a polar solvent, by acetonitrile, for several hours.

Alternatively, compounds of general formula (I) can be prepared by conventional peptide condensation of a primary amine derivative of formula General (VII) (For a practical preparation see Wu, YH et al., J. Med Chem 12: 876 (1969)) with a acid derivative of general formula (III).

As shown in Scheme II, compounds of the general formula (VI), by the formulas (VIa), (VIb) and (VIc), with a lower alkyl, a hydroxyalkyl, or a Alkoxyalkyl substituents can generally be prepared.

-22-Scheme II
O

H
noun ekNT
O
N (VIII) R-MgX RX, PPh3 OH

RR
(IX) Subst Subst N ~ (XI) NO ~
~ NO
~

R Subst R Subst (VIc) Subst N
N ~ i 1N OH
(VIa) N (X) R
(VI
Subst o b) HDans in Scheme II, R6 as defined above, represents a group alkyl, Subst represents a substituent as defined in R5, and X represents a removable group, for example the methanesulfonyloxy, p-toluenesulfonyloxy, chlorine, bromine or iodine.
The condensation between benzaldehyde derivatives of general formula (VIII) (Walter, HN et al., Synthesis, pp. 641-645 (1987)) and Grignard alkyl reagents in diethyl ether or THF makes it possible to obtain the corresponding secondary alcohol of general formula (IX), as

-23-as illustrated by 36.2. Compounds of general formula (VIa) are obtained by deprotection of compounds of general formula (IX) according to general methods known from debenzylation, for example catalytic hydrogenation or reaction with a chloroformate, such vinylchloroformate or α-chloroethylchloroformate, followed by hydrolysis or methanolysis. Other debenzylation methods such as those found in Green, TW
and Wuts, PGM, Protective Groups in Organic Synthesis, 2d ed., 364, (John Wiley & Sons Inc., 1991) can also be used provided they are compatible with substituents of the aryl ring of the compound of general formula (IX). Compounds Formula (IX) may be O-alkylated under anhydrous conditions at ambient temperature in presence of a strong base, for example NaH, and an alkylating agent R6-X, as defined above, in a dry polar solvent, for example DMF or THF. The debenzylation of compounds of general formula (X) according to the procedure already described allows obtaining compounds of general formula (VIb).

Alternatively, the compounds of general formula (VIII) can be transformed into a compound of general formula (XI) via a reaction of the type Wittig's reaction involving an alkylphosphorane reagent generated from a salt of alkylphosphonium and a strong base, for example nBuLi or phenyllithium, in THF or diethyl ether dry. The compounds of the general formula (VIc) are obtained via a reduction of double bond and a concomitant debenzylation under conditions hydrogenation Catalytic.

Compounds of general formula (I), in which R2 represents OH, can be O-alkylated under anhydrous conditions in the presence of a strong base such as NaH and an agent R6-X alkylation in a dry polar solvent, for example DMF or THF.
Compounds of general formula (I), wherein R2 represents a modified amine (by example a sulphonyl amide or a carboxamide), are synthesized by reaction of a chlorosulfonyl or of a halogenated acid derivative to a free amino acid under conditions similar to those of the Schotten-Baumann procedure (Bodanszky, M. and Bodanszky, A., The Practice of peptide Synthesis, 9 (Springer-Verlag, 1984)).

The following describes the specific chemical synthesis of compounds 1 to 56.
Other compounds according to the invention can be prepared in a similar manner by a man of ordinary art.
Example 1: α-hydroxy-N- [3- {4- (3-methylphenyl) -1-piperazinyl} -propyl]
α-phenylbenzeneacetamide, dihydrochloride (Compound 1):
1.1) α-hydroxy-N- (3-hydroxypropyl) -α-phenyl-benzeneacetamide:

11.34 g (55 mmol) of dicyclohexylcarbodiimide are added at once to a cold solution (0-5 C) 3.82 ml (50 mmol) 3-amino-1-propanol, 7.43 g (55 mmol)

-24-of hydroxybenzotriazole and 11.4 g (50 mmol) of benzylic acid in 60 ml of DMF. The solution is allowed to warm to room temperature and is agitated for 15 hours.
Filtration of precipitated dicyclohexylurea followed by evaporation of mother liquor allows obtaining an oily residue which is dissolved in 150 ml of acetate ethyl. This solution is rinsed successively with water (2 x 100 ml), 1N NaOH (2 x 100 ml) and a saturated solution of NaCl (100 ml). The organic phase is dried on sodium sulfate and the solvent is evaporated under reduced pressure to yield 12.8 g (89%) of compound title as a white solid; mp: 126-127C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.40 (m, 10H, 2 x Ph); 6.95 (m, 1H, CO-NH);
3.98 (s, 1H, OH); 3.45 (m, 4H, C₁ ,H₁ -NH, JZZ); 2.88 (m, 1H, CH 2 -Q, $) 1.63 (m, 2H, CH 2).

1.2) α-hydroxy-N- (3-iodopropyl) -α-phenylbenzeneacetamide 14.26 g (56 mmol) of iodine are added several times to a cold solution (0-5 C) 14.7 g (56 mmol) of triphenylphosphine and 3.82 g (56 mmol) of imidazole in a mixed 90 ml of diethyl ether and 30 ml of acetonitrile. A yellow precipitate forms quickly during stirring at room temperature for one hour. At this yellow suspension, one add a solution of 8 g (28 mmol) of α-hydroxy-N- (3-hydroxypropyl) -a-phenyl-benzeneacetamide in 90 ml of diethyl ether and 30 ml of acetonitrile, and agitation is continued for 15 hours. The resulting mixture is filtered and concentrated in order to obtain a brown oily residue which is purified by flash chromatography (eluent:
light oil (bp 40-65 C) / ethyl acetate: 8/2 then 6/4). Phase evaporation appropriate under reduced pressure makes it possible to obtain 8.86 g (80%) of the title compound under form of a solid pale yellow; mp 105-106C.

1 H-NMR (100 MHz, CDCl3, δ): 7.35 (m, 10H, 2 x Ph); 6.57 (m, 1H, CO-NH);
3.81 (s, 1H, OH); 3.40 (m, 2H, -CH 2 -NH); 3.09 (t, 2H, CH 2 -I); 2.00 (m, 2H, CH2).
1.3) α-hydroxy-N- [3- {4- (3-methylphenyl) -1-piperazinyl} -propyl] -α-phenyl-benzeneacetamide, dihydrochloride:

A mixture of 0.6 g (3.4 mmol) of 1- (3-methylphenyl) piperazine and 1.34 g (3.4 mmol) of α-hydroxy-N- (3-iodopropyl) -α-phenylbenzeneacetamide in 20 ml of acetonitrile is refluxed for 3 hours. After cooling to temperature ambient, the The reaction mixture is concentrated under reduced pressure. The oily residue is dissolved in 50 ml of ethyl acetate and rinsed with 1N NaOH (2 x 50 ml) and water (2 x 50 ml). After the usual treatment, the crude product is purified by flash chromatography (eluent: acetate ethyl). Evaporation of the solvent under reduced pressure gives 0.78 g (52%) from the base of the

-25-Compound 1 which is converted into its hydrochloride salt by a solution ethereal chloride hydrogen; mp 195-196 C.

1 H-NMR (400 MHz, DMSO d6.8): 11.04 (bs, 1H, + NH); 8.42 (t, 1H, NH-CO);
7.35 (m, 10H, 2 x Ph); 7.14 (m, 1H, ph-CH 3); 6.80 (m, 2H, p H-CH 3); 6.70 (m, 1H, Eh-CH3); 6.34 (bs, 1H, OH); 3.75 (d, 2H, + NH-f: 12); 3.45 (d, 2H, C, J7-NH-CO);
3.10 (m, 8H, piperazine); 2.27 (s, 3H, CH 3); 1.91 (m, 2H, CH 2).

Elemental analysis for C28H33N3O2, 2HCl:% Calc: C, 65.11; H, 6.83; NOT, 8.14;
% obtained: C, 65.02; H, 6.80; N, 8.10.

Example 2: α-Hydroxy-N- [3- {4- (2-methylphenyl) -1-piperazinyl} -propyl]
a-phenyl-benzeneacetamide, dihydrochloride. 0.5 H20 (Compound 2):

Compound 2 is prepared in a manner analogous to that of Example 1 except that the 1- (2-methylphenyl) -piperazine is used in place of 1- (3-methylphenyl) piperazine.
1 H-NMR (400 MHz, DMSO d6, S): 10.97 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.34 (m, 10H, 2 x Ph); 7.18 (m, 2H, Ph-CH 3); 7.00 (m, 2H, ph-CH 3); 4.49 (bs, 1H, OH) ; 3.44 (d, 2H, + NH-? Z); 3.23 (m, 2H, CH2-NHCO); 3.09 (m, 8H, piperazine);
2.26 (s, 3H, CH3); 1.94 (m, 2H, CH 2).

Elemental analysis for C28H33N3O2, 2HCl, 0.5 H2O:% Calc: C, 64.00; H
6.90;
N, 8.00; % obtained: C, 63.89; H, 6.87; N, 7.92; mp: 191-192C.

Exe; p ln e 3: α-hydroxy-N- [3- {4- (4-methylphenyl) -1-piperazinyl} -propyl] -a.-phenylbenzeneacetamide, dihydrochloride (Compound 3):

Compound 3 is prepared in a manner analogous to that of Example 1, except that the 1- (4-methylphenyl) -piperazine is used in place of 1- (3-methylphenyl) piperazine;
mp: 204.5 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 11.00 (bs, 1H, + NH); 8.42 (t, 1H, NH-CO);
7.33 (m, 10H, 2 x Ph); 7.00 (m, 4H, a-CH 3); 6.78 (bs, 1H, OH); 3.68 (d, 2H, + NH-CH2,); 3.45 (d, 2H, CH2 -NH-CO); 3.15 (m, 8H, piperazine); 2.22 (s, 3H, CH3);
1.93 (m, 2H, CH 2).

Elemental analysis for C28H33N3O2, 2HCl:% Calc: C, 65.11; H, 6.83; NOT, 8.14;
% obtained: C, 64.91; H, 6.89; N, 8.11.

-26-Example 4: N- [3- {4- (2,3-dimethylphenyl) -1-piperazinyl} -propyl]
α-hydroxy-α-phenyl-benzeneacetamide, hydrochloride, 0.25 H 2 O
(Compound 4):

Compound 4 is prepared in a manner analogous to that of Example 1 except that the 1- (2,3-dimethylphenyl) -piperazine is used in place of 1- (3-methylphenyl) -piperazine;
mp: 125-126 C.

1 H-NMR (400 MHz, DMSO d6, S): 11.05 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.39 (m, OH, 2 x Ph); 7.07 (m, 1H, Ph-CH 3); 6.93 (m, 1H, Ph-CH 3); 6.89 (m, 1H, ph-CH3); 4.34 (bs, 1H, OH); 3.43 (d, 2H, + NH-CI2); 3.23 (m, 2H, ÇU2 -NH-CO);
3.06 (m, 8H, piperazine); 2.22 (s, 3H, CH3); 2.17 (s, 3H, CH 3); 1.95 (m, 2H, CH2).
Elemental analysis for C29H35N3O2, HCl, 0.25 H2O:% Calc: C, 69.86; H
7.38 N, 8.43; 0, 7.22; % obtained: C, 69.93; H, 7.63; N, 8.53; 0, 7.41.

Example 5: N- [3- {4- (2,4-dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy-a-phenyl-benzeneacetamide, fumarate, monohydrate (Compound 5):

Compound 5 is prepared in a manner analogous to that of Example 1 except that the 1- (2,4-dimethylphenyl) -piperazine is used in place of 1- (3-methylphenyl) -piperazine;
mp: 177 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.35 (t, 1H, NH-CO); 7.35 (m, 10H, 2 x Ph);
6.93 (m, 3H, Ph-CH 3); 6.75 (bs, OH, COOH); 6.62 (s, 2H, CH = CH); 3.39 (m, 2H, ,, H2-NH-CO); 2.87 (bs, 4H, piperazine); 2.71 (bs, 4H, piperazine); 2.56 (m, 2H, N-CH2); 2.20 (s, 6H, 2 x CH 3); 1.71 (m, 2H, CH 2).

Elemental analysis for C29H35N302, fumarate, monohydrate:% Calc: C, 66.99 ;
H, 6.98; N, 7.10; 0, 18.93; % obtained: C, 67.21; H, 6.72; N, 6.87; 0 18.80.
Example 6 N- [3- {4- (2,6-dimethylphenyl) -1-piperazinyl} -propyl]
α-hydroxy-α-phenyl-benzeneacetamide, hydrochloride, 0.5 H2O
(Compound 6):

Compound 6 is prepared in a manner analogous to that of Example 1 except that the 1- (2,6-dimethylphenyl) -piperazine is used instead of 1- (3-methylphenyl) -piperazine;
mp 183-184C.

1 H-NMR (400 MHz, DMSO d6, S): 10.69 (bs, 1H, + NH); 8.44 (t, 1H, NH-CO);
7.35 (m, 10H, 2 x Ph); 7.04 (m, 1H, Eh-CH 3); 6.97 (m, 2H, Eh-CH 3); 3.65 (t, 2H,

-27-+ NH- ~ 2); 3.34 (bs, 1H, OH); 3.71-2.93 (m, 8H, piperazine); 3.22 (m, 2H, ,, Hz-NHCO); 2.29 (s, 3H, CH3); 2.27 (s, 3H, CH 3); 1.93 (m, 2H, CH 2).

Elemental analysis for C29H35N3O2, HCl, 0.5 H2O:% Calc: C, 69.24; H, 7.41 N, 8.35; 0, 7.95%, obtained: C, 69.59; H, 7.72; N, 8.42; 0, 7.65.

Example 7: N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
α-hydroxy-α-phenyl-benzeneacetamide, 1.5 HCl, 0.25 H 2 O
(Compound 7):

Compound 7 is prepared in a manner analogous to that of Example 1, except that the 1- (2,5-dimethylphenyl) -piperazine is used in place of 1- (3-methylphenyl) -piperazine;
t0 pf: 171-172C.

1 H-NMR (400 MHz, DMSO d6, S): 11.01 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.34 (m, 10H, 2 x Ph); 7.06 (d, 1H, Ph-CH 3, J = 7.5 Hz); 6.82 (d, 2H, Ph-CH3);
6.90 (bs, 1H, OH); 3.43 (m, 2H, + NH-Ca 2); 3.22 (m, 2H, Ce-NHCO); 3.10 (m, 8H, piperazine); 2.26 (s, 3H, CH3); 2.20 (s, 3H, CH 3); 1.93 (m, 2H, CH 2).

Elemental analysis for C30H37N3O2, 1.5 HCl, 0.25 H2O:% Calc: C, 67.40;
H, 7.22; N, 8.13; 0.69; % obtained: C, 67.10; H, 7.17; N, 8.22; 0 7.25.
Example 8: N- [3- {4- (2-ethoxyphenyl) -1-piperazinyl} -propyl] -α-hydroxy α-phenylbenzeneacetamide, 2 HCl, 0.25 H 2 O (Compound 8):
Compound 8 is prepared in a manner analogous to that of Example 1, except that the 1- (2-ethoxyphenyl) -piperazine is used in place of 1- (3-methylphenyl) piperazine;
mp: 189 C.

1 H-NMR (400 MHz, DMSO d6.8): 11.01 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.34 (m, 10H, 2 x Ph); 6.96 (m, 4H, E-N); 5.36 (bs, 1H, OH); 4.04 (q, 2H, OCH 2, J = 6.95 Hz); 3.48 (m, 4H, + NH 2 CI 2 + piperazine); 3.22 (m, 2H, -H 2 -NHCO);
3.05 (m, 6H, piperazine); 1.93 (m, 2H, CH 2); 1.37 (t, 3H, CH 3).

Elemental analysis for C29H35N3O3, 2HCl, 0.25 H2O:% Calc: C, 63.21; H
6.86;
N, 7.63; 0, 9.44; % obtained: C, 63.16; H, 6.85; N, 7.60; 0, 9.64.

-28-Example 9 N- [3- {4- (2-chlorophenyl) -1-piperazinyl} -propyl] -α-hydroxy a-phenyl-benzeneacetamide fumarate (Compound 9):

Compound 9 is prepared in a manner analogous to that of Example 1 except that the 1- (2-chlorophenyl)) piperazine is used instead of 1- (3-methylphenyl) -piperazine;
mp: 190 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.38 (t, 1H, NH-CO); 7.34 (m, 12H, 2 x Ph +
Ph-Cl); 7.16 (m, 1H, Ph-Cl); 7.03 (m, 1H, Ph-Cl); 6.68 (bs, 1H, OH); 6.61 (s, 2H, CH = CH); 3.20 (m, 2H, Na-NHCO); 3.00 (bs, 4H, piperazine); 2.58 (bs, 4H, piperazine); 2.43 (m, 2H, CH 2 -N); 1.66 (m, 2H, CH 2).

Elemental analysis for C27H30ClN2O2, fumarate:% Calc: C, 64.19; H, 5.91 N, 7.24; % obtained: C, 64.13; H, 5.90; N, 7.27.

Example 10 N- [3- {4- (2-cyanophenyl) -1-piperazinyl} -propyl] -α-hydroxy a-phenylbenzeneacetamide hydrochloride monohydrate (Compound 10):

Compound 10 is prepared in a manner analogous to that of Example 1 except that the 1- (2-cyanophenyl) -piperazine is used in place of 1- (3-methylphenyl) -piperazine;
mp: 168 C.

1 H-NMR (400 MHz, DMSO d6, S): 10.91 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.78 (m, 1H, Ph-CN); 7.66 (m, 1H, Ph-CN); 7.34 (m, 12H, 2 x Ph + Ph-CN);
3.57 (m, 4H, + NH 4 + 12 + piperazine); 3.35 (m, OH + piperazine); 3.18 (m, 2H, U2-NHCO); 3.10 (m, 4H, piperazine); 1.93 (m, 2H, CH 2).

Elemental analysis for C 28 H 30 N 4 O 2, HCl, H 2 O:% Calc: C, 66.07; H, 6.53 N, 11.01%, obtained: C, 65.91; H, 6.50; N, 11.01.

Example 11: N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-methoxy-a-phenyl-benzeneacetamide hydrochloride, monohydrate (Compound 11):

0.51 g (1 mmol) of N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a-hydroxy a-phenyl-benzeneacetamide (Example 7) is introduced into a three-necked flask anhydrous equipped a nitrogen inlet and "septa" type plugs. Dry DMF (10 ml) is added and the solution is cooled to 0-5 C with an ice bath. Hydride sodium (0.08 g, 2 mmol) is then added all at once and the mixture is allowed to warm up up to temperature room. After one hour, 0.06 ml (1 mmol) of methyl iodide is introduced drip

-29-using a syringe in the balloon. After mixing for two other hours the The mixture is concentrated and the residue dissolved in 25 ml of ethyl acetate.
This solution is rinsed successively with water (2 x 20 ml) and a saturated solution of NaCl (20 ml). The organic phase is dried over sodium sulfate and evaporated under pressure reduced so to obtain an oil which is purified by flash chromatography (eluent dichloromethane / methanol 95/5). Evaporation of the phases collected under reduced pressure gives 0.18 g (38%) of the base of Compound 11. This is converted into its salt of hydrochloride as described above; mp: 125-126 C.

1 H-NMR (400 MHz, DMSO d6, S): 10.82 (bs, 1H, + NH); 8.57 (t, 1H, NH-CO);
7.37 (m, 10H, 2 x Ph); 7.07 (d, 1H, M-CH 3); 6.82 (m, 2H, Ph-CH 3); 3.38 (m, 2H, + NH-Cli2); 3.21 (m, 2H, _-2-NHCO); 3.17-2.80 (m, 8H, piperazine); 2.98 (s, 3H, OCH3); 2.26 (s, 3H, CH3); 2.21 (s, 3H, CH3); 1.90 (m, 2H, CH 2).

Elemental analysis for C30H37N3O2, HCl, H2O:% Calc: C, 68.49; H, 7.66;
N, 7.99; % obtained: C, 68.24; H, 7.52; N, 7.99.

Example 12: α-Benzyloxy-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl}
propyl] -oc-phenyl-benzeneacetamide (Compound 12):

Compound 12 is prepared in a manner analogous to that of Example 11 except only benzyl bromide is used instead of methyl iodide in the stage O-alkylation;
mp: 171 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.53 (m, 1H, NH-CO); 7.32 (m, 10H, 2 x Ph);
7.07 (d, 1H, P H-CH 3, J = 7.5 Hz); 6.82 (d, 2H, F - CH 3); 3.54 (m, 2H, U2-NHCO); 3.28-3.10 (m, 8H, piperazine); 2.27 (s, 3H, CH 3); 2.18 (s, 3H, CH3) 2.10 (m, 2H, CH 2).

Example 13: N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] -α-phenyl benzeneacetamide, dihydrochloride (Compound 13):

0.424 g (2 mmol) of diphenylacetic acid, 0.498 g (2 mmol) of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl-1-amine (Wu, YH et al., J. Med Chem., 12: 876 (1969)) and 0.297 g (2.2 mmol) of hydroxybenzotriazole are dissolved in 15 ml of THF. The solution is cooled to 0-5 C before addition of 0.453 g (2.2 mmol) of dicyclohexylcarbodiimide. We continue stirring at room temperature for 15 hours. The mixture resulting is filtered, the insoluble materials are rinsed with the minimum of THF and the filtrate is evaporated under pressure scaled down. The oily residue is dissolved in 50 ml of ethyl acetate and rinsed successively with H 2 O (2 x 25 ml), 0.1 N NaOH (25 ml) and saturated chloride solution sodium.
The organic phase is dried over sodium sulfate and evaporated to dryness. The residue

-30-is subjected to flash chromatography on silica gel (eluent dichloromethane / methanol 95/5). Evaporation of the phases collected under reduced pressure gives 0.505 g (55%) of the title compound which is salt form by the use of a anhydrous solution of hydrogen chloride in diethyl ether; pf: 198-199 vs.

1 H-NMR (100 MHz, CDCl 3, δ [free base]): 7.30 (m, 11H, 2 x Ph + NH-CO);
6.90 (m, 4H, Ph-OCH 3); 4.88 (s, 1H, CH); 3.90 (s, 3H, OCH3); 3.40 (m, 2H, (1-NH-CO); 3.15-2.50 (m, 8H, piperazine); 2.50 (m, 2H, NH-Cl2); 1.70 ( m, 2H, CH2).

Elemental analysis for C28H33N3O2, 2HCl:% Calc: C, 65.11; H, 6.83; NOT, 8.14;
% obtained: C, 64.82; H, 6.90; N, 8.01.

Example 14: α-Hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propylate]
α-phenylbenzeneacetamide, dihydrochloride, 0.25 H 2 O
(Compound 14):

Compound 14 is prepared in a manner analogous to that of Example 13 except that the acid benzyl is used in place of diphenylacetic acid; pf: 191-192 vs.

1 H-NMR (400 MHz, DMSO d6, S): 10.93 (bs, 1H, + NH); 8.43 (t, 1H, NH-CO);
7.36 (m, 10H, 2 x Ph); 6.95 (m, 4H, α-OCH 3); 4.85 (bs, 1H, OH); 3.80 (s, 3H, OCH3); 3.45 (m, 2H, + NH-çH,; 3.21 (m, 2H, -11-NHCO); 3.40-2.95 (m, 8H, piperazine); 1.92 (m, 2H, CH 2).

Elemental analysis for C28H33N3O3, 2HCl, 0.25 H2O:% Calc: C, 62.63; H
6.66;
N, 7.82; 0, 9.68; % obtained: C, 62.59; H, 6.88; N, 7.93; 0, 9.59.

Example 15: N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] -9H-xanthene-9-carboxamide, dihydrochloride (Compound 15):

Compound 15 is prepared in a manner analogous to that of Example 13 except that the acid 9H-xanthene-9-carboxylic acid is used in place of diphenylacetic acid ;
mp: 257-258 ° C.

1 H-NMR (100 MHz, CDCl 3, δ [free base]): 7.50-6.80 (m, 12H, xanthene + Ph-OCH3);
6.27 (m, 1H, NH-CO); 4.92 (s, 1H, CH); 3.85 (s, 3H, OCH 3); 3.25 (m, 2H, C12H-NH-CO); 3.00-2.30 (m, 8H, piperazine); 2.25 (m, 2H, NH-m 2); 1.60 (m, 2H, CH2).

Elemental analysis for C28H31N3O3, 2HCl:% Calc: C, 63.40; H, 6.27; NOT, 7.92;
% obtained: C, 63.22; H, 6.30; N, 7.74.

-31 Example 16: 9-hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl]
9H-Fluorene-9-carboxamide, dihydrochloride, monohydrate (Compound 16):

Compound 16 is prepared in a manner analogous to that of Example 13 that the acid 9-hydroxy-9-fluorene carboxylic acid is used in place of the acid diphenylacetic;
mp 186-187C.

1 H-NMR (100 MHz, CDCl 3, δ [free base]): 7.70-7.25 (in, 8H, fluorene); 6.97 (m, 4H, OCH3); 6.30 (m, 1H, NH-CO); 3.85 (s, 3H, OCH 3); 3.30 (m, 2H, CH 2 -NH-CO) ;
2.90-2.30 (m, 8H, piperazine); 2.20 (m, 2H, NH-Cl2); 1.65 (m, 3H, OH +
CH2).

Elemental analysis for C28H31N3O3, 2HCl, H2O:% Ca1: C, 61.31; H, 6.43 ;
N, 7.66; % obtained: C, 61.32; H, 6.25; N, 7.64.

Example 17: 2-Chioro-α- (2-chlorophenyl) -α-hydroxy-N-[3- {4- (2-methoxyphenyl) -1 = piperazinyl} -propyl] -benzeneacetamide, monohydrochloride, monohydrate (Compound 17):

Compound 17 is prepared in a manner analogous to that of Example 13 except that the acid 2,2'-dichlorobenzyl is used in place of diphenylacetic acid;
mp 185-186C.
1 H-NMR (100 MHz, CDCl3, S [free base]): 7.75 (m, 1H, NH-CO); 7.30 (m, 8H, 2 x Ph-Cl); 6.90 (m, 4H, Ph-OCH 3); 3.88 (s, 3H, OCH3); 3.52 (m, 2H, ~, RI-NH-CO); 3.10 - 2.40 (m, 8H, piperazine); 2.50 (m, 2H, NH₂Cl₂); 1.80 (m, 2H, CH2).
Elemental analysis for C28H31Cl2N3O3, HCl, H2O:% Calc: C, 57.69; H, 5.88 ;
N, 7.21; % obtained: C, 57.42; H, 5.84; N, 6.67.

Example 18: (t) -α-cyclohexyl-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl}
propylJ-benzeneacetamide, dihydrochloride, monohydrate (Compound 18):

Compound 18 is prepared in a manner analogous to that of Example 13 except that the acid () -cyclohexylphenyl acetic acid is used in place of the acid diphenylacetic;
mp: 160-161C.

1 H-NMR (400 MHz, DMSO d6, S): 10.94 (bs, 1H, + NH); 8.32 (m, 1H, NH-CO);
7.28 (m, 5H, Ph); 6.95 (m, 4H, Ph-OCH 3); 3.80 (s, 3H, OCH3); 3.42 (m, 2H, + NH- ~ Hz); 3.42-2.90 (m, 8H, piperazine); 3.05 (m, 2H, -NH-NH-CO); 2.00 to 0.68 (M, 13H, cyclohexyl + CH2).

-32-Elemental analysis for C28H39N3O2, 2HCl, H2O:% Calc: C, 62.21; H, 7.83;
N, 7.77; % obtained: C, 62.09; H, 7.89; N, 7.60.

Example 19: (t) -oc-hydroxy-N- [3- {4- (2-methoxyphenyl) -1-piperazinyl} -propyl] benzeneacetamide, dihydrochloride, monohydrate (Compound 19):

Compound 19 is prepared in a manner analogous to that of Example 13 except that the acid () Mandelic is used in place of diphenylacetic acid; pf: 169 vs.

1 H-NMR (400 MHz, DMSO d6, S): 10.94 (bs, 1H, + NH); 8.27 (m, 1H, NH-CO);
7.35 (m, 5H, Ph); 6.95 (m, 4H, Ph-OCH 3); 5.70 (bs, OH); 4.95 (s, 1H, CH);
3.80 (s, 3H, OCH3); 3.42 (m, 2H, + NH - CH 2 --H 2); 3.25-3.02 (m, 10H, piperazine + cu2-NH-CO); 1.90 (m, 2H, CH 2).

Elemental analysis for C22H29N3O3, 2HCl, H2O:% Calc: C, 55.70; H, 7.01 N, 8.86%, obtained: C, 55.23; H, 6.90; N, 8.84.

Example 20: N- [3- {4- (2,5-Dimethyl-phenyl) -1-piperazinyl} -propyl]
α-Phenyl-benzeneacetamide, 1.5 HCl, H 2 O (Compound 20):
20.1) 3- [4- (2,5-Dimethylphenyl) -1-piperazinyl] propyl-1-amine:

This intermediate is synthesized using the same procedure as that described by Wu, YH
et al., J. Med. Chem., 12: 876 (1969); mp: 102 C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.10 (d, 1H, 6H-CH 3, J = 7.5 Hz); 6.80 (m, 2H, ? -CH3); 3.10 (m, 12H, CH 2 -N + CH 2 -NH 2 + piperazine); 2.30 (s, 3H, CH 3) 2.26 (s, 3H, CH3); 1.70 (m, 2H, CH 2); 1.62 (s, NH 2).

20.2) N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-phenyl-benzeneacetamide, 1.5 HCl, H 2 O:

Compound 20 is prepared in a manner analogous to that of Example 13 except that the 3- [4- (2,5-dimethylphenyl) -1-piperazinyl] -propyl-1-amine is used in the place of the 3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl-1-amine; mp: 151 C.

1 H-NMR (400 MHz, DMSO d6, S): 10.96 (bs, 1H, + NH); 8.62 (m, 1H, NH-CO);
7.27 (m, 10H, 2 x Ph); 7.06 (d, 1H, Ph-CH 3, J = 7.5 Hz); 6.82 (d, 1H, Ph-CH3) 4.99 (s, 1H, CH); 3.44 (m, 2H, + NH 2 CI 2); 3.18 (m, 2H, CEZ-NH-CO); 3.12 (m, 8H, piperazine); 2.26 (s, 3H, CH3); 2.19 (s, 3H, CH 3); 1.91 (m, 2H, CH 2).

-33-Elemental analysis for C29H35N3O, 1.5 HCl, H20:% Calc: C, 67.72; H, 7.55 N, 8.17; 0, 6.22; % obtained: C, 67.56; H, 7.51; N, 8.17; 0, 6.48.

Example 21: 4-chloro-α- (4-chlorophenyl) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] benzeneacetamide fumarate (Compound 21) Compound 21 is prepared in a manner analogous to that of Example 20 except that the acid 4,4'-dichloro-diphenylacetic is used instead of acid diphenylacetic;
mp: 139 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.36 (m, 1H, NH-CO); 7.34 (m, 8H, 2 x Ph-Cl);
7.01 (d, 1H, Ph-CH 3, J = 8 Hz); 6.79 (s, 1H, a-CH 3); 6.75 (d, 1H, ph-CH3) 6.61 (s, 2H, CH = CH); 4.95 (s, 1H, CH); 3.13 (m, 2H, CH 2 Z -NH-CO); 2.81 (bs, 4H, piperazine); 2.52 (bs, 4H, piperazine); 2.38 (m, 2H, CH 2 -N); 2.23 (s, 3H, CH3) 2.17 (s, 3H, CH 3); 1.62 (m, 2H, CH 2).

Elemental analysis for C29H33Cl2N3O fumarate:% Calc: C, 63.26; H, 5.95 N, 6.71; % obtained: C, 63.60; H, 6.03; N, 6.78.

Example 22: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
α-hydroxy-α-methyl-benzeneacetamide, 1.25 HCl, 0.75 H 2 O
(Compound 22):

Compound 22 is prepared in a manner analogous to that of Example 20 except that the acid () -atrolactic is used in place of diphenylacetic acid; pf:
155 C.

1 H-NMR (400 MHz, DMSO d6, S): 10.82 (bs, 1H, + NH); 8.16 (m, 1H, NH-CO);
7.56 (m, 2H, Ph); 7.34 (m, 2H, Ph); 7.24 (m, 1H, Ph); 7.06 (d, 1H, a-CH 3, J = 8 Hz); 6.82 (m, 2H, Ph-CH 3); 4.87 (bs, OH); 3.39 (m, 2H, + NH-CII);
3.17-2.97 (m, 10H, piperazine + α-Z-NH-CO); 2.26 (s, 3H, Ph-3); 2.20 (s, 3H, Ph-BC3); 1.86 (m, 2H, CH 2); 1.64 (s, 3H, CH3).

Elemental analysis for C24H33N3O2, 1.25 HCl, 0.75 H2O:% Calc: C, 63.41 H, 7.93; N, 9.24; 0, 9.68; % obtained: C, 63.56; H, 7.83; N, 9.15; 0 9.46.
Example 23: N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
α-methyl-α-phenyl-benzeneacetamide, 1.5 HCl, 1.25 H 2 O
(Compound 23):

Compound 23 is prepared in a manner analogous to that of Example 20 except that the acid 2,2-diphenylpropionic acid is used in place of diphenylacetic acid;
mp: 90 C.

-34-1 H-NMR (400 MHz, DMSO d6, S): 7.67 (m, 1H, NH-CO); 7.26 (m, 10H, 2 x Ph);
7.07 (d, 1H, -CH 3, J = 8 Hz); 6.82 (m, 2H, M-CH 3); 6.56 (bs, 1H, + NH) 3.39 (m, 2H, + NH-LUZ); 3.20-2.97 (m, 10H, piperazine + CH2-NH-CO); 2.26 (s, 3H, Ph-.-1g); 2.21 (s, 3H, Ph-CH3.); 1.88 (m, 5H, CH 2 + CH 3).

Elemental analysis for C30H37N3O, 1.5 HCl, 1.25 H20:% Calc: C, 67.62 H, 7.76; N, 7.89; 0, 6.76; % obtained: C, 67.82; H, 7.80; N, 7.51; 0 6.57.
EXAMPLE 24: N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-ethylthio-α-phenylbenzeneacetamide, 0.5 fumarate (Compound 24):

Compound 24 is prepared in a manner analogous to that of Example 20 except that the acid 2-ethylthio-2,2-diphenylacetic is used in place of the acid diphenylacetic;
mp: 157C

1 H-NMR (400 MHz, DMSO d6, S): 7.94 (m, 1H, NH-CO); 7.32 (m, 10H, 2 x Ph);
7.01 (d, 1H, p H-CH 3, J = 7.4 Hz); 6.75 (m, 2H, P H - CH 3); 6.60 (s, 1H, 1/2 CH = CH); 3.60 (bs, COOH); 3.19 (m, 2H, CBZ-NH-CO); 2.77 (bs, 4H, piperazine); 2.50 (m, 4H, piperazine); 2.33 (m, 2H, CII 2 -N); 2.24 (s, 3H, Ph-CA3.) 2.16 (m, 5H, Ph-3 + S-1H1); 1.62 (m, 2H, CH 2); 0.99 (t, 3H, CHI-CH 2 -S, J = 7.5 Hz).

Elemental analysis for C31H39N3OS, 0.5 fumarate:% Calc: C, 70.81; H
7.38 N, 7.51; S, 5.73; % obtained: C, 70.69; H, 7.33; N, 7.11; S, 5.96.

EXAMPLE 25 N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy-4-methoxy-a- (4-methoxyphenyl) -benzeneacetamide, HCl, 0.5 H2O (Compound 25):

Compound 25 is prepared in a manner analogous to that of Example 20 except that the acid 4,4'-Dimethoxybenzyl (Toda, F. et al Chem Chem Letts, pp. 373-376 (1990)) is used at the diphenylacetic acid; mp: 173 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 11.19 (bs, 1H, + NH); 8.37 (m, 1H, NH-CO);
7.70 (bs, OH); 7.29 (d, 4H, 2 x P -h-OCH 3, J = 8.6 Hz); 7.05 (d, 1H, n-CH 3, J = 7.7 Hz); 6.87 (d, 4H, 2 x P h -OCH 3); 6.83 (m, 2H, n-CH 3); 3.73 (s, 6H, 2 x OCH3); 3.42 (m, 2H, + NH-Cl2); 3.30-2.95 (m, 10H, piperazine + ~ Hj-NH-CO); 2.26 (s, 3H, Ph-Cl, 1); 2.20 (s, 3H, Ph-Cl3); 1.94 (m, 2H, CH 2).

-35-Example 26: N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
2-ethyl-2-phenyl-butyramide, dihydrochloride, monohydrate (Compound 26):

Compound 26 is prepared in a manner analogous to that of Example 20 except that the acid 2-ethyl-2-phenylbutyric acid is used in place of diphenylacetic acid;
mp 195 C.
1 H-NMR (400 MHz, DMSO d6, S): 11.12 (bs, 1H, + NH); 7.65 (m, 1H, NH-CO);
7.28 (m, 10H, 2 x Ph); 7.06 (d, 1H, Ph-CH 3, J = 8 Hz); 6.82 (m, 2H, a-CH 3);
3.40 (m, 2H, + NH - I2); 3.05 (m, 8H, piperazine); 2.92 (m, 2H, CH 2 -NH-CO);
2.26 (s, 3H, Ph-3-1); 2.20 (s, 3H, Ph-Cl3); 1.91 (m, 6H, 3 x CH 2); 0.63 (t, 6H, 2 x ~-13-CH 2, J = 7.2 Hz).

Elemental analysis for C27H39N3O, 2HCl, H20:% Calc: C, 63.27; H, 8.46;
N, 8.20; 0, 6.24; % obtained: C, 63.67; H, 8.57; N, 8.19; 0.63.

Example 27: (f) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -2-hydroxy-2-phenyl-butyramide, fumarate (Compound 27):

Compound 27 is prepared in a manner analogous to that of Example 20 except that the acid a-hydroxy-cc-phenyl-butyric acid is used in place of the acid diphenylacetic;
mp 179 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.03 (m, 1H, NH-CO); 7.55 (d, 2H, Ph, J = 7.5 Hz); 7.30 (m, 2H, Ph); 7.22 (m, 1H, Ph); 7.02 (d, 1H, ph-CH3, J = 7.5 Hz); 6.81 (s, 1H, P 1 -CH 3); 6.76 (d, 1H, a-CH 3); 6.60 (s, 2H, CH = CH) 3.10 (m, 2H, 2H-NHCO); 2.86 (bs, 4H, piperazine); 2.58 (bs, 4H, piperazine) 2.41 (m, 2H, CH 2 -N); 2.24 (s, 3H, CH 3); 2.21 (m, 1H, CH 2 -CH 3); 2.17 (s, 3H, CH3); 1.86 (m, 1H, C16-CH3); 1.60 (m, 2H, CH 2); 0.79 (t, 3H, CH 2 -Clil, J = 7.2 Hz).

Elemental analysis for C25H35N302, fumarate:% Calc: C, 66.27; H, 7.48 N, 7.99; % obtained: C, 66.28; H, 7.35; N, 7.98.

Example 28: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -2-hydroxy-2-phenylhexanamide, fumarate (Compound 28):
28.1) (2-hydroxy-2-phenylhexanoic acid):

This intermediate is described by Newcomb M., et al. (J. Org Chem., 43: 3963 (1978));
mp: 102 C.

-36-1 H-NMR (100 MHz, CDCl 3, δ): 7.52 (m, 5H, Ph); 5.75 (bs, OH + COOH); 2.10 (M, 2H, CH2-C-OH); 1.33 (m, 4H, CH 2 -CH 2); 0.90 (m, 3H, CH 3).

28.2) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -2-hydroxy-2-phenylhexanamide, fumarate:

Compound 28 is prepared in a manner analogous to that of Example 20 except that the acid (t) -2-hydroxy-2-phenyl-hexanoic acid is used instead of acid diphenylacetic;
mp: 147 ° C

1 H-NMR (400 MHz, DMSO d6, S): 8.01 (m, 1H, NH-CO); 7.55 (d, 2H, Ph, J = 7.5 Hz); 7.25 (m, 3H, Ph); 7.02 (d, 1H, Ph-CH 3, J = 7.5 Hz); 6.81 (s, 1H, Pji-CH3); 6.76 (d, 1H, a-CH 3); 6.60 (s, 2H, CH = CH); 5.85 (bs, OH + COOH);
3.10 (m, 2H, -12-NHCO); 2.85 (bs, 4H, piperazine); 2.57 (bs, 4H, piperazine) ;
2.39 (m, 2H, CH 2 -N); 2.24 (s, 3H, Ph-C3); 2.17 (s, 3H, Ph-CH-3.); 2.14 (m, 1H, 1/2 Cl2-C-OH); 1.84 (m, 1H, 1/2 .B2-C-OH); 1.59 (m, 2H, CH 2); 1.25 (m, 4H, CE.2-,, U2, -CH3); 1.18 (t, 3H, CH 2 -Cl-1-3, J = 6.9 Hz).

Elemental analysis for C27H39N3O2, fumarate:% Calc: C, 67.25; H, 7.83;
N, 7.59; % obtained: C, 66.76; H, 7.69; N, 7.58.

Example 29: () -2-Chloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy- (x-methyl-benzeneacetamide, fumarate, monohydrate (Compound 29):

29.1) () -2-Chloro-α-hydroxy-α-methyl-benzeneacetonitrile This compound is synthesized using the same procedure as described by Gassman, PG
et al., Tetrahedron Lett., 40: 3773 (1978).

1 H-NMR (100 MHz, CDCl 3, δ): 7.50 (m, 4H, Ph); 3.78 (bs, 1H, OH); 2.06 (s, 3H, CH3).

29.2) (2-Chloro-α-hydroxy-α-methyl-benzeneacetic acid) A mixture of 2.3 g (12.7 mmol) of (t) -2-chloro-α-hydroxy-α-methyl-benzèneacétrônitrile and 20 ml of concentrated HCl is heated at 60 ° C for 3 hours and then reflux during 2 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is separated between diethyl ether (50 ml) and 1N NaOH (50 ml). The sentence organic is extracted twice with 25 ml of 1N NaOH, and all the basic phases are united together before acidification with concentrated HCl. The product is extracted with 2 x 50 ml of

-37-diethyl ether, then the solution is dried over sodium sulphate and evaporated under vacuum for give 930 mg (36%) of a white powder; mp: 110-111 C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.50 (m, 4H, Ph); 6.47 (bs, 2H, OH + COOH);
1.90 (s, 3H, CH3).

29.3) (t) -2-Chloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-benzeneacetamide, fumarate, monohydrate:

Compound 29 is prepared in a manner analogous to that of Example 20 except that the acid (t) -2-chloro-α-hydroxy-α-methyl-benzeneacetic acid is used in place of acid diphenylacetic; mp: 84C

1 H-NMR (400 MHz, DMSO d6, S): 7.90 (m, 1H, NU-CO); 7.62 (m, 1H, pjl-Cl) 7.34 (m, 3H, bp CI); 7.03 (d, 1H, Eh-CH 3, J = 7.5 Hz); 6.78 (m, 2H, n-CH 3) 6.61 (s, 2H, CH = CH); 6.02 (bs, OH + COOH); 3.19 (m, 2H, CH -NHCO); 2.90 (Bs, 4H, piperazine); 2.76 (bs, 4H, piperazine); 2.62 (m, 2H, CH 2 -N); 2.24 (s, 3H, CH3) 2.18 (s, 3H, CH 3); 1.72 (m, 5H, CH 2 + CH 3).

Elemental analysis for C24H32ClN3O2, fumarate, H2O:% Calc: C, 59.62; H
6.79;
N, 7.45; % obtained: C, 59.54; H, 6.47; N, 7.10.

Example 30: (4) -Chloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] - (x-hydroxy-α-methyl-benzeneacetamide, 1.25 HCl, 0.5 H2O (Compound 30):

30.1) (4-Chloro-α-hydroxy-α-methyl-benzeneacetic acid:

This compound is prepared in a manner analogous to that of intermediate 29.2 except that the (4-chloro-α-hydroxy-α-methyl-benzeneacetonitrile (Gassman, PG et al.
Tetrahedron Lett., 40: 3773 (1978)) is used in place of () -2-chloro-a-hydroxy-a-methyl benzeneacetonitrile.

1 H-NMR (100 MHz, CDCl 3, δ): 7.45 (m, 4H, Ph); 6.80 (bs, 2H, OH + COOH);
1.80 (s, 3H, CH 3).

30.2) () -4-Chloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-benzeneacetamide, 1.25 HCl, 0.5 H2O Compound 30 is prepared in a manner analogous to that of Example 20 except that the acid (f) 4-chloro-α-hydroxy-α-methyl-benzeneacetic acid is used in place of acid diphenylacetic; mp: 161.5 ° C.

-38-1 H-NMR (400 MHz, DMSO d6, S): 10.95 (bs, 1H, + NH); 8.20 (m, 1H, NH-CO);
7.56 (m, 2H, Ph-Cl); 7.39 (m, 2H, Ph-Cl); 7.06 (d, 1H, Eh-CH 3, J = 8 Hz);
6.82 (m, 2H, CH 3); 5.70 (bs, OH); 3.44 (m, 2H, + NH-C11); 3.16-2.99 (m, 10H, piperazine + H2-NH-CO); 2.26 (s, 3H, Ph-CH-3); 2.20 (s, 3H, Ph-Cl3); 1.87 (M, 2H, CH 2); 1.62 (s, 3H, CH 3).

Elemental analysis for C24H32ClN2O2, 1.25 HCl, 0.5 H2O:% Calc: C, 59.49;
H, 7.12; N, 8.67; % obtained: C, 59.46; H, 7.01; N, 8.51.

Example 31: () -3-Chloro-N- [3 {4- (2,5-dimethylphenyl) -1-piperazinyl}
propyl] -α-hydroxy-α-methyl-benzeneacetamide, fumarate (Compound 31) 31.1) Ethyl ester of () -3-chloro-α-hydroxy-α-methyl-benzeneacetic:

In an anhydrous three-neck flask equipped with a nitrogen inlet, a funnel, and a reflux condenser are introduced 400 mg (0.016 ag) of powder of magnesium, some drops of a solution of 3-bromochlorobenzene (1.94 ml, 16.5 mmol) in 10 ml of dry diethyl ether, and a crystal of iodine. The mixture is gently heated until reaction begins, then the residue of 3-bromochlorobenzene is added drop drop to a flow that keeps the reflux. The agitation is continued until disappearance full of magnesium (about 1 hour). The bromide of 3-chlorophenylmagnesium thus formed is then brought via a tubing into a previously cooled solution (-78 C) 1.64 ml (15 mmol) ethyl pyruvate in 15 ml dry diethyl ether. After this addition either complete, let the reaction temperature slowly increase to 20 C and the mixture is restless all night. The reaction mixture is cooled rapidly to 0 C by the addition of 3N HCl (10ml) and extracted with 2 x 20ml diethyl ether. Organic extract is then rinsed with water (2 x 20 ml), saturated sodium chloride solution (20 ml), and dried on sodium sulphate. Evaporation of the solvent under reduced pressure allows to obtain of a yellow oil which is purified on a chromatography column (eluent:
light oil (bp 40-65 ° C) / ethyl acetate 95/5). 2.16 g (57%) pure oil colorless are obtained.

RM N - 1 H (100 MHz, CDCl3, δ): 7.60 - 7.25 (m, 4H, Ph); 4.23 (q, 2H, CH 2, J = 7.0 Hz); 3.89 (s, 1H, OH); 1.75 (s, 3H, CH 3); 1.29 (t, 3H, CH 2 -M 3 .).
31.2) () -3-Chloro-α-hydroxy-α-methyl-benzeneacetic acid:

To a solution of 2.16 g (9.44 mmol) of ethyl ester of (3-chloro-a) hydroxy a-methyl-benzeneacetic acid in 20 ml of cooled ethanol (0-5 C) is added drip

-39-a solution of 1.24 g (18.8 mmol) of KOH in 10 ml of H 2 O. The agitation is continued for 3 hours at 25 ° C., and the solvent is evaporated. The residue is separated between H20 and diethyl ether. After decantation, the aqueous layer is acidified at 0 C with 3N HC1 and extracted with 2 x 50 ml of diethyl ether. The diethyl ether extract is dried over sodium sulphate and the solvent is evaporated under reduced pressure to obtain 1.76 g (93%) a powder white pf: 110-111 C.

1 H-NMR (100 MHz, CD3OD, S): 7.80-7.42 (m, 4H, Ph); 1.89 (s, 3H, CH 3).
31.3) () -3-chloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-benzeneacetamide fumarate Compound 31 is prepared in a manner analogous to that of Example 20 except that the acid (t) -3-chloro-α-hydroxy-α-methyl-benzeneacetic acid is used in place of acid diphenylacetic: mp: 80-81C.

1 H-NMR (400 MHz, DMSO d6, S): 8.17 (m, 1H, NH-CO); 7.57 (s, 1H, Ph-Cl);
7.49 (d, 1H, Ph-Cl, J = 7.63 Hz); 7.34 (m, 2H, Ph-Cl); 6.61 (s, 2H, -CH = CH-) ;
3.10 (m, 2H, Cl-12-NHCO); 2.86 (bs, 4H, piperazine); 2.58 (bs, 4H, piperazine);
2.40 (m, 2H, CH 2 -N); 2.24 (s, 3H, Ph-Cl-II); 2.18 (s, 3H, Ph-Cl3); 1.59 (m, 5H, CH2 + CH3).

Elemental analysis for C24H32ClN3O2, fumarate:% Calc: C, 61.59; H, 6.65 N, 7.70%, obtained: C, 61.18; H, 6.60; N, 7.60.

Example 32: () - α-amino-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl}
propyl] benzeneacetamide, difumarate (Compound 32):
32.1) (f) -α-tert-butoxycarbonylamino-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -benzeneacetamide:

This compound is prepared in a manner analogous to that of Example 20 except that the () -Boc-phenylglycine is used in place of diphenylacetic acid.

1 H-NMR (100 MHz, CDCl 3, δ): 7.35 (m, 6H, Ph + NH-CO); 7.01 (d, 1H, Eh-CH 3, J = 7.5 Hz); 6.85 (s, 1H, a-CH 3); 6.79 (d, 1H, ph-CH 3); 5.90 (m, 1H, N
Boc);
5.10 (d, 1H, CH); 3.38 (m, 2H, Cl 2 -NHCO); 3.00-2.30 (m, 10H, piperazine + CH2-N); 2.35 (s, 3H, CH3); 2.25 (s, 3H, CH3); 1.65 (m, 2H, CH2) 1.40 (s, 9H, tBu).

-40-32.2) {) -oc-amino-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -benzeneacetamide, difumarate:

A solution of 1.47 g (3 mmol) of () -α-tert-butoxycarbonylamino-N-[3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] benzeneacetamide in 20 ml of 1,4-dioxane is cooled to 0 ° C. before adding 7.5 ml (30 mmol) of solution of 4N HCl in 1,4-dioxane. After stirring overnight at room temperature ambient, the mixture The reaction is concentrated under vacuum. The residue is suspended in 50 ml of acetate of ethyl and rinsed with 2 x 50 ml of 1N NaOH. After drying on sulphate sodium anhydrous, the organic phase is concentrated to give 1.10 g (95%) of colorless oil.
This is converted into its fumarate salt as described above; mp : 122-123 C.

1 H-NMR (400 MHz, DMSO d 6, S): 9.90 (bs, NH 3 +); 8.52 (m, 1H, NH-CO); 7.47 (M, 5H, Ph); 7.03 (d, 1H, Ph.-CH 3, 3 = 7.5 Hz); 6.79 (s, 1H, Ph-CH 3); 6.75 (d, 1H, ? -CH3); 6.55 (s, 4H, 2 x - CH = CH-); 4.82 (s, 1H, CH); 3.12 (m, 2H, CI: 12-NHCO);
2.80 (bs, 4H, piperazine); 2.50 (bs, 4H, piperazine); 2.32 (m, 2H, CH 2 -N);
2.23 (s, 3H, CH3); 2.17 (s, 3H, CH 3); 1.59 (m, 2H, CH 2).

Elemental analysis for C23H32N4O, difumarate:% Calc: C, 60.77; H, 6.58 N, 9.14; % obtained: C, 60.61; H, 6.51; N, 8.87.

Example 33: () - N - [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -a- (methylsulfonylamino) -benzeneacetamide, HCl, 0.5 H2O
(Compound 33):

33.1) (-) - (Methylsulfonylamino) -benzeneacetic acid To a stirred suspension of 3.78 g (25 mmol) of () -phenylglycine in 10 ml H20 is added dropwise a solution of 1N NaOH (25 ml) until dissolved complete. Under stirring strongly, 2.7 ml (35 mmol) of methanesulfonyl chloride are added followed by 1N NaOH in small amount to maintain the alkalinity of the mixture at approximately pH
9. After pH stabilization, stirring is continued at room temperature for one o'clock. The reaction mixture is then acidified with 4N HCl and extracted with 2 x 50 ml acetate ethyl. The organic phase is rinsed with 50 ml 1N HCl followed by 2 x 25 ml a solute saturated with sodium chloride and finally dried over sodium sulphate sodium. The filtration and evaporation of the solvent make it possible to obtain an oil yellow that crystallizes slowly when left overnight at room temperature. The yellow crystals are filtered and rinsed with a mixture of light petroleum (bp, 40-65 C) and diethyl ether to give 1.87 g (32%) of a white powder; mp = 117 C.

-41 -1 H-NMR (100 MHz, CDCl 3, δ): 9.79 (bs, 1H, COOH); 7.40 (bs, 5H, Ph); 5.93 (D, 1H, SO2NH, J = 7.0 Hz); 5.25 (d, 1H, CH); 2.74 (s, 3H, CH 3).

33.2) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a- (methylsulfonylamino) -benzeneacetamide, HCl, 0.5 H2O

Compound 33 is prepared in a manner analogous to that of Example 20 except that the acid () -a- (methylsulfonylamino) -benzeneacetic acid is used in place of the acid diphenylacetic; mp: 151-152C.

1 H-NMR (400 MHz, DMSO d6, S): 11.05 (bs, 1H, + NH); 8.64 (m, 1H, NH-CO);
7.98 (m, 1H, NHSO 2); 7.50 (d, 2H, Ph, J = 7.55 Hz); 7.36 (m, 3H, Ph); 7.06 (D, 1H, Ph-CH 3, J = 7.5 Hz); 6.82 (m, 2H, t-CH3); 5.03 (d, 1H, CH, J = 6.8 Hz) ;
3.48 (m, 2H, + NH-CE2); 3.09 (m, 10H, piperazine + CUZ-NH-CO); 2.76 (s, 3H, CH3-SO2); 2.26 (s, 3H, p H -CH 3); 2.20 (s, 3H, p-CH3); 1.90 (m, 2H, CH 2) ;
1.62 (s, 3H, CH 3).

Elemental analysis for C24H34ClN4O3S, HCl, 0.5 H2O:% Calc: C, 57.19; H
7.20;
N, 11.11; S, 6.36; % obtained: C, 57.27; H, 7.09; N, 11.04; S, 6.09.

Example 34: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
2-hydroxy-2-methyl-4-methoxy-benzenepropionamide, fumarate (Compound 34):

34.1) () -2-hydroxy-2-methyl-4-methoxybenzenepropionitrile This compound is synthesized using the same procedure as described by Gassman, PG
et al., Tetrahedron Lett., 40: 3773 (1978).

1 H-NMR (100 MHz, CDCl 3, δ): 7.10 (m, 4H, Ph); 3.81 (s, 3H, OCH3); 2.98 (AB, 2H, CH 2, JAB = 14 Hz); 2.70 (bs, 1H, OH); 1.64 (s, 3H, CH3).

34.2) () -2-Hydroxy-2-methyl-4-methoxybenzenepropionic acid:

This compound is prepared in a manner analogous to that of intermediate 29.2 except that the () -2-hydroxy-2-methyl-4-methoxybenzenepropionitrile is used instead (f) -2-chloro a-hydroxy-a-methyl-benzéneacétronitrile.

1 H-NMR (100 MHz, CDCl 3, δ): 7.00 (m, 4H, Ph); 5.66 (bs, 2H, OH + COOH);
3.79 (s, 3H, OCH3); 3.00 (AB, 2H, CH 2, JAB = 13.7 Hz); 1.51 (s, 3H, CH3).

- 42 -34.3) (t) -N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -2-hydroxy-2-methyl-4-methoxybenzenepropionamide, fumarate:

Compound 34 is prepared in a manner analogous to that of Example 20 except that the acid () -2-hydroxy-2-methyl-4-methoxy-benzenepropionic is used in place of acid diphenylacetic; mp: 142 C.

1 H-NMR (400 MHz, DMSO d6, S): 7.66 (m, 1H, NH-CO); 7.08-6.73 (m, 7H, Eh-CH3 + Ph-OCH3); 6.61 (s, 2H, CH = CH); 5.30 (bs, OH + COOH); 3.69 (s, 3H, OCH3); 3.16 (m, 1H, 1/2 CH 2, -NHCO); 2.95 (m, 1H, 1/2 NJ 2 -NHCO); 2.82 (bs, 4H, piperazine); 2.78 (AB, 2H, CH 2 -PhOCH 3, JAB = 13.35 Hz); 2.50 (bs, 4H, piperazine);
2.22 (m, 2H, CH2-N); 2.25 (s, 3H, CH3); 2.17 (s, 3H, CH 3); 1.47 (m, 2H, CH2);
1.26 (s, 3H, CH 3).

Elemental analysis for C26H37N3O3, fumarate:% Calc: C, 64.85; H, 7.44;
N, 7.56%, obtained: C, 64.59; H, 7.42; N, 7.49.

Example 35: N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -N-methyl-oc-phenyl-benzeneacetamide, 0.75 fumarate (Compound 35):

35.1) N- (3-hydroxypropyl) -N-methyl-a-phenylbenzeneacetamide The title compound is prepared in a manner analogous to that of the intermediate 1.1 except that the N-methyl-3-hydroxypropylamine (Koepke, SR et al., J. Org Chem 44: 2718 (1979)) is used in place of 3-amino-1-propanol.

1 H NMR (400 MHz, CDCl 3, δ): 7.29 (m, 10H, 2 x Ph); 5.24 (s, 1H, CH); 3.58 (M, 2H, CH 2 -NCO); 3.48 (m, 2H, CH 2 OH); 3.00 (s, 3H, CH 3); 1.71 (m, 2H, CH 2).
35.2) N- (3-iodopropyl) -N-methyl-a-phenylbenzeneacetamide:

The title compound is prepared in a manner analogous to that of the intermediate 1.2 except that the N- (3-hydroxypropyl) -N-methyl-α-phenylbenzeneacetamide is used instead of a-hydroxy-N- (3-hydroxypropyl) -a-phenyl-benzeneacetamide.
1 H-NMR (400 MHz, CDCl 3, δ): 7.32 (m, 10H, 2 x Ph); 5.18 (s, 1H, CH); 3.50 (M, 2H, CH 2 -NCO); 3.12 (m, 2H, CH 2 -I); 3.00 (s, 3H, CH 3); 2.10 (m, 2H, CH 2).

-43-35.3) N- [3- (4- (2,5-dimethylphenyl) -1-piperazinyl) -propyl] -N-methyl-cc-phenyl-benzeneacetamide, 0.75 fumarate:

A mixture of 2 g (5 mmol) of N- (3-iodopropyl) -N-methyl-a-phenyl-benzeneacetamide and 970 mg (5 mmol) of 1- (2,5-dimethylphenyl) piperazine in 15 ml of acetonitrile is heated under reflux for 4 hours. After cooling, the solvent is evaporated under pressure reduced, and the residue is treated as described in Example 1 except for the column of chromatography (eluent: ethyl acetate / ethanol: 90/10). The setting salt form is carried out in the presence of an equivalent of fumaric acid in ethanol at reflux for give the title compound as a white solid; mp: 192 C.

1 H-NMR (400 MHz, DMSO d6, S): 7.25 (m, 10H, 2 x Ph); 7.02 (d, 1H, Ph-CH 3, 7 = 7.5 Hz); 6.77 (m, 2H, Ph-CH 3); 6.61 (s, 1.5H, 0.75 CH = CH); 5.52 (s, 0.5 H, CH); 5.45 (s, 0.5H, CH); 3.37 (m, 2H, C12-12 (CH3) -CO); 2.98 (s, 1.5H, NCH 3) 2.86 (s, 1.5H, NCH 3); 2.82 (bs, 4H, piperazine); 2.60 (bs, 4H, piperazine);
2.40 (m, 1H, CH 2 -N); 2.34 (m, 1H, CH 2 -N); 2.23 (s, 3H, Ph, C, U3); 2.17 (s, 3H, Ph-The latter) 1.67 (m, 2H, CH 2).

Elemental analysis for C30H37N3O, 0.75 fumarate:% Calc: C, 73.04; H
7.43 N, 7.74; % obtained: C, 72.54; H, 7.30; N, 7.29.

Example 36: () - N - [3- {4- (2- (1-hydroxypropyl) phenyl) -1-piperazinyl} -propyl] - (x-phenylbenzeneacetamide, fumarate (Compound 36):
36.1) 2- (4-benzyl-1-piperazinyl) benzaldehyde:

4.24 ml (40 mmol) 2-fluorobenzaldehyde, 8.34 ml (48 mmol) N
benzylpiperazine and 6.62 g (48 mmol) of K 2 CO 3 in 60 ml of DMF are heated at 150 ° C. for 7 hours.
hours.
After cooling, the mixture is covered with 200 ml of ethyl acetate, and the phase The organic material is rinsed successively with 2 × 50 ml of H 2 O and 2 × 50 ml of solution saturated with NaCl. After drying over Na 2 SO 4, the ethyl acetate is evaporated to give get a brown oil which is purified by chromatography on silica gel (eluent:
light oil (bp 40-65 C) / ethyl acetate: 9/1 then 8/2). Evaporation of fractions appropriate under reduced pressure gives 10.91 g (91%) of a white solid; mp: 60 C.

1 H-NMR (100 MHz, CDCl 3, δ): 10.32 (s, 1H, CHO); 7.78 (m, 1H, p-CHO) 7.47 (m, 1H, EA-CHO); 7.32 (s, 5H, Ph); 7.10 (m, 2H, n-CHO); 3.60 (s, 2H, , ~ -Ph); 3.12 (m, 4H, piperazine); 2.68 (m, 4H, piperazine).
~ L, WO 97/37983 PCT / FR971'00615

-44-36.2) (t) -2- (4-benzyl-1-piperazinyl) -α-ethyl-benzenemethanol:

In an anhydrous three-neck flask equipped with a nitrogen inlet is introduced a 1.8 ml solution (5.3 mmol, 3M solution in diethyl ether) of ethylmagnesium bromide in 10 ml of dry diethyl ether. To this previously cooled solution (0 to 5 C) is added drop by drop 1 g (3.5 mmol) of 2- (4-benzyl-1-piperazinyl) benzaldehyde diluted in 5 ml of diethyl ether The stirring is continued for 30 minutes at room temperature. The n racial mixture is then hydrolysed at 0 ° C. with a concentrated solution of ammonium chloride and finally diluted with 50 ml of ethyl acetate. After decantation, the organic phase is flushed successively with 2 x 20 ml of water and 20 ml of a concentrated solution of NaCl. After drying over Na 2 SO 4, the ethyl acetate is evaporated in vacuo to give 880 mg (81%) a colorless oil that crystallizes slowly at room temperature; pf:
97 C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.25 (m, 9H, 2 x Ph); 6.55 (bs, OH); 4.70 (t, 1H, CH, J = 7 Hz); 3.55 (s, 2H, CI-1H); 2.98 (m, 4H, piperazine); 2.60 (m, 4H, piperazine); 1.78 (m, 2H, CEZ-CH 3); 1.00 (t, 3H, CH 2 -f-1, J = 7 Hz).

36.3) (t) -2- (1-piperazinyl) -α-ethyl-benzenemethanol:

456 mg (1.5 mmol) of 2- (4-benzyl-1-piperazinyl) -α-ethyl-benzenemethanol are dissolved in 30 ml of ethanol and hydrogenated on Pd / C 10% at 40 PSI 40 = C in a : Parr.Mc appliance MC
After 4 hours, the reaction mixture is filtered through celite, and the filtrate is concentrated under reduced pressure to give 330 mg (100%) of title compound in form solid White ; mp: 95 C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.21 (m, 4H, Ph); 4.72 (t, 1H, CH, J = 7 Hz);
3.00 (m, 8H, piperazine); 2.30 (bs, OH); 1.80 (m, 2H, f: 1-CH 3); 1.05 (t, 3H, CH 2 -Cl 2, J = 7 Hz).

36.4) N- (3-hydroxypropyl) -α-phenylbenzeaeacetamide:

The title compound is prepared in a manner analogous to that of the intermediate 1.1 except that diphenylacetic acid is used in place of benzyl acid; pf:
85 C.

1 H-NMR (400 MHz, CDCl 3, δ): 7.26 (m, 10H, 2 x Ph); 6.18 (m, 1H, NH-CO);
4.92 (s, 1H, CH); 3.55 (m, 2H, CH 2 -NHCO); 3.41 (m, 2H, CHOH); 3.18 (bs, OH) ;
1.60 (m, 2H, CH 2).

- 45 -36.5) N- (3-iodopropyl) -α-phenylbenzeneacetamide The title compound is prepared in a manner analogous to that of the intermediate 1.2 except that the N- (3-hydroxypropyl) -α-phenylbenzeneacetamide is used in place of the hydroxy-N-(3-hydroxypropyl) -α-phenylbenzeneacetamide; mp: 114 C.

1 H-NMR (400 MHz, CDCl 3, δ): 7.30 (m, 10H, 2 x Ph); 5.75 (m, 1H, NH-CO);
4.92 (s, 1H, CH); 3.38 (q, 2H, C11-NHCO, J = 6.53 Hz); 3.09 (t, 2H, CH2I, J = 6.75 Hz); 2.02 (m, 2H, CH 2).

36.6) () -N- [3- {4- (2- (1-hydroxypropyl) phenyl) -1-piperazinyl} -propyl]
a-phenyl-benzeneacetamide, fumarate:

710 mg (3.22 mmol) of () -2- (1-piperazinyl) -α-ethylbenzenemethanol and 1.21 g (3,22 mmol) N- (3-iodopropyl) -α-phenylbenzeneacetamide are refluxed.
in 20 ml acetonitrile for 4 hours. After cooling, the solvent is removed under pressure reduced, and the residue is treated as described in Example 1 except for the column of chromatography (eluent: ethyl acetate / methanol: 98/2). Evaporation of fractions collected under reduced pressure gives 0.74 g (49%) of the base of the compound title that is converted to its fumarate salt by heating with an acid equivalent fumaric in absolute ethanol; mp: 76 C.

1 H-NMR (400 MHz, DMSO d6.8): 8.29 (m, 1H, NH-CO); 7.41-7.09 (m, 14H, 2 x Ph + Ph-N); 6.61 (s, 2H, CH = CH); 4.92 (s, 1H, CH); 4.85 (m, 1H, US (OH)) 3.13 (m, 2H, CH 2 -NHCO); 2.95 (m, 2H, piperazine); 2.69 (m, 2H, piperazine) 2.50 (bs, 4H, piperazine); 2.37 (m, 2H, CH 2 N); 1.55 (m, 4H, CH 2 + CH 2 -CH 3) 0.86 (t, 3H, CH 2 -Cl 3, J, 7.4 Hz).

Elemental analysis for C30H37N3O2, fumarate:% Calc: C, 69.49; H, 7.03 N, 7.15; % obtained: C, 69.31; H, 7.22; N, 7.33.

Example 37: () - N - [3- {4- (2- (1-methoxypropyl) phenyl) -1-piperazinyl} -propyl] -α-phenyl-benzeneacetamide, fumarate (Compound 37):
37.1) () -1-Benzyl-4- [2- (1-methoxypropyl) -phenyl] -piperazine:

In an anhydrous three-neck flask equipped with a nitrogen inlet are dissolved 1.55 g (5 mmol) Intermediate 36.1 in 50 ml dry DMF. 220 mg (5.5 mmol) of hydride sodium (one 60% dispersion in the oil) are added at one time and the mixture reaction is stirred throughout the overnight at room temperature before addition of 0.22 ml (5.5 mmol) of iodide diluted methyl with 2 ml of dry DMF. Stirring is continued for another 2 hours, the mixture is

-46-concentrated under reduced pressure and the residue fractionated between 50 ml of acetate of ethyl and 25 ml 1N NaOH. After decantation, the organic phase is rinsed successively with 25 ml of 1N NaOH and 25 ml of a concentrated solution of sodium chloride. The filtration and Evaporation of the solvent gives an oil which is purified by Flash chromatography (eluent:
light oil (bp 40-65 C) / ethyl acetate: 80/20). Pure fractions are collected and concentrated to give 0.71 g (68%) of a colorless oil.

1 H-NMR (100 MHz, CDCl 3, δ): 7.30 (m, 9H, 2 x Ph); 4.70 (m, 1H, CH); 3.60 (S, 2H, ChZ-Ph); 3.19 (s, 3H, OCH3); 3.10-2.40 (m, 8H, piperazine); 1.70 (m, 2H, CJJZ-CH3); 0.92 (t, 3H, CH 2 -LH 3, J 7.0 Hz).

37.2) () -1- [2- ~ 1-methoxypropyl) -phenyl] -piperazine The hydrogenation is carried out as described for Intermediate 36.3.

1 H-NMR (100 MHz, CDCl 3, δ): 7.28 (m, 4H, Ph); 4.70 (m, 1H, CH); 3.18 (s, 3H, OCH3); 3.12-2.70 (m, 8H, piperazine); 1.70 (m, 2H, CH 2 -CH 3); 0.92 (t, 3H, CH 2 -CHH 3, J = 7.0 Hz).

37.3) (t) -N- [3- {4- (2- (1-methoxypropyl) -phenyl) -1-piperazinyl} -propyl] -a-phenyl-benzeneacetamide, fumarate:

Compound 37 is prepared in a manner analogous to that of Example 36 except that the () -1- [2- (1-methoxypropyl) -phenyl] -piperazine is used in place of () -2-(1-piperazinyl) -a-ethyl-benzenemethanol.

1 H-NMR (400 MHz, DMSO d6, S): 8.31 (m, 1H, NH-CO); 7.22 (m, 14H, 2 x Ph + Ph-N); 6.61 (s, 2H, CH = CH); 4.93 (s, 1H, CH); 4.59 (m, 1H, CH (OCH3)); 3.14 (m, 2H, CH 2 -NHCO); 3.07 (s, 3H, OCH3); 2.95-2.50 (m, 8H, piperazine); 2.43 (m, 2H, CH 2 N); 1.60 (m, 4H, CH 2 + CH 2 -CH 3); 0.86 (t, 3H, CH 2 -3, _3, J = 7.33 Hz).

Example 38: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-methyl-benzeneacetamide fumarate (Compound 38):

The title compound is prepared in a manner analogous to that of Example 20 except that the acid () -2-phenylpropionic acid is used in place of diphenylacetic acid;
mp: 136 C.
1 H-NMR (400 MHz, DMSO d6, S): 7.97 (m, 1H, NH-CO); 7.25 (m, 5H, Ph); 7.02 (D, 1H, Ph-CH3, J = 7.5 Hz); 6.80 (s, 1H, Ph-CH 3); 6.78 (d, 1H, Ph-CH 3); 6.60 (s, 2H, CH = CH); 3.58 (m, 1H, CH); 3.07 (m, 2H, CH 2 -NHCO); 2.82 (bs, 4H, piperazine) ;

-47-2.57 (bs, 4H, piperazine); 2.39 (m, 2H, CH 2 -N); 2.23 (s, 3H, Ph-C3); 2.17 (s, 3H, Ph-C, H-3); 1.59 (m, 2H, CH 2); 1.32 (d, 3H, CH 3, J = 7 Hz).

Elemental analysis for C24H33N3O, fumarate:% Calc: C, 67.86; H, 7.52; NOT, 8.48 % obtained: C, 67.51; H, 7.44; N, 8.19.

Example 39: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxymethyl-benzeneacetamide, monohydrochloride, 0.5 H2O (Compound 39):

Compound 39 is prepared in a manner analogous to that of Example 20 except that the acid () -tropic is used instead of diphenylacetic acid; pf: 168-169 C.

1 H-NMR (400 MHz, DMSO d6, S): 10.77 (bs, 1H, + NH); 8.34 (m, 1H, NH-CO);
7.28 (m, 5H, Ph); 7.06 (d, 1H, M-CH 3, J = 7.6 Hz); 6.82 (m, 2H, M-CH 3);
4.48 (bs, 1H, OH); 3.96 (m, 1H, CH); 3.61 (m, 1H, 1/2 ~-12-OH); 3.53 (m, 1H, 1/2HH -OH); 3.45 (m, 2H, + NH-? LIZ); 3.17 (m, 2H, SO2-NH-CO) 3.10 (m, 10H, piperazine); 2.26 (s, 3H, Ph-Cl3); 2.20 (s, 3H, Ph-CH3); 1.87 (m, 2H, CH 2).

Elemental analysis for C24H33N3O2, HCl, 0.5 H2O:% Calc: C, 65.36; H, 8.00 ;
N, 9.53%, obtained: C, 65.72; H, 7.85; N, 9.31.

EXAMPLE 1Fe 40: () -N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy- (x-methyl-4-methoxy-benzeneacetamide, 1.25 fumarate, 0.6 H2O (Compound 40):

40.1) Ethyl ester of () -α-hydroxy-α-methyl-4-methoxy-benzeneacetic:

Intermediate 40.1 is prepared in a manner analogous to that of intermediary 31.1 except that 4-bromoanisole is used in place of 3-bromochlorobenzene.

1 H-NMR (100 MHz, CDCl 3, δ): 7.51-6.82 (m, 4H, Ph); 4.25 (q, 2H, CH 2, J = 7.0 Hz); 3.81 (s, 3H, OCH3); 3.65 (s, 1H, OH); 1.82 (s, 3H, CH 3); 1.30 (t, 3H, CH2-C H3).

40.2) () - α-Hydroxy-α-methyl-4-methoxy-benzeneacetic acid Intermediate 40.2 is prepared in a manner analogous to that of intermediate 31.2 except that the ethyl ester of () - α-hydroxy-α-methyl-4-methoxy-benzeneacetic acid is used to instead of the ethyl ester of (-) -3-chloro-α-hydroxy-α-methyl-benzeneacetic;
mp: 129-130 ° C.

- 48 1 H-NMR (100 MHz, CDCl 3, δ): 7.52-6.85 (m, 4H, Ph); 4.70 (bs, 2H, OH + CO2H) 3.81 (s, 3H, OCH3); 1.75 (s, 3H, CH 3).

40.3) (t) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -hydroxy α-methyl-4-methoxybenzeneacetamide, 1.25 fumarate, 0.6H2O:

Compound 40 is prepared in a manner analogous to that of Example 20 except that the acid () -α-hydroxy-α-methyl-4-methoxy-benzeneacetic acid is used in place of acid diphenylacetic; mp: 90-91 C.

1 H-NMR (400 MHz, DMSO d6, 8): 8.12 (m, 1H, NH-CO); 7.45 (d, 2H, Ph-OCH 3, J = 8.7 Hz); 7.06 (d, 1H, Ph-CH 3, J 7.57 Hz); 6.86 (d, 2H, P11-OCH3); 6.81 (S, 1o 1H, Ph-CH3); 6.76 (d, 1H, Ph-CH 3); 6.60 (s, 2.5H, 1.25-CH = CH-); 3.71 (s, 3H, OCH3); 3.10 (m, 2H, CH 2 -NHCO); 2.86 (bs, 4H, piperazine); 2.59 (bs, 4H, piperazine); 2.41 (m, 2H, CH 2 -N); 2.24 (s, 3H, Ph-CH3); 2.17 (s, 3H, Ph-CH3);
1.59 (m, 5H, CH 2, CH 3).

Elemental analysis for C25H35N303, 1.25 fumarate, 0.6 H2O:% Calc: C, 61.97 ;
H, 7.14; N, 7.23; % obtained: C, 62.41; H, 7.02; N, 7.22.

Example 41: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -α-hydroxy (x-methyl-4-methyl-benzeneacetamide, dihydrochloride (Compound 41):

41.1) Ethyl ester of () - α-hydroxy-α-methyl-4-methyl-benzeneacetic:

Intermediary 41.1 is prepared in a manner similar to that of intermediary 31.1 except that 4-bromotoluene is used instead of 3-bromochlorobenzene.

1 H-NMR (100 MHz, CDCl 3, δ): 7.51-7.11 (m, 4H, Ph); 4.24 (q, 2H, CH 2 -CH 3, J = 7.0 Hz); 3.78 (s, 1H, OH); 2.40 (s, 3H, Ph-Cl); 1.75 (s, 3H, CH 3);
1.30 (t, 3H, CH2-CE3).

41.2) - (α-α-hydroxy-α-methyl-4-methyl-benzeneacetic acid:
Intermediate 41.2 is prepared in a manner similar to that of intermediate 31.2 except that the ethyl ester of () -α-hydroxy-α-methyl-4-methyl-benzeneacetic acid is used at the place of the ethyl ester of (t) -3-chloro-a-hydroxy-α-methyl-benzeneacetic mp 105-106C.

-49-1 H-NMR (100 MHz, CDCl 3, δ): 7.55-7.15 (m, 4H, Ph); 4.80 (bs, 2H, OH + CO2H) 2.41 (s, 3H, Ph-CHH); 1.81 (s, 3H, CH 3).

41.3) () -N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-4-methyl-benzeneacetamide, dihydrochloride:

Compound 41 is prepared analogously to that of Example 20 except that acid (t) -α-hydroxy-α-methyl-4-methyl-benzeneacetic acid is used in place of acid diphenylacetic; mp: 145-147 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 10.93 (bs, 1H, + NH); 8.12 (m, 1H, NH-CO);
7.42 (d, 2H, Ph-C (OH), J = 8Hz); 7.20 (d, 2H, Li-C (OH)); 7.06 (d, 1H, a-CH3, J = 7.9 Hz); 6.82 (m, 2H, Ph-CH 3); 5.23 (bs, OH); 3.41 (m, 2H, + NH-ç-Hz) 3.10 (m, 10H, piperazine + C12-HNCO); 2.26 (s, 6H, 2 x Ph-, C11); 2.20 (s, 3H, Ph-CH ~ j); 1.86 (m, 2H, CH 2); 1.61 (s, 3H, CH3).

Elemental analysis for C25H35N3O2, 2HCl:% Calc: C, 62.23; H, 7.73; NOT, 8.71 % obtained: C, 62.24; H, 7.94; N, 8.76.

Example 42: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy- (x-methyl-1-naphthaleneacetamide, fumarate (Compound 42):

42.1) (t) -α-Hydroxy-α-methyl-1-naphthaleneacetic acid ethyl ester Intermediary 42.1 is prepared in a manner similar to intermediary 31.1 except that 1-bromonaphthalene is used in place of 3-bromochlorobenzene.

1 H-NMR (100 MHz, CDCl 3, δ): 8.30-7.35 (m, 7H, naphthalene); 4.19 (q, 2H, CH 2, J = 7 Hz); 3.69 (s, 1H, OH); 2.01 (s, 3H, CH3); 1.09 (t, 3H, CH 2 -I 3, 3).

42.2) () - α-Hydroxy-α-methyl-1-naphthaleneacetic acid:

Intermediary 42.2 is prepared in a manner similar to that of intermediate 31.2 except that the () -α-hydroxy-α-methyl-1-naphthaleneacetic acid ethyl ester is used instead () -3-Chloro-α-hydroxy-α-methyl-benzeneacetic acid ethyl ester mp: 152-153C.

1 H-NMR (100 MHz, CD3OD, S): 8.54 (m, 1H, naphthalene); 8.10-7.50 (m, 6H, naphthalene); 2.18 (s, 3H, CH3).

WO 97/37983 PCT / FR.97 / 00615

-50-42.3) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-a-methyl-1-naphthaleneacetamide fumarate Compound 42 is prepared in a manner analogous to that of Example 20 except that the acid () -α-hydroxy-α-methyl-1-naphthaleneacetic acid is used in place of the acid diphenylacetic; mp: 136-137C.

1 H-NMR (400 MHz, DMSO d6, S): 8.41 (d, 1H, naphthalene); 8.29 (m, 1H, NH-CO) ;
7.89 (d, 1H, naphthalene, J = 7.39 Hz); 7.84 (d, 1H, naphthalene, J = 8.10 Hz) ;
7.63 (d, 1H, naphthalene, J = 7.21 Hz); 7.45 (m, 3H, naphthalene); 7.01 (d, 1H, p-CH3, J = 7.52 Hz); 6.79 (s, 1H, p-h-CH 3); 6.74 (d, 1H, M-CH 3); 6.60 (s, 2H, -CH = CH-); 6.25 (bs, 1H, OH); 3.19 (m, 2H, CH 2 -NHCO); 2.84 (bs, 4H, piperazine);
2.56 (bs, 4H, piperazine); 2.43 (m, 2H, CH 2 -N); 2.22 (s, 3H, Ph-CH3); 2.17 (s, 3H, Ph-3); 1.83 (s, 3H, CH 3); 1.66 (m, 2H, CH 2).

Elemental analysis for C28H35N302, fumarate:% Calc: C, 68.43; H, 7.00 N, 7.48; % obtained: C, 68.58; H, 7.16; N, 7.53.

Example 43: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy- (x-methyl-2-naphthaleneacetamide, 0.75 fumarate (Compound 43):

43.1) Ethyl ester of () - α-hydroxy-α-methyl-2-naphthaleneacetic acid:
Intermediate 43.1 is prepared in a manner analogous to that of intermediary 31.1 except that 2-bromonaphthalene is used instead of 3-bromochlorobenzene.

1 H-NMR (100 MHz, CDCl 3, δ): 8.10-7.40 (m, 7H, naphthalene); 4.25 (q, 2H, CH 2, J = 7 Hz); 3.95 (s, 1H, OH); 1.90 (s, 3H, CH 3); 1.29 (t, 3H, CH 2 -Cl 3).

43.2) () - α-Hydroxy-α-methyl-2-naphthaleneacetic acid:

Intermediate 43.2 is prepared in a manner similar to that of intermediate 31.2 except that the () -α-hydroxy-α-methyl-2-naphthaleneacetic acid ethyl ester is used instead () -3-Chloro-α-hydroxy-α-methyl-benzeneacetic acid ethyl ester mp: 169-170C.

1 H-NMR (100 MHz, CD3OD, S): 8.75-7.56 (m, 7H, naphthalene); 2.05 (s, 3H, CH3).

51 43.3) () -N- [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-2-naphthaleneacetamide, 0.75 fumarate:

Compound 43 is prepared in a manner analogous to that of Example 20 except that the acid () -α-hydroxy-α-methyl-2-naphthaleneacetic acid is used in place of the acid diphenylacetic; mp: 132-133C.

1 H-NMR (400 MHz, DMSO d6, S): 8.17 (m, 1H, NH-CO); 8.03 (s, 1H, naphthalene) ;
7.89 (m, 3H, naphthalene); 7.71 (dd, 1H, naphthalene, J12 = 8.60 Hz, J13 = 1.42 Hz) 7.47 (m, 2H, naphthalene); 7.02 (d, 1H, Ph-CH 3, J = 7.57 Hz); 6.80 (s, 3H, hr) CH3) 6.76 (d, 1H, Ph-CH 3); 6.61 (s, 1.5H, 0.75 x-CH = CH-); 3.12 (m, 2H, Ca2-NHCO) lo 2.82 (bs, 4H, piperazine); 2.54 (bs, 4H, piperazine); 2.39 (m, 2H, CH 2 -N) ; 2.24 (s, 3H, Ph-CH3.); 2.16 (s, 3H, Ph-CH3); 1.73 (s, 3H, CH 3); 1.16 (m, 2H, CH 2).

Elemental analysis for C28H35N3O2, 0.75 fumarate:% Calc: C, 69.90; H
7.19;
N, 7.89; % obtained: C, 69.64; H, 7.12; N, 7.56.

EXAMPLE 44: () - N - [3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-1,1'-biphenyl-3-acetamide, fumarate (Compound 44):

44.1) Ethyl ester of () - α-hydroxy-α-methyl-1,1'-biphenyl-3-acetic acid:

Intermediary 44.1 is prepared in a manner similar to that of intermediary 31.1 except 3-bromobiphenyl is used instead of 3-bromochlorobenzene.

1 H-NMR (100 MHz, CDCl 3, δ): 7.80-7.35 (m, 9H, biphenyl); 4.25 (q, 2H, CH 2, J = 7.0 Hz); 3.83 (s, 1H, OH); 1.81 (s, 3H, CH 3); 1.29 (t, 3H, CH 2 -m3).

44.2) () - α-hydroxy-α-methyl-1,1'-biphenyl-3-acetic acid:
Intermediary 44.2 is prepared in a manner similar to that of intermediate 31.2 except that the ethyl ester of () -α-hydroxy-α-methyl-1,1'-biphenyl-3-acetic acid is used at the (3-chloro-α-hydroxy-α-methyl) ethyl ester benzeneacetic mp 118-119C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.82-7.35 (m, 9H, biphenyl); 6.20 (bs, 2H, OH, CO2H); 1.90 (s, 3H, CH3).

-52-44.3) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-1,1'-biphenyl-3-acetamide, fumarate:

Compound 44 is prepared in a manner analogous to that of Example 20 except that the acid (t) -α-hydroxy-α-methyl-1,1'-biphenyl-3-acetic acid is used in place of acid diphenylacetic; mp: 90-91 C.

1 H-NMR (400 MHz, DMSO d6, S): 8.19 (m, 1H, NH-CO); 7.83 (s, 1H, biphenyl);
7.63-7.34 (m, 8H, biphenyl); 7.02 (d, 1H, n-CH 3, J = 7.54 Hz); 6.79 (s, 1H, Eh-CH3); 6.75 (d, 1H, Eh-CH 3); 6.61 (s, 2H, -CH = CH-); 3.12 (m, 2H, NHCO);
2.89 (bs, 4H, piperazine); 2.50 (bs, 4H, piperazine); 2.39 (m, 2H, CH 2 -N);
2.23 (s, 3H, Ph-CI3). 2.15 (s, 3H, Ph +); 1.68 (s, 3H, CH3); 1.16 (m, 2H, CH 2).

Elemental analysis for C30H37N3O2, fumarate:% Calc: C, 69.49; H, 7.03;
N, 7.15;
% obtained: C, 69.65; H, 6.94; N, 7.38.

Example 45: S - (+) - N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-hydroxy-a-methyl-benzeneacetamide fumarate (Compound 45):

Compound 45 is prepared in a manner analogous to that of Example 20 except that the acid S - (+) - atrolactic is used in place of diphenylacetic acid; pf:

([a] D = + 10.75 (c = 0.12, EtOH, temp = 20 ° C)).

1 H-NMR (400 MHz, DMSO d6, S): 8.09 (m, 1H, NH-CO); 7.53 (m, 2H, Ph);
7.31 (m, 2H, Ph); 7.22 (m, 1H, Ph); 7.02 (d, 1H, α-CH 3, J = 7.57 Hz); 6.81 (S, 1H, gh-CH3); 6.76 (d, 1H, Ph-CH 3); 6.60 (s, 2H, -CH = CH-); 3.10 (m, 2H, ?, H? NHCO); 2.86 (bs, 4H, piperazine); 2.58 (bs, 4H, piperazine); 2.41 (m, 2H, CH2-N); 2.24 (s, 3H, Ph-CH 2); 2.17 (s, 3H, Ph-Cl3); 1.61 (s, 3H, CH3);
1.59 (m, 2H, CH2).

Elemental analysis for C24H33N3O2, fumarate:% Calc: C, 65.73; H, 7.29;
N, 8.21%, obtained: C, 65.78; H, 7.51; N, 8.07.

Example 46: R - (-) - N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
α-hydroxy-α-methyl-benzeneacetamide, 0.8 fumarate (Compound 46):

Compound 46 is prepared in a manner analogous to that of Example 20 except that the acid R - (-) - atrolactic is used in place of diphenylacetic acid; pf:

([a] D = -7.25 (c = 0.10, EtOH, temp = 20 ° C)).

-53-Elemental analysis for C24H33N3O2, 0.8 fumarate:% Calc: C, 66.89; H, 7.47 N, 8.60%, obtained: C, 66.43; H, 7.25; N, 8.56.

Example 47: (f) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-benzylaminocarbonyl-benzeneacetamide, fumarate (Compound 47) 47.1) Benzyl-benzylaminocarbonylbenzeneacetic acid benzyl ester 4.05 g (15 mmol) of the monobenzyl ester of phenylmalonic acid, 1.64 ml (15 mmol) of benzylamine and 2.23 g (16.5 mmol) of hydroxybenzotriazole are dissolved in 40 ml of dichloromethane. After cooling to 0-5 ° C, 3.4 g (16.5 mmol) of dicyclohexylcarbodiimide are added at one time, and stirring is continued at 20 C during 4 hours. The white precipitate formed during the reaction is filtered, and the filtrate is successively rinsed with 1N NaOH (2 x 50 ml) and saturated sodium chloride solution (50 ml).
After drying over sodium sulphate, the solvent is evaporated, and the residue is precipitated in presence of dichloromethane. Filtration gives 3.19 g (59%) of a powder white;
mp: 150-151 C.

1 H-NMR (100 MHz, CD3OD, S): 7.70-7.35 (m, 15H, Ph); 5.35 (s, 2H, CH 2 -O);
5.05 (s, 1H, CH); 4.51 (d, 2H, CH 2 -N).

47.2) () - α-benzylaminocarbonyl-benzeneacetic acid:

In a Parr bottle are introduced 1 g (2.78 mmol) of benzyl ester of acid () -a-benzylaminocarbonyl-benzeneacetic acid dissolved in a mixture of 40 ml ethanol and ml of acetic acid and 200 mg of 10% Pd / C. Hydrogenation is carried out under H2 at 30 C. After stirring for 15 hours, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue is fractionated between 30 ml of diethyl ether and 30 ml of a saturated solution of NaHCO3. The aqueous extract is decanted and rinsed with 30 ml of Diethyl ether. After acidification with 3N HCl at 0 ° C., the aqueous phase is extracted with 2 x 30 ml of diethyl ether. The ethereal solution is dried over sodium sulfate sodium, filtered, and evaporated solvent to give 451 mg (60%) of a white powder; pf: 132-133 C.
1 H-NMR (100 MHz, CD3OD, S): 7.70-7.35 (m, 10H, Ph); 4.80 (s, 1H, CH); 4.57 (M, 2H, CH2-N).

54 47.3) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a-benzylaminocarbonyl-benzeneacetamide, fumarate:

Compound 47 is prepared in a manner analogous to that of Example 20 except that the acid () -a-benzylaminocarbonyl-benzeneacetic acid is used in place of the acid diphenylacetic;
mp: 90-91 C.

1 H-NMR (400 MHz, DMSO d 6, S): 8.69 (m, 1H, NH-CH 2 Ph); 8.26 (m, 1H, NH-CO);
7.32 (m, 10H, 2 x Ph); 7.02 (d, 1H, n-CH 3, J 7.51 Hz); 6.80 (s 1H, pjl-CH 3) 6.76 (d, 1H, a-CH 3); 6.61 (s, 2H, -CH = CH-); 4.47 (s, 1H, CH); 4.31 (m, 2H, NH ?, H, -Ph); 3.15 (m, 2H, CH 2 -NHCO); 2.83 (bs, 4H, piperazine); 2.58 (bs, 4H, piperazine); 2.42 (m, 2H, CH 2 -N); 2.23 (s, 3H, Ph-L3); 2.17 (s, 3H, Ph-Ç.â3) 1.63 (m, 2H, CH 2).

Elemental analysis for C31H38N4O2, fumarate:% Calc: C, 68.38; H, 6.89 N, 9.11; % obtained: C, 68.70; H, 7.06; N, 8.81.

Example 48: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a- (4-methylphenyl) sulfonylamino-benzeneacetamide, 1.5 HCl, 0.5 H2O (Compound 48):

48.1) (-) - (4-Methylphenyl) -sulfonylamino-benzeneacetic acid:
Intermediate 48.1 is prepared in a manner similar to that of intermediate 33.1 except that p-toluenesulfonyl chloride is used in place of the chloride of methanesulfonyl;
mp: 188-189 C.

1 H-NMR (100 MHz, CD3OD, S): 7.65 (m, 4H, p-toluene); 7.42 (s, 5H, Ph); 5.09 (D, 1H, CH); 2.55 (s, 3H, CH 3).

48.2) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α- (4-methylphenyl) -sulfonylamino-benzeneacetamide, 1.5 HCl, 0.5 H20 Compound 48 is prepared in a manner analogous to Example 20 except that acid () - (4-methylphenyl) -sulfonylamino-benzeneacetic acid is used in place of acid diphenylacetic; mp: 180-181 C.

1 H-NMR (400 MHz, DMSO d6, S): 11.19 (bs, 1H, + NH); 8.54 (m, 2H, NH-CO, NH-SO2); 7.63 (m, 2H, Ph-SO 2); 7.26 (m, 7H, Ph-SO 2, Ph); 7.06 (d, 1H, Eh-CH3, J = 7.05 Hz); 6.83 (bs, 2H, Ph-CH 3); 4.92 (d, 1H, CH, J = 8.80 Hz); 3.37 (m, 2H,

-55-+ NH-C, H2); 3.12 (bs, 4H, piperazine); 2.97 (m, 6H, piperazine, CUN-NHCO);
2.35 (s, 3H, LIII-PhSO2); 2.26 (s, 3H, Ph-LH-3); 2.20 (s, 3H, Ph-C-H-1); 1.77 (m, 2H, CH2).
Elemental analysis for C30H38N4O3S, 1.5 HCl, 0.5 H2O:% Calc: C, 60.21 H, 6.82; N, 9.36; S, 5.36; % obtained: C, 60.59; H, 6.81; N, 9.21; S
5.69.

Example 49: (t) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-benzylcarbonylamino-benzeneacetamide, fumarate, 0.5 H2O
(Compound 49):

49.1) () - α-Benzylcarbonylamino-benzeneacetic acid:

Intermediate 49.1 is prepared in a manner similar to that of intermediate 33.1 except that phenylacetyl chloride is used in place of the chloride of methanesulfonyl.
1 H-NMR (100 MHz, CDCl 3, δ): 8.80 (bs, 1H, CO2H); 7.30 (bs, 10H, 2 x Ph);
5.52 (d, 1H, NHCO, J = 7.0 Hz); 3.60 (m, 3H, CH + CH 2).

49.2) (t) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a-benzylcarbonylamino-benzeneacetamide, fumarate, 0.5 H2O

Compound 49 is prepared in a manner analogous to that of Example 20 except that the acid () -a-benzylcarbonylamino-benzeneacetic acid is used in place of the acid diphenylacetic;
mp: 158-159C.

1 H-NMR (400 MHz, DMSO d6.8). 8.73 (d, 1H, CH-EH-CO, J = 8.0 Hz); 8.32 (m, 1H, NH-CO); 7.42-7.20 (m, 10H, 2 x Ph); 7.02 (d, 1H, Ph-CH 3, J = 7.52 Hz);
6.80 (s, 1H, Ph-CH 3); 6.75 (d, 1H, Ph-CH 3); 6.61 (s, 2H, -CH = CH-); 5.43 (d, 1H, CH); 3.56 (s, 2H, ~? -Ph); 3.10 (m, 2H, 1H-NHCO); 2.80 (bs, 4H, piperazine) ;
2.50 (bs, 4H, piperazine); 2.34 (m, 2H, CH 2 -N); 2.23 (s, 3H, Ph-C13); 2.17 (s, 3H, Ph. 1.58 (m, 2H, CH 2).

Elemental analysis for C31H38N4O2, fumarate, 0.5 H2O:% Calc: C, 67.40;
H, 6.95; N, 8.98; % obtained: C, 67.57; H, 6.86; N, 8.98.

-56-Example 50: () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
a-benzylaminocarbonyl-a-methyl-benzeneacetamide, fumarate, 0.5 H2O (Compound 50):

50.1) Diethyl ester of () -a-methyl-phenylmalonic acid Intermediate 50.1 is prepared in a manner analogous to that of the example 11 except that the diethyl ester of phenylmalonic acid is used instead of (t) -N-[3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide.
1 H-NMR (100 MHz, CDCl 3, δ): 7.39 (bs, 5H, Ph); 4.28 (q, 4H, OCH 2, J = 7.0 Hz);
1.88 (s, 3H, CH3); 1.26 (t, 3H, CH 2 - 3).

50.2) () -α-methyl-phenylmalonic acid monoethyl ester Intermediate 50.2 is prepared in a manner analogous to intermediate 31.2 except that the () -α-methyl-phenylmalonic acid diethyl ester is used instead of the ethyl ester of () -3-chloro-α-hydroxy-α-methyl-benzeneacetic acid.

1 H-NMR (100 MHz, CDCl 3, δ): 9.38 (bs, 1H, CO2H); 7.38 (m, 5H, Ph); 4.25 (q, 2H, OCH2, J = 7.0 Hz); 1.90 (s, 3H, CH 3); 1.28 (t, 3H, CH 2 -CAB 3).

50.3) Ethyl ester of () -a-benzylaminocarbonyl-a-methyl-benzeneacetic:

Intermediate 50.3 is prepared in a manner analogous to that of intermediary 47.1 except that the () -α-methyl-phenylmalonic acid monoethyl ester is used in the place of monobenzyl ester of phenylmalonic acid.

1 H-NMR (100 MHz, CDCl 3, δ): 7.30 (m, 10H, 2 x Ph); 6.82 (m, 1H, NH-CO);
4.48 (m, 2H, CH 2); 4.27 (q, 2H, OCH 2, J = 7.0 Hz); 1.87 (s, 3H, CH 3); 1.26 (T, 3H, CH2-C, a1).

50.4) () - α-Benzylaminocarbonyl-α-methyl-benzeneacetic acid:

Intermediate 50.4 is prepared in a manner analogous to that of intermediate 31.2 except that the ethyl ester of (f) -α-benzylaminocarbonyl-α-methyl-benzeneacetic is used to the place of the ethyl ester of (f) -3-chloro-a-hydroxy-α-methyl-benzeneacetic.
1 H-NMR (100 MHz, CDCl 3, δ): 7.25 (m, 10H, 2 x Ph); 6.26 (m, 1H, NH-CO);
4.45 (m, 2H, CH 2); 1.95 (s, 3H, CH3).

-57-50.5) () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a-benzylaminocarbonyl-a-methyl-benzeneacetamide, fumarate, 0.5 H2C? :

Compound 50 is prepared in a manner analogous to that of Example 20 except that the acid (t) -α-benzylaminocarbonyl-α-methyl-benzeneacetic acid is used in place of acid diphenylacetic mp: 159-160 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 8.40 (m, 1H, PhCH2-n-CO); 7.93 (m, 1H, NH-CO); 7.26 (m, 10H, 2 x Ph); 7.02 (d, 1H, Ph-CH 3, J 7.52 Hz); 6.79 (s, 1H, Ph.-CH3); 6.75 (d, 1H, Eh-CH 3); 6.61 (s, 2H, -CH = CH-); 4.33 (d, 2H, α-Ph, J = 5.85 Hz); 3.19 (m, 2H, CI3.2-NHCO); 2.79 (bs, 4H, piperazine); 2.54 (bs, 4H, piperazine); 2.39 (m, 2H, CH 2 -N); 2.24 (s, 3H, Ph-C13); 2.17 (s, 3H, Ph-Çji3-) 1.71 (s, 3H, CH 3); 1.63 (m, 2H, CH 2).

Elemental analysis for C32H40N4O2, fumarate, 0.5 H2O:% Calc: C, 67.80;
H, 7.11; N, 8.78; % obtained: C, 68.20; H, 7.08; N, 8.91.

Example 51 :() -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-methoxy-α-methyl-benzeneacetamide, 0.5 fumarate (Compound 51):

Compound 51 is prepared in a manner analogous to that of Example 11 except that the (t) -N-[3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-benzeneacetamide is used in place of () -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide; mp: 172.5-173.5 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 8.16 (m, 1H, NH-CO); 7.35 (m, 5H, pH); 7.02 (D, 1H, n-CH3, J = 7.54 Hz); 6.80 (s, 1H, a-CH 3); 6.75 (d, 1H, EI, -CH3); 6.60 (S, 1H, 0.5 x-CH = CH-); 3.13 (m, 5H, 11H-NHCO + OCH 3); 2.84 (bs, 4H, piperazine) ;
2.54 (bs, 4H, piperazine); 2.37 (m, 2H, CH 2 -N); 2.23 (s, 3H, Ph-3); 2.18 (s, 3H, Ph-3); 1.64 (s, 3H, CH3); 1.61 (m, 2H, CH 2).

Elemental analysis for C25H35N3O2, 0.5 fumarate:% Calc: C, 69.35; H
7.98 N, 8.99%, obtained: C, 69.34; H, 7.99; N, 8.69.

Example 52: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -a-benzyloxy-a-methyl-benzeneacetamide, 0.5 fumarate (Compound 52):

Compound 52 is prepared in a manner analogous to that of Example 11 except that the (t) -N-[3- {4- (2,5-Dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-methyl-benzeneacetamide and

-58-benzyl bromide are used in place of (t) -N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenyl-benzeneacetamide and iodide of methyl;
mp: 153-154C.

1 H-NMR (400 MHz, DMSO d6, S): 7.94 (m, 1H, NH-CO); 7.50-7.26 (m, 10H, 2 x Ph); 7.00 (d, 1H, ph-CH 3, J = 7.46 Hz); 6.74 (d, 1H, p 1 -CH 3); 6.71 (s, 1H, p11-CH3); 6.61 (s, 1H, 0.5 x-CH = CH-); 4.35 (AB, 2H, - ~ Z-Ph, JAB = 12.25 Hz) ;
3.17 (m, 2H, CH - Z-NHCO); 2.73 (bs, 4H, piperazine); 2.50 (bs, 4H, piperazine);
2.34 (m, 2H, CH 2 -N); 2.22 (s, 3H, Ph-3); 2.15 (s, 3H, Ph-3); 1.74 (s, 3H, CH3); 1.61 (m, 2H, CH 2).

Elemental analysis for C31H39N3O2, 0.5 fumarate:% Calc: C, 72.90; H
7.60;
N, 7.73; % obtained: C, 73.01; H, 7.46; N, 7.27.

Example 53: () -3,4-Dichloro-N- [3- {4- (2,5-dimethylphenyl) -1-piperazinyl}
propyl] -α-hydroxy-α-methyl-benzeneacetamide, fumarate (Compound 53):

Compound 53 is prepared in a manner analogous to that of Example 31 except that the 1-bromo-3,4-dichlorobenzene is used in place of 3-bromochlorobenzene;
mp 174-175 ° C.

1 H-NMR (400 MHz, DMSO d6, S): 8.19 (m, 1H, NH-CO); 7.73 (d, 1H, Ph-Cl, J = 1.17 Hz); 7.59 (d, 1H, PhCl, J = 8.44 Hz); 7.50 (dd, 1H, PhCl); 7.02 (d, 1H, Eh-CH 3, J 7.52 Hz); 6.81 (s, 1H, Ph-CH 3); 6.76 (d, 1H, Ph.-CH3); 6.60 (s, 2H, -CH = CH-); 3.10 (m, 2H, CH 2 -NHCO); 2.85 (bs, 4H, piperazine); 2.56 (bs, 4H, piperazine); 2.38 (m, 2H, CH 2 -N); 2.24 (s, 3H, Ph-C13); 2.17 (s, 3H, Ph-ÇJJ3);
1.59 (m, 5H, CH3 + CH2).

Elemental analysis for C24H31Cl2N3O2, fumarate:% Calc: C, 57.93; H, 6.08 ;
N, 7.24; % obtained: C, 57.99; H, 6.24; N, 7.03.

Example 54: () - N - [3- {4- (2,5-dimethylphenyl) -1-piperazinyl} -propyl]
2-hydroxy-2-methyl-propionamide, fumarate (Compound 54):
Compound 54 is prepared in a manner analogous to that of Example 20 except that the acid 2-hydroxyisobutyric acid is used in place of diphenylacetic acid;
mp: 150-151 C.

1 H-NMR (400 MHz, DMSO d6, S): 7.85 (m, 1H, NH-CO); 7.02 (d, 1H, p HZ-CH 3, J = 7.52 Hz); 6.81 (s, 1H, p -h-CH3); 6.76 (d, 1H, -1) -CH3); 6.60 (s, 2H, -CH = CH-);
3.13 (m, 2H, CH 2 -NHCO); 2.88 (bs, 4H, piperazine); 2.67 (bs, 4H, piperazine) ;

-59-2.38 (m, 2H, CH2-N); 2.24 (s, 3H, Ph-C-U3); 2.18 (s, 3H, Ph-CII); 1.66 (m, 2H, CH2); 1.24 (s, 6H, 2 x CH3).

Elemental analysis for C19H31N3O2, fumarate:% Calc: C, 61.45; H, 7.85 N, 9.35; % obtained: C, 61.00; H, 7.89; N, 9.22.

Example 55: () - N - [3- {4- (2- (cyclopropylhydroxymethyl) phenyl) -1-piperazinyl} -propyl] -a-phenyl-benzeneacetamide, 1.25 fumarate, 0.5 H2O (Compound 55):

Compound 55 is prepared in a manner analogous to that of Example 36 except that the cyclopropylmagnesium bromide is used in place of bromide ethylmagnesium;
lo pf: 151-152C.

1 H-NMR (400 MHz, DMSO d6, S): 8.31 (m, 1H, NH-CO); 7.49-7.09 (m, 14H, 3 x Ph); 6.61 (s, 2.5H, 1.25 x-CH = CH-); 4.92 (s, 1H, Ph-Cl, 4.51 (d, 1H, UU (OH), J = 6.71 Hz); 3.13 (m, 2H, C₁₂-NHCO); 3.00 (bs, 2H, piperazine);
2.72 (bs, 2H, piperazine); 2.58 (bs, 4H, piperazine); 2.41 (m, 2H, CH 2 -N);
1.63 (m, 2H, CH 2); 1.05 (m, 1H, CH); 0.36 (m, 4H, cyclopropane).

Elemental analysis for C31H37N302, 1.25 fumarate, 0.5 H2O:% Calc: C, 67.80; H
6.80; N, 6.59%, obtained: C, 68.21; H, 6.82; N, 6.12.

Example 56: (t) -N- [3- {4- (2- (propyl) -phenyl) -1-piperazinyl) -propyl]
α-hydroxy-α-phenyl-benzeneacetamide, 0.75 fumarate (Compound 56):

56.1) (Z, E) -1-Benzyl-4- [2- (1-propenyl) -phenyl] -piperazine In an anhydrous three-neck flask provided with a nitrogen inlet containing 80 ml of Dry THF are introduced 5.7 g (15.3 mmol) of ethyltriphenylphosphonium bromide. At this mix are added dropwise at 20 C, 8.45 ml (16.9 mmol) of a solution of phenyllithium (2M
in cyclohexane / diethyl ether: 7.3). The agitation is continued during a time and at this mixture of a dark red, cooled to 0 C, is added dropwise a 4.3 g solution (15.3 mmol) of Intermediate 36.1 in 30 ml of dry THF. After agitation all night, the The precipitate is filtered and rinsed with ethyl acetate. The filtrate is concentrated under vacuum, and the brown oily residue is subjected to chromatography on silica gel (eluent:
light oil (bp 40-65 C) / ethyl acetate: 90/10) to give 2.71 g (60%) of a pure yellow oil blade.

-60-1 H-NMR (100 MHz, CDCl3, S): 7.45-6.90 (m, 9H, 2 x Ph); 6.60 (m, 1H, Ph-CH = fJL-); 6.20 (m, 1/2 CH, 1/2 x Ph-CH = -CU-); 5.79 (m, 1/2 CH, 1/2 x Ph-CH = M-); 3.60 (m, 2H, LU2-Ph); 3.00 (m, 4H, piperazine); 2.60 (m, 4H, piperazine); 1.90 (m, 3H CH 3).

56.2) 1- [2- (1-Propenyl) -phenyl] -piperazine:

A mixture of 2.71 g (9.3 mmol) of (Z, E) -1-benzyl-4- [2- (1-propenyl) phenyl] -piperazine and 100 mg of Pd / C 10% in 30 ml of ethanol are hydrogenated under 40 PSI H2 at 40 VS
for 15 hours in a Parr device. Then the reaction mixture is filtered on a layer MC
Celite, and the solvent was evaporated under reduced pressure to give 1.78 g.
(94%) of White powder ; mp: 145-146 ° C.

1 H-NMR (100 MHz, CDCl 3, δ): 7.18 (m, 4H, Ph); 4.55 (bs, NH); 3.30-2.90 (m, 8H, piperazine); 2.60 (m, 2H, CI-Ph); 1.68 (m, 2H, CH 2); 1.00 (t, 3H, CH 3, J = 7.0 Hz).

56.3) (t) -N- [3- {4- (2- (propyl) -phenyl) -1-piperazinyl} -propyl] -α-hydroxy-α-phenylbenzeneacetamide, 0.75 fumarate:

Compound 56 is prepared in a manner analogous to that of Example 1 except that the (t) -1- [2- (1-propenyl) -phenyl] -piperazine is used instead of 1- (3-methylphenyl) -piperazine; mp: 152-153C.

1 H-NMR (400 MHz, DMSO d6, S): 8.37 (m, 1H, NH-CO); 7.40-6.99 (m, 14H, 3 x Ph); 6.60 (s, 1.5H, 0.75 x -CH = CH-); 3.20 (m, 2H, CH 2 L -NHCO); 2.84 (m, 4H, piperazine); 2.59 (m, 6H, piperazine + Ph-fJ2); 2.44 (m, 2H, CH 2 -N); 1.67 (m, 2H, CH2); 1.60 (m, 2H, CIIZ-CH 3); 0.92 (t, 3H, CH 3, J = 7.46 Hz).

Elemental analysis for C30H37N3O2, 0.75 fumarate: 96 Calc: C, 70.94; H
7.22;
N, 7.52; b obtained: C, 70.71; H, 7.28; N, 7.07.

Aladrenergic receptor binding assay:

The affinity of various compounds of the invention for the receptors adrenergic is determined measuring the inhibition of [3H] prazosin binding (DuPont NEN, Ulis, France) at rat cerebral cortex according to a method derived from that of Morrow and Creese, Mol.
Pharmacol. 29: 321 (1986). The cerebral cortex of male Sprague Dawley rats are homogenized at 4 ° C. in 50 mM Tris-HCl pH = 7.7 and centrifuged at 50,000 g while 30 minutes at 4 C. The pellets are again suspended in the same buffer and centrifuged again at 50,000 g for 30 minutes at 4 C.

i WO 97/37983 PCT / FR971b0615

-61-Competitive inhibition of the binding of 0.2 nM [3H] prazosin is performed in triplicate with unlabeled test compounds of the invention in concentrations varying from 10 -15 to 10-21VI.
Rat cerebral cortex membranes (5 mg (wet) / ml) are incubated while 30 minutes at 25 ° C. in Tris-HC150 mM, pH = V. The [3H) bound prazosin is separated from the [3H] free prazosin by immediate filtration through fibrous fiber glass Whatman GFB using Brandel cell recuperators ~ Filters are rincks three twice with the same buffer at 0-4 C and test their radioactivity by liquid spectrometry at scintiUation.

Specific binding is obtained by subtracting non-binding specific (determined 10 in the presence of 10 M phentolamine (Sigma Chemical Co., St. Louis MO) links Total. The data relating to the links are analyzed by analysis by regression non-linear iterative computer-assisted, using the program Ligand (Munson, PJ., Rodbard, D. Anal. Biochem. 107: 220 (1980)).

ICgO (concentration needed to inhibit 50% of specific binding) of each of test compounds is given in Table L

-62-TABLE I

AFFINITY OF BINDING OF THE RECEPTOR a1.ADRENERGIC
Compound No. Ki (nM) Compound No. Ki (nM) 6,480 34,45 WO 97137983 -63 PCT / FR97I ~ 0061s -Contraction test of the urethra:

Urethras are extracted from New Zealand male rabbits, and cleaned from related fabrics surrounding. Strips of urethra of the prostate (3 mm wide, 10-15 mm long) are suspended (1 g of tension) in organ baths containing 10 ml of solution physiological (pH 7.4) at 37 ° C under an atmosphere of 95% O 2/5% CO 2; NaC1 (118 mM); KCl (4.7 mM); CaCl2 (2.5 mM); KH2PO4 (1.2 mM); MgSO4 (1.2 mM);
NaHCO3 (25 mM); glucose (11 mM). Contractile responses are measured in using force displacement transducers coupled with Gould 8000S polygraph. An equilibration or balancing period of one hour is planned i0 before the experiment. After balancing, the preparations are sensitized by a submaximal concentration of phenylephrine. Forty five minutes after the sensitization, a concentration-effect curve for phenylephrine is established. In order to determine the effect of test compounds, different preparations from the same animal are used in parallel.
One preparation serves as a counterfeit while others receive concentration of a compound test introduced into the bath 30 minutes before phenylephrine (Auguet, M., and al., European J. Pharmacol. 217: 153 (1995)).

The dissociation constants (Kb) of the -test compounds are de-arrested in using the equation following: Kb = [B] 1 (dosing ratio - 1); in iaqirelle [B] is the concentration of test compound and (dosed ratio) is the EC50 of phenylephrine in the presence test compound divided by the EC50 of the control preparation. These results are then expressed as the negative log of Kt ,. ECgp values are calculated from the contractile response maximum to phenylephrine by computer analysis using a linear regression on the average voltage values. The maximum contractile response of each preparation that has subjected to the test compound is determined by comparing the response caused by the application the sensitizing phenylephrine concentration with the response provoked in the separation of control (which did not receive test compounds).

The results obtained for the test compounds are given in Table II.

TABLE II

INHIBITION OF THE CONTRACT OF THE URETRE
Compound N -log Kb 7 8.1 8 8.2 9 8.1 8.2 11 6.9 13 8.2 14 7.8 7.9 16 7.8 17 7.7 7.5 22 8.3 7.6 27 7.6 38 7.5 39 7.3 42 7.68 45 8.3 46 7.5 47.07 48 7.02 50 6.92 Contraction test of the portal vein and the rat aorta:

The aorta and portal vein are extracted from male Sprague Dawley rats (275 -350 g, 5 Charles River, France) after cervical dislocation and cleaned tissues Related surrounding. Longitudinal strips (one per animal) of the portal vein (3 mm wide, 10 - 15 mm long) and bare rings of the endothelium (= 2 mm wide) of the aorta are suspended (tension: portal vein = 0.5 g, aorta = 2 g) in baths for organs containing 10 ml of saline (composed of NaCl (118 mM), KCl (4.7 mM) CaCl 2 (2.5 mM), KH 2 PO 4 (1.2 mM), MgSO 4 (1.2 mM), NaHCO 3 (25 mM), glucose (11 mM)) at 37 ° C and gassed with 95% O 2/5% CO 2. Contractile responses are measured using force displacement transducers be coupled to a polygraph Gould 8000S, either connected to a data recovery system (IOS, Dei Ivy, Mitry-Mory, France). A balancing or equilibration period of one hour is planned before experimentation. After equilibration, the preparations are sensitized with a submaximal concentration of phenylephrine (1 M for the aorta, 3 M for the vein portal). When the contraction caused by phenylephrine is stable, a failure relaxation after addition of carbachol (10 M) indicates disorganization successful the endothelium of the aorta. Seventy-five minutes after the sensitization, a curve concentration-effect for phenylephrine is established. To determine the effect compounds tests, different preparations are used in parallel. One serves as control, while the others receive the different test compounds introduced into the bath 60 minutes before the administration of phenylephrine.

The results are expressed as mean SEM or percentage of contraction. The maximum contractile response of each preparation that has been submitted to a compound test is determined by comparing the response caused by the application of the concentration sensitizing phenylephrine with the response provoked in the preparation control (which received only phenylephrine). The EC50 values are calculated from the contractile response maximum by computer analysis using a linear regression on the values of average voltage. The dissociation constants (Kb) of the test compounds are determined for each test compound according to the following equation: Kb = [B] / (ratio dosic - 1);
wherein [B] is the concentration of the test compound and (dosing ratio) is the EC50 of the agonist in the presence of the test compound divided by the EC50 control. Table III gives the Kb compound 45 and the antagonist Prazosine (Sigma, Clery en Vescin, France).

TABLE III

Compound 45 Prazosin Kb (Aorta) 45 nM 5M
K (portal vein) 1.4 nM 400 μM
Selectivity 32 0.01 Kb (Aorta) / Kb (Vein) Contraction test of the rabbit aorta and portal vein The aorta and portal vein are extracted from New Zealand male rabbits (2.5 -3.5 kg, Dombes Romans, France) after cervical dislocation, and cleaned of related tissues surrounding.

Longitudinal bands (4 per animal - 3 mm wide, 10 to 15 mm long) or some denuded rings of the endothelium (1 mm wide) of the aorta are suspended (tension: vein portal = 0.5 g; aorta = 2 g) in organ baths containing 10 ml of solution physiological (composed of NaCl (118 mM), KCl (4.7 mM), CaCl2 (2.5 mM), KH2PO4 (1.2 mM), MgSO4 (1.2 mM), NaHCO3 (25 mM), glucose (11 mM)) at 37 ° C and gassed with 95% 02/5% C02. Contractile responses are measured using transducers to force displacement coupled to a Gould RS3400 polygraph. A period equilibration or Balancing of one hour is planned before experimentation. After balancing, the preparations are sensitized with a submaximal concentration of phenylephrine (1 gM
for the vein portal; 3 M for the aorta). When the contraction caused by the phenylephrine is stabilized, carbachol (10 M) is administered for the purpose of controlling the disorganization of the endothelium in the vessels. Seventy-five minutes after awareness, a curve concentration-effect for phenylephrine is established. To determine the effect of compounds tests, different preparations are used in parallel. One serves as control, while the others receive different concentrations of test compound introduced into the bath 60 minutes before phenylephrine.

The results are expressed as mean SEM or percentage of the contraction.
The maximum contractile response of each preparation was subjected to compound test is determined by comparing the response triggered by the application of the concentration sensitizing phenylephrine with the response triggered in the preparation control (which received only phenylephrine). EC50 values are calculated from the answer maximum contractile by computer analysis using regression linear about average voltage values. The dissociation constants of the test compounds (Kb) are determined for each antagonist according to the following equation: Kb = [B] /
(report dosic - 1); wherein [B] is the concentration of the test compound and (dosic ratio) is the EC50 of the agonist in the presence of the test compound divided by the EC50 control.
Table IV
gives the Kb of compound 45 and Prazosine.

TABLE IV

Compound 45 Prazosin Kb (Aorta) 63 nM 2 nM
Kb (portal vein) 1.6 nM 4 nM
Selectivity 40 0.5 Kh (Aorta) / Kh (Vein) Contraction of the rabbit saphenous vein The caudal saphenous vein is extracted from New Zealand male rabbits (2.5 to 3 kg, Dombes Romans, France) after cervical dislocation and cleansing of related tissues surrounding. of the Rings 2-3 mm wide are cut under a dissecting lens.
The rings are suspended under a tension of 1 g at 37 C in organ baths containing 10 ml of physiological solution (composed of NaCl (118 mM), KCl (4.7 mM), CaCl2 (2.5 mM) KH2PO4 (1.2 mM), MgSO4 (1.2 mM), NaHCO3 (25 mM), glucose (11 mM)) at 37 ° C and gassed with 95% O 2/5% CO 2. Contractile responses are measured in using force displacement transducers coupled to a Gould RS3400 polygraph.
The endothelium 1o is removed by gently rolling small forceps on the surface luminale of the rings arterial and by infusing a gentle flow of carbogen for 5 minutes at through the vein.
An equilibration or balancing period of one hour is planned before experimentation.
During this balancing period, the tension of the venous rings is left to relax and the final tension is maintained at 0.5 g. After balancing, the preparations are sensitized by a submaximal concentration (3 M) of phenylephrine. When the contraction triggered phenylephrine is stabilized, carbachol (10 M) is administered to to control the disorganization of the endothelium in the vessels. Seventy-five minutes After the sensitization, a concentration-effect curve for phenylephrine is established. In order to determine the effect of the test compounds, different preparations are used in parallel. Moon serves as control while others receive different test compounds introduced in the bath 60 minutes before phenylephrine administration.

The results are expressed as mean SEM or percentage of the contraction.
The maximum contractile response of each preparation submitted to the compound test is determined by comparing the response triggered by the application of the concentration sensitizing phenylephrine with the response triggered in the preparation control (which received only phenylephrine). The EC50 values are calculated from the contractile response maximum by computer analysis using a linear regression on the values of average voltage. The dissociation constants of the test compound (Kb) are determined for each test compound according to the following equation: Kb = [B] / (dosic ratio -1); in which [B] is the concentration of the test compound and (dosing ratio) is the EC50 of the agonist in presence of the test compound divided by the EC50 control. Table V gives the Kb of compound 45 and Prazosine.

WO 97/37983 -68 PGT / P'R971'00615 -TABLE V

Compound 45 Prazosin K} ~ (saphenous vein) 15 nM 13 nM
Selectivity 9.4 3.3 ICb (saphenous vein) / Kb (portal vein) Other ways of realizing:

It is understood that while the invention has been described in connection with its detailed description, This description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the appended claims.

Claims (16)

- 69- 1. Compound either of formula I:

in which R1 represents hydrogen or lower alkyl R2 represents hydrogen, lower alkyl, OR6, S(O)m R6 in which m is 0, 1 or 2, NHS(O)n R6 where n is 1 or 2, C(O)NR6R7, NR6R7 or N(R7)C(O)R6;
each of R3 and R4, independently of one another, represents one from following groups substituted by one or more substituents or not substituted:
lower alkyl, cyclohexyl, phenyl, napthyl or benzyl wherein said substitute is lower alkyl, halogen, OR6, SR6, NR6R7, CN, NO2, CF3 or phenyl, or R3 and R4, together with the carbon atom to which they are jointly bonded, form the 9-xanthenyl or 9-fluorenyl radical;

R5 represents a phenyl substituted by one or more substituents chosen among alkyl lower, CN, halogen, hydroxy-lower alkyl, cyclopropylhydroxymethyl, a lower alkoxy-lower alkyl, or OR6 where R6 is alkyl lower ; and each of R6 and R7, independently of one another, represents a hydrogen or one of the following groups substituted by one or more substituents or Nope-substituted: lower alkyl, phenyl or benzyl wherein said substituent is a lower alkyl, halogen, or lower alkoxy;

Being heard that if R2 represents OR6 and R6 represents lower alkyl, then R4 does not not represent the halophenyl or lower alkoxy-phenyl radical; and R2, R3 and R4 cannot simultaneously represent a lower alkyl"; and if R2 represents OR6 and R6 represents hydrogen, then R3 and R4, so independent each other, do not represent one of the substituted or unsubstituted groups substituted following: phenyl, napthyl or benzyl;

either corresponding to one of the following formulas:
.alpha.-hydroxy-N-[3-{4-(3-methylphenyl)-1-piperazinyl}-propyl]-.alpha.-phenyl-benzeneacetamide;

.alpha.-hydroxy-N-[3-{4-(2-methylphenyl)-1-piperazinyl}-propyl]-.alpha.-phenyl-benzeneacetamide;

.alpha.-hydroxy-N-[3-{4-(4-methylphenyl)-1-piperazinyl}-propyl]-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2,3-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2,4-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2,6-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2-ethoxyphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2-chlorophenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

N-[3-{4-(2-cyanophenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide, hydrochloride;

.alpha.-hydroxy-N-[3-{4-(2-methoxyphenyl)-1-piperazinyl}-propyl]-.alpha.-phenyl-benzeneacetamide;

2-Chloro-.alpha.-(2-chlorophenyl)-.alpha.-hydroxy-N-[3-{4-(2-methoxyphenyl)-1-piperazinyl}-propyl]-benzeneacetamide;

.alpha.-hydroxy-N-[3-{4-(2-methoxyphenyl)-1-piperazinyl}-propyl]-benzeneacetamide;

N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-4-methoxy-.alpha.-(4-methoxyphenyl)-benzeneacetamide;

.alpha.-amino-N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-benzeneacetamide;
N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-(methylsulfonylamino)-benzeneacetamide;

N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-benzylaminocarbonyl-benzeneacetamide;

N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-(4-methylphenyl)-sulfonyl amino-benzeneacetamide;

N-[3-{4-(2,5-dimethylphenyl)-1-piperazinyl}-propyl]-.alpha.-benzylcarbonylamino-benzeneacetamide (~)-N-[3-{4-(2-(propyl)-phenyl)-1-piperazinyl}-propyl]-.alpha.-hydroxy-.alpha.-phenyl-benzeneacetamide;

or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, in which R2 represents a hydrogen, an alkyl lower, OR6 in which R6 represents hydrogen, lower alkyl or benzyl, SR6 in which R6 represents lower alkyl, NH2, NHSO2R6 in which R6 represents lower alkyl or benzyl, C(O)NR6R7 or N(R7)C(O)R6 in which R7 represents hydrogen and R6 represents benzyl; or a salt thereof pharmaceutically acceptable. 3. A compound according to claim 2, in which each of R3 and R4, so as independent of each other, represents one of the following groups substituted or not substituted: lower alkyl, cyclohexyl, phenyl or naphthyl, in which said substituent is halogen, OR6 wherein R6 is lower alkyl, or phenyl; Where a pharmaceutically acceptable salt thereof. 4. Compound according to claim 3, in which R1 represents a hydrogen and represents 2,5-dimethyl-phenyl; or an acceptable salt thereof pharmaceutically. 5. Compound according to claim 4, in which R2 represents OR6 in which represents hydrogen, lower alkyl, or benzyl; or a salt thereof acceptable pharmaceutically. 6. Compound according to claim 4, in which R3 represents an alkyl lower and R4 represents phenyl; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 2, wherein R3 and R4, together with the atom of carbon to which they are jointly bonded, form the 9-xanthenyl radical or fluorenyl; or a pharmaceutically acceptable salt thereof. 8. Compound according to claim 7, in which R1 represents hydrogen and represents 2-methoxy-phenyl or 2,5-dimethyl-phenyl; or a salt thereof pharmaceutically acceptable. 9. Compound according to claim 8, in which R2 represents OR6 in which represents hydrogen, lower alkyl or benzyl; or a salt thereof acceptable pharmaceutically. 10. A compound according to claim 1, wherein said compound meets the formula chosen from:

or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 1, wherein said compound meets the formula:
or a pharmaceutically acceptable salt thereof. 12. Pharmaceutical composition comprising, as active principle, a compound according to one of claims 1 to 11, in association with a support pharmaceutically acceptable. 13. Use of a compound according to one of claims 1 to 11, for the preparation of a drug intended to treat portal hypertension. 14. Use of a compound according to one of claims 1 to 11, for the preparation of a drug intended to treat cirrhosis. 15. Use of a compound of formula I' in which R'1 represents hydrogen or lower alkyl;

R'2 represents hydrogen, lower alkyl, OR6, S(O)m R6 in which m is 0, 1 or 2, NHS(O)n R6 where n is 1 or 2, C(O)NR6R7, NR6R7 or N(R7)C(O)R6;
each of R'3 and R'4, independently of one another, represents one from following groups substituted by one or more substituents or not substituted:
lower alkyl, cyclohexyl, phenyl, napthyl or benzyl wherein said substitute is lower alkyl, halogen, OR6, SR6, NR6R7, CN, NO2, CF3 or phenyl, or R'3 and R'4, together with the carbon atom to which they are jointly bonded, form the 9-xanthenyl or 9-fluorenyl radical;

R'5 represents a phenyl substituted by one or more substituents chosen among alkyl lower, CN, halogen, hydroxy-lower alkyl, cyclopropylhydroxymethyl, a lower alkoxy-lower alkyl, or OR6 where R6 is alkyl lower ; and each of R6 and R7, independently of one another, represents a hydrogen or one of the following groups substituted by one or more substituents or Nope-substituted: lower alkyl, phenyl or benzyl wherein said substituent is a lower alkyl, halogen, or lower alkoxy;

it being understood that if R'2 represents OR6 and R6 represents a lower alkyl, then R'4 does not does not represent the halophenyl or lower alkoxy-phenyl radical; or a salt thereof pharmaceutically acceptable, for the preparation of a medicament intended for treat portal hypertension. 16. Use of a compound of formula I' as defined according to claim 15, for the preparation of a medicament intended to treat cirrhosis.