SK129297A3 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Description

The invention relates to piperazine compounds capable of inhibiting farnesyltransferase resulting in the farnesylation of Ras oncogenic proteins. The invention also relates to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) form part of the pathway linking cell surface growth factor receptors to cell nucleus signals resulting in the onset of cell proliferation. Biological and biochemical studies of the effects of Ras have shown that these proteins act as G-driving proteins. In the inactive state, Ras proteins are bound to GDP. Upon activation of the growth factor receptors, GDP is replaced by GDP for GTP on the Ras protein, and GTP-bound form of Ras delivers growth stimulatory signals until the Ras activity is terminated by GTP -ase, which again converts the protein into their ineffective form, linked to GDP, as described by DR Lowy and DM Villumsen, Ann. Rev. Biochem., 62, 851-891 (1993). Mutated Ras genes (Ha-ras,

Ki4a-ras and N-ras) can be detected in a variety of human cancers, including colorectal cancer, pancreatic cancer, and myeloid leukemias. The protein products of the expression of these genes do not possess the intrinsic activity of GTPase and consequently sell a growth stimulating signal continuously.

Ras must be located in the plasma membrane for both normal and oncogenic function. At least three post-translational modifications occur, all of which appear at the C-terminus of Ras proteins. The C-terminus of Ras proteins contains the CAAX motif or Cys-Aaa -Aaa -Xaa ', wherein Cys is cysteine, Aaa is aliphatic amino acid, and Xaa is any amino acid as described in Villumsen et al., Nature, 310, 583-586, 1984. Depending on the specific sequence, this group of amino acids serves as a signal sequence for protein farnesyltransferase or geranylgeranyltransferase, these enzymes catalyze the alkylation of the cysteine residue of the CAAX group by C 1 - or C 20 -isoprenoid, according to S. Čiarke, Ann. Rev. Biochem. 61: 355-386 (1992) and V. R. Schafer and J. Rine, Ann. Rev. Genetics, 30, 209-237 (1992). Ras is one of a series of proteins known to undergo post-translational farnesylation. Other such proteins are, for example, proteins that are related to Ras and are also capable of binding to GTP, such as Rho, certain fungal factors, core lamina, and the gamma transducin subunit. James et al., J. Biol. Chem., 269, 14182, 1994 discloses a peroxisome-associated protein Pxf, which is also farnesylated. The authors also assume the existence of other farnesylated proteins with unknown structure and function.

Inhibition of protein farnesyltransferase demonstrably blocks the growth of cells transformed with Ras on soft agar and also modifies other manifestations of the transformed phenotype. Certain protein farnesyltransferase inhibitors have also been shown to selectively block processing of Ras oncoprotein within cells according to NE, Kohl et al., Science, 260, 1934-1937, 1993, and GL James et al., Science, 260, 1937-1942, 1993. Recently, it has been shown that a certain protein farnesyltransferase inhibitor blocks the growth of ras-dependent tumors in nude mice by NE Kohl et al., Proc. Natl. Acad. Sci., USA, 91, 9141-91 (1994) and induces the recession of mammary and salivary gland carcinomas in ras-transgenic mice according to N. E. Kohl et al. Nature Medicine, 1: 792-797, 1995.

Indirect inhibition of protein farnesyltransferase in vivo has been demonstrated using lovastatin (Merck & Co., Rahway, NH) and compactin according to Hancock et al., Et al., Times. Et al., Et al. And Schafer et al., Science, 245, 379, These compounds cause inhibition of HMG-CoAreductase, which limits the rate of production of polyisoprenoids including farnesylpyrophosphate. Protein farnesyltransferase utilizes farnesyl pyrophosphatase to covalently modify the thiol group Cys in the CAAX group of the Ras protein by the farnesyl group of Reiss et al., Cell, 62, 81-88, 1990; Schaber et al., J. Biol. Chem., 265, 14701-14704, 1990, Schafer et al., Science, 249, 1133-1139, 1990, and Manne et al., Proc. Natl. Acad. Sci. USA 87: 7541-7545 (1990). Inhibition of farnesyl pyrophosphate biosynthesis due to inhibition of HMG-CoA reductase blocks membrane deposition of cultured cells. However, direct inhibition of farnesyltransferase would be more specific and would be accompanied by fewer side effects than when the desired dose of a general isoprene biosynthesis inhibitor was administered.

Two general classes of protein farnesyltransferase inhibitors, FTPase, have been described. The first group consists of FPP analogs of farnesyl diphosphate; the second group consists of substances which are related to the protein substrate for the enzyme, for example the Ras protein. The peptides-derived inhibitors described are usually molecules containing cysteine and a related group of CAAX, which is a signal for protein transfer by Schaber et al., Also there, Reiss et al., Also there and Reiss et al., PNAS, 88, 732-736, Such inhibitors may cause inhibition of protein prenylation by providing a further substrate for the farnesyltransferase enzyme or may be purely competitive inhibitors according to US 5,141,851 (University of Texas); NE Kohl et al., J. Med. Chem., 37, 725? In general, disruption of the thiol group in a CAAX derivative dramatically reduces the inhibitory capacity of a compound. However, the thiol group usually also requires limiting the use of FTPase inhibitors for therapeutic purposes with respect to the pharmacokinetics, pharmacodynamics and toxicity of these agents. It would therefore be desirable to find a functional replacement for the thiol group.

In recent months, protein farnesyltransferase inhibitors have been reported to be inhibitors of smooth muscle vascular cell proliferation and can therefore be used to prevent and treat arteriosclerosis and vascular disorders in diabetes according to JP H7-112930.

Recently, it has also been shown that some tricyclic compounds optionally containing a piperidine ring are also inhibitors of FTPase, for example according to WO 95/10514, WO 95/10515 and WO 95/10516. Inhibitors of the same enzyme containing an imidazole ring have also been described, for example according to WO 95/09001 and EP 0 675 112 A1.

SUMMARY OF THE INVENTION It is an object of the present invention to provide peptide-like substances which do not contain a thiol group and which inhibit protein farnesyltransferase and thus post-translational farnesylation of proteins. These substances should be used in the manufacture of pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention provides peptidomimetic compounds containing a piperazine moiety and inhibiting protein farnesyltransferase. These substances do not contain a thiol group and are therefore highly advantageous in that their use does not result in chemical reactions induced by the presence of a thiol group, for example rapid autooxidation and formation of disulphides with endogenous thiols, they also have reduced systemic toxicity and more favorable pharmacokinetic properties. .

The piperazine compounds may be represented by formulas A, B and C

V-A '(CR ¹ > 2) n A ² (CR 1 2) _n - (CR ^1b a).

O (A)

(R ⁸ ) r

V-A '(CR ^{' a} 2) _n A ² (CR ' ^a 2)'

- (CR ^b 2) _p \

(B)

According to a first embodiment, the present invention provides piperazine compounds of formula A (R ⁸ ) r

V - A '(CR ^{, a} 2) n A ² (CR ^{, a} 2) _n

(And where

R ^a and R ¹ b are independently selected from

(a) a hydrogen atom;

b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R 4 O-, R 1 S (O) _m -,

N0->.

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, CN, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3 or R ^{1 L} OC (O) NR ¹⁰ -,

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl

-N (R ¹⁰⁾ ₂ with each R ¹⁰ 2 C (O) NR ¹⁰ -C 6 alkyl, CN, ^(R10) _2NC (0) -,

R ¹⁰ C

R ¹⁰ 0-, R ¹¹ S (O) m -, (R ¹⁰ ) 2 -N-C (NR ¹⁰ ) -,

R ¹⁰ OC (O) -, N ,, -N (R ¹⁰ ) ₂ and R ¹¹ OC (O) NR ¹⁰ -, v *

9 ,.

R and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted,

6 _D 7

FrR or

A heterocyclic radical optionally substituted wherein the substituted groups are substituted with at least one substituent from the group

1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group

(a) alkyl of 1 to 4 carbon atoms, (CH ₂ ) _p OR ⁶ ,

b)

c)

d) halogen atom,

e) CN, C 3-6 cycloalkyl, (CH ₂ ) _p NR ⁶ R ⁷

2)

3) OR,

4)

5)

SR ^6a , S (O) R ^6a , SO ₂ R ^6a ,

6)

-NR ⁶ R ⁷ R

-N

R '

7)

8)

Y o

? ⁶ —N ^ NR ⁷ R ^7a

T

O = O / NR ⁶ R ⁷

T o

9) -θγ «'

ABOUT

6d7

10)

NR R

11) -so ₂ -nr ⁶ y ⁷ y

12) - N-SO ₂ -R ^6a 3)

ABOUT

14) —fT ° ^R6

ABOUT

15) N3 or

16) F or o * 2

R and R are attached to the same carbon atom and together form - _{(CH2) u,} wherein one of the carbon atoms is optionally replaced by a group selected from 0, S (0) _m,

-NC (O) - or -N (COR ¹⁰ ) -,

R 6 and R 5 are independently selected from hydrogen or methyl, wherein any two of R ⁷ , R ⁷ , R 6 and R 6 may be bonded to the same carbon atom, r 6, R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals are optionally substituted with a substituent from the group

(a) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO,

e)

R ¹¹

ABOUT

f) -SC 1 R 4 or;

g) N (R ¹ ®) ₂ or r 6 and R 6? may together form a circle; or

R 7 and R may form ^a ring, R 6 ^and is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, a heterocyclic radical or aryl moieties are optionally substituted by one

from groups a) (C 1 -C 4) alkoxy b) aryl or heterocyclic radical, c) halogen atom, d) HO e) p11 Ύ 0 f) -SO ₂ R ^ · ¹ · or g) N (R ¹⁰ ) ₂ the independently selected from the group a) a hydrogen atom, b) aryl, heterocyclic radical, cycloalkyl

carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (0) -, (R ^L0) 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3,

-N (R ¹⁰ ) ₂ or R ^1: LOC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms optionally substituted by a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, -θΟ- R, R ^^ S (O) _m -, R ¹⁰ C (O) NH-, (R ¹⁰⁾ 2 N-C (O) -, (R ¹⁰⁾ 2 N-C (NR ¹⁰⁾ -, CN,

R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or

R ¹⁰ OC (O) NH-,

R 6 is selected from the group

(a) a hydrogen atom;

b) alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, Β ^ θΟ-,

L 9 _

R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ ,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, r 11 is independently selected from hydrogen, alkyl of 1 to carbon atoms, benzyl or aryl, rH is independently selected from alkyl of 1 to 6 carbon and aryl,

A and A independently represent a chemical bond, CH = CH-, -C = C-,

-C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -,

-S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -,

V is selected from the group

(a) a hydrogen atom;

b) heterocyclic radical,

c) aryl,

d) alkyl of 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom of the groups O, S and N; and

(e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from hydrogen when A ¹ is S (O) m or when A ¹ is a chemical bond, n = 0 and A is S (O) m

V is a heterocyclic radical,

X is -CH ₂ , -C (= O) -, or -S (= O) _m -,

V represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic radical, wherein the substituent on these groups is at least one substituent from the group

1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ⁶ R ⁷ ;

c) cycloalkyl of 3 to 6 carbon atoms,

- 10 (d) aryl or heterocyclic radical,

e) HO,

f) -S (O) _m R ^6a; or

) -C (O) NR ⁶ R ^7,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷

6) CN,

7) N0 ₂

8) CF ₃

(9) -S (O) _m ^R6a ;

10) -C (O) NR ⁶ R ⁷ or

11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5 provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or 1 and u is 4 or 5, or pharmaceutically acceptable salts of these compounds.

According to a second embodiment, the present invention provides piperazine compounds of formula B (R ®),

V-A '(CR' ^a 2) 'A ² (CR ^{1 and} 2) _n v

N ^X NZ

W / - (CR ^{, b} 2) _pX ^x v y (B) where

R 6a ^and R ^6-6 are independently selected from the group

(a) a hydrogen atom;

- clay (b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,

R ¹⁰ OR ^{11 '} S (O)

R ¹⁰ C (O) NR ¹⁰ -, CN (R ¹⁰ ) ₂ NC (0) -, CN, NO,

R ¹⁰ C

R ¹⁰ OC

N (R ¹⁰⁾ ₂

c) (R ^{± u} ) ₂ NC (NR ^{± u} ) or R ¹¹ OC (O) NR ¹⁰ -, alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 6 10 carbon atoms, alkenyl or alkynyl 6 carbon atoms, R R -θΟ-, R ^^ S S (O) _m -, and each with 2 R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, CN, (NC ¹⁰ ) ₂ NC (NC ¹⁰ )

R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -,

R ² and R ³ are independently selected from hydrogen, alkyl of 1 to carbon atoms, optionally substituted, alkenyl or alkynyl, each of from 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, r ⁶ r ⁷ or

R ^{e is a} heterocyclic radical, optionally substituted, wherein the substituted groups are at least substituted with an aryl or heterocyclic radical, optionally substituted with a C 1 -C 4 alkyl substituent;

H _{(CH2) p} OR ^b, _{(CH2) p} NR ⁶ R ^7, halogen,

2)

3)

4)

5)

6)

a)

b)

c)

d)

e) CN, cycloalkyl of 3 to 6 carbon atoms, OR ⁶ ,

SR ^6a , S (O) R -NR ⁶ R ⁷ ,

R ⁶

6a so ₂ y

6a

7)

8)

9) —N, NR ⁷ R ^7a

T

O = O / NR ⁶ R ⁷

T o

- O ^ / OR ⁶

T o

10)

6 _d 7

NR ^b R

11)

12) —so ₂ -nr ⁶ r ⁷ y

- N-SO ₂ -R ^6a

13)

14)

V o

x o

r ^£

OR ^e

15) Ng or

16) F or

Ί

R ^z and R ^J are attached to the same carbon atom and together form - _{(CH2) u,} wherein one of the carbon atoms is optionally replaced by a group selected from 0, S (0) _m,

-NC (O) - or -N (COR ¹⁰ ) -,

R is hydrogen or methyl, wherein any two of R ^6, R ^~> and can be attached to the same carbon atom,

R 1, R 7 _and R 7 ' _are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted with a substituent from

(a) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO,

ABOUT

f) -SO2RH; or

(g) N (r10) 2 or

R ⁶ and R ⁷ may together form a ring or a ring

R ⁷ and R ^7a may together form a ring,

R ^a is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, a heterocyclic radical or aryl radicals being optionally substituted by one of R

(a) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO,

f) -SO2RH; or

g) N (R ¹⁰⁾ ₂

R 8 is independently selected from the group

(a) a hydrogen atom;

b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ ,

-N (R ¹⁰ ) ₂ or R ^11L OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms optionally substituted by a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, R (O) _m , R ( ¹⁰⁾ C (O) NH-, (R ( ¹⁰ ) 2N-C (O) -, (R ( ¹⁰ )) 2N-C (NR ¹⁰ ) -, CN .

R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-,

R 6 is selected from the group

(a) a hydrogen atom;

(b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 6 O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (O) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, R 10 is independently selected from hydrogen, alkyl of 1 to carbon atoms, benzyl or aryl,

R ¹¹ is independently selected from C 1 -C 6 alkyl and aryl,

A ^ and A ^ independently represent a chemical bond, CH = CH-, -C = C-,

-C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -,

-S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -,

G is H ₂ or O,

V is selected from the group

(a) a hydrogen atom;

b) heterocyclic radical,

c) aryl,

(d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and

e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A · ¹ · is S (O) _m or when A 40 is. chemical bond, n = 0 and A represents a group

V is a heterocyclic radical,

X is -CH ₂ , -C (= O) -, or -S (= O) _m -,

Z is substituted or unsubstituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituent is at least one substituent from the group

1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ⁶ R ⁷ ;

c) cycloalkyl of 3 to 6 carbon atoms,

d) aryl or heterocyclic radical,

e) HO,

f) -S (O) _m R ^6a; or

) -C (O) NR ⁶ R ^7,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷

6) CN,

7) N0 ₂

8) CF ₃

(9) -S (O) _m ^R6a ;

10) -C (O) NR ⁶ R ⁷ or

11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5 provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or 1 and u is 4 or 5, or pharmaceutically acceptable salts of these compounds.

In a third embodiment, the present invention provides piperazine compounds of formula (C)

(C) where

R ^1a and R ^1b are independently selected from the group

(a) a hydrogen atom;

b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R ^1b O-, (O) _m -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, CN, NO ₂ , (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC ( O) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -,

c) alkyl of 1 to 6 carbon atoms, optionally substituted by a substituent from the group of unsubstituted or substituted aryl, heterocycle, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl with 2 to 6 carbon atoms, R ¹ ®!) -, R S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, CN, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -,

R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -,

R ² and R ² are independently selected from hydrogen, alkyl of 1 to carbon atoms, optionally substituted, alkenyl or alkynyl of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted,

ABOUT

or

a heterocyclic radical optionally substituted wherein the substituted groups are substituted with at least one substituent from the group

1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group

(a) alkyl of 1 to 4 carbon atoms,

(b) (CH ₂ ) _p OR ⁶ ,

- 17 (c) (CH ₂ ) _p NR ⁶ R ⁷ ,

d) halogen atom,

e) CN, cycloalkyl of 3 to 6 carbon atoms,

OR ⁶ ,

SR ^6a , S (O) R ^6a , SO ₂ R ^6a , -NR ⁶ R ⁷ ,

P ⁶

R ⁷ —N., NR ⁷ R ^7a

T

O ~ O \ / NR ⁶ R ⁷

T o

—O ^ -OR ⁶

T o

nr ⁶ r ⁷ —so ₂ -nr ⁶ r ⁷ y

N-SO ₂ -R ^{6 a}

R ⁶ O

OR ⁶

O or F or

0 7

R and R are attached to the same carbon atom and together form a - (CH 2) _{u group} , one of which carbon atoms is optionally replaced by one of 0, 5 (0), -NC (O) -, or -N (COR ¹⁰⁾ is hydrogen or methyl, with any two 974.

of R, R ^J and R to be attached to the same carbon atom, and R 5 are independently selected from hydrogen or methyl, wherein any two of R ²

R @

R 5 and R 5 can

R ^c be bound to the same carbon atom,

R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted with a substituent from the group

a) alkoxy; b) aryl i c) atom] d) HO e) Y 0 f) -SO ₂ R with) N (R ¹⁰ and R ⁷ they can : ΤΆ 7 Λ E and R brain

R or 12 or

6a is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical or aryl, the radicals being optionally substituted by one of the groups

a)

b)

c)

d)

e) C 1 -C 4 alkoxy, aryl or heterocyclic radical, halogen atom,

HO,> 11

f) -SO ₂ R ^III or

(g) N (R ¹⁰ ) ₂ o

R is independently selected from the group

(a) a hydrogen atom;

b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) ) r -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) - R ¹⁰ OC (O) -, n ₃ ,

-N (R ¹⁰ ) ₂ or R ^11L OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, R ¹ ® O-, R ' ^L1 S (O) m-, R ¹⁰ C (O) NH-, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN .

R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-,

R 6 is selected from the group

(a) a hydrogen atom;

(b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 6 O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (O) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (0) ~, R ¹⁰ OC (O) -, N 3,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -,

R 1 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, benzyl or aryl; R 1 is independently selected from C 1 -C 6 alkyl and aryl;

A ¹ and A independently represent a chemical bond, CH = CH-, -C = C-,

-C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -,

-S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -,

G is an oxygen atom,

is selected from the group a) a hydrogen atom, b) heterocyclic radical, c) aryl, d) alkyl of 1 to 20 carbon atoms in which are 0 to 4 carbon atoms replaced by the heteroatom of Group 0 S and N a e) alkenyl of 2 to 20 carbon atoms,

provided that V is different from hydrogen when S (O) _{m is,} or when A 1 is a chemical bond, n = 0 and A is ^S (°) m V is a heterocyclic radical,

X is -Cl 1, -C (= O) - or -S (= O) _m -,

Z represents a substituted or unsubstituted radical from the group aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, the substituted groups being substituted by one or more of the following groups

1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ⁶ R ⁷ ;

c) cycloalkyl of 3 to 6 carbon atoms,

d) aryl or heterocyclic radical,

e) HO,

f) -S (O) _m R ^6a; or

) -C (O) NR ⁶ R ^7,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷

6) CN,

7) N0 ₂

8) CF ₃

(9) -S (O) _m ^R6a ;

10) -C (O) NR ⁶ R ⁷ or

11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5 provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or 1 and u is 4 or 5, or pharmaceutically acceptable salts of these compounds.

In a preferred embodiment, the invention relates to piperazine compounds of formula A

R ⁴ R ⁵ where

R ^a is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms,

R 1b is independently selected from the group

(a) a hydrogen atom;

-i n

b) aryl, heterocyclic radical, cycloalkyl, R 0 -, -N (R 10) 2 or alkenyl of 2 to 6 carbon atoms,

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl, alkenyl, R ¹⁰ O- and -N (R ¹⁰ ) ₂ ;

R ³ , R ⁴ and r ⁵ are independently selected from hydrogen or methyl, R ² represents a hydrogen atom, a group of formula # ⁶ r ⁷ or a straight or branched chain alkyl of 1 to 5 carbon atoms, unsubstituted or substituted by at least one of the following groups:

1) aryl;

2) heterocyclic radical,

3) OR ⁶ ,

SR ^6a , SO ₂ R ^6a or

5) nr ⁶ r ⁷ wherein any two of R 6, R 6, R 6 and R ⁶ may be attached to the same carbon atom,

R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heterocyclic radicals, which groups are unsubstituted or substituted by any of the following groups:

(a) C 1 -C 4 alkoxy;

(b) a halogen atom; or

c) an aryl or heterocyclic radical is selected from. (C 1 -C 4) alkyl or (C 3 -C 6) cycloalkyl optionally substituted by one of the groups

(a) C 1 -C 4 alkoxy;

(b) a halogen atom; or

c) an aryl or heterocyclic radical, independently selected from the group

(a) a hydrogen atom;

b) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, per 1 to 6 carbon atoms, F

6a

R ^c fluoroalkyl with R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN,

NO.

Cl, R ¹⁰ O-, R ¹⁰ C (O) -,

c)

R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - and alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, R ¹⁰ O -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -,

R 6 is selected from the group

(a) a hydrogen atom;

(b) alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -,

-N (R ¹⁰ ) ₂ or R ^11L OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R 6, St 10),

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -,

R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ^{11 L} OC (O) NR ¹⁰ -, R ¹⁰ is independently selected from hydrogen, alkyl of 1 to carbon atoms, benzyl or aryl, r H is independently selected C1-6alkyl and aryl;

-I o

A and A independently represent a chemical bond, CH = CH-, -C = C-,

-C (O) -, -C (O) NR ¹⁰ -, -O-, -N (R ¹⁰ ) - or -S (O) _m ) -,

V is selected from the group

(a) a hydrogen atom;

b) a heterocyclic radical from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl,

c) aryl,

(d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and

(e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from hydrogen when it is S (O) _m or when A ^ is C ^ ^ ^;

O represents a chemical bond, n = 0 and A represents a group

WITH"".·

V is a heterocyclic radical selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl,

X is -CH 2 or -C (= O) -,

Y represents a mono- or bicyclic aryl or a mono- or bicyclic heterocyclic radical, unsubstituted or substituted by at least one of the following groups

(a) alkyl of 1 to 4 carbon atoms,

(b) C 1 -C 4 alkoxy;

(c) a halogen atom; or

(d) NR ⁶ R ⁷ ;

m means 0 1 or 2, n means 0 1 2, 3 or 4 P means 0 1 2, 3 or 4 r means 0 until 5, provided that r = 0 if

represents a hydrogen atom, s represents 0 or 1, t represents 0 or 1, or pharmaceutically acceptable salts of these compounds.

A second preferred embodiment of the invention relates to the piperazine compounds of formula B

R ³ R ⁴

where R ^1a the independently selected from hydrogen or alkyl r! b s 1 the up to 6 carbon atoms, independently selected from the group a) b) hydrogen atom, aryl, heterocyclic radical, cycloalkyl, Ε ¹ θΟ-, c) -N (R 10) 2 or C 2 -C 6 alkenyl C 1 -C 6 alkyl, optionally alkyl, of substituted

substituted with unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, R ¹⁰ O- and -N (R ¹⁰ ) ₂ ;

R ³ and R ⁴ are independently selected from hydrogen or methyl,

9

R is hydrogen, a group of formula NR ⁶ R ⁷ or C 1 -C 5 straight or branched chain, unsubstituted or substituted by at least one of the following:

R ^c

1) aryl, 2) heterocyclic radical, 3) OR ⁶ , 4) SR ^6a , SO ₂ R ^6a or 5) NR ⁶ R ⁷ 0 with any two of the symbols R ^2, R ³ bonded to the same atom alkyl, R ⁷ and R ^7a is independently elected from groups s 1 up to 4 carbon atoms, cycloalkyl with 3 to

6a is a aryl, heterocyclic radical, these groups being unsubstituted or substituted by any of the following groups:

(a) C 1 -C 4 alkoxy;

(b) a halogen atom; or

c) an aryl or heterocyclic radical is selected from the group consisting of alkyl having 1 to 4 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, optionally substituted by one of the groups

(a) C 1 -C 4 alkoxy;

(b) a halogen atom; or

c) aryl or heterocyclic radical,

R 8 is independently selected from the group

(a) a hydrogen atom;

b) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, C1, R RO-,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -,

R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, R ¹⁶ O-, R ¹⁶ C (O) NR ¹⁶ -, (R ¹⁰ ) 2N-C (NR ¹⁰ ) - R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) 2 or R ^{1: L} OC (O) NR ¹⁰ -,

R 6 is selected from the group

(a) a hydrogen atom;

b) alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -,

-N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹¹ S (O) _m -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -,

R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, r 11 is independently selected from hydrogen, alkyl of 1 to carbon atoms, benzyl or aryl, r H is independently selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl,

9

A and A independently represent a chemical bond, CH = CH-, -C = C-,

-C (O) -, -C (O) NR ¹⁰ -, -O-, -N (R ¹⁰ ) - or -S (O) _m ) -,

V is selected from the group

(a) a hydrogen atom;

b) a heterocyclic radical from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl;

c) aryl,

(d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and

(e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A ⁷ is S (O) _m or when A ⁷

- 27 means a chemical bond, n

O and A ^z represent a group

V is a heterocyclic radical selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl,

G stands for Η ₂ · or 0,

Z represents mono- or bicyclic aryl or mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, these groups being unsubstituted or substituted by at least one of the following groups

1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ⁶ R ⁷ ;

c) cycloalkyl of 3 to 6 carbon atoms,

d) aryl or heterocyclic radical,

e) HO,

f) -S (O) _m R ^6a; or

) -C (O) NR ⁶ R ^7,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷

6) CN,

7) N0 ₂

8) CF ₃

(9) -S (O) _m ^R6a ;

10) -C (O) NR ⁶ R ⁷ or

(11) cycloalkyl of 3 to 6 carbon atoms,

m means about, 1 or 2, n means 0 1 2, 3 or 4 P means 0 1 2, 3 or 4 r means 0 until 5, provided that r = 0 if V means atom H,

p is O or 1, t is 0 or 1, u is 4 or 5, provided that, if G is H2 and W is imidazolyl, then the substituent (R ^{8) rV-A1} (CR ^and 2) nA ^{2 (Ia} CR '2) _n is other than a hydrogen atom, and provided that when X is -C (= 0) - or -S (0) _m -, then t = Ia, (R ⁸ N-A ¹ (CR ^{13 '} ) nA ² (CR ^13' ) n has a meaning different from that of the hydrogen atom, or a pharmaceutically acceptable salt thereof.

Preferred piperazine compounds of the invention include:

2 (S) -butyl-1- (2,3-diaminoprop-yl) -4- (l-naphthoyl) -piperazine,

1- (3-amino-2- (2-naphtylmethylamino) prop-l-yl) -2 (S) -butyl-4 (l-naphthoyl) piperazine,

2 (S) -butyl-1 - [(l-naphthyl-2-ylmethyl) -lH-imidazole-5-yl) ethyl] -4- (l-naphthoyl) piperazine,

1- (2 (R) -amino-3-hydroxy-propyl) -2 (S) -butyl-4 (l-naphthoyl) piperazine,

1- (2 (R) -amino-4-hydroxybutyl) -2 (S) -butyl-4 (l-naphthoyl) piperazine,

1- (2-Amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1naftoyl) piperazine,

1- (2-Amino-3- (2-hydroxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

1- [3- (4-imidazolyl) propyl] -2 (S) -butyl-4 (l-naphthoyl) piperazine,

2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (l-naphthylmethyl) imidazole-5-ylmethyl] -piperazine,

2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (2-naphthylmethyl) imidazole-5-ylmethyl] -piperazine,

2 (S) -n-butyl-l- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (1naftoyl) piperazine,

2 (S) -N-butyl-1- [1- (4-methoxybenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine,

2 (S) -N-butyl-1- [1- (3-methyl-2-butenyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine,

2 (S) -n-butyl-l- [1- (4-fluorobenzyl) imidazol-5-ylmethyl] -4- (1naftoyl) piperazine,

2 (S) -n-butyl-l- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1naftoyl) piperazine,

1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl 4- (1naftoyl) piperazine,

2 (S) -butyl-1- [5- [1- (2-naphthylmethyl)] - 4,5-dihydro-imidazol] methyl-4- (1-naphthoyl) piperazine,

1- [5- (1-Benzylimidazol) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine,

1- [5- [1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-4- (1naftoyl) piperazine,

1- (3-acetamidomethylthio-2 (R) aminoprop-l-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

2 (S) -butyl-1- [2- (1-imidazolyl) ethyl] sulfonyl-4- (1-naphthoyl) piperazine,

2 (R) -butyl-l-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine,

2 (S) -Butyl-4- (1-naphthoyl) -1- (3-pyridylmethyl) piperazine,

1-2 (S) -butyl- (2 (R) - (4-nitrobenzyl) amino-3-hydroxy-propyl) -4- (1-naphthoyl) piperazine,

1- (2 (R) -amino-3-hydroxyheptadecyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

2 (S) -benzyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine,

1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1naftoyl) piperazine,

1- (2 (R) -amino-3- [3- (4-nitrobenzyltio) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine,

2 (S) -butyl-l - [(4-imidazolyl) ethyl] -4- (l-naphthoyl) piperazine,

2 (S) -butyl-l - [(4-imidazolyl) methyl] -4- (l-naphthoyl) piperazine,

2 (S) -Butyl-1 - [(1-naphthyl-2-ylmethyl) -1H-imidazol-5-yl] acetyl] -4- (1-naphthoyl) piperazine,

1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl 4- (1naftoyl) piperazine,

2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethylbenzyl) imidazol-5-ylmethyl] -piperazine,

2 (S) -n-butyl-l- [1- (4-methylbenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine,

2 (S) -n-Butyl-1- [1- (3-methylbenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine,

1- [1- (4-Phenylbenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl-4- (1-naphthoyl) piperazine,

2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (2-phenylethyl) imidazole-5-y1metyl] piperazine,

2 (S) -N-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethoxy) imidazol-5-ylmethyl] piperazine,

1 - [[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl] -2 (S) -N-butyl 4- (1-naphthoyl) piperazine,

5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- (4-ylmethyl) piperazin-2-one,

5 (S) -N-butyl-4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) piperazin-2-one,

4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) -5 (S) - (2-methoxyethyl) piperazin-2-one, (S) -1- ( 3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) ) -5-imidazolylmethyl] -5- [N-ethyl-2-acetamide] -2-piperazinone, (±) -5- (2-butynyl) -1- (3-chlorophenyl) -4- [1- (4) -kyanobenzyl) -5imidazolylmetyl] -2-piperazinone,

1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolemethyl] -2piperazinón,

5 (S) -butyl-4- [1- (4-cyanobenzyl-2-methyl) -5-imidazolylmethyl] -1- (2,3-dimethylphenyl) -piperazin-2-one,

4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one,

5 (S) -n-butyl 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2metylfeny1) piperazin-2-one,

4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5 (S) - (2-fluoroethyl) -1- (3-chlorophenyl) piperazin-2-one,

4- [3- (4-cyanobenzyl) piperidin-4-yl] -1- (3-chlorophenyl) -5 (S) (2-metylsulfonylety1) -piperazin-2-one,

4- [5- (4-cyanobenzyl) -1-imidazolylethyl] -1- (3-chlorophenyl) piperazin-2-one ', or a pharmaceutically acceptable salt thereof.

Specific examples of the Piperazine Compounds of the Invention include:

1- [5- [1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-4- (1naftoyl) piperazine

0 ₂ ΎΎ / _)

N

I

1- [5- (l-Benzylimidazol) methyl] -2 (S) -butyl-4 (l-naphthoyl) piperazine

1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1naftoyl) piperazine

1- (2 (R) -amino-3- [3- (4-nitrobenzylthio) propyl] -2 (S) -butyl-4 (1-naphthoyl) piperazine

- 34 2 (S) -n-Butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine

2 (S) -N-Butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (2,3-dimethylphenyl) piperazin-5-one

2 (S) -n-Butyl-1- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1naftoyl) piperazine

1 - [[i- (4-cyanobenzyl) imidazol-5-yl] acetyl] -2 (S) -n-butyl 4- (1-naphthoyl) piperazine

1- [1- (4-Cyanobenzyl) imidazol-5-ylmethyl] -4- (2,3-dimethylphenyl) -2 (S) - (2-methoxyethyl) piperazin-5-one

5 (S) -n-butyl 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2-methylphenyl) piperazin-2-one

- 36 (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (methanesulfonyl) ethyl] -2-piperazinone

(S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone

(S) -1- (3-chlorophenyl) -4- [1- (4-cyanophenyl) -5-imidazolylmethyl] 5- [2- (ethanesulfonyl) methyl] -2-piperazinone

1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone

NC

N

Cl or a pharmaceutically acceptable salt thereof.

The compounds of the invention may contain centers of asymmetry and are therefore present as racemates, racemic mixtures and as individual diastereomers, all isomers including optical isomers being included within the scope of the invention. In the event that any group or symbol, for example aryl, a heterocycle, R, R and the like occurs more than once in the formula or part thereof, each occurrence is independent of any other occurrence. Combinations of substituents are only permissible if the result is still products.

Alkyl radicals include straight or branched chain aliphatic hydrocarbon groups having the indicated number of carbon atoms. Alkoxy groups are alkyl groups with the indicated number of carbon atoms, linked through an oxygen bridge. The halogen atom may be a fluorine, chlorine, bromine or iodine atom.

Aryl means any stable monocyclic or bicyclic group having carbon atoms of up to 7 members in each ring, wherein at least one of the rings is aromatic. Examples are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

Heterocyclic radical means a stable monocyclic radical of 5 to 7 members or a permanent bicyclic heterocyclic radical of 8 to 11 members, in each case saturated or unsaturated and consisting of carbon atoms together with 1 to 4 heteroatoms of N, O and S, and any bicyclic is also included a group in which any of the above heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached by any heteroatom or carbon atom as long as a stable structure is formed. Examples of heterocyclic groups include azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranazolyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranazol, , isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthylridinyl, oxadiazolyl, 2-ozoazepinyl, oxazolyl, 2-ozopiperazinyl, 2-oxopiperidinyl, 2-oxopyrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyridyl, pyrazinyl, pyridyl, pyrazol, , pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiazolyl, thiazolinyl, thianofuryl, thienothienyl and thienyl.

Heteroaryl means any permanent monocyclic or bicyclic radical having up to 7 members in each ring, at least one of which is aromatic and at the same time 1-4 carbon atoms being replaced by heteroatoms from the groups N, O and S. As examples of these heterocyclic radicals benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, isohydrobenzothiapyranyl, dihydrobenzothiopynyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl and thienyl.

Q

In the meanings of R ⁶ and R ³ , all the abovementioned groups, i.e. C 1 -C 8 alkyl, C 2 -C 8 alkynyl or alkenyl, substituted aryl or heterocyclic radical, can be substituted.

Similarly, R ⁶ , R ⁷ and R ^{7a can} all be substituted, i.e., alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, aroyl, aryl, heteroaryl, arylsulfonyl, heteroarylsulfonyl and a heterocyclic radical, these groups may contain one to three substituents in addition to the site of attachment to the rest of the molecule.

Substituted aryl includes aryl groups substituted with 1 or 2 substituents from F, Cl, Br, CF 3, NH ₂ , N (C 1 -C 6 alkyl) ₂ , NO ₂ , CN, (C 1 -C 6 alkyl) carbon atoms) O-, -OH, (alkyl of 1 to 2 atoms and up to carbon atoms) S (O) 2 -, (alkyl with carbon) C (O) NH-, H ₂ NC (NH) -, (alkyl C (O) -, (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) C (O) NH- and C 1 -C 20 alkyl.

When R and R together form - (CH ₂ ) _U -, cyclic groups are formed. Examples of such cyclic groups include, for example, carbon) OC (O) -, N 4,

XA y-sx 'v

In addition, these cyclic groups may contain heteroatoms. Exemplary heteroatom-containing cyclic groups include

Lines that extend from the ring systems towards the substituents, for example R, R, R and the like, mean that the substituent located at the end of such a bond can be bonded to any of the substitutable carbon atoms in the ring.

Preferably, R 6 ^and R 6 are independently selected from hydrogen, -N (R 10) 2, Κ Κ (Ο) ΝΚ ¹ ΝΚ- or unsubstituted or substituted C 1-6 alkyl, wherein the substituent is selected from the group unsubstituted or substituted phenyl, - (R ¹⁰ ) ₂ , R ¹⁰ O-, and R ¹⁰ C (O) NR ¹⁰ -.

Preferably, R ^{2 is} selected from hydrogen,

O 0 or substituted or unsubstituted alkyl groups having from 1 to 8 carbon atoms, alkenyl or alkynyl groups having from 2 to 8 carbon atoms each, wherein the substituent is at least one of:

1) aryl or a heterocyclic radical, optionally substituted with a substituent from the group:

(a) alkyl of 1 to 4 carbon atoms,

(b) (CH ₂ ) _p OR ⁶ ,

(c) (CH ₂ ) _p NR ⁶ R ⁷ ,

d) halogen atom,

2) cycloalkyl of 3 to 6 carbon atoms,

3) OR ⁶ ,

4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a ,

5) -NR ⁶ R ^7,

R ⁶ o

7) ip ⁶ —N NR ⁷ R ^7a

T

ABOUT

8) -O_NR ⁶ R ⁷ ο

9)

10)

O ^ OR ⁶

T o

nr ⁶ r ⁷

11) —so ₂ -nr ⁶ r ^{7 12)} -N-SO ₂ -R ^6a

13) o

r ^£

14) ~ ΊΤ o

OR ^fc

Or

16) F.

R 3 is preferably selected from hydrogen or C 1 -C 6 alkyl.

preferably r 4 and r 5 are hydrogen atoms.

R 6, R ⁷ and R ^7a are preferably selected from hydrogen, unsubstituted or substituted alkyl of 1 to 6 carbon atoms, unsubstituted or substituted aryl, and unsubstituted or substituted cycloalkyl.

^And R is preferably an unsubstituted or substituted alkyl of 1 to 6 carbon atoms, unsubstituted or substituted aryl or unsubstituted or substituted cycloalkyl.

R preferably is hydrogen or methyl, most preferred value of R is ^a hydrogen atom.

R @ 6 is preferably selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl.

A and A are preferably independently selected from the group consisting of a chemical bond, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, O, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰⁾ ) and -N (R ¹⁰⁾ S (O) 2.

V is preferably selected from hydrogen, heterocyclic and aryl, especially phenyl.

V is preferably selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl, and unsubstituted or substituted thienyl. A highly preferred value for Y is unsubstituted or substituted phenyl.

Z is preferably selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl, and unsubstituted or substituted thienyl. A particularly preferred value for Z is unsubstituted or substituted phenyl.

V is preferably selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. Particularly preferred are imidazolyl and pyridyl.

N and r independently represent 0, 1 or 2.

Preferably p is 1 or 3.

Preferably, the symbol is 0.

Preferably t is 1.

In compounds of formula B in which G is H ₂ and V is imidazolyl, the substituent of formula ( _{r 8} ) _{r is} -VA 1 (CR 2 ^and 2) _η Α 2 - (CR 2 ^and 2) _n - preferably meaning other than hydrogen atom.

In the compounds of formula B, wherein X is -C (= 0) -, or -5 (= 0) ^ - v = 1, a radical of formula (R®) _r-V-A ^'1 · (^ CR ^a 2) _n A @ 1 (CR @ 1 ^and 2) _n - preferably has a meaning different from hydrogen.

As above mentioned, the meaning of any substituent or symbol, e.g., R ^a, R, on the like at a location in a molecule be independent of the meaning of that sym43 bolus at another site in the molecule. That is, -N (R 10) 2 can mean -NHH, -NHCH ₃ , -NHC 2 H 5 and the like in the same molecule. It will be understood that the substituents or substituent system in the compounds of the invention may be selected in a conventional manner to obtain compounds that are chemically stable and readily synthesized from the available materials.

catches up, from organic amber, glycol, lemon, ascorbic,

Pharmaceutically acceptable salts of the compounds of the invention include conventional non-toxic salts formed, for example, with non-toxic inorganic or organic acids. Inorganic acids include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and guinea acid acetic, propionic, stearic, lactic, malic, tartaric, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, sulfamic, benzoic, benzoic 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

Pharmaceutically acceptable salts of the compounds of the invention which contain a basic group can be formed by conventional chemical methods. This may be, for example, ion exchange chromatography or the reaction of the free base with a stoichiometric amount or an excess of the desired inorganic or organic acid in a suitable solvent, or in various combinations of solvents.

The compounds of the invention can be prepared using the reactions shown in Schemes 1-22 and other simple conventional reactions such as ester hydrolysis, cleavage of protecting groups and the like, such reactions are known in the literature. The substituents R, R ^a and R, shown in the Schemes, represent the substituents R ^2, R ^3, R and R ^3, except that the bond to the ring is illustrative only.

Said reactions may be used as a whole to obtain the resulting products of the invention or in part 11a to obtain fragments which are then coupled by the alkylation reactions described in the schemes.

In some cases, the intermediates for carrying out the reactions of Schemes 1 to 22 are commercially available or can be prepared by procedures described in the literature.

For example, Scheme 1 synthesizes 2-alkylsubstituted piperazines, which is generally described in JS Kiely and SR Priebe, Organic Preparations and Proceedings Int., 1990, 22, 761-768. The Boc-protected amino acids of formula I , commercially available or obtained by known methods, can be coupled to N-benzylamino acid esters using a variety of dihydrating agents such as dicyclohexylcarbodiimide DCC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC.HCl in a solvent such as methylene chloride, chloroform , dichloroethane or dimethylformamide. The product of formula (II) is then deprotected by treatment with an acid such as hydrogen chloride in chloroform or ethyl acetate or trifluoroacetic acid in methylene chloride and then cyclized under mildly basic conditions to give diketopiperazine III. This material is reduced with lithium aluminum hydride in ether at reflux to give piperazine of formula IV which is protected with Boe to give a derivative of formula V. The N-benzyl group can be cleaved under standard hydrogenation conditions, for example in the presence of 10% palladium on active coal at a hydrogen pressure of 0.42 MPa in a Parr apparatus for 24 to 48 hours. Per product

VI can be treated with acid chloride or carboxylic acid under standard dehydration conditions to form carboxamides of formula VII, cleavage of the acid protecting group as described above yields an intermediate of formula VIII according to Scheme 2. This intermediate can be subjected to alkylation, particularly reductive alkylation with various aldehydes, for example of formula IX. These aldehydes can be obtained by conventional procedures, for example, according to O. P. Goel, U. Krolls, M. Stier, and S. Kesten, Organic Syntheses, 1988, 67, 69-75 from the corresponding amino acids according to Scheme 3. Reductive alkylation is possible. at pH 5-7 with various reducing agents such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give products XI by treatment with trifluoroacetic acid in methylene chloride. The resulting product XI is isolated in the form of a salt, for example trifluoroacetate, hydrochloride or acetate. Furthermore, the diamine XI can be selectively protected to give intermediate XII, which can then be subjected to reductive alkylation with a second aldehyde to give compound XIII. Deprotection and conversion to cyclized products such as dihydroimidazole XV may be accomplished by literature procedures.

Alternatively, the protected piperazine intermediate VII can be subjected to reductive alkylation with aldehydes other than 1-trityl-4-imidazolylcarboxaldehyde or 1-trityl-4-imidazolyl acetaldehyde to give the product XVI according to Scheme 4. The trityl protecting group can be removed to give of the product XVII or it is first possible to treat the intermediate XVI with an alkyl halide and then remove the protecting group to obtain the alkylated imidazole XVIII. Intermediate VIII can also be acylated or sulfonylated by conventional methods. The imidazole acetic acid of formula XIX can be converted to acetate XXI by conventional methods. This material can then be reacted first with an alkyl halide and then refluxed in methanol to form the regionally specifically alkylated imidazole acetic acid ester of formula XXII. Hydrolysis and reaction with piperazine of formula VIII in the presence of a condensing agent, for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC, can afford acylated products, for example a compound of formula XXIV.

When piperazine VIII is subjected to reductive alkylation with a protected hydroxyl-containing aldehyde, for example, compound XXV in Scheme 6, the hydroxyl group of Schemes 6 and 7 can be cleaved and released after the deprotection reaction is complete. to aldehyde, which can then be reacted with various organometallic reagents, for example Grignard reagents under

- 46 formation of secondary alcohols, for example of formula XXIX. In addition, an amino alcohol XXX, completely deprotected, subjected to reductive alkylation under the above conditions, using various aldehydes to form secondary amines, for example Formula XXXI according to Scheme 7 or tertiary amines.

The Boc-protected amino alcohol can also be used to obtain 2-aziridinylpiperazines, for example Formula XXXII according to Scheme 8. Treatment of intermediate XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformaide produces aziridine of Formula XXXII. This material is reacted with a nucleophile, such as a thiol, in the presence of a base to give the ring-opened product of formula XXXIII.

In addition, the piperazine of formula VIII can be reacted with amino acid-derived aldehydes, for example O-alkylated tyrosines, according to standard procedures to give compounds of formula XXXIX. When R 'is an aryl group, it is then possible to first hydrogenate the compounds to release the phenol and then cleave the amino-protecting group by treatment with an acid to form the compound of formula XL.

It is also possible to remove the amino-protecting group from the compound of formula XXXIX and prepare O-alkylated phenolamines, for example compounds of formula XLI.

Depending on the nature of the amino acid of formula I, various side chains may be included in the piperazine compounds. For example, when the compound of formula I is a Boc-protected beta-benzyl aspartate, the intermediate diketopiperazine XLII is obtained, in which n = 1 and R is benzyl, as shown in Scheme 10. Subsequent reduction with lithium aluminum hydride reduces the ester to an alcohol of formula XLIII, which can then be reacted with a number of alkylating agents, for example an alkyl iodide under basic conditions, for example by treatment with sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ester XLIV is

47 can then be processed to the resulting products by the method of Schemes 3 to 9.

The N-arylpiperazines can be prepared according to Scheme 11. The arylamine XLV is reacted with the bis-chloroethylamine hydrochloride XLVI to give the title compound. refluxing in n-butanol to give compounds XLVII. These resulting piperazines can then be processed to the resulting products according to Schemes 3 to 9.

Piperazin-5-ones can be prepared according to Scheme 12. Reductive amination of the Boe-protected aminoaldehydes XLIX prepared from the compounds of Formula I by the above method yields intermediates of Formula L. These are then reacted with bromoacetyl bromide under Schotten-Baumann conditions. The ring is closed by treatment with a base such as sodium hydride in a polar aprotic solvent such as dimethylformaide to give compound LI. The carbamate protecting group is removed in an acidic environment, for example by treatment with trifluoroacetic acid in methylene chloride or with hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be processed to the products of the invention according to Scheme 3 to 9.

Isomeric piperazin-3-ones can be prepared according to Scheme 13. The imine formed from the arylcarboxamide of formula LII and the 2-aminoglycinaldiethylacetal LIII can be reduced under a variety of conditions, for example by treatment with sodium triacetoxyborohydride in dichloroethane to give amine LIV. The amino acids of formula I can be coupled to amines LIV under standard conditions, and the resulting amide LV can then be treated with aqueous acid in tetrahydrofuran to cyclize the unsaturated intermediate of formula LVI. Catalytic hydrogenation under standard conditions then affords the corresponding intermediate of formula LVII, which can then be processed to the resulting products according to Schemes 3 to 9.

Alternatively substituted piperazine compounds can be obtained as described in Scheme XIV. After cleavage of the protecting group with trifluoroacetic acid, the N-benzylpiperazine of formula V can be acylated by treatment with an arylcarboxylic acid. The resulting N-benzylarylcarboxamide of formula LIX is

- \ \

It is possible to hydrogenate in the presence of a catalyst to give the piperazinecarboxamide of formula LX, which can then be further processed to the resulting products by the method of Schemes 3 to 4.

9 · i

Reaction Scheme 15 describes an example of the synthesis of piperazine compounds of the invention in which the substituents R a and R ^j together form a - (CH 2) _U - group. For example, 1-aminocyclohexane-1-carboxylic acid is converted to spiropiperazine of formula LXVI essentially as described in Schemes 1 and 2. The piperazine intermediate LXIX can then be deprotected as described above and then further processed to give the It is understood that the reagents used to attach the Y substituent 2-naphthyl and the imidazolylalkyl substituent can be replaced by other reagents commonly used in the art to the same purpose and by which additional N-substituents can be introduced into the piperazine compounds.

The aldehyde XLIX of Scheme 12 can also be subjected to reductive alkylation with aniline, as shown in Scheme

16. The product LXXI can then be converted to the piperazine derivative by acylation with chloroacetyl chloride to give intermediates of formula LXXII, which can then be cyclized with base to give compounds of formula LXXIII. These are cleaved and the deprotected compounds are treated with reductive alkylation protected with imidazolecarboxaldehyde to produce intermediates LXXV, which can be converted to the imidazolium salt LXXVI by alkylation with an arylmethyl halide. Final deprotection can be accomplished with a solvent, for example, treatment with a lower alkyl alcohol such as methanol or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid to give the final products LXXVII.

Scheme 17 illustrates the use of an optionally substituted homoserine lactone of formula LXXIX for the preparation of a Boc-protected piperazine derivative LXXXII. This intermediate can be deprotected and then subjected to reductive alkylation or acylation as described in the preceding schemes.

Alternatively, the hydroxyl group in intermediate LXXXII can be subjected to mesylation and replaced with suitable nucleophiles such as sodium ethanethiol to produce intermediate LXXXIII. The intermediate of formula LXXXII can also be oxidized to form the carboxylic acid intermediate LXXXIV, and the carboxyl group can then be used to form esters or amides.

Amino acids of formula LXXXVI that contain a side chain not found in natural amino acids can be prepared by a series of reactions as shown in Scheme 18, starting from a readily prepared imine of formula LXXXV.

Schemes 19 to 22 describe a process for the preparation of suitably substituted aldehydes useful in the preparation of the piperazine compounds of the invention wherein V is a pyridyl group. Similar synthetic procedures can be used to prepare alkanols that contain other heterocyclic groups as defined by V and are known in the art.

- 50 Scheme 1, OR ^and

Α ^λ Λ ^οη

H O (I)

PhCH ₂ NHCHCO ₂ C ₂ H ₅

1) HCl, CH ₂ Cl ₂

2) NaHCO ₃

(III)

Boc ₂ O ch ₂ or ₂

10% Pd / C

R ^{a 0} M '

R ^b

H ₂ ch ₃ oh (VI)

Scheme 2

EDC-HCl, HOBT R, ^and DMF

(VII)

HCl, EtOAc

-II

(VIII)

- 52 Scheme 3

R ^b

BocNH ^ (x)

Boe NH OHO »

NaBH (OAc) 3 Et ₃ N, Cich ₂ CH ₂ Cl

(X)

CF ₃ CO ₂ H ₂ CH ₂ or ₂

(XII)

Scheme 3 continued

cf ₃ co ₂ h, ch ₂ ci

NaHCO ₃

AgCN A

-4-NO

(XV)

- 54 Diagram 4

- 55 Diagram 5

CH 3 OH

HCl

ch ₂ co ₂ ch ₃

H + HCl (XX) (δ θ6 ^) ^3θθ Γ (C ₂ H _{5) 3} N

DMF

N

I

T (XXI)

CH ₂ CO ₂ CH ₃ 1) ArCH ₂ X CH ₃ CN reflux

2) CH ₃ OH, reflux

Ar ^

CH ₂ CO ₂ H

2.5N HCl _aq

55 ° C

Ni (XXIII) i

56 Scheme 5 - continued

Ar 1, CH ₂ CO ₂ H n

N (XXIII)

- S7 -

NaBH (OAc) ₃

BnO.

BocNf-CHO-1

(XXVI)

(XXVII)

CICOCQCI DMSO CH ₂ Cl ₂ (ο ₂ η ₅ ) ₃ ν

Scheme 6 - continued

1. R'MgX (C ₂ H _{5) 2} O

2. TFA, CH ₂ Cl ₂

CXXVIII)

- 59 Scheme 7 ^R to U]

HO r-N N-V \ = / \ - (\ - (Q

NHBoc R ^b (XXVII)

CF ₃ CO ₂ H ₂ CH ₂ or ₂

C XXXI)

R'CHO

NaBH (OAc) ₃

CICH ₂ CH ₂ Cl

- to Scheme 8

(XXVII)

H H

N = \ / = N

O ₂

NaH, DMF 0 ° C

i — N N

R'SH (2 2 5 5) 3 A A

CH 3 OH

XXX (XXXII)

- 61 Scheme 9

(XXXIV)

1) Boc ₂ O, K ₂ CO ₃ thf-h ₂ o

2) CH ₂ N ₂ , EtOAc

LiAlH4

THF

0-20 ° C

R'CH ₂ X - £ -C ₂ CO ₃

DMF

R'CH ₂ O.

pyridine · S0 ₃

DMSO (C ₂ H ₅ ) 3 N

20 ° C

BocNH CHO (XXXVII) (XXXVII)

Scheme 9

- continuation

R'CH ₂ O _x ^

Λ

BocNH CHO XXXVIII

(VIII)

NaBH (OAc) ₃

CICH ₂ CH ₂ Cl

(XL)

- 63 Scheme 10 co ₂ y

(XLII)

1) LAH, Et ₂ O

2) Boc ₂ O

(XLIII)

Scheme 11

₂ (XLV)

Cl

R ^a ) ₂ NH · HCl (XLVI) n-butanol reflux

R ^and R ^b ) - (

ArN NH HCl

M

R ^a R ^b (XLVII)

Scheme 12

CH3NHOCH3 · HCl

EDC. HCl, HOBT, DMF, Et ₃ N, pH 7> JCN W _{N (CH3) OCH3} HO ^{Et 2} ° CXLVIII)

about

H (L)

NHCH ₂ Ar

ArCH ₂ NH ₂

NaBH (OAc) ₃ CICH ₂ CH ₂ Cl pH 6

1) BrCH ₂ COBr EtOAc, H ₂ O, NaHCO 3

2) NaH, THF, DMF

Scheme 12 - continued

R ^j

ABOUT ,

Vn n <T M

ABOUT

Ar

1) TFA, CH ₂ Cl ₂ (Ll)

ABOUT

Scheme 13

ArCHO + NH ₂ CH ₂ CH (OC ₂ H ₅ ) ₂ CLU _(L ||,)

NaBH (OAc) ₃

Ar CH ₂ NHCH ₂ CH (OQ ₂ H ₅ ) ₂ (LIV)

IOR ^L

Ν ^Λ ^ γ ^0γ

I ^H o

EDC. HCl, HOBT DMF, Et ₃ N, pH 7

OR ^a (

X = A ^ n ^ .ch (oc ₂ h ₅ ) ₂

6N HCl

THF

H O (LV)

R ^and O) -

N N

H ₂ 10% Pd / C CH ₃ OH

Ar (LIV)

CLVII) <58 Scheme 14

R ^b

ArCO ₂ H

EDC HCl HOBT, DMF

n to> - / Ar

^And R (LIX)

R ^b

10% Pd / Ch ₂ ch ₃ oh

R ^b / - ( ⁰

HN N— {

Ar

^And R (LXJ

Scheme l · ⁵

(ίχνΟ • i *

- 70 Scheme 15 - continued

(LXVII)

(LXVIII)

(a) TFA, CH ₂ Cl ₂

(b) NaBH (OAc) ₃

• 2 TFA (LXX) $

CPh <

, C (= O) H

TFA CH ₂ Cl ₂ (C ₂ H ₅ ) ₃ SiH

- 71 Scheme 16

BocNH

R

CHO

ArNH ₂

NaBH (OAc) ₃

CICH ₂ CH ₂ Cl zi

BocNH '' Ar (XLIX) (LXXI)

ABOUT

EtOAc / H ₂ O NaHCO ₃ ) - \

BocNH N-Ar / X

Cl O (LXXII)

R

NaHI) HCl

- BocN N-Ar DMF-EtOAc

O (LXXIII)

- 72 Scheme 16 - continued) - \

HCIHN N-Ar

M

CHO

K o

(LXXIV)

C (Ph) ₃

NaBH (OAc) ₃ CICH ₂ CH ₂ Cl pH 5-6

-N (Ph) ₃ C (LXXV)

ArCH ₂ X

CH ₃ CN

MeOH or

TFA, CH ₂ Cl (C ₂ H ₅ ) ₃ SiH) - \

(LXXVII)

Scheme 17

1. Boc ₂ O, i-Pr ₂ EtN

2. DIBAL

BocHN

OH (LXXIX)

ArNH ₂

NaBH (OAc) ₃

CICH ₂ CH ₂ Cl

(LXXX)

HO sub

ABOUT

EtOAc / H ₂ O NaHCO ₃

BocNH N-Ar

CI O (LXXXI)

Cs ₂ CO ₃

DMF

HO sub

IN,

BocN N-Ar

M

O (LXXXII)

- 74 Figure 17 - Continued

HO sub

IN

BocN N ~ Ar

M

ABOUT

1. MsCI, iPr ₂ NEt _/ 2. NaSEt, DMF / (LXXXII)

1. (COCl) ₂ , Et ₃ N DMSO

2. NaClO ₂ , t-BuOH 2-Me-2-butene NaH ₂ PO ₄

EtS sub

IN

BocN N — Ar

M

O (LXXXIII)

HO sub yk ⁰ / - \

BocN N — Ar

M

O (LXXXIV)

Scheme 18 / -CO ₂ Et

2. 5% aqueous HCl

CLXXXV)

1. KOtBu.THF R ² X

R ² ) -CO ₂ Et

H ₂ N

HCl

1. Boc ₂ O, NaHCO ₃

2. LiAlH ₄ , Et ₂ O

R ²⁾ -CO ₂ H,

BOCHN (LXXXVI)

- 76 Scheme 19

DMSO

SO 3'Py, Et ₃ N

R ⁶

CHO

Scheme 20

br

1. EtO (CO) Cl

MgCl

NaBH ₄

Br.

3. S, xylene, heat

NaBH ₄

SO ₃ Py, Et ₃ N

DMSO

R ⁶

CHO

Br.

IN. in. .

- 78 Scheme 21

1. LDA, C0 ₂

2. MeOH, H &lt; ^{+ &gt;.}

- 79 Scheme!

br

1. LDA, C0 ₂

2 (CH _{3) 3} ny ₂

The compounds of the invention may be used for therapeutic purposes in mammals, particularly humans, in particular for the treatment of malignant tumors. Examples of cancers that can be treated include colon and rectal carcinoma, pancreatic exocrine carcinoma, myeloid leukemia, and neurological tumors. These tumors can arise from mutations in ras genes, protein mutations that can direct Ras activity, such as neurofibromine (NF-1), neu, scr, abl, lck, fyn, or other mechanisms.

The compounds of the invention cause inhibition of protein farnesyltransferase and farnesylation of the oncogenic protein Ras. The compounds of the invention may also inhibit tumor angiogenesis, thereby affecting their growth according to J. Rak et al., Cancer Research, 55, 4575-4580, 1995. These anti-angiogenic properties of the compounds of the invention may also be utilized in the treatment of certain forms of blindness induced by retinal vascularization.

The compounds of the present invention can be used to inhibit other proliferative diseases, benign and malignant, in which the activation of the Ras protein is due to oncogenic mutation in other genes (i.e., the Ras protein gene is not itself activated by mutation to the oncogenic form) wherein said inhibition is achieved by administering an effective amount of a compound of the invention. For example, some of the components of NF-1 cause benign proliferative disorders.

The compounds of the invention may also be used for the treatment of certain viral infections, in particular for the treatment of delta hepatitis and diseases caused by related viruses according to J. S. Glenn et al., Science, 256, 1331-1333, 1992.

The compounds of the present invention are also useful for the prevention of restenosis following transluminal coronary angioplasty, since they cause the inointiation of neointima formation according to C. Indolfi et al., J. Nature Medicine, 1, 541-545 (1995).

The compounds of the invention can be used to treat and prevent polycystic kidney disease according to D. L. Schaffner et al., American Journal of Pathology, 142, 1051-1060, 1993; et al., FASEB Journal, 2, A3160, 1998.

The piperazine compounds of the invention may also be useful in the treatment of fungal infections.

The compounds of the invention can be administered to mammals, including humans, as such or preferably with pharmaceutically acceptable carriers or diluents and optionally with known excipients such as alum in the form of pharmaceutical compositions in a conventional manner. The compounds may be administered orally or parenterally, for example, intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally or topically.

For oral administration, the compounds may be formulated into tablets or capsules, aqueous solutions or suspensions, for example. In the case of tablets for oral administration, conventional carriers are, for example, lactose and corn starch, and glidants such as magnesium stearate are also commonly added. In the case of capsules, conventional diluents are also lactose and dried corn starch. In the case of an aqueous suspension for oral administration, the active ingredient is mixed with emulsifiers and suspending agents. If desired, sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and their pH adjusted with a buffer. For intravenous use, it is possible to adjust the total concentration of solutes so that the composition is isotonic.

The active compounds according to the invention can also be administered concomitantly with known active compounds which are chosen according to their efficacy in the conditions to be treated. For example, the compounds of the invention may be combined with other antitumor and cytotoxic agents, or with other agents effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infectious hepatitis delta, and related viral and some fungal diseases.

When processed into a pharmaceutical composition together with another active ingredient, both of the active ingredients may be administered within their effective length range. Alternatively, the compounds of the invention may also be administered alternately with known agents when a direct combination is not appropriate.

Accordingly, the present invention also provides a pharmaceutical composition for treating cancer comprising an effective amount of the Piperazine Compounds of the Invention, optionally together with a pharmaceutical carrier or diluent. Suitable compositions are, for example, aqueous solutions containing a compound of the invention and, for example, physiological saline solution having a pH of, for example, 7.4 as carrier. These solutions can be administered directly into the patient's bloodstream as intravenous injections.

The daily dose of the compounds of the invention for use in humans will be determined by the attending physician, and the doses employed will vary depending on the age, weight and also the response of the patient to the administration of the compounds and the severity of the disease symptoms.

By way of example, suitable dosages are for use in cancer mammals. In this case, 0.1 to 60 mg / kg per day, preferably 0.5 to 40 mg / kg per day is administered.

The compounds of the invention may also be used to rapidly determine the presence and amount of farnesyltransferase in a mixture of substances. This is done by dividing the test mixture into two portions which are contacted with a mixture comprising a known substrate for farnesyltransferase, an FTPase such as a tetrapeptide that contains a cysteine at the amino terminal end and, in addition, farnesyl pyrophosphate, one of which contains and a compound of the invention. Both mixtures are incubated in a known manner for a sufficient period of time to allow farnesylation of the substrate to be used by farnesyltransferase, then determining the chemical content of the resulting mixture after incubation by commonly used immunological, radiochemical or chromatographic techniques.

Since the Piperazine Compounds of the Invention are selective inhibitors of protein farnesyltransferase, the absence or quantitative reduction in the amount of substrate in the assay mixture that did not contain the piperazine compounds of the invention relative to the amount of unchanged substrate in the assay mixture that contained piperazine compounds of the invention by indicating the presence of protein farnesyltransferase in the original mixture of interest.

Obviously, the assay described above is a very useful procedure for identifying protein farnesyltransferase in a tissue sample of interest and for quantitating the enzyme in that tissue. That is, the piperazine compounds of the invention, which are potent enzyme inhibitors, can be used for titration to determine the amount of this enzyme. A series of samples containing a proportion of tissue extract with an unknown amount of farnesyltransferase enzyme, an excess of a known substrate for this enzyme, for example tetrapeptide and a cysteine residue at the amino terminal end, and farnesyl pyrophosphases, are incubated for an appropriate time in the presence of various concentrations of the compounds.

The concentration of a sufficiently potent inhibitor (i.e., an inhibitor whose Ki is substantially lower than the enzyme concentration in the sample being examined) required to inhibit the enzymatic activity of the sample to 50% is approximately equal to half the enzyme concentration in that sample.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention. HPLC was performed using a 40 x 100 mm Vaters PrepPak® column (Delta-Pak ™ C18g, 15 gm, 100X). Gradient elution with 0.1% TFA in water (solvent A) and 0.1% trifluoroacetic acid TFA in acetonitrile (solvent B). Chlorides were obtained by passing an aqueous TFA salt solution through a Biorad AG ^ 3X4 column

Cl-form). HPLC purification was used 27, 48 and 49.

(100 to 200 mesh, in Examples 1 to 23,

Examples of embodiments of the invention

Example 1

Preparation of 3 (S) -Butyl-1- (2,3-diaminoprop-1-yl) -4- (1-naphthoyl) piperazine trihydrochloride

Grade A

Preparation of 1-benzyl-3 (S) -n-butylpiperazine-2,5-dione

The title compound was prepared in an analogous manner to that described in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990) by S. Kiely and Stephen R. Priebe.

To 250.0 mL of dichloromethane was added 9.33 g (45.20 mmol) of dicyclohexylcarbodiimide in dichloromethane (0.50 M). To the resulting solution, cooled to 0 ° C under nitrogen, was added 10.50 g (45.20 mmol) of N-tert-butyloxycarbonyl-L-leucine (BOC-L-norleucine).

The resulting slurry was stirred for 5.0 minutes and then 8.72 g (45.20 mmol) of N-benzylglycinate was added. The reaction mixture was then stirred at 0 ° C for 2 hours and then at 20 ° C overnight. The resulting precipitate was removed by filtration and the dichloromethane solution was bubbled with hydrogen chloride gas for 2 to 4 hours until completion of the reaction was shown by thin layer chromatography.

The solvent was removed in vacuo and the residue was partitioned between 150.0 mL of ethyl acetate and 42.0 mL of saturated sodium bicarbonate solution. After separation of the organic and aqueous phases, the organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and, after filtration, evaporated.

The crude diketopiperazine was mechanically treated and taken up with hexane.

The title compound was obtained in the form of a white colored powder.

- 85 - * 1 H NMR (300 MHz, CDCl ₃ ):

δ 7.24 - 7.40 (5H, m), 6.22 (1H, bs), 4.07 (1H, dt, J = 3.60 Hz), 3.87 (1H, d, J = 17.0 Hz), 3.80 (1H, d, J = 17.0 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J = 7.0 Hz).

Grade B

Preparation of 4-benzyl-1-tert-butoxycarbonyl-2 (S) -n-butylpiperazine

The product prepared in the preceding step A, i.e. 4.95 g (0.019 mol) was dissolved in 200 mL tetrahydrofuran and the resulting solution was cooled to 0 ° C under nitrogen with mechanical stirring. To this solution was added 2.60 g (0.0685 mol) of lithium aluminum hydride and the resulting reaction mixture was heated to reflux for 18 hours and then cooled to 0 ° C, followed by slow gradual stirring with 5.0. ml of water, 5.0 ml of 10% aqueous sodium hydroxide solution and then with 5.0 ml of water.

The reaction mixture was stirred for 30 minutes and then filtered. After removal of the solvent in vacuo, the crude product was taken up with dichloromethane and the solution was dried over magnesium sulfate. The desiccant was then removed by filtration and the filtrate was mixed with 4.35 g (0.020 mol) of di-tert-butyl dicarbonate. After 2 hours, saturated sodium bicarbonate solution was added to the reaction mixture at 20 ° C.

After separation of the organic and aqueous phases, the organic layer was washed with saturated sodium chloride solution and then dried over magnesium sulfate. After filtration and subsequent evaporation, a crude product was obtained, which was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexane.

The title compound was obtained

- 86 in the form of a foamy substance.

^X H NMR (300 MHz, DMSO-d):

δ 7.25 (5H, m), 3.90 (1H, bs), 3.73 (1H, d, J = 13.0 Hz),

3.51 (1H, d, J = 13.0 Hz), 3.34 (1H, d, J = 13.0 Hz), 2.93 (1H, m), 2.75 (1H, d, J = 11.0 Hz), 2.62 (1H, d, J = 11.0 Hz), 1.90 (2H, m), 1.60 (2H, m), 1.38 (9H, s) 1.26 (2H, m), 1.04 (2H, m), 0.84 (3H, t, T = 7.0 Hz).

Grade C

Preparation of 1-tert-butoxycarbonyl-2 (S) -n-butylpiperazine

The product prepared as described in Step B above (3.75 g, 11.30 mmol) was dissolved in 75.0 mL of methanol in a Parr apparatus vessel and the vessel was purged with argon. 0.80 g of 10% palladium on charcoal was added to the solution, and the reaction mixture was hydrogenated at 40 psi hydrogen for 24 hours.

The catalyst was removed from the reaction mixture by filtration through silica and the filtrate was evaporated in vacuo.

The title compound was obtained as an oily consistency.

¹ H NMR (300 MHz, DMSO-d 6):?

δ 4.08 (1H, bs), 3.90 (1H, d, J = 12.0 Hz), 2.50 - 3.80 (6H, m), 1.80 (1H, m) 1.60 (1H, m), 1.46 (9H, s), 1.30 (4H, m), 0.90 (3H, t, J = 7.0 Hz).

Grade D

Preparation of 1-tert-butoxycarbonyl-2 (S) -n-butyl-4- (1-naphthoyl) piperazine

Mixture prepared by mixing 0.325 g (1.34 mmol) of 1-tert-butyloxycarbonyl-2 (S) -n-butylpiperazine obtained in the previous step C, 0.203 g (1.34 mmol) of 1-hydroxybenzotriazole (HOBT) 1) and 0.254 g (1.34 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC) were added to 7.0 ml of dried, degassed dimethylformamide.

Then, the pH of the resulting reaction mixture was adjusted to pH 7.0 with triethylamine, and the reaction mixture was stirred for 2 hours. Then, dimethylformamide was distilled off from the reaction mixture in vacuo, and the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed successively with a 2% aqueous potassium hydrogensulfate solution, a saturated sodium bicarbonate solution, a saturated aqueous sodium chloride solution, and then dried with magnesium sulfate.

The title compound was obtained as a thick oil.

Grade E

Preparation 2 (S) -n-butyl-3- (1-naphthoyl) -piperazine hydrochloride

The product prepared in Step D above was dissolved in ethyl acetate and the resulting solution was cooled to -40 ° C under nitrogen and then saturated with hydrogen chloride gas. After warming to 0 ° C for 30 minutes, the solution was purged with nitrogen.

The solvent was then removed in vacuo and the residue was evaporated 3 times from ethyl acetate.

The title compound was obtained as a white solid.

Grade F

Preparation of 2,3- (bis- (tert-butoxycarbonylamino) propanoic acid)

Diaminopropanoic acid monohydrochloride (2.86 g, 0.0204 mol) was suspended in 100.0 mL water: dioxane (1: 1) containing 5.97 mL (0.0204 mol) triethylamine. To this reaction mixture was added 11.0 g (0.0448 mol) of 2- (tert-butoxycarbonyloxyimino) -2-phenyl-acetonitrile (BOC-ON), together with an additional amount of triethylamine to bring the pH to pH. 9.50.

The reaction mixture was then stirred under a nitrogen atmosphere at 20 ° C overnight. The clear reaction mixture was diluted with water and then shaken 5 times with 100.0 mL of diethyl ether. The pH of the aqueous phase was adjusted to 1.0 with cold 5% aqueous hydrochloric acid and the aqueous phase was extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed successively with water and saturated aqueous sodium chloride solution and then dried with magnesium sulfate.

The resulting foamed material (5.46 g) was recrystallized from ethyl acetate to give the title compound as a white solid.

Grade G

Preparation of N-methoxy-N-methyl-2,3- (bis-tert-butoxycarbonylamino) -propionamide

The mixture, prepared from 1.80 g (5.92 mmol) of 2,3-bis (tert-butoxycarbonylamino) propanoic acid obtained in the previous step F, above, in 25.0 ml of dimethylformamide, was stirred overnight with 0.635 g (6.51 mmol) of N-methoxy-N-methylamine hydrochloride, 1.24 g (6.51 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), 0.80 g (5, 92 mmol) of N-hydroxybenzotriazole and 0.825 ml (5.92 mmol) of triethylamine.

After the dimethylformamide was removed from the reaction mixture in vacuo, the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated brine solution and then dried with magnesium sulfate.

The crude product was re-chromatographed on silica gel using 30% ethyl acetate in hexane as eluent. The title compound was obtained as a foam.

and ¹ H-NMR (CDC1 _3, 300 MHz):

1 5.51 (1H, bs), 4.87 (1H, bs), 4.72 (1H, bs), 3.77 (3H, s), 3.50 (1H, bs) 1H, m), 3.40 (1H, dt, J = 12.6 Hz), 3.20 (3H, s), 1.44 (9H, s), 1.42 (9H, s).

Grade H

Preparation of 2,3- (bis-tert-butoxycarbonylamino) propanol

To 20.0 mL of diethyl ether was suspended 0.384 g (1l, 14 mmol) of lithium aluminum hydride and the resulting suspension was cooled to -45 ° C under nitrogen. To this reaction mixture was added 2.07 g (5.96 mmol) of N-methoxy-N-methyl-2,3- (bis-tert-butoxycarbonylamino) propionamide obtained in the previous step G above, in the mixture. 60.0 mL of ether and tetrahydrofuran (1: 1) at a rate such that the temperature of the reaction mixture was maintained at less than -35 ° C.

The reaction mixture was then allowed to warm to 5 ° C and then re-cooled to -45 ° C and then treated with a solution of 3.08 g (22.6 mmol) of potassium bisulfate in 20.0 mL of water. The reaction mixture was stirred at 20 ° C for 1 hour and then filtered through silica. The organic phase was then washed successively with a 10% aqueous citric acid solution (2-hydroxypropane-1,2,3-tricarboxylic acid) and a saturated aqueous brine solution, and then dried over magnesium sulfate.

The title compound was obtained as a foam-like substance.

¹ H-NMR (CDCl ₃ , 300 MHz):

δ 9.61 (1H, s), 5.60 (1H, bs), 4.88 (1H, bs), 4.24 (1H, bs, J = 6.0 Hz), 3.68 (1H, m), 1.40 (9H, s), 1.39 (9H, s).

Stage I

Preparation of 1 - [(2,3-bis-tert-butoxycarbonylamino) prop-1-yl] 2 (S) -butyl-4- (1-naphthoyl) piperazine

90 Solution prepared by mixing 1.83 g (6.20 mmol) of 3 (S) butyl-1- (1-naphthoyl) piperazine (as the free base) obtained under the above step E and 0.17 above. ml (2.90 mmol) of acetic acid in 20.0 ml of dichloromethane was adjusted to pH 5.50 with triethylamine. To the resulting reaction mixture was added 1.0 g of crushed molecular sieve and 1.87 g (8.79 mmol) of sodium trecethoxytetraborohydride and the mixture was cooled to 0 ° C under nitrogen.

Then, a solution prepared by dissolving the 2,3- (bis-tert-butoxycarbonylamino) propanol (1.69 g, 5.86 mmol) obtained in the above step H, at 10, was added dropwise to the reaction mixture. 0 mL of dichloroethane and the reaction mixture was stirred at 20 ° C overnight. Upon completion of the above operation, the mixture was cooled to 0 ° C, mixed with saturated aqueous sodium bicarbonate solution and then stirred for 1 hour.

After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and dried with magnesium sulfate.

The crude product was then chromatographed on silica gel using 40-50% ethyl acetate in hexane as eluent.

The title compound was obtained as a foam-like substance.

Rf = 0.30, (50% ethyl acetate in hexane).

Grade J

Preparation of 1- (2,3-diaminoprop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine trihydrochloride

To a solution prepared by dissolving 2.13 g (3.75 mmol) of 1 - [(2,3-bis-tert-butoxycarbonylamino) prop-1-yl] -2 (S) -butyl-4- (1-naphthoyl) piperazine obtained in Step I above, in 75.0 ml of dichloromethane, 25.0 ml of trifluoroacetic acid was added. After 25 minutes of leaving the reaction mixture at room temperature, the solvent was evaporated and the residue was partitioned between chloroform and a 20% aqueous sodium hydroxide solution.

After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and then dried with magnesium sulfate. The free base of the title compound was obtained as a yellow gummy consistency (1.72 g).

A portion of the above material (52.0 mg) was purified by preparative high performance liquid chromatography, using a Vaters PrepPak reverse phase column (Delta Pa TM C18, 50 mM, 100X) and the pure product was isolated by gradient elution using 100-50 % solvent A (0.1% trifluoroacetic acid in water) and 50% solvent B (0.1% trifluoroacetic acid in acetonitrile).

The pure fractions were combined and the solvent was evaporated, and the obtained crude product was dissolved in water and further processed on an ion chromatography column (Biorad AG 3x4, ion exchange resin, chloride form).

Subsequent lyophilization afforded the title compound as a white solid. Analytical evaluation of the compound according to the formula:

^C 22 ^H 32 ^N 4 ⁰ · ^{4 '45 HC1:} C 49.78, H 6.92, N 10.56% Found: C 49.75, H 6.72, N 10.36%.

Example 2

Preparation of 1- (3-amino-2- (2-naphthylmethylamino) -prop-1-yl) -2 (S) butyl-4- (1-naphthoyl) piperazine trihydrochloride

Grade A

Preparation of 1 - [(2-amino-3-tert-butoxycarbonylamino) -prop-lyl]] - (S) -butyl-4- (1-naphthoyl) piperazine

To a solution prepared by dissolving 0.476 g (1.29 mmol) of 4- (2,3-dimainoprop-1-yl) -2 (S) -butyl-1- (1-naphthoyl) piperazine in 10.0 ml of dichloromethane, 0.282 g (1.29 mmol) of di-tert-butyl dicarbonate was added and the resulting reaction mixture was stirred at 20 ° C for a total of 2 hours. The reaction was then discontinued and the mixture was shaken with water.

After separation of the organic from the aqueous phase, the organic layer was washed with saturated brine solution and then dried over magnesium sulphate. The crude product was then chromatographed on silica gel, eluting first with 5% methanol in chloroform and then with 5% (9: 1, methanol: ammonium hydroxide) in chloroform.

The title compound was isolated as the main product.

FAB-MS (m + 1) (fast atom ionization) (AB-MS) = 469.0.

Grade B

Preparation of 1- (3-tert-butoxycarbonylamino-2- (naphthylmethylamino) prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine

The title compound was prepared in an analogous manner to that described in Example 1, Step D, except that 0.287 g (0.613 mmol) of 1 - [(2-amino-3-tert-butoxycarbonylaminoprop) was used in the reaction. -1yl)] - 2 (S) -butyl-4- (1-naphthoyl) piperazine, 0.95 g (0.613 mmol) of naphthalene-2-carboxaldehyde and 0.194 g (0.919 mmol) of sodium triacethoxytetraborohydride in 15.0 ml of dichloroethane at pH 6.

The crude product was chromatographed on silica gel, eluting with 5% methanol in chloroform (Rf = 0.30).

The title compound was isolated as a foam-like substance.

Mass Spectroscopy (FAB) = 609 (m + 1).

Grade C

Preparation of 1- (3-amino-2- (2-naphthylmethylamino) -prop-1-yl) -2 (S) butyl-4- (1-naphthoyl) piperazine trihydrochloride

The intermediate prepared in the above-described step B, i. 1- (3-tert-butoxycarbonylamino-2- (naphthylmethylamino) -prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine (0.313 g, 0.514 mmol) was in 10, 0 ml of dichloromethane deprotected with 5.0 ml of trifluoroacetic acid protecting group and converted to the free base (255.0 mg) by an analogous procedure to that described in Example 1, step E above.

Purification of 40.0 g of the product was performed by preparative high performance liquid chromatography, using gradient elution with solutions A and B (described in Example 1, 95% to 5% solution A).

Subsequent work-up on ion exchangers and lyophilization afforded the title compound as a white solid.

MS-FAB = 509 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 33 ^H 40 ^N 4 · ° ^{0 '05} _H2 O.4,45 HC1: C 59.00, H 6.68, N 8.34% Found: C 59.00, H 6.51, N 8 , 44%.

Example 3

Preparation 2 (S) -Butyl-1- {5- [1- (2-naphthylmethyl)] - 4,5-dihydroimidazole} methyl 4- (1-naphthoyl) piperazine.ditrifluoroacetate

Mixture prepared by mixing 0.105 g (0.207 mmol) of 1- (3 amino-2- (2-naphthylmethylamino) -prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1.50 mL tert-butyl isocyanate and 0.023 g (0.207 mmol) of silver cyanide were heated in a sealed tube under nitrogen atmosphere at 90 ° C overnight.

After removal of the volatiles from the reaction mixture under vacuum, the residue was chromatographed on silica gel using 5-10% methanol in chloroform as eluent. The free base (73.0 mg) was obtained, which was purified by preparative, high-performance liquid chromatography (analogous to that described in Example 1 above), gradient elution with solutions A and B (described in Example 94 above, 95%). to 5% solution A).

Subsequent lyophilization afforded the title compound as a white solid.

FAB-MS = 519 (m + 1).

Analytical evaluation of the compound according to the formula:

. · 0.85 H ₂ 0.3,75 trifluoroacetic acid: C, 51.84; H, 4.55; N, 5.83% Found: C 51.83, H 4.56, N 6.32%.

Example 4

Preparation of 1- [5- (1-benzylimidazole) methyl] -2 (S) -butyl-4- (1-naphthyl) piperazine dihydrochloride

To a solution prepared by dissolving 63.0 mg (0.103 mmol) of 2 (S) -butyl-1- [5- (3-triphenylmethylimidazole)] methyl-4- (1-naphthoyl) piperazine in 0.50 mL of acetonitrile was added under atmosphere of nitrogen at 20 ° C 0.012 ml (0.103 mmol) of benzyl bromide. The resulting reaction mixture was stirred overnight and then concentrated in vacuo and taken up in 2.0 mL of dichloromethane containing 0.10 mL of triethylsilane.

To this reaction mixture was added trifluoroacetic acid, and the mixture was stirred at 20 ° C for 1 hour. Then the solvent was evaporated and the residue was purified by high performance liquid chromatography (95% to 5% solvent A).

Pure fractions were combined and converted to the hydrochloride salt by a procedure analogous to that described in Example 1, step E above. After subsequent lyophilization, the title compound was obtained as a white solid. MS-FAB = 467 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 3 O ^H 34 ^N 4 ° - ° 'O ⁵ · ^H 2 ° ^{3' 70 HC1:} C 59.81, H.6,32, N 9.30% Found: C 59.78, H 6.33, N, 9.30%.

95 Example 5

Preparation of 1- {5- [1- (4-nitrobenzyl) imidazolylmethyl]} - 2 (S) -butyl 4- (1-naphthoyl) piperazine di-trifluoroacetate

The title compound was prepared in an analogous manner to Example 4 above except that 0.043 g (0.199 mmol) of p-nitrobenzyl bromide and 123.0 mg (0.199 mmol) of 2 (S) -butyl- 1- [5- (3-triphenylmethylimidazole)] methyl-4- (1-naphthoyl) piperazine in 2.0 mL acetonitrile. The crude product was further processed

I with 0.127 ml (0.80 mmol) of triethylsilane and 2.0 ml of trifluoroacetic acid in 4.0 ml of dichloroethane followed by preparative HPLC (95% -5% of solvent A).

The title compound was obtained as a white solid.

MS-FAB = 512 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 30 ^H 33 ^N 5 ° ^{2 CF} 3 ^C0 2 ^H 2 · ^{0 '03} ° ^H 2: C 41.42, H 3.98, N 10.18% Found: C 41.43, H 3.96; N 10.51%.

Example 6

Preparation of 1- (3-acetamidomethylthio-2 (R) -aminoprop-1-yl) -2 (S) butyl-4- (1-naphthoyl) -piperazine di-trifluoroacetate

Dissolve 1- (3-acetamidomethylthio-2 (R) -aminoprop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine dihydrochloride and 0.010 g (0.105 mmol) of N in trifluoroacetic acid hydroxymethyl acetamide, prepared analogously to The Practice of Peptide Synthesis, Springer Verlag, 1984, p. 82 (M. Bodansky, A. Bodansky), over 0.5 hour.

After removal of the solvent in vacuo, the residue obtained was purified by preparative high-performance liquid chromatography (96-60% of solvent A) and subsequently lyophilized.

The title compound was obtained as a solid. j

FAB-MS = 457 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 25 ^H 36 ^N 4 ° 2 ^S - 2 ^CF 2 ^CO 2 ^{H 1 '90 H} 2 ° calculated: C 44.38, H 5.12, N 6.64% found: C 44.35, H 5.11, N 6.97%.

Example 7

Preparation 2 (S) -Butyl-1- [2- (1-imidazoyl) ethyl] -sulfonyl-4- (1-naphthoyl) -piperazine.ditrifluoroacetate

I

Grade A

Preparation 2 (S) -Butyl-4- (1-naphthoyl) -1-vinylsulfonylpiperazine

To a solution prepared by mixing 0.095 g (0.285 mmol) of 3 (S) -butyl-1- (1-naphthoyl) piperazine and 0.119 mL (0.685 mmol) of diisopropylethylamine in 3.0 mL of dichloromethane was added 0.038 mL (0.314 mmol) of chloroethylsulfonyl chloride. and the resulting reaction mixture was stirred under a nitrogen atmosphere overnight and after mixing with saturated sodium bicarbonate solution was taken up in ethyl acetate.

After drying with magnesium sulfate, the title compound is isolated.

Grade B

Preparation 2 (S) -Butyl-1- [2- (1-imidazolyl) ethyl] -sulfonyl-4- (1-naphthoyl) -piperazine.ditrifluoroacetate

To 0.024 g (0.598 mmol) of sodium hydride (60% dispersion in oil) suspended in 2.0 ml of dimethylformamide was added 0.043 g (0.627 mmol) of imidazole and the resulting reaction mixture was cooled to 0 ° C under nitrogen. and then 0.011 g (0.29 mmol) was added.

2 (S) -Butyl-4- (1-naphthoyl) -1-vinylsulfonylpiperazine in 5.0 mL of dimethylformamide.

After the reaction mixture was stirred overnight at 20 ° C and after the removal of dimethylformamide in vacuo, the residue was dissolved in ethyl acetate.

The ethyl acetate solution was shaken successively with saturated sodium bicarbonate solution and saturated brine solution, and then dried with magnesium sulfate. The crude product was first purified by silica gel chromatography using 8% methanol in chloroform and then preparative HPLC (80-40% solvent A).

The trifluoroacetate salt was dissolved in water and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and dried with magnesium sulfate.

The title compound was obtained in the form of a foam.

MS-FAB = 455 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 25 ^H 36 ^N 4 ° 2 ^S · 0- ^{8 H} 2 ° calculated: C 61.46, H 6.79, N 11.95% found: C 61.44, H 6.97, N 10.72% .

Example 8

Preparation 2 (R) -Butyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) -piperazine

Grade A

Preparation 2 (R) -Butyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl) methylpiperazine

In the presence of crushed molecular sieves, 7.0 ml of dichloroethane was treated with 0.202 g (0.607 mmol) of 3, (R) -butyl-1- (1-naphthoyl) piperazine obtained in an analogous manner to that described in Example 1; for the preparation of the (S) -enantiomer with 0.226 g (0.667 mmol) of 1-triphenylmethylimidazole-4-carboxaldehyde and 0.321 g (1.52 mmol) of sodium triacethoxytetraborohydride.

The pH of the resulting reaction mixture was adjusted to 5.0-6.0 with triethylamine / acetic acid, and after stirring overnight, the mixture was mixed with saturated aqueous sodium bicarbonate. Then, the organic layer was washed with saturated brine solution and then dried with magnesium sulfate.

The crude product was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane followed by 5% methanol in chloroform.

The title compound was obtained.

Grade B

Preparation 2 (R) -Butyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a solution prepared by dissolving 0.381 g (0.616 mmol) of 2 (R) -butyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl) methylpiperazine in dichloromethane, was added 1 mL (11.8 mmol) of triethylsilane and After 1 hour, the solvent was evaporated from the reaction mixture and the residue was partitioned between water and hexane.

After separation of the aqueous and organic phases, the aqueous layer was injected onto a preparative HPLC column (100-40% solvent A) and the title compound was isolated after lyophilization.

FAB-MS = 377 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 25 ^H 36 ^N 4 ° 2 · 2.35 CF ₃ CO ₂ -0.32 H ₂ 0 calculated: C 48.93, H 4.52, N 7.98% found: C 48.93, H 4, 55, N 8.26%.

99 Example 9

Preparation 2 (S-Butyl-4- (1-naphthoyl) -1- (3-pyridylmethyl) piperazine Dihydrochloride

In analogy to the procedure described in Example 8, Step A, above, 7 ml of dichloroethane, in the presence of crushed molecular sieves, 0.200 g (0.601 mmol) of 3 (S) -butyl-1- (1-naphthoyl) piperazine hydrochloride with 0.062 ml. (0.661 mmol) pyridine-3-carboxaldehyde and 0.321 g (1.52 mmol) sodium triacethoxytetraborohydride.

The crude product was purified by silica gel chromatography eluting with 30% acetone in hexane followed by preparative HPLC (80-75% solvent A). After further ion exchange work-up, the title compound was isolated.

FAB-MS = 388.0 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 25 ^H 29 ^N 3 ° · ² »3 HCl · 0.95 H ₂ O calculated: C 61.49, H 6.85, N 8.60% found: C 61.49, H 7.01, N 8 , 76%.

Example 10

Preparation of 1-2 (S) -butyl- (2 (R) - (4-nitrobenzyl) amino-3-hydroxypropyl) -4- (1-naphthoyl) piperazine dihydrochloride

An analogous procedure to that described in Example 8, Step A above, using 0.493 g (0.327 mmol) of 4-nitrobenzaldehyde and 0.173 g (0.817 mmol) of sodium triacethoxytetraborohydride converted in dichloroethane was 120.0 mg (0.326 mmol) of 1- (2). (R) -amino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, the title compound, which was purified as a crude product by preparative HPLC (100-75% solvent) A) and subsequent conversion of the ion exchangers to the hydrochloride salt and lyophilization afforded the title compound.

FAB-MS = 505 (m + 1).

Analytical evaluation of the compound according to the formula:

ioo ^C 25 ^H 29 ^N 3 · ° ³ 'HCl.0,10 ⁶ H ₂ 0: C 54.69, H 6.30 Found: C 54.66, H 5.85,

N 8.80% N 8.31%.

Example 11

Preparation of 1- (2 (R) -amino-3-hydroxyheptadecyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine.ditrifluoroacetate

Grade A

Preparation of 1- (2 (R) -tert-butoxycarbonylamino-2-formylethyl) 2 (S) -butyl-4- (1-naphthoyl) piperazine

To a solution prepared by dissolving oxalyl chloride (1.36 mL, 14.9 mmol) in dichloromethane (35.0 mL) and cooled to -65 ° C under a nitrogen atmosphere, was added dimethyl sulfoxide (2.30 mL, 32.40 mmol) in 7 mL. 0 ml of dichloromethane and the resulting reaction mixture was stirred for 2 minutes. A solution of 1- (2 (R) -amino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine (3.19 g, 6.79 mmol) was then added at -10 ° C. The reaction mixture was stirred at this temperature for 15 minutes. After further cooling to -55 ° C, 4.76 mL (34.0 mmol) of triethylamine was added to the reaction mixture and allowed to warm to room temperature after stirring for 5 minutes.

After further addition of dichloromethane, the mixture was shaken with water and after separation of the organic phase and the aqueous phase, the organic layer was washed with 2% potassium hydrogen sulphate solution and then with water, dilute sodium hydrogen carbonate solution and finally saturated aqueous brine solution and then dried with magnesium sulfate.

The title compound was obtained.

ioi Stage B

Preparation of 1- (2 (R) -amino-3-hydroxyheptadecyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a solution prepared by dissolving 0.25 g (0.53 mmol) of 1- (2 (R) -tert-butoxycarbonylamino-2-formylethyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine in 5, 0 mL of dried tetrahydrofuran and cooled to 0 ° C under nitrogen in a three-necked, flame-dried flask was added via syringe a solution of heptadecylmagnesium chloride (1.01 mL of IM solution in ether, 1.01 mmol) and the resulting reaction mixture was allowed to warm. to room temperature. The reaction mixture was then rapidly quenched with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. After drying over magnesium sulfate, the crude product was chromatographed on silica gel, eluting with 25% ethyl acetate in hexane and then with 5% methanol in chloroform.

The purified product was dissolved in 7.0 mL of dichloromethane and treated with 3.5 mL of trifluoroacetic acid. After 45 minutes the solvent was removed in vacuo and the residue was purified by preparative HPLC (95-40% solvent A).

The 2-isomers were isolated. After lyophilization, the title compound was isolated as diastereoisomer A (retention time 8.405 minutes, gradient of 100 to 50% solvent A, &gt; 15 minutes).

FAB-MS = 566 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 36 ^H 59 ^N 3 ° 2 · ^{2 '35} CF ₃ CO ₂ H.0.35 H ₂ 0 calculated: C 58.19, H 7.44, N 5.00% found: C 58.21, H 7 N, 5.36%.

After lyophilization, the title compound was also isolated as diastereoisomer B (retention time 9.269 minutes, gradient 100 to 50% solvent A, &gt; 15 minutes).

FAB-MS = 566 (m + 1).

- Ô2 Analytical evaluation of the compound according to the formula:

^C 36 ^H 59 ^N 3 ° 2 · ^{2 '35} CF ₃ CO ₂ H.0.05 H ₂ 0 calculated: C 58.56, H 7.42, N 5.03% found: C 58.53, H 7 N, 5.17%.

Example 12

Preparation of 2 (S) -benzyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) -piperazine

Grade A

Preparation of 1-3 (S) -dibenzylpiperazine-2,5-dione

The title compound was prepared in an analogous manner to that described in Example 1, Step A except that 12.80 g (48.20 mmol) of N-tert-butyloxycarbonyl-L-phenylalanine, 9.32 g ( 48.20 mmol) of ethyl N-benzylglycinate and 96.5 mL of dicyclohexylcarbodiimide (0.5 M in dichloromethane, 48.20 mmol).

The crude diketopiperazine was mechanically treated and taken up with hexane to give the title compound as a white powder. ¹ H-NMR (300 MHz, CD ₃ OD):

δ 7,00 - 7.40 (10H, m), 4.61 (1 H, d, J = 16.00 Hz), 4.37 (1 H, t, J = 5.00 Hz), 4, 24 (1 H, d, J = 16.00 Hz) 3.42 (1 H, d, J = 18.00 Hz), 3.28 (1 H, d.d., J = 4.16 Hz), 2.96 (1 H, d.d., J = 6.16 Hz), 2.55 (LH, d, J) = 18700 Hz).

Grade B

Preparation of 1-tert-butoxycarbonyl-2 (S) -4-dibenzylpiperazine

The title compound was prepared in an analogous manner to that described in Example 1, Step B above, except that 1.01 g (17.10 mmol) of 1,3- (S) -dibenzylpiperazine-2 was used in the reaction. 5-dione, 2.33 g (61.40 mmol) of sodium tetrahydroaluminate followed by 4.02 g (18.40 mmol) of di-tert-butyl dicarbonate.

The crude product was purified by silica gel column chromatography using a mixture of 7.50% ethyl acetate in hexane.

The title compound was obtained as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD):

δ 7.20 - 7.40 (5H, m), 7.00 - 7.20 (5H, m), 4.15 (1H, m),

3.90 (1H, d, J = 15.0 Hz), 3.60 (1H, d, J = 15.00 Hz), 3.15 (1H, m), 2.95 (3H, m), 2.70 (1H, d, J = 13.00 Hz), 2.02 (1H, dt, J = 6.13 Hz), 1.95 (1H, bd), 1.35 (9H, s) ).

Grade C

Preparation 2 (S) -benzyl-1-tert-butoxycarbonylpiperazine

The title compound was prepared in an analogous manner to that described in Example 1, Step C above, except that 4.78 g (11.30 mmol) of 1-tert-butoxycarbonyl-2 (S) -4 was used in the reaction. -dibenzylpiperazine and 10% palladium on charcoal (1.04 g).

The title compound was obtained as an oily consistency.

^X H-NMR (300 MHz, CD ₃ OD):

δ 7.25 (5H, m), 5.35 (1H, m), 4.00 (1H, d, J = 12.00 Hz),

2.70-3.30 (7H, m), 1.25 (9H, s).

Grade D

Preparation 2 (S) -benzyl-1-tert-butoxycarbonyl-4- (1-naphthoyl) piperazine

The title compound was prepared in an analogous manner to that described in Example 1, Step A above, except that 0.292 g (1.06 mmol) of 2 (S) -benzyl-1-tert-butoxycarbonylpiperazine, 0.159 was used in the reaction. g (1.06 mmol) of 2,3-dimethylbenzoic acid, 0.157 g (1.02 mmol) of 1-hydroxybenzotriazole hydrate, 0.213 g (1.11 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and adjusting the pH of the reaction mixture to pH 7.0, triethylamine was used.

104

The title compound was obtained as a thick oil.

¹ H-NMR (DMSO-d 6, 300 MHz):

δ 7.15 (2H, m), 6.06 (1H, m), 4.42 (1H, m), 3.60-4.20 (2H, m), 2.70-3.24 (4H) , m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.60 (15H, m), 0.72-1.00 (3H, m) ).

Grade E

I

Preparation 2 (S) -benzyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl) methylpiperazine

In analogy to the procedure described in Example 8, Step A above, in the presence of a crushed molecular sieve, in 7 ml of dichloroethane, 0.173 g (0.472 mmol) of 2 (S) benzyl-1- (1-naphthoyl) piperazine was reacted with 0.160 g (0.472). mmol) of 1-triphenylmethylimidazole-4-carboxaldehyde and 0.300 g (1.42 mmol) of sodium triacethoxytetraborohydride.

The title compound was obtained as a thick oil.

Grade F

Preparation 2 (S) -benzyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a solution prepared by mixing 0.310 g (0.472 mmol) of 2 (S) -benzyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl)] methylpiperazine with 5.0 mL of dichloromethane was added 0.300 mL of triethylsilane followed by 5.0 ml of trifluoroacetic acid.

After 1 hour the solvents were evaporated and the remaining residue was partitioned between water and hexane. After separation of the aqueous and organic phases, the aqueous phase was injected directly onto a preparative HPLC column (85-45% solvent A) and the title compound was isolated after lyophilization.

FAB-MS = 411 (m + 1).

105

Analytical evaluation of the compound according to the formula:

^C 26 ^H 26 ^N 4 ° 2 · ^{2 '75} CF ₃ CO ₂ H.0.05 H ₂ 0 calculated: C 52.11, H 4.14, N 7.72% found: C 52.10, H 4 N, 8.16%.

Example 13

Preparation of 1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine di-trifluoroacetate

Grade A

Preparation of 1 - [(1-aziridinyl) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine

To a solution prepared by dissolving 1.67 g (3.56 mmol) of 1- (2 (R) -butoxycarbonylamino-3-hydroxypropyl) -2 (S) -butyl-4 (1-naphthoyl) -piperazine in 10.0 ml dimethylformamide and cooled to 0 DEG C. under nitrogen, 0.427 g (10.6 mmol) of sodium hydride (60% dispersion in oil) was added followed by 0.704 g (3.56 mol) of 1,1'-sulfonyldiimidazole.

The resulting reaction mixture was allowed to warm to 20 ° C over 1.0 h and then cooled to 0 ° C and treated with water.

Dimethylformamide was distilled off in vacuo and the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed with saturated aqueous brine solution and then dried with magnesium sulfate.

The crude product was chromatographed on silica gel using 70% ethyl acetate and then 5% methanol in chloroform as eluents.

The title compound was obtained as the main product.

MS-FAB = 352 (m + 1).

A minor amount of 1 - [(1-butoxycarbonylaziridinyl) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine was also isolated.

106

Grade B

Preparation of 1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4 (1-naphthoyl) piperazine di-trifluoroacetate

Mixture prepared by mixing 0.050 g (0.142 mmol) of 1 - [(1aziridinyl) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine and 0.100 mL (0.852 mmol) of benzyl mercaptan and 0.200 mL of triethylamine in 4.0 ml of methanol was heated at reflux for 18 hours.

The crude product was first chromatographed on silica gel using 3% methanol in chloroform as eluent and purified by high pressure preparative liquid chromatography (85% to 10% solvent A).

The title compound was obtained after subsequent lyophilization.

FAB-MS = 476 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 29 ^H 37 ^N 3 ^OS · ² ' ⁶ CF ₃ CO ₂ H.0.3 H ₂ O calculated: C 52.83, H 5.21, N 5.40% found: C 52.78, H 5, 17, N 5.66%.

Example 14

Preparation of 1- (2 (R) -amino-3- [3- (4-nitrobenzylthio) propyl)] - 2 (S) butyl-4- (1-naphthoyl) piperazine ditrifluoroacetate

A solution prepared by dissolving 0.050 g (0.111 mmol) of 1 - [(1-butoxycarbonyl-aziridinyl) -methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine in 4.0 mL of methanol was heated to at reflux with 0.070 g (0.333 mmol) of p-nitrobenzylthioacetate and 0.200 ml of triethylamine for 2 hours.

The crude product was chromatographed on silica gel using 3% methanol in chloroform as eluent.

The purified product was then treated with 33% trifluoroacetic acid in dichloromethane for

- 107 20 minutes. After evaporation of the solvents, the product was purified by preparative high performance liquid chromatography (85% to 10% of solvent A).

The title compound was obtained after subsequent lyophilization.

MS-FAB = 529 (m + 1).

Analytical evaluation of the compound according to the formula:

^C 29 ^H 36 ^N 4 ° 3 ' ² CF ₃ CO ₂ H 0.08 H ₂ O calculated: C 51.94, H 5.23, N 7.34% found: C 51.87, H 5.06 N, 7.47%.

Example 15

Preparation 2 (S) -Butyl-1 - [(4-imidazolyl) ethyl] -4- (1-naphthoyl) piperazine dihydrochloride

Grade A

Preparation of N-methyl-N-methoxy-2- (1-triphenylmethyl-1H-imidazol-4-yl) acetamide

To a solution prepared by dissolving 1.04 g (6.40 mmol) of 4-imidazoleacetic acid and 2.48 g (7.68 mmol) of triphenylmethyl bromide in 40.0 mL of dimethylformamide was added 4.46 mL (32.0 mmol) triethylamine and the resulting suspension was stirred at room temperature for 18 hours.

After the above operation, the reaction mixture was treated with 1.31 g (8.0 mmol) of 3-hydroxy-1,2,3-benzotriazin-4 (3) -one (HOOBT) with 1.56 g (16.0 mmol of N, O-dimethylhydroxyamine hydrochloride (EDC) (1.53 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 24 hours.

After completion of the above operation, 50 mL of saturated aqueous sodium bicarbonate solution and 50.0 mL of water were added to the mixture, and the mixture was shaken with 2 x 100.0 mL of ethyl acetate.

The combined extracts were washed with 100.0 ml of saturated aqueous sodium bicarbonate solution and then with 50.0 ml of brine and the solvents were then evaporated in vacuo. Rest

108 was suspended in 20.0 ml of ether and the white solid was filtered off to give the title compound as a white solid.

¹ H-NMR (CD ₃ OD, 300 MHz):

δ 7.37 (10H, m), 7.16 (6H, m), 6.84 (1H, s), 7.37 (2H, s), 3.68 (3H, s), 3.18 ( 3H, s) ppm.

Grade B

Preparation of 2- (1-triphenylmethyl-1H-imidazol-4-yl) acetaldehyde

To a solution prepared by dissolving 300.0 mg (0.73 mmol) of the product obtained under Step A above, in 15.0 ml of freshly distilled tetrahydrofuran and cooled to -40 ° C, with a cooling bath prepared from the mixture. of solid carbon dioxide and acetone, 33.20 mg (0.874 mmol) of lithium tetrahydroaluminate were added.

The resulting suspension was then allowed to warm to +5 ° C and the reaction mixture was then held at 0 ° C for 30.0 minutes.

At the end of the above operation, the reaction mixture was again cooled to -40 ° C and then gradually mixed with 33.0 μΐ water, 33.0 μΐ IN aqueous sodium hydroxide solution and 100.0 μΐ water. The resulting suspension was stirred for 30.0 minutes and then filtered and the solvents were removed in vacuo.

The residue was dissolved in 5.0 mL of dichloromethane and the resulting solution was washed with 10% aqueous citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid (5.0 mL) and then with 5.0 mL). water.

After separation of the organic and aqueous phases, the organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo.

The title compound was obtained. ¹ H-NMR (CDCl ₃ , 300 MHz):

δ 9.79 (1H, t, J = 3.0Hz), 7.44 (1H, s), 7.40-7.10 (15H, m), 6.76 (1H, s), 3, 63 (2H, d, J = 3.0Hz) ppm.

109

Grade C

Preparation 2 (S) -Butyl-1 - [(4-imidazolyl) ethyl] -4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a solution prepared by dissolving 89.0 mg (0.263 mmol) of the product obtained in Step B, above, and 3 (S) -butyl-1-naphthoylpiperazine hydrochloride (62.60 mg, 0.188 mmol) in 4.0 mL 1,2-dichloroethane, 400.0 mg of 3 molecular sieve and 200.0 mg (0.94 mmol) of sodium triacethoxytetraborohydride were added.

The resulting reaction mixture was stirred at room temperature for 4 days. After completion of the operation, the reaction mixture was filtered through a glass sinter filter and the filtrate was diluted with 50.0 mL of dichloromethane and then washed with 25.0 mL of water. Then the solvent was evaporated in vacuo and the residue was purified by flash chromatography, eluting with 2-5% methanol in dichloromethane.

The tritylated protected title compound was obtained as an oily consistency which was dissolved in 2.0 mL of dichloromethane and 1.0 mL of trifluoroacetic acid and mixed with 2 drops of triethylsilane to give a colorless solution which was stirred at at room temperature for 3 hours and then the solvent was evaporated in vacuo.

The resulting residue was dissolved in 20.0 mL of water and washed with 20.0 mL of hexanes. After lyophilization of the aqueous layer, the title compound was obtained.

¹ H-NMR (CD ₃ OD, 300 MHz):

δ 8.83 (1H, s), 8.08-7.75 (3H, m), 7.67-7.49 (4H, m),

7.45 (1H, s), 4.50-3.80 (2H, m), 3.65-2.95 (9H, m), 2.00-1.30 (4H, m), 2, 20-0.20 (5H, m) ppm.

Analytical evaluation of the compound according to the formula:

^C 24 ^H 30 ^N 4 ° - ³ '45 ^TFA · ⁰ · ^{75 H} 2 ° calculated: C 46.54, H 4.42, N 7.03% found: C 46.54, H 4.41, N 7 , 35%.

Mass Spectroscopy-FAB (High Resolution110):

Exact Mass Calculation Calculated for Compound of Formula ^C 23 ^H 31 ^N 4 ° ⁼ 391.249787 (MH ⁺ ) found = 391.249028 i

Example 16 i

Preparation 2 (S) -butyl-1 - [(4-imidazolyl) methyl] -4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a solution prepared by dissolving 102.0 mg (0.30 mmol) of the product obtained under the above step C and 0.62.6 mg (0.188 mmol) of 3 (S) -butyl-1-naphthoylpiperazine hydrochloride in 1, 2-dichloroethane (5.0 mL), 200.0 mg (0.94 mmol) of sodium triacethoxytetraborohydride and triethylamine were added to bring the pH of the reaction mixture to 5.50. The reaction mixture was stirred at room temperature for 18 hours.

After completion of the above operation, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo and dissolved in 25.0 mL of ethyl acetate and washed sequentially with 10.0 mL of saturated aqueous sodium bicarbonate solution followed by 10.0 mL of brine. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography using a 3 to 8% methanol in dichloromethane mixture to give the tritylated, protected title compound. This oily consistency was dissolved in 4.0 mL of dichloromethane and 2.0 mL of trifluoroacetic acid, and then the solution was treated with triethylsilane until the yellow color disappeared and a colorless solution was obtained, which was then further stirred at room temperature for 10.0 minutes and then the solvent was evaporated in vacuo.

The resulting white colored solid was partially dissolved in 7.0 mL of water and then filtered. The filtrate was purified by preparative, high-performance liquid chromatography, using Prep.

5000 semi-preparative syschromatography, 300 mm cartridge, C18, 15 μm, 100 high performance liquid (Vaters PrepPak) with 47 x A parameters) and a mixture of 5 to 95% acetonitrile and water (0.1% trifluoroacetic acid) as eluent , at a flow rate of 100 ml / minute (chromatography A). ₍

After lyophilization, the title compound was obtained.

¹ H-NMR (DMSO-d 6, 400 MHz, 150 ° C)?

7.79 (1H, m), 7.53 (3H, m), (1H, d, J = 4.80Hz), 3.95 s), 3.63 (1H, s), 3.48 ( 1H, 2.82 (1H, s), 2.74 (1H, s), (2H, s), 1.08 (2H, s), 0.77 and 8.53 (1H, s), 7, 94 (2H, m);

7.41 (1H, m), 7.40 (1H, s), 4.1?

(1H, d, J = 4.80Hz), 3.70 (1H

s), 3.40 (1H, s), 3.01 (1H, s) J 1.70 (1H, m), 1.49 (1H, s), 1.18 (3H, t, J = 5) (50 Hz) ppm. j j

Analysis for the Formula ^C 23 ^H 29 ^N 4 ° · ^{2 TFAO} > ^{70 H} 2 ° f calculated: C 52.55, H 5.13, N; Found: C, 52.54; H, 5.11; 9.35%.

Mass Spectroscopy-FAB:)

Mass calculation calculated for ^C 23 ^H 30 ^N 4 ^O: calculated = 377.0, (MH ⁺ ) found = 377.0.

of formula

Example 17

Preparation 2 (S) -Butyl-1 - [(1-naphth-2-ylmethyl) -1H-imidazol-5-yl) -acetyl] -4- (1-naphthoyl) piperazine dihydrochloride i

Stage A I l

I

Preparation of 1H-imidazole-4-acetic acid methyl ester hydrochloride

The solution, prepared by dissolving 4.00 g (24.6 mmol) of 1H-imidazole-4-acetic acid hydrochloride in 100.0 mL of methanol, was bubbled with hydrogen chloride gas until

- 112!

saturated solution. The solution was then allowed to stand at room temperature for 18 hours. Evaporation of the solvent in vacuo from the mixture gave the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz):

δ 8.85 (1H, s), 7.45 (1H, s); 3.89 (2H, s) and 3.75 (3H, s) ppm.

Grade B

Preparation of 1- (triphenylmethyl) -1H-imidazol-4-yl-acetic acid methyl ester

To a slurry prepared by mixing 7.48 g (42.40 mmol) of the product obtained under Step A above in 200.0 mL of dichloromethane was added 17.70 mL of triethylamine (127.0 mmol) and 16 mL of triethylamine. 4 g (50.80 mmol) of triphenylmethyl bromide. The resulting reaction mixture was stirred for 72 hours. After completion of the above operation, the reaction mixture was washed with 100.0 mL saturated aqueous sodium bicarbonate and 100.0 mL water.

After separating the organic from the aqueous phase, the organic layer was evaporated in vacuo and the residue was purified by flash chromatography, using 30 to 100% ethyl acetate in hexane, for gradient elution.

The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz):

δ 7.35 (1H, s), 7.31 (9H, m), 7.22 (6H, m), 6.76 (1H, s),

3.68 (3H, s) and 3.60 (2H, s) ppm.

Grade C

Preparation of 2- [1- (Naphth-2-ylmethyl) -1H-imidazol-5-yl] -acetic acid methyl ester

To a solution prepared by dissolving 4.36 g (11.4 mmol) of the product obtained under Step B above, in 70.0 mL of acetonitrile was added 2- (bromo).

- 113 -

methyl) naphthalene and the resulting reaction mixture was heated at 55 ° C for 4 hours. Then the reaction mixture was allowed to warm to room temperature and the resulting white precipitate was collected by filtration. The resulting filtrate was concentrated to a volume of 30.0 mL and then heated to 55 ° C for 18 hours. jj ¹

Upon completion of the above operation, the reaction mixture was stirred

After cooling to room temperature, it was filtered and the resulting, white precipitate was collected by filtration. The filtrate was then concentrated to a volume of 10.0 ml and then heated at 55 ° C for 1 hour.

The reaction mixture was then cooled back to room temperature and diluted with 25.0 mL of ethyl acetate. The resulting precipitate was collected by filtration and combined with the 2 previous precipitates in 100.0 mL of methanol, and the mixture was heated to reflux for 30 minutes.

After completion of the above operation, the solvent was removed in vacuo and the remaining residue was partitioned between 200.0 mL of dichloromethane and 100.0 mL of sodium bicarbonate solution. After separation of the organic and aqueous phases, the organic layer was concentrated to dryness in vacuo and the residue was purified by flash chromatography (0-6% methanol / dichloromethane as gradient eluent).

The title compound was obtained as an off-white solid.

¹ H-NMR (CDCl ₃ , 400 MHz):

δ 7.82 (2H, m), 7.75 (1H, m), 7.70 (1H, s), 7.49 (3H, m), 7.20 (1H, d, J = 8.40 Hz), 7.06 (1H, s), 5.32 (2H, s), 3.57 (3H, s), 3.49 (2H, s), ppm.

Grade D

Preparation of 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetic acid hydrochloride

In the previous step C above, the obtained 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetic acid methyl ester (0.92 g, 3.28 mmol) was dissolved in 50.0 ml 2.5N

114 of the hydrochloric acid solution and the resulting solution was heated at 55 ° C for 3 hours.

After completion of the above operation, the reaction mixture was concentrated to dryness in vacuo to give the title compound as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz):

δ 8.92 (1H, s), 7.94 (1H, d, J = 8.60Hz), 7.88 (2H, m),

7.83 (1H, s), 7.54 (3H, m), 7.43 (1H, d, J = 14.00 Hz), 5.60 (2H, s) and 3.82 (2H, s) ), ppm.

Grade E

Preparation 2 (S) -Butyl-1 - [(1-naphth-2-ylmethyl) -1H-imidazol-5-yl) acetyl] -4- (1-naphthoyl) piperazine dihydrochloride

To a mixture prepared by mixing 100.0 mg (0.330 mmol) of the product obtained under Step D above, 100.0 mg of 3 (S) -butyl-1-naphthoylpiperazine hydrochloride (0.300 mmol) and 54.0 mg. (0.33 mmol) of 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one (HOOBT) in 2.0 mL of dimethylformamide was added 63.0 mg (0.33 mmol) of 1- (3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (EDC) and 161.0 μΐ (1.16 mmol) of triethylamine and the resulting reaction mixture as a suspension was stirred for 18 hours.

After the above operation, a saturated aqueous sodium bicarbonate solution (7.0 mL) was added to the mixture, and the resulting precipitate was filtered off. The solid material was redissolved in dichloromethane and the resulting solution was washed with 25.0 mL water and 20.0 mL brine. After evaporation of the solvent in vacuo, the residue was purified by preparative HPLC (chromatography A), followed by freeze-drying. the title compound obtained. j ¹ H-NMR (CDCl ₃ , 400 MHz): δ δ 8.98 (1H, m), 8.03-7.27 (15H, m), 5.69-5.50 (2H, m), 4.79-4.44 (2H, m), 4.15-2.50 (7H, m), 1.80-0.20 (9H, m), ppm.

115 ι

Anal. Calcd for ^C 35 ^H 35 ^N 4 ° 2 · ^HCl · ⁰ · ^{65 H} 2 ° C: C 67.30, H 6.16, N 8.97 Found: C 67.25, H 6, 16, N 9.15%.

Mass Spectroscopy-FAB:

Mass calculation calculated for ^C 35 ^H 36 ^N 4 ^O 2 ^: calculated = 545.291652 (MH ⁺ ) found = 545.292050.

Example 18

Preparation 2 (S) -Butyl-1 - [(1-naphth-2-ylmethyl) -1H-imidazol-5-yl) acetyl] -4- (1-naphthoyl) piperazine.ditrifluoroacetate

Grade A

Preparation of N-methyl-N-methoxy-2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetamide

To a solution prepared by dissolving 0.819 mg (2.70 mmol) of 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetic acid hydrochloride in 15.0 mL of dimethylformamide was added sequentially 293 0 mg (3.0 mmol) of N, O-dimethylhydroxylamine hydrochloride, 489.0 mg (3.0 mmol) of 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one (HOOBT), 575 1.0 mg (3.0 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl (EDC) and 1.67 mL (12.0 mmol) of triethylamine.

The resulting reaction mixture was stirred at room temperature for 18 hours, and after completion of the operation, 30.0 ml of a saturated aqueous sodium bicarbonate solution and 30.0 ml of water were added and the mixture was extracted with 2 x 50.0 ml of dichloromethane. The combined organic extracts were washed with brine (50.0 mL) and the solvent was evaporated in vacuo.

The residue was purified by flash chromatography using a mixture of 2-4% methanol in dichloromethane as a gradient eluent.

1Ϊ6

The title compound was obtained as an oil.

¹ H-NMR (CDCl ₃ , 400 MHz):

δ 7.80 (2H, m), 7.74 (1H, m), 7.56 (1H, s), 7.47 (3H, m), 7.22 (1H, d, J = 8.60) Hz), 6.97 (1H, s), 5.37 (2H, s), 3.58 (2H, s), 3.51 (3H, s) and 3.12 (3H, s), ppm.

Grade B

Preparation of 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetaldehyde

To a suspension of lithium tetrahydroaluminate (40.80 mg, 1.07 mmol) in tetrahydrofuran (5.0 mL) cooled with a solid carbon dioxide / acetone cooling bath to -45 ° C was added a solution of 243.0 mg ( 0.895 mmol) of the product obtained in Step A above, in 5.0 ml of tetrahydrofuran, at a rate such that the temperature of the reaction mixture is maintained below -35 ° C.

After completion of the above operation, the mixture was allowed to warm to +5 ° C and then cooled to -35 ° C. A solution prepared by dissolving 272.0 mg of potassium bisulfate in 1.0 mL of water was added to the reaction mixture, which was stirred at room temperature for 30 minutes and then filtered through silica. The silica filter cake was washed with 25.0 mL of ethyl acetate, and the combined filtrates were washed with 10.0 mL of saturated aqueous sodium bicarbonate, followed by 10.0 mL of water.

After separation of the organic and aqueous phases, the organic layer was dried over magnesium sulphate and evaporated after filtration. The title compound was obtained as a clear oil.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 9.50 (1H, t, 2 Hz), 7.85-7.70 (3H, m), 7.64 (1H, s), 7.53 7.40 (3H, m), 7.16 (1H, d, J = 12.0 Hz), 7.06 (1H, s), 5.20 (2H, s) and 3.53 (2H, s), m), ppm.

- 117 Grade C

Preparation 2 (S) -Butyl-1 - [(1-naphth-2-ylmethyl) -1H-imidazol-5-yl) acetyl] -4- (1-naphthoyl) piperazine.ditrifluoroacetate

To a mixture prepared by mixing 58.40 mg (0.232 mmol) of the product obtained in the previous step B above and 3 (S) -butyl-1-naphthylpiperazine hydrochloride (96.50 mg, 0.279 mmol) in 10.0 ml of 1,2-dichloroethane and 5.0 ml of dimethylformamide, 250.0 mg of 3Å molecular sieve and 236.50 mg (1.12 mmol) of sodium triacethoxytetraborohydride were added.

The resulting reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting filtrate was diluted with 100.0 mL of dichloromethane and washed with 50.0 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo.

The residue was purified first by flash chromatography using a mixture of 2-5% methanol in dichloromethane followed by preparative, high-performance liquid chromatography (chromatography A).

The title compound was obtained. ¹ H-NMR (CD ₃ OD, 400 MHz):

δ 9.04 (1H, s), 8.17-7.30 (15H, m), 5.65 (2H, s), 4.60

2.20 (11H, m) and 1.60-0.20 (9H, m) ppm.

Mass Spectroscopy-FAB (High Resolution):

Exact mass calculation calculated for C ₃₅ H ₃₉ N ₄ O:

calcd = 531.312387 (MH ⁺ ) found = 531.313011.

Example 19

Preparation of 1- (2 (R) -amino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine-bis-trifluoroacetate salt

118

Grade A

Preparation of N-tert-butyloxycarbonyl-O-benzylserine- (N'-methoxy) methylamide

5.0 J g (16.90 mmol (Bachem)) of N-tert-butyloxycarbonyl-O-benzylserine and 2.29 g (16.90 mmol) of 1-hydroxybenzotriazole were dissolved in 100.0 ml of dried dimethylformamide under argon. hydrate (HOBT).

To the resulting reaction mixture was added 1.98 g (20.30 mmol) of N, O-dimethylhydroxylamine hydrochloride followed by 3.56 g (18.60 mmol) of 1- (3-dimethylaminoropropyl) -3 at 0 ° C. -etylkarbodiimid.hydrochloridu. The pH of the mixture was adjusted to pH 7.0 by the addition of 4.50 mL of 4-methylmorpholine, and the reaction mixture was stirred at room temperature for 3 hours and after this operation was diluted with ethyl acetate and poured into 0.5N hydrochloric acid solution. .

After shaking twice with ethyl acetate, after separation of the organic layer, they were washed with water and then with brine, dried with magnesium sulfate and evaporated in vacuo.

The obtained pale yellow compound was further subjected to silica gel column chromatography, using hexane: ethyl acetate (2: 1). j

The title compound was obtained as an oily consistency.

= 0.45 (silica, hexane: ethyl acetate (1: 1))

Grade B

Preparation of N-tert-butyloxycarbonyl-O-benzylserine aldehyde

The amide (5.70 g, 16.90 mmol) obtained in the previous step A above in 20.0 mL of dried ether was added dropwise at -50 ° C to a suspension prepared from 0.705 g (18, 50 mmol) of lithium aluminum hydride in 80.0 ml of ether. After completion of the above operation, the reaction mixture was stirred at 0 ° C for 45 minutes and then re-cooled to -50 ° C, followed by the slow addition of a solution prepared by dissolving 4.0 g.

- 119 i, potassium hydrogen sulphate in 11.0 ml of water.

The reaction mixture was stirred at room temperature for 1 hour, filtered through silica, and then was washed intensively, successively with 10% citric acid solution, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated. .

The title compound was obtained as an oily consistency which was used directly as such in the next step C.

= 0.58 (silica, hexane: ethyl acetate (2: 1))

Grade C

Preparation of 1- (2 (R) -N-tert-butyloxycarbonylamino-3-benzyloxypropyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine

Freshly added to the solution prepared by dissolving 1.70 g (574 mmol) of piperazine hydrochloride obtained in Example 1, step E, described above, in 25.0 ml of pH-adjusted dichloromethane (triethylamine to pH 6.0) was added freshly. Crushed and activated 4A molecular sieves and then 4.85 (22.90 mmol) sodium triacethoxytetraborohydride was added dropwise over 20 minutes at 0 ° C by dissolving 2.08 g (747 mmol). of the aldehyde obtained in Step B above, in 20.0 ml of dichloromethane.

The resulting reaction mixture was then stirred at room temperature for 16 hours, then filtered through silica, diluted with ethyl acetate and vigorously and washed sequentially with water, potassium hydrogen sulphate solution, sodium bicarbonate solution and finally brine. The magnesium sulfate-dried solution was then evaporated in vacuo.

A pale yellow oil of oily consistency was obtained which was further processed by silica gel column chromatography using hexane: ethyl acetate (1: 1) as eluent.

120

The title compound was obtained as a foam.

Rj? = 0.15 (silica, hexane: ethyl acetate (2: 1))

Grade D

Preparation of 1- (2 (R) -N-BOC-amino-3-hydroxypropyl) -2- (S) -butyl4- (1-naphthoyl) piperazine

Mixture prepared by dissolving 700.0 mg (1.25 mmol) of the benzyl ether obtained in the previous step C above in 20.0 ml of methanol and adding 150.0 μ oct of acetic acid and then 20% palladium hydroxide to 500 ml. 0 mg of charcoal was hydrogenated at 50 psi for 16 hours.

After filtration through silica, the solvent was removed and the remaining residue was chromatographed on silica gel using ethyl acetate: hexane (1: 1) followed by 5% methanol in ethyl acetate as eluents.

The title compound was obtained as an oily consistency.

Grade E

Preparation of 1- (2 (R) -amino-3-hydroxy-propyl-2 (S) -butyl-4- (1-naphthoyl) -piperazine-bis-trifluoroacetate salt

The solution, prepared by dissolving the N-BOC-amine (140 mg) obtained in Step D above, in 10.0 mL of ethyl acetate, was bubbled with hydrogen chloride gas until the solution was saturated. After 5 minutes, the solution was bubbled with argon and the solvent was removed. The solid residue was purified by preparative, high performance liquid chromatography (C18 column, water / methyl cyanide / 0.1% trifluoroacetic acid gradient).

The aqueous solution was freeze-dried and lyophilized and the title compound was obtained as a hygroscopic powder.

Mass Spectroscopy-FAB (m / z) = 370 (M + 1).

121

Anal compound of formula ^ 22 ^ 32 ^ 3θ2 · ^{2 '33} TFA (trifluoroacetic acid):

H, 5.27; N, 6.59. Found: C, 50.28; H, 5.49; N, 6.70.

Example 20

Preparation of 1- (2 (R) -amino-4-hydroxybutyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine.bis hydrochloride salt

The title compound was prepared in analogy to Example 19, steps A to E, except that N-BOC-O-benzylhomoserine (Bachem) was used as the starting material and the title compound was obtained as the bis-hydrochloride salt.

FAB-MS (m / z) = 384 (M + 1).

Anal compound of the formula ^C 23 ^H 33 ^N 3 ¹ ° 2 ^{'5 HC1:} C 54.04, H 7.20, N 8.22% Found: C 53.95, H 7.23, N 8 , 50%.

Example 21

Preparation of 1- (2-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl4- (1-naphthoyl) piperazine.bis-trifluoroacetate salt

Grade A

Preparation of D, L-N-BOC-ortho-tyrosine methyl ester

The title compound was prepared as a crystalline solid in two steps (BOC) 20 / potassium carbonate in tetrahydrofuran / water and then using diazomethane in ethyl acetate from D, L-orthotyrosine (Sigma).

122 Step B Preparation of 3- (2-hydroxyphenyl) -2- (N-tert-butyloxycarbonyl (BOC) 1 amino) propanol!

To a solution prepared by dissolving 1.34 g (4.54 mmol) of the ester obtained in the previous step A above in 20.0 ml of tetrahydrofuran, added in portions at 0 ° C, 400 mg (10.50). mmol) of lithium aluminum hydride.

After 4 hours at room temperature, 0.40 mL of water was added dropwise followed by 0.40 mL of 1N sodium hydroxide solution followed by an additional 1.20 mL of water.

The slurry was stirred for 1 hour and then filtered through silica and rinsed with tetrahydrofuran. After removal of the solvent, the residue was chromatographed on silica gel, eluting with hexane: ethyl acetate (1: 1).

The title compound was obtained as a solid.

= 0.45 (silica, hexane: ethyl acetate (1: 1)).

Grade C

Preparation of 3- (2-benzyloxyphenyl) -2- (N-tert-butyloxycarbonyl (BOC) amino) propanol

Mixture prepared by mixing 280,0 mg (1,05 mmol) of the alcohol obtained in Step B above, 150,0 μΐ of benzyl bromide (1,26 mmol) and 513,0 mg (1,57 mmol) of cesium carbonate in 10.0 mL of dimethylformamide, was stirred under argon at room temperature for 16 hours.

The reaction mixture was then poured into water and washed twice with ethyl acetate, washed with water and then brine, dried over magnesium sulfate and evaporated.

The residue, as an oily consistency, was purified by silica gel chromatography using a mixture of:

123 hexane: ethyl acetate (2: 1) as eluent.

The title compound was obtained as an oily consistency.

Melting point = 0.36 (silica, hexane: ethyl acetate (2: 1)).

Grade D

Preparation of 3- (2-benzyloxyphenyl) -2- (N-BOC-amino) propanol

To a mixture prepared by mixing 280.0 mg (0.78 mmol) of the alcohol obtained in Step C above, in 3.0 mL of dimethylsulfoxide, 3.0 mL of dichloromethane and 0.55 mL of triethylamine was added under atmosphere. Argon, at room temperature 500.0 ml (3.14 mmol) of pyridine-sulfur trioxide complex and the resulting reaction mixture was poured into saturated aqueous sodium bicarbonate solution, then shaken twice with ethyl acetate, washed with water followed by brine and dried magnesium sulfate, concentrated in vacuo.

The title compound was obtained as an oil and was used as such in the following step E.

Rf = 0.41 (silica, hexane: ethyl acetate (4: 1)).

Grade E

Preparation of 1- (2-N-BOC-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) butyl-4- (1-naphthoyl) piperazine

The aldehyde obtained in the previous step D and the piperazine hydrochloride obtained in Example 1, step E, described above were coupled by reductive alkylation, using the procedure described in Example 19, step C. Purification by column chromatography on Silica gel, eluting with hexane: ethyl acetate (3: 2) gave the title compound as a 1: 1 mixture of diastereomers).

Rf = 0.51 and 0.45, silica, hexane: ethyl acetate (1: 1).

124

Grade F

Preparation of 1- (2-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl 4- (1-naphthoyl) piperazine-bis-trifluoroacetate salt

The solution, prepared by dissolving 70.0 mg of the N-BOC-amine obtained in Step E above, in 15.0 mL of ethyl acetate, was bubbled until saturated with hydrogen chloride gas. After 15.0 minutes, the reaction was bubbled with argon and the solvent was removed until a solid residue was obtained, which was purified by preparative HPLC (column C-18, water / methyl cyanide / 0.1% trifluoroacetic acid gradient) ).

After lyophilization, the title compound was obtained as a powder.

Mass Spectroscopy-FAB (m / z) = 536 (M + 1).

Analytical evaluation of the compound according to the formula? 35? 41? 3? ^{2? 2? 2?} TFA (trifluoroacetic acid). 0.35 H ₂ 0: C, 59.68, H, 5.58, N, 5.30% Found: C 59.70, H 5.60, N 5.56%.

Example 22

Preparation of 1- (2-amino-3- (2-hydroxyphenyl) propyl) -2 (S) -butyl (1-naphthoyl) piperazine-bis-trifluoroacetate salt, diastereomer A

Grade A

Preparation of 1- (2-N-BOC-amino-3- (2-hydroxyphenyl) propyl) -2 (S) butyl-4- (1-naphthoyl) piperazine

Mixture prepared by mixing 290.0 mg (0.50 mmol) of 1- (2-NBOC-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, obtained in Example 19, step E, 60 μ 60 (1.0 mmol) of acetic acid and 20% palladium hydroxide on activated carbon (100.0 mg) in 20.0 ml of methanol was hydrogenated at 461, 97 KPa for

125 hours. The reaction mixture was then filtered through silica, and after evaporation of the solvent, an oily consistency was obtained which, in thin layer chromatography using silica, showed 2 well-distinguishable spots.

Column chromatography on silica gel, using ethyl acetate: hexane (1: 1), gave:

(a) Diastereomer A, in the title compound:

Rj? = 0.49 (silica, hexane: ethyl acetate (1: 1))

(b) Diastereomer B, in the title compound:

Rf = 0.35 (silica, hexane: ethyl acetate (1: 1))

Grade B

Preparation of 1- (2-amino-3- (2-hydroxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine-bis-trifluoroacetate salt, diastereomer A

The diastereomer A, of the N-BOC-amine obtained in the previous step A above, was deprotected by bubbling hydrogen chloride gas in ethyl acetate. After solvent removal, preparative high performance liquid chromatography (C-18 column, water / methyl cyanide with 0.1% trifluoroacetic acid, gradient) was followed by lyophilization to give the title compound as a powder.

FAB-MS (m / z) = 466.0 (M + 1)

Analytical evaluation of the compound of the formula

C28H35N3O2.2 TFA (trifluoroacetic acid):

H, 5.54; N, 6.24 Found: C, 57.08; H, 5.64; N, 6.32%.

Example 23

Preparation of 1- [3- (4-imidazolyl) propyl] -2 (S) -butyl-4- (1-naphthoyl) -piperazine-bis-trifluoroacetate salt

126

Grade A

Preparation of ethyl 3- (4-imidazolyl) propionate

The title compound was prepared in 2 steps from urocanoic acid (Aldrich) using standard chemical procedures (esterification with hydrogen chloride in ethanol followed by hydrogenation with 10% palladium on charcoal in ethanol).

¹ H-NMR (CDCl ₃ ):

Ô 1.23 (3H, t), 2.65 (2H, t), 2.94 (2H, t), 4.15 (2H, k),

6.81 (1H, s); 7.56 (1H, s).

Grade B

Preparation of 3- (4-imidazolyl) propanol

To a solution prepared by dissolving 120.0 g (71.40 mmol) of the ester obtained in Step A above above in 230.0 mL of tetrahydrofuran was added portionwise over 30 minutes at 0 ° C 2, 99 g (78.6 mmol) of lithium tetrahydroaluminate.

The resulting reaction mixture was then stirred at room temperature for 2 hours, and after cooling to 0 ° C, very carefully dropwise addition of 4.20 ml of water was added dropwise. 10.60 ml of 1N sodium hydroxide solution was then added dropwise and the resulting slurry was stirred at room temperature for 1 hour. After filtration through silica and subsequent washing of the filter with ethyl acetate, the solvent was removed.

The title compound (8.16 g) was obtained as a clear oil of oily consistency. ¹ H-NMR (CD ₃ OD):

δ 1.84 (2H, pentet), 2.68 (2H, t), 3.58 (2H, t), 6.88 (1H,

s), 7.80 (1 H, s).

Grade C

Preparation of 3- (4-N-BOC-imidazolyl) propanol

127

A mixture of Intermediate 166.0 mg (1.32 mmol) imidazole obtained in the previous, the above-described Step B, (N-tert-butyloxycarbonyl) ₂ θ (302.0 mg, 1.38 mmol) and 190.0 mg (1.38 mmol) of potassium carbonate was stirred in 10.0 mg of tetrahydrofuran for 2 hours.

After filtration of the reaction mixture, the solvent was removed in vacuo to give the title compound as an oily consistency.

= 0.17, (silica, 5% methanol in chloroform).

The above compound was used in the next step D as such.

Grade D

Preparation of 1- [3- (4-imidazolyl) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine. bis-trifluoroacetate salt

To a mixture prepared by mixing 1.32 mmol of the alcohol obtained in Step C above, dissolved in 4.0 mL of dimethylsulfoxide, 4.0 mL of dichloromethane and 0.92 mL of triethylamine, was added portionwise a total of 600.0 mg. (5.28 mmol) of pyridine sulfur trioxide complex.

After three hours, the resulting reaction mixture was poured into ethyl acetate and then shaken with saturated sodium bicarbonate solution, then brine, then dried and evaporated.

The corresponding aldehyde was obtained and used further without any purification.

The above aldehyde was coupled with piperazine obtained as described in Example 1, step E above, by reductive alkylation analogous to that described in Example 19, step C and subjected to subsequent column chromatography on silica gel using 5% methanol. in chloroform. The product was dissolved in 10.0 ml of ethyl acetate saturated with previously hydrogen chloride gas. After removal of the solvent, the residue was purified by preparative, high-performance liquid chromatography (column C-18, water / methyl cyanide / 0.1% trifluoroacetic acid, gradient).

After freeze drying of the frozen aqueous solution, the title compound was obtained as a hygroscopic powder.

FAB-MS (m / z) = 405.0 (M + 1)

Analytical evaluation of the compound of formula ^C 25 ^H 32 ^N 4 ° ' ² ' ^{35 tfa} - °> ^{4 H} 2 ^0: calculated: C 52.48, H 5.21, N 8.23% found: C 52.45, H 5.22, N 8.27%.

Example 24

Preparation 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (1-naphthylmethyl) imidazol-5-ylmethyl] piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethyliidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.046 g (0.21 mmol) of 1-bromomethylnaphthalene. The title compound was obtained after purification of the reverse phase by preparative HPLC (gradient elution with 30-75% acetonitrile / 0.1% trifluoroacetic acid, 70-25% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m / z) = 517.0

Analytical evaluation of the compound of formula ^c 34 ^H 36 ^N 4 ° .0.05 H ₂ 0.2.0 TFA:

calculated: C 60.55, H 5.22, N 7.43%. Found: C 60.48, H 5.12, N 7.42%.

Example 25

Preparation 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (2-naphthylmethyl) imidazol-5-ylmethyl] piperazine, ditrifluoroacetic acid salt

129

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.046 g (0.21 mmol) of 2-bromomethylnaphthalene. The title compound was obtained after purification of the reverse phase by preparative high-performance liquid; chromatography (gradient elution with 30-75% acetonitrile / 0.1% trifluoroacetic acid, 70-25% 0.1% aqueous trifluoroacetic acid, over 50 min) and lyophilization.

FAB-MS (m + 1) = 492.0.

Analytical evaluation of the compound of formula ^C 34 ^H 36 ^N 4 ° · ¹ ' ^{7 H} 2 ° · ^{2.0 TFA:} calculated: C 58.87, H 5.38, N 7.23% found: C 58.90, H 4.93, N 7.13%.

Example 26

Preparation 2 (S) -n-butyl-1- [1- (4-cyanobenzyl) imidazol-5-yl] -4 (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.041 g (0.21 mmol) of 4-cyanobenzyl bromide.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 25-65% acetonitrile / 0.1% trifluoroacetic acid, 75-35% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 492.0.

Analytical evaluation of the compound of formula ^C 31 ^H 33 ^N 5 ° .0.35 H ₂ O.2.0 TFA:

calculated: C 57.91, H 4.96, N 9.65% found: C 57.93, H 4.91, N 9.55%.

130

Example 27

Preparation 2 (S) -n-butyl-1- [1- (4-methoxybenzyl) imidazol-5-yl] -4 (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and from 0.041 mL (0.21 mmol) of 4-methoxybenzyl bromide with additional addition of 100.0 mg of potassium dihydrochloride to the reaction mixture.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 5-95% acetonitrile / 0.1% trifluoroacetic acid, 95-5% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 497.0.

For ^C 31 ^H 36 ^N 4 ° 2 ' ¹ ' ^{70 H} 2 ° · ² ' ^{0 TFA:} calculated: C 53.40, H 5.30, N 7.12% found: C 53.37, H, 4.78; N, 7.00%.

Example 28

Preparation 2 (S) -n-butyl-1- [2- (3-methyl-2-butenyl) imidazol-5-yl] -4- (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and from 0.024 mL (0.21 mmol) of 4-bromo-2-methyl-2-butene.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 5-95% acetonitrile / 0.1% trifluoroacetic acid, 95-5% 0.1%).

131 of aqueous trifluoroacetic acid (50 min) and lyophilization.

FAB-MS (m + ϊ) = 445.0.

Analytical evaluation of the compound of formula ^C 28 ^H 36 ^N 4 ° ¹ ' ^H 2 ° · ^{2.0 TFA:} calculated: C 54.51, H 5.95, N 7.95% found: C 54.54, H 5 N, 7.73%.

Example 29

Preparation 2 (S) -n-butyl-1- [1- (4-fluorobenzyl) imidazol-5-yl] -4 (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

I

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.026 mL (0.21 mmol) of 4-fluorobenzyl bromide. The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 25-65% acetonitrile / 0.1% trifluoroacetic acid, 75-35% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 485.0.

Analytical evaluation of the compound of the formula

C30H33FN4O.3H2O.2.0 TFA (trifluoroacetic acid):

H, 5.39; N, 7.31. Found: C, 53.21; H, 4.56; N, 7.08%.

Example 30

Preparation 2 (S) -n-butyl-1- [1- (4-chlorobenzyl) imidazol-5-yl] -4 (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) - 132 µl methyl] - 4- (1-naphthoyl) piperazine and 0.034 mg (0.21 mmol) of 4-chlorobenzyl chloride, with additional addition of 100.0 mg of sodium iodide to the reaction mixture. The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 25-65% acetonitrile / 0.1% trifluoroacetic acid, 75-35% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 501.0.

Analytical evaluation of the compound of the formula

0.2,0 C30H33CIN4O.4,80H ₂ TFA (trifluoroacetic acid): C, 50.07; H, 5.51; N, 6.87% Found: C 50.10, H 4.25, N 6.48%.

Example 31

Preparation of 1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.053 g (0.21 mmol) of 4-bromobenzyl bromide, with the additional addition of 100.0 mg of sodium iodide to the reaction mixture.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 30-65% acetonitrile / 0.1% trifluoroacetic acid, 70-35% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 545.0.

Anal compound of formula ^ 30 ^ ^Γ ^ 33® 4θ '' ^ θ ^ 2θ''θ TFA (calculated: C 50.78, H 4.81, N 6.97 Found: C 50.81, H 4 , 39, N 6.88 trifluoroacetic acid):

133

Example 32

Preparation 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethylbenzyl) imidazol-5-ylmethyl] piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.053 g (0.21 mmol) of 4-trifluoromethylbenzyl bromide.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 30-65% acetonitrile / 0.1% trifluoroacetic acid, 70-35% 0.1% aqueous trifluoroacetic acid, over 50 minutes) and lyophilization.

FAB-MS (m + 1) = 535.0.

Analytical evaluation of the compound of the formula

030 ^ 33 ^ X40.2,0 TFA (trifluoroacetic acid):

H, 4.63; N, 7.35. Found: C, 57.46; H, 4.98; N, 7.84.

Example 33

Preparation 2 (S) -n-butyl-1- [1- (4-methylbenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.029 mL (0.21 mmol) of 4-methylbenzyl bromide, with the additional addition of 100.0 mg of sodium iodide to the reaction mixture.

The title compound was obtained after purification of the reverse phase by preparative high performance quartz palladium chromatography (gradient elution with 30% to 65% acetonitrile / 0.1% trifluoroacetic acid, 70% to 35% 0.1% aqueous trifluoroacetic acid, over a period of 50 minutes) and lyophilization.

FAB-MS (m + 1) = 481.0.

Analytical evaluation of the compound of the formula

C31H36N4O.2,6 H2O.2,0 TFA (trifluoroacetic acid):

calculated: C 55.64, H 5.76, N 7.42%. Found: C 55.61, H 5.09, N 7.43%.

Example 34

Preparation 2 (S) -n-butyl-1- [1- (3-methylbenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.029 mL (0.21 mmol) of 3-methylbenzyl bromide. The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 25% to 65% acetonitrile / 0.1% trifluoroacetic acid, 75% to 35% 0.1% aqueous trifluoroacetic acid, over 50%). minutes) and lyophilization.

FAB-MS (m + 1) = 481.0.

Analytical evaluation of the compound of the formula

C31H36N4O.2.0 TFA (trifluoroacetic acid):

H, 6.92; N, 10.12 Found: C, 69.60; H, 6.98; N, 10.51.

Example 35

Preparation of 1- [1- (4-phenylbenzyl) -imidazol-5-ylmethyl] -2 (S) -n-butyl-4- (1-naphthoyl) piperazine, ditrifluoroacetic acid salt

135

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.029 mL (0.21 mmol) of 4-phenylbenzyl bromide.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 30% to 65% acetonitrile / 0.1% trifluoroacetic acid, 70% to 35% 0.1% aqueous trifluoroacetic acid, over 50%). minutes) and lyophilization.

FAB-MS (m + 1) = 543.0.

Anal compound of formula ^ 36 ^ 38 ^ Η 4θ · 4.95 ₂ 0.2,0 TFA (trifluoroacetic acid): C 55.87, H 5.85, N 6.52% Found: C 55.55, H, 4.58; N, 6.23%.

Example 36

Preparation 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (4-phenylethyl) imidazol-5-ylmethyl] piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and from 0.029 mL (0.21 mmol) of 2-phenylethyl bromide, with an additional addition of 120.0 mg of sodium iodide to the reaction mixture and heating the mixture at reflux for 12 hours.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 30% to 65% acetonitrile / 0.1% trifluoroacetic acid, 70% to 35% 0.1% aqueous trifluoroacetic acid, over 50%). minutes) and lyophilization.

FAB-MS (m + 1) = 481.0.

Analytical evaluation of the compound of the formula

C36H38N4O.4,20 H ₂ O.2,0 TFA (trifluoroacetic acid):

calculated: found:

C 53.60, C 53.54,

H 5, H 4,

96

86.

N 7.14% N 6.86%.

Example 37

Preparation 2 (S) -n-butyl-4- (1H-naphthoyl) -1- [1- (4-trifluoromethoxy) imidazol-5-ylmethyl] piperazine, ditrifluoroacetic acid salt

In analogy to the procedure described in Example 4 above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] -4- (1- naphthoyl) piperazine and 0.032 mL (0.21 mmol) i

Of 4-trifluoromethoxybenzyl bromide, with the additional addition of 120.0 mg of sodium go to the reaction mixture and heating the mixture at reflux for 12 hours.

The title compound was obtained after purification of the reverse phase by preparative high performance liquid chromatography (gradient elution with 35% to 70% acetonitrile / 0.1% trifluoroacetic acid, 65% to 30% 0.1% aqueous trifluoroacetic acid, over a period of time). 50 minutes) and lyophilization.

FAB-MS (m + 1) = 551.0.

Anal compounds of formula ^ 31 ^ 33 ^ 4θ2''θθ 0.2,0 H ₂ TFA (trifluoroacetic acid): C 49.42, H 5.09, N 6.59% Found: C 48.95, H 4.06, N 6.26%.

Example 38

Preparation of 1 - {[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} -2 (S) -n-butyl-4- (1-naphthoyl) piperazine trifluoroacetate

137

Grade A

Preparation of 1H-imidazole-4-acetic acid methyl ester hydrochloride

The solution, prepared by dissolving 4.00 g (24.60 mmol) of 1H-imidazole-4-acetic acid hydrochloride in 100.0 ml of methanol, was saturated with hydrogen chloride gas and the resulting mixture was allowed to stand at room temperature for 18 hours. hours.

Evaporation of the solvent in vacuo gave the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz):

δ 8.85 (1H, s), 7.45 (1H, s), 3.89 (2H, s) and 3.75 (3H, s), ppm.

Grade B

Preparation of 1- (triphenylmethyl) -1H-imidazol-4-yl-acetic acid methyl ester

To a solution prepared by dissolving 24.85 g (0.141 mmol) of the product obtained under Step A, above, in 115.0 mL of dimethylformamide was added 57.20 mL (0.412 mmol) of triethylamine and 55.30 g (0.171 mmol). mmol) triphenylmethyl bromide and the resulting suspension was stirred for 24 hours.

After completion of the above operation, the reaction mixture was diluted with 1.0 L of ethyl acetate and 350.0 mL of water. After separation of the organic and aqueous phases, the organic layer was washed with 350.0 ml of a saturated aqueous solution of sodium bicarbonate, then dried over sodium sulfate and then evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with 0 to 100% ethyl acetate in hexane, for gradient elution.

The title compound was obtained as a white solid.

- 138 ¹ H-NMR (CDCl ₃ , 400 MHz):

δ 7.35 (1H, s), 7.31 (9H, m), 7.22 (6H, m), 6.76 (1H, s),

3.68 (3H, s) and 3.60 (2H, s) ppm.

Grade C

Preparation of [1- (4-cyanobenzyl) -1H-imidazolyl] acetic acid methyl ester

To a solution prepared by dissolving 8.00 g (20.90 mmol) of the product obtained in Step B above, in 70.0 mL of acetonitrile, was added 4.10 g (20.92 mmol) of bromo-p-. toluene nitrile and the resulting reaction mixture was heated at 55 ° C for 3 hours.

After completion of the above operation, the reaction mixture was cooled to room temperature and the resulting imidazole salt (white precipitate) was isolated by filtration. The resulting filtrate was heated at 55 ° C for 18 hours. The reaction mixture was then cooled to room temperature and evaporated in vacuo. To the residue was added 70.0 mL of ethyl acetate, and the resulting white precipitate was collected by filtration. The resulting imidazole salt was combined, suspended in 100.0 mL of methanol, and heated to reflux for 30 minutes.

At the end of this operation, the solvent was removed from the mixture in vacuo and the resulting residue was suspended in 75.0 ml of ethyl acetate and the solid was collected by filtration and washed with ethyl acetate. The solid was treated with 300.0 mL of saturated aqueous sodium bicarbonate and 300.0 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours.

After separation, the organic layer was dried with magnesium sulfate and evaporated in vacuo. The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz):

δ 7.65 (1H, d, J = 8.0 Hz), 7.53 (1H, s), 7.15 (1H, d, J% 8.0 Hz), 7.04 (1H, s) 5.24 (2H, s), 3.62 (3H, s) and 3.45 (2H, s) ppm.

139

Grade D

I

Preparation of [1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetic acid

Mixture prepared by mixing 4.44 g (17.4 mmol) of [1- (4-cyanobenzyl) -1H-imidazol-5-yl] -acetic acid methyl ester obtained in the previous step C above in 100.0 ml of tetrahydrofuran and 17.40 ml (17.40 mmol) of lithium hydroxide were stirred at room temperature for 18 hours. Then, 1N hydrochloric acid solution was added to the reaction mixture, and tetrahydrofuran was removed from the reaction mixture in vacuo.

The aqueous solution was lyophilized to give the title compound containing lithium chloride as a white solid.

¹ H-NMR (CD ₃ OD, 400 MHz):

δ 8.22 (1H, s), 7.74 (1H, d, J = 8.40 Hz), 7.36 (1H, d, J = 8.40 Hz), 7.15 (1H, s) 5.43 (2H, s) and 3.49 (2H, s) ppm.

Grade E

Preparation of 1 - {[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl} 2 (S) -n-butyl-4- (1-naphthoyl) piperazine trifluoroacetate

To the mixture prepared by mixing 100.0 mg (0.35 mmol) of the acid obtained in the preceding step D, 117.0 mg (0.35 mmol) of the amine hydrochloride salt obtained in Example (?), Step (?), 58.0 mg (0.35 mmol) of 1-hydroxy-1,2,3-benzotriazin-4 (3) -one (HOOBT) and 0.123 mL (0.88 mmol) of triethylamine in 2.0 ml of dimethylformamide, 75.0 mg (0.38 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl was added.

The resulting reaction mixture was stirred at room temperature for 16 hours and, after dilution with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate, evaporated in vacuo.

The residue was purified by preparative, high performance

140 by liquid chromatography (C-18, 95: 0.5 to 5:95 water: methyl cyanide containing 0.1% trifluoroacetic acid, gradient elution).

After lyophilization of the combined fractions, the title compound was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz):

δ 9.00 - 8.90 (1H, m), 8.05 - 7.94 (2H, m), 7.94 - 7.40 (10H, m), 5.60 - 5.40 (2H, m), 5.00-2.80 (9H, m), 1.90 1.15 (4H, m) and 1.05-0.40 (5H, m), ppm.

Anal compound of the formula ^C 32 ^H 33 ^N 5 · ¹ ° 2 ^'40 TFA.0,55 H ₂ 0:

calculated: C 60.65, H 5.19, N 10.16% found: C 60.66, H 5.17, N 10.06%.

Example 39

Preparation of 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- (4-imidazolylmethyl) piperazin-2-one, ditrifluoroacetic acid salt

Grade A

Preparation of N-methoxy-N-methyl-2 (S) - (tert-butoxycarbonylamino) hexanamide

Mixture prepared by mixing 24.60 g (0.106 mol) of 2 (S) - (t-butoxycarbonylamino) hexanoic acid, 15.50 g (0.15 mol) of N, O-dimethylhydroxylamine hydrochloride, 22.30 g (0.117 mol) 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) and 14.30 g (0.106 mol) of 1-hydroxybenzotriazole hydrate (HOBT) were stirred in 300.0 ml of dried, of degassed dimethylformamide under a nitrogen atmosphere at 20 ° C.

To this reaction mixture was added N-methylmorpholine and the pH of the mixture was adjusted to pH 7.0. After stirring overnight, dimethylformamide was distilled off under high vacuum and the residue was partitioned between ethyl acetate and 2% potassium bisulfate solution. After separation of the organic and aqueous phases, the organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water and saturated brine solution, and was then dried with magnesium sulfate.

Removal of the solvent in vacuo gave the title compound.

Grade B

Preparation 2 (S) -tert-butoxycarbonylamino) hexanal

To a mechanically stirred suspension of lithium tetrahydroaluminate (5.0 g, 0.131 mol) in ether (250.0 ml) and cooled to -45 ° C under nitrogen, was added a solution prepared by dissolving 28.30 g (0.103 mol) of the product of Step A above, in 125.0 ml of ether while maintaining the temperature of the reaction mixture below -35 ° C.

Upon completion of the above operation, the reaction mixture was allowed to warm to 5 ° C and then recooled to -45 ° C. A solution prepared by dissolving 27.3 g (0.200 mol) of potassium hydrogen sulphate in water was then added slowly while maintaining the reaction temperature below -5 ° C. After stirring, the reaction mixture was stirred at room temperature for 1.0 hour and then filtered through silica, the ether was evaporated and the residue was partitioned between ethyl acetate and 2% aqueous potassium hydrogen sulphate solution.

After washing (organic layer) with saturated brine solution, drying over magnesium sulfate and removing the solvent, the title compound was obtained.

Grade C

Preparation of N- (2,3-dimethylphenyl) -2 (S) - (tert-butoxycarbonylamino) hexanamine

To a solution prepared by dissolving 8.32 mL (68.30 mmol) of 2,3-dimethylaniline under nitrogen in dichloromethane, acetic acid was added to adjust the pH to 5.0, and 17.20 g was added to the reaction mixture.

142 (80.80 mmol) of sodium triacetoxyborohydride and 4.0 g of crushed molecular sieve.

1

To the resulting reaction mixture was slowly added dropwise at 20 ° C a solution prepared by dissolving 13.3 g (62.10 mmol) of the product obtained in the previous step B above in 80.0 ml of dichloromethane. The reaction mixture was stirred overnight and then treated with saturated aqueous sodium bicarbonate. After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and then dried with magnesium sulfate.

Crystallization from hexane gave the title compound.

Grade D

Preparation of 4-tert-butoxycarbonyl-5 (S) -n-butyl-1- (2,3-dimethylphenyl) piperazin-2-one

The solution, prepared by dissolving 8.50 g (26.50 mmol) of the product obtained under Step C above, in 250.0 mL of ethyl acetate, was stirred vigorously at 0 ° C with 150.0 mL of saturated aqueous bicarbonate solution. solution. To this reaction mixture was added 2.33 mL (29.10 mmol) of chloroacetyl chloride and the mixture was stirred at 0 ° C for 1 hour.

After separation of the organic and aqueous phases, the ethyl acetate layer was washed with a saturated brine solution and dried with magnesium sulfate.

The crude product was dissolved in 300.0 mL of dimethylformamide and cooled to 0 ° C under nitrogen. To the reaction mixture was added 1.79 g of sodium hydride (60% dispersion in oil, 44.90 mmol). ) in portions to maintain a still slight evolution of hydrogen. After 30 minutes, an additional 0.80 g of sodium hydride was added and the reaction mixture was stirred for an additional 30 minutes and then quenched with saturated aqueous ammonium chloride solution.

143

Dimethylformamide was then distilled off in vacuo and the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed with water and then with a saturated brine solution and dried over magnesium sulfate.

The crude product was chromatographed on silica gel using 20-30% ethyl acetate in hexane as eluent. The title compound was obtained.

Grade E

Preparation 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- [4- (1-triphenylmethylimidazolyl) methyl] piperazin-2-one

The solution, prepared by dissolving 0.570 g (1.58 mmol) of the product obtained under Step D above, in 50.0 mL of ethyl acetate, was cooled to -15 ° C under nitrogen, and then bubbled for 15 minutes. with hydrogen chloride gas.

The reaction mixture was allowed to warm to 0 ° C over 2 hours and, after removal of the solvent in vacuo, the resulting solid was dissolved in 20.0 mL of dichloroethane. To the resulting solution was then added 0.502 g (2.37 mmol) of sodium triacethoxytetraborohydride and 0.534 g (1.58 mmol) of 1-triphenylmethyl-4-imidazolyl carboxaldehyde.

The reaction mixture was stirred at 20 ° C overnight and then poured into saturated aqueous sodium bicarbonate. After separation, the organic phase was washed with a saturated aqueous brine solution and then dried over magnesium sulfate.

Chromatography on silica gel, eluting with 4% methanol in dichloromethane afforded the title compound.

Grade F

Preparation of 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- (4-imidazolylmethyl) piperazin-2-one, ditrifluoroacetic acid salt

To a solution prepared by dissolving 0.233 g (0.40 mmol) of the product obtained in Step E above, in 6.0 mL of dichloromethane was added 0.254 mL of triethylsilane and 2.0 mL of trifluoroacetic acid.

After the reaction mixture was stirred at 20 ° C for 2 hours, the volatiles were removed in vacuo and the residue was partitioned between hexane and a mixture of water and methanol. The aqueous phase was injected onto a preparative HPLC column and purified with a mixed gradient of 15% to 60% acetonitrile / 0.1% trifluoroacetic acid, 85% to 40% 0.1% aqueous trifluoroacetic acid over 50 minutes.

After lyophilization, the title compound was obtained. j

FAB-MS (m + 1) = 341.0.

¹ μ

Anal compound of formula ^ 20 ^ 28 ^ ² 4θ · "θ TFA (trifluoroacetic acid): C 50.80, H 5.15, N 9.87% Found: C 51.31, H 5.41, N 10.11%.

Example 40

Preparation of 5 (S) -n-butyl-4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) piperazine, ditrifluoroacetic acid salt

To a solution prepared by dissolving 0.120 g (0.21 mmol) of 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -5- [4- (1-triphenylmethylimidazolyl) methyl] piperazine-2- One of the above obtained step E, from Example 39 above, in 10.0 ml of acetonitrile was added 1,4-cyanobenzyl bromide (0.043 g, 0.22 mmol) at 20 ° C. After 48 hours, the crude solvent was removed from the reaction mixture in vacuo and the crude product obtained was dissolved in 6.0 mL of dichloromethane. To the resulting solution was added 0.13 mL of triethylsilane and 2.0 mL of trifluoroacetic acid, and the reaction mixture was stirred at 20 ° C for 2 hours.

After removal of the volatiles from the mixture under vacuum, the residue was partitioned between hexane and a mixture of water and methanol. The aqueous phase was injected onto a preparative high performance liquid chromatography (reverse phase) column and purified with a mixed gradient of 30% to 60% acetonitrile / 0.1% trifluoroacetic acid, 70% to 40% 0.1% aqueous trifluoroacetic acid over 50 minutes .

The title compound was isolated after freeze drying from water-acetonitrile.

FAB-MS (m + 1) = 456.0.

Analytical evaluation of the compound according to formula C28H33N5O.0.75 H2O.2.0 TFA (trifluoroacetic acid) calculated:

found:

C 55.28, C 55.27,

H 5.13, N 10.07% H 5.20, N 10.41%.

Example 41

Preparation of 4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) -5 (S) - (2-methoxyethyl) piperazin-2-one, ditrifluoroacetic acid salt

Grade A

Preparation of N-methoxy-N-methyl-4-benzyloxy-3 (S) - (t-butoxycarbonylamino) butanamide

An analogous procedure to that described in Example 39, Step A above, using 0.680 g (3.55 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), followed by 0.436 g (3.23) mmol) of 1-hydroxybenzotriazole hydrate (HOBT) and 0.473 g (4.85 mmol) of N, O-dimethylhydroxylamine hydrochloride in 50.0 ml of dimethylformamide and at pH 7.0, converted 1.0 g (3.23 mmol) 4-Benzyloxy-2 (S) - (tert-butoxycarbonylamino) butanoic acid, the title compound.

After further work-up, the title compound was obtained as a clear gum.

146

Grade B

Preparation of 4- (1-benzyloxyethyl) -2 (S) - (tert-butoxycarbonylamino) -butanal

In analogy to the procedure described in Example 39, Step B, the title compound was obtained by reduction of the product prepared under Step A above with lithium aluminum hydride.

Grade C

Preparation of N- (2,3-dimethylphenyl) -4- (2-benzyloxyethyl) -2 (S) (tert-butoxycarbonylamino) butanamide

In an analogous manner to that described in Example 39, Step B, it was prepared using 0.505 ml (4.14 mmol) of 2,3-dimethylaniline, 1.20 g (5.65 mmol) of sodium triacethoxytetraborohydride and 1.0 g of crushed molecular weight. The residue was purified by chromatography on silica gel, eluting with 15% ethyl acetate in hexane.

Grade D

Preparation 5 (S) - (2-Benzyloxyethyl) -4-tert-butoxycarbonyl-1 (2,3-dimethylphenyl) piperazin-2-one

The title compound was prepared from the product obtained under Step C above as described in Example 39, Step D above using chloroacetyl chloride (0.21 mL, 2.57 mmol) in 60 mL of the mixture. ethyl acetate and saturated aqueous sodium bicarbonate solution (1: 1) followed by reaction of the crude product with 0.373 g of sodium hydride (60% dispersion in oil, 9.32 mmol) in 30.0 mL of dimethylformamide. After further work-up, the crude product was chromatographed on silica gel, eluting with 30% ethyl acetate in hexane. The title compound was obtained.

147

Grade E

Preparation of 4-tert-butoxycarbonyl-1- (2,3-dimethylphenyl) -5 (S) (2-hydroxyethyl) piperazin-2-one

To the product obtained under Step D above, dissolved in 40.0 mL of methanol, was added 0.160 g of 10% palladium on charcoal and the resulting mixture was hydrogenated at 40 psi.

After removal of the catalyst by filtration, the solvent was evaporated and the title compound was obtained.

Grade F

Preparation of 4-tert-butoxycarbonyl-1- (2,3-dimethylphenyl) -5 (S) (2-methoxyethyl) piperazin-2-one

The solution, prepared by mixing 0.241 g (0.688 mmol) of the product obtained in Step E above, with 10.0 mL of dimethylformamide containing 0.21 mL (3.44 mmol) of methyl iodide, was stirred under nitrogen at 0. C. The reaction mixture was then added

0.070 g of sodium hydride (dispersion in oil, 1.72 mmol) was stirred for 1 hour.

The reaction mixture was then treated with water and the DMF was removed in vacuo. The residue was partitioned between ethyl acetate and water and after separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and dried with magnesium sulfate.

The crude product was chromatographed on silica gel using 40% ethyl acetate in hexane as eluent. The title compound was obtained.

Grade G

Preparation of 1- (2,3-dimethylphenyl) -5 (S) - (2-methoxyethyl) -4- [4- (1-triphenylmethylimidazolyl) methyl] piperazin-2-one

148

The product obtained in the previous step F described above, i. 0.113 g (0.312 mmol) was converted to the title compound in an analogous manner to that described in Example 39, step E above, except that 30% trifluoroacetic acid in 10.0 mL was used for the initial deprotection. dichloromethane.

The volatiles were then removed in vacuo and the residue was dissolved in dichloromethane. Triethylamine was added to the resulting solution to pH 5.0, followed by the addition of 0.100 g of sodium triacethoxytetraborohydride (0.468 mmol) and 0.1164 g (0.343 mmol) of 1-triphenylmethyl-4-imidazolylcarboxaldehyde. The reaction mixture was stirred at 20 ° C overnight and then poured into saturated aqueous sodium bicarbonate.

The organic phase was washed with saturated brine solution and then dried with magnesium sulfate.

Chromatography on silica gel, eluting with 5% methanol in chloroform gave the title compound.

Grade H

Preparation of 4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) -5 (S) - (2-methoxyethyl) piperazin-2-one, ditrifluoroacetic acid salt

In the previous step G, the product obtained (0.182 g, 0.312 mmol) was converted to the title compound in an analogous manner to that described in Example 40 above using 0.061 g (0.312 mmol) of 4-cyanobenzyl bromide in 10.0 mL. acetonitrile followed by reaction of the crude imidazole salt with 0.13 ml of triethylsilane and 2.0 ml of trifluoroacetic acid in 6.0 ml of dichloromethane.

Purification was performed by reverse phase preparative high performance liquid chromatography using a mixed gradient of 0% to 70% acetonitrile / 0.1% trifluoroacetic acid, 100% to 30% 0.1% aqueous acid.

149 trifluoroacetic acid for 60 minutes.

The title compound was isolated after lyophilization from water.

FAB-MS (m + 1) = 458.0.

Anal compounds of formula ^ 27 ^ 31 ^ 5θ2 · θ _'2 ³⁶ Η Ο.2,0 TFA (trifluoroacetic acid): C 53.81, H 4.91, N 10.21% Found: C 53, H, 4.95; N, 10.29%.

Example 42

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (methanesulfonyl) ethyl] -2-piperazinone dihydrochloride

To a solution prepared by dissolving 35.0 g (260.0 mmol) of 4- (hydroxymethyl) imidazole hydrochloride in 250.0 mL of dried dimethylformamide was added at room temperature 90.60 mL (650.0 mmol) of triethylamine. To a solid white solid precipitated from solution was added dropwise 76.10 g (273.0 mmol) of chlorotriphenylmethane in 500.0 mL of dimethylformamide.

The reaction mixture was stirred for 20 hours and then poured onto ice, filtered and washed with ice-cold water. The resulting product was slurried with cooled dioxane, then filtered and dried under vacuum.

The title compound was obtained in the form of a white solid which was pure enough to be used in the next step B.

Grade B

Preparation of 1-triphenylmethyl-4- (acetoxymethyl) imidazole

The alcohol (260.0 mmol) prepared above in Step A above was suspended in 500.0 ml of pyridine. To the resulting suspension was added dropwise 78.0 mL (780 mmol) of acetic anhydride and the reaction mixture thus prepared

150 was stirred for 48.0 hours. During this operation, the mixture was homogenized and was then poured into 2.0 liters

I of ethyl acetate. After washing the mixture three times with 1.0 L of water and 2 x 1.0 L of 5% aqueous hydrochloric acid solution with saturated aqueous sodium bicarbonate solution and brine, the mixture was dried with sodium sulfate and concentrated in vacuo to give crude crude. product.

The acetate was isolated as a white powder which was pure enough to be used in the next reaction.

Grade C

Preparation of 1- (4-cyanobenzyl) -5- (acetoxymethyl) imidazole hydrobromide

A solution prepared by mixing 85.80 g (225.0 mmol) of the product obtained in the previous step B above and 50.10 g (232.0 mmol) of α-bromo-p-toluenenitrile in 500.0 ml of ethyl acetate, was stirred at +60 ° C for 20 hours. A light yellow precipitate formed during this operation. The reaction mixture was then allowed to warm to room temperature and filtered to obtain a solid imidazolium bromide salt. The filtrate was concentrated under vacuum to 200.0 mL and reheated at 60 ° C for 2 hours. It was then cooled again to room temperature and filtered again.

The filtrate was concentrated in vacuo to a volume of 100.0 mL again at 60 ° C for 2 hours, then cooled to room temperature and concentrated in vacuo to give a light yellow solid.

All the solids obtained were combined and dissolved in 500.0 mL of methanol and heated to 60 ° C.

After 2 hours, the solution was concentrated again in vacuo to give a white solid which was mechanically treated and taken up with hexane to remove soluble components.

After removal of the solvent residues under vacuum, it was obtained

151 of the title compound, the desired hydrobromide in the form of a white solid, which can be used in the next stage D without further purification.

Grade D

Preparation of 1- (4-cyanobenzyl) -5- (hydroxymethyl) imidazole

To a solution prepared by dissolving 50.40 g (150.0 mmol) of the acetate obtained in the previous step C above in 1.50 L of tetrahydrofuran: water (3: 1) was added at 0 ° C 18, 90 g (450.0 mmol) of lithium hydroxide monohydrate.

After 1 hour, the reaction mixture was concentrated in vacuo, diluted with 3.0 L of ethyl acetate, and washed sequentially with water and saturated aqueous sodium bicarbonate and brine. The mixture was dried with sodium sulfate, filtered and concentrated in vacuo.

The crude product of the title compound was obtained as a pale yellow friable solid which was sufficiently pure to be used in the next step without further purification.

Grade E

Preparation of 1- (4-cyanobenzyl) -5-imidazolecarboxaldehyde

To a solution prepared from 21.50 g (101 mmol) of the alcohol obtained in Step D above, in 500.0 mL of dimethylsulfoxide, 56.0 mL (402.0 mmol) of triethylamine was added at room temperature, followed by 40 mL 50 g (254.0 mmol) of pyridine-sulfur trioxide complex.

After 45 minutes, the reaction mixture was poured into 2.50 L of ethyl acetate, washed 4 times with 1.0 L of water and brine, and dried over sodium sulfate, filtered and concentrated in vacuo.

The title aldehyde was obtained in the form of a white powder which was pure enough to be used in the next step (step L) without further purification.

152

Grade F of methionine, rochloride,

Preparation of (S) -2- (tert-butoxycarbonylamino) -N-methoxy-N-methyl-4- (methylthio) butanamide

Mixture prepared by mixing 30.0 g (0.120 mol) of LN-BOC14.10 g (0.144 mol) of N, O-dimethylhydroxylamine.hyd27.70 g (0.144 mol) of EDC.HCl (1- (3-dimethylaminopropyl) -3- ethyl carbodiimide hydrochloride) and 19.50 g (0.144 mol) of HOBT (1-hydroxybenzotriazole hydrate) were stirred in 300.0 mL of dimethylformamide at 20 ° C under a nitrogen atmosphere. Then, more (2.30 g, 23.0 mmol) of N, O-dimethylhydroxylamine hydrochloride was added to the reaction mixture until a pH in the range of 7.0 to 8.0 was reached.

The reaction mixture was then stirred overnight and dimethylformamide was distilled to half its original volume under high vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.

After separation of the organic from the aqueous phase, the organic layer was washed with saturated aqueous sodium bicarbonate solution, water, 10% citric acid solution and brine. After drying with sodium sulfate, the solvent was removed in vacuo to give the title compound.

Grade G

Preparation of (S) -2- (tert-butoxycarbonylamino) -4- (methylthio) butanal

The suspension, prepared in 500.0 ml of ether from 5.02 g (0.132 mol) of lithium aluminum hydride was stirred at room temperature for 1 hour. The reaction mixture was then cooled to -50 ° C under a nitrogen atmosphere and a solution prepared by dissolving 39.80 g (about 0.120 mol) of the product obtained under the above-described step F in 30 minutes. ml of ether, maintaining the temperature of the reaction mixture below -40 ° C.

153

After completion of the above operation, the reaction mixture was allowed to warm to 5 ° C and then recooled to -45 ° C.

Analysis by thin layer chromatography showed insufficient reaction.

The mixture was again warmed to 5 ° C, then stirred for 30 minutes and then cooled again to -50 ° C. To the reaction mixture was slowly added a solution prepared by dissolving 72.0 g (0.529 mol) of potassium bisulfate in 200.0 mL of water, maintaining the temperature below -20 ° C.

The mixture was then allowed to warm to 5 ° C, filtered through silica and finally concentrated in vacuo.

The desired aldehyde was obtained.

Grade H

Preparation of (S) -2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 4- (methylthio) butanamine

To the mixture prepared by mixing 10.30 ml (97.40 mmol) of 3-chloroaniline, 23.90 g (97.40 mmol) of the product obtained under the above step G and 27.80 ml (487.0 mmol) Nitric acid 41.30 g (195.0 mmol) of sodium triacethoxytetraborohydride.

The resulting reaction mixture was stirred overnight and then treated with saturated aqueous sodium bicarbonate. The mixture was then diluted with chloroform and the organic phase was washed sequentially with water, 10% citric acid solution and brine, then dried over sodium sulfate and concentrated in vacuo.

The crude product (34.80 g) was obtained, which was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane.

The title compound was obtained.

154

Stage I

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (methylthio) ethyl] piperazin-2-one

The solution, prepared by dissolving 22.0 g (63.80 mmol) of the product obtained from step H above, in 150.0 mL of ethyl acetate, was stirred vigorously at 0 ° C with 150.0 mL of saturated aqueous sodium bicarbonate solution. .

To the resulting reaction mixture was added dropwise 5.60 mL (70.20 mmol) of chloroacetyl chloride, and the reaction mixture was stirred at 0 ° C for 2 hours. After separation of the organic and aqueous phases, the ethyl acetate layer was washed with 10% citric acid solution and saturated brine solution, and then dried with sodium sulfate. After concentration in vacuo, the resulting crude product (27.60 g) was dissolved in 300.0 mL of dimethylformamide and cooled to 0 ° C under argon.

Then, cesium carbonate (63.90 g, 196.0 mmol) was added to the above solution, and the reaction mixture was stirred for 2 days, allowing it to warm to room temperature. An additional portion of cesium carbonate (10.0 g, 30.0 mmol) was then added to the reaction mixture and stirred for 16 hours. After distilling off the dimethylformamide under vacuum, the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and dried over sodium sulfate.

The crude product was chromatographed on silica gel, eluting with 20-25% ethyl acetate in hexane. The title compound was obtained.

Grade J

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (methanesulfonyl) ethyl] piperazin-2-one

To the solution prepared by dissolving 14.20 g (37.0 mmol)

155 of the product obtained in Step I above in 300.0 ml of methanol and cooled to 0 DEG C. was added over 20 minutes a solution prepared by dissolving 54.90 g (111.0 mmol) of magnesium monoperoxyphthalate in 210, 0 ml of methanol. After the cooling bath was removed, the reaction mixture was allowed to warm to room temperature. After 45 minutes, the mixture was concentrated to its original volume and then half-mixed with 2N sodium thiosulfate solution under vacuum. The reaction mixture was then poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. After separation of the organic and aqueous phases, the organic layer was washed with brine, dried with sodium sulfate and concentrated in vacuo.

The crude sulfone obtained was chromatographed on silica gel, eluting with 60 to 100% ethyl acetate in hexane.

The title compound was obtained.

Grade K

Preparation of (S) -1- (3-chlorophenyl) -5- [2- (methanesulfonyl) ethyl] piperazin-2-one

A solution prepared by dissolving 1.39 g (3.33 mmol) of the BOC protected product obtained in Step J above in 30.0 mL of ethyl acetate was bubbled with anhydrous hydrogen chloride gas at 0 ° C. The resulting, saturated solution was stirred for 35 minutes and then concentrated in vacuo. The obtained hydrochloride salt, as a white powder, was suspended in ethyl acetate and mixed with dilute aqueous sodium bicarbonate. After separation, the aqueous phase was extracted with ethyl acetate and the combined organic mixture was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The resulting amine was re-concentrated after treatment with toluene.

The title compound was obtained, suitable for further use in the next step.

156

Grade L

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (methanesulfonyl) ethyl] -2-piperazinone dihydrochloride

To a solution prepared from 898.0 mg (2.83 mmol) of the amine obtained in the previous step K above and 897.0 mg (4.25 mmol) of the imidazole carboxaldehyde obtained in the above step E, at 15, 0 ml of 1,2-dichloroethane, 1.21 g (5.70 mmol) of sodium triacethoxytetraborohydride was added.

The resulting reaction mixture was stirred for 23 hours and then treated at 0 ° C with saturated aqueous sodium bicarbonate solution and then poured into chloroform. The aqueous layer was back-shaken with chloroform, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.

The resulting product was purified by silica gel chromatography eluting with ethyl acetate: methanol: ammonium chloride (95: 5: 0.5 to 90: 10: 0) and the resulting product was taken up in a mixture of ethyl acetate and methanol and then treated with 2: 1. , 1 equivalents of 1M hydrochloric ether solution.

After concentration in vacuo, the title compound was isolated as the desired dihydrochloride as a white powder.

Example 43

Preparation of (S) - (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone dihydrochloride

Grade A

Preparation of (S) -N- (tert-butoxycarbonyl) homoserine lactone

To a solution prepared from 11.0 g (79.9 mmol) of (S) -homosenine lactone hydrochloride and 19.20 g (88.00 mmol) of di-tert-butyl butyl carbonate in 160.0 ml of dichloromethane was at 0 ° C. 13.90 ml of diisopropylethylamine was added over 3 minutes. The resulting reaction mixture was allowed to warm to room temperature and after 3 hours an additional 1.75 g (8.0 mmol) of di-tert-butylpyrocarbonate and 0.70 mL (4.00 mmol) of diisopropylethylamine was added.

The reaction mixture was then stirred for an additional 2.5 hours and then washed with 10% citric acid solution, saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated in vacuo.

The resulting material was purified by silica gel chromatography using 50% ethyl acetate as eluent.

The pure title compound was obtained.

Grade B

Preparation of (S) -N- (tert-butoxycarbonyl) homoserine lactone

To a solution prepared from 7.0 g (35.0 mmol) of the lactone obtained in Step A above, in 175 mL of tetrahydrofuran and cooled to -78 ° C, was added dropwise 72.0 mL (1M). solution in tetrahydrofuran, 72.0 mL) of diisobutylaluminium hydride while maintaining the temperature of the reaction mixture below -72 ° C. After 3 hours, another portion was added to the reaction mixture, i. 10.0 ml (10.0 mmol) of diisobutylaluminum hydride and after another hour an additional 20.0 ml (20.0 mmol) of diisobutylaluminum hydride was added.

After an additional 1 hour, the mixture was mixed at -78 ° C with ethyl acetate followed by a saturated aqueous solution of sodium potassium tartrate * and then allowed to warm to room temperature and poured into ethyl acetate, washed with brine and dried with sodium sulfate. was filtered and concentrated in vacuo.

The resulting material was purified by chromatography on silica gel using 50% ethyl acetate in hexane as eluent. ;

The title compound, the desired lactol, was obtained.

*) sodium-potassium tartrate = sodium-potassium salt of 2,3-dihydroxybutanedioic acid.

I

Grade C

Preparation of (S) -3- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 4-hydroxy-1-butanamine

To the solution prepared by mixing 4.49 g (22.20 mmol) of the lactol obtained in step B above and 2.58 ml (24.4 mmol) of 3-chloroaniline in 50.0 ml of dichloromethane was added at a temperature of room temperature, 1.27 mL (22.20 mmol) of acetic acid was added, and after 10 minutes 6.59 g (31.10 mmol) of sodium triacethoxytetraborohydride was added and the reaction mixture was stirred for 1.5 hours.

The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and diluted with dichloromethane, and then the aqueous and organic phases were separated. The organic material was dried over sodium sulfate, filtered, and concentrated in vacuo.

A solid was obtained which was purified by silica gel chromatography using ethyl acetate: hexane as eluent.

The title amine was obtained.

Step D aniline derivative (5.29 60.0 ml ethyl acetate and sat

Preparation of (S) -N- [2- (tert-butoxycarbonylamino) -4-hydroxybutyl] -2-chloro-N- (3-chlorophenyl) acetamide

In the previous step C (g, 16.90 mmol) obtained above, was mixed with 60.0 mL of saturated aqueous sodium bicarbonate solution and the reaction mixture was cooled to 0 ° C. At the end of this operation, 1.48 ml was added dropwise to the mixture with vigorous stirring

159 (18.50 mmol) of chloroacetyl chloride and after 2 hours, the reaction mixture was diluted with water and ethyl acetate.

After separation of the organic and aqueous phases, the organic layer was washed with brine, dried with sodium sulfate and concentrated in vacuo.

The title was obtained, the desired chloroacetamide, which was used without further purification.

Grade E

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- (2-hydroxyethyl) piperazin-2-one

To a solution prepared by dissolving 6.32 g (16.10 mmol) of the product (chloroacetamide) obtained in the previous step D above in 80.0 ml of dimethylformamide was added 15.80 h (48 ° C) at 0 ° C. , 30 mmol) of cesium carbonate and the resulting reaction mixture was stirred until thin layer chromatography showed that all of the starting material was consumed (about 5 hours).

The reaction mixture was then poured into ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and finally concentrated in vacuo.

The crude product obtained was purified by silica gel chromatography using chloroform: methanol: ammonium hydroxide (99: 1.0: 0 to 95: 5.0: 0.15) as eluent.

The title product contaminated with a minor amount of dimethylformamide was obtained.

Grade F

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (methanesulfonyloxy) ethyl] piperazin-2-one

To a solution prepared by dissolving 3.58 g (10.10 mmol) of the alcohol obtained in Step E above, in 50.0 mL of dichloromethane was added 3.50 mL (20.20 mmol) at 0 ° C. of diisopropylethylamine followed by 0.936 ml (12.10 mmol) of methanesulfonyl chloride.

The resulting reaction mixture was stirred for 45 minutes and then mixed with 10% citric acid solution, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.

The crude product obtained, i. the title compound was used in the next step without further purification.

Grade G

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (ethylthio) ethyl] piperazin-2-one

To a solution prepared by dissolving 3.60 g (8.30 mmol) of the mesylate obtained in Step F above, in 100.0 mL of dimethylformamide was added 1.40 g (16.60 mmol) at 0 ° C. ) of sodium methanethiolate.

The resulting reaction mixture was poured into ethyl acetate after 2 hours, washed with saturated aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate, filtered, and finally concentrated in vacuo.

The title compound was obtained as a crude product in the next step without further purification.

Grade H

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2- (ethanesulfonyl) ethyl] piperazin-2-one

To a solution prepared by dissolving 3.12 g (7.82 mmol) of the product obtained in Step G above, in 50.0 mL of methanol, was added a solution of 11.60 g (23.50 mmol) of magnesium monoperoxyphthalate at room temperature. in 50.0 ml of methanol.

After 45 minutes, the resulting reaction mixture was treated with 2N sodium thiosulfate solution and then poured into ethyl acetate and saturated aqueous bicarbonate solution.

- 161 sodium. After separating the organic layer and the aqueous layer, the organic layer was washed with brine, dried with sodium sulfate, filtered, and finally concentrated in vacuo.

The crude sulfone obtained was chromatographed on silica gel using 2% methanol in chloroform as eluent.

The title compound was obtained.

Stage I

Preparation of (S) -1- (3-chlorophenyl) -5- [2- (ethanesulfonyl) ethyl] piperazin-2-one

A solution prepared by dissolving 1.75 g (4.06 mmol) and the BOC-protected piperazinone obtained in the previous step H above with 20.0 mL of ethyl acetate was bubbled with hydrogen chloride gas at 0 ° C. The hydrogen chloride-saturated solution was stirred for 30 minutes and then concentrated in vacuo to give the title compound as a white powder, which was suspended in ethyl acetate and treated with dilute aqueous sodium bicarbonate.

After separation, the aqueous phase was extracted with ethyl acetate, and the combined organic mixture was washed with brine, dried with sodium sulfate, and, after filtration, concentrated in vacuo.

The resulting amine was dissolved and re-concentrated from toluene to give the title compound, suitable for use in the next step.

Grade J

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone dihydrochloride

To the solution prepared by mixing 480.0 mg (1.45 mmol) of the amine obtained in the foregoing, previously described

162 step I, 460.0 mg (2.20 mmol) of imidazolecarboxaldehyde obtained as described in step E above (Example 42) and 0.415 ml (7.25 mmol) of acetic acid in 10.0 ml 1,2-dichloroethane were 615.0 mg (2.90 mmol) of sodium triacethoxytetraborohydride were added and the resulting mixture was stirred for 18 hours and then treated with saturated aqueous sodium bicarbonate at 0 ° C.

Upon completion of the above operation, the reaction mixture was poured into dichloromethane and the separated organic layer was washed with brine, then dried over sodium sulfate, and filtered, and concentrated in vacuo.

The resulting product was purified by silica gel chromatography eluting with 2-5% methanol in chloroform to give a less polar borate complex which was taken up in a mixture of 1.0 mL of dichloromethane and 5.0 mL of benzene and it was then treated with 1.0 ml of n-propylamine for 18 hours and the reaction mixture was then concentrated in vacuo.

The residue was purified by silica gel chromatography using 2 to 5% methanol in chloroform, then combined with the product from the previous batch and after removal of the ethyl acetate: methanol mixture was reacted with 2.10 equivalents of 1M hydrogen chloride in ether.

Concentration in vacuo afforded the title product as a dihydrochloride and a white powder.

Example 44

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone dihydrochloride

Grade A

Preparation of (S) -2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 3 - [(triphenylmethyl) thio] -1-propanamine

163 To a solution prepared from 0.709 mL (6.70 mmol) of 3-chloroaniline in 30.0 mL of dichloromethane was added at 0 ° C 1.20 g of crushed 4Å molecular sieve. To this mixture was first added 3.55 g (16.70 mmol) of sodium triacethoxytetraborohydride and then dropwise enough N-methylmorpholine to achieve a pH of 6.50.

After completion of the above operation, 3.15 g (7.04 mmol) of L-S-trityl-N-BOVC-cysteinal, prepared in a manner analogous to that described in J. Med. Chem. vol. 37, 725-732 (1994) by S. L. Graham et al. And the reaction mixture was stirred for 48 hours.

The mixture was then mixed with saturated aqueous sodium bicarbonate, diluted with ethyl acetate, and the aqueous and organic phases were separated.

The organic layer was washed with brine, dried with sodium sulfate, and filtered, concentrated in vacuo. The oil obtained was of an oily consistency and was purified by silica gel chromatography eluting with 15% ethyl acetate in hexane.

The title compound (amine) was obtained.

Grade B

Preparation of (S) -N- [2- (tert-butoxycarbonylamino) -3 - ((triphenylmethyl) thio) propyl] -2-chloro-N- (3-chlorophenyl) acetamide

In the previous step A, the obtained aniline derivative (2.77 g, 4.95 mmol) was dissolved in 73.0 mL ethyl acetate and 73.0 mL saturated aqueous sodium bicarbonate and the reaction mixture was cooled to room temperature. 0 'C. With vigorous stirring, 0.533 mL (6.69 mmol) of chloroacetyl chloride was added dropwise and after 3 hours the reaction mixture was diluted with water and ethyl acetate.

After separation, the organic layer was washed with brine, dried with sodium sulfate, and then concentrated in vacuo.

164 The title compound, the desired chloroacetamide in crude form, was obtained and was used without further purification.

Grade C

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5 [(S) - (triphenylmethyl) thiomethyl] piperazin-2-one

To a solution of 3.29 g of the crude form (theoretically 4.85 mmol) of the chloroacetamide obtained in Step B above, in 53.0 mL of dimethylformamide, was added 4.84 g (14.85 mmol) at 0 ° C. ) cesium carbonate.

The resulting reaction mixture was poured into ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered, and concentrated in vacuo.

The crude product was obtained as an oily substance which was purified by chromatography on silica gel using 20% ethyl acetate / hexane as eluent.

The title product was obtained as a white solid.

Grade D

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5 (thiomethyl) piperazin-2-one

The mixture, prepared by mixing 625.0 mg (1.04 mmol) of piperazinone obtained in the above step C, in 38.0 ml of degassed ethyl acetate and 12.0 ml of ethanol, was heated to 30 ° C. To this reaction mixture was added a mixture prepared from 177.0 mg of silver nitrate (1.04 mmol) and 0.084 mL (1.04 mmol) of pyridine, in 8.0 mL of ethanol, and the resulting reaction mixture was heated to reflux. condenser for 45 minutes. The mixture was concentrated in vacuo and redissolved in 26.0 mL of degassed ethyl acetate. The resulting solution was bubbled with hydrogen sulfide gas for 2 minutes, and after 4 minutes activated carbon was added to the mixture. This material was then filtered through silica, rinsed with degassed ethyl acetate and concentrated in vacuo. After further dissolution and subsequent concentration from degassed dichloromethane, the title product was obtained, which was used without further purification.

Grade E

Preparation of (S) -4- (tert-butyloxycarbonyl) -1- (3-chlorophenyl) -5 [(ethylthio) methyl] piperazin-2-one

A solution of the thiol (ca. 1.04 mmol) obtained in Step D above, in 3.0 mL of tetrahydrofuran, was added via a lance to a suspension (at 0 ° C) prepared by mixing 51.40 mg of sodium hydride. (60% dispersion in mineral oil, 1.28 mmol) in 2.0 mL tetrahydrofuran.

After 10 minutes, 0.079 mL (0.988 mmol) of ethyl iodide was added to the reaction mixture, which was then stirred for 1.5 hours. The mixture was then poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, then dried with sodium sulfate, and, after filtration, concentrated in vacuo.

The crude product obtained was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent. The desired title product was obtained.

Grade F

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5 [(ethanesulfonyl) methyl] piperazin-2-one

To a solution of 217.0 mg (0.563 mmol) of the sulfide obtained in Step E above, in 3.0 mL of methanol, was. added at 0 ° C a solution prepared from 835.0 mg (1.69 mmol) of magnesium monoperoxyphthalate in 2.0 mL of methanol.

166 The resulting reaction mixture was stirred overnight, allowing the temperature to rise to room temperature spontaneously. The mixture was cooled to 0 ° C and treated with 4.0 mL of 2N sodium thiosulfate solution and then concentrated in vacuo. The residual residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and after separation of the aqueous and organic phases, the organic layer was washed with brine, then dried with sodium sulfate and filtered under vacuum to concentrate.

The desired crude sulfone was obtained as a white waxy solid.

Grade G

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone dihydrochloride

To a solution prepared by mixing 224.0 mg (0.538 mmol) of the BOC-protected piperazinone obtained in step F above, in 5.0 mL of dichloromethane at 0 ° C was added 2.50 mL of trifluoroacetic acid.

After 45 minutes, the resulting reaction mixture was concentrated in vacuo and then azeotroped with benzene to remove excess trifluoroacetic acid. The residue was taken up in 4.0 mL of 1,2-dichloroethane and cooled to 0 ° C. To this reaction mixture was added 340.0 mg of 4Å molecular sieve in powder form, followed by 285.0 mg (1.34 mmol) of sodium triacethoxytetraborohydride and a few drops of triethylamine to reach a pH of 6.0.

Then, 125.0 mg (0.592 mmol) of the imidazolecarboxaldehyde obtained in Step E (Example 42) described above was added to the reaction mixture, and the reaction mixture was stirred at 0 ° C. After 2 days, the reaction mixture was poured into ethyl acetate, washed with dilute aqueous sodium hydrogencarbonate solution and brine, and then dried

The reaction mixture was concentrated in vacuo.

The crude product was taken up in methanol and injected onto a preparative HPLC column and purified using a mixed gradient of 15% to 50% acetonitrile / 0.1% trifluoroacetic acid, 85% to 50% 0.1% aqueous acid. trifluoroacetic acid, for 60 minutes.

After concentration in vacuo, the resulting product was partitioned between dichloromethane and aqueous sodium bicarbonate. After separation of the organic and aqueous phases, the aqueous layer was shaken with dichloromethane. The organic solution was then washed with brine, dried over sodium sulfate and concentrated to dryness under vacuum.

The obtained free base product was taken up in dichloromethane and then treated with 2.10 equivalents of a 1M solution of hydrogen chloride in ether. After concentration in vacuo, the title dihydrochloride was isolated as a white powder.

Example 45

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [N-ethyl-2-acetamido] -2-piperazinone dihydrochloride

Grade A

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (oxo) ethyl] piperazin-2-one

To a solution prepared from oxalyl chloride (0.608 mL, 6.97 mmol) in dichloromethane (40.0 mL) was added dimethyl sulfoxide (0.990 mL, 13.90 mmol) at -78 ° C over 2 to 3 minutes. The reaction mixture was stirred for 10 minutes and then a solution prepared by dissolving 2.06 g (5.81 mmol) of the alcohol obtained in Step E (Example 43) above in 10 minutes. 0 mL of dichloromethane while maintaining the temperature of the reaction mixture

- 168 at values below -70 ° C.

After the reaction mixture was stirred for 10 minutes, triethylamine (2.43 mL) was added and the reaction mixture was allowed to warm to room temperature after stirring for 5 minutes at -78 ° C. After 45 minutes, the reaction mixture was poured into dichloromethane and washed successively with saturated aqueous ammonium chloride solution, 10% citric acid solution, water and brine. The mixture was dried with sodium sulfate, filtered and concentrated in vacuo.

The title aldehyde was obtained.

Grade B

Preparation of (S) -4- (tert-butyloxycarbonyl) -5- (carboxymethyl-1- (3-chlorophenyl) piperazin-2-one)

To a solution prepared from 1.52 g (4.31 mmol) of the aldehyde obtained in Step A above, in a mixture of 50.0 ml of 2-methyl-2-propanol and 10.0 ml of 2-methyl-2-butene A solution prepared by dissolving 585.5 mg (5.17 mmol) of sodium chlorite and 595.0 mg (4.31 mmol) of sodium dihydrogen phosphate in 10.0 ml of water was added at room temperature.

The resulting reaction mixture turned yellow and then slowly turned to a light pink color over 45 minutes. The mixture was then poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate.

The aqueous layer was acidified to pH 3.0 with 2.75 M potassium bisulfate solution and then shaken several times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo.

The title carboxylic acid was obtained.

Grade C

Preparation of (S) -4- (tert-butoxycarbonyl) -5- [N-ethyl-2-acetamido] 1- (3-chlorophenyl) -piperazin-2-one.

169 A mixture prepared by mixing 200.0 mg (0.56 mmol) of the product obtained under Step B, above, 114.0 mg (1.40 mmol) of ethylamine hydrochloride, 140.0 mg (0.73). mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) and 113.0 mg (0.84 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) were stirred in 3.0 mL of dried dimethylformamide in nitrogen atmosphere at 0 ° C.

After 1 hour, the reaction mixture was allowed to warm to room temperature and stirred overnight. After removal of the dimethylformamide under vacuum, the residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed successively with 10% citric acid solution, saturated aqueous sodium bicarbonate solution, water and brine, and then dried with sodium sulfate. Removal of the solvent in vacuo gave the title compound.

Grade D

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [N-ethyl-2-acetamido] -2-piperazinone dihydrochloride

The title compound was prepared from 184.0 mg (0.47 mmol) of the product obtained under previous step C above in analogy to the procedures described above for example 42, steps K and L.

The title compound was isolated as a white solid.

Example 46

Preparation of (±) -5- (2-butynyl) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone dihydrochloride

Grade A

Preparation of 1- (methanesulfonyl) -2-butyne

170

To the solution prepared by mixing 10.0 ml (134.0 mmol)

Of 2-butinol in 200.0 ml of dichloromethane, 23.40 g (134.0 mmol) of methanesulfonyl chloride was added at 0 ° C, followed by dropwise addition of 30.0 ml (174.0 mmol) of diisopropylethylamine.

After 1.5 hours, the reaction mixture was poured into 0.5N potassium hydrogen sulphate solution, and the organic layer was washed with brine, dried over sodium sulfate and filtered, and concentrated in vacuo.

The title compound was obtained.

Grade B

Preparation of (±) -ethyl 2 - [(phenylmethyl) imino] -4-hexynoate

To a solution prepared by mixing 10.11 g (72.40 mmol) of glycine hydrochloride ethyl ester in 200.0 mL of dichloromethane was added 7.36 mL (72.40 mmol) of benzaldehyde, 20.0 mL (143.0 mmol). triethylamine and 6.0 g magnesium sulfate.

The resulting reaction mixture was stirred at room temperature for 16 hours and then filtered through a glass frit and concentrated in vacuo. The residue was partitioned between ether and water, and after separation of the organic and aqueous phases, the organic layer was washed with brine, dried over sodium sulfate and concentrated by evaporation in vacuo.

A pale yellow oil of oily consistency was obtained from which a portion (9.90 g, 51.80 mmol) was dissolved in 200.0 mL of tetrahydrofuran and the resulting solution was cooled to -78 ° C under nitrogen. To this solution was added dropwise a solution of potassium tert-butoxide (51.80 mL of IM solution, 51.80 mmol) to give a clear red solution.

After 20 minutes, a solution of the mesylate obtained in the above-described step A (8.05 g, 54.40 mmol) in 20.0 mL of tetrahydrofuran was added dropwise via a lance, and the mixture was allowed to warm to room temperature. to room temperature. After 2 hours, the reaction mixture was poured into ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution171 and brine, then dried over sodium sulfate and filtered, and concentrated in vacuo.

The title compound was obtained.

Grade C

Preparation of (±) -ethyl 2 - [(tert-butoxycarbonyl) amino] -4-hexynoate

The solution prepared from the product obtained in the previous step B above (ca. 51.80 mmol) in 100.0 ml of 5% aqueous hydrochloric acid was stirred at room temperature. After 12 hours, the reaction mixture was concentrated in vacuo to give an orange oil of oily consistency which was taken up in 50.0 ml of tetrahydrofuran and to this solution was first added 50.0 ml of saturated aqueous sodium hydrogen carbonate solution and then 11.30 g. (51.80 mmol) of di-tert-butylpyrocarbonate at room temperature. After 6 hours, the reaction mixture was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo.

The title compound was obtained.

Grade D

Preparation of (±) -2- [tert-butoxycarbonyl) amino] -4-hexynoic acid

To a solution prepared by mixing the product obtained in the previous step C above (ca. 51.80 mmol) in 100.0 mL of tetrahydrofuran and 20.0 mL of water, was added a solution of 6.50 g (0 ° C) at 0 ° C. 155.0 mmol) of lithium hydroxide monohydrate. The resulting reaction mixture was stirred at 0 ° C for 1 hour and after 48 hours the mixture was concentrated in vacuo.

The aqueous mixture was extracted with ethyl acetate, acidified at 0 ° C with a 10% aqueous hydrochloric acid solution and then extracted three times with dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate

172 and after filtration were concentrated in vacuo.

The title compound was obtained in i

in the form of an orange substance, of oil consistency.

¹ i

Stage E '

Preparation of (±) -2- (tert-butoxycarbonylamino) -N-methoxy-N-methyl-4-hexynamide

A mixture prepared by mixing 10.58 g (46.60 mmol) of the product obtained in the preceding step D, 9.09 g (93.20 mmol) of N, O-dimethylhydroxylamine hydrochloride, 9.44 g (69). , 90 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) and 13.0 ml (93.20 mmol) of triethylamine were stirred under nitrogen atmosphere and at 0 ° C in 150.0 ml of dried dimethylformamide.

To this reaction mixture was added 11.50 g (60.60 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbonylimide hydrochloride (EDC.HCl) and the reaction mixture was stirred for 3 hours. The mixture was partitioned between ethyl acetate: hexane (2: 1) and water, then washed successively with water, 10% aqueous (10%) hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. It was then dried over sodium sulfate and the solvent was removed in vacuo.

The title compound was obtained as an orange oil of oily consistency.

Grade F

Preparation of (±) -2- (tert-butoxycarbonylamino) -4-hexynal

The suspension, prepared from 1.56 g (41.10 mmol) of lithium aluminum hydride in 150 ml of ether, was stirred at room temperature for 30 minutes and, after cooling to -55 ° C under an argon atmosphere, was added to the above suspension during The product obtained in Step E above (11.10 g, 41.10 mmol) in 150.0 mL of ether was maintained for 15 minutes while maintaining the reaction temperature at -50 ° C.

After completion of the above operation, the reaction mixture was allowed to warm to 5 ° C and then recooled to -40 ° C and slowly added a solution prepared by dissolving 21.80 g of potassium hydrogen sulphate in 25.0 ml of water at a temperature of of the reaction mixture was kept below -35 ° C. The reaction mixture was then allowed to warm to room temperature, stirred for 1 hour, filtered through silica and finally concentrated in vacuo. The title compound was obtained.

Grade G

Preparation of (±) -2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 4-butinamine

To the solution prepared by mixing 4.33 mL (40.90 mmol)

3-chloroaniline, the product obtained under the preceding step (F) above (about 41.0 mmol) and crushing the 4Å molecular sieve (10.0 g) in 100.0 mL of dichloroethane and cooled to 0 ° C under nitrogen, 12.90 g (61.5 mmol) of sodium triacethoxytetraborohydride was added.

The resulting reaction mixture was stirred for 1 hour and then allowed to warm to room temperature. After 3 hours the mixture was poured into ethyl acetate and washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The mixture was dried with sodium sulfate and concentrated in vacuo.

The title compound was obtained as a crude product.

Grade H

Preparation of (±) -N- [2- (tert-butoxycarbonylamino) -4-hexinyl] -2-chloro-N- (3-chlorophenyl) acetamide

To a solution prepared by dissolving 1.68 g (5.22 mmol) of the product obtained in the preceding step (G) above and 1.20 ml (8.61 mmol) of triethylamine in 15.0 ml of dichloromethane and cooled to 0 ° C. At 0 ° C, chloroacetyl chloride (0.457 mL, 5.74 mmol) was added dropwise and the resulting mixture was stirred at 0 ° C. After 30 minutes, an additional portion (0.20 mL) of chloroacetyl chloride and 0.50 mL of triethylamine was added dropwise to the mixture.

After 30 minutes, the reaction mixture was poured into ethyl acetate and washed with 10% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo.

The product as a brown oil was purified by silica gel chromatography eluting with 20-35% ethyl acetate: hexane. The desired product was obtained.

Stage I

Preparation of (±) -4- (tert-butoxycarbonyl) -5- (2-butynyl) -1- (3-chlorophenyl) -2-piperazinone

To a solution prepared from 1.68 g (4.23 mmol) of the product (chloroacetamide) obtained in Step H above, in 15.0 mL of dried dimethylformamide was added at 0 ° C, 3.08 g. (9.48 mmol) cesium carbonate.

The resulting reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature. After 14 hours, the reaction mixture was poured into a mixture of 50% ethanol with hexane, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo.

The crude product obtained was purified by chromatography on silica gel, eluting with 20 to 40% ethyl acetate / hexane. The desired title product was obtained.

175

Grade J

Preparation of (±) -5- (2-butynyl) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone dihydrochloride

To a solution prepared from 1.03 g (2.85 mmol) of the BOC-protected product obtained in the preceding step I above in 7.0 mL of dichloromethane was added at 0 ° C, 4.0 mL trifluoroacetic acid. After 4 hours, the reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was then concentrated in vacuo and azeotroped with benzene to remove excess trifluoroacetic acid.

A portion of the obtained residue (255.0 mg, 0.678 mmol) was dissolved in 6.0 mL of 1,2-dichloroethane and the solution was cooled to 0 ° C and 600.0 mg of 4A powdered molecular sieve and 0 mg (1.02 mmol) of sodium triacethoxytetraborohydride and then 186.0 mg (0.881 mmol) of the imidazole carboxaldehyde obtained in step E above in Example 42. After the reaction mixture was stirred at 0 ° C for 24 hours The mixture was poured into ethyl acetate, washed with dilute aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate and concentrated by filtration in vacuo.

The material was purified by silica gel chromatography using 2.0-5.0% methanol in dichloromethane. The obtained white foam was taken up in dichloromethane and treated with 2.1 equivalents of a 1M solution of hydrogen chloride in ether. Concentration in vacuo afforded the title dihydrochloride as a white powder.

Example 47

Preparation of 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -imidazolylmethyl] -2-piperazinone dihydrochloride

176

Grade A

Preparation of N- (3-chlorophenyl) -ethylenediamine hydrochloride

To the solution prepared by mixing 30.0 ml (284.0 mmol)

Of 3-chloroaniline with 500.0 mL of dichloromethane was added dropwise a mixture of 4 mL of 1 N hydrochloric acid in 1,4-dioxane (80.0 mL, 320 mmol HCl) dropwise at 0 ° C. The resulting reaction mixture was allowed to warm to room temperature and then concentrated to dryness in vacuo.

A white powder was obtained, which was mixed with 24.60 g (282.0 mmol) of 2-oxazolidinone and the mixture was heated under nitrogen at 160 ° C for 10 hours. During this operation, the solids in the reaction mixture melted, and gas evolution was observed. Upon cooling, the crude diamine hydrochloride salt was obtained as a brown solid.

Grade B

Preparation of N- (tert-butoxycarbonyl) -N '- (3-chlorophenyl) ethylenediamine

The amine hydrochloride (ca. 282 mmol), obtained as a crude material from the above step A, was mixed with 500.0 mL of tetrahydrofuran and 500.0 mL of saturated aqueous sodium bicarbonate of the reaction mixture, cooled to 0 ° C. 61.60 g (282.0 mmol) of di-tert-butylpyrocarbonate. After 30 hours, the reaction mixture was poured into ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered, and concentrated in vacuo.

The title carbamate was obtained in the form of a brown, oily consistency which was used in the next step without further purification.

and added to it

- 177 Grade C

Preparation of N- [2- (tert-butoxycarbamoyl) -ethyl] -N- (3-chlorophenyl) 2-chloroacetamide

The mixture prepared by mixing 77.0 g (ca. 282.0 mmol) of the product obtained under the above step Ba above, 67.0 mL (480.0 mmol) of triethylamine in 500.0 mL of dichloromethane was cooled to 0. C. Chloroacetyl chloride (25.50 mL, 320.0 mmol) was then added dropwise to the resulting reaction mixture, and the reaction mixture was stirred at 0 ° C.

After 3 hours, another portion (3.0 mL) of chloroacetyl chloride (dropwise) was added to the mixture, and after 30 minutes the reaction mixture was poured into 2.0 L of ethyl acetate. It was then washed sequentially with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution and brine. The mixture was dried over sodium sulfate and concentrated in vacuo after filtration.

The desired title chloroacetamide was obtained as a brown oil of oily consistency which was used in the next step without further purification.

Grade D

Preparation of 4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -2-piperazinone

To a solution prepared by dissolving the chloroacetamide (ca. 282.0 mmol) obtained in the previous step C above in 700.0 mL of dried dimethylformamide was added 88.0 g (0.64 mmol) of potassium carbonate and the reaction mixture formed. was heated in an oil bath at 70-75 ° C for 20 hours.

The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove about 500.0 mL of dimethylformamide. The remaining material was poured into a mixture of 33% ethyl acetate and hexane, and this solution was washed successively with water and brine, then dried with sulfate.

Sodium hydroxide and, after filtration, concentrated in vacuo.

The product was obtained as a brown oil, which was purified by chromatography on silica gel, eluting with 25.0-50% ethyl acetate / hexane.

The desired title product was obtained, containing less polar impurities, which, after analysis of the sample by high performance liquid chromatography, corresponded to a purity of about 65%.

Grade E

Preparation of 1- (3-chlorophenyl) -2-piperazinone

A solution prepared by dissolving 17.19 g (55.40 mmol) of the BOC-protected product (piperazinone) obtained in the previous step D above in 500.0 ml of ethyl acetate was bubbled with anhydrous gaseous at -78 ° C. HCI. The resulting saturated solution was allowed to warm to 0 ° C and then stirred for 12 hours.

Nitrogen gas was then bubbled through the reaction mixture to remove excess hydrogen chloride gas, and the mixture was allowed to warm to room temperature and then concentrated in vacuo.

The hydrochloride obtained as a white powder was taken up in dichloromethane and treated further with dilute aqueous sodium bicarbonate solution.

After separation of the aqueous and organic phases, the aqueous layer was shaken with 8x 300.0 mL of dichloromethane until complete extraction was confirmed by thin layer chromatography analysis.

The title, desired free amine was obtained as a light brown oil of oily consistency.

Step F Preparation of 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone dihydrochloride

179

To a solution prepared by dissolving the product of Step E above (55.40 mmol) in 200.0 mL of 1,2-dichloroethane was added 10.0 g of 4Å powdered molecular sieve at 0 ° C and then 17.70 g (83.30 mmol) of sodium triacethoxytetraborohydride.

The resulting reaction mixture was then treated with 11.90 g (56.40 mmol) of imidazolecarboxaldehyde obtained as described in Step E, Example 42, above, and stirred at 0 ° C. After 26 hours, the reaction mixture was poured into ethyl acetate, washed with dilute aqueous sodium bicarbonate, and then the aqueous layer was shaken back with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated by vacuum filtration.

The resulting product was taken up in 500.0 mL of benzene: dichloromethane (5: 1) and 20.0 mL of propylamine was added to the mixture. The reaction mixture was stirred for 12 hours and then concentrated in vacuo to give a light yellow foam. This material was purified by silica gel chromatography eluting with 2-7% methanol in dichloromethane and the resulting white foam was taken up in dichloromethane and then treated with 2.10 equivalents of 1M hydrogen chloride in ether.

Concentration in vacuo afforded the title dihydrochloride as a white powder.

Example 48

Preparation 5 (S) -Butyl-4- [1- (4-cyanobenzyl) -2-methyl-5-imidazolylmethyl] -1- (2,3-dimethylphenyl) -piperazin-2-one dihydrochloride

Grade A

Preparation of 4-bromo-2-methylimidazole-5-carboxaldehyde

Analogous to Synthetic Communications, 22, 2971-2977 (1992) by SP Vatson, 4-bromo-5-hydroxymethyl-2-methylimidazole was prepared (4.18 g, 21.90). mmol) was heated to reflux in 200.0 mL of dichloromethane: dioxane (1: 1) along with 16.10 g of manganese dioxide for 16 hours.

After the above operation was complete and the reaction mixture was cooled, the mixture was filtered through silica and concentrated. The title compound was obtained as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz): δ 9.57 (1H, s), 2.52 (3H, s).

Grade B

Preparation of 4-bromo-1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde

To a solution prepared by dissolving 1.02 g (5.39 mmol)

4-Bromo-2-methylimidazole-5-carboxaldehyde in 15.0 mL of dimethylacetamide, 1.05 g (5.39 mmol) of 4-cyanobenzyl bromide was added, and the resulting reaction mixture, cooled to -10 ° C, was treated with 0.745 g. Potassium carbonate (5.39 mmol) in powder form.

The reaction mixture was stirred at -10 ° C for 2 hours and then for an additional 4 hours at room temperature. The mixture was then diluted with water and shaken with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed successively with water, saturated brine, and then dried with magnesium sulfate, and the solvent was evaporated. The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 9.68 (1H, s), 7.64 (2H, d, J = 7.0 Hz), 7.15 (2H, d, J = 7, 0 Hz), 5.59 (2H, s), 2.40 (3H, s).

Grade C

Preparation of 1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde

181

A solution prepared by mixing 1.33 g (4.37 mmol) of 4-bromo-1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde obtained as described in step B above and 0.600 mg (8.74 mmol). of imidazole in 150 ml of ethyl acetate-ethanol (1: 1) was stirred under 1 atm of hydrogen in the presence of 0.020 g of 10% palladium on charcoal. After 2 hours, the reaction mixture was filtered through silica and then concentrated in vacuo. The title compound was obtained as a white solid.

1 H-NMR (DMSO-d ₆ , 400 MHz):

δ 9.62 (1H, s), 7.90 (1H, s), 7.81 (2H, d, J = 8.00 Hz),

7.20 (2H, d, J = 8.0 Hz), 5.64 (2H, s), 2.33 (3H, s).

T

Grade D

Preparation 5 (S) -Butyl-4- [1- (4-cyanobenzyl) -2-methyl-5-imidazolylmethyl] -1- (2,3-dimethylphenyl) piperazin-2-one dihydrochloride

To the mixture prepared by mixing 0.190 g (0.843 mmol) of 1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde obtained in the previous step C above, followed by 0.250 g (0.843 mmol) of 5 (S) -butyl. 1- (2,3-dimethylphenyl) piperazin-2-one hydrochloride and 0.093 ml (0.843 mmol) of N-methylmorpholine in 10 ml of dichloromethane were analogous to those described in Example 39, step E above, and treated with 0.265 g (1.25 mmol) of sodium triacethoxytetraborohydride. The title compound was purified by preparative high performance liquid chromatography, using a gradient of 70% to 45% solvent A. After isolation, the free base was converted to the dihydrochloride salt to afford the title compound as a white solid.

FAB-MS (m + 1) = 470.0.

Analytical evaluation of the compound according to the formula:

^C 29 ^H 35 ^N 5 ° · ^2HCl · ¹ ' ^45H 2 ° ^: calculated: C 61.25, H 7.07, N 12.32% found: C 61.56, H 6.99, N 11.3244% .

Example 182

Preparation of 4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazinone dihydrochloride

Grade A

Preparation of 4- (tert-butyldimethylsilyloxymethyl) -1-triphenylmethyl-imidazole

To a suspension prepared by mixing 5.80 g (17.05 mmol) of 4-hydroxymethyl-1-triphenylmethylimidazole with 200.0 µl of dimethylformamide containing 3.48 g (51.10 mmol) of imidazole was added 2.83 g (18 mmol) of the title compound. (76 mmol) of tert-butyldimethylsilyl chloride and after 15 minutes a clear, colorless solution was formed which was stirred at room temperature. After the reaction was complete, dimethylformamide was removed in vacuo and the residue was partitioned between ethyl acetate and water.

After separation of the organic and aqueous phases, the organic layer was washed with water and a saturated brine solution and then dried with magnesium sulfate.

The title compound was obtained as a colorless gum.

Grade B

Preparation of 5-tert-Butyldimethylsilyloxymethyl-1- (4-cyanobenzyl) imidazole

A solution prepared by mixing 4.66 g (10.26 mmol) of 4- (tert-butyldimethylsilyloxymethyl) -1-triphenylmethylimidazole obtained in the above step A and 2.10 g (10.26 mmol) of 1-bromomethyl. Of 4-cyanobenzene in 50.0 ml of acetonitrile, was heated at reflux for 4 hours.

The reaction mixture was then cooled and, after removal of the acetonitrile in vacuo, the residue was dissolved in 30.0 ml of methanol. The resulting solution was heated at reflux below

183 was refluxed for 2 hours, then cooled and the methanol was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.

The crude product was chromatographed on silica gel using 3% methanol in chloroform.

The title compound was obtained as a white solid.

Grade C

Preparation of 5-tert-butoxydimethylsilyloxymethyl-1- [2- (4-cyanophenyl) -2-propyl] -imidazole

Solution prepared by dissolving 1.005 g (3.07 mmol)

The 5-tert-butyldimethylsilyloxymethyl-1- (4-cyanobenzyl) imidazole obtained in step B above, in 25.0 ml of tetrahydrofuran and cooled to -78 ° C under nitrogen, was mixed with 4.61 ml. Of a 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran and the resulting reaction mixture was stirred at -78 ° C for 1 hour and then allowed to warm to -60 ° C over 30 minutes.

After the reaction mixture was recooled to -78 ° C, methyl iodide (0.287 mL, 4.61 mmol) was added thereto, and the mixture was further stirred at -78 ° C for 2 hours and then again for 2 hours. Allow to warm to 0 ° C.

After 30 minutes, the reaction mixture was cooled to -78 ° C and then 4.61 mL of a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran was added. After 1 hour, methyl iodide (0.287 mL, 4.61 mmol) was added again and the reaction was allowed to warm to room temperature overnight.

The mixture was stirred with water and then extracted with ethyl acetate. After separation of the organic and aqueous layers, the organic layer was washed with saturated brine solution.

The crude product was chromatographed on silica gel using ethyl acetate / dichloromethane (6: 4) as eluent.

184 ί

The title compound was obtained in the form of a golden-colored, oily consistency.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.78 (1H, s), 7.61 (2H, d, J = 8.00 Hz), 7.15 (2H, d, J = 8, 00 Hz), 7.02 (1H, s), 4.00 (2H, s), 1.99 (6H, s), 0.79 (9H, s), 0.74 (6H, s).

Grade D

Preparation of 1- [2- (4-cyanophenyl) -2-propyl] -5-hydroxymethylimidazole

To a solution prepared by dissolving 0.750 g (2.72 mmol) of 5-tert-butoxydimethylsilyloxymethyl-1- [2- (4-cyanophenyl) -2-propyl] imidazole obtained as described in Step C above, at 10, 0 ml of tetrahydrofuran, 2.99 ml of 1M solution of tetra-N-butylammonium fluoride was added. After 2 hours at room temperature, the resulting reaction mixture was poured into ethyl acetate and then shaken with saturated aqueous sodium bicarbonate.

After separation of the organic and aqueous phases, the organic layer was washed with saturated brine solution and then dried with magnesium sulfate. The crude product was then chromatographed on silica gel using 3% methanol in ethyl acetate. The title compound was obtained as a semi-solid.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.77 (1H, s), 7.62 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8, 00 Hz), 7.02 (1H, s), 4.01 (2H, s), 2.57 (1H, bs), 2.01 (6H, s).

Grade E

Preparation of 1- [2- (4-cyanophenyl) -2-propyl] -imidazole-5-carboxaldehyde

The solution prepared by dissolving 0.450 g (1.78 mmol) of 1- [2- (cyanophenyl) -2-propyl] -5-hydroxymethylimidazole in 20 ml of dioxane was in the presence of 1.62 g (18.70 mol) of manganese dioxide, heated at reflux for 5 hours.

185

The reaction mixture was then cooled and, after filtration through silica, was concentrated. The crude product was purified by silica gel chromatography and the title compound was isolated as a semi-solid.

1 H-NMR (CDCl ₃ , 400 MHz): δ 9.37 (1H, s), 8.11 (1H, s), 7.92 (1H, s), 7.58 (2H, d, J = 8.00 Hz), 7.15 (2H, d, J 8.00 Hz), 2.01 (6H, s).

Grade F

Preparation of 4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one dihydrochloride

The title compound was prepared in an analogous manner to that described in Example 39, step E above, except that 0.297 g (0.84 mmol) of 1- (3-chlorophenyl) -5 (S) - ( 2-methylsulfonylethyl) piperazin-2-one hydrochloride, followed by 0.200 g (0.84 mmol) of 1- [2- (4-cyanophenyl) -2-propyl] imidazole-5-carboxaldehyde, 0.092 ml of N-methylmorpholine (0.84 mmol) ) and 0.267 g (1.26 mmol) of sodium triacethoxytetraborohydride.

The crude product was purified by preparative high performance liquid chromatography, using a gradient of 80-58% solvent A. The pure fractions were combined and converted to the hydrochloride salt.

The title compound was obtained. FAB-MS (m + 1) = 540.0.

Anal compound of Formula ^C 27 ^H 30 ^C1N 5 ^S · 3 ° ^2HC1 · ^3H 2 ^°: C, 48.62, H, 5.74, N, 10.50% Found: C 48.62, H 5.73, N, 9.89%.

Example 50

Preparation 5 (S) -n-butyl-4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2-methylphenyl) piperazin-2-one dihydrochloride

186

Step A Preparation of N- (2-methylphenyl) -2 (S) - (tert-butoxycarbonylamino) hexanamine

The title compound was prepared in an analogous manner to that described in Example 39, Step C above, except that the reaction mixture was a mixture prepared from 0.32 mL (3.0 mmol) of o-toluidine, 0.538 (2, 50 mmol),

2 (S) - (tert-butoxycarbonylamino) hexanal and 0.795 g (3.75 mmol) sodium triacethoxytetraborohydride in 10.0 ml dichloroethane.

The crude product was purified by column chromatography to give the title compound.

Grade B

Preparation of 4-tert-butoxycarbonyl-5 (S) -n-butyl-1- (2-methylphenyl) piperazin-2-one

The title compound was essentially prepared in analogy to the procedure described in Example 39, Step D above, except that the mixture was prepared from 0.506 g (1.65 mmol) of N- (2-methylphenyl) - 2 (S) (tert-butoxycarbonylamino) hexanamine, obtained as described above in Step A above, and 0.158 mL (1.98 mmol) of chloroacetyl chloride in ethyl acetate / saturated aqueous sodium bicarbonate at 0 ° C.

The crude product obtained in the above operation was dissolved in 15.0 ml of dimethylformamide and treated with 1.61 g (4.95 mmol) of cesium carbonate after cooling to 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C for 2 hours.

The reaction mixture was then treated with a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The extracts were dried and evaporated.

The title compound was obtained.

187

Grade C

Preparation 5 (S) -n-butyl-4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2-methylphenyl) piperazin-2-one dihydrochloride

The product obtained in Step B above (0.534 g, 1.50 mmol) was deprotected with 4.0 mL of trifluoroacetic acid in 10.0 mL of dichloromethane.

The title compound was prepared in an analogous manner to that described in Example 39, Step E above except that the reaction mixture was a mixture prepared from 5 (S) -n-butyl- (2-methylphenyl) -piperazine-2. salt of ditrifluoroacetic acid, 1- (4-cyanobenzylimidazole) -5-carboxaldehyde (0.317 g, 1.50 mmol) and 0.477 g (2.25 mmol) of sodium triacethoxytetraborohydride in 15.0 mL of dichloroethane.

The crude product was injected onto a preparative HPLC column and purified using a mixed gradient of acetonitrile / 0.1% trifluoroacetic acid and 0.1% aqueous trifluoroacetic acid.

The pure fractions were combined and converted to the hydrochloride salt. The title compound was obtained as a white solid.

FAB-MS (m + 1) = 442.0.

For ^C 27 ^H 31 ^N 5 ° · ² ' ^5HCl · ² ' ^05H 2 ° ^: calculated: C 56.95, H 6.66, N 12.30% found: C 56.93, H 5, 75, N 11.55%.

Example 51

Preparation of 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5 (S) - (2-fluoroethyl) -1- (3-chlorophenyl) piperazin-2-one dihydrochloride

Grade A

Preparation of 4-tert-butoxycarbonyl-1- (3-chlorophenyl) -5 (S) - (2-fluoroethyl) -piperazin-2-one

188

Mixture prepared by mixing 0.433 g (1.00 mmol) of 4-tert-butoxycarbonyl-1- (3-chlorophenyl) -5 (S) - (2-methylsulfonyloxyethyl) piperazin-2-one and 3, 0 ml of a 1M solution of tert-butylammonium fluoride in tetrahydrofuran, was stirred at room temperature in 5.0 ml of acetonitrile for 72 hours.

The reaction mixture was mixed with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using 20% ethyl acetate in hexane.

The title compound was obtained as a thick, oily consistency.

I

Grade B

Preparation of 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5 (S) - (2-fluoroethyl) -1- (3-chlorophenyl) piperazin-2-one dihydrochloride

In the above step A, the obtained 4-tert-butoxycarbonyl-1- (3-chlorophenyl) -5 (S) - (2-fluoroethyl) piperazin-2-one (0.191 g, 0.54 mmol), deprotected with 4.0 mL of trifluoroacetic acid in 10.0 mL of dichloromethane.

The title compound was prepared in an analogous manner to that described in Example 39, step E, except that the reaction mixture was a mixture prepared from 1- (3-chlorophenyl) -5 (S) - (2-fluoroethyl) - piperazin-2-one, ditrifluoroacetic acid salts, 1- (4-cyanobenzylimidazole) -5-carboxaldehyde (0.114 g, 0.54 mmol) and 0.172 g (2.25 mmol) of sodium triacethoxytetraborohydride in 5.0 mL of dichloromethane.

The crude product was injected onto a preparative HPLC column and was purified using a mixed gradient of acetonitrile / 0.1% trifluoroacetic acid and 0.1% aqueous trifluoroacetic acid.

The pure fractions were combined and converted to the hydrochloride salt. The title compound was obtained as a white solid.

189

FAB-MS (m + 1) = 452.0.

Anal compound of the formula ^C 24 ^H 23 · 5 ° ^C1FN 2HC1.1,70H ₂ 0:

H, 5.15; N, 12.61. Found: C, 52.22; H, 5.10; N, 12.22.

Example 52

Preparation of 4- [3- (4-cyanobenzyl) pyridin-4-yl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one

Grade A

Preparation of 3- (4-cyanobenzyl) -pyridine-4-carboxylic acid methyl ester

A solution prepared by dissolving 625.0 mg (3.27 mmol) of 4-cyanobenzyl bromide in 4.0 mL of dry tetrahydrofuran was added slowly, over 3 minutes under argon at 0 ° C, to a suspension prepared from 250.0 mg. of activated zinc (dust) in 2.0 mL of dried tetrahydrofuran.

The ice-cooled bath was removed and the slurry was stirred at room temperature for an additional 30 minutes. 3-Bromopyridine-4-carboxylic acid methyl ester (540.0 mg, 2.50 mmol) was added to the reaction mixture followed by 50.0 mg of dichloro-bis- (triphenylphosphine) nickel (II). The resulting red-brown reaction mixture was then stirred for 3 hours at 40-45 ° C. It was then cooled and partitioned between 100.0 mL of ethyl acetate and 5% aqueous citric acid (50.0 mL).

After separation of the organic and aqueous phases, the organic layer was washed with 2 x 50.0 ml of water and then dried with sodium sulfate. After evaporation of the solvent, the residue was purified on silica gel, eluting with 35% ethyl acetate in hexane. 420.0 mg of the title compound was obtained as a colorless gum.

FAB-MS (m + 1) = 253.0.

190

Grade B

Preparation of 3- (4-cyanobenzyl) -4- (hydroxymethyl) pyridine

The title compound was obtained using 300.0 mg of sodium borohydride to reduce 415.0 mg of the ester obtained in the above step A in 5.0 ml of methanol at room temperature. After the reaction mixture was stirred for 4 hours, the solvent was evaporated and the product was purified on silica gel eluting with 2% methanol in chloroform. The title compound was obtained. FAB-MS (m + 1) = 225.0.

Grade C

Preparation of 3- (4-cyanobenzyl) -4-pyridinal

The title compound was obtained by oxidizing 240.0 mg (1.07 mmol) of the alcohol obtained under the previous step B above in 10.0 mL of dioxane with 1.0 g of activated manganese dioxide and heating the reaction mixture at reflux under reflux condenser, for 30 minutes.

After filtration and evaporation of the solvent, the title compound is obtained.

Melting point: 80-83 ° C.

Grade D

Preparation of 4- [3- (4-cyanobenzyl) -pyridin-4-yl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one

The title compound was prepared in an essentially analogous manner to that described in Example 39, step E, except that the imidazolylcarboxaldehyde was replaced with an equal amount of the product obtained under the preceding step C, and piperazinone was replaced with an equal amount of 1- (3-Chloro-phenyl) -5 (S) - (2-methylsulfonylethyl) -piperazin-2-one. The title compound was obtained.

191

FAB-MS (m + 1) = 523.0. Analytical evaluation of the compound of formula ^C 27 ^H 27 ^ClN 4 ° 3 ^N · ^{0 '15} CHCl ₃ :

H, 5.06; N, 10.36. Found: C, 60.37; H, 5.03; N, 10.64.

Example 53

Preparation of 4- [4- (4-cyanobenzyl) -1-imidazolylethyl] -1- (3-chlorophenyl) piperazin-2-one

Grade A

Preparation of 1-trityl-4- (4-cyanobenzyl) imidazole

To a suspension prepared from 3.57 g (54.98 mmol) of activated zinc dust in 50.0 mL of dichloromethane was added 0.315 mL (3.60 mmol) of dibromomethane and the resulting reaction mixture was stirred under an argon atmosphere at 20 ° C. . The reaction mixture was cooled to 0 ° C as a slurry, and α-bromo-p-toluenenitrile (9.33 g, 47.60 mmol) in 100.0 mL of tetrahydrofuran was added dropwise over 10 minutes.

Then the reaction mixture was stirred at 20 ° C for 6 hours and bis- (triphenylphosphine) nickel (II) chloride (2.40 g, 3.64 mmol), 15.95 g (36.60 mmol) was added. 5-iodo-tritylimidazole (in one dose = 5-iodo-triphenylmethylimidazole).

The resulting reaction mixture was stirred for 16 hours at 20 ° C and then treated with 100 mL of saturated aqueous ammonium chloride solution and stirred. After addition of saturated aqueous sodium hydroxide solution, the pH of the mixture was adjusted to pH 8.0 and then the mixture was stirred. The mixture was extracted with ethyl acetate (2.times.250.0 ml), dried (MgSO4) and the solvent evaporated in vacuo. The residue was then re-chromatographed (silica, 0-20% ethyl acetate / dichloromethane as eluent).

for 2 hours, of bicarbonate

192 The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.54 (2H, d, J = 7.90 Hz), 7.38 (1H, s), 7.36-7.29 (11H, m), 7, 15-7.09 (6H, m), 6.58 (1H, s) and 3.93 (2H, s), ppm.

Grade B

Preparation of 1-methyl-acetyl-5- (4-cyanobenzyl) imidazole

To a solution prepared by dissolving 3.01 g (6.91 mmol) of 1-phenylmethyl-4- (4-cyanobenzyl) imidazole obtained as described above in Step A in 50.0 ml of acetonitrile was added 0.687 ml (7 ml). (26 mmol) of methyl bromoacetate and the resulting reaction mixture was heated at 55 ° C for 16 hours and then the solvent was evaporated in vacuo.

The solids were mechanically treated and taken up with ethyl acetate, isolated by filtration and dissolved in 60.0 mL of methanol.

The reaction mixture, as a suspension, was heated to reflux for 20 minutes. It was then cooled and evaporated to dryness.

The residue was worked up and taken up in ethyl acetate and the title compound was obtained as a white solid after filtration.

¹ H-NMR (CDCl ₃ ): δ 7.61 (2H, d, J = 7.90 Hz), 7.53 (1H, s), 7.27 (2H, d, J = 7.90 Hz) 6.89 (1H, s), 4.47 (2H, s), 3.98 (2H, s), and 3.66 (3H, s), ppm.

Grade C

Preparation of 1-hydroxyethyl-5- (4-cyanobenzyl) imidazole

The solution, prepared by dissolving 0.113 g (0.472 mmol) of 1-methyl-acetyl-5- (4-cyanobenzyl-imidazole, obtained as described above in Step B) in 2.0 mL of methanol, was allowed to react at 0 ° C. with 80.70 mg (1.10 mmol) of sodium borohydride.

193

After 1 hour, the reaction mixture was mixed with 2.0 mL of saturated aqueous ammonium chloride solution, and after addition of saturated aqueous sodium bicarbonate, the reaction mixture was shaken with 3 x 25.0 mL of ethyl acetate. The organic extracts were then dried with magnesium sulfate and evaporated in vacuo. The title compound was isolated by silica chromatography, eluting with 10% methanol in dichloromethane as a white solid. | ¹ H-NMR (CDCl ₃ ): δ 7.61 (2H, d, J = 7.90 Hz), 7.55 (1H, s), 7.27 (2H, d, J = 7.90 Hz) ), 6.83 (1H, s), 4.05 (2H, s), 3.87 (2H, t, J = 5.10 Hz) and 3.74 (2H, t = 5.10 Hz), ppm.

Grade D

Preparation of 2- (5- (4-cyanobenzyl) imidazolyl) ethyl methanesulfonate

A solution prepared from 0.532 g (2.34 mmol) of 1-hydroxyethyl 5- (4-cyanobenzyl) imidazole obtained in the above step C in 70.0 ml of dichloromethane was allowed to react at 0 ° C with 0.489 ml (2.81 mmol) of Hunings base and 0.219 ml (2.81 mmol) of methanesulfonyl chloride. After 2 hours, the reaction mixture was mixed with 50.0 mL of saturated aqueous sodium bicarbonate, and the mixture was shaken with 50.0 mL of dichloromethane, dried with magnesium sulfate, and then the solvent was removed in vacuo.

The title compound was used without further purification.

¹ H-NMR (CDCl ₃ ): δ 7.62 (2H, d, J = 7.90 Hz), 7.54 (1H, s), 7.29 (2H, d, J = 7.90 Hz) 6.87 (1H, s), 4.25 (2H, t), 4.10-4.00 (4H, m), 3.74 (2H, t, J = 5.10 Hz) and 2, 90 (3H, s) ppm.

Grade E

Preparation of 4- [5- (4-cyanobenzyl) -1-imidazolylethyl] -1- (3-chlorophenyl) piperazin-2-one

194

A solution prepared from 24.0 mg (0.079 mmol) of 2- (5- (4-cyanobenzyl) imidazolyl) ethyl methanesulfonate obtained as described above in Step D in 0.20 ml of dimethylformamide was added to the mixture. , prepared by mixing 17.70 mg (0.084 mmol) of 3- (chlorophenyl) piperazin-2-one, followed by 50.0 mg (0.336 mmol) of sodium iodide and 0.0146 ml of Hunings base, and the resulting reaction mixture was stirred at 55 ° C for 12 hours.

The solvent was evaporated in vacuo and the residue was purified by preparative thin layer chromatography, eluting with 10% saturated ammonia in acetonitrile.

The title compound was obtained. TH-NMR (CDCl ₃ ): δ 7.61 (2H, d, J = 8.40 Hz), 7.56 (1H, s), 7.35-7.20 (7H, m), 7.16 (1H, d, J = 8.00Hz), 6.85 (1H,

s), 4.03 (2H, s), 3.83 (2H, t, J = 6.50 Hz), 3.61 (2H, t,

J = 5.50 Hz), 3.27 (2H, s), 2.68 (2H, t, J = 5.40 Hz) and 2.57 (2H, t, J = 6.50 Hz), ppm .

195

Table 1

FAB ms (m + 2)

formula

Analysis (calculated, found)

526

506

F

ABOUT

CHI

494

C ₃₃ H ₃₉ N ₃ OS2.3 TFA0.9 H ₂ OC, 56.16; H, 5.40; N, 7.22.

C, 56.12; H, 5.37; N, 7.39.

C ₃₀ H ₃₉ N ₃ O ₂ S · 2.55 TFA 0.5 H ₂ OC, 53.19; H, 5.46; N, 5.36.

C, 53.17; H, 5.46; N, 5.60.

C ₂ 9H ₃₆ N ₃ OS-2.25 TFA 0.35 H ₂ O C, 53.19; H, 5.18; N, 5.55.

C, 53.16; H, 5.18; N, 5.68.

F

490

512

C ₃ H ₃₉ N ₃ OS 2 TFA 0.9 H ₂ O C, 55.64; H, 5.88; N, 5.73.

C, 55.57; H, 5.81; N, 5.83.

C ₂₉ H ₃₅ F ₂ N ₃ OS ^- 2.4 TFA 0.6 H ₂ C, 50.99; H, 4.89; N, 5.28.

C, 50.98; H, 4.86; N, 5.56.

I

- 196 Table 2

FAB wt.

amine spectrum

Stereo. X Y_ (M + 1) Analysis (calculated, found) n-Bu 2-O (CH 2) 13 CH 3 642.5 C42H63N3O2´2.55HC1

C, 68.46; H, 8.97; N, 5.70. C, 68.40; H, 8.70; N, 5.61.

n-Bu 2-O (CH 2) 13 CH 3 642.6 C42H63N3O2-2.65HCl C, 68.63; H, 8.99; N, 5.72. C, 68.66; H, 8.90; N, 5.70.

n-Bu 2-O (CH 2) 11 CH 3 614.4 C 40 H 59 N 3 O 2 2.8 HCl C, 67.09; H, 8.70; N, 5.87. C, 67.03; H, 8.66; N, 5.76.

B n-Bu 2-O (CH 2) 11 CH 3 614.4 C 40 H 59 N 3 O 2 * 2.85HCl * 0.05H 2 O C, 66.84; H, 8.69; N, 5.85.

C, 67.20; H, 8.70; N, 5.45.

- 197 Table 2 - continued amine stereo. X

FAB wt.

spectrum (M + 1) Analysis (calculated, found)

A n-Bu 2-O (CH 2) 9 CH 3 586.5 C 38 H 55 N 3 O 2 * 3 HCl * 0.25hexane C, 66.18; H, 8.65; N, 5.86.

C, 66.14; H, 8.44; N, 5.50.

B n-Bu 2-O (CH 2) 9 CH 3 586.5 C 38 H 55 N 3 O 2 * 3HCl * 0.15hexane C, 65.97; H, 8.55; N, 5.93.

C, 66.04; H, 8.41; N, 5.57.

A n-Bu 2-O (CH 2) 7 CH 3 558 C 36 H 51 N 3 O 2 * 2.15HCl * 0.65H2 C, 66.73; H, 8.47; N, 6.49.

C, 66.74; H, 8.46; N, 6.52.

B n-Bu 2-O (CH 2) 7 CH 3 558 C 36 H 51 N 3 O 2 * 2.15HCl * 0.65H2O

C, 66.82; H, 8.42; N, 6.49.

C, 66.85; H, 8.43; N, 6.52.

A n-Bu 2-O (CH 2) 3 Ph 564 C37H45N3O2 * 2HCl * 1.05H2O

C, 67.78; H, 7.55; N, 6.41.

C, 67.78; H, 7.52; N, 6.26.

B n-Bu 2-O (CH 2) 3 Ph 564 C37H45N3O2-2HCl-1O5H2O

C, 67.78; H, 7.55; N, 6.41.

C, 67.78; H, 7.44; N, 6.33.

A n-Bu 3-OCH 2 Ph 536 C 35 H 41 N 3 O 2 * 3.55HCl

C, 63.19; H, 6.75; N, 6.32.

C, 63.12; H, 6.61; N, 6.47.

B n-Bu 3-OCH2Ph 536 C35H4lN3O2'3.55HCl * 0.4H2O

C, 62.52; H, 6.80; N, 6.25.

C, 62.14; H, 6.69; N, 6.65.

198

Table 2 - continued amui 'stereo.

X

FAB wt. spectrum (M + 1)

Analysis (calculated, found)

A n-Bu 3-O (CH 2) 13 CH 3 642 C42H63N3O2-2.4HC1 C, 69.15; H, 9.04; N, 5.76. C, 69.08; H, 9.08; N, 5.73. B n-Bu 3-O (CH 2) 13 CH 3 642.5 C42H63N3O2-2.35HClO.25H2O C, 69.15; H, 9.04; N, 5.76. C, 69.08; H, 9.08; N, 5.73. R n-Bu 4-O (CH 2) 13 CH 3 642 C42H63N3O2-2.2HCMH2O C, 68.14; H, 9.15; N, 5.68. C, 68.13; H, 9.03; N, 5.68. WITH n-Bu 4-O (CH 2) 13 CH 3 642 C42H63N3O2'2.8HC1 C, 67.79; H, 8.91; N, 5.65. C, 67.77; H, 9.80; N, 5.64. WITH n-Bu 4-OCH 2 Ph 536 C35H4lN3O2 * 2.15HCMH2O C, 66.49; H, 7.20; N, 6.65. C, 66.48; H, 7.15; N, 6.62.

R / S H 2-O (CH2) 13CH3 586 C38H55N3O2'1.5HCl * 0.3H2O

C, 66.88; H, 8.58; N, 6.16.

C, 66.82; H, 8.64; N, 6.15.

- 199 Table 3

FAB wt.

spectrum fM + 1)

Analysis (calculated, found)

3-SO ₂ Me-506 C27H31N5O3S 3.0 _H2O HC1-0.10

C, 52.61; H, 5.59; N, 11.36. C, 52.63; H, 5.41; N, 10.72.

3-OCF3

512.23

C27H28N5O2F HC1-0.50 ₃ -2.30 H ₂ OC, 53.66; H, 5.22; N, 11.59.

C, 53.73; H, 5.23; N, 10.86.

200

Table 4

FAB wt. spectrum

X Y (M + N Analysis (calculated, found CH ₂ OCH ₂ Ph cf ₃ 574 C32H30N5O2F ₃ · 1.40HCl * 0.30H ₂ C, 61.02; H, 5.12; N, 11.12. C, 61.01; H, 5.10; N, 10.78. CH ₂ SO ₂ Et cf ₃ 560 C27H28N5O3F _3S 3.20HCb0.10H • ₂ 0 C, 47.86; H, 4.67; N, 10.34. C, 47.89; H, 4.49; N, 9.92. CH ₂ SO ₂ Ph cf ₃ 608 C 31 H 28 N ₅ O ₃ F ₃ S · 2.10HCl C, 54.42; H, 4.43; N, 10.24. C, 54.43; H, 4.42; N, 9.98. CH ₂ SO ₂ Me C1 512 C25H26N5O3C1S • 2.0HCl ^much 0.25CHCl ₃ * 0.25H ₂ 0 C, 48.97; H, 4.68; N, 11.31. C, 48.95; H, 4.64; N, 11.51.

201 Table 4 - continued

FAB wt. spectrum

X Y (M + 1) Analysis (calculated, found) CH ₂ SO ₂ Et Cl 526 C 26 H 28 N ₅ O ₃ ClS · 2HCl · 0.25CHCl ₃ C, 50.14; H, 4.85; N, 11.14. C, 50.20; H, 4.91; N, 10.93. CONHMe cf ₃ 511 C26H25N602F ₃ '1.90HC1 * 1.70H ₂ 0 C, 51.20; H, 5.01; N, 13.78. C, 51.17; H, 4.99; N, 13.36. CONHEt cf ₃ 525 C27H27N602F ₃ '1.60HC1 * 0.10H ₂ 0 C, 55.54; H, 4.97; N, 14.39. C, 55.57; H, 4.87; N, 15.28. CH ₂ SO ₂ Ph Cl 574 C30H28N503C1S * 2HC1 «0.30H ₂ 0

C, 55.23; H, 4.73; N, 10.73. C, 55.25; H, 4.57; N, 10.61.

- 202 Table 4 - continued

FAB wt. spectrum

X Y (M + 1) Analysis (calculated, found CONHMe Cl 477 C25H25N6O2CF2HC1 • 0.105CHCl3 * 0.85H20 C, 52.24; H, 5.03; N, 14.56. C, 52.21; H, 5.07; N, 14.98. CONHEt Cl 491 C26H27N6O2C1-2HC1-0.25CHC13 C, 53.10; H, 4.97; N, 14.15 C, 53.32; H, 5.21; N, 13.77. Ex-CONHC Cl 503 C27H27N6O2Cl '2HCl'0.40CHCl ₃ C, 52.77; H, 4.75; N, 13.47. C, 53.01; H, 4.99; N, 13.32. Ex-CONHC cf ₃ 537 C28H27N6O2F3 • 2.45HCl'0.55dioxane C, 53.81; H, 5.06; N, 12.47. C, 53.76; H, 5.09; N, 12.44.

- 203 Table 4 - continued

FAB wt. spectrum

X Y (M + 1) Analysis (calculated, found) NHCOMe Cl 477 C25H25N6O2C1 • 2HCl-0.60CHCl3-2.0H2O C, 46.76; H, 4.84; N, 12.78. C, 46.79; H, 4.46; N, 12.37. CONMe ₂ CF3 525 C27H27N6O2F3-2.0HC1-0.10H ₂ O C, 54.12; H, 4.91; N, 14.02. C, 54.10; H, 4.96; N, 13.79. SO ₂ Et Cl 512 C25H26N503C1S-2.0HC1-0.10H ₂ 0 C, 51.18; H, 4.84; N, 11.94. C, 51.24; H, 5.19; N, 11.10. CH ₂ SMe Cl 480 C25H26N5OC1S -0.15CHC1 ₃ -0.05H ₂ 0 C, 52.83; H, 4.98; N, 12.25. C, 52.82; H, 5.36; N, 11.85.

204

Table 4 - continued

FAB wt.

spectrum (M + 1) Analysis (calculated, found) (±) C = CMe Cl 458 C26H24N50CF2.0HCl-1.00H2O

C, 56.89; H. 5.14; N, 12.76. C, 56.99; H, 5.20; N, 12.42.

- 205 Table 5

FAB wt. spectrum

X Y (M + N Analysis (calculated, found CH2CH2 H 386 C23H23N5O · 1.40HCl · 0.40H ₂ O C, 62.29; H, 5.73; N, 15.79. C, 26.26; H, 5.71; N, 15.43. 2 CO H 400 C23H21N5O2-2.6HCl · 1.70H ₂ O C, 52.71; H, 5.19; N, 13.36. C, 52.82; H, 5.21; N, 13.04. ch ₂ H 372 C22H21N5O2.OHO2.6OH2O C, 53.80; H, 5.79; N, 14.26. C, 52.86; H, 5.98; N, 13.92. CH2 3-C1 406 C22H20N50Cl * 2.50HCl * 0.90H ₂ 0

C, 51.48; H, 4.77; N, 13.65. C, 51.55; H, 4.75; N, 13.34.

- 206 Table 5

- continuation

FAB wt.

spectrum (M + 1) Analysis (calculated, found)

NHSO 2 H C21H20N6O3S · 1 ΌΗΟ2.6ΟΗ2Ο C, 48.53; H, 5.08; N, 16.17 C, 48.60; H, 5.19; N, 15.80. CH2CH2CO 3-C1 448 C24H22N5O2Cl · 1.0HCl · 1.10H ₂ O C, 57.17; H, 5.04; N, 13.89. C, 57.22; H, 4.94; N, 13.47. ch ₂ 2,3-Cb 440 C22Hl9N50Cl2 * 2.0HCl * 0.60H ₂ 0 C, 50.42; H, 4.27; N, 13.36. C, 50.51; H, 4.56; N, 12.18. ch ₂ 2-Br 450 C22H20N50Br 2.0HCl * * 0.30H20

C, 49.98; H, 4.31; N, 13.25. C, 49.94; H, 4.47; N, 12.53.

207 Table 5 - continued

spectrum χ Y (M + 1) Analysis (calculated, detected)

ch ₂ 3-CF3 440 C23H20N5OF3 · 1.70HC1 * 0.40H ₂ 0 C, 54.40; H, 4.47; N, 13.79. C, 54.45; H, 4.49; N, 13.82. ch ₂ 4-0 C22H20N50CM.50HC1 * 0.80H ₂ 0 C, 55.71; H, 4.91; N, 14.77. C, 55.81; H, 4.94; N, 14.11. ch ₂ co 3-C1 C23H20N5O · C ₂ · 1.10H 1.40HC1 ₂ O C, 54.73; H, 4.71; N, 13.87. C, 54.80; H, 4.73; N, 13.46. ch ₂ 3-F C22H20N5OF-2HCl • 0.35CHCl ₃ '0.95H ₂ O C, 51.50; H, 4.69; N, 13.44. C, 51.56; H, 4.73; N, 13.30.

- 208 Table 5 continued

FAB wt. spectrum

Y (M + 1) Analysis (calculated, found) ch ₂

3-Br C22H20N5OBp1.40HCM.30H2O

C, 50.35; H, 4.61; N, 13.34. C, 50.36; H, 4.63; N, 12.84.

209

Table 6

FAB wt. spectrum

X Y from (M + N Analysis (calculated, found) 4-CN ch ₂ 5-CH ₂ CH ₂ CO 554 C27H28N5O4CIS · 1.30HCl · 1.20H ₂ O C, 52.05; H, 5.13; N, 11.24. C, 52.09; H, 5.15; N, 10.95. 3-CN ch ₂ 5-CH ₂ 512 C25H26N5O3CIS · 2.0HCF0.10CHCl ₃ -0.60H ₂ C, 49.61; H, 4.86; N, 11.52. C, 49.63; H, 5.01; N, 11.14. 2-CN ch ₂ 5-CH ₂ 512 C25H26N5O3ClS * 2HCl 0.35H ₂ O C, 50.79; H, 4.89; N, 11.84. C, 50.82; H, 5.29; N, 11.90. 4-CN ch ₂ 4-CH ₂ CH ₂ CO 554 • C27H28N5O4CIS 2.0HC1 0.50CHC1 * ₃ * 0.60H ₂ 0 C, 47.36; H, 4.58; N, 10.04. C, 47.35; H, 4.60; N, 9.66.

- 210 Table 6 - continued

FAB wt. MS χ_y_ £ _ (M + 1) ^{Analysis for} Y (Calculated, Found)

4-CN (CH ₂ ) 2 4 -CH ₂ CH ₂ CO

C28H30N5O4CIS • 1.0HCl · 0.40CHCl ₃ * 0.95H 2 O

C, 50.96; H, 5.01; N, 10.46. C, 50.91; H, 5.02; N, 10.13.

211

Table 7

FAB wt. spectrum χ γ (M + 1) Analysis (calculated, detected)

4-Me CH2CH2SO2Me 526 C26H28N5O3C1S • 2HCl-0.35CHCl3-0.85H ₂ O C, 48.24; H, 4.92; N, 10.67. C, 48.25; H, 4.93; N, 10.36. 4-Me H 420 C23H22N50Cl * 2.0HCl · 0.90H ₂ C, 54.27; H, 5.11; N, 13.76. C, 54.21; H, 5.37; N, 12.97. 2-Me H 420 C23H22N50C1'3.20HC1'0.10H20

C, 51.31; H, 4.76; N, 13.01. C, 51.30; H, 4.74; N, 12.87.

212

Table 8

FAB ms (m + 2)

3-CF ₃ 496

3 _CH-3442

formula

Analysis (calculated, found) C ₂₇ H ₂₈ F ₃ N ₅ O · 2 HCl 1.55 H ₂ C

C, 54.36; H, 5.59; N, 11.74 C, 54.40; H, 5.29; N, 11.26

C ₂₇ H ₃₁ N ₅ O 2 HCl

C, 63.01; H, 6.47; N, 13.61 C, 63.45; H, 6.71; N, 13.53

2,3- _{(CH2) 4} 482

C ₃₀ H ₃₅ N ₅ 0 · 5.2 HCl · 0.1 H ₂ C

C, 53.66; H, 6.06; N, 10.43 C, 53.62; H, 5.30; N, 9.35

3-OCH 3 458

C ₂₇ H ₃₁ N ₅ O ₂ '2 HCl

C, 61.13; H, 6.27; N, 13.20 C, 62.43; H, 6.53; N, 13.24

213

Table 8 - continued

3-C1

463

C ₂₆ H ₂₈ C1N ₅ O 2 HCl · 0.75 H ₂ C

C, 56.94; H, 5.79; N, 12.77 C, 56.92; H, 5.59; N, 12.30

2-CH ₃ 3-Cl 477

C ₂₇ H ₃ oC ₁ N ₅ 0 ₂ · 2 HCl · 3.1 H ₂ O

C, 53.62; H, 6.37; N, 11.58 C, 53.44; H, 5.37; N, 10.76

428

C ₂₆ H ₂₉ N ₅ O · 3.9 HCl 2 H ₂ O

C, 51.63; H, 6.51; N, 11.58 C, 51.59; H, 5.10; N, 10.35

214

Table 8 - continued

3-F

446 C ₂₆ H ₂₈ FN ₅ O · 2 HCl · 2.55 H ₂ C

C, 55.87; H, 6.22; N, 12.53 C, 55.83; H, 5.84; N, 11.71

- 215 Table 9

Analysis (calculated, found)

CH ₂ CH ₂ OCH ₂ CF ₃ 566

C ₂₇ H ₂₅ F ₆ N ₅ O ₂ · 2 HCl '0.67 H ₂ O

C, 49.85; H, 4.39; N, 10.77 C, 49.86; H, 4.26; N, 10:33 t> ~ _OCH2 CH ₂₅₂₄

C ₂₈ H ₂₈ F ₃ N ₅ O ₂ · 2 HCl

C, 56.38; H, 5.07; N, 11.74 C, 56.21; H, 5.27; N, 11.46

CH ₂ CH ₂ N ₃ 509

C ₂₅ H ₂₃ F ₃ N ₈ O ₂ · 2 HCl · 2.35 H ₂ O

C, 48.14; H, 4.80; N, 17.96 C, 48.79; H, 4.38; N, 16.99

CH ₂ CH ₂ NHCOCH ₃ 525

C ₂₇ H ₂₇ F ₃ N ₆ O ₂ '2 HCl · 0.7 H ₂ O

C, 53.16; H, 5.02; N, 13.78 C, 53.30; H, 5.07; N, 13.39

CH ₂ CH ₂ NHCOC ₂ H ₅

539 C ₂₈ H ₂₉ F ₃ N ₆ O ₂ · 2 HCl · 3.66 H ₂ O

C, 52.43; H, 5.39; N, 13.10

C, 52.44; H, 5.20; N, 12.48

216

Table 9 - continued

Analysis (calculated, found)

CH ₂ CH ₂ SO ₂ CH (CH ₃ ) ₂ 574 C ₂₈ H ₃₀ F ₃ N ₅ O ₃ S · 2 HCl ¹ 1.35 H ₂ C

C, 50.13; H, 5.21; N, 10.44 C, 50.10; H, 4.88; N, 10.08

CH ₂ CH ₂ SCH (CH ₃ ) ₂ 542 C ₂₈ H ₃₀ F ₃ N ₅ OS · 2 HCl · 0.75 H ₂ O C, 53.55; H, 5.38; N, 11.51 C, 53.57; H, 5.33; N, 11.04 CH ₂ CH ₂ S (O) CH (CH ₃ ) ₂ 558 C ₂₈ H ₃₀ F ₃ N ₅ O ₂ S · 2 HCl- 0.7 H ₂ O

C, 52.29; H, 5.23; N, 10.89 C, 52.27; H, 5.08; N, 10.35

217

Table 10

R FAB ms (m + 2)

formula

Analysis (calculated, found)

C ₂₆ H ₃₁ N ₅ O ₃ · 2 CF ₂ CO ₂ H · 2.8 H ₂ C

C, 48.69; H, 5.26; N, 9.46 C, 48.70; H, 4.42; N, 9.12

C ₂₉ H ₃₅ N ₅ O · 2 HCl · 0.3 CH ₂ Cl ₂ • 0.6 C ₆ H ₁₄

C, 63.76; H, 7.48; N, 11.30 C, 64.77; H, 7.07; N, 11.26 C ₂₇ H ₃₄ N ₄ O · 2 HCl

C, 64.41; H, 7.21; N, 11.13 C, 66.35; H, 7.28; N, 11.25 C ₂₈ H ₃₆ N ₄ O · 2 HCl · 1.3 H ₂ O

C, 62.17; H, 7.56; N, 10.36 C, 62.15; H, 7.09; N, 9.83

C ₂₉ H ₃₅ N ₅ O 2HCl · 3.05 H ₂ O

C, 58.30; H, 7.27; N, 11.72 C, 58.30; H, 6.28; N, 10.90 ^CH2 548.550 NC ^ ^ _ν Αβγ

C ₂₉ H ₃₄ BrN ₅ O 2 HCl ¹ 0.1 H ₂ O

C, 55.89; H, 5.85; N, 11.24

C, 55.91; H, 5.96; N, 10.73

- 218 -

Ο

FAB ms Formula (m + 1) Analysis (calculated, calculated)

511 C ₂₆ H ₂₇ C1N ₄ O ₃ S • 2 HCl · 2.85 H ₂ 0

C, 49.16; H, 5.51; N, 8.82 C, 49.17; H, 4.74; N, 8.87

496 C ₂₅ H ₂₆ FN ₅ O ₃ S • 2HCl · 1.65 H ₂ 0

C, 50.20; H, 5.27; N, 11.71 C, 50.19; H, 4.90; N, 11.44 ₅₂₇ C ₂₆ H ₂₈ ClN ₅ O ₃ S • 2 HCl · 0.55 H ₂ O

C, 51.29; H, 5.15; N, 11.50 C, 51.32; H, 5.39; N, 11.31

530 C ₂₆ H ₃₂ C ₁ N ₅ O ₃ S • 3 HCl · 0.6 HCl

C, 48.02; H, 5.61; N, 10.77 C, 48.30; H, 5.91; N, 9.78

219

Table 12

R

FAB ms (m + 1) Formula

Analysis (calculated, found) ₅₄ , c ₂₆ h ₃₀ c, ₅ o ₄ s

HCl 0.75 H ₂ 0

C, 49.53; H, 5.36; N, 11.11 C, 49.56; H, 5.58; N, 10.65

C ₂₈ H ₂₉ ClN ₅ O ₃ S • 2 HCl

C, 53.90; H, 5.01; N, 11.22 C, 54.06; H, 5.78; N, 10.67

c ₁₇ h ₂₀ cin ₄ o ₃ sec. • 2 HCl · 0.7 H ₂ O

C, 42.41; H, 4.90; N, 11.64 C, 42.98; H, 5.49; N, 11.06

C ₂₆ H ₃₀ ClN ₅ O ₄ S • 2 HCl · 0.75 H ₂ O

C, 49.51; H, 5.36; N, 11.11

C, 49.74; H, 5.66; N, 10.11

220

Table 12 - continued

FAB ms (m + 1) Formula

Analysis (calculated, found)

524 C ₂₇ H ₂ 7ClN ₄ O3S · 0.55 CHCl ₃

C, 58.67; H, 4.92; N, 10.03 C, 58.71; H, 4.94; N, 9.95

CN

523 C ₂₈ H ₂₈ C 1 N ₃ O ₃ S '0.1 CHCl · 0.2 CH ₃ OH

C, 62.89; H, 5.39; N, 7.78 C, 62.87; H, 5.37; N, 7.84

221

Table 13

FAB ms Formula (m + 1) Analysis (calculated, calculated)

563

540

512

415

HN

CH.

N • S

0 ₂

\ /

CN

580

C ₃₀ H ₃₁ ClN ₄ O ₃ S • 2HCl ₁₁ .8H ₂ O

C, 53.90; H, 5.52; N, 8.38 C, 53.90; H, 5.38; N, 7.82

C ₂₇ H ₃₀ ClN ₅ O ₃ S • 2HCl · 1.35 H ₂ O

C, 50.88; H, 5.49; N, 10.99 C, 51.37; H, 5.51; N, 10.20

C ₂₅ H ₂₆ ClN ₅ O ₃ S · 2HCl · 0.3 H ₂ O

C, 50.86; H, 4.88; N, 11.86 C, 51.06; H, 5.33; N, 10.87

C ₂ 8H ₂₇ C1N ₄ O ₃ S • 3 HCl · 4 H ₂ O

C, 36.25; H, 6.42; N, 9.39 C, 38.12; H, 5.91; N, 7.41

C ₂₅ H ₃₀ ClN ₅ O ₅ S ₂ • 2 HCl · 0.85 H ₂ O

C, 44.93; H, 5.08; N, 10.48

C, 44.96; H, 5.08; N, 9.96

222

Table 14

R ¹

FAB ms

R ² (m + l) Formula

Analysis (calculated, found)

NC

C ₁₉ H ₁₉ C 1 N ₄ O • 2HCl · 0.5 H ₂ O

C, 52.25; H, 5.08; N, 12.83 C, 52.31; H, 5.14; N, 12.23

C ₂₄ H ₂₃ ClFN ₅ O • 2 HCl 1.70 H ₂ O

C, 51.90; H, 5.15; N, 12.61 C, 52.22; H, 5.10; N, 12.22

C ₂₄ H ₂₂ C1N ₅ O ₂ 1 HCl • 0.30 CHCl ₃ · 0.85 H ₂ O

C, 54.50; H, 4.71; N, 13.08 C, 54.51; H, 4.69; N, 12.87

- 223 Table 15

R-N

Y FAB ms Formula (m + 1) Analysis (calculated, calculated)

2,3- _(CH2) 4 426 C26H27N5O

2HCr0.15H ₂ O

C, 62.31; H, 5.89; N, 13.97 C, 62.38; H, 6.18; N, 13.27

2-CH ₃ , 3-C 420 C ₂₃ H ₂₂ C 1 N ₅ O • 2HCl ₁₁ H ₂ O

C, 54.08; H, 5.13; N, 13.71 C, 54.57; H, 5.77; N, 12.92

3-C1 420 C ₂₂ H ₁₈ C1N ₅ O ₂ • 2HC10.5 H ₂ O

C, 56.78; H, 4.33; N, 15.05 C, 56.79; H, 4.69; N, 13.47

- 224

Table 16

C, 54.14; H, 5.75; N, 9.15 C, 54.15. H, 5.74; N, 9.18

C ₂₉ H ₃₃ N ₅ O ₂ '4 HCl' 3 H ₂ 0

C, 51.03; H, 6.35; N, 10.26 C, 51.02; H, 5.66; N, 9.67

C ₃₂ H ₃₅ N ₅ O '2 HCl' 1.7 H ₂ C

C, 63.09; H, 6.68; N, 10.26 C, 51.02; H, 5.66; N, 9.67

- 225 Table 17

RN ^n_O

FAB ms (m + 1) Formula

Analysis (calculated, found) ³⁴⁷ C ₂₁ H ₂₂ N ₄ O · 0.2 CHCl ₃ • 0.4 CH 3 OH

C, 67.71; H, 6.26; N, 14.62 C, 67.71; H, 6.26; N, 14.53

358 C ₂ H ₂₃ N ₃ O · 0.55 CHCl ₃

C, 66.85; H, 5.61; N, 9.93 C, 66.87; H, 5.70; N, 10.03

226

Table 18

FAB wt.

spectrum Formula (M + 1) Analysis (calculated, found)

C29H33N5O2-1.0HC1 ·

0.25CHC13-0.70H20

C, 62.45; H, 6.39; N, 12.45. C, 62.45; H, 6.46; N, 12.37.

406 C22H20N5OCl * 2.60HCl * C, 53.97; H, 4.78; N, 14.30

C, 53.97; H, 5.21; N, 13.10.

526 C26H28N501C1S-2.0HO 1.20H ₂ O

C, 50.32; H, 5.26; N, 11.28 C, 50.31; H, 5.31; N, 10.72.

227

Table 18 FAB wt.

continue

Analysis (calculated, found)

Cl tí

C23H22N5OF2.0HCF2.10H2O C, 52.06; H, 5.36; N, 13.20 C, 51.99; H, 5.36; N, 12.57.

Claims (11)

- 228 PATENT CLAIMS 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1 to 6 atoms CH = CH-C = CN (R ¹⁰ ) is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or aryl, R ¹ ! are independently selected from the group consisting of alkyl with carbon and aryl, 19th A and A independently represent a chemical bond, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is H ₂ or O, V is selected from the group (a) a hydrogen atom, a heterocyclic radical, an aryl, an alkyl of 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from hydrogen b) c) d) when S is (O) _m or A 'is a chemical bond, = 0 and A ^z is a group 305 V is a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Z is substituted or unsubstituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituent is at least one substituent from the group 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms, (b) (CH ₂ ) _p OR 0, (CH ₂ ) _p NR ⁶ R ⁷ , halogen, CN, c) d) e) 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group 296 (a) alkyl of 1 to 4 carbon atoms, (b) (CH ₂ ) _p OR ⁶ , (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; b) c) d) e) f) g) cycloalkyl of 3 to 6 carbon atoms, aryl or heterocyclic radical, HO, -S (O) _m R ^6a or -C (O) NR ⁶ R ^7, 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms, (b) (CH ₂ ) _p OR ⁶ , (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms, (b) (CH ₂ ) _p OR ⁶ , (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN 1- (3-Chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone and pharmaceutically acceptable salts or optical isomers thereof. 22. A pharmaceutical composition comprising as its active ingredient a piperazine compound according to claim 1 dispersed in a pharmaceutical carrier. 23. A pharmaceutical composition comprising as its active ingredient a piperazine compound according to claim 2 dispersed in a pharmaceutical carrier. 282 24. A pharmaceutical composition comprising as its active ingredient a piperazine compound according to claim 3 dispersed in a pharmaceutical carrier. 25. A pharmaceutical composition comprising as its active ingredient a piperazine compound according to claim 6 dispersed in a pharmaceutical carrier. 26. A method of inhibiting farnesyltransferase comprising administering to a mammal an effective amount of a pharmaceutical composition according to claim 22. 27. A method of inhibiting farnesyltransferase comprising administering to a mammal an effective amount of a pharmaceutical composition according to claim 23. 28. A method of inhibiting farnesyltransferase comprising administering to a mammal an effective amount of a pharmaceutical composition according to claim 24. 29. A method of inhibiting farnesyltransferase comprising administering to a mammal an effective amount of a pharmaceutical composition according to claim 25. 30. A method of inhibiting farnesyltransferase, comprising administering to a mammal an effective amount of a pharmaceutical composition comprising a pharmaceutical carrier in which an effective amount of a piperazine compound of formula B (B) is dispersed. 283 where R ^1a and R ^1b are independently selected from the group (a) a hydrogen atom; b) aryl, heterocycle, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R ^b 0-, R ^^ S (O) m NO. c) R ² R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, CN, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3 or R ^{1: 1} OC (O) NR ¹⁰ -, alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl 2 to 6 carbon atoms, R ^1b 0-, R 1 -S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, CN, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -, and R are independently selected from hydrogen, alkyl of 1 to 8 optionally substituted, alkenyl or alkynyl, each having 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or -N (R ¹⁰ ) ₂ R R 6 _d 7 or ^Wherein the substituted groups are substituted with at least one substituent from the group 1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (2,3-dimethylphenyl) -2 (S) - (2-methoxyethyl) piperazin-5-one and pharmaceutically acceptable salts or optical isomers thereof. 280 The piperazine compound of claim 6, 1 - [[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl] -2 (S) -n-butyl-4- (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. A piperazine compound according to claim 6, 1- (2 (R) -amino-3- [3- (4-nitrobenzylthio) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, 1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine and its pharmaceutically acceptable salts or optical isomers - 11. A piperazine compound according to claim 6, 1- [5- (1-Benzylimidazole) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine and its pharmaceutically acceptable salts or optical isomers 1- [5- [1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine and its pharmaceutically acceptable salts or optical isomers 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolemethyl] -2piperazinón, 1 - [[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetyl] -2 (S) -N-butyl 4- (1-naphthoyl) piperazine, 1- [1- (4-phenylbenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl 4- (1naftoyl) piperazine, 1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl 4- (1naftoyl) piperazine, 1- (2 (R) -amino-3- [3- (4-nitrobenzyltio) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1naftoyl) piperazine, 1- (2 (R) -amino-3-hydroxyheptadecyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1-2 (S) -butyl- (2 (R) - (4-nitrobenzyl) amino-3-hydroxy-propyl) -4- (1-naphthoyl) piperazine, 1- (3-acetamidomethylthio-2 (R) aminoprop-l-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- [5- [1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-4- (1naftoyl) piperazine, 1- [5- (l-Benzylimidazol) methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl 4- (1naftoyl) piperazine, 1- [3- (4-Imidazolyl) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2-Amino-3- (2-hydroxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2-Amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1naftoyl) piperazine, 1- (2 (R) -amino-4-hydroxybutyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2 (R) -amino-3-hydroxy-propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (3-amino-2- (2-naphtylmethylamino) prop-l-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1) aryl; 1 9 A and A independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -O-, -N (R ¹⁰ ) - or -S (O) _m ) -, V is selected from the group (a) a hydrogen atom; b) a heterocyclic radical from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl, ΪΑΊ c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A ^ is S (O) _m or when A ^ 9 is a chemical bond, n = 0 and A represents the group ^S (°) m> V is a heterocyclic radical selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl, X is -CH ₂ or -C (= O) -, Y represents a mono- or bicyclic aryl or a mono- or bicyclic heterocyclic radical, unsubstituted or substituted by at least one of the following groups (a) alkyl of 1 to 4 carbon atoms, (b) C 1 -C 4 alkoxy; (c) a halogen atom; or (d) NR ⁶ R ⁷ ; m means 0 • 1 or 2, n means 0 1 , 2, 3, or 4 P means about, 1 , 2,3 or 4, r means 0 until 5, provided that r = 0 if V means a hydrogen atom, with means 0 or 1 T means 0 or 1 or optical isomers thereof, or a pharmaceutically acceptable salt thereof. 1) aryl; 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or - 244 ) -C (O) NR ⁶ R ^7, 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms, b) c) d) e) CN, (CH _{2) p} 0R ^b, (CH _{2) p} NR ⁶ R ^7, halogen, 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁶ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _m R ^6a; or ) -C (O) NR ⁶ R ^7, 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group I (a) alkyl of 1 to 4 carbon atoms, b) (CH ₂ ) _p OR ⁶ ; (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN A piperazine compound of the general formula A wherein R ^1a and R ^1b are independently selected from the group (a) a hydrogen atom; (b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R ^ O-, R ^ ³ S (O) (R ¹⁰ ) ₂ NC ( O) -, m NO. R ² c) R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) or R ¹¹ OC (O) NR ¹⁰ -, alkyl of 1 to 6 carbon atoms, optionally substituted with unsubstituted or substituted aryl, heterocyclic C 3 -C 10 cycloalkyl, alkenyl or alkynyl 6 carbon atoms; CN, always with 2 R ¹⁰ C (O) NR ¹⁰ -, az R ¹⁰ C (O) ( ¹⁰ ) ₂ NC (0) CN, ^{Ly <J} 2 ' R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 ' ⁰ 0 -, R ¹¹ S (O) (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -, Q and R are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or R ⁶ R ⁷ or R ^e 229 wherein the substituted groups are substituted with at least one substituent from the group I 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 2 (S) -N-butyl-1- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. 15. The piperazine compound of claim 6, 2 (S) -n-butyl-1- [1- (4-cyanobenzyl) imidazol-5-yl] -4- (2,3-dimethylphenyl) piperazin-5-one and its pharmaceutically acceptable salts or optical isomers. 279 The piperazine compound of claim 6, 2 (S) -N-butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, 2-CH ₃ , 3-Cl 2,3- _{(CH2) 4} NC NC NC // // ABOUT, 2-CH 3 3-Cl H 2,3- _{(CH2) 4} 2-Me H - 265 Table 8 2 (S) -n-butyl 4- (l-naphthoyl) -1- [1- (4-trifluoromethoxy) imidazol-5-ylmethyl] -piperazine, 2 (S) -N-butyl-4- (1-naphthoyl) -1- [1- (2-phenylethyl) imidazol-5-ylmethyl] piperazine, 2 (S) -N-butyl-1- [1- (3-methylbenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -n-Butyl-1- [1- (4-methylbenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethylbenzyl) imidazol-5-ylmethyl] piperazine, 2 (S) -Butyl-1 - [(1-naphthyl-2-ylmethyl) -1H-imidazol-5-yl] acetyl] -4- (1-naphthoyl) piperazine, 2 (S) -butyl-1 - [(4-imidazolyl) methyl] -4- (l-naphthoyl) piperazine, 2 (S) -butyl-1 - [(4-imidazolyl) ethyl] -4- (1-naphthoyl) piperazine, 254 2 (S) -benzyl-l-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine, 2 (S) -butyl-4- (1-naphthoyl) -1- (3-pyridylmethyl) piperazine; 2 (R) -butyl-1-imidazolyl-4-methyl-4- (1-naphthoyl) piperazine, 2 (S) -butyl-1- [2- (1-imidazolyl) ethyl] sulfonyl-4- (1-naphthoyl) piperazine, 2 (S) -butyl-1- [5- [1- (2-naphthylmethyl)] - 4,5-dihydro-imidazol] methyl-4- (1-naphthoyl) piperazine, 2 (S) -n-butyl-l- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1naftoyl) piperazine, 253 2 (S) -N-butyl-1- [1- (4-fluorobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-1- [1- (3-methyl-2-butenyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-1- [1- (4-methoxybenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (2-naphthylmethyl) imidazole-5-ylmethyl] -piperazine, 2 (S) -N-butyl-4- (1-naphthoyl) -1- [1- (1-naphthylmethyl) imidazol-5-ylmethyl] piperazine, 2 (S) -butyl-l - [(1-napthyl-2-ylmethyl) -lH-imidazole-5-yl) ethyl] -4- (l-naphthoyl) piperazine, 252 2 (S) -butyl-l- (2,3-diaminoprop-yl) -4- (l-naphthoyl) -piperazine, 2) aryl or heterocyclic radical, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl, G is H or O, Z represents mono- or bicyclic aryl or mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, these groups being unsubstituted or substituted by at least one of the following groups 2) heterocyclic radical, 2) heterocyclic radical, 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, Piperazine Compounds of Formula B wherein R ^1a and R ^1b are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R ^1b 0-, R 3 'S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, NC (R ¹⁰⁾ 2 N-C (0) -, CN, N0 _2, (R ¹⁰⁾ ₂ NC (NR ¹⁰⁾ -, R ¹⁰ C (0) ~, R ¹⁰ OC ( O) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -, 234 R ^z c) alkyl of 1 to 6 carbon atoms, optionally substituted by a substituent from the group of unsubstituted or substituted aryl, heterocycle, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl 6 carbon atoms, R ^lb 0-, R? SiO) ,, , -, ¹⁰⁾ 2 N-C (O) -, CN, (R ¹⁰⁾ 2 N-C (NR ¹⁰⁾ -, 3, N (R ¹⁰⁾ 2 and R ¹¹ OC (O) NR ¹⁰ -, hydrogen , alkyl of 1 to substituted, alkenyl or always of 2 to 3 R ¹⁰ C (O) NR ¹⁰ - R ¹⁰ C (O) -> R ¹⁰ OC (O) -, N and R are independently selected from 8 carbon atoms, optionally (R ¹ alkynyl, each having 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic optionally substituted or r ⁶ r ⁷ or R ^e wherein the substituted groups are substituted with at least one substituent from the group of 2) aryl or heterocyclic radical, 2) cycloalkyl of 3 to 6 carbon atoms, 3) halogen atom, 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 3-C1 274 Table 16 nC ₄ H - 275 Table 17 - 276 Table 18 or the pharmaceutically acceptable salts or optical isomers of these compounds. 277 3-F - 266 Table 9 CH ₂ CH ₂ OCH ₂ CF ₃ t 2 OCH ₂ CH ₂ CH ₂ CH ₂ N ₃ ch ₂ ch ₂ nhcoch ₃ ch ₂ ch ₂ nhcoc ₂ h ₅ CH ₂ CH ₂ SO ₂ CH (CH ₃ ) ₂ CH ₂ CH ₂ SCH (CH ₃ ) ₂ CH ₂ CH ₂ S (O) CH (CH ₃ ) ₂ Table 10 268 Table 11 ABOUT R Y 269 Table 12 ABOUT R - 270 Table 12 - continued CN - 271 Table 13 ABOUT - 2YŽ Table 14 R ¹ R ² NC 273 Table 15 CH ₂ N \ = N 3-C1 3-OCH3 3-CH ₃ 3-CF ₃ 3-OCF3 260 Table 4 X_Y CH ₂ OCH ₂ Ph cf ₃ CH ₂ SO ₂ Et cf ₃ CH ₂ SO ₂ Ph cf ₃ CH ₂ SO ₂ Me Cl CH ₂ SO ₂ Et Cl CONHMe cf ₃ CONHEt cf ₃ CH ₂ SO ₂ Ph Cl CONHMe Cl CONHEt Cl Ex-CONHC Cl Ex-CONHC cf ₃ Table 4 261 continued NHCOMe Cl C0NMe2 cf ₃ SO ₂ Et Cl CH ₂ SMe Cl (±) CsCMe Cl 262 Table 5 X Y CH2CH2 H CH ₂ CO H ch ₂ H ch ₂ 3-C1 NHSO 2 H CH2CH2CO 3-0 ch ₂ 2,3-Cb ch ₂ 2-Br ch ₂ 3-CF3 ch ₂ 4-C1 ch ₂ co 3-C1 ch ₂ 3-F ch ₂ 3-Br - 263 Table 6 X Y from 4-CN ch ₂ 5-CH2CH2CO 3-CN ch ₂ 5-CH 2 2-CN ch ₂ 5-CH 2 4-CN ch ₂ 4-CH2CH2CO 3-SO ₂ Me 3) halogen atom, 251 3) OR ⁶ , 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 3) halogen atom, 3) OR ⁶ , 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 4) OR ⁶ , 300 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 284 4-Me H 4-Me CH ₂ CH ₂ SO ₂ Me 4-CH2CH2CO 264 Table 7 4-CN (CH ₂ ) 2 4- [5- (4-cyanobenzyl) -1-imidazolylethyl] -1- (3-chlorophenyl) piperazin-2-one, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof. 256 4- [3- (4-cyanobenzyl) piperidin-4-yl] -1- (3-chlorophenyl) -5 (S) (2-metylsulfonylety1) piperazin-2-one, 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5 (S) - (2-fluoroethyl) -1- (3-chlorophenyl) piperazin-2-one, 4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one, 4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) -5 (S) - (2-methoxyethyl) piperazin-2-one, 255 (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone, (S) -1- (3-Chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone, (S) -1- (3-chlorophenyl) -4 - [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [N-ethyl-2-acetamide] -2-piperazinone, (±) -5- (2-butynyl) -1- (3-chlorophenyl) 4- [1- (4-cyanobenzyl) -5imidazolylmetyl] -2-piperazinone, 4) OR ⁶ , SR ^6a , SO ₂ R ^6a or SR ^6a , SO ₂ R ^6a or Piperazine compounds according to claim 1, of the general formula A V - A ¹ (CR ^{1 a} 2) _n A ² (CR ^{1 a} 2) _n - \ W - (CR ^1b 2), O (A) where R ^a is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, · R ^{'-' 3} are independently selected from (a) a hydrogen atom; 245 b) aryl, heterocyclic radical, cycloalkyl, ΪΙΪΙ ΟΟ, -N (R ¹⁰ ) 2 or alkenyl of 2 to 6 carbon atoms, c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl, alkenyl, R- ^ΟΟ and -N (R R ^) ₂ , R ³ , R 4 and R 4 are independently selected from hydrogen or methyl, ABOUT R represents a hydrogen atom, a group of the formula or a straight or branched chain alkyl of 1 to 5 carbon atoms, unsubstituted or substituted by at least one of the following groups: 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 4) OR ⁶ , 4) SR ^6a , S (O) R ^6a , SO ₂ R ^6a , 5) NR ⁶ R ⁷ 5) -NR ⁶ R ^7, 5) NR ⁶ R ⁷ 5) -NR ⁶ R ^7, 5) NR ⁶ R ⁷ 5) -NR ⁶ R ⁷ ·, R® 5) NR ⁶ R ⁷ 5) -NR ⁶ R ⁷ 6) r V ⁷ 0 7) F 8) —N _x .NR ⁷ R ^{7 and} Y 0 —Ck.NR ⁶ R ⁷ Y 0 9) —Ov OR ⁶ Y 0 10) NR ⁶ R ⁷⁰ 11) - SO ₂ -NR ⁶ R ⁷ r 12) N-SO ₂ -R ^{6 a} 13) xr ^R6 0 14) xr ^0R6 0 15) N ₃ or 16) F or R ² and R are attached to the same carbon atom and together form ^_ (CH _{2) u} wherein one of the carbon atoms is 285, optionally replaced by one of the groups 0, S (0) _m , -NC (O) - or -N (COR ¹⁰ ) -, R is hydrogen or methyl, wherein any two of R, R ^J and R to be attached to the same carbon atom, R 6, R ^7, and R ⁷ are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, (C 3 -C 6) cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals are optionally substituted with a substituent from the group of (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ (f) -SO ₂ R ⁷¹ or g) N (R ¹⁰ ) ₂ or -7 R and R may be taken together to form a ring or R ⁷ and R ^7a may together form a ring, R ^a is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, a heterocyclic radical or aryl radicals being optionally substituted by one of R (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -SO ₂ R ^III or g) N (R ¹⁰⁾ ₂ 286 Ο R is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -> R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, (R ¹⁰ ) 2N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ^1: LOC (O) NR ¹⁰ -a c) alkyl of 1 to 6 carbon atoms optionally substituted by a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, -θΟ- R, R ^^ S (O) _m -, R ¹⁰ C (O) NH-, (R ¹⁰⁾ 2 N-C (O) -, (R ¹⁰⁾ 2 N-C (NR ¹⁰⁾ -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-, R 6 is selected from the group (a) a hydrogen atom; b) alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R? θΟ-, R ¹¹ S (O) m, R ¹⁰ C (0) NR ¹⁰ -, (R ^L0) 2 n-C (O) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3, -N (R ¹⁰ ) ₂ or R ^1: LOC (O) NR ¹⁰ -a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, (R ¹⁰ ) 2N-C (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) ₂ or R ^{11 L} OC (O) NR ¹⁰ -, R ¹⁰ is independently selected from hydrogen, alkyl of 1 to 10 5 (S) -n-butyl-4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2- and pharmaceutically acceptable salts or optical isomers thereof). The piperazine compound of claim 6, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (methanesulfonyl) ethyl] -2-piperazinone and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone and pharmaceutically acceptable salts or optical isomers thereof. 281 The piperazine compound of claim 6, (S) -1- (3-chlorophenyl) -4- [1- (4-cyanophenyl) -5-imidazolylmethyl] 5- [2- (ethanesulfonyl) methyl] -2-piperazinone, and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, 5 (S) -n-butyl 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -1- (2-methylphenyl) piperazin-2-one, 5 (S) -butyl-4- [1- (4-cyanobenzyl-2-methyl) -5-imidazolylmethyl] -1- (2,3-dimethylphenyl) -piperazin-2-one, 5 (S) -N-butyl-4- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) piperazin-2-one, 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- (4-ylmethyl) -piperazin-2-one, 5) NR ⁶ R ⁷ 5) nr ⁶ r ⁷ t 9 7 4 wherein any two of R, R and R may be attached to the same carbon atom, R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heterocyclic radicals, which groups are unsubstituted or substituted by any of the following groups: (a) C 1 -C 4 alkoxy; (b) a halogen atom; or c) aryl or heterocyclic radical, 249 R ^6a is selected from alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) a halogen atom; or c) aryl or heterocyclic radical, Q R is independently selected from the group (a) a hydrogen atom; b) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹⁰ C (O) NR ¹⁰ - (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ^{1: L} 0C (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms optionally substituted by a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, R 10 O-, R 10c (O) Nr ^{10 -} , (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) 2 or R ^{1: L} OC (O) NR ¹⁰ -, R 6 is selected from the group (a) a hydrogen atom; b) alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ^11L OC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R 6 O-, R 6 S (O) _{n 1} -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, R ¹ ® is independently selected from hydrogen, alkyl of 1 to 5 carbon atoms; Piperazine compounds according to claim 2 of formula B 248 where ^And R? Are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R 6b is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl, R 10 -O-, -N (R 10) 2 or alkenyl of 2 to 6 carbon atoms, c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl, alkenyl, R ¹⁶ O- and -N (R ¹⁶ ) 2 _> R ³ and R ⁴ are independently selected from hydrogen or methyl, R is hydrogen, a group of formula NR ⁶ R ⁷ or C 1 -C 5 straight or branched chain, unsubstituted or substituted by at least one of the following: 5) \, NR ⁶ R ⁷ of wherein any two of R ² , R ³ , R 3 and R ³ may be bonded to the same carbon atom, R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heterocyclic radicals, which groups are unsubstituted or substituted by any of the following groups: (a) C 1 -C 4 alkoxy; (b) a halogen atom; or c) aryl or heterocyclic radical, R is selected from alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; 246 (b) a halogen atom; or c) aryl or heterocyclic radical, Q R is independently selected from the group (a) a hydrogen atom; (b) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, per 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, fluoroalkyl with R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, c) R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - and alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group consisting of perfluoroalkyl of 1 to 6 carbon atoms, R ' b) (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, R ¹⁰ C (O) or R ¹¹ OC (O) NR ¹⁰ -, is selected from the group consisting of: (a) hydrogen, alkenyl of 2 to 6 atoms R ¹⁰ O-, R ¹⁰ OC (O) -, R ¹⁰ C (O) NR ¹⁰ - N (R ¹⁰⁾ 2 aleuhlíka, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ O-, R ¹¹ S (O) m, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with from perfluoroalkyl having 1 to 6 carbon atoms, F, Cl, Η θΟ- ^7, R ^^ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, or aryl, is independently selected from: (C 1 -C 6) alkyl and aryl groups 5) NR ⁶ R ⁷ 5) -NR ⁶ R ⁷ ', 5) NR ⁶ R ⁷ 5) -NR ⁶ R ^7, R ⁶ At ⁷ o —N _x. NR ⁷ R ^7a Y ABOUT 5) NR ⁶ R ⁷ 233 5) -NR ⁶ R ^7, R ^e 6) CN, 6) f ⁶ - N R ' 302 6 carbon atoms, R f O-, R ^ S (0) _m -, (R ¹⁰⁾ 2 N-C (0) -, CN, (R ^10)? NC ^(NR10) -,, 10> R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ · R ² and R ³ are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or ABOUT R ⁶ R ⁷ or Wherein the substituted groups are substituted with at least one substituent from the group 6) CN, 6) 6 carbon atoms, Ρ ^ θΟ-, R ^ S (O) (R ¹⁰ ) ₂ NC (O) -, CN, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) r ⁶ r ⁷ or ABOUT ^Wherein the substituted groups are substituted with at least one substituent from the group 6) CN, 6) ABOUT 6 carbon atoms, Ρ ⁷ θΟ-, R ⁷ - * - S (O) (R ¹⁰ ) ₂ NC (0) -, 10 cN, (R ^{1 O)} 2 N-C (NR ^{1 u)} -, -N (R ^10)? and R ¹¹ OC (O) NR ¹⁰ -, 289 and R 6 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or wherein: the substituted groups are substituted with at least one substituent from the group 6) CN, 6 carbon atoms, benzyl or aryl, R 11 are independently selected from C 1 -C 6 alkyl and aryl, -i 9, A and A independently represent a chemical bond, CH = CH-, -OC-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is H ₂ or O, V is selected from the group (a) a hydrogen atom; 287 - b) heterocyclic radical, c) aryl, d) alkyl of 1 to 20 carbon atoms in which are 0 to 4 carbon atoms replaced by the heteroatom of Group 0 S and N a e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when it is S (O) _m or when A 1 is a chemical bond, n = 0 and A is a group with (O) _m , V is a heterocyclic radical, X is -O- ₂ , -C (= O) - or -S (= O) _m -, Z is substituted or unsubstituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituent is at least one substituent from the group Piperazine compounds according to claim 1, 2 or 3 of the group: 6) CN, 6 carbon atoms, benzyl or aryl; rH is independently selected from alkyl having 1 to 6 carbon atoms and aryl; A and A independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -O-, -N (R ¹⁰ ) - or -S (O) _m ) -, 250 V is selected from the group (a) a hydrogen atom; b) a heterocyclic radical from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl, c) aryl, d) alkyl of 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from hydrogen when it is S (O) _m or when A 1 is a chemical bond, n = 0 and A is a group V is a heterocyclic radical selected from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 6) CN, 6 carbon atoms, benzyl or aryl, R ¹¹ is independently selected from C 1 -C 6 alkyl and aryl, -i 2 A and A independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰⁾ -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is an oxygen atom, V is selected from the group (a) a hydrogen atom; b) heterocyclic radical, c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from hydrogen when A A represents S (O) _m or when A ^ represents a chemical bond, n = 0 and A represents a group with (O) m, V is a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Z represents a substituted or unsubstituted radical from the group aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, the substituted groups being substituted by one or more of the following groups 6) Y ⁷ o B ⁶ 6) CN, 6 carbon atoms, benzyl or aryl, r H are independently selected from alkyl of 1 to 6 carbon atoms and aryl, A ^ and A ^ independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is H ₂ or O, V is selected from the group (a) a hydrogen atom; b) heterocyclic radical, c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A ¹ is S (O) _m or when A ¹ Ί is a chemical bond, n = 0 and A represents a group with (0) _m , V is a heterocyclic radical, - 238 X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Z is substituted or unsubstituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituent is at least one substituent from the group 6) 6) CN, 6) 7) N0 ₂ 7) 7) N0 ₂ 7) Art -Ν _γ Π ⁷ ABOUT N _x. NR ⁷ R ^7a T o 7) N0 ₂ 7) ABOUT NR ⁷ R ^7a 7) N0 ₂ Piperazine compounds according to claim 1, 2 or 3 of the group Table 1 - 257 Table 2 stereo. X Y R n-Bu 2-O (CH2) 13CH3 WITH n-Bu 2-O (CH2) 13CH3 R n-Bu 2-O (CH 2) llCH3 WITH n-Bu 2-O (CH 2) llCH3 R n-Bu 2-O (CH2) 9CH3 WITH n-Bu 2-O (CH2) 9CH3 R n-Bu 2-O (CH2) 7CH3 WITH n-Bu 2-O (CH2) 7CH3 R n-Bu 2-O (CH2) 3Ph WITH n-Bu 2-O (CH2) 3Ph Rn-Bu 3-OCH 2 Ph 258 Table 2 - continuation of stereo.X_Y with n-Bu 3-OCH ₂ Ph R n-Bu 3-O (CH2) 13CH3 WITH n-Bu 3-O (CH2) l3CH3 R n-Bu 4-O (CH2) l3CH3 WITH n-Bu 4-O (CH2) l3CH3 WITH n-Bu 4-OCH 2 Ph R / S H 2-O (CH2) l3CH3 259 Table 3 Y_ 7) N0 ₂ 7) N0 ₂ 7) —N _x NR ⁷ R ^7a T o 7) no ₂ , 7) 235 7) N0 ₂ 7) r N NR ⁷ R ^7a 8) CF ₃ 8) 8) CF ₃ 8) - O..NR ⁶ R ⁷ n o —CX OR ⁶ 8) CF ₃ 8) o nr ⁶ r ⁷ 290 8) CF ₃ A piperazine compound according to claim 6, 8) CF ₃ 8) CF ₃ 8) - NR ⁶ R ⁷ T o Optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or 6 _d 7 J \ R ° IR R ⁶ or wherein the substituted groups are substituted with at least one substituent from the group 240) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms, (b) (CH ₂ ) _p OR ⁶ , (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN 8) CF ₃ 8) -CH / NR ⁶ R ⁷ Π o 8) CF _3> 8) —Or. NR ⁶ R ⁷ T ABOUT (9) -S (O) _m ^R6a ; 9 α R and R are attached to the same carbon atom and together form - _{(CH2) u,} wherein one of the carbon atoms is optionally replaced by one of the groups O, S (0) _m, -NC (O) - or -N ( C0R ¹⁰ ) -, R is hydrogen or methyl, wherein any two of R, R and R ³ may be attached to the same carbon atom, R 1, R 7 _and R 7 ^' _are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, 303 arylsulfonyl, heteroarylsylphonyl and said radicals are optionally substituted with a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -502 ^ 1 or g) N (r 10) ₂ or / r * 7 R ° and R 'can be taken together to form a ring or R ⁷ and R ^7a may together form a ring, R ^6a is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic or aryl, the radicals being optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, f) -SO ² R ¹¹ or g) N (R ¹⁰⁾ ₂ Q R is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰⁾ ₂ R ^11, or 0C (0) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted by a substituent from the group aryl, cyanophenyl, hete304 rocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ 0 -, R ¹¹ S (O) R ¹⁰ C (O) NH-, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 g R is selected from the group (a) a hydrogen atom; b) alkenyl of 2 to 6 carbon atoms, or R ¹⁰ OC (O) NH-, alkynyl of 2 to 6 F, Cl, Br, R ¹⁰ O-, (c) perfluoroalkyl; R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - and alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) - NC (O) -, R ¹¹ S (O) (R ¹⁰ ) ₂ NC (0) -, m 'i ₂ i CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N ₃ N (R ¹⁰ ) ₇ or R ¹¹ OC (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, 9) Art —N - NFfR ⁷³ T o ^ O / NR ⁶ R ⁷ T o —O .. OR ⁶ T o (9) -S (O) _m ^R6a ; 9) H O 6 _D 7 (9) -S (O) _m ^R6a ; 9 Q R and R are attached to the same carbon atom and together form a - (CH 2) _{u group} , one of which carbon atoms is optionally replaced by one of the groups 0, S (O) _m , -NC (O) - or -N (COR ¹⁰ ) -, R1 is hydrogen or methyl, wherein any two of R, R and R may be attached to the same carbon atom, R ⁷ , R ⁷ and R ^7a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted with a substituent from groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, 291 e) ABOUT R ¹¹ (f) -SO ₂ R ^{1: L} or g) N (R ¹ ®) ₂ or x 7 R c and R c can be taken together to form a ring or R ⁷ and R ^7a may together form a ring, R ^6a is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic or aryl, the radicals being optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -SO ₂ R ^{X 1} or g) N (R ¹⁰⁾ ₂ ABOUT R is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group aryl, cyanophenyl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, R ¹⁰ 0-, R ¹¹ S (O) m -, R ¹⁰ C (O) NH-, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-, 292 is selected from the group (a) a hydrogen atom; (b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 6 O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (0) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3, -N (R ¹⁰ ) ₂ or R ^1: LOC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (O) -, R ^L0 OC (O) -, N 3, N (R ¹⁰⁾ ₂ or R ¹¹ OC (O) NR ¹⁰ - R 10 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or aryl, r H is independently selected from alkyl of 1 to 6 carbon atoms, and aryl, -i o A and A independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is H ₂ or O, V is selected from the group (a) a hydrogen atom; b) heterocyclic radical, c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A ³ is S (O) _m or O represents a chemical bond, n = 0 and A represents a group V is a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Z represents a substituted or unsubstituted radical from the group aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, the substituent being 293 is at least one substituent from the group 9) (9) -S (O) _m ^R6a ; A piperazine compound according to claim 6, (9) -S (O) _m ^R6a ; (9) -S (O) _m ^R6a ; 9) -O 2 OR ⁶ O (9) -S (O) _m ^R6a ; 9) O ^ / OR ⁶ T o (9) -S (O) _m ^R6a ; 9) ABOUT 10) -C (O) NR ⁶ R ⁷ or 10) 6 _D 7 NR R 11) 12) 13) —so ₂ -nr ⁶ r ⁷ y N-SO ₂ 'R ^{6 a} R ⁶ 14) T o about OR ⁶ 15) N ₃ or 16) F or 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, is 0 to 5, provided that r = 0 when V is hydrogen, with means 0 or 1 T means 0 or 1 a at means 4 or 5 provided that (R ®) _r VA ⁷ (CR ^{7 and} 2) _n A ² (CR 1 ^and 2) _n - represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 42. A method of treating or preventing cancer, neurofibromin, retinal vascularization, infections of hepatitis delta and the like, restenosis and polycystic kidney, characterized in that an effective amount of a pharmaceutical composition containing the piperazine compound of the formula B (R ^8), V - A ¹ (CR ^{1 and} 2) _n A ² (CR ^{1 and} 2) _n (B) R ^1a and R ^1b are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, al301 (c) 2 to 6 R ¹⁰ C (O) NR ¹⁰ -, carbon atoms, NC (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ O-, R ¹¹ S (O) m -, no 2, -N (R ¹⁰ ) 2 CN,. No (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) or R ¹¹ OC (O) NR ¹⁰ -, alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case R ¹⁰ C (O) NR R ¹⁰ C (O) -, with 2 to 10 10) NR ^b R ^{11 L} ) ~ SO ₂ -NR ⁶ R ⁷ □ 6 l 12) N-SO ₂ -R ^{6 a} 297 )3) γΒ Ο 14) Ο OFr Or 16) F or R and R are attached to the same carbon atom and together form - _{(CH2) u,} wherein one of the carbon atoms is optionally replaced by a group selected from 0, S (0) _m, -NC (O) - or -N (COR ¹⁰ ) -, R1 is hydrogen or methyl, OQA wherein any two of R, R ^J and R to be attached to the same carbon atom, R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted with a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -SO ₂ rH or g) N (R ^) ₂ or ✓r * 7 R ° and R 'can be taken together to form a ring or R ⁷ and R ^7a may together form a ring, R ^6a is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic or aryl, the radicals being optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; 298 b) an aryl or heterocyclic radical, c) halogen atom, d) HO, p11 (e) V ABOUT f) -SC 1 R 3 or; g) N ^(R10) ₂ ABOUT R is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰⁾ ₂ R ^11, or 0C (0) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, R-θΟ-, R ^^ S (0) _m -, R ¹⁰ C (0) NH-, (R ¹⁰⁾ 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN . R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-, R 6 is selected. from the group (a) a hydrogen atom; (b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 6 O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (O) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n _3, -N (R ¹⁰⁾ ₂ R ^11, or 0C (0) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (0) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) ₂ or R ¹¹ C (O) NR ¹⁰ -, R ^ -θ is independently selected from hydrogen, alkyl of 1 to 6 299 carbon atoms, benzyl or aryl, rH are independently selected from alkyl of 1 to 6 carbon atoms and aryl, A and A independently represent a chemical bond, CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N (R ¹⁰⁾ -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, G is H ₂ or O, V is selected from the group (a) a hydrogen atom; b) heterocyclic radical, c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A ^ is S (O) _m or when A ^ o is a chemical bond, n = 0; A represents a group V is a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Z is substituted or unsubstituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituent is at least one substituent from the group 10 ') ₂ NC (0) -, CN, R ¹⁰ OC (O) -, N 3, -N (R - * - ^u ) 2 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5, provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or 1 and u is 4 or 5, provided that when t = 1 is a substituent ( _R ¹ ) _r VA ¹ (CR ^{1 and} 2) _n A ² (CR 1 ^and 2) _n - a hydrogen atom, or a pharmaceutically acceptable salt thereof. 32. A method of treating cancer, comprising administering to the mammal an effective amount of a pharmaceutical composition according to claim 22. 294 33. A method of treating malignant tumors, comprising administering to a mammal the pharmaceutical composition of claim 23. 34. A method of treating malignant tumors, comprising administering to a mammal the pharmaceutical composition of claim 24. 35. A method of treating malignant tumors, comprising administering to a mammal the pharmaceutical composition of claim 25. Effective quantity Effective quantity Effective quantity 36. A method of treating benign neurofibromine comprising administering to the mammal an effective amount of a pharmaceutical composition according to claim 23. 37. A method of treating blindness caused by retinal vascularization, comprising administering to the mammal an effective amount of a pharmaceutical composition according to claim 23. 38. A method of treating a hepatitis delta virus infection and the like, comprising administering an effective amount of the pharmaceutical composition of claim 23. 39. A method of preventing restenosis, comprising administering the composition of claim 23. 40. A method of treating a polycystic kidney comprising administering the composition of claim 23. 41. A method of treating or preventing cancer, neurofibromine, retinal vascularization, delta hepatitis and the like, restenosis and polycystic kidney, comprising administering an effective amount of a piperazine containing pharmaceutical composition. 295 compound of formula B (R ⁸ ), VA ^, (CR '2) nA ² (CR' * 2) ' - (CR ^{, b} 2) _p (B) R ^3a and R ³ ® are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alatoms of carbon, 10 R ¹⁰ OR ¹¹ S (O) 2 to 6 R ¹⁰ C (O) NR ¹⁰ -, NC (R ^J (R ¹⁰ ) ₂ NC (NR ¹⁰ ) -, or R ¹¹ OC (O) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms in each case R ¹⁰ C (O) NR ¹⁰ - R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -, and and R is independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or R ¹⁰ C (O) m no ₂ 10) 11) 12) 13) 14) O ^ OR ⁶ T o o nr ⁶ r ⁷ —so ₂ -nr ⁶ r ⁷ f ⁶ —N-SO ₂ -R ^6a R ⁶ O OR ⁶ ABOUT Or 16) F or 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, 288 p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5, provided that r = 0 when V is hydrogen, with means 0 or 1 T means 0 or 1 a at means 4 or 5 for provided that substituent (R ⁸ ) _r VA ¹ (CR ^{1 and} 2) _R A ² (CR 1 ^and 2) _n represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 31. A method of inhibiting farnesyltransferase, comprising administering a pharmaceutical composition comprising a piperazine compound of formula B1a and 1b and R1. a) b) are independently selected from the group consisting of hydrogen, aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R (O) -, R (S) (O) m; NO. c) R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, CN, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) ) -, N ₃ or R ^1: LOC (O) NR ¹⁰ -, alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl -n (r ¹⁰ ) ₂ each with 2 R ¹⁰ C (O) NR ¹⁰ R ¹⁰ C (O) -, R ¹⁰ OC (O) -, az A piperazine compound according to claim 6, 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 up to 6 carbon atoms, m means 0, 1 or 2 n means 0, 1, 2, 3 or 4, P means 0, 1, 2, 3 or 4, r means 0 to 5 per assuming that r = 0 means a hydrogen atom, with means 0 or 1, T means 0 or 1, at means 4 or 5, for provided that in when G is imidazolyl, then substituent (R &lt; 1 &gt;). VA ¹ (CR ^{1 and} 2) _n A ² (CR 1 ^and 2) _n has a meaning different from that of the hydrogen atom and provided that when X is -C (= O) - or -S (O) _m -, then t = 1 and the substituent ( _R ¹ ) _r VA ¹ (CR ^{1 and} 2) _n A ² (CR 1 ^and 2) _n has a meaning different from the hydrogen atom, or optical isomers thereof or their pharmaceutically acceptable salts. 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5, provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or 1 and u is 4 or 5, or the optical isomers thereof, or a pharmaceutically acceptable salt thereof. 10) 11) o NR ⁶ R ⁷ —so ₂ -nr ⁶ r ⁷ f ⁶ —N-SO ₂ -R ^6a 12) - 241 13) O ¹⁴⁾ T o OR ^e 15) Nj or 16) F or o and w. R and R are attached to the same carbon atom and together form - (CH _{2) u} wherein one of the carbon atoms is optionally replaced by a group selected from 0, S (0) _m, -NC (O) - or -N (COR ¹⁰ ) -, R ^ is hydrogen or methyl, wherein any two of the R ^, R a and R 9 may be bonded to the same carbon atom, R ⁴ * and R ³ are independently selected from hydrogen or methyl, wherein any two of R ² , R ³ , R 6 and R ³ may be bonded to the same carbon atom, r 6, R ⁷ and R ^7a are independently selected from the group of hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals are optionally substituted with a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -SO ² R ¹¹ or (g) N (r10) 2 or R ° and R 'can be taken together to form a ring or R ⁷ and R ^7a may together form a ring, ^And R is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, a heterocyclic radical 242 or aryl, the radicals being optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, i e) d1 1 Ύ f) g) ABOUT -SO 2 RH or N (R ¹⁰ ) ₂ R c is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, (R ¹⁰ ) ₂ NC (NR ¹⁰ ) m CN, NO ₂ , R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ c) or R ¹¹ OC (O) NR ¹⁰ - and alkyl of 1 to 6 carbon atoms optionally substituted with aryl, cyanophenyl, heterocyclic, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 atoms each alkyl, perfluoroalkyl, F, C1, Br, R ¹⁰ 0-, R ¹¹ S (O) m, R ¹⁰ C (O) NH-, (R ¹⁰⁾ 2 N-C (0) -, (R ¹⁰⁾ ₂ NC (NR ¹⁰ ) - CN -N (R ¹⁰ ) ₂ R ¹⁰ OC (O) -, is selected from the group (a) a hydrogen atom; (b) alkenyl of 2 to 6 carbon atoms, R ¹¹ S (O) _m -, R ¹⁰ C Nn (r ¹⁰ ) ₂ or R ¹⁰ OC (O) NHalkynyl with 2 F, Cl, Br, az R ¹⁰ 0 (R ¹⁰ ) ₂ NC (R) ₂ NC (NR ¹⁰ ) (c) carbon atoms, perfluoroalkyl, R ¹⁰ C (O) NR ¹⁰ - CN, NO ₂ , R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ^{11 L} OC (O) NR ¹⁰ - and alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, 243 (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, R ¹⁰ is independently selected from hydrogen, alkyl of 1 to 10 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl of 3 to 6 carbon atoms, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, q is 1 or 2, r is 0 to 5, provided that r = 0 when V is hydrogen, with means 0 or 1 T means 0 or 1 a at means 4 or 5 or optical isomers thereof, or a pharmaceutically acceptable salt thereof. - 239 3. Piperazine compounds of general formula C (R ^e ), V - A ¹ (CR ^{1 and} 2) _n A ² (CR ^{1 and} 2) _n F '(CR ^1b 2) _P \ .N ^to NZ x \ / / (C) R ⁴ where R ^1a and R ^1b are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, R ^1b 0 -O, R ^{3b (} S) O-, R ¹⁰ C (O) ^NR10 -, ^(R10) 2NC (O) -, CN, N0 _2, (R ¹⁰⁾ 2 NC (NR ¹⁰⁾ -, R ^{1 O} (O) -, R ¹⁰ OC (O) - , Νβ, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R 6 -ΟΟ-, R 6- S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, CN, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) NR ¹⁰ -, and R are independently selected from hydrogen, alkyl of 1 to 10 10) NR ^b R 11) 12) - SO ₂ -NR ⁶ R ⁷ f ⁶ - N-SO ₂ -R ^6a 13) R ^fc 14) o T o OR ^fc 15) N ₃ or 16) F or R ² and R ³ are attached to the same carbon atom and together form a - (CH 2) _{U group} , one of which carbon atoms is optionally replaced by one of the groups 0, S (O) _m , -NC (O) - or -N (COR ¹⁰ ) -, R ⁴ is H or methyl, O and A wherein any two of R, R °, and R may be attached to the same carbon atom, R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted with a substituent from the group (A) an alkoxy group having 1 to 4 carbon atoms, b) an aryl or heterocyclic radical, c) halogen atom, d) HO, ABOUT (f) -SO ₂ R ^{1: L} or (g) Ν (Ρ ^ θ) ₂ or R ⁶ and R ⁷ may together form a ring or a ring R ⁷ and R ^7a may together form a ring, R ^6a is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic or aryl, the radicals being optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ (f) -SO ₂ R ^{1: L} or g) N (R ¹⁰ ) ₂ r ⁸ is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group aryl, cyanophenyl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl F, Cl, Br , R ¹⁰ O-, R ¹¹ S (O) m, R ¹⁰ C (O) NH-, (R ¹⁰⁾ 2 N-Q (O) -, (R ¹⁰⁾ ₂ NC ^(NR10) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-, is selected from group j (a) a hydrogen atom; (b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 0-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰⁾ 2 N-C (O) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3 - N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R 6 SiO), -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -, R ^ -θ is independently selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms; 10) -C (O) NR ⁶ R ⁷ or (11) cycloalkyl of 3 to 6 carbon atoms, m means 0, , 1 or 2 n means 0, , 1, 2, 3, or 4, P means 0, , 1, 2, 3, or 4, q means 1 or 2, r means 0 to 5 provided means a hydrogen atom, with means 0 or 1, T means 0 or 1 a at means 4 or 5, that r = 0 when the V or optical isomers of these compounds or pharmaceutically acceptable salts. 10) nr ⁶ r ^{7 1: L} ) --so _{2 -} nr ⁶ r ⁷ Τθ? 2) - _{N -SO2} - R ^{6 a} 230 13) y'R ⁶ o 14) · —Y- OR ⁶ ABOUT 15) N ₃ or 16) F or R and R are attached to the same carbon atom and together form a - (CH 2) _{u group} , one of which carbon atoms is optionally replaced by one of O, S (O) _m , -NC (O) -, or -N (COR) ¹⁰ ) -, R ⁴ and R ⁵ are independently selected from hydrogen or methyl, 9 Q 4 S wherein any two of R, R, R and R may be bonded to the same carbon atom, R 6, R ^ _and R ^ a _{is than} independently, an selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsylphonyl and said radicals optionally substituted by a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, e) ABOUT R ¹¹ f) -SO ₂ R ^{1: L} or g) N (r 10) ₂ or r 6 and R ⁷ may together form a ring or a ring; R ⁷ and R ^7a may together form a ring, R ^a is selected from alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, a heterocyclic radical or aryl radicals being optionally substituted by one of R (a) C 1 -C 4 alkoxy; - 231 (b) an aryl or heterocyclic radical, c) halogen atom, d) HO, ABOUT f) -S0 ₂ R ^III or g) N (R ¹⁰⁾ ₂ ABOUT R is independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m-> R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (O) -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, n ₃ , -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from aryl, cyanophenyl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, C1, Br, -θΟ- R, R ^'L S (O) m, R ¹⁰ C (O) NH-, (R ¹⁰⁾ 2 N-C (0) -, (R ¹⁰⁾ ₂ NC (NR ¹⁰⁾ -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NH-, R 6 is selected from the group (a) a hydrogen atom; (b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 6 O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ - , (R ¹⁰⁾ 2 n-C (O) -, (R ¹⁰⁾ 2 n-C ^(NR10) -, CN, N02, R ^{1 O} (O) -, R ¹⁰ OC (O) -, n _3, -N (R ¹⁰ ) ₂ or R ^11L OC (O) NR ¹⁰ - a c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent selected from the group of perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (0) -, (R ¹⁰⁾ 2 N-C ^(NR10) -, CN, R ¹⁰ C (0) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) ₂ or R ^11] OC (O) NR ¹⁰ -, - R 232 is independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or aryl, R &lt; ¹ & gt ^; are independently selected from alkyl of 1 to 6 carbon atoms and aryl; A ^x and A independently represent a chemical bond, CH = CH-, -OC-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ C (O) -, -O-, -N ( R ¹⁰ ) -, -S (O) ₂ N (R ¹⁰ ) -, -N (R ¹⁰ ) S (O) ₂ - or -S (O) _m ) -, V is selected from the group (a) a hydrogen atom; b) heterocyclic radical, c) aryl, (d) alkyl having 1 to 20 carbon atoms in which 0 to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and N; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom when A 1 is S (O) _m or when A 1 is a chemical bond, n = 0 and A is S (0) _m group V is a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, V represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic radical, wherein the substituent on these groups is at least one substituent from the group 11) cycloalkyl of 3 up to 6 carbon atoms, m means 0, 1 or 2 n means 0, 1, 2, 3 or 4, P means 0, 1, 2, 3 or 4, q means 1 or 2, r means 0 to 5 per assuming that r = 0 if V means a hydrogen atom, with means 0 or 1, T means 0 or 1 and at means 4 or 5, for provided that in when t = 1, then the substituent ( _R ¹ ) _r VA ¹ (CR ^{1 and} 2) _n A ² (CR 1 ^and 2) _n - represents a hydrogen atom, or a pharmaceutically acceptable salt thereof.