CZ306297A3 - Piperazine compounds and pharmaceutical compositions containing thereof - 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

Piperazine Compounds and Pharmaceutical Compositions

Technical field

The present invention relates to piperazine compounds capable of inhibiting farnesyltransferase resulting in the farnesylation of oncogenic Ras 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 that result 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 growth factor receptors, GDP is replaced by GDP for GTP on the Ras protein, and the GTP-bound form of Ras delivers growth stimulatory signals until this Ras activity is terminated by the action of GTP -ase, which again turns the protein into its ineffective form, linked to GDP, as described by DR Lowy and DM Willumsen, Ann. Roar. Biochem., 62, 851-891 (1993). Mutated Ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) can be detected in a number of human cancers, including colorectal cancer, pancreatic cancer and in myeloid leukemias. The protein products of the expression of these genes do not possess the intrinsic GTPase activity and consequently transmit a growth-stimulating signal.

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 1 2 proteins contains the CAAX motif or Cys-Aaa - Aaa -Xaa, where Cys is cysteine, Aaa is aliphatic amino acid, and Xaa is any amino acid as described in Willumsen et al., Nature, 310, 583-586 Depending on the specific sequence, this group of amino acids serves as a signal sequence for the protein farnesyltransferase or geranylgeranyltransferase, which enzymes catalyze by alkylation of the cistein residue of the CAAX group by treatment with a C 1 - or C 20 -isoprenoid, according to S. Clarke,

Ann. Roar. Biochem., 61, 355-386, 1992; and W. R. Schafer and J. Rine, Ann, Rev. Biochem. Genetics, 30, 209-237, 1992. Ras is one of a series of proteins known to undergo posttranslational 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 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 has been shown to block growth of cells transformed with Ras on soft agar, and also modifies other manifestations of the transformed phenotype. It has also been shown that some protein farnesyltransferase inhibitors selectively block processing of Ras oncoprotein within cells according to N. E. Kohl et al., Science, 260, 1934-1937, 1993 and G. L. James et al., Science, 260, 1937-1942, 1993. Recently

Certain protein farnesyltransferase inhibitors have been shown to block the growth of ras-dependent tumors in hairless mice according to Ν. E. Kohl et al., Proc. Nati. Acad. Sci, USA, 91, 9141-9145, 1994 and induces the recession of mammary and salivary carcinomas in ras-transgenic mice according to podle. E. Kohl et al., Nature Medicine, 1, 792-797, 1995.

Indirect inhibition of protein farnesyltransferase in vivo has been demonstrated using lovastatin (Merck and Co., Rahway, NH) and compactin according to Hancock et al., Ibid., Et al., Schafer et al., Science,

245, 379, 1989. These compounds inhibit HMG-CoA reductase, which limits the rate of production of polyisoprenoids including farnesylpyrophosphate. Protein farnesyltransferase utilizes farnesypyrophosphate for covalent modification of the Cys thiol group in the CAAX protein group by the Ras 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. Nati. Acad. Sci., USA, 87, 7541-7545, 1990. Inhibition of farnesylpyrophosphate biosynthesis due to inhibition of HMG-CoA reductase blocks membrane deposition of cultured cells. However, direct inhibition of farnasyltransferase would be more specific and would be accompanied by fewer side effects than when a desired dose of a general isoprene biosynthesis inhibitor was administered.

Two general classes of protein farnesyltransferase inhibitors, FTP-aase, have been described. The first group consists of FPP analogs of farnesyl diphosphate, the second group consists of substances which are related to a protein substrate for an enzyme, for example the Ras protein. The disclosed peptide-derived inhibitors are typically cysteine-containing molecules and related CAAX group, which is a signal for protein prenylation according to Schaber et al, ibid, Reiss et al, ibid and Reiss et al, PNAS, 88, 732-736, 1991. Such inhibitors may inhibit protein prenylation by providing an additional substrate for the farnesyltransferase enzyme or may be purely competitive inhibitors of US 5,141,851 (University of Texas), NE Kohl et al., Science, 260, 1934 1937, 1993 and Graham et al., J. Med. Chem., 37, 725, 1994. 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 due 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 it has been reported that inhibitors of protein farnesyltransferase are inhibitors of smooth muscle cell proliferation and can therefore be used to prevent and treat areriosclerosis and vascular disorders in diabetes

JP H7-112930.

It has also recently 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 thiol-group-free peptide-like substances which inhibit protein farnesyltransferase and thus post-translational farnesylation of proteins. These substances should be useful in the manufacture of pharmaceutical compositions.

• • • • 4 4 4 4 4 4 4 • • • • · · • • · • • · · 4 • • 4 4 4 4 4 4 4 4 4 4 4 4 4 4

SUMMARY OF THE INVENTION

The present invention provides peptidomimetic compounds containing a piperazine group and inhibiting protein farnesyltransferase. These substances do not contain a thiol group and are therefore very 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 disulfides 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 (R ^a ) _r

V.A '(CFt ^{, and} 2) nAW ^and 2) n

R ²

Y

Λ

VA \ CR ' ^and 2) nA ² (CR ^{, a} 2) _n

R ^ť //

W / - (CR ^1D 2) ₀ \ .N ^x nz ' ^Z ' kk E / ' ¹ m \

R ² R ⁴

, 4 c

In a first embodiment, the present invention provides piperazine compounds of formula A (A (A

V-AVCR ^ W ^ lý W / - (03 ¹ ¾ ^N

N-ý

A / \ J y / US \

R ⁴ R = where

2 ^ T it

R ⁴ and R ⁴ are independently selected from the group

(a) a hydrogen atom;

(b) aryl, heterocyclic radical, C 3 -C 6 cycloalkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, R ¹⁰ O-, R ¹¹ S (O) -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, CN, NO 2> (R ¹⁰ ) 2N-C (NR ¹⁰ ) -, R ¹⁰ C (0) -, 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 unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R ¹⁰ O-, R 6 SiO ) -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, CN, (R ¹⁰ ) 2N-C (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 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 or

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 ,

(c) (CH) NR ⁶ R ⁷

d) halogen atom,

e) CN

2) cycloalkyl of 3 to 6 carbon atoms, i

3) CRA

4) SRfo, S (O) R ^a, ^ SOČR,

5)

6)

NR ° R '

R ³

IN

3) —N_NR ⁷ R ^7a

T o

T o

9) ^-O-OR3

T

O

6q7

NR R

10)

- 8 • · tt tttt

11) - SO ₂ -NR ⁵ R ⁷

Γ

12) - N-SO ₂ -R ^6a

13)

14)

15) N ₃ , or

16) F; or

3

R 1 and R 2 are bonded to the same carbon atom and together form a group (CH 3) wherein one of the carbon atoms is optionally replaced by one of the groups O, S (O), in ^m

-NC (O) - or -N (COR) -,

R and R are independently selected from hydrogen or methyl; • 2 3 4 5 wherein any two of R, R, R, and R may be bonded to the same carbon atom, δ 7 7 H

R, R ^a and R ^z are independently selected from hydrogen, alkyl of 1-4 carbon atoms, cycloalkyl of 3-6 carbon atoms, a heterocyclic radical, an aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, and said radicals are optionally substituted with a substituent selected from groups

(a) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO, E) V, 0 0 —SO ₂ R ^t1 or G) N (R 10) 2; or

7

R and R may together form a ring or

7a

R and R may together form a ring, cl

R 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) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO,

(e) V

f) —so ₂ n

g) N (R 10) 2;

or independently is selected from a) hydrogen, from the group consisting of

b) aryl, 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 (0) NR ¹⁰ -, (R ¹⁰ ) NC (0) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, CN, no ₂ , R ¹⁰ C (0) -, r ¹⁶ oc (o) -,

N ₃ , -B (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -a

- 10 ·· ····

c) alkyl of 1 to 5 carbon atoms, optionally substituted by 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 R ¹⁰ S (O) m-, R ¹⁰ C (O) NH-, (R ¹⁰ ) 2NC (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-, g

R is selected from the group

(a) a hydrogen atom;

b) C 2-6 alkneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _m -,

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

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl,

F, Cl., 3r, R ¹⁰ 0-, R ¹¹ S (O) -, R ¹⁰ C (O) NR ¹⁰ -, (r ^1o ) ₂ nc (o) -, r ¹⁰ 2n-c (nr ¹ ®) R ¹⁰ OC (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NR ¹⁰ -, r ¹⁰ is independently selected from hydrogen, alkyl of up to 6 carbon atoms, benzyl or aryl,

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

2

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

-C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰ ) -, N - ^(R1O) S (O) 2- or -S (0) _m -,

- 0 • 0 0000

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 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 1 is S (O) or 1 m 2 that A is a chemical bond, n = 0 and A represents a group S (0),

W represents a heterocyclic radical,

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

Y 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

L) alkyl of 1 to 4 carbon atoms optionally substituted by 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) R ^6a or m

g) -C (O) NR ° R ^Z ,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷

- 12 ·· ····

6) CN, 7) N0 _2, 8) CF _3, 9) -S (0) R ^SA 10) -C (O) NR ⁶ R ⁷ or 11) cycloalkyl o 3 up to 6 atoms means 0, 1. or 2, means 0, 1, 2.3 or 4, means 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, and pharmaceutically acceptable salts of these compounds .

In a second embodiment, the present invention provides piperazine compounds of formula (B)

R ⁴ //

W / - (CR ^1D 2) _PX NZ ¹ \ r V \ J

R ³ R ⁴ B (R ³ ) r

VA ¹ (CR ^{1 and} 2) nA ² (CR ^{1 and} 2) _n where "1a""1b. ,,.

R and R are selected from the group

(a) a hydrogen atom;

b) aryl, heterocycle, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl each of up to 6 carbon atoms, R ¹⁰ 0-, R ^U S (O) ^R10, C (0) NR ¹⁰ -, CN, ^(R1O ) ₂ NC (O) -, R ¹⁰ 2N-C ^(NR10) -, CN, NO 2, R ¹⁰ C (O) -, R ¹⁰ 0C (0) -, N3, -N ^(R10) _2, or R ¹¹ OC (O) NR ¹⁰ -,

c) alkyl of 1 to 6 carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms each, R ¹⁰ O- , R ^U S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2NC (0) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, cn, r ^1o c (o) - , r ^1o oc (o) -, n ₃ ,

-N (R ¹⁰ ) ₂ and R ¹¹ OC (O) -NR ¹⁰ -, o '

R is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 3 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or

NR ° R 'or

R ^g wherein the substituted groups are substituted at least one substituent selected 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 ^S ,

(c) (CH ₂ ) _p NR ^S R ⁷ ,

d) halogen atom,

e) CN

2) cycloalkyl of 3 to 6 carbon atoms,

(3) 0R °,

4) ° ^SR, S (O) R ^a, SOCR ^ -NR ° R '

3) s °

AND

—NR'R ' ^a

3)

10) O ^ • NFýR ⁷

T

NR ° R '

9)

-Q ^ OA ⁵

T

O

11) - 3O ₂ -NR ⁶ R ⁷

Γ

12) - N-SO ₂ -R ^oa

13)

14)

QR ^C

O

15) N ₃ , or

16) F; or

3

R and R are attached to the same carbon atom and together form a group - (CH _2), wherein one of the carbon azomů is optionally replaced by a group selected from 0, S (C).

i n

-NC (O) - or -N (COR) -,

R2 ^{* 4} represents a hydrogen atom or a methyl group, wherein any two of the substituents R, R and R may be bonded to the same carbon atom;

R, R and R 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, heteroarylsulfonyl 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,

- 16 d)

β)

HIM,

F)

S) -SO ₂ R N (RIO) 2; or, or

7

R and R may together form a ring or

7a

R and R may together form a ring,

6a

R 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) 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;

G

R is independently selected from the group

(a) a hydrogen atom;

b) aryl, heterocycle, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl each of up to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ 0-, R ⁿ S (O) _m -, R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) NC (O) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, cn, no ₂ , R ¹⁰ C (O) -, R ¹⁰ 0C (0) -,

N ₃ , -B (R ¹⁰ ) ₂ or R 6 CClONR ¹⁰ a

- 16 • * · *

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 ^^ O-, R ¹¹ S (O) m R ¹⁰ C (0) NH-, (R ^{1 O)} 2 NC (O) -, R ¹⁰ 2NC ^(NR10 j CN, R ^{1 O} C ( O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 - or R ¹⁰ OC (O) NH-,

R is selected from the group

(a) a hydrogen atom;

b) C 2-6 alkyneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _n -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (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 ¹⁰ OC (O) NR ¹⁰ -, and

c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl,

F, Cl ·, 3r, R ¹⁰ 0-, R ¹¹ S (O) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR ¹ ®) ) -, CN, R ¹⁰ C (0) -, R ¹⁰ 0C (0) -, N3, -N ^(R10) 2 or R ¹¹ OC (0) NR ¹⁰ -,

R ¹⁰ is independently selected from hydrogen, alkyl of up to 6 carbon atoms, benzyl or aryl, Rh independently selected from alkyl of 1-6 carbon atoms and aryl,

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 (0) 2- or -S (0) _m -,

G is H ₂ or O,

··· ·· · · · · · · · · · · · · · · · · · · · ·

(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 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 in that A ¹ is S (O) or, in the case of ^m 2, that A is a chemical bond, n = 0 and A means group S (0),

W represents a heterocyclic radical,

X is -CH., -C (= O) - or -3 (= O) _-,

Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical, wherein the substituent is at least one of (1) C1-C4 alkyl optionally substituted by one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ^S R ⁷

c) cycloalkyl of 3 to 5 carbon atoms,

d) aryl or heterocyclic radical,

e) HO,

f) -3 (0) R ^Sa or mc ₇

g) -C (O) NR ° R ^Z ,

2) aryl or heterocyclic radical,

3) halogen atom,

(4) 0R ^S ,

5) NR ⁵ R ⁷

- 19 ·· ····

5) CN,

7) 20 ₂

8) CF ₃

9) -S (0) R ^Sa , m λ -

10) -G (O) NR ° R; or

11) cycloalkyl of 3 up to β carbon atoms, m means 0, 1 or 2, n represents 0, 1, 2,3 or 4, P means 0, 1, 2,. 3 or 4, q is 1 or 2 r means 0 to 5 per assuming that r = 0 that V is an atom hydrogen, WITH is 0 or 1,

t is 0 or 1 and u is 4 or 5, and pharmaceutically acceptable salts of these compounds.

In a third embodiment, the present invention relates to piperazine compounds of formula C ^{( β) 3} KTO

V - A ¹ (CR ^{1 a} 2) "A ² (CR ^{1 a} 2) n yVyJ * ( ^CR ' ^b a) p \

R ² R ³

N ^{x Z} N — Z

Wherein, and R 4 is independently selected from the group

(a) a hydrogen atom;

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

R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN,

NO ?, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N _q , -N (R ¹⁰ ) - or R ^10? OC (O) NR ¹⁰ -,

c) unsubstituted or substituted C 1 -C 5 alkyl in which the substituent is selected from unsubstituted or substituted aryl, heterocyclic radical, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl or alkynyl, R ¹⁰ O-; R ¹¹ S (O) m R ¹⁰ C (0) NR ¹⁰ - ^(R1O) 2 NC (O) -, R ¹⁰ 2NC ^(NR10) -, CN, R ^{1 O} C (O) - , R ¹⁰ OC (O) -, N g, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) -NR ¹⁰ -,

3. .

R 'and R' are independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 8 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or 1; | or O ⁰ 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 ) ₀ or ^s ,

(c) (CH ₂ ) _O NR ^S R ⁷ ,

d) halogen atom,

e) CN

2) cycloalkyl of 3 to 6 carbon atoms) OR) ° ^SR, S (O) R ^OA SOČR ^Qa

μ. - NR ° R '

3)

iaii

X, NR'R

and)

with)

OR ⁵

10)

- 22 11) - Sat ₂ -nr ⁶ y ⁷

Β ⁵ τ

12) -N-SO ₂ -R ^oa

13)

14)

Ο

15) Ν ₃ , or

16) =; or

3

R 1 and R 2 are bonded to the same carbon atom and together form a - (CH 3) group, one of which carbon atoms is optionally replaced by one of O, S (O), -NC (O) _7, or -N (COR ^L0 ) -,

R is hydrogen or methyl, whereby any two of R, R and R are optionally bonded to the same carbon atom,

R 5 and R 5 are independently selected from hydrogen or methyl, wherein any two of R 6, R ³ , R ⁴ and R ⁵ may be bonded to the same carbon atom,

A 7 7a.

R, R and R are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to β carbon atoms, heterocyclic radical, aryl, aroyl, heeroaroyl, arylsulfonyl, heteroarylsulfonyl 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,

(f) SO ₂ fi ⁿ , or

g) N (R 10) ?; or

R ⁵ and R ⁷ may together form a ring or 7 7a

R and R may together form a ring,

^Sa R is selected from alkyl of 1-4 carbon atoms, cycloalkyl of 3 to δ carbon atoms, heterocyclyl or aryl are optionally substituted zbyzky one of the groups

(a) C 1 -C 4 alkoxy;

b) an aryl or heterocyclic radical,

c) halogen atom,

d) HO,

O

(f) —SO2R ' ¹ , or

S) 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 or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, H ¹⁰ O-, R ¹¹ S (O) _m -, H ¹⁰ C (0) NH ¹⁰ - (R ¹⁰⁾ NC (0) - R ¹⁰ 2 N-C ^(NR10) -, CN, W0 _2, R ^{1 O} C (O) -, R ^treatment OC (0) -,

N ₂ , -3 (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ -a

c) alkyl of 1 to 5 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 “0-,

R ¹¹ S (O) R ¹⁰ C (C) NH-, (R ¹⁰ KNC (O) -, R ¹⁰ NC (NR ¹⁰ ) -, m 4 and

CN, R ^{1 O} C (O) -, ^R1O OC (O) -, Ng, -N (R ¹⁰⁾ 2 R ^10, or 0C (0) NH-, g

R is selected from the group

(a) a hydrogen atom;

(b) C 2 -C 8 alkneyl or alkynyl, perfluoroalkyl, F, Cl, 3r, R "% -, R ¹¹ 3 (0) _m -,

R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, 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 ¹¹ OC (O) NR ¹⁰ -, and

c) alkyl of 1 to 8 carbon atoms, optionally substituted by a substituent from the group perfluoroalkyl,

F, Cl, Sr, R ¹⁰ 0-, R ¹¹ 3 (0) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2NC (0) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, R ^{1 O} C (O) -, ^R1O OC (O) -, N3, -N ^(R10) 2, or R ⁿ QC (O) NR ¹⁰ -,

R ¹⁰ is independently selected from hydrogen, alkyl of up to δ carbon atoms, benzyl or aryl,

- 25 ·· ····

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

12.

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

G -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -3 (0) ₂ N (R ¹⁰ ) -, N- (R ¹⁰ ) S (O) ₂ - or -3 (O) 2 -, represents an oxygen atom, IN se elect from the group and) hydrogen atom, (b) heterocyclic radical, C) aryl, (d) alkyl of 1 to 20 carbon atoms in which they are 0 to 20 carbon atoms

carbon atoms replaced by a heteroatom from the group

0, S and N and

(e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from a hydrogen atom in that A 1 is S (O) or, when ^m _2, A is a chemical bond, n = 0; A denotes the group S (0), m

W represents a heterocyclic radical,

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

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

• · · ·

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

L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups

(a) C 1 -C 4 alkoxy;

(b) NR ^S R ⁷ ;

c) cycloalkyl of 3 to 6 carbon atoms,

d) aryl or heterocyclic radical,

e) HO,

f) -S (O) R ^5a or tn _{K 7}

g) -c (o) nrV

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁵ ,

5) NR ⁵ R ⁷

6) CN,

7) N0 ₂

8) CF ₃

9) -S (O) -R ^5a ,

10) -C (O) NR ° R; or

11) cycloalkyl of 3

m means 0, , 1 or n means 0, , 1, 2.3 P means 0, , 1,2 ,: q means 1 or 2, r means 0 up to 5 per

that V is s is 0 or 1, up to 5 carbon atoms,

2, or 4, or 4, provided that r = 0 hydrogen, when t is 0 or i and u is 4 or 5, and pharmaceutically acceptable salts of these compounds.

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

where la

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

Tlo

R ^x is independently selected from the group

(a) a hydrogen atom;

b) aryl, heterocyclic radical, cycloalkyl, R < ^{1 &gt};

-N (R 6) ₂ or alkenyl of 2 to 6 carbon atoms,

c) unsubstituted or substituted alkyl of 1 to carbon atoms, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, R 10a -n (R ¹⁰ ) ₂ ,

4 5

R, R and R are independently selected from hydrogen and methyl,

- R represents a hydrogen atom, a group of the formula

O or C 1 -C 5 alkyl, straight or branched, unsubstituted or substituted by at least one of the following groups:

1)

2)

3)

4)

5) aryl, heterocyclic radical, OR ⁶ ,

SR ^6a , SO ₂ R ^6a or

Where any two of R, R, K and R ³ may be attached to the same carbon atom,

R, R, and R ^z are independently selected from hydrogen, or alkyl of 1-4 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heterocyclic radical, these radicals being unsubstituted or substituted by one of the following groups:

(a) C 1 -C 4 alkoxy;

(b) a halogen atom; or

c) aryl or heterocyclic radical,

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) hydrogen,

b) alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms each, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl 1, R 2, O-,

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

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

(c) alkyl of 1 to 6 carbon atoms substituted by a perfluoroalkyl group 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 is selected from the group

(a) hydrogen,

b) alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl,

R ¹⁰ 0-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, CN, NO 2>

(R ¹⁰ ) _? NC (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ A or R OC (O) NR - a

(c) alkyl of 1 to 6 carbon atoms, unsubstituted or substituted by 1 to 6 perfluoroalkyl, F, Cl, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, CN, (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 ¹⁰ is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl and aryl,

R ¹¹ independently represents alkyl of 1 to 6 carbon atoms or aryl,

12A and A independently represent a single 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 selected 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 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 and provided that V has a different meaning from hydrogen when A ¹ is S (O) or when A ¹ is a chemical bond, n = 0 and A 1 is S (0),

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

X is 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 , stands for 0, 1 or 2, stands for 0, 1, 2, 3 or 4 stands for 0, 1, 2, 3 or 4 stands for 0 to 5, provided that r = 0 if V represents a hydrogen atom, represents 0 or 1 and represents 0 or 1, or a pharmaceutically acceptable salt thereof

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

·· · φ φφ (Rť v-aWW ¹ ' ¹ !) »

(Ca ^{, Da} ).

_Z N p \.

V..V

N-Z

R ^from O * s \ where

R ^1a is independently selected from hydrogen or C 1-6 alkyl,

R ^1b 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) unsubstituted or substituted alkyl of 1 to carbon atoms, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, R ^{10 and} -N (R ¹⁰ ) ₂ ;

4 5 _z

R, R and R are independently hydrogen or methyl,

- R represents a hydrogen atom, a group of formula JMR ° R '

O í

or straight or branched chain alkyl of 1 to 5 carbon atoms, unsubstituted or substituted by at least one of the following groups:

- 32 ·· ····

1) aryl;

2) heterocyclic radical,

3) OR ⁶ ,

(4) SR ^6a , SO ₂ R ^6a or

5)

O □ 2 3 -4 wherein any two of R, R, and R may be bonded to the same carbon atom,

R ⁶ , R ⁷ and R ^7a are independently selected from hydrogen or C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 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 ^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) an aryl or heterocyclic radical; g

R is independently selected from the group

(a) hydrogen,

b) alkyl of 1 to 6 carbon atoms, alkenyl or 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 -, CN, N02, ^(R10) 2N-C ^(NR10) -, R ^{1 O} C (O) -, ···· ··

^R1O OC (O) -, -N (R ¹⁰⁾ ₂ ^or R OC (0) NR ¹⁰ -, and

(c) alkyl of 1 to 6 carbon atoms substituted by a perfluoroalkyl group 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 -, g

R is selected from the group

(a) hydrogen,

b) alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl,

R ¹⁰ 0-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, CN, NO 2>

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

c) alkyl of 1 to 6 carbon atoms, unsubstituted or substituted by a perfluoroalkyl group of 1 to 6 carbon atoms, F, Cl, R ^ O-, R ^ ^ S (O)

R ¹⁰ C (O) NR ¹⁰ -, CN, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, -N (R ¹⁰ ) 2 or R ^1X OC (0) NR ¹⁰ -,

R ¹⁰ is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl and aryl, r H is independently alkyl of 1 to 6 carbon atoms or aryl,

12,

A and A independently represent a single 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 selected from the group of pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl;

- 34 (c) aryl,

d) alkyl of 1 to 20 carbon atoms in which 0 to 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 and provided that V has a different meaning from hydrogen when A ¹ is S. (O) or when A is gil · a chemical bond, n = 0; and A is S (O) _m +

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

G is or O,

Z represents mono- or bicyclic aryl, 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 ^S R ⁷ ;

(c) cycloalkyl of 3 to 6 carbon atoms;

d) aryl or heterocyclic radical,

e) HO,

f) -S (O) R ^6a or m 2 -, 7

g) -C (O) NR ° R ^Z ,

2) aryl or heterocyclic radical,

3) halogen atom,

4) OR ⁶ ,

5) NR ⁶ R ⁷ · 4 4 · 4 · 4 · 44 4 4

4 · · 4 4 •• 4,444 444 4444 44 4

S) CN,

7) N0 ₂

3) CF ₃ ,

9) -s (a) and ^Sa , lil / ·

10) -C (Q) NR 0 K ^/ or

11) cycloalkyl of 3 up to β carbon atoms, m means 0, 1 or 2, n represents 0, 1, 2,3 or 4, p means 0, i, 2, 3 or 4, r » means 0 to 2 per assuming that r = 0 that V is azome hydrogen, WITH is 0 or 1, - is 0 or 1 and AT means 4 or 5,

provided that when G is h ' ₂ and W is imidazolyl then (R ⁸ ) -VA ¹ (CR ^1a -) A ² (CR ^1a ) r 2 n 2 n has the meaning different from hydrogen and provided that when X is -C (= O) - or —S (O) - then t = 1 and the substituent ( ^r8 ) pVA ¹ (CR ^and 2) ^ A ² (CR ^{and (} 2) - has the meaning different to the hydrogen atom, or a pharmaceutically acceptable salt thereof.

Preferred piperazine compounds of the invention include:

2 (S) -Butyl-1- (2,3-diaminoprop-1-yl) -4- (1-naphthoyl) piperazine, 1- (3-amino-2- (2-naphthylmethylamino) prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

4 · · ···

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

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

1- (2 (R) -amino-4-hydroxybutyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, - (2-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, - (2-amino-3- (2-hydroxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

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

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

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

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

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

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

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

4444

4 4

4 4

4

4 (S) -butyl-1- [5- (1- (2-naphthylmethyl)] - 4,5-dihydroimidazole / methyl-4- (1-naphthoyl) piperazine; 1- [5- (1-benzylimidazole) methyl] / -2 (S) -Butyl-4- (1-naphthoyl) piperazine,

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

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

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

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

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

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

1- (2 (R) -amino-3- (3-benzylthio) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, (2 (R) -amino-3- / 3- ( 4-nitrobenzylthio-propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine,

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

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

- 38 ··· ··· ··· ··· ·· ·

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

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

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

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- (2-methylphenyl) 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-methylsulfonylethyl) 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- (1-naphthoyl) piperazine

1- / 5- (1-benzylmimidazole) methyl / -2 (S) -butyl-4- (1-naphthoyl) piperazine

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

9999

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

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- (1-naphthoyl) piperazine

1- [1- (4-cyanobenzyl) -1H-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

CH ₃

O.

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

(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-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone

CH ₃ <

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

or a pharmaceutically acceptable salt thereof.

The compounds of the invention may contain asymmetric centers and thus occur as racemates, racemic mixtures and as individual diastereomers, all isomers including optical isomers being included within the scope of the invention

When any group or symbol, for example, 12 aryl, heterocyclic, R, R and the like occurs more than once in the formula or a portion thereof, each occurrence is independent of any other occurrence. Combinations of substituents are permissible only if they result in stable products.

· · ·

Alkyl radicals include straight or branched chain aliphatic hydrocarbon groups having the specified 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, at least one of which 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 stable 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, any bicyclic group is also included wherein 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, dihydrobenzofazolyl, dihydrobenzothienyl, dihydrobenzothiopyran, dihydrobenzothiopyran, dihydrobenzothiopyran, dihydrobenzothiopyran, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyllinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridazinyl, piperazinyl, pyridazinyl, pyridazinyl, pyridazinyl »444444 • · · 4 4 4 · 4 4 · · 4 · 4 <

4,444,444 4444,444 pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinylsulphi thio, thiazolyl thiophenyl, thiazolyl thienyl, thiazolyl thio, thiazolyl thienyl, thiazolyl thienyl, thiazolyl thienyl, thiazolyl thiophenyl;

Heteroaryl means any stable monocyclic or bicyclic radical of up to 7 members in each ring, at least one of which is atomatic and at the same time 1 to 4 carbon atoms being replaced by N, O, and S heteroatoms. benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiapyranol, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl and thienyl.

In the meanings of R and R, all of the above groups may be substituted, i.e. alkyl of 1 to 8 carbon atoms, alkynyl or alkenyl of 2 to 8 carbon atoms, substituted aryl or heterocyclic radicals.

θ * 7 7 cl

Similarly, R, R and R may all be substituted, i.e., alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, aroyl, aryl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, and a heterocyclic radical; 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 4, CN, (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) S (O) -, (C 1 -C 6 alkyl) C (O) NH-, H ₂ NC (NH) -, (alkyl of 1 to 6 carbon atoms) C (O) -, (alkyl of 1 to 6 carbon atoms) OC (O) -, θ, (alkyl of 1 to 6 carbon atoms) OC (O) NH- and alkyl o 1 to 20 carbon atoms.

3

When R 1 and R 2 together form a group ^ ^H 2 u ~, cyclic groups are formed. Examples of such cyclic groups include, for example

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

The lines that extend from the ring systems towards the 2 3 4 substituents, for example R, R, R and the like. means • · «·

• 9 9

9 9 9

9,999 9

9 9

9900 99 +

49 that the substituent located at the end of such a bond may be bonded to any of the substitutable carbon atoms in the ring.

Preferably, R ^x and R ^{x are} independently selected from hydrogen, -N (R ¹⁰ ) 2, R ¹⁰ C (O) NR ¹⁰ - or unsubstituted or substituted alkyl of 1 to 6 carbon atoms, wherein the substituent is selected from unsubstituted or substituted phenyl, - (R ¹⁰ ) 2, R ¹⁰ O -, and R ¹⁰ C (O) NR ¹⁰ -.

Preferably R is selected from hydrogen,

or substituted or unsubstituted C 1 -C 8 alkyl, C 2 -C 8 alkenyl or alkynyl groups wherein the substituent is at least one of:

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 ⁵ ,

(c) (CH ₂ ) _p NR ⁶ R ⁷ ,

d) halogen atom,

2) cycloalkyl of 3 to 6 carbon atoms,

3) ORO,

(4) SR & S (O) Róa, sCbRÓa,

5) —NR ^S R ⁷

WITH)

'0

- 50 ”N ^ NF | 7 _R 7a —Q ^ NR ^and R '

a) γ o

9) in ^R3

O

10)

NR ° R '

11) ^{_-SO2-NR 7} R Γ 12) -N-SO ₂ -R ⁵ 13)' yt ^r5 0 AT) ^ -QR ^S H 0

15)

16) or • 9 9 9 9 9

Preferably, R is selected from hydrogen or alkyl of 1 to 6 carbon atoms.

5

Preferably R and R are hydrogen.

7 7 o

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

θ Si

Preferably R is unsubstituted or substituted alkyl of 1 to 6 carbon atoms, unsubstituted or substituted aryl or unsubstituted or substituted cycloalkyl.

,,

Preferably R is hydrogen or methyl, most preferably R is hydrogen.

R @ ¹ is preferably selected from hydrogen, alkyl of 1-6 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 O 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.

Y 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. Very advantageous meaning 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 highly preferred value for Z is unsubstituted or substituted phenyl.

W 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 _H2 and W is imidazolyl, has a substituent of the formula (R ⁶⁾ R-V-A ^'1' (CR ^Ia '2) _n A ^{2 (CR'! 'And} 2) _n - with preferably a meaning different from a hydrogen atom.

In the compounds of formula B wherein X is -C (= O) - or -S (= O) -, t = 1, the substituent (r ⁸ ) - - VA ¹ (CR ^{1 and} 2) _n A ² (CR ^{1 and} 2) _n - preferably a meaning different from hydrogen.

It has already been stated that the meaning of any substituent 9 t or a general symbol, for example R, R, at a similar location in a molecule, is independent of the meaning of that symbol elsewhere in the same molecule. This means that -N (R ^XU ) ₂ can be -NHH in the same molecule,

- 52 • 4 4 4 4 4

-NHCH 3, -NHC ₂ H ₃ -, and the like. It will be understood that the substituents or substituent system in the compounds of the invention may be selected in conventional manner to provide compounds that are chemically stable and readily synthesized from available starting materials.

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 the like; , phenylacetic, glutamic, benzoic, salicylic, sulfanil, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

Pharmaceutically acceptable salts of the compounds of the invention containing a basic group may 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 solvent combinations.

The compounds of the present invention can be prepared using the reactions shown in Schemes 1-22 and other simple conventional reactions such as ester hydrolysis, deprotection, and the like, such reactions are well known in the literature. The substituents R, R and R, known in the schemes, are R, R,

R ⁴ and R ⁵ , however, the ring bond site is illustrative only.

«· Φ« φφ φ φ φ

ΦΦ φφφφ

The reactions may be used in whole to obtain the resulting products of the invention or in part to obtain fragments which are then joined by the alkylation reactions described in the schemes.

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

For example, Scheme 1 synthesizes 2-alkylsubstituted piperazines, generally described in

JS Kiely and SR Priebe, Organic Preparations and Proceedings Int., 1990, 22, 761-768. The procedure is such that the Boc-protected amino acids of formula (I), commercially available or obtained by known methods, can be coupled to N-benzylamino acid esters using all 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 mild 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 Boc 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 in 24 to 48 hours. The product VI can be treated with an acid chloride or carboxylic acid under standard dehydration conditions to form the carboxamides of formula VII by cleavage of the acid protecting group as described above to give an intermediate of formula VIII according to Scheme 2. This intermediate can be alkylated, especially reductive alkylation.

····

various aldehydes, e.g. IX. These aldehydes can be obtained by conventional procedures, for example, by P. Goel, U. Krolls, M. Stier, and S. Kesten, Organic Syntheses, 1988, 67, 69-75, from the corresponding amino acids of Scheme 3. Reductive alkylation may be carried out. may be carried out at a pH of 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. Further, 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, protected piperazine intermediate VII can be subjected to reductive alkylation with other aldehydes such as 1-trityl-4-imidazolylcarboxaldehyde or 1-trityl-4-imidazolylacetaldehyde to give stream XVI of Scheme 4. The trityl protecting group can be removed to form of the product XVII, or the intermediate XVI can first be treated with an alkyl halide and then deprotected to provide the alkylated imidazole XVIII. Intermediate VIII can also be acylated or sulfonylated by conventional methods. The imidazole acetic acid XIX can be converted to the acetate XXI by conventional methods. This may then first be reacted with an alkyl halide and then refluxed in methanol to form a region-specific alkylated imidazole acetic acid ester of formula XXII. Hydrolysis and reaction with piperazine of formula VIII in the presence of condensation

- 56 ♦ MM »9

Κ Φ «

Φ Φ agents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC can be used to obtain 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 liberated upon completion of the reaction of the protecting group. to an aldehyde which can then be reacted with various organometallic reagents, for example Grignard reagents, to form secondary alcohols such as XXIX. In addition, the deprotected amino alcohol XXX can be subjected to reductive alkylation under the above conditions using various conditions. of aldehydes to form secondary amines, for example Formula XXXI of Scheme 7 or tertiary amines.

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

In addition, 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, these may first be hydrogenated to liberate the phenol and then cleaved off the amino protecting group by treatment with an acid to form the compound of formula XL.

- 44 44 4444

Alternatively, the amino group may be removed from the compound of formula XXXIX to 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, wherein 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 can then be processed to the resulting products according to Schemes 3 to 9.

The N-arylpiperazines can be prepared according to Scheme 11. Arylamine XLV is reacted with bis-chloroethylamine hydrochloride XLVI at reflux 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 Boc-protected aminoaldehydes XLIX prepared from the compounds of Formula I as described above yields intermediates of Formula L. These are then reacted with bromoacetyl bromide under Schotten-Baumann conditions. The ring is sealed with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give compound LI. Carbamate Protection ···· Α · A AAA # AA A • A A AAAA · · · · · A · A A · A A A A A

AAA AAA · AA ·· ·· ·

The 58 group is removed under acidic conditions, 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 Schemes 3 to 9.

The isomeric piperazin-3-ones can be prepared according to Scheme 13. The imine formed from the arylcarboxamide of formula LII and the 2-aminoglycinaldiethylacetal LII can be reduced under various 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 with an arylcarboxylic acid. The resulting N-benzylarylcarboxamide of formula LIX can be hydrogenated in the presence of a catalyst to give the piperazinecarboxamide of formula LX, which can then be further processed to the resulting products according to Schemes 3 to 9.

Reaction Scheme 15 describes an example of the synthesis of piperazino compounds of the invention in which the substituents R q and R together form a group ^- ( ^CH 2 u ^{- Ρθ3Ϊυ} Ρ ^α 3 ^{θ) by,} for example, substituting 1-aminocyclohexane-1-carboxylic acid. 9 99 99 99999999 999999

999 999 999

It is then converted to the 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 the resulting products as described in Schemes 3 to 9. It will be appreciated that the reagents used to attach the 2-naphthyl substituent Y and the imidazolylalkyl substituent may be replaced by other reagents commonly used in the art for introducing additional N-substituents into the piperazine compounds.

The aldehyde XLIX of Scheme 12 may also be subjected to reductive alkylation with aniline as shown in Scheme 16. The LXXI product may then be converted to the piperazinone derivative by acylation with chloroacetyl chloride to give intermediates of Formula LXXII, which may then be cyclized by treatment to form compounds of Formula LXXIII.

These are cleaved and the deprotected compounds are treated with reductive alkylation protected with imidazole carboxaldehyde to give intermediates LXXV, which can be converted to the imidazolium salt LXXVI by alkylation with an arylmethyl halide. Final deprotection may 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 provide the final products LXXVII.

Scheme 17 illustrates the use of an optionally substituted homoserinlactone of formula LXXIX for the preparation of a Boc-protected piperazinone derivative of 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 mesylated and replaced with a suitable nucleophile, for example, 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 an easily 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 W is a pyridyl group. Similar synthetic procedures can be used to prepare alkanols containing other W heterocyclic groups known in the art.

·· ··· «··· · • 9

9

- 61 SCHEME 1

1) HCl, CH ₂ Cl ₂

2) NaHCO ₃

R ^a

- _ ch ₂ or ₂ \ T_ / ~ \ h ₂ ch ₃ oh

BoCoO

10% Pd / C

R ^a ° a / —N NH o M

R ^b

VI

- 62 ·· ············

DIAGRAM

EDC-HCl, HOBT DMF

Vlil ·· ·· · * ··

- 63 S C Η E MA 3

BocNH

IX

Boc NH CHO

NaBH (OAc) 3 Et ₃ N, Cich ₂ CH ₂ Cl

CF ₃ CO ₂ H ₂ or Cl ₂

• · · 44 44 ···· • • • • · 4 4 • • • 4 • · · 444 4 • • • · • • 444 444 444 4444 44 4

Scheme 3 - cont.

CF ₃ CO ₂ H, CH ₂ or ₂ ; NaHCOg

AgCN £

XV

- 65 DIAGRAM 4 • β · · · · · · · · · · · · · · · · · 4

444 · 4 4

XVIII »· · · · · · · · · · · · · ·

SCHEME 5 ^N_ í

N

H

XIX .CH ₂ CO ₂ H

CHgOH

HCl .CH ₂ CO ₂ CH ₃ ^N Λ o

H 1 HCl XX (C ₈ H ₅ ) ₃ CBr

CH ₂ CO ₂ CH ₃ 1) ArCH ₂ X CH ₃ CN reflux (C ₂ H ₅ ) ₃ N

DMF

N

Tr

XXI

2) CH ₃ OH, reflux

2.5N HCl

55 ^and C aq

Ar 2 .CH ₂ CO ₂ H b

N

XXIII • 000

Scheme 5 - cont.

XXIV

• · · · · ·

- 68 DIAGRAM 6

VIII

NaSH (OAc) ₃ Et ₃ N, ClCH ₂ CH ₂ Cl

BnCL ·

BocNH CHO

XXV

CICOCQCI

DMSO CH ₂ Cl ₂ (C ₂ H _s ) ₃ N φ φ ΦΦΦ ·

- 69 ·· · · · φ · ·

Scheme 6 - cont.

2. TFA, CH ₂ Cl ₂

1. R’MgX

• »· · · ·

SCHEME 7

CF ₃ CO ₂ H ₂ or Cl ₂

XXX

R'CHO

NaBH (OAc) ₃

Cich ₂ CH ₂ C!

NH R ^b

R'CH ₂

XXX!

·· ··· ·

- 71 SCHEME 8

XXVII

Η H

N = \ / = ^N

0 ₂

NaH, DMF 0 ° C

IZ

XXXII

R'SH (C ₂ H ₅ ) ₃ N ₃ O ₃ °

XXXIII

- 72 SCHEME 9

1) Boc 2 O, K ₂ CO ₃ thf-h ₂ o

YEAH

2) CH ₂ N ₂ , EtOAc

LiAIH ₄

THF

0-20 ° C

BocNH CO ₂ CH _;

XXXV

R'CH ₂ X

Cs ₂ CO ₃

DMF

XXXVII

DMSO (C ₂ H ₅ ) 3 N

20 ° C pyridine · SO ₃

XXXVIII *

Scheme 9 - cont.

NaBH (OAc) ₃

Cl ₂ CH ₂ CH ₂ Cl

XL • 0 0

- 74 SCHEME 10

1) LAH, Et ₂ O

2) Boc ₂ O

XLÍII

- 75 SCHEME 11

ΑγΝΗ ₂

XLV

HCl

XLVI π - butanol reflux

R ^and R ^b

R ^and R ^b

XLVII ··

- 76 SCHEME 12

CH ₃ NHOCH ₃ · HCl

EDC. HCl, HOBT DMF, E ₃ N, pH 7 ^ 'O' ^ 'N' \ ' ^{N (CH3) OCH3 LAH} ' ^Eaa HO

XLVIII

ArCH ₂ NH ₂

NaBH (OAc) ₃ CICH ₂ CH ₂ Cl pH 6

R ^a

NHCH ₂ Ar

1) BrCH ₂ COBr

EtOAc, H ₂ O, NaHCO ₃

2) NaH, THF, DMF

-77 Scheme 12 - cont.

Vn Ν-Λ • O M Ar

O

1) TFA, CH ₂ Cl ₂ ; ₂

IF

R ^a

HN N ~ \

M Ar O • ·

9999

- 78 SCHEME 13

ArCHO + NH ₂ CH ₂ CH (OC ₂ H ₅ ) ₂

NaSH (OAc) ₃

Hive

Lili

Ar CH ₂ NHCH ₂ CH (OQ ₂ H ₅ ) ₂ UV

DMF, Et ₃ N, pH 7

6N HCI 99

OR ^a

AND.

O N H O LV

Ar r

N, CH (OC ₂ H ₅ ) ₂

THF

R ^and O.) -

O Ar

H ₂ 10% Pd / C CH ₃ OH

LVI

R ^and O

V> -N N -O /

Ar

LVU ·· 44 ··

- 79 SCHEME 14

4 4

4 4 4 4 4 4 • 4 4 4444 • · · 4

4444443 44 4

R ^b

10% Pd / CH ₂ ch ₃ oh

ArCO ₂ H

EDC · HCI HOBT, DMF

R ^£

HN N— /

Y-y Ar

R ^a

LX

SCHEME 15

PhCH ₂ NHCH ₂ CO ₂ C ₂ H _with DCC, CH ₂ Cl ₂

BocNH CO ₂ H LXI

O LXII

(a) TFA, CH ₂ Cl ₂

b) NaHCO ₃

LXIII (CH ₃ ) ₃ Al

CHCU

Boc ₂ O

CH ₂ Cl ₂

7— \

BocN NH ₂ Pd / C CH ₃ OH

LXVI ·· ····

Scheme 15 - cont.

LXX ·· ·· »3 ··

SCHEME 16

R

BocNH

XLIX

ArNH ₂

NaBH (OAc) ₃

CICH ₂ CH ₂ Cl

BocNH '

Ar

LXXI

O

EtOAc / H ₂ O NaHCO ₃

R

R

NaH '·) \ HC!

- BocN N-Ar DMF-EtOAc

O

LXXIII

Scheme 16 - cont.

R

ΗΟΙΉΝ N — Ar

M o

LXXIV

CHO

C (Ph) ₃

NaBH (OAc) ₃ CICH ₂ CH ₂ Cl pH 5-6 (Ph) ₃ C

• • • 44 44 4444 • • • • 44 • • 4 • 4 * 4 • 4 4 4 4 4 4 4 4444 4 4 4

LXXV

ArCH ₂ X

CH ₃ CN

MeOH or

TFA, CH ₂ Cl (C ₂ H _s) 3 SiH

Ar-

N N-Ar

M

O

LXXVII

• · • ·· ·· ···· • • • « • · · • • · • · · ··· • • • • · • • ··· ··· * - ·· ···· • A •

SCHEME 17

1. Boc ₂ O, i-Pr ₂ EtN

2. DIBAL sub

-Q

BocHN \

OH

ArNHNaBH (OAc) ₃

Cich ₂ CH ₂ C!

OH

'Ar

O

EtOAc / H ₂ O NaHCO ₃

HO sub

Cl O

LXXXI

Cs ₂ CO ₃

DMF

HO sub

BocN N-Ar

O

LXXXII

- 85 Scheme 17 - cont.

HO sub v,

BocN N — Ar /

1. MsCI, iPr ₂ NE _/ 2. NaSEt, DMF /

O

LXXXII

1. (COCl) ₂ , Et ₃ N DMSO

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

EtS sub

BocN N-Ar

M

O

HO sub ⁰ / “BocN

N-Ar

LXXXHI

LXXXIV

SCHEME 18

I.KtBu, THF? CO, E! ^{r2x = N}

Pb 2.5 5% aqueous HCl

LXXXV

R ^{1 2} ) —CO ₂ Et H ₂ N

HCl

1. Boc ₂ O, NaHCO ₃ R ² - CO ₂ H

BocHN

2. LiAlH ₄ , Et ₂ O

LXXXVI

0 0 0 0

0

0 0

- 87 SCHEME 19

CO ₂ CH ₃

NaBH ₄ (excess)

CH ₂ OH

DMSO

SO ₃ -Py, EtsN

CHO

SCHEME 20

NaBH ₄ excess

SO _{3 -} Py, E ₃ N

DMSO

CHO · · · ·························

- 89 SCHEME 21

Br.

IN

1. lda, what ₂

2. MeOH, H *

·· ·

SCHEME 22

t.LDA, CO ₂

Second (CH3) ₃ ny ₂

CHO

The compounds of the invention may be used for therapeutic purposes in mammals, particularly humans, in particular for the treatment of cancer. Examples of cancers that can be treated include cancer of the colon and rectum, carcinoma of the pancreas, myeloid leukemia, and neurological tumors. These tumors can arise from mutations in ras genes, protein mutations that can direct Ras activity, such as neurofibromin (NF-1), neu, ser, abl, lek, fyn, or other mechanism.

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 useful 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, both benign and malignant, that activate Ras protein as a result of oncogenic mutation in other genes (i.e., the Ras protein gene is not itself activated by mutation to the oncogenic form). wherein the inhibition is achieved by administering an effective amount of the compounds of the invention. For example, some of the components of NF-1 cause benign proliferative disorders.

The compounds of the present invention may also be used to treat certain viral infections, particularly for the treatment of delta hepatitis and related viral diseases as described in J. S. Glenn et al., Science, 256, 1331-1333, 1992.

The compounds of the invention are also useful for the prevention of restenosis following transluminal coronary angioplasty, since they cause inhibition of neointima formation according to C. Indolfi et al.

541-545, 1995.

The compounds of the invention can be used for the treatment and prevention of polycystic kidney disease according to D. L. Schaffner et al., American Journal of Pathology, 142, 1051-1060, 1993; et al., FASEB Journal, 2, A3160, 1988.

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

The compounds of the invention may be administered as such or preferably together with a pharmaceutically acceptable carrier or diluent and optionally with known excipients such as alum in the form of pharmaceutical compositions in a conventional manner to mammals including humans. 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, for example, as tablets or capsules, aqueous solutions or suspensions. 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, intra- peritoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and their pH adjusted with a buffer. For intravenous use, the total concentration of solutes may be adjusted to render the composition 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 that are effective in treating and preventing NF-1, restenosis, polycystic kidney disease, infectious hepatitis delta, and related viral as well as 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 in alternation with known agents when a direct combination is not suitable.

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, usually

the doses employed will vary depending on the age, weight, as well as the patient's response to the administration of the agents and the severity of the symptoms of the disease.

By way of example, suitable dosages are for use in a mammal having cancer. 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. The test mixture is divided into two parts which are contacted with a mixture comprising a known substrate for farnesyltransferase, an FTPase, for example a tetrapeptide which contains an amino-terminal cysteine and, in addition, farnesyl pyrophosphate, one of which also contains 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 the action of farnesyltransferase, followed by determination of the chemical content of the resulting mixture after incubation by conventional 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 the Piperazine Compounds of the invention presence of protein farnesyltransferase in the original mixture of interest.

- 95 ·· ····

Obviously, the above assay 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 that are potent enzyme inhibitors can be used for titration to determine the amount of the enzyme. A series of samples containing a portion of a tissue extract with an unknown amount of farnesyltransferase enzyme, an excess of a known substrate for this enzyme, for example a tetrapeptide with a cysteine residue at the amino terminal end and farnesyl pyrophosphase, is 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 test sample) required to inhibit the enzymatic activity of the sample to 50% is approximately equal to half the enzyme concentration in that sample.

The following examples are intended to illustrate the invention. HPLC was performed using a 40 x 100 mm Waters PrepPak ^R column (Delta-Pak ™ C. _o , 15 µm, 100 S) 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 solution

R salts with TFA over a Biorad AG 3X4 column (100-200 mesh, Cl-form). HPLC purification was used in Examples 1-23, 27, 48 and 49.

• 0 0000

-2-Z-Z-Z-Z_Z_2_2_i_®_5_3.

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.J 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, 10.50 g (45.20) was added. 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 were added. Then the reaction mixture was stirred at 0 ° C for 2.0 h and then at 20 ° C overnight. The resulting precipitate was removed by filtration; and hydrogen chloride gas was bubbled through the solution in dichloromethane for 2.0 to 4.0 hours until completion of the reaction was shown by thin layer chromatography.

The solvent was then removed from the reaction mixture under vacuum; and the residue was partitioned between 150.0 mL of ethyl acetate; and 42.0 mL of saturated sodium bicarbonate solution. After separation of orga-

97% of the organic and aqueous phases, the organic layer was washed with saturated sodium chloride solution; dried with magnesium sulfate; and evaporated after filtration.

The crude diketopiperazine was mechanically processed; and taken out with hexane.

The title compound was obtained as a white powder.

^ H-NME (300 MHzJCDCl ^):

.delta.7, 24-7.4O (5H, m); 6.22 1H-1H; š.s.); 4.07 (1H; dt, J = 3.60 Hz); 3.87 <th; d .; j = 17.0 Hz); 3.80 (ih; 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 as described in Step A above, 4.95 g (0.019 mol), was dissolved in 200.0 ml of tetrahydrofuran and the resulting solution was cooled and cooled. to 0 ° C. Lithium aluminum hydride (2.60 g, 0.0685 mol) was then slowly added to the solution, and the resulting mixture was heated to reflux for 18 hours; and then cooled to 0 ° C; and then slowly mixed slowly with 5.0 ml of water and 5.0 ml of 10% aqueous sodium hydroxide; and then with 5.0 ml of water.

Then the reaction mixture was stirred for 30.0 minutes; and then filtered. After removal of the solvent under vacuum, 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 mole) of di44 4444 4444 4444 4444 4444 4444 4444 4444 4444 4444

- 98 target: butyldicarhonate. After 2.0 hours, saturated sodium bicarbonate solution was added to the reaction mixture at 20.0 ° C.

After separation of the organic and aqueous phases, the organic layer was washed with saturated sodium chloride solution; and then dried with magnesium sulfate. Filtration followed by evaporation afforded the crude product which was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent.

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

¹ H-NMR (300 MHz; LMSO-d 6):

delta 7.25 (5H, m); 3.90 '(1H;bs); 3.73 (1H J d J J = 13.0 Hz); 3.51 (ih; d, J = 13.0 Hz); 3.34 (ih; d, J = 13.0 hr _z ); 2.93 (1h, m); 2.75 (1H, dJ, J = 11.0 Hz); 2.62 (1Η, J = dJ n _r o 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, J = 7.0 h _z ).

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; and the vessel was purged with argon. To this solution was added 0.80 g of 10% palladium on charcoal, and the reaction mixture was hydrogenated at 40 psi hydrogen for 24.0 hours.

The catalyst was then 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):?

delta 4.08 (1HJ bs); 3.90 (1H; dJ J = 12.0 Hz); 2.50 3.80 (6h, m); 1.80 (1H, _m ); 1.60 (ih, _m ); 1.46 (9h, _s ); 1.30 (4h, m); 0.90 (3h; t, J = 7.0 h _z ).

S p a r D D

Preparation 1-target. butoxycarbones of 1-2 (S) -n-butyl-4- (1-nontoxyl) piperazine

A mixture prepared by mixing 0.325 g (1.34 mmol) of 1-tert-butyloxycarbonyl-2 (S) -n-butylpiperazine, obtained under the above-described Step C; 0.203 g (1.34 mmol)

1-hydroxybenzotriazole (HOBT); and 0.254 g (1.34 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC); was added to 7.0 mL of dried, degassed dimethylformamide.

Thereafter, the pH of the resulting reaction mixture was adjusted to pH 7.0 with triethylamine and the reaction mixture was stirred for 2.0 hours. Dimethylformamide was then 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 hydrogen sulfate solution; saturated sodium bicarbonate solution; saturated aqueous sodium chloride solution; and then dried with magnesium sulfate.

The title compound was obtained in the form of a thick, oily consistency.

Grade E

100 ALIGN!

Preparation of 2 (S) -n-butyl-3- (1-naphthyl) -piperazine. hydrochloride

The product prepared as described in Step D above; was dissolved in ethyl acetate; and the resulting solution was brought to a temperature of minus 40 ° C under a nitrogen atmosphere; and then saturated with hydrogen chloride gas. After warming to 0 ° C in 30 minutes; the solution was purged (bubbled) with nitrogen.

Then the solvent was removed from the reaction mixture 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) of triethylamine. To this reaction mixture was added 11.0 g (0.0448 mol) of [2- (tert-butoxycarbonyloxy) amino] -2-phenylacetonitrile (BOC-OK) J along with an additional amount of triethylamine to reach a pH of 9.50.

Then, the reaction mixture was 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. Thereafter, the aqueous phase was adjusted to pH 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 a saturated aqueous solution of sodium chloride; and was subsequently dried with magnesium sulfate.

The resulting substance of a masterly nature (5.46 g); was recrystallized from ethyl acetate; to give the title compound as a white solid.

• • •

- 101 Degrees CL

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

The mixture, prepared from 1.80 g (5.92 mmol) of 2,3-bis (tert-butoxycarbonylamino) -propanoic acid, obtained as described in Step FJ above, in 25.0 ml of dimethylformamide, was stirred overnight with 0.635 g (6.51 mmol) of N-methoxy-N-methylamine hydrochloride; 6 (4 mmol) 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide (EDC); 0.80 g (5.92 mmol) of N-hydroxybenzotriazole; and g 0.825 ml (5.92 mmol) of triethylamine.

After being removed from the reaction mixture under vacuum dimethylform8mid _of 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; saturated brine solution; and then dried with magnesium sulfate.

The crude product was re-chromatographed on silica gel, eluting with 30% ethyl acetate in hexane.

The title compound was obtained as a foam.

¹ H-NMR (CPCl ₃ ; 300 MHz):

delta 5.51 (1H; bd); 4.87 (1H, bs); 4.72 (b); 3.77 (3h, s); 3.50 (ih, m); 3.40 (1H, dt, J = 12.60 Hz); 3.20 (3h, s); 1.44 (9h, s); 1.42 (9h, s).

Grade H

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

To 20.0 mL of diethyl ether was suspended 0.384 g (10.14 mmol) of lithium aluminum hydride; and the resulting suspension was cooled to minus 45.0 ° C under a nitrogen atmosphere. Then 2.07 g (5.96 mmol) was added to the reaction mixture.

N-methoxy-N-methyl-2,3,3- (bis-tert-butoxycarbonylamino) -propionamide obtained as described in Step G above; in a mixture of 60.0 mL of ether and tetrahydrofuran (1: 1); at a rate such that the temperature of the reaction mixture was maintained below minus 35.0 ° C.

The reaction mixture was then allowed to warm to 5 ° C; and then cooled again to a temperature of minus 45 [deg.] C. and then mixed with a solution of 3.08 g (22.60 mmol) of potassium hydrogen sulfate in 20.0 ml of water. Then the reaction mixture was stirred at 20.0 ° C for 1.0 hour; and then filtered through silica. The organic phase was then washed sequentially 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):

delta 9.61 (1H, s) J 5.60 (1H, bs) ,; 4.88 (1H, bs); 4.24 (1H, broad d, J = 6.0 Hz); 3.68 (ih, m); 1.40 (9h, s); 1.39 (9h, s).

Stage 1

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

- 103 A solution prepared by mixing 1,83 g (6,20 mmol) of 3 (S) butyl-1- (1-naphthoyl) -piperazine; (as free base)] obtained in the preceding step Ε ^ ^0 as described above. 17 ml (2.90 mmol) of acetic acid; in 20.0 mL of dichloroethane, was adjusted to pH 5.50 with triethylamine. To the resulting reaction mixture was added. 1.0 g of ice was added, cooled to 0 ° C.

The solution prepared by dissolving 2,3- (bis-tert-butoxycarbonylamino) -propenel (1.69 g, 5.86 mmol) obtained as described in Step HJ at 10, above, was then added dropwise to the reaction mixture. 0 ml dichloroethane; and the reaction mixture was stirred at 20 ° C overnight. Upon completion of the operation, the mixture was cooled to 0 ° C; mixed with a saturated aqueous solution of sodium bicarbonate; 8 was then stirred for 1.0 hour.

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

The crude product was then chromatographed on silica gel, eluting with 40-50% ethyl acetate in hexane.

The title compound was obtained as a foam.

Rf = 0.30J (50% ethyl acetate in hexane)

S t u p e ni J '

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

To the solution prepared by dissolving 2,13 g (3,75 mmol)

104

1- [(2,3-β-tert-butoxycarbonylamino) -prop-1-yl] -2- (S) -butyl-4- (1-naphthoyl) -piperazine; diethyl oxalate, the above-described Steps IJ in 75.0 ml dichloromethane was added 25 _r 0 ml of trifluoroacetic acid »After 25,0 minutes the reaction mixture was allowed to stand at a temperature of 20.0 ° C; the solvent was evaporated and the residue was partitioned between chloroform and 20% aqueous sodium hydroxide solution.

After separation of the organic and aqueous phases, the organic layer was washed with a saturated brine solution; and then dried with magnesium sulfate. The free base of the title compound was obtained as a yellowish gum.

(1.72 g).

A portion of the above material (52.0 mg) was purified by preparative high performance liquid chromatography, using a Waters PrepPak reverse phase column (Delta Pak G18; 50 mM J 100 5); and the pure product was isolated by gradient elution using 10CP to 50¾ 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 crude product obtained is dissolved in water; and screened further 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:

^G 22 ^H 32 ^N 4 ° · ⁴ » ^{45 HCl}

C, 49.78; 6.92 *, N 10.56%

Found: C, 49.75; 6.72; N 1O _r 36%

- 105

Example: 2

Preparation of 1- (3-amino-2- (2-naphthylmethylamine) -prop-1-yl) -2 (S) butyl-4- (1-naphthoyl) -piperazine. Trihydrate chloride • 4 ····

S p a r A

Preparation of 1- (2-Amino-3-tert-butyloxybonyl8-aminoprop-1-yl) -2 (S) -butyl-4- (T-naphthyl) piperidine

To a solution prepared by dissolving 0.476 g (1.29 mmol)

4- (2,3-diaminoprop-1-yl) -2 (S) -butyl-1- (1-naphthyl) -piperazine, in 10.0 mL of dichloromethane, was added 0.282 g (1.29) mmol) of di-tert-butyl dicarbonate and the resulting reaction mixture was stirred at 20.0 ° C for a total of 2.0 hours. The reaction was then discontinued and the mixture was shaken with water.

P _for separating the organic and aqueous phases, the organic layer washed with saturated brine; and then dried with magnesium sulfate. The crude product was then chromatographed on silica gel using 5% methanol in chloroform first and then 5% (9% 1-methanol-ammonium hydroxide) in chloroform; as eluents.

The title compound was isolated as the main product.

Mass Spectroscopy-FAB (m + 1) (FAB-MS) - 469, OJ

Grade B ·· ···

- 106 • · · ·

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

The title compound was prepared in a manner analogous to that described in Example 1J, Step QJ, except that 0.287 g (0.613 mmol) of 1- (2-amino-3-tert-but) was used in the reaction. oxycarbonylaminopropyl-1-yl / -2 (S5) butyl-4- (1-naphthoyl) -piperazine, 0.95 g (0.613 mmol) of naphthalene-2-carboxaldehyde, and 0.194 g (0.919 mmol) Sodium triacethoxytetrahydroborate in 15.0 ml of dichloroethane at pH 6.0.

The crude product was chromatographed on silica gel using 5% methanol in chloroform (Rf = 0.30) * as the eluent.

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

Mass Spectroscopy (FAB) »609J (m + 1)

Grade C

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

Intermediate prepared in the preceding Step B, i.e. 1- (3-tert-butoxycarbonylamino-2- (2-naphthylmethylamino) -prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine (0.313 _r GJ 0.514 mmol); was deprotected in 10.0 ml of dichloromethane with 5.0 m 3 of trifluoroacetic acid; and converted to the free base (255.0 mg) in an analogous manner to that described in Example 1J, Step E. above.

Purification of 40.0 mg of the product was performed by preparative high-performance liquid chromatography _/ using gradient elution with Solutions A and B1 (described in Example 1J, 95% to 5%).

- 107

Solution A) ..

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

Mass Spectroscopy-FAB = 5O9J (m + 1)

Analytical evaluation of the compound of formula ^C 33 ^H 4 O ^N 4 ° · ° '° ^{5 Η} 2 ^σ · ^{: 4} » ^{45 18311}

C, 59.00; H, 6.68; 8.34%

Found: C, 59.00; H6.51J N 8.44%

Example 3;

Preparation 2 (S ^-.) - butyl-1- [5- / 1 - (2-naphthyl methyl) / - 4,5-dihydroimidazole zolj -methy1-4- (1-naphthoyl) -piperazine. ditrifluoroacetate

A mixture prepared by mixing 0.105 g (0.207 mmol) / 1- (3 amino-2- (2-naphthylmethylamino) -prop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine * 1. 50 ml of tert-butyl isocyanate; and 0.023 g (0.207 mmol) of silver cyanide were heated in a sealed tube under a nitrogen atmosphere; at 90.0 ° C; overnight.

After removal of volatile components from the reaction mixture, z.a_vakus _y _ · The rest was chromatographed on silica, eluting

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 the procedure described in Example 1 above); gradient elution with Solutions A and B (described in Example 1 above; 95% to 5% of Solution A).

Subsequent lyophilization afforded the title compound as a white solid.

108

Mass Spectroscopy-FAB = 519J (m + 1)

Analytical evaluation of the compound of Formula ^C 34-38 ^N 4 ° · 0.85 H ₂ 0.3.75 trifluoroacetic acid

Calculated: C 51.84; H, 4.55; N 5.83% Found: C, 51.83; ti 4.56; N 6.32%

Example 4

Preparation of 1- [5- (1-benzylimidazole) -methyl] -2 (S) -butyl-4- (1-naphthoyl) -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 a nitrogen atmosphere at 20.0 ° C; 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 20.0 ° C for 1.0 hours. After that, the solvent was evaporated, and the residue was purified by HPLC (95%? To 5% Solvent A). .

the pure fractions were combined, and converted to the hydrochloride salt, in an analogous manner to that described in Example 1 above; Step E. Following lyophilization, the title compound was obtained as a white solid.

Mass Spectroscopy-FAB-467; (m + 1) ·· ··· ·

- 109 Analytical evaluation of the compound according to the formula ^{C 3} O ^H 34 ^N 4 ° · ° ^{'05 H} 2 °' ³ » ^{70 HCl}

Calculated: C 59.81 * Η 6.32ζ N 9.30% Found: C 59.78; H6.33; N 9.30%

Example 5

Preparation of 1- [5- (1- (4-nitrobenzyl) imidazolylmethyl) -2 (S) butyl-4- (1-naphthoyl) piperazine. difluoroacetate

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

The title compound was obtained as a white solid.

Mass spectroscopy-PAB = 512; (m + 1) Analytical evaluation of the compound according to the formula ^{C 3} O ^H 33 ^I 5 ° 3 · ^2GF 2 ^C0 2 ^H · ° ^{03 H} 2 ^0: Calcd .: C 41.42; H, 3.98; N, 10.18 % Found: C, 41.43; H, 3.96; N. 10.51 %

·· 4999

- 110 -

Example 6

Preparation of 1- (3-acetylmethylthi (R) -aminopropyl-1-yl) -2 (S) butyl-4- (1-naphthoyl) -piperazine. of difluoroacetate

1- (3-Acetamidomethylthio-2 (R) -aminoprop-1-yl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine dihydrochloride (4) and 0.010 g (0.105 mmol) were dissolved in trifluoroacetic acid. N-hydroxymethylacetamide; prepared by a method analogous to that described in, Ther Practice of Peptide Synthesis; Springer-Verlag; 1 984 p.82 (authors M. Bodansky; A. Bodansky); within 0.50 hours.

After removal of the solvent under vacuum, the residue obtained was purified by preparative HPLC. (85-60% Solvent A); and then lyophilized.

The title compound was obtained as a solid.

Mass Spectroscopy-FAB = 457; (m + 1)

Analytical evaluation of the compound of formula ^C 25 ^H 36 ^N 4 ° 2 ^S · ^2GF 2 ^CO 2 ^B · M ^0H 2 ° '

Calcd .: C 44.38; H, 5.12; N 6.64%

Found: G 44.35 ´, H 5.11; N 6.97%

Example. 7

Preparation 2 (S) -Butyl-1- [2- (1-imidazoyl) -ethyl] -sulfonyl-4- (1-naphthyl) -piperazine. m.p. trifluoroacetate

Grade A ·· · »· ♦

- 111

Preparation 2 (S) -Butyl-4- (1-naphthoyl) -1-vinyl-3-sulfonylpiperazine

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, 0.038 mL (0.314 mmol) of chloroethylsulfonyl chloride was added; and the resulting reaction mixture was stirred under a nitrogen atmosphere overnight; and after mixing with saturated sodium bicarbonate solution was shaken into ethyl acetate.

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

Grade B

Preparation of 2 (S) -Butyl-1- [2- (1-imidazolyl) -ethyl] -sulfonyl-4- (1-naphthyl) -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 a nitrogen atmosphere and then 0.011 g (0.29 mmol) of 2 (S) -butyl-4-O-naphthoyl) -1-vinylsulfonylpiperazine * was added. , in 5.0 ml of dimethylformamide.

The reaction mixture was then stirred overnight at 20.0 ° C; and after subsequent 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, followed by preparative HPLC (80-40% Solvent A).

The trifluoroacetate salt was dissolved in water; and shaken out between saturated aqueous sodium bicarbonate; After separating the organic and aqueous phases, the organic layer was washed with a saturated brine solution, and dried with magnesium sulfate.

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

Mass Spectroscopy-FAB = 455 (m + 1)

Analytical evaluation of the compound of formula ^C 25 ^H 36 ^N 4 ^O 2 ^S · ° » ^{8 H} 2 ° ^:

Calcd: C 61.46; H, 6.79; N 11.95%

Found: C, 61.44; H, 6.97; N. 10,72%

Example 8

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

Grade A

Preparation of 2 (R) -Butyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl) methyl] piperazine

In the presence of a comminuted molecular sieve, 0.202 g (0.607 mmol) of 3 (R) -butyl-1 (1-naphthyl) -piperazine, obtained in a manner analogous to that described in Example 1, was reacted in 7.0 ml of dichloroethane; preparing the (S) -enantiomer; with 0.226 g (0.667 mmol) of 1-triphenylmethylimidazole-4-carboxaldehyde; and with 0.321 g (1.52 mmol) of sodium triacethoxytetraborohydride.

The pH of the resulting reaction mixture was adjusted to 5.0-6.0% by addition of diethylamine / acetic acid, and after stirring overnight, the mixture was mixed with a saturated aqueous solution of sodium bicarbonate. The organic layer was then washed with a 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 of 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-triphenylmethyl-imidazolyl) methylpiperazine in dichloromethane was added 1.0 ml (11.80 mmol) of triethylsilane followed by 8.0 ml of trifluoroacetic acid After 1.0 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.

Mass Spectroscopy-FAB = 377; (m + 1)

Analytical evaluation of the compound according to formula ^G 25 ^H 36 ^N 4 ° 2 · ^{2.35 CF} 3 ^CO 2 ^H · ⁰ » ^{32 h} 2 ° ^:

Calcd: C 48.93; H, 4.52; N 7.98%

Found: C, 48.93; H, 4.55; N 8.26%

- 114

Example 9

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

In an analogous manner to that described in Example 8 above, Step AJ was reacted in 7.0 mL of dichloroethane in the presence of a comminuted molecular sieve; 0.200 g (0.601 mmol) of 3 (S) butyl-1- (1-naphthoyl) -piperazine hydrochloride; with 0.062 ml (0.661 mmol) of pyridine-3-carboxaldehyde; and 0.321 g (1.52 mmol), friction sodium toxytetraborohydride ·

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

Mass Spectroscopy-FAB - 388.0 (m + 1)

Analytical evaluation of the compound of formula ^C 25 ^H 29 ^N 3 ° · ² » ^{3 Ησι} * °» ^{95 H} 2 ^0:

Calcd: C 61.49; H, 6.85; N 8.60% Found: 061.49; H7, O1; N 8.76%

Example 10

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

In an analogous manner to that described in Example 8 above;

Grade A; using 0.493 g (0.327 mmol) of 4-nitrobenzal.

- 115 sodium triacethoxytetraborohydride; dehydrate and 0.173 g (0.817 mmol) of t-converted in dichloroethene 120.0 mg (0.326 mmol) of 1- (2 (R) -amino-3-hydroxypropyl) -2 (S) butyl-4- (1-naphthoyl) -piperazine; to the title compound which was purified as a crude product by preparative, high performance liquid chromatography (100 75% Solvent A), and then converted to the hydrochloride salt on ion exchangers and lyophilized to afford the title compound; compound.

Mass Spectroscopy-FAB-505; (m + 1)

Analytical evaluation of the compound according to the formula

C ₂₅ H2 ₉ N ₃ O. 3.60 HCl.0.10 H ₂ 0:

Calculated: C 54.69; H, 6.30; N 8.80%

Found: C, 54.66; H, 5.85; N 8.31%

Example 11

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

Grade A

Preparation of 1- (2 (R) -t-butyloxycarbonylamino-2-formylethyl) -2 (S) butyl-4- (1-naphthoyl) -piperazine

To a solution prepared by dissolving 1.36 mL (14.90 mmol) of oxalyl chloride in 35.0 mL of dichloromethane; and cooled under a nitrogen atmosphere to a temperature of minus 65.0 ° C; 2.30 mL of dimethylsulfoxide (32.40 mmol), * in 7.0 mL of dichloromethane was added; and the resulting reaction mixture was stirred for 2.0 minutes. Then a solution of 1- (2 (R) -8mino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine (3.19 g *) was added at minus 10 ° C,

6.79 g of jelly), and the reaction mixture was stirred at this temperature for 15.0 minutes.After cooling the mixture to minus 55.0 ° C, 4.76 ml (34.0 mmol) was added to the mixture. triethylamine; and the mixture was allowed to reach room temperature after stirring for 5 minutes.

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

The title compound was obtained.

Grade B

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

To the solution prepared by dissolving 0,25 g (0,53 mmol)

1- (2 (R) -1-butoxycarbonylamino-2-formylethyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine; in 5.0 mL of dried tetrahydrofuran; and cooled in a nitrogen atmosphere at 0 ° C in a three-necked, flame-dried flask, a solution of heptadecylmagnesium chloride (1.01 mL of a 1M solution in ether (1.01 mmol) was added via syringe, 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 shaken out with ethyl acetate. After drying over magnesium sulfate, the crude product was chromatographed on silica gel using 25% ethyl acetate in hexane, followed by 5% strength. • • •

- 117

methanol in chloroform as eluents.

The purified product was dissolved in 7.0 mL of dichloromethane, and treated with 3.50 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).

Two isomers were isolated. After lyophilization, the title compound was isolated as diastereoisomer A (retention time 8.405 minutes, gradient 100-50% Solvents 1 &gt; 15 minutes).

Mass Spectroscopy-FAB = 566 (m + 1)

Analytical evaluation of the compound of formula ^C 36 ^H 59 ^N 3 ° 2 · ² » ^{35 CF} 3 ^CO 2 ^H · ^{35 H} 2 ^0:

Calcd .: 58.19; H, 7.44; N 5,00%

Found: 58.21; H, 7.46; N 5.36%

After lyophilization, the title compound was also isolated as diastereoisomer B (retention time 9.269 minutes; gradient of 100-50% Solvent A over 15 minutes).

Mass Spectroscopy-FAB-566 (m + 1)

Analytical evaluation of the compound of formula ^C 36 ^H 59 ^N 3 ° 2 · ² » ^{35 CF} 3 ^CO 2 ^H · ° ⁵ ° ^H 2 ^0:

Calcd .: 58.56; H, 7.42; N 5.03%

Found: 58.53; H7.41; N 5.17%

Example 12

- 118

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

Grade A

Preparation of 1- (3S) -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 was used in the reaction; 9.32 g (48.20 mmol) of ethyl N-benzylglycine and 96.50 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):

delta 7.00 - 7.40 (10H, m); 4.61 (1H; d; J = 16.00 Hz) δ, 4.37 (ih; t, J = 5.0 Hz); 4.24 (ih; d .; j - δδ, οο hz); 3.42 (ih; d, J = 18.00 Hz); 3.28 (1H, dd, J = 4.16 Hz); 2.96 (1H; dd, J = 6.16 Hz); 2.55 (1H; d, J = 18.00 Hz).

Grade H

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

The title compound was prepared in an analogous manner to that described in Example 1 above; Grade B; except that 1.01 g (17.10 mmol) of 1,3 (S) dibenzylpiperazine-2,5-dione was used in the reaction; 2.33 g (61.40 mmol) of tetrahydro-aluminate lithium * 119 _F followed by 4.02 g (18.40 mmol) of di-tert-butyl ldikarbonátu.

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 _T solid.

@ ¹ H-NMR (300 MHz) .delta.

delta 7.20-7.40 (5HJ m); 7.00 - 7.20 (5H, m); 4.15 OH; m.); 3.90 (ih; d, J = 15.0 Hz); 3.60 (ih; d, J = 15.00 Hz); 3.15 (ih, m); 2.95 (3h, m); 2.70 (ih; a, J = 13.00 Hz); 2.02 (ih; dt; J = 6.13 Hz) »1.95 (ih; b.a.); 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 above; Stage C; except that 4.78 g (11.30 mmol) of 1-tert-butoxycarbonyl-2 (S), 4-dibenzylpiperazine was used in the reaction; and 10% palladium on activated carbon (1.04 g).

The title compound was obtained as an oil.

@ ¹ H-NMR (300 MHz; CD3 JOB):.

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

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

Grade B

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Preparation of 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 above; Step AJ with the difference that 0.292 g (1.06 mmol) of 2 (S) benzyl-1-tert-butoxycarbonylpiperazine used 0.159 g (1.06 mmol) of the reaction

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 to adjust the pH of the reaction mixture to pH 7.0; triethylamine was used.

The title compound was obtained in the form of a thick, oily consistency.

¹ H-NMR (DMSO-d 6; 300 MHz):

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

Stage E '

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

In an analogous manner to that described in Example 8 above; Degree k ' _r . was reacted in the presence of a comminuted molecular sieve] in 7.0 ml of dichloroethane, 0.173 g (0.472 mmol) of 2 (S) benzyl-1- (1-naphthoylpiperazine) with 0.160 g (0.472 mmol) of 1-triphenylmethylimidazole-4-carboxaldehyde; with 0.300 g (1.42 mmol) of sodium triacethoxytetraborohydride.

The title compound was obtained in the form of a thick, oily consistency.

- 121

Grade F

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

To a solution prepared by mixing 0.310 g (0.472 mmol)

2 (S) -benzyl-4- (1-naphthoyl) -1- [4- (1-triphenylmethylimidazolyl) methylpiperazine] with 5.0 ml dichloromethane, 0.300 ml triethylsilane was added followed by 5.0 ml trifluoroacetic acid.

After 1.0 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.

Mass Spectroscopy-FAB = 411J (τη + 1)

Analytical evaluation of the compound of formula ^G 26 ^H 26 ^N? 4 ° 2 * ^{2.75 CF} 3 ^C0 2 ^H * ⁰ ° 5 * 2® '

H, 4.14; C, 52.11; N 7.72%

Found C, 52.10; H, 4.03; N 8.16%

Example 13

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

Grade A

- 122

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

To the solution prepared by dissolving 1,67 g (3,56 mmol)

- (2 (R) -Butoxycarbonylamino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine in 10.0 ml of dimethylformamide; and cooled to 0 ° C under nitrogen atmosphere 0.427 g (10.60 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 recooled to 0 ° C; and mixed with water.

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

The crude product was chromatographed on silica gel; 70% ethyl acetate / hexane; and then a mixture of 5% methanol in chloroform as eluents.

The title compound was obtained as the main product. ·

Mass Spectroscopy-FAB »352; (m + 1)

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

Stupen B.

Preparation of 1- (2 (R) -amino-3- (3-benzylthio) -propyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine. ditrifluoroacetate • · · · · · ««

- 123

A mixture prepared by mixing 0.050 g (0.142 mmol) of 1- [(1-aziridinyl) 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 to reflux for 18.0 hours.

The crude product was first chromatographed on silica gel, eluting with 3% methanol in chloroform; and purified by high performance preparative liquid chromatography (85% to 10% Solvent A).

The title compound was obtained after subsequent lyophilization.

Mass Spectroscopy-FAB = 476J (m + 1)

Analytical evaluation of a compound of the formula ^C 29 ^H 37 ^N 3 O .2 ^{to 6} CF ₃ CO ₂ HO, H-3:

Calcd. 1 C, 52.83; ,2 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. Dad difluorination

A solution prepared by dissolving 0.050 g (0.111 mmol) of 1- (1-butoxycarbonylaziridinyl) -methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine; in 4.0 mL of methanol, was heated to reflux, along with 0.070 g (0.333 mmol) of p-nitrobenzylthioacetate; and 0.200 ml of triethylamine; for 2.0 hours.

The crude product was chromatographed on silica gel, eluting with 3% methanol in chloroform.

124

The purified product was then treated with 33% trifluoroacetic acid in dichloromethane for 20.0 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 lyophilization.

Mass Spectroscopy-FAB - 529 (m + 1) Analytical evaluation of the compound according to formulas ^G 29 ^H 36 ³⁶ 1 4 4 ^Q 3 · 2GF ₃ C0 ₂ H.0; 08 H ' ₂ O :: Calculated: G 51.94; H, 5.23; N. 7.34 % Found: G, 51.87; H, 5.06; N, 7.47 %

Example 15

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

S p a p A 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'-imidazole acetic acid; and 2.48 g (7.68 mmol) of triphenylmethyl bromide, in 40.0 ml of dimethylformamide, were added 4.46 ml (32.0 mmol) of triethylamine; and the resulting suspension was stirred at room temperature for 18.0 hours.

When the above operation was completed, the reaction mixture was reago · »» ···

125 cm 3 with 1.31 g (8.0 mmol) of 3-hydroxy-1,2,3-benzotriazin-4 (3) one (HOOBT); and 1.56 g (16.0 mmol) of Ν, dimethyl-dimethylhydroxyamine hydrochloride, and 3- 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.53 g 8,0 8.0 mmol) and this reaction the mixture was stirred for 24.0 hours at room temperature.

After completion _of the above operation to the mixture was added 50.0 mL of saturated aqueous sodium bicarbonate solution; and 50.0 ml of water; and this mixture was shaken twice with 100.0 mL of ethyl acetate.

The combined extracts were washed successively with 100.0 mL of saturated aqueous sodium bicarbonate; and then with 50.0 ml of brine; and the solvents were then evaporated in vacuo. The residue was suspended in 20.0 mL of ether; and after filtering off the white solid, the title compound was obtained as a white solid.

¹ H-NMR (CD ₃ OD; 300 MHz):

delta 7.37 (1H, m); 7.16 (6H, m); 6.84 <1H; and.); 7.37 (2H, s); 3.68 (3H, s) and 3.18 (3H, s) ppm.

Degree. (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 as described in Step AJ above in 15.0 ml of freshly distilled tetrahydrofuran; and cooled to minus 40 ° C by cooling bath, prepared from a mixture of solid carbon dioxide and acetone; 33.20 mg (0.874 mmol) of lithium aluminum hydride was 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.

- 126

At the end of the above operation, the reaction mixture was again cooled to minus 40 ° C, and then gradually mixed with 33.0 µl of water and 33.0 µl of 1N aqueous sodium hydroxide solution; and still with 100.0 µl of water. The resulting suspension was stirred for 30.0 minutes 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 a 10% aqueous solution of citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid) (5.0 mL); and then with 5.0 ml of water.

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

The title compound was obtained.

¹ H-NME (CDCl ₃ ; 300 MHz):

delta 9.79 (1HJ i.e. J = 3.0 Hz); 7.44 (1H, s); 7.40-7.10 (15H, m); 6.76 (1H, s); and 3.63 (2H; d, J = 3.0 Hz) ppm.

Grade C

Preparation of 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 of 1,2-dichloroethane; 400.0 mg of 3 δ molecular sieve were added; and 200.0 mg (0.94 mmol) of sodium triacethoxytetraborohydride.

The resulting reaction mixture was stirred at room temperature for 4 days. After completion of the operation, the reaction mixture was filtered through a sintered glass filter; and the filtrate was ·· ····

undiluted with 50.0 ml of dichloromethane; and then washed with 25.0 ml of water. The solvent was then evaporated under vacuum; and the remaining residue was purified by flash chromatography, using 2-5% mixture. methanol in dichloromethane as eluent.

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 after mixing with 2 drops of triethylasilane, a colorless solution was obtained which was stirred at room temperature for 3.0 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):

delta 8.83. dHJs.); 8.08-7.75 (3H, m); 7.67 - 7.49 (4HJ m) J

7.45 (1H, s); 4.50-3.80 (2H, m); 3.65-2.95 (9H; m);

2.00-1.30 (4H, m); and 2.20-0.20 (5H; _m , T, ppm).

Analytical evaluation of the compound of formula ^C 24 ^H 30 ^N 4 ° · ^{3 '45} °' ^{75 H} 2 ^0:

Calcd: G, 46.54; H 4.42J N 7.03%

Found: 0 46.54; H, 4.41; N 7.35%

Mass Spectroscopy-FAB (High Resolution): Calculated

Exact Mass Calculation for Compound of Formula:

^G 23 ^H 31 ^N 4 ° ⁼ 391.249787 (MH ⁺ )

Found: = 391.249028

Example 16 ·· ····

- 128 * · 128 128 128 128 128 128 128 128 128 128

Preparation of 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 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 µmol) of sodium triacethoxytetraborohydride and triethylamine were added to bring the pH of the resulting reaction mixture to pH 5.50. The reaction mixture was stirred at room temperature for 18.0 hours.

After completion of the above operation, the reaction mixture was filtered and the filtrate was concentrated in vacuo; and dissolved in 25.0 mL of ethyl acetate; and washed successively with ΐϋ0.0 mL of saturated aqueous sodium bicarbonate; and then with 10.0 ml of brine. After evaporation of the solvent in vacuo, the remaining residue was purified by flash chromatography using a mixture of 3-8% methanol in dichloromethane; and was tritylated _; a protected title compound. This oily consistency was dissolved in 4.0 mL of dichloromethane; and 2.0 m. of trifluoroacetic acid; and then the resulting solution was treated with triethylsilane until the yellow color disappeared; to give a colorless solution which was further stirred at room temperature for 10.0 minutes; and then the solvent was evaporated in vacuo.

The resulting white solid was partially dissolved in 7.0 mL of water; and then filtered. The filtrate was purified by preparative / high performance liquid chromatography, using a Prep 5000 semi-preparative high performance liquid chromatography system; inserts (Waters PrepPak); with parameters 47 x 300 mm; C18J 15 yum; 100 S), and a mixture of 5-95% acetonitrile and water (0.1% trifluoroacetic acid); as eluent, at a flow rate of 100 ml / min (Chromatography A).

The title compound was obtained after lyophilization.

φφ φφφφ • φ φ

- 129

• φ • φ · · · φφφ • φ * · · ¹ H-NMR (DMSO-d ₆ 400 MHz is J 15O ° C):

δ 8.53 <1H; m.) J 7.41 (1H; 3.95 (1H; d; 3.48 (ih; s)); 2.74 (ih; a.); 1.08 (2H; a.);

3.); 7.94 (2H, m); 7.79 <1H; m.); 7.53 (3H, m); 7.40 (1H, a.); 4.12 (1H; d, J = 4.80 Hz); J = 4.80 Hz); 3.70 (ih; a.); 3.63 (ih; g.);

3.40 (1H, g); 3.01 (1H, a.); 2. S2 (1H; a);

1.70 (ih, m); 1.49 (1H, a.); I, is (2H; _3. ); and 0.77 (3H; ie J = 5.50 Hzppm).

Analytical evaluation of the compound of formula ^C 23 ^H 29 ^N 4 ° · 2TFA.0,70 H ₂ 0:

Calculated: 0 52.55; H 5.13 ‘, N 9.08%

Found: C, 52.54; H, 5.11; N 9.35%

Mass spectroscopy-FAB:

Mass calculation calculated for compound ^C '23 ^{H 3} O ^N 4 ° ^:

Calculated: = 377, OJ (MH ⁺ )

Found: = 377, OJ

Example 17

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

Grade A

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

- 130

The solution prepared by dissolving 4.00 g (24.6 mmol) of 1H-imidazol-4-ol hydrochloride with hydrogen chloride gas until the solution was saturated. The solution was then allowed to stand at room temperature for 18.0 hours. After evaporation of the solvent in vacuo from the mixture, the title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ; 400 MHz):

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

Degree fi

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

To a suspension, prepared by mixing 7.48 g (42.40 mmol) of the product obtained under the above Step A; in 200.0 ml of dichloromethane; 17.70 ml of triethylamine (127.0 mmol) and 16.40 g (50.80 mmol) of triphenylmethyl bromide were added. The resulting reaction mixture was stirred for 72.0 hours. After the above operation, the reaction mixture was washed with 100.0 mL of saturated aqueous sodium bicarbonate solution *, and with 100.0 mL of water.

After separation of the organic and aqueous phases, 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):

4444

- 131

444 444 δ 7.35 (1H; a.); 7.31 (9H, _m ); 7.22 (6H, m); 6.76 (1H, s); 3.68 (3H, s); and 3.60 (2H; a.); ppm.

Grade C

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

To a solution prepared by dissolving 4.36 g (11.4 mmol) of the product obtained as described in Step B above. in 70.0 ml of acetonitrile, 2- (bromoethyl) naphthalene was added. and the resulting reaction mixture was heated to 55.0 ^ο 0 _; · For 4.0 hours. The reaction mixture was then 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 18.0 hours.

Upon completion of the above operation, the reaction mixture was cooled to room temperature; then filtered; and the resulting white colored precipitate was isolated by filtration. The filtrate was then concentrated to a volume of 10.0 ml and then heated at 55.0 ° C for 1.0 hour.

The reaction mixture was then cooled again to room temperature, and diluted with 25.0 mL of ethyl acetate. The resulting precipitate was isolated 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 sorbic bicarbonate solution. after separating the organic and aqueous phases, the organic layer was concentrated to dryness under vacuum; and the residue was purified by flash chromatography (0-6% methanol / dichloromethane); as a gradient eluent).

• ·

132 The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ; 400 MHz):

delta 7.82 (2H, m); 7.75 (1H, m); 7.70 (1H, s); 7.49 (3H, m); 7.20 (ih; d, J = 8.40 Hz); 7.06 (ih; _3rd ); 5.32 (2h, s); 3.57 (3Η, S.); and 3.49 (2Η; 3); ppm.

Grade B

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

In the above Step C, 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetic acid, methyl ester obtained; (0.92 g, 3.28 mmol) was dissolved in 50.0 mL of a 2.5N hydrochloric acid solution; and the resulting solution was heated at 55.0 ° C for 3.0 hours.

Upon 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 (CE ₃ 0DJ400 MHz)

δ 8.92 (1H; s) J 7.94 (1H; d, J = 8.60 Hz); 7.88 (2H, m); 7.83 (ih; a.); 7.54 (3h, m); 7.43 (ih; d, J = 14.00: Hz); 5.60 (2H, 8th); and 3.82 (2H, 3); ppm.

Grade E ·· ····

- 133

Preparation of 2 (S) -Butyl-1 - [(1- (naphth-2-ylmethyl) -1H-imidol-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 the above Step D; 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, 63.0 mg (0.33 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was added; and 161.0 µi; 1.16 mmol) of triethylamine; and the resulting reaction slurry form was stirred for 18.0 hours.

After the above operation, 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 of water, and 20.0 mL of brine. After evaporation of the solvent in vacuo, the residue was purified by preparative HPLC. The title compound was obtained after lyophilization.

¹ H-NMR (CDCl ₃ ; 400 MHz):

delta 8.98 (1Η>.) ´, 8.03 - 7.27 O5H; m.); 5.69 -5.50 (2Η>); 4.79 - 4.34 (2H, m); 4.15-2.50 (7H, m); 1.80-0.20 (9H; m) J ppm.

Analytical evaluation of the compound according to the formula

C ₃₅ H ₃₅ N 2 O ₂ . H, 0.65 H 2 O:

Calcd: 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 compound of formula ^G 35 ^H 36 ^N 4 ° 2 ^: 0 · 0

0 0

134 «0 0 •

000 000 • ·· 0

Calcd .: 545.291652 (MH ⁺ )

Found: = 545.292050 /

Example. 18

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

Grade A

Preparation of N-methyl 1-N-methoxy-2- [1- (naphth-2-ylmethyl) -1H-imidazole

5-yl) -acetamide (HOOBT); 5g 0 0 mg carbodiimidyl EDC

To a solution prepared by dissolving 0.819 mg (2.7 mmol) of 2- [1- (naphth-2-ylmethyl) -1H-imidazol-5-yl] acetic acid hydrochloride; in 15.0 ml of dimethylformamide, 293.0 mg (3.0 mmol) of N, O-dimethylhydroxylamine hydrochloride were added sequentially; 489.0 mg (3.0 mmol) of 3-hydroxy-ly2,3-benzotriazin-4 (3H) -one;

(3.0 mmol) of 1- (3-dimethylaminopropyl) -3-ethyl); and 1.67 mL (12.0 mmol) of triethylamine.

The resulting reaction mixture was stirred at room temperature for 18.0 hours; and after completion of the operation, 30.0 ml of a saturated aqueous sodium bicarbonate solution and 30.0 ml of water are added to the mixture; and this mixture was shaken twice with 50.0 mL of dichloromethane. The combined organic extracts were washed with 50.0 ml of brine, 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.

The title compound was obtained as an oily substance.

- 135 · ¹ H-OTR (CDCl ₃ ; 400 MHz):

delta 7.80 (2HJ m); J 7.74 (1HJ m); 7.56 (1H, a.); 7.47 (3H, 1H); 7.22 (ih; d; j = s, 60 Hz); 6.97 (ih, _s ); 5.37 (2h, s); 3.58 (2H, 3); 3.51 (3Η; 3); and 3.12 (3Η; 3); ppm.

Stage B:

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

To a suspension of 40.80 mg (1.07 mmol) of lithium aluminum hydride; in 5.0 mL of tetrahydrofuran; cooled with a solid carbon dioxide / acetone mixture at minus 45.0 ° C; a solution of 243.0 mg (0.895 mmol) of the product obtained under Step A * above in 5.0 ml tetrahydrofuran was added via a lance at a rate such that the temperature of the reaction mixture was kept below -35.0 ° C .

After the above operation, the mixture was allowed to warm to + 5 ° C; and then re-cooled to minus 35.0 ° C. A solution prepared by dissolving 272.0 mg of potassium hydrogen sulfate in 1.0 ml of water was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 30 minutes; and then filtered through silica. The silica 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, and then with 10.0 mL of water.

After the organic and aqueous phases were separated, the organic layer was dried over magnesium sulfate; and evaporated after filtration.

The title compound was obtained as a clear oil.

¹ H-NMR (CDCl ₃ ; 400 MHz):

.delta. 9.50 (1H; tt, 2Hz); 7.85-7.70 (3H; m); 7.64 (1H, s);

136 ·· · ··· ·

·· 0000 • · · ··· ·

0 0 · 0 • 0 ·

7.53-7.40) (3Η; m) J 7.16 (1Η; d; J = 12.0 Hz); 7.06 (, m, s); 5.20 (2H; a.); and 3.53 (2H, m); ppm.

tupen C

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

To a mixture prepared by mixing 58.40 mg (0.232 mmol) of the product obtained under the above Step B; and 3 (S) -butyl-1-naphthoylpiperezine hydrochloride (96.50 mg; 0.279 mmol); in 10.0 ml of 1,2-dichloroethane; 8 5.0 ml of dimethylformamide, 250.0 mg of $ 3 molecular sieve was added; and 236.50 mg (1.12 mmol) of sodium triacethoxytetraborohydride.

The resulting reaction mixture was stirred at room temperature for 18.0 hours; and then filtered. The obtained 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 2-5% methanol in dichloromethane *, and then by preparative / high-performance liquid chromatography (Chromatography A).

The title compound was obtained.

¹ H-NMR (CD-iodo; 400 MHz):

Mass Spectroscopy-FAB (High Resolution) Exact Mass Calculation Calculated for Compound of Formula

137

Calculated

Found

531.312387 LMH ⁺ ) 531.313011;

Example 19

Grade A

Preparation of N-tert-butyloxycarbonyl-O-benzylserine- (N-methoxy) methyl amide

5.0 g (16.90 mmol; (Bachem), N-tert-butyloxycarbonyl-O-benzylserxine) and 2.29 g (16.90 mmol) were dissolved in 100.0 ml of dried dimethylformamide. 1-hydroxybenzotriazole hydrate (HOBT).

To the resulting reaction mixture was added 1.98 g (20.30 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride; and then, at 0 ^° C; 3.56 g (18.60 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The pH of the mixture was then 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 3.0 hours; and after the operation was diluted with ethyl acetate; and poured into a 0.5N hydrochloric acid solution.

řečnátým _y and evaporated under vacuum.

The obtained slightly yellow colored compound was further subjected to silica gel column chromatography, using a mixture of 00000 00000 · · 00 «00 • 0 0 00000 00 00000 00000 00 00 00 00 00 00

- 138 - .............. ’· hexane. : ethyl acetate (2: 1).

The title compound was obtained as an oil.

Rf = 0.45% (silica: hexane: ethyl acetate (1: 1)).

Grade B

Preparation of N-tert-butyloxycarbonyl-O-benzylserinaldehyde.

Amide (5.70 g, 16.90 mmol); obtained in the framework of the above-described Step A; in 20.0 mL of dried ether was added at minus 50 ° C; pa drops; to a suspension prepared from 0.705 g (18.50 mmol) of lithium aluminum hydride in 80.0 mL of ether. After the above operation, the reaction mixture was stirred at 0 ° C for 45.0 minutes; and then recooled to minus 50 ° C; and slowly added a solution prepared by dissolving 4.0 g of potassium hydrogen sulfate in 11.0 ml of water.

The reaction mixture was then stirred at room temperature for 1.0 hour; filtered through silica; and then washed extensively with 10% citric acid solution; a saturated aqueous solution of sodium bicarbonate, and brine; and then dried with magnesium sulfate; and evaporated.

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

Rf = 0.58; (silica: hexane: ethyl acetate (2: 1)

- 139 • * ·· ···· β · · · ·

Grade C

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

To a solution prepared by dissolving 1.70 g (574 mmol) of piperazine hydrochloride; obtained in Example 1; Step S, described above; in 25.0 ml of dichloromethane; and adjusting the pH (triethylamine) to pH 6.0; freshly ground, and activated $ 4 molecular sieve was added first; and then 4.85 g (22.90 mmol) of sodium triacethoxytetraborohydride. To this reaction mixture was added dropwise; within 20 minutes; and at 0 ° C; a solution prepared by dissolving 2.08 g (747 mmol) of the aldehyde obtained in the above step (výše) in 20.0 ml of dichloromethane.

The resulting reaction mixture was then stirred at room temperature for 16.0 hours, then filtered through silica; undiluted with ethyl acetate; and vigorously, and washed successively with water; potassium hydrogen sulphate solution; sodium bicarbonate solution, and finally with brine. The magnesium sulfate-dried solution was then evaporated in vacuo.

A yellowish oil was obtained, which was further subjected to silica gel column chromatography, eluting with hexane: ethyl acetate (1: 1).

The desired title compound is obtained as a foam.

Rf = 0.15 (silica; hexane: ethyl acetate (2: 1))

Grade H

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

-140 • A • A • A b

L. Mixture prepared by dissolving 700.0 mg (1.25 mmol) of benzyl ether obtained in Step C * above in 20.0 mL of methanol; and adding 150.0 µl of acetic acid; followed by 20% palladium hydroxide to 500.0 mg of activated carbon; was hydrogenated at 40 psi for 16.0 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 oil.

Grade E

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

A solution prepared by dissolving N-BOC-amine (140 mg); obtained in the framework of the above-described Step D; in 10.0 mL of ethyl acetate was bubbled with hydrogen chloride gas until saturation of the solution. After 5.0 minutes, the solution was purged with argon and the solvent was removed. The solid residue was purified by preparative; HPLC (Column C-18; water / methyl cyanide / 0.1% trifluoroacetic acid; gradient).

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

FAB-MS (m / z) = 370; (M + 1)

141%

%

Analytical evaluation of the compound of formula ^C 22 ^H 32 ^W 3 ° 2 * TFA (trifluoroacetic acid) ·

Calculated: Found:

50.31; H, 5.27; N 6.59 0 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 salts

To prepare the title compound, a procedure analogous to that described in Example 19J, Steps A to E; except that the starting material was N-BOC-O-benzylhromol and the title compound was obtained as the bis-hydrochloride salt.

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

Analysis of the Formula ^C 23 ^H 33 ^N 3 ^Q 2 · ¹ · ^{5 HCl:} Calculated: C 54.04;

Found: C, 53.95;

H, 7.20; N, 8.22% H, 7.23; N 8.50%

Example 21

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

142

Grade A

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

The title compound was prepared as a crystalline solid, two steps of ((BOC) 4 potassium carbonate, tetrahydrofuran / water, followed by diazomethane in ethyl acetate, from D, L-orthotyrosine (Sigma).

Grade B

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

To a solution prepared by dissolving 1.34 g (4.54 mmol) of the ester obtained in the above described Step AJ in 20.0 mL of tetrahydrofuran; 400.0 mg (10.50 mmol) of lithium aluminum hydride was added portionwise at 0 ° C.

After 4.0 hours at room temperature, 0.40 mL of water was added dropwise, followed by 0.40 mL of 1N sodium hydroxide solution; and then another 1.20 ml of water.

the slurry was stirred for 1.0 hour; and then filtered through silica; and rinsed with tetrahydrofuran. After removal of the solvent, the residue was chromatographed on silica gel * using hexane: ethyl acetate (1: 1); as eluent.

The title compound was obtained as a solid.

Rf = 0.45; (silica: hexane: ethyl acetate (1: 1)).

143 · ······ · · 4 · 4 · · · · · · · · · · · · · · · ·

Stage C

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

The mixture prepared by mixing 280.0 mg (1.05 mmol) of the alcohol obtained in the above step Stage B1 150.0 / µl 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 16.0 hours.

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

The residue, as an oily substance, was purified by chromatography over silica gel, eluting with hexane: ethyl acetate (2: 1).

The title compound was obtained as an oil.

Rf = 0.36 (silica: hexane: ethyl acetate (2: 1)).

Grade D

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

To the mixture, prepared by mixing 280.0 mg (0.78 mmol) of the alcohol obtained under Step CJ above, in 3.0 mL of dimethyl sulfoxide; 3.0 ml of dichloromethane; and 0.55 ml of triethylamine was added under argon at room temperature, 500.0 mg (3.14 mmol) of pyridine-sulfur trioxide complex; and the resulting reaction mixture was stirred for 1.0 hour. The mixture was then poured into a saturated aqueous solution of sodium bicarbonate; then shaken twice with s-ethyl acetate; washed with water, followed by brine; and dried over magnesium sulfate and concentrated in vacuo.

The title compound was obtained as an oily substance; and in the next Step E; was used as such.

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

Grade E

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

The aldehyde obtained in the foregoing Step D above; and piperazine hydrochloride; obtained in Example 1; Step E; described above, were subjected to reductive alkylation, using the procedure described in Example 19; Step C. Purification by silica gel column chromatography using hexane: ethyl acetate (3: 2) as eluent gave the title compound as a mixture of diastereoisomers (1: 1).

R f = 0.51 and 0.45; silica; hexane: ethyl acetate;

(1: 1)

Stupen P

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

The solution prepared by dissolving 70.0 mg of N-BOC-amine gave 145

* κ

In the previous step, step EJ, in 15.0 mL of ethyl acetate, was bubbled until saturated with hydrogen chloride gas. After 15.0 minutes, the reaction mixture was purged with argon; the solvent was removed until a solid residue was obtained which was purified by preparative / high performance liquid chromatography (column C-18J with water / methyl cyanide with 0.1% trifluoroacetic acid; gradient).

The title compound was obtained after lyophilization as a powder.

FAB-MS (m / z) = 536 (M + 1)

Analytical evaluation of the compound according to Formula ^C 35 ^H 41 ^N 3 ° 2 * · 2> 20 TPA (trifluoroacetic acid) .0,35 H ₂ 0:

Calcd: 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-hydroxy-phenyl) -propyl) -2 (S) -butyl-4- (1-naphthoyl) -piperazine. bis-trifluoroacetate salt $; diastereoisomer 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- (24NBOC-amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) - 146

Piperazine obtained as described in Example 19J, Step E above; 60.0 µL (1.0 mmol); acetic acid; and 20% palladium hydroxide on activated carbon (400.0 mg); in 20.0 mL of methanol, was hydrogenated at 50 psi; for 5.0 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) Diastereoisomer A; title compound:

Rf = 0.49 (silica; hexane: ethyl acetate (1: 1);

(b) Diastereoisomer BJ in the title compound:

R f = 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 salts) diastereoisomer A

The diastereoisomer AJ of N-BOC-amine obtained in the foregoing Step A above; was removed from the protecting group by bubbling hydrogen chloride gas in ethyl acetate. After solvent removal, preparative, high-performance liquid chromatography (column C-18; water / methyl cyanide / 0.1% trifluoroacetic acid; gradient) was performed; and after freeze-drying the title compound is obtained as a powder.

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

- 147 * · ttn ······· Μ

Analytical evaluation of the compound according to formula ^G 28 ^H 35 ^N 3 ° 2 · ² (K / 3.trifluoroacetic) ^:

Calculated: Found:

C, 57.05; H, 5.54; N. 6.24 C 57.08; H, 5.64; N, 6.32

Example 23

Preparation of 1- [3- (4-Imidazolyl) -propyl] -2 (S) -butyl-4- (1-naphthyl) piperazine. bis-trifluoroacetate salts

Grade A

Preparation of ethyl 3- (4-imidazolyl) propionate

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

¹ H-NMR (CDCl 3):

delta 1.23 (3HJ) J 2.65 (2H; t) *, 2.94 (2H; t) J 4.15 (2h; k); 6, si (ih; p.); 7.56 (ih, s).

Grade B

Preparation of 3- (4-imidazolyl) -propanol

148

• · · ··· · · ··· ♦

To a solution prepared by dissolving 120.0 g (71.40 mmol) of the ester obtained under the above described Step AJ in 230.0 mL of tetrahydrofuran was added portionwise, over 30 minutes *, at 0 ° C. ° C; 2.99 g (78.6 mmol) of lithium tetrahydrofuran.

The resulting reaction mixture was then stirred at room temperature for 2.0 hours; e after cooling to 0 ° C; has been added; very carefully; 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 1.0 hour. After filtration through silica; followed by washing the filter with ethyl acetate; the solvent was removed.

The title compound (8.16 g) was obtained; in the form of a clear substance, oily consistency.

¹ H-NMR (CDCl 3 OD):

δ 1.84 (2H, _β entet); 2.68 (2HJ t); 3.58 (2H; t); 6.88 (1H, s); 7.80 (ih; _a .).

C p e c

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

The mixture prepared by mixing 166.0 mg (1.32 mmol) of the imidazole obtained in the previous step B above; (N-tert-butyloxycarbonyl) O (302.0 mg, 1.38 mmol) and 190.0 mg (1.38 mmol) of potassium carbonate were stirred in 10.0 mg of tetrahydrofuran for 2.0 hours.

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

·· ····

149 - <* · · ·· ·· ···· • · · · »· ··· · • · · · · · · · • · ·

Sf = 0.17; silica; 5% methanol in chloroform)

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

Grade D

Preparation of 1- [3- (4-Imidazolyl) -propyl] -2 (S) -butyl-4- (T-naphthoyl) piperazine. bis-trifluoroacetate salts

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

After three hours, the resulting reaction mixture was poured into ethyl acetate; and then shaken with 3 saturated sodium bicarbonate solution; followed by brine, and then dried and evaporated.

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

The aforementioned aldehyde was coupled with the piperazine obtained in Example 1 above; Step E; reductive alkylation analogous to that described in Example 19; Step c; and further worked up by subsequent silica gel column chromatography, using a 5% methanol in chloroform mixture. 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 HPLC (C18J column water / methyl cyanide / 0.1% trifluoroacetic acid; gradient).

Ofil lyophilization of the frozen aqueous solution was obtained

150% of the title compound in the form of a hygroscopic, powdery substance.

Mass Spectroscopy-FAB (m / z)

405, o; (M + 1)

Analytical ^G 25 ^H 32 ^N 4 ° *

Calculated

Compound rating of 2.35 TFA found. 0.4 H ₂ 0>

C, 52.48; H, 5.21;

C, 52.45; H, 5.22;

formulas

N 8.23% N 8.27%

Example 24

Preparation 2 (S) -N-Butyl-4- (1-naphthoyl) -1- [1- (1-naphthylmethyl) imidazol-5-ylmethyl] piperazine. salts of ditrifluoroacetic acid

In an analogous manner to that 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-triphenylmethyl-imidazolyl) -methyl] -4- (1-naphthoyl) -piperazine; and from 0.046 g (0.21 mmol) of 1-bromomethyl naphthalene.

The title compound was obtained after purification by reverse phase preparative HPLC. Gradient elution with 30-75% acetonitrile / 0.1% trifluoroacetic acid; 70% -25% 0.1% aqueous trifluoroacetic acid; 50 minutes) and lyophilization.

FAB-MS (m / z) = 517.0;

Analytical evaluation of the compound of formula ^c 34 ^H 36 ^N 4 ° · °, ° ^{5 H} 2 ° · ² »° ^:

Φ

151

C 60.55; ,2 5.22; ,4 7.43%

C 60.48; Η 5.12; Ν 7.42% • φ φ ··· • · φ φ φφφφ

Calculated

Found

Example 25

Preparation 2 (S) - n-Butyl-4- (1-naphthyl) -1- [1- (2-naphthylmethyl) imidazol-5-ylmethyl] piperazine. salts of ditrifluoroacetic acid

In an analogous manner to that described in Example 4 above; the title compound was prepared from 0.124 g (0.200 mmol); 2 (S) -n-butyl-1- [5- (3-triphenylmethyldidazolyl) -methyl] -4-O-naphthoyl) -piperazine; and from 0.046 g (0.21 mmol) of 2-bromomethyl naphthalene.

The title compound was obtained after preparative reverse-phase high-performance liquid chromatography (gradient elution with 30-75% acetonitrile / 0.1% trifluoroacetic acid; 70-25% 0.1% aqueous trifluoroacetic acid over a period of time). (50 minutes) by lyophilization.

Mass Spectroscopy-FAB (m +1)

492, o;

Analytical evaluation of the compound of formula ^C 34 ^H 36 ^N 4 ° · ¹ ' ^{7 H} 2 ° · ² ' °

Calcd .: C 58.87; H, 5.38. N, 7.23

Found: C, 58.90; H, 4.93; N, 7.13

Example

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

152

· · ·

0 «

0 0 0 ··

In an analogous manner to that described in Example 4 *, the title compound was prepared from 0.124 g (0.200 mmol); 2 (S) -n-butyl-1- [5- (3-triphenylmethylimide from olyl) methyl] -4- (1-naphthoyl) -piperazine; and from 0.041 g (0.21 mmol) of 4-cyanobenzyl bromide.

The title compound was obtained after purification by reverse phase high-performance prep-chromatography (gradient elution with 25¾ - 65% acetonitrile); 0.1% trifluoroacetic acid; 75% - 35% 0.1 % n trifluoroacetic acid (over 50 minutes); and lyophilization.

FAB-MS (m + 1) = 492.100

Analytical evaluation of the compound of formula ^C 31 ^H 33 ^N 5 ° · ^{0.35 H} 2 ° · ^2.0

Calculated: G 57.91; H, 4.96; N 9.65%

Found: C, $ 7.93; H 4.91 J N 9.55%

Example · 27

Preparation of 2 (S) -n-butyl-1- [1- (4-methoxybenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperszine. salts of ditrifluoroacetic acid

By the analogous procedure described above in Example 4; 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 chloride add additional 100 mg of potassium iodide to the reaction mixture.

The title compound was obtained after purification by reverse phase preparative high-performance liquid chromatography (gradient elution with 5% -95% acetonitrile).

153 water

0.1% trifluoroacetic acid; 95% -5% 0.1% Ni / N trifluoroacetic acid; within 50 minutes); and lyophilization.

FAB-MS (m + 1) = 497.0;

Analytical evaluation of the compound of formula C C-H ^N N ^. 1.70 H ₂ O, 2.0 TFA:

H, 5.30; N, 7.12

Found: C, 53.37; H, 4.78; N, 7.00

Example 28

Preparation of 2 (S) -n-butyl-1- [2- (3-methyl-2-butenyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperazine. salts of ditrifluoroacetic acid

In an analogous manner to that described in Example 4J, the title compound was prepared from 0.124 g (0.200 mmol); 2 (S) -n-butyl-1- [5- (3-triphenylmethylimide from olyl) -methyl] -4- (1-n-phthyl) -piperazine; and from 0.024 mL (0.21 mmol) of 4-bromo-2-methyl-2-butene.

The title compound was obtained after purification by reverse phase preparative / high performance liquid chromatography (gradient elution with 5% -95% acetonitrile / JO, 1% trifluoroacetic acid; 95% -5% 0.1% aqueous trifluoroacetic acid). (within 50 minutes); and lyophilization.

FAB-MS (m + 1) = 445.0;

Analytical evaluation of the compound of formula ^c 28 ^H 36 ^N 4 ° · ^{1,80 H} 2 ° * ^{2,0 m:}

Calculated :; C54.5i; H, 5.95; N 7.95%

Found: 0 54.54 ;, H ´ 5.39; N. 7,73%

154

Example 29

Preparation of 2 (S ') - n-butyl-1- [1- (4-fluorobenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperazine. salts of ditrifluoroacetic acid

In an analogous manner to that 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 0.026 ml (0.21 mmol) of 4-fluorobenzyl bromide.

The title compound was obtained after purification by reverse phase preparative HPLC. Gradient elution with 25% -65% acetonitrile / 0.1% trifluoroacetic acid; 75% -35% 0.1% aqueous trifluoroacetic acid; 50 minutes); and lyophilization.

FAB-MS (m + 1) = 485.0;

Analytical evaluation of the compound according to the formula

G3QH33FN4O .. 3Η ₂ 0. 2,0 TFA (trifluoroacetic acid):

Calcd: C 53.26; H, 5.39; N 7.31%

Found: C, 53.21; H, 4.56; N 7.08%

Example 30

Preparation of 2 (S) -N-butyl-1- [1- (4-chlorobenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperazine. salts of ditrifluoroacetic acid

Analogous to the procedure described in Example 4 above; the title compound was prepared; from 0.124 g (0.200 mmol); 2 (S) -n-Butyl-1- [5- (3-triphenylmethylimide from olyl) -methyl] -4- (1-naphthoyl) -piperazine; and Z. 0.044 mg (0.21 mmol) of 4-chlorobenzyl chloride with additional addition of 100.0 mg of sodium iodide

155

Do Φ φφφφ to the reaction mixture.

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

Mass Spectroscopy-FAB (m + 1) = 501 _r0 *

Analytical evaluation of the compound according to the formula

C3O ^H 33 ^C 1 ^N 4 ⁰ · 4.80 H ₂ 0. 2,0'TFA (trifluoroacetic acid):

Calcd .: C 50.07; H, 5.51; N 6.87%

Found: C, 50.10; H, 4.25; N 6.48%

Example 3.1

Preparation of 1- [1- (4-Bromobenzyl) -imidazol-5-ylmethyl] -2H-5-butyl-4- (1-naphthoyl) -piperazine. salts of ditrifluoroacetic acid

In analogy to Example 4J, 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 _z to the reaction mixture.

The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30% -65% acetonitrile / 0.1% trifluoroacetic acid; 70.0% -35% 0.1% aqueous trifluoroacetic acid). within 50 minutes by lyophilization.

FAB-MS (m + 1) = 545;

156 • · ·· ·

Analytical evaluation of the compound of formula ¹ H 2 O. 2,0 TPA (trifluoroacetic acid)

Calcd: C 50.78;

Found: C, 50.81;

H, 4.81; N. 6.97% H 4.39; N 6.88%

Example. 32

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

In an analogous manner to that described in Example 4 above, the title compound (0.124.0 g; 0.200 mmol) was prepared; 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazole) 1-methyl-4- (1-naphthoyl) -piperazine; and from 0.053 mg (0.21 mmol) of 4-trifluoromethylbenzyl bromide.

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

Mass Spectroscopy-FAB (m + 1) =

Analytical evaluation of a compound of the formula ^ ^ 3 ^ 3Ο ^{ΓΝ 4θ} * acid. Trifluoroacetic acid):

Calculated: C 55.12; H, 4.63; N 7.35%

Found: C, 57.46; H, 4.98; N 7.84%

157 • 4 4 · ·· ·

Example 33

Preparation 2 (S) -n-butyl-1- [1- (4-methylbenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperazine salts of difluoroacetic acid

In an analogous manner to that described in Example 4J 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). -naphthyl) -piperazine from 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 by reverse phase preparative high performance liquid chromatography (gradient elution with 30% - 65% acetonitrile / 0.1% trifluoroacetic acid; 70% - 35% 0.1% aqueous trifluoroacetic acid; 50 minutes); and lyophilization.

FAB-MS (m + 1) 481.0;

Analytical evaluation of the compound according to the formula

^C 31 ^H 36 ^N 4 ^{O (} 2.60) ^H 2 °. 2.0 Calcd: 0 55.64; TFA (trifluoroacetic acid): H, 5.76; N, 7.42 % Found: C, 55.61; H, 5.09; N, 7.43 %

Example 34

Preparation of 2 (S) -n-butyl-1- [1- (3-methylbenzyl) -imidazol-5-ylmethyl] -4- (1-naphthoyl) -piperazine. salts of difluoroacetic acid

In an analogous manner to that described in Example 4 above;

the title compound was prepared from 0.124.0 g (0.200 mg)

158 9 9 9 9 9 99 99 9 9 99 99 9 mmoles) 2 (S) -n- butyl-1- [5- (3-triphenylmethylimidazoyl) -methyl] -4- (1-naphthoyl) -piperazine; and from 0.029 ml (0.21 mmol) of 3-methylbenzyl bromide.

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

Mass Spectroscopy-FAB (m + 1)

481, o;

Analytical ^C 31 ^ 36 ^ 4 ° *

Calculated

Found compound evaluation according to formula 2.0 TFA (/ acid, trifluoroacetic):

C 67.26; H, 6.92; N, 10.12; 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. salts of difluoroacetic acid

In an analogous manner to that described in Example 4J, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylimidazolyl) methyl] 4- (1). -naphthyl) -piperazine; and from 0.029 mL (0.21 mmol) of 4-phenylbenzyl bromide.

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

444

159

4444

Mass Spectroscopy-FAB (m + 1)

543, o;

Analytical ^C 36 ^H 38 ^N 4 ° ·

Calculated

Found compound evaluation according to formula

4.95 ^ 0. 2.0 TFA (trifluoroacetic acid):

C 55.87 *, H 5.85 *, N 6.52%

C 55.55; H, 4.58; N 6.23%

Example 36

Preparation of 2 (S) -N-Butyl-4- (1-naphthoyl) -1- [1- (2-phenylethyl) imidazol-5-ylmethyl] piperazine. ditrifluoroacetic acid salts

In an analogous manner to that 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; 8 by heating the mixture at reflux for 12 hours.

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

FAB-MS (m + 1) = 481.0;

Analytical evaluation of the compound according to the formula ^σ 36 ^ 38 ^Ν 4θ * »20 H ^ O. 2.0 TFA (trifluoroacetic acid):

Calcd: 53.60; H, 5.96; N 7.14%

Found: 53.54; H, 4.86; N 6.86%

160

Example 37

Preparation 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethoxy) imidazol-5-ylmethyl] -piperazine. salts of difluoroacetic acid

In analogy to the procedure described in Example 4J above, the title compound was prepared from 0.124 g (0.200 mmol) of 2 (S) -n-butyl-1- [5- (3-triphenylmethylamide) from oly 1]. -methyl / 4- (1-naphthoyl) -piperszine; and from 0.032 mL (0.21 mmol); 4-trifluoromethoxybenzyl bromide with additional addition of 120.0 mg sodium iodide to the reaction mixture; and heating the mixture at reflux under: reflux for 12.0 hours.

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

FAB-MS (m + 1) = 551.0;

Analytical evaluation of the compound according to the formula ^C 31 ^H 33 ^F 3 ^N 4 ^Q 2 * ^H 2 ° * ² »°° trifluoroacetic acid):

H, 5.09; C, 49.42; N 6.59%

Found: C 48.95 £ Η 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

161

Grade A

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

A solution prepared by dissolving 4.00 g (24.6 mmol); 1H-imidazole-4-acetic acid hydrochloride; in 100.0 mL of methanol; was saturated with hydrogen chloride gas; and the resulting reaction mixture was allowed to stand at room temperature for 18.0 hours.

Evaporation of the solvent in vacuo gave the title compound as a white solid.

¹ H-NMR (CDCl 3, 400 MHz):

delta 8.85 (1H, s); 7.45 (1H, s); 3.89 (2HJ s) J and 3.75 <3K; s (ppm) 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 as described above in Stage AJ above in 115.0 ml dimethylformamide was added 57.20 ml (0.412 mol) triethylamine and 55.30 g (0.171 mmol). ) triphenylmethyl bromide and the resulting suspension was stirred for 24.0 hours.

After completion of the above operation, the reaction mixture was diluted with 1.0 L of ethyl acetate; and with 350.0 ml of water. After separation of the organic and aqueous phases, the organic layer was washed with 350.0 ml of saturated aqueous sodium bicarbonate solution;

- 162 was dried with sodium sulfate; and then evaporated under vacuum. The residue was purified by flash chromatography on silica using 0-100% ethyl acetate in hexane; as eluent, for gradient elution.

The title compound was obtained as a white solid.

¹ H-NMR (CDCl 3; 400 MHz):

delta 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-imidazol-5-yl] acetic acid methyl ester

To a solution prepared by dissolving 8.00 g (20.90 mmol) of the product obtained as described in Step B above. in 70.0 ml of acetonitrile, 4.10 g (20.92 mmol) of bromo-p-toluonitrile was added; and the resulting reaction mixture was heated at 55.0 ° C for 3.0 hours.

Upon completion of the above operation, the reaction mixture was cooled to room temperature; and the resulting imidazolium salt (white precipitate) / was collected by filtration. The obtained filtrate was heated at 55.0 ° C for 18.0 hours. The reaction mixture was then cooled to room temperature; and evaporated under vacuum. To the residue was added 70.0 mL of ethyl acetate; and the resulting white precipitate was collected by filtration. The precipitated imidazolium 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 under vacuum, and the resulting residue was suspended to 75.0.

163 ml of ethyl acetate and the solid was isolated by filtration; and washed with ethyl acetate. The solid was then treated with 300.0 mL of saturated aqueous sodium bicarbonate; and with 300.0 ml of dichloromethane; and the mixture was stirred at room temperature for 2.0 hours.

After separation, the organic layer was dried with magnesium sulfate; and evaporated under vacuum.

The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ; 400 MHz):

δ 7.65 (1H; dJ J = 8.0 Hz); 7.53 UH; and.); 7.15 (1H; a, u = 8.00 Hz); 7.04 (ih; s); 5.24 (2H, s); 3.62 (3h; _a .); and 3.45 (2H, s); ppm.

Grade D

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

Mixture prepared by mixing 4.44 g (17.40 mmol) of methyl 1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetic acid; obtained in the framework of the above-described Step C; in 100.0 mL of tetrahydrofuran; and 17.40 mL (17.40 mmol) of lithium hydroxide; was stirred at room temperature for 18.0 hours. A 1N hydrochloric acid solution was then added to the reaction mixture; and tetrahydrofuran was removed from the reaction mixture under vacuum,

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):

164

delta 8.22 (1H, s) J 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; a.); ppm.

Grade E

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

To the mixture prepared by mixing 100.0 mg (0.35 mmol) of the acid obtained under the above Step D; 117.0 mg (0.35 mmol) of the amine hydrochloride salt; obtained in Example (?); Degree (?); 58.0 mg (0.35 mmol) of 3-hydroxy-1,2,3-benzotriazin-4 (3) -one (HOOBT) and 0.123 ml (0.88 mmol) of triethylamine, 75 ml of di-methylformamide were added in 75 ml. 0 mg (0.38 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl.

The resulting reaction mixture was stirred at room temperature for 16.0 hours; and after dilution with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate; and brine; and dried over sodium sulfate, evaporated in vacuo.

The residue was purified by preparative high performance liquid chromatography (C-18; 95: 5.0 to 5: 95 water: methyl cyanide; containing 0.1% trifluoroacetic acid; gradient elution);

After freeze-drying the combined fractions, the title compound was obtained; in the form of a white colored solid. ¹ H-NM'R (CD ₃ QD, 400MHz):

delta 9.00 - 8.90 (1HJ 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.

- 165

Analytical evaluation of the compound according to the formula

^C 32 ^H 33 ^N 5 ° 2 ' 1.40 TFA. 0.55 H ₂ 0: Calculated: 60.65; H 5.19; N 10.16 Found: 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. salts of difluoroacetic acid

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) - (tert-butoxycarbonylamino) -hexanoic acid; 15.50 g (0.15 mol) of Ν, Ο-dimethylhydroxylamine hydrochloride; 22.30 g (0.117 mol) of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl); and 14.30 g (0.106 mol) of 1-hydroxybenzotriazole hydrate (HOBT); was stirred in 300.0 ml of dried, degassed dimethylformamide under a nitrogen atmosphere at 20.0 ° C.

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

166

Removal of the solvent in vacuo gave the title compound.

P r es B

Preparation 2 (S) - (tert-butoxycarbonylamino) - nexanal

To a mechanically stirred suspension of 5.0 g (0.131 mol) of lithium tetrahydroaluminium; in 250.0 mL of ether; and cooled under a nitrogen atmosphere to a temperature of minus 45.0 ° C; a solution prepared by dissolving 28.30 g (0.103 mol) of the product obtained in the above step a) was added; in 125.0 mL of ether while maintaining the temperature of the reaction mixture below minus 35 ° C.

Upon completion of the above operation, the reaction mixture was allowed to warm to 5 ° C; The solution was prepared by dissolving 27.3 g (0.200 mol) of potassium bisulfate in water, keeping the temperature of the reaction mixture below minus 5. Deň: 32 ° C. After mixing, the reaction mixture was stirred at room temperature for 1.0 hour, and then the mixture was filtered through silica; the ether was evaporated, and the residue was partitioned between ethyl acetate) and a 2% aqueous potassium hydrogen sulfate solution.

After washing (organic layer) with saturated brine solution; drying over magnesium sulphate) and removing the solvents to give the title compound.

Stage C

167

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

To a solution prepared by dissolving 8.32 ml (68.30 mmol)

2,3-dimethylaniline, under nitrogen, in dichloroethane, was adjusted to pH 5.0; acetic acid * was added, and to this reaction mixture was added 17.20 g (80.80 mmol) of sodium triacethoxytetraborohydride; and 4.0 g of comminuted molecular sieve.

The reaction mixture was then slowly added dropwise at 20.0 ° C; a solution prepared by dissolving 13.30 g (62.10 mmol) of the product obtained as described in Step B above; in 80.0 ml of dichloroethane.

The reaction mixture was then stirred overnight; and then mixed with a saturated aqueous solution of sodium bicarbonate. Pp separating the organic and aqueous phases, the organic layer was washed with a 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

A solution prepared by dissolving 8.50 g (26.5 mmol) of the product obtained as described in Step c above; in 250.0 mL of ethyl acetate was stirred vigorously at 0 ° C with 150.0 mL of saturated aqueous sodium bicarbonate. To this reaction mixture was then added 2.33 ml (29.10 mmol) of chloroantyl chloride and the mixture was stirred at 0 ° C for 1.0 hour.

- 168

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 the resulting solution was cooled to 0 ° C under nitrogen atmosphere. Then, 1.79 g of sodium hydride (60% dispersion in oil; 44.90 mmol) was added portionwise to maintain a slight hydrogen evolution. After 30.0 minutes an additional 0.80 g of sodium hydride was added; and the reaction mixture was stirred for an additional 30.0 minutes and then rapidly mixed with a saturated aqueous ammonium chloride solution.

Dimethylformamide was then distilled off in vacuo; and the residue obtained 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 with magnesium sulfate.

The crude product was chromatographed on silica gel; eluent 20-30% ethyl acetate in hexane.

The title compound was obtained.

Grade E

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

A solution prepared by dissolving 0.570 g (1.58 mmol) of the product obtained as described in Step d above; in 50.0 ml of ethyl acetate; was cooled under a nitrogen atmosphere to a temperature of minus 15.0 ° C; and then bubbled with hydrogen chloride gas for 15 minutes.

The reaction mixture was then allowed to warm to 0 ° C over 2.0 hours; and after removal of the solvent under vacuum, it was found to be preferred

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 carboxyldehyde.

The reaction mixture was stirred at 20.0 ° C overnight and then poured into saturated aqueous sodium bicarbonate. The organic phase was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate.

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

P r I *

Preparation of 5 (S) -n-butyl-1- (2,3-dimethylphenyl) -4- (4-imidazolylmethyl) -piperazin-2-one. salts of difluoroacetic acid

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

After the resulting reaction mixture was stirred at 20.08 for 2.0 h, 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 the preparative column; high performance liquid chromatography; and purified by mixed gradient of 15% -60% acetonitrile / 0.1% trifluoroacetic acid; 85% -40% 0.1% aqueous trifluoroacetic acid; within 50 minutes.

The title compound was obtained after lyophilization.

170 • 0 · 0

FAB-MS (m + 1) = 341.0;

Analytical evaluation of the compound of formula ^C 20 ^H 28 ^N 4 ^G · ^{2, G TFA} (trifluoroacetic acid):

Calcd: C 50.80; Η 5.15 *, N 9.87%

Found: C, 51.31; H 5.41J N 10.11%

Example 40

Preparation of 5 (S) -N-butyl-4- [1- (4-cyanobenzyl) -imidazol-5-ylmethyl] -1- (2,3-dimethylphenyl) -piperazin-2-one. salts of difluoroacetic acid

To the solution prepared by dissolving 0,120 g (0,21 mmol)

5 (S) -N-Butyl-1- (2,3-dimethylphenyl) -5- [4- (1-triphenylmethylimidazolyl) methyl] piperazin-2-one; obtained in the framework of the preceding step E above from Example 39; in 10.0 mL of acetonitrile was added at 20.0 ° C; 4-Acidbenzyl bromide (0.043 g, 0.22 mmol).

After 48 hours, the 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 20.0C for 2.0 hours.

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

70% -40% 0.1% aqueous trifluoroacetic acid; within 50 minutes,

The title compound was isolated after lyophilization from a water-acetonitrile solution.

FAB-MS (m + 1) = 456.0;

171 · ♦ ··

Analytical evaluating the compound according to the formula ^C 28 ^H 33 ^N 5 ⁰ 0.70 H ₂ 0. 2.0 TPA (trifluoroacetic acid): Calculated: C 55.28; H 5.13; N, 10.07 % Found: C 55.27; ,2 5.2O; H 10.41 % Example 1 a d 41

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

Grade A

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

Analogous to the procedure described above for Example 3 $; Step AJ was using 0.680 g (3.55 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl); and 0.436 g (3.23 mmol) of 1-hydroxybenzotriazole. hydrate (HOBT); and 0.473 g (4.85 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride; in 50.0 ml of dimethylformamide; and at pH 7.0, 1.0 g (3.23 mmol) of 4-benzyloxy-2 (S) - (tert-butoxycarbonylamino) -butanoic acid was converted; to the title compound.

For further work-up, the title compound was obtained as a clear gummy consistency.

Grade B

- 172

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

In an analogous manner to that described in Example 39 above; Step b; the title compound was obtained; by reducing the product prepared as described in Step A above with lithium aluminum hydride.

Stage C

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

In an analogous manner to that described in Example 39 above; Grade B; was prepared using 0.505 ml (4.14 mmol)

2,3-dimethylaniline; 1.20 g (5.65 mmol) of sodium triacethoxytetrahydrate; and 1.0 g of comminuted molecular sieve; at pH 5; in 20.0 ml of dichloroethane, from the product obtained under Step; E; the title compound, which was further purified on silica gel, eluting with 15% ethyl acetate in hexane.

Stupen 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 the above Step C; as described above in Example 39; Grade D; using 0.21 ml (2.57 mmol) of chloroacetyl chloride; in 60.0 ml of the mixture

- a saturated aqueous solution of sodium bicarbonate (1: 1) J followed by reaction of the crude product and 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.

Grade E

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

To the product obtained under the above-described DJ stage and dissolved in 40.0 ml of methanol was added 0.160 g of 10% palladium on activated carbon; and the resulting reaction mixture was hydrogenated at 40 psi.

After removal of the catalyst by filtration, the solvent was evaporated; to give the title compound.

Grade F

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

A solution prepared by mixing 0.241 g (0.688 mmol) of the product obtained under the above Step E; with 10.0 ml of dimethylformamide; containing 0.21 mL (3.44 mmol) of methyl iodide was stirred under nitrogen at 0 ° C. Then, 0.070 g of hydride was added to the reaction mixture

• · 174 solution (dispersion in oil; 1.72 mmol) _{of R,} and the mixture was stirred for 1.0 hours.

The reaction mixture was then mixed with water; and dimethylformamide was removed in vacuo. The residue was partitioned between ethyl acetate and water; After separating the organic and aqueous phases, the organic layer was washed with a saturated brine solution; and dried with magnesium sulfate.

The crude product was chromatographed on silica gel, eluting with 40% ethyl acetate in hexane. The title compound was obtained.

Degree. G.

Preparation of 1- (2 3rdimethylfenyl _R) -5 (S) - (2-methoxyethoxy ethyl) -4- / 4- (1trifenyImethylimidazolyl) methyl / piperazine-2-one

The products obtained in the preceding step FJ, i.e. 0.113 g (0.312 mmol); was converted to the title compound by the analogous procedure described above for Example 39J, Step EJ, except that a 1 hour treatment with 30% trifluoroacetic acid in 10.0 mL of dichloromethane was used to remove the protecting group.

The volatiles were then removed from the reaction mixture in vacuo; and the residue was dissolved in dichloroethane. To the resulting solution was added to pH 5.0; triethylamine, 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-imidazolylkarboxaldehydu.Poté reaction mixture was stirred at 20 ^G C overnight; and then poured into a saturated aqueous solution of sodium bicarbonate.

The organic phase was washed with a saturated brine solution;

and then dried with magnesium sulfate.

After chromatography on silica gel, using a 5% mixture

- 175

Methanol in chloroform as eluent gave the title compound.

Grade H

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

Within the above Grade G; the obtained product (0.182.0 g; 0.312 mmol) was converted to the title compound by a procedure analogous to that described in Example 40 above; using 0.061 g (0.312 mmol) of 4-cyanobenzyl bromide; in 10.0 ml of acetonitrile, followed by reaction of the crude imidazolium salt with 0.13 ml of triethylasilane 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% -70% acetonitrile / 0.1% trifluoroacetic acid; 100% -30% 0.1% aqueous trifluoroacetic acid; within 60.0 minutes.

The title compound was isolated from water after lyophilization.

FAB-MS (m + 1) = 458.0;

Analytical evaluation of the compound according to the formula

Ο ₂ γΗ ₃₁ Ν ₅ Ο ₂ »0.35 H ₂ 0. 2.00 TFA (trifluoroacetic acid):

Calculated: 53.81J H 4.91J N 10.21%

Found: 53.83; H, 4.95; N 10.29%

176

• · ·

Example 42

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (methanesulfosyl) ethyl] -2-piperazinone. dihydrochloride

Grade A

Preparation of 1-triphenylmethyl-4- (hydroxymethyl) -imidazole

KU solution, prepared by dissolving 35.0 g (260.0 mmol)

4- (hydroxymethyl) -1-imidazole hydrochloride; in 250.0 ml of dried dimethylformamide; 90.60 ml (650.0 mmol) of triethylamine was added at room temperature. To the solid, white solid precipitated from solution was added dropwise 76.10 g (273.0 mmol) of chlorotrifenylmethane in 500.0 ml of dimethylformamide.

The reaction mixture was stirred for 20.0 hours; and then filtered on Xx; and washed with ice-cold water. The resulting product was slurried with chilled dioxane; it was then filtered; and dried under vacuum.

The title compound was obtained as a white solid which was pure enough to be used in the next Step B.

Grade B

Preparation of 1-triphenylmethyl-4- (aethoxymethyl) -imidazole

In the foregoing, Stage A described above; prepared alcohol (260.0 mmol) was suspended in 500.0 ml of pyridine.

78.0 ml (780 ml) was added dropwise to the resulting suspension.

177 · olu olu φ olu olu mol) acetic anhydride; The mixture was stirred for 48 hours. During this operation the mixture was homogenized and then poured into 2.0 L of ethyl acetate. After washing the mixture three times; with 1.0 liter of water; and 2 x with 1.0 L of 5% aqueous hydrochloric acid; with a saturated aqueous solution of sodium bicarbonate; and with brine, the mixture was dried with sodium sulfate; and concentrated under vacuum; and the crude product was obtained.

The acetate was isolated in the form of a white colored powder which was pure enough to be used in the next reaction.

Stage 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 under the above Step B; and 50 _r, 10 g (232.0 mmol) of .alpha.-bromo-p-tolunitrile; in 500 ml of ethyl acetate was stirred at + 60.0 ° C; During this operation, a light yellow colored precipitate formed. The reaction mixture was then allowed to warm to room temperature; and after filtration a solid salt of imidazolite NH bromide was obtained. The filtrate was concentrated to 200.0 mL under vacuum; and reheated at 60.0 ° C for 2.0 hours. Subsequently, it was cooled again to room temperature and filtered again.

The filtrate was then concentrated in vacuo to a volume of 100.0 ml, heated again at 60.0 ° C for 2.0 hours, then cooled to room temperature; and, after concentration in vacuo, a slightly yellow solid was obtained.

All obtained solid materials were combined; and dissolved in 500.0 mL of methanol, and heated to 60.0 ° C.

178 • · · · ·

44 4 404440

0 0 0 4 0 • 00 0 ··. 000 4 ··· · 4 4

After 2.0 hours, the solution was concentrated again in vacuo to give a white solid, which was mechanically treated with hexane to remove soluble components.

Removal of the solvent residues under vacuum gave the title hydrobromide as a white solid, which could be used without further purification in the next Step D.

S p a r D 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 under the above-described Step C; in 1.50 L of tetrahydrofuran: water (3: 1); 18.90 g (450.0 mmol) of lithium hydroxide monohydrate was added at 0 ° C.

After 1.0 hour, the reaction mixture was concentrated in vacuo, diluted with 3.0 L of ethyl acetate; and then washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The mixture was then dried with sodium sulfate; filtered and concentrated in vacuo.

The crude product was obtained as a pale yellow solid (crumbly) which was sufficiently pure to be used in the next step without further purification.

Grade E

Preparation of 1- (4-cyanobenzyl) -5-imidazolecarboxaldehyde

179

To a solution prepared from 21.50 g (101 mmol) of the alcohol obtained in the above step DJ in 500.0 ml of dimethylsulfoxide was added 56.0 ml (402.0 mmol) of triethylamine at room temperature; followed by 40.50 g (254.0 mmol) of pyridine-sulfur trioxide complex.

After 45.0 minutes, the reaction mixture was poured into 2.50 L of ethyl acetate; washed 4x with 1.0 L water and brine; and dried over sodium sulfate, filtered, and concentrated in vacuo.

The title aldehyde was obtained in the form of a white colored powder which was pure enough to be used in the next step (Step L); without further cleaning.

Grade E

Preparation of (S) -2- (tert-butoxycarbonylamino) -N-methoxy-N-methyl-4- (methylthio) -butanamide

A mixture prepared by mixing 30.0 g (0.120 mol) of L-N-BOCmethionine; 14.10 g (0.144 mol) of Ν, Ο-dimethylhydroxylamine hydrochloride; 27 ', 70 g (0.144 mol) EDC.HCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) J and 19.50 g (0.144 mol) HOBT (1-hydroxybenzotriazole hydrate); was stirred in 300.0 mL of dimethylformamide, at 20.0 ° C under a nitrogen atmosphere. Then, more (2.30 g, 23.0 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride was added to the reaction mixture until a pH in the range of 7.0 - 8.0 was reached.

The reaction mixture was then stirred overnight; and dimethylformamide was distilled off 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 and aqueous phases, the organic layer was washed with saturated aqueous sodium bicarbonate;

- 180a with water; 10% citric acid solution; 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 1.0 hour. Then, the reaction mixture was cooled under a nitrogen atmosphere to a temperature of minus 50.0 ° C; to this reaction mixture was added within 30.0 minutes a solution prepared by dissolving 39.80 g (about 0.120 mol) of the product obtained under the above described Step PJ in 200.0 ml of ether, maintaining the temperature of the reaction mixture at lower than minus 40.0 ° C.

After completion of the above operation, the reaction mixture was allowed to warm to 5.0 ° C; and then recooled to minus 45.0 ° C.

Analysis by thin layer chromatography showed insufficient reaction.

The mixture was reheated to 5.0 ° C; it was then stirred for 30.0 minutes and then cooled again to minus 50.0 ° 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 20.0 ° C.

The mixture was then allowed to warm to 5 ° C; filtered through silica; and finally concentrated in vacuo.

The desired title aldehyde was obtained.

*

181

S t u p e and K

Preparation of (S) -2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 4- (methylthio) butanamine

Ku Mixture with |, not prepared. mixing 10.30 mL (97.40 mmol) of 3-chloroaniline; 23.90 g (97.40 mmol) of the product obtained in the preceding step GJ and 27.80 ml (487.0 mmol) of acetic acid; in 250.0 ml of dichloroethane, under a nitrogen atmosphere, was added 41.30 g (195.0 mmol) of sodium triacethoxytate borohydride.

The resulting reaction mixture was stirred overnight and then mixed with saturated aqueous sodium bicarbonate. Then the mixture was diluted with chloroform, and the organic phase after separation was washed successively with water; 10% citric acid solution, and brine; and then dried with sodium sulfate; and was 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.

Stage I

Preparation of (S) -4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -5- [2 (methylthio) ethyl] piperazin-2-one

A solution prepared by dissolving 22.0 g (63.80 mmol) of the product obtained as described in Step H above; in 150 ml of ethyl acetate, was stirred vigorously at 0 ° C with 150 ml of saturated aqueous sodium bicarbonate.

5.60 ml was added dropwise to the resulting reaction mixture

182 (70.20 gimol) chloroacetyl chloride and the reaction mixture was stirred at 0 ° C for 2.0 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 was 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 the resulting solution was cooled to 0 ° C under argon.

Cesium carbonate (63.90 g, 196.0 mmol) was then added to the above solution; and the reaction mixture was stirred for 2 days while allowing it to warm to room temperature. Then a further portion of cesium carbonate (10.0 g, 30.0 mmol) was added to the mixture; and the reaction mixture was stirred for 16.0 hours. After dimethylformamide was distilled off in vacuo, the aryl residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed with saturated brine and dried with 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

PKu ': once flow, prepared by dissolving 14.20 g (37.0 mmol) of the product obtained under the preceding step i; in 300.0 mL of methanol; and cooled to 0 ° C; a solution prepared by dissolving 54.90 g (111.0 mmol) of magnesium monoperoxyphthalate was added over 20 minutes; The reaction mixture was allowed to warm to room temperature. At 45.0 minutes, the mixture was

183 was concentrated under vacuum to half its original volume, 'and then mixed with 2N. sodium thiosulphate solution. The reaction mixture was then poured into a mixture of ethyl acetate and an aqueous saturated sodium bicarbonate solution. After separation of the organic and aqueous phases, the organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo.

The obtained crude sulfone was chromatographed on silica gel using 60-100% ethyl acetate in hexane as eluent.

The title compound was obtained.

Grade K

Preparation of (S) -1- (3-chlorophenyl) -5- [2- (methanesulfonyl) ethyl] piperazin-2-one

The solution, prepared by dissolving 1.39 g (3.33 mmol) of the BOC protected product obtained in Step JJ above in 30.0 mL of ethyl acetate, was bubbled through anhydrous hydrogen chloride gas at 0 ° C. . The resulting, saturated solution was stirred for 35.0 minutes; The hydrochloride salt obtained as a white powder was suspended in ethyl acetate and mixed with dilute aqueous sodium bicarbonate solution. After separation, the aqueous phase was extracted with ethyl acetate, and the combined organic mixture was washed with brine; dried with 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.

Grade L

- 184 • · 0 · · ·

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 under Step K above. and 897.0 ml (4.25 mmol) of imidazole carboxaldehyde obtained as described above in Step EJ in 15.0 ml of 1,2-dichloroethane, 1.21 g (5.70 mmol) of sodium triacetoxytetraborohydride were added. .

The resulting reaction mixture was stirred for 23.0 hours; and then mixed with a saturated aqueous sodium bicarbonate solution at 0 ° C; and then poured into chloroform. The aqueous layer was shaken back with chloroform; and the spent organic extracts were washed with brine; dried with sodium sulfate, filtered; and concentrated in vacuo.

The resulting product was purified by silica gel chromatography. eluent ethyl acetate: methanol *: ammonium chloride (95: 5: 0.5 - 90: 10: (X); as eluent; and the resulting product was taken up in a mixture of ethyl acetate and methanol; equivalents of 1M hydrogen chloride ether solution.

After concentration in vacuo ,, isolated in the trihydrochloride dihydrochloride as a white powdery £ _r substances.

Example 43

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone dihydrochloride

Grade A

185

Preparation of (S) -N- (tert-butoxycarbonyl) -homoserinlactone

Bi solution prepared from 11.0 g (79.90 mmol) of (S) -homoserin lactone hydrochloride; and 19.20 g (88.00 mmol) of di-tert-butylpyrocarbonate in 160.0 ml of dichloromethane were added at 0 ° C over 3.0 minutes _; 13.9 ml of diethyl ether and ethylamine. The resulting reaction mixture was allowed to warm to room temperature; and after 3.0 hours a further 1.75 g (8.0 mmol) of di-tert-butylpyrocarbonate and 0.70 ml (4.00 mmol) of diisopropylethylamine were added to the mixture.

The reaction mixture was then stirred for an additional 2.50 hours; and then washed with a 10% citric acid solution; saturated aqueous sodium bicarbonate; and brine; and then dried over sodium sulphate;, filtered, and concentrated in vacuo.

The resulting material was purified by silica gel chromatography; eluent 50% ethyl acetate in hexane.

Pure title compounds were obtained.

B e '

Preparation of (S) -N- (tert-butoxycarbonyl) -homoaerinlactol

To a solution prepared from 7.0 g (35.0 mmol) of the lactone obtained in the preceding step a); in 175.0 mL of tetrahydrofuran; and cooled to minus 78.0 ° C; 72.0 mL (1M solution in tetrahydrofuran; 72.0 mmol) of diisobutylaluminum hydride was added dropwise while maintaining the temperature of the reaction mixture at a temperature of less than minus 72.0 ° C. Pb 3.0 hours the reaction mixture was added to a further portion of 10.0 ml (£ _θ φ 0 mmol) of diisobutylaluminum hydride; and after the next hour, more were added

186

20.0 ml (20.0 mmol) of diisobutylaluminum hydride.

After an additional 1.0 hour, the mixture was mixed at minus 78.0 ° C with ethyl acetate; followed by a saturated aqueous solution of sodium potassium tartrate and then the mixture was allowed to warm to room temperature; and poured into ethyl acetate; washed with brine; and dried over sodium sulfate and filtered. and was concentrated in vacuo.

The resulting material was purified by silica gel chromatography eluting with 50% ethyl acetate in hexane.

&lt; / RTI &gt; obtained the title, desired, lactol.

(sodium-potassium-tartrate - sodium-potassium salt of 2,3dihydroxybutanedioic acid)

Grade G

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 lactol obtained in the previous step B above; and III, 58 mL (24.40 mmol) of 3-chloroaniline; in 50.0 mL of dichloromethane, 1.27 mL (22.20 mmol) of acetic acid was added at room temperature; and after 10.0 minutes, 6.59 g (31.10 mmol) of sodium triacethoxytetraborohydride were added to the mixture; and the reaction mixture was stirred for 1.50 hours.

Then, the reaction mixture was mixed with a saturated aqueous solution of sodium bicarbonate; diluted with dichloromethane, and then the aqueous and organic phases were separated. The organic material was dried with sodium sulfate; filtered, and concentrated in vacuo.

A solid was obtained which was purified by silica gel chromatography using ethyl acetate: hexane as eluent.

- 187 · ♦ ·

The title amine was obtained.

Grade H

Preparation of (S) -N- [2- (tert-butoxycarbonylamino) -4-hydroxybutyl] -2-chloro-N- (3-chlorophenyl) acetamide

The aniline derivative obtained (5.29 g, 16.90 mmol) obtained above in Step C ₍ mixed with 60.0 ml of ethyl acetate; and 60.0 ml of a saturated aqueous sodium bicarbonate solution; and this reaction mixture was cooled to After completion of this operation, 1.48 ml (18.50 mmol) of chloroacetyl chloride was added dropwise with vigorous stirring, and after 20 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 was concentrated in vacuo.

The title, desired, chloroacetamide was obtained, 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) J obtained as described in 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 the reaction was complete

188 by thin layer chromatography, it was not found that all of the starting material was consumed (about 5.0 hours).

The reaction mixture was then poured into ethyl acetate; washed with water and brine; dried with 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: OJ - 95: 5.0: 0.15) as eluent.

The desired title compound was obtained; and the desired product contaminated with less dimethylformamide.

Stupen 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 the previous step EJ described above in 50.0 mL of dichloromethane was added 3.50 mL (20.20 mmol) at 0 ° C. diisopropylethylamine followed by 0.936 ml (12.10 mmol) of methanesulfonyl chloride.

The resulting reaction mixture was stirred for 45.0 minutes; and then mixed with a 10% citric acid solution, washed with brine; and after drying with sodium sulfate, it was filtered; and was concentrated in vacuo.

The crude product obtained, i.e. 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) -ethylthi-piperazin-2-one

9

189

To a solution prepared by dissolving 3.60 g (8.30 mmol) of the meaylate obtained in the preceding step F; in 100.0 ml of dimethylformamide, 1.40 g (16.60 mmol) of sodium ethanethiolate was added at 0 ° C.

The resulting reaction mixture was poured into ethyl acetate after 2.0 hours; washed with saturated aqueous sodium bicarbonate; afšátsolánkou; 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 as described above in Step GJ in 50.0 mL of methanol, a solution of 11.60 g (23.50 mmol) was added at room temperature. magnesium monoperoscop phthalate, in 50.0 mL of methanol.

The resulting reaction mixture was mixed with 2N sodium thiosulfate solution after 45.0 minutes; and then poured into ethyl acetate and saturated aqueous sodium bicarbonate. After separating the organic 8 aqueous phase, 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, eluting with 2% methanol in chloroform.

The title compound was obtained.

- 190 • φ φφφφ ► · φ

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 preceding step H; in 20.0 ml of ethyl acetate, anhydrous hydrogen chloride gas was bubbled through at 0 ° C. The hydrogen chloride gas saturated solution was stirred for 30.0 minutes; and then concentrated in vacuo; to give the title compound as a white powder, which was suspended in ethyl acetate; and treated with a dilute aqueous solution of sodium bicarbonate.

After separation, the aqueous phase was shaken with ethyl acetate; and the combined organic mixture was washed with brine; dried over sodium sulphate, filtered and concentrated in vacuo.

The resulting title amine was dissolved and re-concentrated from toluene; and yielding the title compound suitable for use in the next step.

Grade J

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -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 preceding step I above. 460.0 mg (2.20 mmol) of imidazole carboxaldehyde obtained,.

'(7 ~ 25 mmol) within Step E described above; (Example 42); and 0.415 of acetic acid; in 10.0 mL of 1,2-dichloroethane was added

191

615.0 mg (2.90 mmol) of sodium triacethoxytetraborohydride; and the resulting reaction mixture was stirred for 18.0 hours; and then mixed with a saturated aqueous sodium bicarbonate solution at 0 ° C.

After the above operation, the reaction mixture was poured into dichloromethane; and the separated organic layer was washed with brine; then dried with sodium sulfate; and after filtration, it was concentrated under vacuum.

The resulting product was purified by silica gel chromatography eluting with 2-5% methanol in chloroform; to obtain 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 then he was responsive. with 1.0 ml of n-propylamine for 18.0 hours; and the reaction mixture was then concentrated in vacuo.

The residue was purified by silica gel chromatography using 2-5% methanol in chloroform, then combined with the product from earlier batches and, after removal of ethyl acetate: methanol, was treated with 2.10 equivalents of a 1M solution of 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 ·· ··· «

192

Preparation of (S) -2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 3 - [(triphenylmethyl) thio] -1-propanamine

To a solution prepared from 0.709 mL (6.70 mmol) of 3-chloroaniline in 30.0 mL of dichloromethane; was at 0 ° C; 1.20 g of a comminuted $ 4 molecular ate was added. 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 pH.

After completion of the above operation, 3.5 g (7.04 mmol) of L-S-trityl-N-BOC-cysteinal were added to the reaction mixture; prepared by the anlogic procedure described in J. Med.Chem., vol. 37J725-732; (1994) by S. L. Graham et al .; and the reaction mixture was stirred for 48.0 hours.

Then the mixture was mixed with a saturated aqueous solution of 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 after filtration was concentrated in vacuo. The resulting oil was purified by silica gel chromatography. eluent 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

The aniline derivative obtained (2.77 g, 4.95 mmol) was dissolved in 73.0 ml of ethyl acetate; and 73.0 ml of a saturated aqueous solution of sodium hydrogen carbonate, and this reaction mixture was cooled to room temperature

fence 0 ° C. With vigorous stirring, 0.533 ml (6.69 mmol) of chloroacetyl chloride was added dropwise to the mixture, and after 3.0 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. The title, desired, chloroacetamide was obtained in crude form, which 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 chloroacetamide * obtained in the previous step B above; in 53.0 ml of dimethylformamide; was added at 0 ° C, 4.84 g (14.85 mmol) of cesium carbonate.

The resulting reaction mixture was poured into ethyl acetate; washed with water and brine; dried with sodium sulfate; and after filtration was concentrated in vacuo.

The crude product was obtained as an oily substance which was purified by silica gel chromatography using 20% ethyl acetate in 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

194 • 4 4 444444

4 4 4 4 4

444 444 444 4444 44

Mixture _r prepared by mixing 625.0 mg (1.04 mmol) of piperazinone; obtained in the preceding step O) in 38.0 ml of degassed ethyl acetate 1 and in 12.0 ml of ethanol; was heated to 30.0 ° C. To this reaction mixture was then 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 for 45 minutes. The mixture was then concentrated in vacuo; and redissolved in 26.0 mL of degassed ethyl acetate. The resulting solution was bubbled with hydrogen sulfide gas for 2.0 minutes; The mBterial was then filtered through silica, rinsed with degassed ethyl acetate, and concentrated in vacuo.

After further dissolution and subsequent concentration from degassed dichloromethane, the desired crude 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

Thiol solution (about 1.04 mmol); obtained in the framework of the above-described Step D; in 3.0 mL of tetrahydrofuran; was added via a feed tube 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 of tetrahydrofuran.

After 10.0 minutes, 0.079 mL (0.988 mmol) of ethyl iodide was added to the reaction mixture, which was then stirred for 1.50 hours. The mixture was then poured into ethyl acetate; washed with saturated aqueous sodium bicarbonate solution and brine, then dried with sulphate

195 sodium; and after filtration was concentrated in vacuo.

The crude product obtained was purified by silica gel chromatography; eluent of 1% methanol in dichloromethane.

The 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 sulfide obtained as described above in Step EJ in 3.0 mL of methanol at 0 ° C was added a solution prepared from

835.0 mg (1.69 mmol) of megnasium monoperoxyphthalate in 2.0 mL of methanol. _ ~ night,

The resulting reaction mixture was stirred through the mixture at which the temperature rose spontaneously to room temperature. The mixture was then cooled to 0 ° C; and mixed with 4.0 mL of 2N sodium thiosulfate solution; and then concentrated in vacuo. The remaining residue was partitioned between ethyl acetate; and a mixed aqueous sodium bicarbonate solution; and after separating the aqueous and organic phases, the organic layer was washed with brine, then dried with sodium sulfate; and after filtration was concentrated in vacuo.

The desired crude sulfone was obtained in the form of a white, waxy solid,

Grade G.

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2-piperazinone. dihydro chloride

196 · · · * * * * * * • • • • • • • • • • · ·

To the solution prepared by mixing 224.0 mg (0.538 mmol) / s of the BOC-protected piperazinone obtained under the above-described Step F; in 5.0 mL of dichloromethane, 2.50 mL of trifluoroacetic acid was added at 0 ° C.

After 45.0 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 4A ° molecular sieve in powder form; followed by 285.0 m? (1.34 mmol) of sodium triacethoxytetraborohydride; and to achieve a pH of 6.0 of the mixture; a few drops of triethylamine.

Then, 125.0 mg (0.592 mmol) of the imidazolecarboxaldehyde obtained under Step E (Example 42) J 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 undiluted aqueous sodium bicarbonate; and brine, and then dried over sodium sulfate, and after filtration, concentrated in vacuo.

The crude product was taken up in methanol and applied by syringe to a preparative HPLC column. and purified by mixed gradient with 15% -5% acetonitrile / 0.1% trifluoroacetic acid; 85% - 50% 0.1% aqueous trifluoroacetic acid; within 60 minutes.

After concentration in vacuo, the resulting product was partitioned between dichloromethane and aqueous sodium bicarbonate solution, separating the organic and aqueous phases, and the aqueous layer was extracted with dichloromethane. The organic solution was then washed with brine; dried over sodium sulphate and filtered to dryness in vacuo.

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 dihydride was isolated as a white powder.

·· ··· * • ·

- 197 ·· «

Β · ♦ ·· · Φ ···· ·

Example 45

Preparation of (S) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- (N-ethyl-2-acetamide) -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 0.608 mL (6.97 mmol) of oxalyl chloride in 40.0 mL of dichloromethane; was added over 2-3 minutes at min. 78.0 ° C; 0.990 ml (13.90 mmol) of dimethyl 3-sulfoxide. The resulting reaction mixture was then stirred for 10.0 minutes; and then a solution prepared by dissolving 2.06 g (5.81 mmol) of the alcohol obtained under Step E (Example 43) J in 10.0 ml of dichloromethane was added over 5.0 minutes at the reaction mixture temperature. was maintained below 70.0 ° C.

After the reaction mixture was stirred for 10.0 minutes, triethylamine (2.43 mL) was added thereto, and the reaction mixture was stirred at minus 78.0 ° C for five minutes; at room temperature. After 45 minutes, the reaction mixture was poured into dichloromethane; and washed successively with a saturated aqueous ammonium chloride solution; 10% citric acid solution; with water and brine. The mixture was dried over sodium sulfate, filtered and concentrated in vacuo.

The title aldehyde was obtained.

Grade B

- 198

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 was added at room temperature a solution prepared by dissolving 585.0 mg (5.17 mmol) of sodium chlorite; and 595.0 mg (4.31 mmol) of sodium dihydrogen phosphate in 10.0 mL of water.

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 was forcibly washed with a saturated aqueous solution of sodium hydrogensulfite.

The aqueous layer was acidified to pH 3.0 with a 2.75 M potassium hydrogen sulfate solution; and then shaken several times with ethyl acetate. The combined organic extracts were dried with sodium sulfate; filtered; and concentrated under vacuum.

The title, desired carboxylic acid was obtained

Grade C

Preparation of (S) -4- (tert-butoxycarbonyl) -5- (N-ethyl-2-acetamido) 1- (3-chlorophenyl) -piperazin-2-one

A mixture prepared by mixing 200.0 mg (0.56 mmol) of the product obtained under the above described Step BJ 114.0 mg (1.40 mmol) of ethylamine hydrochloride; 140.0 mg (0.73 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDG.HCl); and 113.0 mg (0.84 mmol) of 1-hydroxybenzotriazole hydrate (HOBT); was stirred in 3.0 ml of dried dimethylformamide under a nitrogen atmosphere; and at 0 ° C.

After 1.0 hour, the reaction mixture was allowed to warm to room temperature; and stirred overnight. After removing the diI · r · * ···· «• ♦ · ·« to

- 199 - ··· .............

methylformamide 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 a 10% citric acid solution; saturated aqueous sodium bicarbonate solution J with 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 Step CJ above as described for Example 42 above; Grades 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 c ·· ·

- 200

Preparation of 1- (methanesulfonyl) -2-butyne

To the solution prepared by mixing 10,0 ml (134,0 mmol)

2-butynol; in 200.0 ml of dichloromethane; 23.40 g (134.0 mmol) of methanesulfonyl chloride was added at 0 ° C; and then sweat dropwise 30.0 ml (174.0 mmol) of diisopropylethylamine.

After 1.50 hours, the reaction mixture was poured into 0.5N potassium hydrogen sulphate solution, and the organic layer was washed with brine for subdivisions; dried with sodium sulphate; and after filtration was 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 ethyl ester ethyl ester in 200.0 ml of dichloromethane was added 7.36 ml (72.40 mmol) of benzaldehyde; 20.0 ml (143.0 mmol) of triethylamine; and 6.0 g magnesium sulfate.

The resulting reaction mixture was stirred at room temperature for 16.0 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 with sodium sulfate, and after filtration was concentrated in vacuo.

A slightly yellowish, oily consistency was obtained from which a portion (9.90 g * _f 51.80 mmol) was dissolved in 200.0 mL of tetrahydrofuran; and the resulting solution was cooled to minus 78.0 ° C under a nitrogen atmosphere. To this solution was added dropwise a solution of potassium tert-butoxide;

(51.80 mL) of 1M solution; 51.80 mmol to give a bright red colored solution.

AA AAAA A A A A A A A A A A A A A

PR for 20 minutes to the above reaction mixture was added dropwise, via a lance, a solution of the mesylate obtained under the above described Step AJ (8.05 g, 54.40 mmol) * in 20.0 mL of tetrahydrofuran; and the mixture was allowed to warm to room temperature. After 2.0 hours; the reaction mixture was poured into ethyl acetate; and washed successively with a saturated aqueous solution of sodium bicarbonate; and with brine, then dried with sodium sulfate; and after filtration was concentrated in vacuo.

The title compound was obtained.

Grade G

Preparation of (+) - ethyl 1-2 - [(tert-butoxycarbonyl) amino] -4-hexynoate

A solution _r prepared from the product obtained in Step B above (ca. 51.80 mmol) in 100.0 mL of 5% aqueous hydrochloric acid was stirred at room temperature. The mixture was concentrated in vacuo to give an orange-colored, 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 bicarbonate, followed by 11.30 g (51.80). mmol) of di-tert-butyl pyrocarbonate at room temperature. after 6.0 hours, the reaction - mixture was poured into ¹ * with ethyl acetate, and washed with saturated aqueous sodium bicarbonate, and brine, then dried over sodium sulfate, and after filtration, was concentrated under vacuum.

The title compound was obtained.

Grade D

202

Preparation of (/)-2-/( tert -butoxycarbonyl)-amino/-4-hexynic acid

To a solution prepared by mixing the product obtained under the above described Step C (ca. 51.80 mmol) [in 100.0 ml tetrahydrofuran; and 20.0 ml water; a solution of 6.50 g (155.0 mmol) of lithium hydroxide was added at 0 ° C. monohydrate. The resulting reaction mixture was stirred at 0 ° C for 1.0 h; and after 48.0 hours, the mixture was concentrated in vacuo.

The aqueous mixture was shaken with ethyl acetate; acidified at 10 ° C with a 10% aqueous hydrochloric acid solution; and then extracted three times with dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate; and were thickened under vacuum.

The title compound was obtained as an orange oil of oily consistency.

Cold

Preparation of (+) - 2- (tert-butoxycarbonylamino) -N-methoxy-N-methyl-14-hexynamide

A mixture prepared by mixing 10.58 g (46.60 mmol) of product; obtained in the framework of the above-described Step D;

9.09 g (93.20 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride; 9.44 g (69.90 mmol) of 1-hydroxybenzotriazole hydrate (HOBT); and 13.0 ml (93.20 mmol) of triethylamine; was stirred in a nitrogen atmosphere _of at 0 ° C, 150 ^ O ^ SyáÉfi fiylformamidu.

To this reaction mixture was then added 11.50 g (60.60 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. hydrochloride (EDC.HCl); and the reaction mixture was stirred for 3.0 hours. The mixture was then shaken between ethyl acetate: hexane (2: 1); and the water was then washed successively with water; 10% him

203 *

• »

aqueous solution (10%) of hydrochloric acid; saturated aqueous sodium bicarbonate; 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 P

Preparation of (+) - 2- (tert-butoxycarbonylamino) -4-hexynal

The suspension, prepared from 1.56 g (41.10 mmol) of lithium aluminum hydride in 150.0 ml of ether, was stirred at room temperature for 30 minutes, and after cooling to minus 55.0 ° C under an argon atmosphere, to the above slurry was added within 15.0 minutes the product obtained as described in the preceding step E (11.10 g, 41.10 mmol) * in 150.0 ml of ether, keeping the temperature of the reaction mixture below than minus 50.0 ° C.

After the above operation, the reaction mixture was allowed to warm to 5 ° C; and then recooled to minus 40.0 ° C; and slowly added a solution prepared by dissolving 21.80 g of potassium bisulfate in 25.0 mL of water, maintaining the temperature of the reaction mixture below / minus 35.0 ° C. The reaction mixture was then allowed to warm to room temperature; stirred for 1.0 hour, filtered through silica; and then concentrated in vacuo.

The title compound was obtained.

Grade G

204

Preparation of (+) - 2- (tert-butoxycarbonylamino) -N- (3-chlorophenyl) 4-butynamine

To the solution prepared by mixing 4.33 ml (40.90 mmol)

3-chloroaniline of the product obtained under the above Step F (about 41.0 mmol); and ground 4 $ molecular sieve (10.0 g) J in 100.0 mL of dichloromethane; 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 1.0 h; and then allowed to warm to room temperature. After 3.0 h, the mixture was poured into ethyl acetate; and washed sequentially with water and saturated aqueous sodium bicarbonate; and brine. The mixture was then dried with sodium sulfate; and was concentrated in vacuo.

The title compound was obtained as a crude product.

Grade H

Preparation of 9 (+) - N- [2- (tert-butoxycarbonylamino) -4-hexynyl] -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 GJ and 1.20 ml (8.61 mmol) of triethylamine; in 15.0 mL of dichloromethane; β cooled to 0 ° C; 0.457 ml (5.74 mmol) of chloroacetyl chloride was added dropwise; and the resulting reaction mixture was stirred at 0 ° C. ^z After 30.0 minutes, an additional portion (0.20 mL) of chloroacetyl chloride was added to the mixture; and 0.50 mL of triethylamine such that the addition was dropwise.

After 30 minutes, the reaction mixture was poured into ethyl

205

acetic acid, and washed with 10% aqueous hydrochloric acid; with a saturated aqueous solution of sodium bicarbonate; and with brine. The solution was then dried with sodium sulfate; filtered; and was concentrated in vacuo.

The product, as a brown oil, was purified by silica gel chromatography; using 20-35% ethyl acetate: hexane; as eluent.

The title 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 as described above in Step HJ in 15.0 mL of dried dimethylformamide, was added at 0 ^° C; 3.08 g (9.48 mmol) of cesium carbonate.

The resulting reaction mixture was stirred for 30.0 minutes and then allowed to warm to room temperature. After 14.0 hours, the reaction mixture was poured into a mixture of 50% ethanol and hexane; washed with water and dried with brine; and after filtration was concentrated in vacuo.

The crude product obtained was purified by silica gel chromatography; eluent 20-40% ethyl acetate / hexane.

The desired title product was obtained,

Grade J

206

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); and Boc-protected product within zištnému foregoing, the above-described Steps IU in 7.0 ml of dichloromethane were added at 0 ^q C, 4.0 ml of trifluoroacetic acid. At 4.0 hours, the reaction mixture was allowed to reach room temperature; and stirred for 6.0 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 resulting solution was cooled.

imidazolecarboxaldehyde obtained under Step E above, Example 42. After the reaction mixture was stirred at 0 ° C for 24.0 hours; was poured into ethyl acetate; washed with dilute aqueous sodium bicarbonate; and brine; then dried ^e ^ r ^ ° poýzťiltrování was concentrated in vacuo.

The material was purified by silica gel chromatography; using a mixture of 2.0 - 5.0% methanol in dichloromethane. The obtained white foam was taken up in dichloromethane and treated with 2.10 equivalents of a 1M solution of hydrogen chloride in ether. Concentration in vacuo gave the title dihydrochloride as a white solid, a powdery solid.

Example 47

207 • · ····

Preparation of 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) imidazolylmethyl] -2-piperazinone dihydrochloride

Grade A

Preparation of N- (3-chlorophenyl) ethylenediamine hydrochloride

To the solution prepared by mixing 30.0 ml (284.0 mmol)

3-chlorophilin; with dichloromethane (500 ml) was added at 0 ° C. 4 ml of a 1N solution of hydrochloric acid in 1,4-dioxane (80,0 ml of 320 mmol of HCl),

The resulting reaction mixture was allowed to warm to room temperature; and then concentrated to dryness under vacuum. White color was obtained; a powdery substance which was mixed with 24.60 g (282.0 mmol) of 2-oxazolidinone; and the mixture was heated under nitrogen at 160.0 ° C * for 10.0 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 raw material within the above-described Stage AJ, was mixed with 500.0 mL of tetrahydrofuran; and 500.0 mL of saturated aqueous sodium bicarbonate; and to the resulting reaction mixture; cooled to 0 ° C; 61.60 was added

208 g (282.0 mmol) of di-tert-butylpyrrolidone after 30.0 hours; the reaction mixture was poured into ethyl acetate; washed with water and ae brine; dried with sodium sulfate; and after filtration was concentrated in vacuo.

The title carbamate was obtained; in the form of a brown-colored oily consistency which was used in the next step for further purification.

Stage C

Preparation of N- [2- (tert-butoxycarbamoyl) -ethyl] -N- (3-chlorophenyl) 2-chloroacetamide

A mixture prepared by mixing 77.0 g (about 282.0 mmol) of the product obtained under the above Step B; and 67.0 ml (480.0 mmol) of triethylamine; in dichloromethane (500.0 mL) 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 3.0 hours, an additional portion (3.0 mL) of chloroacetyl chloride (dropwise) was added to the mixture; and 30.0 minutes, the reaction mixture was charged with 2.0 L of ethyl acetate. It was then washed successively with water; a saturated aqueous ammonium chloride solution; with a saturated aqueous solution of sodium bicarbonate; and brine. The mixture was then dried with sodium sulfate; and after filtration was concentrated in vacuo.

The title chloroacetamide, which was brown in color, had an oily consistency and was used in the next step without further purification.

Grade D • · ·

- 210 ·· »•«

Preparation of 4- (tert-butoxycarbonyl) -1- (3-chlorophenyl) -2-piperazinone

K _{for a} solution prepared by dissolving chloroacetamide (about 282.0 mmol); obtained as described above in the previous step OJ in 700.0 ml of dried dimethylformamide, 88.0 g (0.64 mmol) of potassium carbonate were added; and the resulting reaction mixture was heated in an oil bath at 70.0 to 75.0 ° C for 20.0 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; it was then dried over sodium sulfate, and the filtrate was concentrated in vacuo.

The product was obtained as a brown oil, which was purified by silica gel chromatography using 25.0-50% ethyl acetate / hexane; as eluent.

The desired pure title was obtained; a product containing less polar contaminants which, after analysis of the sample by high performance liquid chromatography, corresponded to a purity of about 65%.

S t u p e η E

Preparation of 1- (3-chlorophenyl) -2-piperazinone

The solution prepared by dissolving 17.19 g (55.40 mmol) of the BOC-protected product (piperazinone) obtained under the above-described Stage Ώ in 500.0 ml of ethyl acetate was at a temperature of minus 78.0 ° C. Hydrogen chloride free gas was bubbled through. The resulting saturated solution was allowed to warm to 0 ° C; and then stirred for 12.0 hours.

210 · e e e e <<<• _{e e e e e e e}

The reaction mixture was then purged with nitrogen gas 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 a dilute aqueous sodium bicarbonate solution. ¹

After separation of the aqueous and organic phases, the aqueous layer was washed 8 times with 300.0 ml of dichloromethane; until complete extraction was confirmed by thin layer chromatography analysis.

The combined organic extracts were dried with sodium sulfate, and concentrated in vacuo.

The title, desired free amine was obtained; in the form of a slightly brown colored substance, oily consistency.

Stage E '

Preparation of 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone. dihydrochloride

To a solution prepared by dissolving the product prepared as described in Step E above (55.40 mmol) in 200.0 mL of 1,2-dichloroethane was added at 0 ° C; molecular sieve; and then again

17.70 g (83.30 mmol) of sodium triacethoxytetraborohydride.

The resulting reaction mixture was then treated with 11.90 g (56.4 mmol) of imidazolecarboxaldehyde obtained in Step E above, in Example 42; and the reaction mixture was stirred at 0 ° C. After 26.0 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 were filtered under vacuum.

The resulting product was taken up in 500.0 mL of 4: 1 benzene: dichloromethane (5: 1); and 20.0 ml of propylamine was added to the mixture. The reaction mixture was then stirred for 12.0 hours; and then concentrated in vacuo to give a slightly yellow colored foam. This material was purified by silica gel chromatography using 2-7% methanol in dichloromethane as eluent; and the resulting white foam was taken up in dichloromethane and then treated with 2.10 equivalents of a 1M solution of hydrogen chloride in ether.

Concentration in vacuo afforded the title dihydrochloride; in the form of a white colored powder.

Example 48

Preparation of 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 that described in Synthetic Communications; 22, 2971-2977 (1992); author 3.P.

Watson; He was prepared 4-bromo-5-hydroxymethyl-2-methylimidazole which was (4.18 g * _t 21.90 mmol) was heated under reflux <^ ^ ^ _t five- Nym condenser in 200.0 ml of dichloromethane: dioxane together with 16.10 g of manganese dioxide for 16.0 hours.

212

After the above operation; and cooling the reaction mixture J, the mixture was filtered through silica; and thickened. The title compound was obtained as a pale yellow solid.

¹ H-NME (CDCl ₃ ; 300 MHz):

delta 9.57 (1HJ a); 2.52 (3H; a.).

Grade B.

Preparation of 4-bromo-1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde

To the 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 to the resulting reaction mixture, cooled to minus 10.0 ° C; 0.745 g (5.39 mmol) of potassium carbonate was added in powder form.

The reaction mixture was stirred at minus 1.0 ° C for 2.0 hours; followed by an additional 4.0 hours at room temperature. Then the mixture was diluted with water and shaken with ethyl acetate. After separating the organic and aqueous phases, the organic layer was washed successively with water; saturated brine, and then dried over 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) J 7.64 (2H; d, J = 7.0 Hz); 7.15 (2H;

d .; j = 7.0 Hz); 5.59 (2h, s); 2.40 (3h; _3. ).

- 213 · to to to to to to to to to to to to toto to to to to to to to to

Grade C

Preparation of 1- (4-cyanobenzyl) -2-methylimidazole from ol-5-carboxaldehyde

A solution prepared by mixing 1.33 g (4.37 mmol) of 4-bromo-1- (4-cyanobenzyl) -2-methylimidazole-5-carboxaldehyde; obtained in the framework of the above-described Step B; and 0.600 mg (8.74 mmol) of imidazole; in 1´50y0 ml ethyl acetate-ethanol (1: 1); The reaction mixture was stirred at 50 psi of hydrogen in the presence of 0.020 g of 10% palladium on charcoal.

P _of 2.0 hours elapsed ^ ^ reaction mixture was filtered through silica; and then thickened.

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

¹ H-NMR (DMSO-d 6) * 400 MHz):

delta 9.62 (1HJ s); 7.90 (1H, a.); 7.81 (2H; d, J = 8.00 Hz); 7.20 (2H; d, J = 8.0 Hz); 5.64 (2H, s); 2.33 (3H, s).

Grade D '

Preparation of 5 (S) -butyl-4- [1- (4-cyanobenzyl) -2-methyl-5-imidazolylmethyl] -1- (2,3,3-dimethylphenyl) piperazin-2-one.dih, hydrochloride

To a mixture prepared by mixing 0.190 g (0.843 mmol) of 1- (4-cyanobenzyl) -2-methylimidazole-5-carboxeldehyde; obtained in the previous step CJ above, 0.250 g (0.843 mmol) of 5 (S) -butyl-1- (2,3-dimethylphenyl) -piperazin-2-one. hydrochloride; e 0.093 ml (0.843 mmol) of N-methylmorpholine; in 10.0 mL of dichloroethane, POP ³⁸¹¹ was above in Example 39; Step e7VO, 265 g (1.25 mmol) of sodium triacethoxytetraborohydride.

The title compound was purified by preparative

214

High performance liquid chromatography, using a gradient of 70% to 45% Solvents A.

After isolation, the free base was converted to the dihydrochloride salt; and the title compound was obtained; in the form of a white solid.

FAB-MS (m + 1) = 470.0;

Analytical evaluation of the compound of formula ^C 29 ^H 35 ^N 5 ° · ^2HCl · ^{1 '45 H} 2 ^0:

Calculated: Found:

C 61.25; H, 7.07; N, 12.32. C, 61.56; H, 6.99; N, 1.32

Example 49

Preparation of 4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one . dihydrochloride

Grade A

Preparation of 4- (tert-butyldimethylsilyloxymethyl) -1-triphenylmethylimidazole

To the suspension, prepared by mixing 5.80 g (17.05 mmol)

4-hydroxymethyl-1-triphenylmethylimidazole; with 200.0 ml of dimethylformamide containing 3.48 g (51.10 mmol) of imidazole; t-butyluimethylsilyl chloride (2.83 g, 18.76 mmol) was added and a clear, colorless solution was formed after 15.0 minutes, which was stirred at room temperature.

215 the 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 saturated brine; and then dried with magnesium sulfate.

The title compound was obtained as a colorless gum-like material.

Stage B:

Preparation of 5-tert-butylsimethylsilyloxymethyl-1- (4-cyanobenzyl) imidazole

A solution prepared by mixing 4.66 g (10.26 mmol) of 4- (tert-butyldimethylsilyloxymethyl) -1-triphenylmethyl imidazole obtained as described above in Step AJ and 2.10 g (10.26 mmol) of 1- of methyl 4-cyanobenzene in 50.0 ml of acetonitrile was heated to reflux for 4.0 hours.

The reaction mixture was cooled, and after removal of the acetonitrile under vacuum, the residue was dissolved in 30.0 ml of methanol. The resulting routok was heated to reflux for 2.0 hours; it was then cooled, and the methanol was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution.

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

The title compound was obtained as a white solid.

-j-S tupen C

- 216 ·· · ···

Preparation of 5-tert-butoxy-thylsilyloxymethyl-1- [2- (4-cyanophenyl) -2-propyl] imidazole

A solution prepared by dissolving 1.005 g (3.07 mmol) of 5-tert-butylsimethylsilyloxymethyl-1- (4-cyanobenzyl) imidazole; Obtained within the framework of the above-described Step B; in 25.0 mL of tetrahydrofuran; and cooled under a nitrogen atmosphere to a temperature of minus 78.0 ° C; was mixed with 4.61 ml of a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran; and the resulting reaction mixture was stirred at minus 78 ° C for 1.0 hour and then allowed to warm to minus 60.0 ° C over 30 minutes.

After the reaction mixture was recooled to minus 78.0 ° C, methyl iodide (0.287 mL; 4.61 mmol) was added; and the mixture was further stirred at minus 78.0 ° C for 2.0 hours, and was then re-tempered to 0 ° C over 2.0 hours.

After 30.0 minutes, the reaction mixture was cooled to minus 78.0 ° C; and 4.61 mL of a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran was added. After 1.0 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 then mixed with water, and then extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed with saturated brine.

The crude product was chromatographed on silica gel using ethyl acetate: dichloromethane (6: 4); as eluent.

The title compound was obtained in the form of a golden color, oily consistency.

¹ H-NMR (CDCl ₃ ; 400 MHz):

delta 7.78 (1H, s); 7.61 (2H; d, J = 8.00 Hz); 7.15 (2H);

d .; j = 8.00 Hz); 7.02 (ih; _s ); 4.00 (2h; _a .); 1.99 (6h;

·· ····

- 217 ·

s.): 0.79 (9h; a.); 0.74 (OH, s).

Grade B

Preparation of 1- [2- (4-cyanophenyl) -2-propyl] -5-hydroxymethylimidazole

To a solution prepared by dissolving 0,750 g (2,72 mmol)

5-tert-butoxydimethylsilyloxymethyl-1- [2- (4-cyanophenyl) -2-propyl) imidazole; obtained in Step CJ above in 10.0 ml of tetrahydrofuran, 2.99 ml of a 1M solution of tetra-N-butylammonium fluoride was added. After 2.0 hours at room temperature, the resulting reaction mixture was poured into ethyl acetate, and then shaken with a saturated aqueous 3-bicarbonate solution.

After separating the organic and aqueous phases, the organic layer was washed with a 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.

218 · · · · · · · · · · · · · · · φ · φ · φ · φ · H · φ · H H φφ ¹ H-NMR (CDCl ₃ ; 400 MHb):

delta 7.77 (1H, a.); 7.62 (2H; d, J J = 8.0 Hz); 7.19 (2H; d .;

J = 8.00 Hz); 7.02 (1H, a.); 4.01 (2H, a.); 2.57 (1H, broad3); 2.01 (6H; a.).

Grade E

Preparation of 1- [2- (4-cyanophenyl) -2-propyl] imidazole-5-carboxaldehyde

Solution prepared by dissolving 0,450 gj; (1.78 mmol) of 1- 2- (4-cyanophenyl) -2-propyl) -5-hydroxymethylimidazole in 20.0 mL of dioxane; was in the presence of 1.62 g (18.70 mmol) of manganese dioxide; heated at reflux for 5.0 hours.

The reaction mixture was then cooled; and 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):

delta 9.37 (1H, s); 8.11 (ih; s); 7.92 (1H, s); 7.58 (2H; d, J J = 8.00 Hz); 7.15 (2H; d, J = 8.0 Hz); 2.01 (6H, s).

Stage E '

Preparation of 4- [1- (2- (4-cyanophenyl) -2-propyl) -5-imidazolylmethyl] -1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) piperazin-2-one. dihydrochloride · 9 9 9 9

999 999 999

219 The title compound was prepared in an analogous manner to that described in Example 39 above; Step E; except that 0.297 g (0.84 mmol) of 1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethylpiperazin-2-one; hydrochloride $ 0.20 g) was used in the reaction. 84 mmol) of 1- [2- (4-cyanophenyl) -2-propyl] imidazole-5-carboxaldehyde; 0.092 ml of N-methylraorpholine (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;

Analytical evaluation of the compound according to the formula

C ₂₇ H 3 _O C ₁ N ₅ O ₃ S. 2HCl ₁ H ₂ O ':

Calculated: C, -48, $ 2; H, 5-74; H 10.50 '%

Found: C 48.62J £ 5.73 ', N 9.89%

Example 50

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

Grade -A

Preparation of N- (2-methylphenyl) -2 (S) - (tert -butylcarbonylamino) hexanamine ·· 0000 • 04 ·

0 0 0 0 0 0

The title compound was prepared in an analogous manner to that described in Example 39J, Step C; except that a mixture prepared from 0.32 mL (3.0 mmol) of o-toluidine, 0.538 (2.50 mmol) / 2 (S) - (tert-butoxycarbonylamino) -hexanal was used in the reaction; and 0.795 g (3.75 mmol) of sodium triaceoxytetraborohydride in 10.0 mL of dichloroethane.

The crude product was purified by column chromatography to give the title compound.

Stupen B ·

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

The title compound was essentially prepared in a manner analogous to that described in Example 39J, Step DJ except that a mixture prepared from 0.506 g (1.65 mmol) of N- (2-methylphenyl) -2 ( S) - (tert-butoxycarbonylamino) -hexamine; obtained in the previous step described above, and in 6.16 ml (1.98 mmol) of chloroacetyl chloride in an ethyl acetate-saturated aqueous solution of sodium bicarbonate; at 0 ° C.

The crude product obtained in the above operation was dissolved in 15.0 ml of dimethylformamide; and the resulting solution was cooled to 0 ° C; under a nitrogen atmosphere, ilegated with 1.61 g (4.95 mmol) of cesium carbonate. The reaction mixture was then stirred at 0 ° C for 2.0 hours.

The reaction mixture was then mixed with a saturated aqueous ammonium chloride solution, followed by shaking with ethyl acetate. The extracts were dried and evaporated.

The title compound was obtained.

·· ·· ····

- 221 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

Stage C

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

The product obtained under Step B (0.534 g, 1.50 mmol) described above 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 39J, Step EJ, except that a mixture prepared from 5 (S) -n-butyl-1- (2-methylphenyl) -piperazin-2-one was used in the reaction. ditrifluoroacetic acid salt of 1- (4-cyanobenzylimidazole) -5-carboxaldehyde (0.317 g, 1.50 mmol); and 0.477 g (2.25 mmol) of sodium triacethoxytetrahydroborate; in 15.0 ml of dichloroethane.

The crude product was applied by syringe to a preparative column ₍ high performance liquid chromatography) and purified using a mixed gradient of acetonitrile / 0.1% trifluoroacetic acid and 0.1% aqueous trifluoroacetic acid.

Pure fractions were combined and converted to the hydrochloride salt. The title compound was obtained as a white solid.

Mass Spectroscopy-PAB (m + 1)

442.0

Analytical ^ 27 ^ 31 Calculated Found guest compound according HCI.2,05 2.5 H ₂ 0:

C 56.95; H, 6.66;

C 56.93; H, 5.75;

formulas

Ni 12.30 N 11.55

Example 51

222

Preparation of 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5 (S) - (2-fluoroethyl) -1- (3-chlorophenyl) piperazin-2-one. dihydrochloride

Stup β'.η A

Preparation of 4-tert-butoxycarbonyl-1- (3-chlorophenyl) -5 (S) - (2-fluoroethyl) -piperazin-2-one

Mixture prepared by mixing 0.433 g (1.00 mmol) of 4-tert-butoxycarbonyl-1- (3-chlorophenyl) -5 (S) - (2-methylsulfonyloxyethyl) -piperzin-2-one and 3.0 ml of a 1M solution of butylammonium fluoride in tetrahydrofuran was stirred at room temperature with 5.0 ml of acetonitrile; for 72.0 hours.

The reaction mixture was then mixed with a saturated aqueous solution of sodium bicarbonate; and then shaken with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using a mixture of field ethyl acetate in hexane.

The title compound was obtained as a thick oil. consistency.

Degree; (B)

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

Within 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) was obtained; deprotected with 4.0 mL of trifluoroacetic acid; in 10.0 ml of dichloromethane.

223

• · · · ·

The title compound was prepared in an analogous manner to that described in Example 39J, step EJ, except that a mixture prepared from 1- (3-chlorophenyl) -5 (S) - (2-fluoroethyl) -piperazine-2- was used in the reaction. onu. ditrifluoroacetic acid salts of 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 dichloroethane.

The crude product was injected onto a prepara- tive, high performance liquid chromatography column, and purified by a mixed gradient of acetonitrile / 0.1% trifluoroacetic acid; and 0.1% aqueous trifluoroacetic acid.

Pure fractions were combined; and converted to the hydrochloride salt. The title compound was obtained as a white-colored solid.

Mass-Spectroscopy-FAB (m + 1) = 452, OJ

Analytical evaluation of the compound of formula ^C 24 ^H 23 ^G1FN 5 ° · ^2HCl · ^ ⁷⁰ ¾ ^0:

Calcd: C 51.90; H 5.15J 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

224

Preparation of 3- (4-cyanobenzyl) -pyridine-4-carboxylic acid methyl ether

A solution prepared by dissolving 625.0 mg (3.27 mmol) of 4-cyanobenzyl bromide; in 4.0 mL of dried tetrahydrofuran, was added slowly, over 3.0 minutes; in an argon atmosphere; and 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 then removed; and the slurry was stirred at room temperature for an additional 30.0 minutes. To this was added 3-bromopyridine-4-carboxylic acid methyl ester (540.0 mg, 2.50 mmol); followed by 50.0 mg of dichloro-bis- (triphenylphosphine) i-nickel (II).

The resulting reddish brown reaction mixture was then stirred for 3.0 hours at 40-45 ° C, 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 twice with 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 / hexane.

420.0 mg of the title compound was obtained as a colorless gum.

FAB-MS (m + 1) = 253, 0.18

Grade B

Preparation of 3- (4-cyenbenzyl) -4- (hydroxymethyl) pyridine

The title compound was obtained using 300.0 mg sodium borohydride with a reduction of 415.0 mg

225 of the ester obtained in Step A, above, in 5.0 ml of methanol at room temperature. After the reaction mixture was stirred for 4.0 hours, the solvent was evaporated; and the product was purified on silica gel, eluting with 2% methanol in chloroform.

The title compound was obtained.

Mass Spectroscopy-FAB (m + 1) - 225, OJ

C p e c

Preparation of 3- (4-cyanobenzyl) -4-pyridinal

The title compound was obtained by oxidation of 240.0 mg (1.07 mmol) of alcohol; obtained as described in Step BJ above in 10.0 ml dioxane, with 1.0 g activated manganese dioxide; and heating the reaction mixture at reflux; for 30.0 minutes.

Afterwards. filtration and evaporation of the solvent gave the title compound.

Melting point: 80.0-83.0 ° 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 39J, step above

226

E; except that imidazolylcarboxaldehyde has been replaced by an equivalent amount of the product obtained in the above step, and piperazinone has been replaced by the same amount of 1- (3-chlorophenyl) -5 (S) - (2-methylsulfonylethyl) - piperazin-2-one.

The title compound was obtained.

FAB-MS (m +) = 523.0;

Analytical evaluation of the compound according to C ₂₇ H ₂₇ ClN ₄ O ₃ S. 0.15 CHCl ₃ :

Calculated: Found:

G 60.28; H, 5.06; C 60.37; H, 5.03;

formulas

N 10.36 N 10.64

Example 5.3

Preparation of 4- [4- (4-cyanobenzyl) -1-imidazolyl] -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 dibromoethane; and the resulting reaction mixture was stirred under an argon atmosphere at 20.0 ° C. Thereafter, the reaction mixture was cooled to 0 ° C as a slurry and alpha-bromo-β-tolunitria (9.33 g; 47.60 mmol) was added dropwise over 10 minutes at 100 ° C. 0 ml of tetrahydrofuran.

- 227 · · 227 227 227 - 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 227 ·· ·

Then the reaction mixture was stirred at 20.0 ° C for 6.0 hours and bis- (triphenylphosphine) nickel (II) chloride (2.40 g, 3.64 mmol) was added; 15.95 g (36.60 mmol) of 5-iodo-trityl imidazoles, (in one dose $ = 5-iodo-triphenylmethyl-imidazole).

The resulting reaction mixture was stirred for 16.0 hours at a temperature of 20.0 ° C, _d ', and then was mixed with 100.0 ml of saturated aqueous sodium chloride smdnného; and the mixture was stirred for 2.0 hours. The pH of the mixture was adjusted to pH 8.0 by addition of saturated aqueous sodium bicarbonate; and then shaken the mixture 2 x with 250.0 ml of ethyl acetate; dried extract with magnesium sulfate; and the solvent was evaporated in vacuo. The residue was then re-chromatographed (silica; 0-20% ethyl acetate: dichloromethane *).

The title compound was obtained as a white solid.

¹ H-NMR (CDCl 3):

delta 7.54 (2H, d. J * _r = 7.90 Hz); 7.38 (1H, s); 7.36-7.29 (11H, m); 7.15 - 7.09 (6E; m); 6.58 (1H, s); and 3.93 (2HJ 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. (7.26 mmol) of methyl bromoacetate, and the resulting reaction mixture was heated at 55.0 ° C for 16.0 hours; and then the solvent was evaporated from the mixture in vacuo

The solids were mechanically treated and taken up with ethyl acetate J collected by filtration, and dissolved in 60.0 ml of methanol.

228 • · · t

The reaction mixture, in the form of a suspension, was heated at 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.

¹H-NMR (CDC1 _3):

.delta.7, βέ (2H; d, J J = 7.90 Hz); 7.53 OH; with.); 7.27 <2H; d J = 7.90 Hz); 6.89 (1H s) J 4.47 (2H s) J 3.98 (2H s); and 3.66 (3H, s); ppm.

Grade C

Preparation of 1-hydroxyethyl-5- (4-cyanobenzyl) imidazoles

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 BJ in 2.0 ml of methanol was reacted at 0 ° C with 80 ° C. 70 mg (1.10 mmol) of sodium tetrahydroborate.

P expiration _of 1.0 hours, the reaction mixture was mixed with 2.0 ml of saturated aqueous ammonium chloride *, and after adding saturated aqueous sodium bicarbonate solution * The mixture was extracted 3 x 25.0 ml ethylacetátu.Oi ^ cal extracts then dried with magnesium sulfate; and evaporated under vacuum.

The title compound was isolated by chromatography on silica; 10% methanol in dichloromethane as a white solid.

^1H-NWR (CDC1 _3):

229 delta .61 (2H; d, J J = 7.90 Hz); 7.55 (1HJ s) J 7.27 <2HJ d .; j = 7.90 Hz); 6.83 Oh; with.); 4.05 (2h, s); 3.87 (2h; t, J = 5.10 Hz); and 3.74 (2H; t; J = 5.10 Hz); ppm.

Grade K

Preparation of 2- (5- (4-cyanobenzyl) imidazolyl) ethyl methanesulfonate

A solution prepared from 0.532 g (2.34 mmol) of 1-hydroxyethyl 15- (4-cyanobenzyl) imidazole obtained as described above in Step C above; in 70.0 ml of dichloromethane, was reacted at 0 ° C and 0.489 ml (2.81 mmol) of Hunings base; and 0.219 ml (2.81 mmol) of methanesulfonyl chloride.

After 2.0 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 obtained was used without further purification.

¹ H-NMR (CDCl 3):

delta 7.62 (2HJ d, J = 7.90 Hz); 7.54 (1H, s); 7.29 (2HJ d, J = 7.90 Hz); 6.87 (1HJ s); 4.25 (2H, t); 4.10-4.00 (4H, m); 3.74 (2HJ, i.e., J = 5.10 Hz); and 2.90 (3H; a.) 'ppm.

Grade E

Preparation of 4- [5- (4-cyanobenzyl) -1-iminoazolylethyl] -1- (3-chlorophenyl) piperazire-2-one

229a

A solution prepared from 24.0 mg (0.079 mmol) of 2- (5- (4-cyanobenzyl) imidazoyl) ethyl methanesulfonate obtained as described in Step LJ above in 0.20 ml of dimethyl formamide was added. to a mixture prepared by mixing 17.70 mg (0.084 mmol) of 3- (chlorophenyl) -piperazin-2-one; and 50.0 mg (0.336 mmol) of sodium iodide; and 0.0146 mL of Hunings base, and the resulting reaction mixture was stirred at 55.0 ° C for 12.0 hours.

The solvent was evaporated in vacuo. The remaining residue was purified by preparative thin layer chromatography, eluting with 10% saturated ammonia in acetonitrile.

The title compound was obtained.

¹ H-NMR (CDCl ₃ ):

δ 7.61 (2H; d, J J = 8.40 Hz); 7.56 (1H, s); 7.35 - 7.20 (7h, m); 7.16 (ih; a, J = 8.00 Hz); 6.85 (ih, 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); _PP m.

230

Example 54

Inhibition of Ras Farnesyl Transferase in. in vitro.

Procedures for evaluation of farnesyl-protein transferase

Partially purified farnesyl-peotein transferase; and Ra peptides (Ras-CVIS); Ras-CVIM and Ras-CAIL); were prepared according to the procedures described in J.Biol.Chem; 265;

14.701-14.704 / 1990 .; by Schaber se sp .; Biochemistry; 31; 3800 (1992); by Pompliano se sp .; and PNAS.U..S.A ,; 86;

6630-6634; (1989).

Evaluation of bovine farnesyl protein transferase was performed in a volume of 100 µl of a mixture containing 100 mM N-hydroxyethyl) piperezine-N - (2-ethanesulfonic acid) = HEPESJ pH 7.4O;

5.0 mM magnesium chloride; 5.0 mM dithiothreitol (DTT);

100.0 mM / ³ H-farnesyl diphosphate = α-FPP; 740 cBq / mmol (New England Nuclear); 650 nM Ras-CVLS; and 10.0 µg / ml farnesyl protein transferase; at 31.0 ° C; for 60 minutes.

The reaction was started with farnesyl protein transferase; and was quenched by the addition of 1.0 mL of a 1.0 M solution of hydrochloric acid in ethanol.

The precipitates were collected using a filter cloth, using a TomTec Mach 1 cell collector; and then washed with 100% ethanol; dried; The evaluation was linear in terms of both farnesyl protein transferase values and time course. Less than 10% / ³ H-farnesyl diphosphate was used during the reaction. The purified components were dissolved in 100% dimethylsulfoxide; and they were diluted twice for evaluation.

Inhibition, expressed as%, was evaluated based on incorporated radioactivity in the presence of test compound, compared to the incorporated amount in the absence of test compound »·· ····

- 231

Human farnesyl protein transferase was prepared in an analogous manner to that described in the journal Biochemistry; 32 * 5167-5176 (1993); By Omer se sp.

Human farnesylv-protene transferase activity was evaluated by the procedure described above except that 0.1% (w / v) polyethylene glycol 20,000 was added to the reaction mixture. 10.0 µM zinc chloride; and 100 nM RasCVIM. The reaction was allowed to proceed for 30.0 minutes; and was discontinued by the addition of 100.0 µl of 30% (v / v) trichloroacetic acid in ethanol; and the same method described above for bovine enzyme evaluation was used.

Compounds included in the present invention; s described in the Examples above; and in the Tables published below, were tested for human farnesyl-protein transferase inhibitory activity as described above.

Test compound values were found to be IC 50/50 50 / µM.

Example -55

Evaluation of Rss coloring in vivo.

The cell line used in this evaluation is the v-Ras line derived either from Rat 1; or N1H3T3 cells that produced viral WTa-Res-p21 ·

This procedure is performed essentially analogously to the evaluation described in Cancer Research, 51, 712, 717; (1991); By DeClue J.E. ae sp.

Cells, placed on average 10.0 cm 3 at concentrations of 50-75%; are contacted with the test compound (final concentration of solvent; methanol or dimethylsulfoxide, 0.1%).

- 232

After 4.0 hours, when the cells are maintained at 37 ° C _r; they are denoted in the mixture (ethylene glycol dimethyl ether); methion-free; and supplemented with 10% normal DMEM; 2% bovine serum; and 400 mCi4S-methionine (1000 Ci / mmol) <

After a further 20.0 hours, cells are disrupted (lysed) with 1.0 ml cleavage buffer (1% NP40 / 20 mM HEPES; pH 7.50; 5.0 mM magnesium chloride; and 1.0 mM dithiothreitol 10, 0 mg / ml retreat with 2.0 mg / ml leupeptin, 2.0 mg / ml antipain, 0.5 mM alpha-toluenesulfonyl chloride The lysate was clarified by centrifugation (100,000 x £) for 45 minutes.

Aliquots of lysates containing equal amounts of acid precipitating particles were transferred to 1.0 ml IP buffer (dithiothreitol-free lysate buffer); and then immunologically precipitated with Ras-specific; monoclonal antibodies Y13-259 (Virol .; 43; 294-304; (1982); Furth M.E. se sp.).

After incubating the antibodies for two hours at 4.0 ° C; a 25% A-Sepharose protein suspension is added over 45 minutes; enriched with rabbit * antipotamin ammunoglobulin. Immunoprecipitates are washed 4 times with IP buffer (20 nM HEPES; pH 7.50; 1 mM EDTA = ethylenediaminetetraacetic acid; 1% Triton X-100; 0.5% deoxycholate 0.1% dodecylsulfate sodium (SDS); 0.1M sodium chloride, buffered boiling SDS-PAGE - * and loaded onto 13% acrylamide gels.

Once the front of the dye reaches the bottom, the gel is fixed and applied to the irradiation device. It is then dried, and autoradiography is performed. The band intensities corresponding to the farnesylated and unarnesylated Ras proteins are comparatively evaluated to determine the percentage inhibition of the farnesyl transfer to the protein.

Example 56

- 233

4 4 ·· 4444

Evaluation of growth inhibition in vivo

In determining the biological consequences of inhibition of farnesyl protein transferase, the effects of the compound of the present invention are tested based on the independent growth of Hat 1 cells transformed with either v-Ras; v-Raf; or v-Mos oncogenes. Cells transformed with v-Raf or v-MQsJ may be included in the assays to assess the specificity of a compound of the invention for Ras-induced cell transformation.

Rat 1 cells transformed with either v-Ras; v-Raf; or with v-MOs, are inoculated at a density of 1 x 10 6 cells per dish (diameter 35 mm) to 0.3% of the top layer of sgarose in medium A (Julleecov4 modified Eagle's medium, supplemented with 10% bovine serum), located above the bottom layer of agarose (0.6%).

Both layers contain 0.1% methanol, or the appropriate concentration of compound included in the patent (dissolved in methanol at 1000 times the concentration used in the evaluation).

Cells are fed twice a week with 0.50 ml of medium A; containing 0.1% methanol, or the concentration of the test compound. Photomicrography is performed 16 days after the cultures have been inoculated, followed by evaluation.

Example 57

The following Tables 1 to 18 show the other compounds of the invention which were prepared by the method of Examples 1 to 53. Table 2 shows the stereochemistry of the amino group on a carbon atom (R or S) or, if not known, the individual stereoisomers are labeled as isomers A or B.

·· ·· ····

- 234 Table 1

FAB ms (m + 1) (formula, calculated, found)

526

506

F

CH _c

494

C ₃₃ H ₃₉ N ₃ OS'2.3 TFA-0.9 H ₂ O C, 56.16; H, 5.40; N, 7.22.

C, 56.12; H, 5.37; N, 7.39.

C ₃₀ H ₃ O _{2 3} g of N S'2.55 TFAO.55 H ₂ OC, 53.19; H, 5.46; N, 5.36.

C, 53.17; H, 5.46; N, 5.60.

C ₂₉ H ₃₆ N ₃ OS 2.25 TFAO.35 H ₂ OC, 53.19; H, 5.18; N, 5.55.

C, 53.16; H, 5.18; N, 5.68.

F

490

512

C ₃₀ H ₃ N _{3 g} OS'2 TFA 0.9 H ₂ 0 C, 55.64; H, 5.88; N, 5.73.

C, 55.57; H, 5.31; N, 5.83.

C ₂₉ H ₃ F ₂ N ₃ OS-2.4 TFA-0.6 H ₂ OC, 50.99; H, 4.89; N, 5.28.

C, 50.98; H, 4.86; N, 5.56.

- 235 Table 2 • ·· 00000 «• 0 0 · 0

anuni10 stereo.

FAB wt.

spectrum

ÍM + n

Analysis (formula, calculated, found)

A n-Bu 2-O (CH 2) 13 CH 3 642.5 C42H63N3O2-2.55HCl C, 68.46; H, 8.97; N, 5.70. C, 68.40; H, 8.70; N, 5.61.

B 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.

A n-Bu 2-O (CH 2) 11 CH 3 614.4 C40H59N3O2-2.8HCl

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 C40H59N3O2-2.85HCl-0.05H2O C, 66.84; H, 8.69; N, 5.85.

C, 67.20; H, 8.70; N, 5.45.

236 amine stereo. X

FAB wt. Spectrum analysis (formula, calculated, found '(M + n,

A n-Bu 2-O (CH 2) 9 CH 3 586.5 C38H55N3O2-3HCl-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 C38H55N3O2-3HCl-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 C36H51N3O2-2.15HCl-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 n-Bu 2-O (CH 2) 3 Ph 564

B n-Bu 2 -O (CH 2) 3 Ph 564

A n-Bu 3-OCH 2 Ph

536

C36H51N3O2-2.15HCl-0.65H2O C, 66.82; H, 8.42; N, 6.49.

C, 66.85; H, 8.43; N, 6.52.

C37H45N3 O2-2HCl-1.05H2O C, 67.78; H, 7.55; N, 6.41.

C, 67.78; H, 7:52; N, 6.26. C37H45N3O2-2HCl-1.05H2O C, 67.78; H, 7.55; N, 6.41.

C, 67.78; H, 7.44; N, 6.33.

C35H41N3O2-3.55HCl C, 63.19; H, 6.75; N, 6.32.

C, 63.12; H, 6.61; N, 6.47.

B n-Bu 3-OCH 2 Ph

536 C35H41N3O2-3.55HCl-0.4H2O

C, 62.52; H, 6.80; N, 6.25.

C, 62.14; H, 6.69; N, 6.65.

- 237 ·· · ···

9 9

9

FAEhmot.

amin spectrum (formula, calculated. found) stereo. X Y (M + 1) ....

5 AND n-Bu 3-O (CH 2) 13 CH 3 642 C42H63N3O2-2.4HCl C, 69.15; H, 9.04; N, 5.76. C, 69.08; H, 9.08; N, 5.73. 10 (B) n-Bu 3-O (CH 2) 13 CH 3 642.5 C42H63N3O2-2.35HCl * 0.25H2O C, 69.15; H, 9.04; N, 5.76. C, 69.08; H, 9.08; N, 5.73. 15 Dec R _n -Bu 4-O (CH 2) 13 CH 3 642 C42H63N3O2-2.2HCHH2O C, 68.14; H, 9.15; N, 5.68. C, 68.13; H, 9.03; N, 5.68. 20 May WITH n-Bu 4-O (CH 2) 13 CH 3 642 C42H22N3O2-2.8Ha C, 67.79; H, 8.91; N, 5.65. C, 67.77; H, 9.80; N, 5.64. 25 WITH n-Bu 4-OCH 2 Ph 536 C35H4lN3O2 * 2.15HCl’lH2O C, 66.49; H, 7.20; N, 6.65. C, 66.48; H, 7.15; N, 6.62. R / S H 2 -O (CH 2) 13 CH 3 586 C38H55xN3O2-1.5HCl-0.3H2O C, 66.88; H, 8.58; N, 6.16. C, 66.82; H, 8.64; N, 6.15.

* ·· ···

- 238 Table 3

FAB hmo t.

specrrum

IM + 1)

Analysis (formula, calculated)

3-SO2Me 506

3-OCF3 512.22 15

C27H31N5O3S-3.0 HCl-0.10HbO C, 52.61; H, 5.59; N, 11.36.

C, 52.63; H, 5.41; N, 10.72.

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.

- 239 Table 4

FAR bnot. . i ¹ Analysis

5 X Y spectrum IM + 1) (formula, calculated 10 CH2OCH2Ph CF ₃ 574 C32H30N5O2F34.40HC1O.30H2O C, 61.02; H, 5.12; N, 11.12. C, 61.01; H, 5.10; N, 10.78. 15 Dec CH2SO2Et CF ₃ 560 C27H28N5O3F3S • 3.20HCl1.10H2O C, 47.86; H, 4.67; N, 10.34. C, 47.89; H, 4.49; N, 9.92. 20 May CH ₂ SO ₂ Ph cf ₃ 608 C31H28N5O3F3S-2.10HCl C, 54.42; H, 4.43; N, 10.24. C, 54.43; H, 4.42; N, 9.98. 25 CH2SO2Me Cl 512 C25H26N5O3CIS

• 2.0HCl-0.25CHCl3-0.25H ₂ 0

C, 48.97; H, 4.68; N, 11.31. C, 48.95; H, 4.64; N, 11.51.

- 240

Table 4 - cont.

0 • • ·· ·· ···· • • • ·· e • • · • ··· • · • · • · ··· ···· • · • ·· • • • •

5 X Y FAB ^mass spectrum (M + n Analysis (formula, calculated 10 CH2SC> 2Et α 526 C26H28N5O3aS 2HCl _0.25CHa-3 C, 50.14; H, 4.85; N, 11.14. C, 50.20; H, 4.91; N, 10.93. 15 Dec CONHMe cf ₃ 511 C26H25N6O2F ₃ · · 1.90HC1 1.7OH2O C, 51.20; H, 5.01; N, 13.78. C, 51.17; H, 4.99; N, 13.36. 20 May CONHEt cf ₃ 525 C27H27N6O2F3-1.60HCl- ₀ . IOH2O C, 55.54; H, 4.97; N, 14.39. C, 55.57; H, 4.87; N, 15.28. 25 CH2SO2Ph α 574 C30H28N5O3aS-2HCl-0.30H2O

C, 55.23; H, 4.73; N, 10.73. C, 55.25; H, 4.57; N, 10.61.

• 6

- 241 Table 4 - cont.

FAB ftnot. Analysis

Spectrum (Formula, Calc, Found) x_y (M + n.

CONHMe and 477 C25H25N6O2Cl * 2HCl • 0.105CHC13-0.85H20 C, 52.24; H, 5.03; N, 14.56. C, 52.21; H, 5.07; N, 14.98. CONHEt and 491 C26H27N6O2Cl-2HaO.25CHa3 C, 53.10; H, 4.97; N, 14.15 C, 53.32; H, 5.21; N, 13.77. CONHc-Pr and 503 C27H27N6O2Cl-2HCl-0.40CHCl3 C, 52.77; H, 4.75; N, 13.47. C, 53.01; H, 4.99; N, 13.32. CONHc-Pr cf ₃ 537 C28H27N6O2F3

2.45HCl * 0.55 dioxane

C, 53.81; H, 5.06; N, 12.47.

C, 53.76; H, 5.09; N, 12.44.

- 242 Table 4 - cont.

FAB wt. spectrum γ µM + n

Analysis (formula, calculated)

10 NHCOMe Cl 477 C25H25N6O2G 2HCl-O.6OCHCl3-2.OH7O C, 46.76; H, 4.84; N, 12.78. C, 46.79; H, 4.46; N, 12.37. 15 Dec CONMe2 cf ₃ 525 C27H27N602F ₃ -2.0HC1-0.10H? O C, 54.12; H, 4.91; N, 14.02. C, 54.10; H, 4.96; N, 13.79. 20 May S02Et Cl 512 C25H26N503C1S-2.0HC1-0.10H20 C, 51.18; H, 4.84; N, 11.94. C, 51.24; H, 5.19; N, 11.10. 25 CLbSMe and 480 C25H26N5OCIS -0.15CHC13-0.05H20 C, 52.83; H, 4.98; N, 12.25. C, 52.82; H, 5.36; N, 11.85.

• · · ·

- 243

Table4 - cont.

X (±) OCMe

FAB wt. spectrum µM + n

Analysis (formula, calculated, found)

Q 458 C26H24N5OCl'2.0HCl-1.00H ₂ 0

C, 56.89; H, 5.14; N, 12.76. C, 56.99; H, 5.20; N, 12.42.

- 244 -

T and bu 1k and 5

FAB wt. Spectrum γ (M + n

Analysis (formula, calculated)

CH ₂ CH ₂ H 386

C23H23N5O · 1.40HCl1.40H2O

C, 62.29; H, 5.73; N, 15.79 C, 26.26; H, 5.71; N, 15.43

CH2CO

400 C23H21N5O2-2.6HCl-1.70H2O

C, 52.71; H, 5.19; N, 13.36. C, 52.82; H, 5.21; N, 13.04.

CH2 H 372

CH2 3-Cl 406

C22H21N50-2.0HCl-2.60H20

C, 53.80; H, 5.79; N, 14.26. C, 52.86; H, 5.98; N, 13.92.

C22H20N50Cl1-2.50HCl-0.90H ₂ 0

C, 51.48; H, 4.77; N, 13.65. C, 51.55; H, 4.75; N, 13.34.

• · ·

- 245

Table 5 - continued.

FAB wt. Spectrum analysis (formula, calculated)

X_Y I + n .... '......

NHSCb H C21H20N603S-1.0HC1-2.60H20 C, 48.53; H, 5.08; N, 16.17 C, 48.60; H, 5.19; N, 15.80. CH2CH2CO 3-C1 C24H22N5O2CM .0HCl · 1. IOH2O C, 57.17; H, 5.04; N, 13.89. C, 57.22; H, 4.94; N, 13.47. CH2 2,3-Ch 440 C22H19N50G2 * 2.0HCl1.60H20 C, 50.42; H, 4.27; N, 13.36. C, 50.51, H, 4.56; N, 12.18. ch ₂ 2-Br 450 C22H20N5OBr2.0HCl * 0.30H2O C, 49.98; H, 4.31; N, 13.25. C, 49.94; H, 4.47; N, 12.53.

• 9 • · ····

- 246 99 9

999 10 • 9 »

Table 5 - cont

NC

FAB mass, spectrum

IM + 1)

Analysis (Formula, Calc, Found

3-CF3 440 C23H20N5OF3 · 1.70HCl-0.40H: 0

C, 54.40; H, 4.47; N, 13.79. C, 54.45; H, 4.49; N, 13.82.

4-C1

3-C1

3-F

C22H20N50a-1.50HClO.80H ₂ 0

C, 55.71; H, 4.91; N, 14.77. C, 55.81; H, 4.94; N, 14.11.

C23H20N5O2Cl · 1.40HCl · 1.1 OHrO

C, 54.73; H, 4.71; N, 13.87. C, 54.80; H, 4.73; N, 13.46.

C22H20N5OF-2HC1 • 0.35CHCl3-0.95H ₂ O

C, 51.50; H, 4.69; N, 13.44. C, 51.56; H, 4.73; N, 13.30.

• ·· ·

- 247

Table 5 - cont.

FAB wt. specrrum MM + n

Analysis (formula, calculated. Found)

CHi

3-Br

C22H20N5OBr * 1.40HCl · 1.30H ₂ O

C, 50.35; H, 4.61; N, 13.34. C, 50.36; H, 4.63; N, 12.84.

- 248 - i

TABLE 6

FAB mass spectrum

IM + 1)

Analysis (formula, calculated, found)

4-CN

CH: 5-CH 2 CH 2 CO 554

C27H28N5O4CIS · 1.30HCl · 1.2OH2O

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

2-CN CH ₂ 5 -CH 2

512 C25H26N5O3QS ·

2.OHCIO.IOCHCI3O.6OH2O

C, 49.61; H, 4.86; N, 11.52.

C, 49.63; H, 5.01; N, 11.14.

512 C25H26N5O3ClS2HCl-0.35H2O

C, 50.79; H, 4.89; N, 11.84. C, 50.82; H, 5.29; N, 11.90.

4-CN CH2 4-CH2CH2CO 554 C27H28N5O4CIS

C, 47.36; H, 4.58; N, 10.04. C, 47.35; H, 4.60; N, 9.66.

- 249

Table 6 - cont.

FAB wt. Specmim analysis (formula, calculated) of (M + n.

4-CN (CH ₂ ) 2 4 -CH ₂ CH ₂ CO

C28H30N5O4GS • 1.0HO0.40CHCl3O.95H2O

C, 50.96; H, 5.01; N, 10.46. C, 50.91; H, 5.02; N, 10.13.

Table 7 * * 7 7 7 7 7 7 7 7 7

- 250 -

FAB wt. Analysis

Spectrum (Formula, Calc, Found) x y_M + n

4-Me CH ₂ CH ₂ SO ₂ Me 526 • C26H28N5O3C1S 2HClO.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 C23H22N50C1-2.0HC1-0.90H ₂ 0 C, 54.27; H, 5.11; N, 13.76. C, 54.21; FT, 5.38; N, 12.97. 2-Me H 420 C23H22N5OC1-3.20HC1-0.10H ₂ O

C, 51.31; H, 4.76; N, 13.01. C, 51.30; H, 4.74; N, 12.87.

- 251 ·· ··· ·

T a b ul k a 8

3-CF,

FAB wt.

(m + l) Analysis (formula, calculated, found)

496 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

3 _CH-3442

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 O · 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 ₃ N ₅ O ₂ 2 HCl

C, 61.13; H, 6.27; N, 13.20 C, 62.43; H, 6.53; N, 13.24

252 · 44

44 4

Table 8 - cont.

FAB wt. Analysis (m + 1) (Formula, calculated, found)

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 ₃₀ ClN ₅ O 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

4

4 4 4

9

- 253

Table 8- cont.

FAB; mass (m + 1)

Analysis formula, calculated, found)

3-F

446 C 18 H 18 FN 3 O 2 HCl · 2.55 H, C

C, 55.87; H, 6.22; N, 12.53 C, 55.83; H, 5.84; N, 11.71 • 4

- 254 · ♦ 44 4444 * · ♦ 5 »

R (m + 1) (formula, calculated, found)

CH ₂ CH ₂ OCH ₂ CF ₃ 566 C 1 H ₂ N ₂ 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? - OCH ₂ CH ₂ ⁵²⁴ 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: H ₂ CH ₂ NHCOCH ₃ 525 C 7 H ₂₇ F ₂ N _{3 O 2} O ₂ O -2HC1-0.7H

C, 53.16; Η, 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

- 255 Table 9 - cont.

FAB

R (m + 1)

CH ₂ CH ₂ SO ₂ CH (CH ₃ ) ₂ 574 wt. Analysis (Formula, Calc, Found

C ₂₈ H ₃₀ F ₃ N ₅ O ₃ S · 2 HCl · 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

- 256 44 ····

4 4 4

OcN

T a cell nC ₄ H _g CH ₃ CH ₃

Ν I = y \ ^ n .ch ₉

NC

FAB wt. (m + l)

Analysis (formula, calculated, found)

462 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

470

431

445

C ₂₉ H ₃₅ N ₅ O 2 HCl · 0.3 CH ₂ C1 ₂ • Ó.6 C _O 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-2HCl-1.3H ₂ O

C, 62.17; H, 7.56; N, 10.36 C, 62.15; H, 7.09; N, 9.83

470 C ₂₉ H ₃₅ N ₅ O 2 2HCl 3.05 H, O

C, 58.30; H, 7.27; N, 11.72 C, 58.30; H, 6.28; N, 10.90

548,550 C ₂₉ H ₃₄ BrN ₅ O '2 HCl Ό 1 H ₂ O

C, 55.89; H, 5.85; N, 11.24 C, 55.91; H, 5.96; N, 10.73 • · · 4 4 4 4 ·

4444 44

- 257 Table 11 • 4 4 44 4

> t. Analysis (formula, calculated, found)

C ₂₆ H ₂₇ C ₁ N ₄ O ₃ S • 2 HCl '2.85 H ₂ O

C, 49.16; H, 5.51; N, 8.82 C, 49.17; H, 4.74; N, 8.87

496 C ^ H ^ OS • 2 HC? 1.65 H ₂ O

C, 50.20; H, 5.27; N, 11.71 C, 50.19; H, 4.90; N, 11.44

Cl

527 hp ₂ / - (

HN NC \ _V h ₂

\ OF

C ₂₆ H ₂ 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

CN Cl 530 C ₂₆ H ₃₂ ClN 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

- 258

Table 12 9

9,999 9 • 9,9

9 9 9 9 9 ·· ·

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

CH ₂ ^h \ _? ⁿ ~ wXD

C ₁₇ H ₂₀ C1N ₄ O ₃ S • 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

CN

544 _C2o H ₃₀ C1N ₅ O ₄ S

HCl · 0.75 H ₂ O

C, 49.51; H, 5.36; N, 11.11

C, 49.74; H, 5.66; N, 10.11

- 259

·· ····

Table 12 - cont.

FAB wt. Analysis (m + 1) (Formula, calculated, found)

524 C ₂₇ H ₂₇ C1N ₄ O ₃ S · 0.55 CHCI,

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

- 260 Table 13 »· ·· ···· 3 ^ ^Η '3Ο ₂ • • · ·« · • · «·· ··« · ··· · * • * • * · · ·

Cl

W

FAB wt. Analysis (m + 1) (formula, calculated, found)

563 C ₃₀ H ₃₁ ClN ₄ O ₃ S • 2 HCl · 1.8 H ₂ O

C, 53.90; H. 5.52; N, 8.38 C, 53.90; H, 5.38; N, 7.82

540 C ₂₇ H ₃₀ ClN ₅ O ₃ S • 2 HCl · 1.35 H ₂ O

C, 50.88; H, 5.49; N, 10.99 C, 51.37; H, 5.51; N, 10.20

512 C ₂ 5H ₂₆ C ₁ N ₅ O ₃ S

2HCl-0.3H ₂ O

C, 50.86; H, 4.88; N, 11.86 C, 51.06; H, 5.33; N, 10.87

415 C ₂₈ H ₂₇ ClN 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

580 ^ Η Ο ₃₀ αΝ _{5 5} 5 _{2 2} O • 2HCr0.85H

C, 44.93; H, 5.08; N, 10.48

C, 44.96; H, 5.08; N, 9.96 φ · · · · ·

- 261 Τ a b u 1 and 14

O

R ¹

R ² wt. Analysis (m + 1) (Formula, calculated)

NC

C ₁₉ H ₁₉ C1N ₄ O • 2 HCl · 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 C1FN 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 H22ClN ₅ O ₂ · 1 HCl • 0.30 CHCl ₃ · 0.85 H ₂ 0

C, 54.50; H, 4.71; N, 13.08 C, 54.51; H, 4.69; N, 12.87

- 262 T a b ul k a

R-f / VL- + CV v-y

FAB wt. Analysis (m + 1) (formula, calculated, found)

2,3- (CH ₂ ) ₄ 4 6 C ₂₆ H ₂₇ N ₅ O • 2 HCl · 0.15 H ₂ O

C, 62.31; H, 5.89; N, 13.97 C, 62.38; H, 6.18; N, 13.27

2-CH ₃ , 3-C1 420 C ₂₃ H ₂₂ C ₁ N ₅ O • 2 HCl · 1.0 H ₂ O

C, 54.08; H, 5.13; N, 13.71 C, 54.57; H, 5.77; N, 12.92

3 — Cl 420 C ^ HHgClCljO?

2HCl-0.5H ₂ O

C, 56.78; H, 4.33; N, 15.05 C, 56.79; H, 4.69; N, 13.47

NC

- 263

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, -4HCl-3H ₂ O

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, 9.67-4

- 264

T a bu 1k and 17

R-N

FABhmot. Analysis (m + 1) (Formula, calculated)

347 C. 1 H 2 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 23 H ₂₃ N ₃ O '0.55 CHC1 ₃

C, 66.85; H, 5.61; N, 9.93 C, 66.87; H, 5.70; N, 10.03 «· • · · ·

- 265

Table

FAB Mass Spectrum Analysis (M + n (Formula, Calc. Found)

C, 62.45; H, 6.39; N, 12.45. C, 62.45; H, 6.46; N, 12.37.

C22H20N5002.6QHC1

C, 53.97; H, 4.78; N, 14.30 C, 53.97; H, 5.21; N, 13.10.

526

C26H28N5O3ClS-2.0Ha-1.20H2O C, 50.32; H, 5.26; N, 11.28 C, 50.31; H, 5.31; N, 10.72.

4 4

- 266

Table 18 - continued.

FAB wt.

Analysis (formula, calculated, found)

C!

d

C23H22N5OC1-2.0HCl-2.10H2O C, 52.06; H, 5.36; N, 13.20

Claims (16)

PATENT CLAIMS Piperazine Compounds of Formula A (Rt, R 'w / - (0R ^ie 2)' _x Ύ / nC x U λ) ^Y / Ή, \ P 'fi polyphosphoric ⁵ wherein "X and R ⁴ are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 5 carbon atoms; 10 carbon atoms, alkenyl of 2 to 5 carbon atoms, i m is C 2 -C 6 alkynyl, R 10 O-, R 13 (Q), 10, 10 10, 10. R ¹⁰ C (O) NR ^iW -, (R ^iW )? NC (O) -, CN, NO 2, (R ^iU ) 2N-C (NR ^iJ ) R ¹⁰ C (O) -, R ¹⁰ OC (O) - N ,, -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 each, S (O) R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2N-C (O) -, CN, (R ¹⁰ ) NC (NR ¹⁰ 'R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3 , -N (R ¹⁰⁾ - ¹¹ RQC (0) -NR ¹⁰ -, R ^D and R are independently selected from hydrogen, alkyl of 1-3 carbon atoms, optionally substituted alkenyl or alkynyl, each of 2-3 carbon atoms, optionally substituted aryl, optionally substituted heterocyclic residue optionally substituted or) R ³ NR ^e R 'or • · · 268 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 ) _? OR ^S , (c) (CH ₂ ) _p NR ⁶ R ⁷ , d) halogen atom, e) CN 2) cycloalkyl of 3 to 6 carbon atoms, 3) 4) OR °, SRa S (O) R ^ ^a , SOcRo * F —K. NR ⁷ R ^7a O <L ^ NR @ ⁷ R 9) 10) O About • ·· · • · • • • · · - 269 - ·· ·· · ”·. ··. ···: •and. · · 11) - SO ₂ -NR ^{* 2 * 5 * 7} R 12) -N-S0 ₂ -R ^Sa 13) ~ V ^R '0 14) --- OR ^á lt 0 15) N ₂ , or 16) R; or q and R are bonded to the same carbon atom and together they form group - (CH ₂ ), one of which is carbon atoms is optionally replaced by any of O, S (O), -NC (O) - or -N (COR ¹⁰ ) -, 4 5 · · ' R and R are independently selected from hydrogen or methyl, 2 3 4 5 wherein any two of R, R, R and R may be bonded to the same carbon atom, 5 7 7cL R, R and R 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, heteroarylsulfonyl and said radicals optionally substituted by a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, (c) a halogen atom; **:. **. (D) HO,. R ^{11 ( b)} Ύ O (f) SO ₂ R ⁿ , or g) N (R 10) 2; or fi 7 R and R may together form a ring or 7 7a R and R may together form a ring, 6 a R 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) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO \ ⁿ R ^9> in f) -50 ^ ” g) N (R ¹⁰ ) 2; or R is independently selected from a) a hydrogen atom, from the group consisting of b) aryl, 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 (0) NR ¹⁰ - (R ¹⁰⁾ "NC (0) -, R ¹⁰ NC (NR ¹⁰ ) -, CN, NO 2, R ¹⁰ C (O) -, R ¹ OC (O) -, N ₃ , -3 (R ^xu ) ₂ or R ^{x x} 0C (0) NR - a · · · · · · - 271 c) alkyl of 1 to 6 carbon atoms, optionally substituted by a substituent from the group aryl, cyanophenyl, heterocyclic, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R O--, R ^LLS <0) m- R ^{1 O} C (O) NH-, ^(R1O) 2NC (0) - R ¹⁰ 2 NC ^(NR10) -, CN, R ^{1 O} C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 - or R ¹⁰ OC (O) NH-, R is selected from the group (a) a hydrogen atom; b) C 2-6 alkynyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (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 ¹¹ OC (O) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl, F, Cl, J 3r, R ¹⁰ 0-, R ¹¹ S (O) R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR ¹ ") -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NR ¹⁰ -, are independently selected from hydrogen, alkyl of 1 to 2 6 carbon atoms, benzyl or aryl, R 6 is independently selected from C 1 -C 6 alkyl and aryl, 1 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 -, ···· - 272 I i ' AND 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 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 in the case where A ¹ is S (O) or in the case where "1, ^{m and} 2 of A is a chemical bond, n = 0" and A is S (O). m W represents a heterocyclic radical, X is -CH ₂ , -C (= O) -, or -S (= O) _m -, Y 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 L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁵ R ⁷ ; c) cycloalkyl of 3 to 6 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) R ^6a; or g) -C (O) NR ° R ^Z , 2) aryl or heterocyclic radical, 3) halogen atom, (4) 0R ^S , 5) NR ⁶ R ⁷ - 273 ···················· 6) CN, 7) 20 ₂ 3) CF ₃ , 9) ~ S (O) R ^Sa , m _ _ 10) -O (O) NR ^and R; 11) cycloalkyl of 3 to 5 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 Γ means 0 to 5 provided that V is hydrogen, with is 0 or 1, at. means 0 or 1 and at means 4 or 5, carbon, that r = 0 in the case or optical isomers of these compounds or their pharmaceutically acceptable salts. 2. Piperazine Compounds of Formula B (p, v. A ^ ca ^^ ca '· ^ G // N-Z .. \ J R ³ R ⁴ - 274 where i T fa R ^x and R ^x are selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case ^- 2 to 6 carbon atoms, R ¹⁰ O-, R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ cn (r ¹⁰ ) 2nc (o) -, r ¹⁰ 2n-c (NR ¹⁰ ) -, CN, NO 2, R ^{1 O} C (O) -, ^R1O 0C (0) -, N3, -N ^(R10) ₂ or R ¹¹ OC (O) NR ¹⁰ -, c) alkyl of 1 to β carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 5 carbon atoms, R ¹⁰ O- R ¹¹ 3 (0) m- R ¹⁰ C (0) ^NR10 -, ^(R10) 2NC (0) -, R ¹⁰ 2N-C ^(NR10) -, CN, R ^{1 O} C (O) - , r ^1o oc (o) -, n ₃ , -N (R ¹⁰ ) ₂ and R ¹¹ OC (O) -NR ¹⁰ -, SR3 is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, in each case of 2 to 3 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or NR ⁵ * 'or wherein the substituted groups are substituted with at least one substituent from the group ·· ··· * - 275 · 275 275 · - 275 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 ^R , (c) (CH ₂ ) _p NR ^S R ⁷ , d) halogen atom, e) CN (2) cycloalkyl of 3 to 5 carbon atoms; (3) 0R °, 4) SRA S (O) RA SO? RA — NR ° R 'aa S) • N ^ R ' II G F ³ AND -ΊΨ .NR'R ' ^a 3) * o ^ nf ³ r ⁷ T o 9) -Q ^ QR ³ O 10) NR ”R '······· · ⁹ · 9 9 9 9 9 999 9 999 999 999 99 99 «» * Ϊ - 11 276) - Sa -Nfi ₂ F ^s; ρ « Τ ' 12) -N-SO ₂ -S ^oa 13) R ^a AND! Ο ¹⁴ ) - ^ - QR ⁵ II 15) Ν ₃ , or 16) F; sky 03 / . ~. -R 'and R' are bonded to the same carbon atom and together: the group ????????????????????????????????????????????????? ⁱ⁰ ) -, R is hydrogen or methyl; Wherein any two of R, R, and R may be attached to the same carbon atom, A 7 7 a R, R and R are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl 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, 44 4444 - 277 d) HO, * ’Y, o (f) SO ₂ phi ^f1 ; or g) N (JR 10) 2; or fi 7 R and R may together form a ring or 7 7a R and R may together form a ring, R ^5a is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heterocyclic or aryl, optionally substituted with one of (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, (f) —SO ₂ fl ^H , 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 or alkynyl in each case 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 ) NC (O) -, ^R10, Ν-C ^(NR10) -, CN, NO ,, R ¹⁰ C (0) -, R ^1G 0C (0) -, N ₃ , -B (R ^{± u} ) ₂ or R ^xx QC (0) NR - 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, Cl, Sr, R ¹⁰ 0-, R ¹¹ S (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-, 9> R is selected from the group (a) a hydrogen atom; b) C 2 -C 6 alkneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R 10 ° O-, R 8 S (O) _m -, R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, NO ₂ , R ¹⁰ C (O) -, R ¹⁰ O (C) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -, and c) alkyl of 1 to 8 carbon atoms, optionally substituted by a substituent from the group perfluoroalkyl, F, Cl _r 3r, R ¹⁰ 0-, R ^U 3 (0) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR ¹ ^) -, CN, R ¹⁰ C (O) -, R ¹⁰ QC (Q) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -, R 10 is independently selected from hydrogen, alkyl C 1 -C 6, benzyl or aryl are independently selected from C 1 -C 6 alkyl and aryl, 1 2 A and A independently represent a chemical bond, -CH = CH -, - C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O 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, - 279 • 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 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 in that A - is S (O) or, in the case of i ' ^m 2, that A' is a chemical bond, n = 0 and A denote the group S (0). m W represents a heterocyclic radical, X is -OH-, -O (= O) - or -S (= O) -, Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical wherein the substituent is at least one of 1) alkyl of 1 to 4 carbon atoms, optionally substituted with one of the groups (a) C 1 -C 4 alkoxy; (b) NR ³ R ⁷ ; c) cycloalkyl of 3 to 5 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -3 (0) R ^Sa or ₇ (g) - ⁷ , 2) aryl or heterocyclic radical, 3) halogen atom, 4) OR ³ , 5) NR ^S R ⁷ - 280 • · ··· · 3) CN, 7) NO ₂ , a) CF ₃ , 9) -s (o) and ^3a , ® and 7 10) -C (O) NR &lt; 8 &gt; li) cycloalkyl of 3 up to 5 carbon atoms, m means 0, 1 or 2, n represents 0, 1, 2,3 or 4, p means 0, 1, 2, 3 or 4, q means i or 2, r means 0 to 5 per assuming that r = 0 that 7 is an atom hydrogen, with means 0 or 1 - r means 0 or 1 a at means α or 5, or optical isomers of the compounds or pharmaceutically acceptable salts thereof. Piperazine Compounds of Formula C C - 281 where 11 to R and Ir are independently selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R ¹⁰ -O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, N0-, R ^{1 O} C (O) -, ^R1O OC (O) -, N_, -N (R ¹⁰ K or R OC (0) NR ¹⁰ -, c) an unsubstituted or substituted alkyl of 1 to 6 carbon atoms wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclyl, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl each having 2 to β carbon atoms; R ⁱ⁰ 0- , R ¹¹ S (O) m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2NC (O) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, R ¹⁰ C (O) - , R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 and R ¹¹ OC (O) -NR ¹⁰ -, 2 3, R and R are independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 3 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or H or O ⁰ wherein the substituted groups are substituted with at least one substituent from the group · · · 0 - 282 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms; (b) (CHJ OR ³ , 4 U O) (CH ₂₎ NR _0, ^with R ^7, d) halogen atom, e) CN 2) cycloalkyl of 3 to 5 carbon atoms, 3) ORR 4) SR6a, S (Q) R6a, SO1R6a ^—NF / R ' R ^Q Ol 3) —N ^ R @ il a qa Ϊ —N ^ NRT. ' ⁴ íl O, NR ° R ' - + CR ⁵ O 9) W) NR ° R ' - 283 11) 12) f N-SO ₂ -H ^ea 13) 14) (15) Nn, or 16) F; or o R @ 2 and R @ 2 are bonded to the same atom and together form a group wherein the barley of the carbon atoms is optionally replaced by one of 0, 3 (O), -NC (Q). or -N (COr ') -, R is hydrogen or methyl, wherein, any two of R, R and R are optionally bonded to the same carbon atom, R ^d and R ⁵ are independently selected from hydrogen or methyl, 2 3 4 5 wherein any two of R, R, R and R may be bonded to the same carbon atom, f * 7 7 and R, R and R are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to β carbon atoms, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl and said radicals optionally substituted by a substituent from the group - 284 (a) alkoxy having 1 to a carbon atoms; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, ^s) Ύ o (f) SO ₂ fl ^t1 ; or (g) Ν (ίίί) 2; or R ⁶ and R ⁷ may together form a ring or r ⁷ and R ^7a may together form a ring, ^Sa R is selected from alkyl of 1 to & carbon atoms, cycloalkyl of 3 to δ carbon atoms, heterocyclic or aryl zbyzek, zbyzky are optionally substituted by a group selected from (a) C 1 -C 6 alkoxy; b) aryl or a heterocyclic radical, c) halogen atom, d) HO, O (f) —SO ₂ R '', or g) N (rW) 2; q R is independently selected from the group (a) a hydrogen atom; -285 b) aryl, heterocycle, cycloalkyl of 3 to LQ carbon atoms, alkenyl or alkynyl each having 2 to δ carbon atoms, perfluoroalkyl,? Cl, 3r, ^W R 0- R ⁿ S (O) m R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ), NC (O) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, NO ₂ , R ¹⁰ C (O) -, R ¹⁰ OC (Q) - , N ₃ , -3 (R ¹⁰ ) ₂ or R ¹¹ QC (O) NR ¹⁰ -a c) alkyl oi to 5 carbon atoms, optionally substituted with a substituent selected from aryl, kyanoťenyl, heterocyclyl, cycloalkyl of 3 to IQ carbon atoms, alkenyl or alkynyl each with 2 to β ¹ 0 carbon atoms, perfluoroalkyl, F, Cl, 3r, S “0-, R ¹⁰ S (O) R ¹⁰ C (O) NH-, (R ¹⁰ ) 5 NC (O) -, R ¹⁰ NC (NR ¹⁰ ) -, mii CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 - or R ¹⁰ OC (O) NH-, Q R is selected from the group (a) a hydrogen atom; (b) C 2 -C 5 alkneyl or alkynyl, perfluoroalkyl, F, Cl, 3r, R 10%, R 3 (O) 2 -, r ^{10 cW} ) n ¹⁰ -, (r ¹⁰ ) ₂ nc ( o) -, r ¹⁰ 2n-c (nr-°) -, CN, N0 _2, R ^I0 C (O) -, R '&gt; OC (O) -, N _3, -N (R °) _2, ^or R OC (O) NR ¹⁰ -, and c) alkyl of 1 to 8 carbon atoms, optionally substituted by a substituent from the group perfluoroalkyl, F, Cl, Br, R ¹⁰ 0-, R ¹⁰ S (Q) R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (Q) -, R ¹⁰ 2N-C (NR ¹ ") -, CN, R ~ C (O) -, ^R1O QC (O) -, N3, -N ^(R10) 2 or R ^il OC (O) NR ¹⁰ -, are independently selected from hydrogen, alkyl of 1 up to δ carbon atoms, benzyl or aryl, - 286 Ί 1 R 2 is independently selected from alkyl of 1 to 6 carbon atoms and aryl, 1 2 A ^4, and A independently represent a chemical bond, -CH = CH -, -O = C-, -O (O) -, -G (Q) NR ¹⁰ -, -NR ¹⁰ G (O) -, -O- , -N (R ¹⁰⁾ -, -5 (0) ₅ N ^(R10) -, N (R ¹⁰⁾ S (0) _o -, or -S (0) 2 2 m G is an oxygen atom, 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 the 0 to a carbon atoms are replaced by a heteroatom selected from the group consisting of O, S and R; and (e) alkenyl of 2 to 20 carbon atoms, provided that V has a different meaning from the hydrogen atom in that A is 3 (O) or, in the case of 2, that A 'is a chemical bond, n = 0 and A is S (Q). m W represents a heterocyclic radical, X is -CH4, -O (= O) -, or Z represents a substituted or unsubstituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, the substituted groups being substituted with one or more of the following groups: - 287 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 L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; (b) NR ^S R ⁷ ; c) cycloalkyl of 3 to 3 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -S (O) _{t N} r ^is or g) -C (0) NR ⁵ R ^7, 2) aryl or heterocyclic radical, 3) halogen atom, (4) 0R ^S , 5) NR ^S R ⁷ 5) CN, 7) N0 ₂ 8) C? ₃ , 9) -S (δ) _m R ^Sa , ^m 3 7 10) -C (O) NR R or (11) C 3 -C 5 cycloalkyl; means 0, 1 or 2, means 0, 1, 2.3 or 4, means 0, 1, 2, 3 or 4, means and. or 2, means 0 to 5 per provided that r - 0 if m n p q r s t wherein V is hydrogen, is 0 or 1, is 0 or 1, and is 4 or 5, 288 or optical isomers thereof, or a pharmaceutically acceptable salt thereof. Piperazine Compounds according to Claim 1, of Formula A And where i and,, ^_ R are independently selected from hydrogen or alkyl of 1 to S carbon atoms, Ρ is independently out of the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl, R 10 -, or alkenyl of 2 to 6 carbon atoms, c) unsubstituted or substituted alkyl 6 carbon atoms wherein the substituent is selected from unsubstituted or substituted aryl, ¹ 0 heterocycle, cycloalkyl, alkenyl, R 0a -N (R ¹⁰⁾ _2, 3 4 5 R, R, and R are independently selected from hydrogen and methyl. . R ~ represents a hydrogen atom, a group of the formula O or C 1 -C 5 alkyl, straight or branched, unsubstituted or substituted by at least one of the following groups: 289 1) aryl; 2) heterocyclic radical, (3) 0R ^S , (4) SR ^5a , SO ₂ R ^Sa or 5) II '2 3 4 5 wherein any two of R, R, R and R may be attached to the same carbon atom, S 7 7 fig R, R ^a and R ^z are independently selected from hydrogen, or alkyl of 1-4 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heterocyclic radical, these radicals being unsubstituted or substituted by one of the following groups: (a) C 1 -C 4 alkoxy; (b) a halogen atom; or c) aryl or heterocyclic radical, A Λ * » R is selected from alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, optionally substituted with 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) hydrogen, b) alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ^{1 (} R ¹⁰ O, R ¹⁰ C (O) NR ¹⁰ -, CN, NO 2, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, - 290 A A A ·· A R ¹⁰ OC (O) -, -N (R ¹⁰ ) ₂ or R ¹¹ OC (O) NR ¹⁰ - a (c) alkyl of 1 to 6 carbon atoms, substituted by a perfluoroalkyl group of 1 to 8 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 is selected from the group (a) hydrogen, b) alkenyl or alkynyl of 2 to β 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 -, CN , NO2> (r ¹⁰ ) 2n-c (nr ¹⁰ ) -, R ¹⁰ O (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, unsubstituted or substituted by 1 to 5 perfluoroalkyl, F, Cl, R ( ^G (O) -, R (SiO)) -, R ¹⁰ C (O) NR ¹⁰ -, CN , ^(R10) 2N-C ^(NR10) -, R ¹⁰ C (C) -, ^R1O OC (O) -, -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 and aryl, R 1 is independently C 1 -C 5 alkyl or aryl; A and A independently represent a single chemical bond, -CH = CH-, -C = C-, -C (O) -, -C (O) NR ¹⁰ -, O, -N (R ¹⁰ ) or S (O) _m , 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, - 291 c) aryl, d) alkyl of 1 to 20 carbon atoms in which is 0 to 20 carbon atoms; 4 carbon atoms replaced by a heteroatom selected from the group consisting of O, S, and N and (e) alkenyl of 2 to 20 carbon atoms and provided that V has a different meaning from hydrogen when A ¹ is S (O) or when A ¹ is a chemical bond, n - 0 and A is S _(0), W represents a heterocyclic radical selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl, X is -CH 2 - or -C (= Q) -, 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 ^S R ⁷ ; m means 0, 1, or 2 n means 0, 1, 2, 3, or 4, ? means 0, 1, 2, 3, or 4, r means 0 to 5, provided that r = 0 if that V is hydrogen, with means 0 or 1 a t means 0 or 1 their pharmaceuticals or optical isomers of these substances or tically acceptable salts thereof. • · · · · · · · · · · · · · · · · · · · - 292 5th Piperazine Compounds according to claim 2 of the formula B (fit (fit in - N ^^ ca ^{ca, 2)} "\ w (03 ¾ ^ ^1. R ² G ^X - ( N ^x NZ λ * \ / ^ H * 'In JS \ -4 r, where when l is independently selected from hydrogen or alkyl of 1 to δ carbon atoms, is independently selected from a) a hydrogen atom, ^one O b) aryl, heterocyclic radical, cycloalkyl, R 10 -, -N (R ~ 0) ₂ or alkenyl of 2 to 8 carbon atoms, c) unsubstituted or substituted alkyl oi to δ carbon atoms wherein the substituent is selected from unsubstituted or substituted aryl, ¹ 0 heterocycle, cycloalkyl, alkenyl, R 0a -N (R ⁱ⁰⁾ _2, 4. 5 R and R are independently hydrogen or methyl, H ³ represents a hydrogen atom, a group of the formula NR 'R' or straight or branched chain alkyl of 1 to 5 carbon atoms, unsubstituted or substituted by at least one of the following groups: • «· · - 293 1) aryl; 2) heterocyclic radical, (3) 0R ^S , (4) SR ^Sa , SO ₂ R ^5a or 5) _e 2 3 -4 wherein any two of R, R, and R may be bonded to the same carbon atom, R c, R ^z and R ^a are independently selected from hydrogen or C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, aryl or heterocyclic radicals, which 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, ^Sa R is selected from alkyl of 1-4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms optionally substituted by a group selected from (a) C 1 -C 4 alkoxy; (b) a halogen atom; or c) an aryl or heterocyclic radical, independently selected from the group (a) hydrogen, b) alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, C1, R2 ^<2 O-, R ¹⁰ C (O) NR ¹⁰ -, CN, NO 2, (R ¹⁰ ) 2N-C (NR ¹⁰ ) -, R ¹⁰ C (Q) -, ···· 294 • · · ··· «··· ··« R ¹⁰ OC (O) -, -N (R ¹⁰ ), or R ¹⁰ QCONON ¹⁰ - a o) C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R ¹⁰ O-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2 N-C (NR ¹⁰ ) -, R ¹⁰ C (O) -, ^R1O OC (O) -, -N (R ¹⁰⁾ 2 ^or R 0C (0) NR ¹⁰ -, R ⁹ is selected from the group (a) hydrogen, b) alkenyl or alkynyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, F, Cl, R ¹⁰ 0-, R ¹¹ 3 (0) tn-, R ¹⁰ C (0) NR ¹⁰ -, CN, NO 2> ^(R10) 2N-C ^(NR10) -, ^io r C (O) -, ^R1O OC (O) -, -N (R ¹⁰⁾ 2 ^or R OC (O) NR ¹⁰ -, and (c) alkyl of 1 to 6 carbon atoms, unsubstituted or substituted by a perfluoroalkyl group of 1 to 8 carbon atoms, F, Cl, R ¹⁰ O -, R 5 (O) m -, R ¹⁰ C (O) NR ¹⁰ -, CN, ( ^R10) 2N-C ^(NR10) -, R ¹⁰ C (C) -, ^R1O OC (O) -, -N (R ⁱ⁰⁾ ₂ or R ^l OC (0) NR ¹⁰ -, R ^G is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, benzyl and aryl, R1 is independently C1-C6 alkyl or aryl, A and A independently represent a simple chemical vase, -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, ··· ··· 295 · · · · · · · · · · · · · · · · · · · · c) aryl, d) alkyl of 1 to 20 carbon atoms in which is 0 to 20 carbon atoms; 4 carbon atoms replaced by a heteroatom selected from O, S, and N and (e) alkenyl of 2 to 20 carbon atoms and provided that V has a different meaning from hydrogen when A 1 is S (O) or when A ¹ is a chemical bond, n = 0 and A is S (0) / W represents a heterocyclic radical selected from pyrrolidinyl, imidazolvl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl or isoquinolinyl, G is or O, Z represents mono- or bicyclic aryl, 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 from the following groups, L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) NR c R ^7, c) cycloalkyl of 3 to 5 carbon atoms, d) aryl or heterocyclic radical, e) RO, E) -3 (O) R ^Sa or ^m 3 7 g) -C (Q) NR ^O R, 2) aryl or heterocyclic radical, 3) halogen atom, 4) QrS, 5) NR ^S R ⁷ - 296 ·· ·· 4 ·· ··· «·· ···· 4 • · 4 · · 5) CN, (7) 5T0-, (a) crZ, - 5a. 9) -3 (0) .3, iii r * * 9 LQ) -3 (G) NR ³ R ^/ Zeba 11) cycloalkyl of 3 to 8 atoms carbon, m means 0, 1 zebe 2, means 0, 1, 3.3 or 4, p means 0, 1, 3, 3 or 4, 7 means 0 to 3 provided that r = Q in the case that 7 is a hydrogen atom, WITH means Q of itself, - means 0 of 1 and a at means - zebe 3, provided that when G is H. and W is α 19 'imidazolyl, then the substituent (R) -N-A' (CR '-) ^- (OΥ) r 2 n 2 n has a meaning different from and provided that when X is -C (= Q) - or -S (O) -, then the substituent (R8) -V-aYCR - ^ ^ A-ICR ^ P ^ - has a meaning other than that of the hydrogen atom or optical isomers thereof or a pharmaceutically acceptable salt thereof. Piperazine compounds according to claim 1, 2 or 3 of the group: 2 (S) -Butyl-1- (2,3-diaminoprop-1-yl) -4- (1-naphthoyl) piperazine, 1- (3-Amino-2- (2-naphthylmethyl-amino) prop-1-yl) -2 (S) -butyl-4- (1-naphthyl) piperazine, 297 2 (S) -butyl-1- [5- [1- (2-naphthylmethyl)] - 4,5-dihydroimidazole / methyl-4- (1-naphthoyl) piperazine, 1- [5- (1-Benzylimidazole) methyl] -2 (S) -butyl-4- (1-naphthyl) piperazine, 1- [5- / 1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (3-acetamidomethylthio-2 (R) -aminoprop-1- yl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 2 (S) -butyl-1- [2- (1-imidazolyl) ethyl] sulfonyl-4- (1-naphthoyl) piperazine, 2 (R) -Butyl-1-imidazolyl-4-methyl-4- (1-nontoxyl) piperazine, 2 (S) -Butyl-4- (1-naphthoyl) -1- (3-pyridylmethyl) piperazine, 1-2 (S) -Butyl- (2 (R) - (4-nitrobenzyl) amino-3-hydroxypropyl) -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- (1-naphthyl) piperazine, 1- (2 (R) -amino-3- [3- (4-nitrobenzylthio) propyl)) - 2 (S) -butyl-4- (1-naphthoyl) piperazine, 2 (S) -butyl-1 - [(4-imidazolyl) ethyl] -4- (1-naphthoyl) piperazine, 2 (S) -Butyl-1 - [(4-imidazolyl) methyl] -4- (1-naphthoyl) piperazine, 2 (S) -Butyl-1- [(1-naphthyl-2-ylmethyl) -1H-imidazol-5-yl] acetyl] -4- (1-naphthyl) piperazine, 298 2 (S) -Butyl-1 - [(1-naphthyl-2-ylmethyl) -1H-imidazol-5-yl) ethyl] -4- (1-naphthoyl) piperazine, 1- (2 (R) -amino-3-hydroxypropyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2 (R) -amino-4-hydroxybutyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2-Amino-3- (2-benzyloxyphenyl) propyl) -2 (S) -butyl-4- (1-naphthoyl) piperazine, 1- (2-amino-3- (2-hydroxyphenyl) propyl) - 2 (S) -Hutyl-4- (1-naphthoyl) piperazine 1- [3- (4-Imidazolyl) propyl] -2 (S) -butyl-4- (1-naphthoyl) piperazine, 2 (S) -n-butyl-4- (1-naphthoyl) -1- [1- (1-naphthylmethyl) imidazol-5-ylmethyl] piperazine, 2 (s) -N-butyl-4- (1-naphthoyl) -1- [1- (2-naphthylmethyl) imidazol-5-ylmethyl] piperazine, 2 (S) -N-butyl-1- [1- (4-cyanobenzyl) 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- (3-methyl-2-butenyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-1- [1- (4-fluorobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-1- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine, 1- [1- (4-bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl-4- (1-naphthoyl) piperazine, 299 • · 1- [1- (4-Bromobenzyl) imidazol-5-ylmethyl] -2 (S) -n-butyl-4- (1-naphthoyl) piperazine, 2 (S) -N-butyl-4- (1-naphthoyl) -1- [1- (4-trifluoromethylbenzyl) imidazol-5-ylmethyl] piperazine, 2 (S) -N-butyl-1- [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) imidazol-5-ylmethyl] 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-imidazolylmethyl) 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- (methanesulfonyl) ethyl] -2-piperazinone, (S) -1- (3-chlorophenyl) - 4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) ethyl] -2-piperazinone, 300 (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) -5-imidazolylmethyl] -2-piperazinone, 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone, 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- (2-methylphenyl) 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-Methylsulfonylethyl) piperazin-2-one, 4- [5- (4-cyanobenzyl) -1-imidazolylethyl] -1- (3-chlorophenyl) piperazin-2-one, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof. Piperazine compounds according to claim 1, 2 or 3 selected from the group consisting of: - 301 302 • · · Table 2 stereo. X Y R n-Bu 2-O (CH 2) 13 CH 3 WITH n-Bu 2-O (CH 2) 13 CH 3 R n-Bu 2-O (CH 2) 11 CH 3 WITH n-Bu 2-O (CH 2) 11 CH 3 R n-Bu 2-O (CH 2) 9 CH 3 WITH n-Bu 2-O (CH 2) 9 CH 3 R n-Bu 2-O (CH 2) 7 CH 3 WITH n-Bu 2-O (CH 2) 7 CH 3 R n-Bu 2-O (CH 2) 3 Ph WITH n-Bu 2-O (CH 2) 3 Ph R n-Bu 3-OCH2Ph 303 Table 2 - cont. Y 5 stereo X Y WITH n-Bu 3-OCH2Ph R n-Bu 3-O (CH 2) 13 CH 3 10 WITH n-Bu 3-O (CH 2) 13 CH 3 R n-Bu 4-O (CH 2) 13 CH 3 WITH n-Bu 4-O (CH 2) 13 CH 3 15 Dec WITH n-Bu 4-0CH2Ph R / S H 2-O (CH 2) 13 CH 3 • · · · - 304 Table 3 Y_ 3-SO2Me 3-OCF3 4 4 4 4 - 305 Table 4 5 X_Y CH ₂ OCH ₂ Ph CF 3 CH ₂ SO ₂ Et CF ₃ 10 CH2SO2Ph _CF3 CH ₂ SO ₂ Me Q CH ₂ SC> ₂ Et Cl CONHMe QF ₃ CONHEt CF ₃ 20 CH2SO2Pi1 Cl CONHMe Cl CONHEt Cl CONHc-Pr a CONHc-Pr CF 3 - 306 • · · · Table4 - cont. NHCOMe Q C0NMe2 CF3 10 SOoEt a CH ₂ SMe Q (±) OCMe - 307 Table 5 X Y CH2CH2 H CH2CO H CH2 H ch ₂ 3-C1 NHSO2 H CH2CH2CO 3-OBJECTIVE CH2 2,3-Cl ₂ CH2 2-Br CH2 3-CF3 CH? 4-C1 CH2CO 3-C1 ch ₂ 3-F CH2 3-Br • ·· · - 308 Table 6 X Y of 4-CN CH2 5-CH 2 CH 2 CO 3-CN CH2 5-CH 2 2-CN CH2 5-CH 2 4-CN ch ₂ 4-CH 2 CH 2 CO 15 4-CN (CH ₂ ) 2 4-CH2CH2CO • 44 4444 44 944 944 444444 444 444 4444 44 4 - 309 T and u 1 k and 7 X 4-Me 10 4-Me 2-Me Y CH2CH2SO2Me H H - 310 Table 8 Υ ·· ·· 3-CF ₃ 3-CH ₃ 2,3 - ((¾ 3-OCH ₃ 3-C1 2-CH ₃ , 3-Cl H 3-F CH ₂ CH ₂ OCH ₂ CF ₃ [> -och ₂ ch ₂ ch ₂ ch ₂ n ₃ CH ₂ CH ₂ x NHCOCH ₃ CH ₂ CH ₂ NHCOC ₂ H _p 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 - 312 ·· ·· ··· * ·· · Table 10 NC Br - 313 ·· ·· ···· Table 11 R Y CN Cl - 314 Table 12 CN ···························· * · * « -315 • 4 · 4 9 · • Φ 44 · Tabullal2'- cont. CN • · · · · · - 316 • 9 99 9 9 9 9 9 Table 13 O CH, HN N-S CN - 317 Table 14 • • • ·· ·· · ·· · • • • • · · · • «· • • · · · · · • • • • · Λ • · · • · · • · · · · · - 318 Table 15 NC 100 4 · · 4 - 319 Table 98 9999 • 9 - 320 9 9 9 9 9 9 9 9 9 9 999 9999 9 9 9 9 9 9 9 9 9 9 9 9 Table 17 321 Table or or a pharmaceutically acceptable salt or optical isomer thereof. 4 · 4444 - 322 A piperazine compound according to claim 6, 1- [5- [1- (4-Nitrobenzyl) imidazolyl] methyl] -2 (S) -butyl-1-4. - (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. A piperazine compound according to claim 5, 1- [5- (1-Benzylmimidazole) methyl] -2- (S) -butyl-4- (1-naphthylpiperazine) and pharmaceutically acceptable salts or optical isomers thereof. 10. Piperazine. the compound of claim 6, 1- (2 (R) -amino-3- (3-benzylthio) petroleum) -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- (4-nitrobenzylthio) propyl) -2 (S) -butyl] -4- (1-naphthoyl) piperazine O, N and pharmaceutically acceptable salts or optical isomers thereof, A piperazine compound according to claim 6, 2 (S) -N-butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) pioerazine 324 and pharmaceutically acceptable salts or optical isomers thereof. A piperazine compound according to claim 6, 2 (S) -n-butyl-1- [1- (4-cyanobenzyl) imidazol-5-ylmethyl] -4- (2,3-dimethylphenyl) piperazin-5-one and its pharmaceutically acceptable salts or optical isomers. The piperazine compound of claim 6, 2 (S) -n-butyl-1- [1- (4-chlorobenzyl) imidazol-5-ylmethyl] -4- (1-naphthoyl) piperazine and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, 1- [1- (4-cyanobenzyl) -1H-imidazal-5-yl] acetyl] -2 (S) -n-butyl-4- (1-naphthyl) piperazine 325 and pharmaceutically acceptable salts or optical isomers thereof A piperazine compound according to claim 6, 1 / 1- (4-cyanobenzyl) imidazol-5-ylmethyl / - ⁴ - (2,3-dxmethy1fenyl) -2 (S) - (2-me tho xye thyA i) pio e once-in-five she her pharmaceutically acceptable salts or optical isomers A piperazine compound according to claim 6, 5 (2) -n-Butyl-4- [1- (4-cyanoisoenzyl) -5-imidazolylmethyl] -L- (2-methylphenyl) piperazin-2-one 326 and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound according to claim 6, (S) -L- (3-chlorophenyl) -4- (1-O-cyano benzyl) -5-imidazolylmethyl) -3- [2- (methanesulfonyl) ethyl] -2 -piperazinone and pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, (2) -1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -3-imidazolylmethyl] -3- [2- (ethanesulfonyl) ethyl] -2 -piperazinone and pharmaceutically acceptable salts or optical isomers thereof. A piperazine compound according to claim 6, (s) -L- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl] -2 -p iperazinone • · • φ · 327 < NC And pharmaceutically acceptable salts or optical isomers thereof. The piperazine compound of claim 6, 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone] NC 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. 24. A pharmaceutical composition comprising as its active ingredient a piperazine compound according to claim 3 dispersed in a pharmaceutical carrier. ·· ··· « 328 25. A pharmaceutical composition comprising as 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 of 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 is dispersed. R ² VA ^ CR ^ nA ^ CR ^ n ^ W / - (CR J pX /? 7 R ³ R ⁴ N — Z ·· 4444 - 329 • 4 <4 4 • 4 · 4 4 * 999 9 9999 99 9 where 1 cl R ^x and R ^x are selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case 2 to S carbon atoms, R ¹⁰ O -, R ^{10 L} (S) m -, R ¹⁰ C (O) NR ¹⁰ -, cn (r ¹⁰ ) 2nc (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 ¹⁰ OC (O) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 8 carbon atoms, R ¹⁰ -O- , R ¹¹ 3 (0) rn -, R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) £ Ν0 (0) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, cn, r ^1o c (o) -, r ^1o oc (o) -, n ₃ , -N (R ¹⁰ ) ₂ and R ¹¹ C (O) -NR ¹⁰ -, R ³ is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 3 carbon atoms, optionally substituted, aryl, optionally substituted, heterocyclic radical, optionally substituted or or Wherein the substituted groups are substituted with at least one substituent from the 5s group 9 9 · · · · - 330 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 ^S , c) _{(CH?) o} NR ^and R ^7, d) halogen atom, e) CN 2) cycloalkyl of 3 to 6 carbon atoms, 3) QR ° 4) SRaa, S (0) R6 \ SOcRCa • NR'R ' 3) R ° I -? <.NR'R ' ^a 3) -V *** 9) W) -C (OR ³⁾ T o NR ° R '* · · · · · · φ · · · · · 331 11) -SO ₂ -NR ^and R ^; Γ 12) —N ”SG << * F ^qa ' 13) R ^á li Q ¹⁴⁾ - ^ - QR ^and Li O 15) N ₂ , or Or R "and R ^j are bonded to the same carbon atom and together form a group" (CH _{2) u} wherein one of the carbon atoms is replaced by one of oooříoadě skuoin 0, S (C). 1Π * -NC (O) - or -N (COR R ⁴ represents a hydrogen atom or methyl, 2 3 4 wherein any two of R, R and R may be attached to the same carbon atom, R ⁵ , R ⁷ and R ^7a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl and said radicals optionally substituted with a substituent from the group (a) C 1 -C 4 alkoxy; b) aryl or heterocyclic radical, o) halogen, - 332 - (d) HIM, E) Y 0 1 n -3O ₂ R ⁿ or WITH) N (RJO) 2 ’, or A 1 R and R may together form a ring or 7 7a R and R may together form a ring, ^Sa R is selected from alkyl of 1-4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclyl or aryl moieties are optionally substituted with one of (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, and ^t1 v O f) “SO ₂ fl i) N (R 10) 2; or ^R are independently selected a) a hydrogen atom, group b) aryl, 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) _in -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ), NC (O) -, R ¹⁰ , NC (NR ¹⁰ ) -, CN, NO, R ¹⁰ C (O) -, R 6 OCCO) -, N _3, -B (R) _2, or R ^II OC (O) NR ~ - and 44 4444 - 333 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 ^ ° 0-, R ¹¹ S (O) R ¹⁰ C (O) NH-, (R ¹⁰ ), NC (0) -, R ^{10 9} N-C (NR ¹⁰ ) -, m CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 - or R ¹⁰ QC (O) NH-, R is selected from the group (a) a hydrogen atom; b) C 2 -C 5 alkneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ^G 0 -, R 5 S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, 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 ⁵ OCCONR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl, F, Cl, Br, R ¹⁰ 0-, R ¹⁰ S (O) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R 8 N-CH ¹ R "- , CN, R ¹⁰ O (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -, R 10 ^-O is independently selected from the group consisting of hydrogen and alkyl 1 to β carbon atoms, benzyl or aryl, R 6 is independently selected from C 1 -C 6 alkyl and aryl, 1 2 A and A independently represent a chemical bond, -CH = CH -, - C = C-, -C (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰ ) -, N - ^(R1O) S (O) 2- or -S (0) _m -, G stands for H _{2 (} ·· ···· - 334 • • 99 9 • 9 9 9 • · ··· 23 groups are selected (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 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 the hydrogen atom in the case that A 'represents S (O) or, in the case of i2, that A represents a chemical bond, n = 0 and A means group S (0), W is imidazolyl, X is -CH-, -C (= O) -, or -S (= O) _-, 4 ^iU Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical wherein the substituent is at least one of L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; b) NR c R ^7, c) cycloalkyl of 3 to 5 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -3 (0) and ^Sa or m-g) -C (O) NRV, 2) aryl or heterocyclic radical, 3) halogen atom, (4) 0R ^S , 5) NR ^S R ⁷ - 335 φφ φφφ • φφ φφφφφφφ 6) CUT, 7) 20 ₂ 3) CF ₃ , 9) -3 (0) _[n R ^Sa , 10) -C (0) NR ^S R ⁷ or 11) cycloalkyl of 3 to 3 carbon atoms, tn is 0, 1 or 2, n is 0, 1, 2,3 or 4, and is 0, L, 2, 3 or 4, q is I or 2, r is 0 to 5, provided that r = 0 when V is hydrogen, s is 0 or 1, t is 1, and u is 4 or 5, and pharmaceutically acceptable salts of these compounds. and I provided that the substituent (R ⁸⁾ RVA ¹ (CR ''^'and 2) _n N (CR 2 ^la), _Ri is hydrogen, or pharmaceutically acceptable salts thereof. 31. A method of inhibiting farnesyl transferase, characterized by administering a pharmaceutical composition containing the piperazine compound of formula B ^(p '^ vA FeV ca ca ^^' ^. Γ / / ^(Ca "^'and V ^N J u N-Z S \ pý 4 4 4 4 4 5 - 336 where "la" lb,. , R and R are selected from the group (a) a hydrogen atom; b) aryl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case 2 to 6 carbon atoms, R ¹⁰ O-, R ¹¹ S (O) rn-, R ¹⁰ C (O) NR ¹⁰ cn (r ¹⁰ ) 2nc (o) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, CN, NO 2, R ¹⁰ C (0) -, R ¹⁰ 0C (0) -, N3, -N ^(R10) ₂ or R ¹¹ 0C (0) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R ¹⁰ -O- R ¹¹ 3 (0) m- R ¹⁰ C (0) ^NR10 -, ^(R10) 2NC (0) -, R ^10, NC ^(NR10) -, CN, R ¹⁰ C (0) -, R ¹⁰ 0C (O) -, N ,, -N (R ¹⁰ ) ₂ and R ¹¹ C (O) -NR ¹⁰ -, R R ⁹ _is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 3 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 337 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 ⁵ , (c) (CH ₂ ) _p NR ^S R ⁷ , d) halogen atom, e) CN 2) cycloalkyl of 3 to 6 carbon atoms, 3) OR ° 4) SR a, S (O) R 6 ^a , SO 7 R ^6a . —NR ° R 'e « 5) -γ, Η ' II O -W suboptions .nr ⁷ and R ^7a, Y ~ ^{and R} '0 10) NR ° R ' 9) -O 2 OR ⁵ T o • · ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 338 11) -3a ₂ -NR ⁵ R ^r Γ 12) -N-SO ₂ -R ^aa 13) ___ * - R ® tl ¹⁴ ) ---- OR ³ II a 15) N _? or 16) R; or R 2 and R 2 are bonded to the same carbon atom and together form a group, one of the carbon atoms optionally being replaced by one of O, S (C), -NC (O) - or -N (COR ¹⁰ ) -, R ⁴ is hydrogen or methyl, "23 4, and any two of R, R and R may be bonded to the same carbon atom, R 0, R ⁷ and R ^7a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, heterocyclic radical, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl 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, 339 or or (d) HO,. R ^{11 s)} Tr o f) -so ₂ n ^-1 g) N (R10) 2 *> or fi 7 R and R may together form a ring 7 7a R and R may together form a ring, R ^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 with one of the groups (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, O ¹¹ (e) V f) - s ₂ and "s) N (R 10) 2; or R ^a is independently selected from a) a hydrogen atom, from the group consisting of b) aryl, heterocyclic radical, cycloalkyl of 3 to 5 carbon atoms; C 10 alkenyl or alkynyl in each case 2 to 6 carbon atoms, perfluoroalkyl, F, Cl, Br, R ¹⁰ 0-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) NC (O) -, ^R10 .NC ^(NR10) -, CN, NO. R ^{1 O} C (O) -, R ^1G 0C (0) -, ID 11 ^ ID N ₃ , -3 (R) ₂ or TQC (Q) NR - a 340 c) alkyl of 1 to 6 carbon atoms, optionally substituted by a substituent from the group aryl, cyanophenyl, heterocyclic radical, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to β carbon atoms, perfluoroalkyl, F, Cl, Br, R O--, R ^LLS (0) m- R ^{1 O} C (O) NH-, ^(R10) 2NC (0) - R ¹⁰ 2 NC ^(NR10) -, CN, R ^{1 O} C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 - or R ¹⁰ OC (O) NH-, g R is selected from the group (a) a hydrogen atom; b) C 2-6 alkyneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _n -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, NO ₂ , R ¹⁰ O (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹¹ OC (O) NR ¹⁰ -, and c) alkyl of 1 to 8 carbon atoms, optionally substituted by a substituent from the group perfluoroalkyl, F, Cl _; .Br, R ¹⁰ 0-, R ¹⁰ S (O) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2NC (O) -, R ¹⁰ 2N-C (NR ¹ ^) -, 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 1 to 6 carbon atoms, benzyl or aryl, R 6 is independently selected from C 1 -C 6 alkyl and aryl, 1 2 A and A independently represent a chemical bond, -CH = CH -, - C = C-, -O (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰ ) -, N - ^(R1O) S (O) 2- or -S (0) _m -, G is H ₂ or O, - 341 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 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 in that A 'is S (O) or, in the case of τ 2, that A is a chemical bond, n = 0 and A is S (0), m W represents a heterocyclic radical, X is -0H-, -0 (= 0) - or -3 (= 0) -, 1 m Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical wherein the substituent is at least one of L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; (b) NR ^S R ⁷ ; (c) cycloalkyl of 3 to 6 carbon atoms; d) aryl or heterocyclic radical, e) HO, f) -S (O) R ^Sa or ro 7 g) -C (O) NR ^and R, 2) aryl or heterocyclic radical, 3) halogen atom, (4) 0R ^S , 5) NR ^S R ⁷ • 0 • W · 4 0 0 0 0 0 • 0 0 0 0 • · • 0 0 0 0 0 0 0 0 0 0 0 0 · 0 0 00 0 00 0 0 0 ♦ 342 (b) CN, 7) 20 ₂ a) c? ₃ , (9) -S (O) R ^Sa , 10) -C (O) NR R or 11) cycloalkyl of 3 to 3 carbon atoms, m is 0, 1 or 2, n is 0, L, 2,3 or 4, o is 0, 1, 2, 3 or 4, and is 1 or 2, r is 0 to 3 provided that r = 0 when V is hydrogen, s is 0 or 1, t is 0 or L, and u is &lt; or 3, and pharmaceutically acceptable salts of these compounds, provided that when, wherein t = 1, the substituent is (R ⁸ ) _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 a mammal an effective amount of a pharmaceutical composition according to claim 22. 33. A method of treating cancer comprising administering to the mammal an effective amount of a pharmaceutical composition according to claim 23. 34. A method of treating cancer comprising administering to a mammal an effective amount of a pharmaceutical composition according to claim 24. - 343 35. A method of treating cancer comprising administering to the mammal an effective amount of a pharmaceutical composition according to claim 25. 36. A method of treating benign neurofibromine comprising administering to a mammal an effective amount of a pharmaceutical composition of claim 23. 37. A method of treating blindness caused by retinal vascularization comprising administering to a mammal an effective amount of a composition of claim 23. 38. A method of treating a hepatitis delta virus infection and the like, comprising administering an effective amount of the composition of claim 23. 39. A method of preventing restenosis by administering a composition according to claim 23. 40. A method of treating polycystic kidney comprising administering the composition of claim 23. 41. A method of treating or preventing cancer, neurofibromin, retinal vascularization, infections of hepatitis delta and the like, restenosis and polycystic kidney disease, characterized by administering an effective amount of a pharmaceutical composition containing the piperazine compound of formula B (H ³⁾ R v.A ^ ca ^ v ^ ca '^) ,, NZ w / - (ca ^ x J •>' ^Z Stí fl ³ R ⁴ • · 0 · - 344 where R 6a ^and R 6a are selected from the group (a) a hydrogen atom; b) aryl, heterocyclic, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case 2 to S carbon atoms, R ¹⁰ 0-, R ¹¹ 3 (0) rn -, R ¹⁰ C (O) NR ¹⁰ -, cn (r ¹⁰ ) 2nc (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 ¹¹ OC (O) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R ¹⁰ -O- , R ¹¹ 3 (0) n 1 -, R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) £ Ν0 (0) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N ₃ , -N (R ¹⁰ ) ₂ and R ¹¹ OC (O) -NR ¹⁰ -, R 1 and R ³ are independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl. or alkynyl, in each case having 2 to 3 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 345 1) an aryl or heterocyclic radical, optionally substituted with a substituent from the group (a) alkyl of 1 to 4 carbon atoms; b) (CKPpOR ⁵ , (c) (CH ₂ ) _p NR ^S R ⁷ , d) halogen atom, e) CN 2) cycloalkyl of 3 to 3 carbon atoms, (3) 0R °, 4) SR ° ^a , S (O) RO ^a , SOcR ⁰ * S) —NR ° R ' R ³ AND -N ^ R ' II G R ³ • —- _t \ L. NR ⁷ R ^7a -G (NR 4 R ³⁾ T 0 W) NR ° R ' 9) -G ^ OR ’ II Q - 346 11) - SO ₂ -NR'R ^r Γ 12) -N-3Q ₂ —R ^qa 13) 14) • OR ” O Or 16) F; or 2 ^q R and R are bonded to the same carbon atom and together form the group '(CHPu, one of which is optionally replaced by one of the groups O, S (C), -NC (O) - or -N (COR ¹⁰ ) -, R is hydrogen or methyl, wherein any two of R, R and R may be attached to the same carbon atom, R, R and R are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclic radical, aryl, aroyl, heceroaroyl, arylsulfonyl, heteroarylsulfonyl and said radicals optionally substituted by a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, (c) a halogen atom; 347 Ο (f) SO ₂ R ^t1 ; or g) N (R 10) 2; or fi 1 R and R may together form a ring or 7 7a R and R may together form a ring, fi and R 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) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, 111 c) halogen atom, d) HO, e) y f) - with ₂ y g) N (R 10) 2; , or a R is independently selected (a) a hydrogen atom from the group; b) aryl, 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 (0) ^NR10 -, ^(R10) NC (0) -, R ¹⁰ 2N-C ^(NR10) -, CN, _NO2, R ¹⁰ C (0) -, R ^1G 0C (0) - , N ₃ , -B (R ¹⁰ ) ₂ or R ^U 0C (0) NR ¹⁰ - 348 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 ^X % -, R ¹¹ S (°) m-, R ¹⁰ C (O) NH-, (R ¹⁰ ) ₂ NC (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 is selected from the group (a) a hydrogen atom; b) C 2 -C 8 alkneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, 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 ¹¹ OC (O) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl, F, Cl, _3r, R ¹⁰ 0-, R ^1X S (O) -, R ¹⁰ 0 (0) NR ¹⁰ -, (R ¹⁰ ) 2NC (O) -, Η ^1Ο 2Ν-Ο (ΝΕ ^Χ ”) - , cn, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NR ¹⁰ -, R &lt; ¹ &gt; is independently selected from hydrogen or alkyl; 1 to 6 carbon atoms, benzyl or aryl, R ^XX is independently selected from C 1 -C 6 alkyl and aryl, 1 2 A and A independently represent a chemical bond, -CH = CH -, - C = C-, -O (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰ ) -, N - ^(R1O) S (O) 2- or -S (0) _m -, G is H ₂ , 349 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 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 the hydrogen atom in the feed, that A - is 3 (O) or 1 ^m 2 that A is a chemical bond, n = 0 and A is a group 3 (0). m W is imidazolyl, X is -CH 2, -O (= O) -, or S (= Q) _m -, Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical wherein the substituent is at least one of L) alkyl of 1 to 4 carbon atoms optionally substituted by one of the groups (a) C 1 -C 4 alkoxy; (b) NR ⁵ R ⁷ ; c) cycloalkyl of 3 to 5 carbon atoms, d) aryl or heterocyclic radical, e) HO, (f) -3 (0) _(n R ^Sa or g) -C (0) ^NR R ^7, 2) ary! or a heterocyclic radical, 3) halogen atom, 4) OR ⁵ , 5) NR ^S R ⁷ , «φ φ · · φ φ φ φ • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ - 350 b) CN, 7) 20 ₂ 8) 0Γ ₃ 9) -S (O) R ^Sa ; 10) -C (O) NR R or 11) cycloalkyl of 3 to 5 atoms carbon, m is 0, 1 or 2, n is 0, 1, 2,3 or 4, p is 0, 1, 2, 3 or 4, q means i or 2, j · is 0 to 2, provided that V is hydrogen, that r = 0 if with means 0 or I, t means' I and at is 4 or 2, for with the proviso that (R®) -V-A (CR (Y) aYcR (Y) - is r 2 n 2 n hydrogen atom. or a pharmaceutically acceptable salt thereof. 42. A method of treatment or prevention and other diseases mentioned in claim 41, characterized in that the mammals are administered an effective amount of a pharmaceutical composition containing the piperazine compound of formula B (Rh-AVCR ^^ ca ^ AW / - (ca ^ra j ) p \ Jý f ^{λ h} R ³ R ^4, N-Z • 4 · 4 4 4 - 351 • 4 4 4 4 4 4 44 4 where R ³ 'and R ³ ' are selected from the group (a) a hydrogen atom; b) aryl, heterocyclic, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl in each case 2 to δ carbon atoms, R ¹⁰ 0-, R ¹¹ S (O) m R ¹⁰ C (0) NR ¹⁰ -, CN, (R ^{1 O)} 2 NC (O) -, R ¹⁰ 2NC ^(NR10) -, CN, _NO2, R ^{1 O} C (O) -, ^R1O OC (O) -, N3, -N ^(R10) 2 or R ¹¹ 0C (0) NR ¹⁰ -, c) alkyl of 1 to 6 carbon atoms, optionally substituted, wherein the substituent is selected from unsubstituted or substituted aryl, heterocyclic radicals, cycloalkyl of 3 to 10 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, R ¹⁰ -O- , R ¹¹ S (O) tn-, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) 2NC (0) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, cn, r ^1o c (o) - , r ^1o oc (o) -, n ₃ , -N (R ¹⁰ ) ₂ and R ¹¹ OC (O) -NR ¹⁰ -, R " R ⁶ is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted, alkenyl or alkynyl, each of 2 to 3 carbon atoms, optionally substituted, aryl, optionally substituted, beterocyclic radical, optionally substituted, or wherein substituted groups are substituted at least one substituent from the group • · · · * 352 · 9999 99 9 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 ⁵ , (c) (CH ₂ ) _p NR ^S R ⁷ , d) halogen atom, e) CN 2) cycloalkyl of 3 to 8 carbon atoms, 3) QRR 4) SR <XS (O) R <k ^SO 2 R ^δa , 3) (3) —NR ° R ' 1 «· —N R ~ II R ⁵ I. N-NR'R ' ^a II _ <·>, NF5R ' 9) -O 2 OR ⁵ T o NR ° R ' 10) ···· 11) - SO ₂ -NR ³ R ^r Γ iq -N-SO ₂ - ^«Qa 12) A ^á ' II O --- OR ³ II O 15) N ₃ , or 16) R; or 2 ^q R and R ^- are bonded to the same carbon atom and are taken together to form - (ΟΗ ^) »wherein one of the carbon atoms is optionally replaced by one of O, S (C), -NC (O) - or -N (COR) ' ⁰ ) -, 4: R is hydrogen or methyl, Wherein any two of R, R and R may be attached to the same carbon atom, R, R and R ^a are independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, heterocyclic, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl and said radicals optionally substituted with a substituent from the group (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, (c) a halogen atom; d) HO, *> Y ⁿ , O (f) “SO2R ¹¹ , or g) N (jRJQ) 2; or R ⁵ and R ⁷ may together form a ring or R ⁷ and R ^7a may together form a ring, R® ^and are selected from alkyl of 1-4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclyl or aryl moieties are optionally substituted with one of (a) C 1 -C 4 alkoxy; b) an aryl or heterocyclic radical, c) halogen atom, d) HO, o ” IN O f) -sc ₂ r ” g) N (R 10) 2; or Q R is independently selected from a) a hydrogen atom, selected from the group consisting of b) aryl, 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) NR ¹⁰ -, (R ¹⁰ ) NC (0) -, r ¹⁰ 2n-c (nr ¹⁰ ) -, CN, no ₂ , R ¹⁰ C (O) -, R 10 OCCO) -, N _3, -B (R ¹⁰⁾ ₂ ^or R OC (0) NR ¹⁰ -, and 355 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, Cl, Br, R ¹⁰ Q-, R ¹¹ s (°) m-, r ^10o c (o) nh-, (r ¹⁰ ) 2nc (0) -, r ^10o 2n-o (nr ¹⁰ ) -, CN, R ¹⁰ C (O ) -, ^R1O OC (O) -, Ng, -N (R ¹⁰⁾ 2 or ^R1O OC (O) NH-, R is selected from the group (a) a hydrogen atom; b) C 2-6 alkneyl or alkynyl, perfluoroalkyl, F, Cl, Br, R ¹⁰ O-, R ¹¹ S (O) _m -, R ¹⁰ C (0) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (0) -, R ¹⁰ 2N-C (NR ¹⁰ ) -, CN, NO ₂ , R ¹⁰ C (O) -, R ¹⁰ C (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NR ¹⁰ -, and c) alkyl of 1 to 6 carbon atoms, optionally substituted with a substituent from the group perfluoroalkyl, F, Cl, .Br, R ¹⁰ 0-, R ¹¹ 3 (0) -, R ¹⁰ C (O) NR ¹⁰ -, (R ¹⁰ ) ₂ NC (O) -, R ¹⁰ 2N-C (NR 1 ^G ) CN, R ¹⁰ C (O) -, R ¹⁰ OC (O) -, N 3, -N (R ¹⁰ ) 2 or R ¹⁰ OC (O) NR ¹⁰ -, R ¹⁰ are independently selected from hydrogen , alkyl o 1 to 5 carbon atoms, benzyl or aryl, R 1 is independently selected from C 1 -C 5 alkyl and aryl, 1 2 A and A independently represent a chemical bond, -CH = CH -, - C = C-, -O (O) -, -C (O) NR ¹⁰ -, -NR ¹⁰ O C (O) -, -O-, -N (R ¹⁰ ) -, -S (O) 2 N (R ¹⁰ ) -, N - ^(R1O) S (O) 2 or -SCO) ^ -, G stands for H ₂ or O, · «···· - 356 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 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 'is S (O) or when A' is a chemical bond, n - O and A is a scouine S (0) _m , m W represents a heterocyclic radical, X is -OH ^, -0 (= O) - or -3 (= O) ^ -, Z is an unsubstituted or substituted aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl radical wherein the substituent is at least one of 1) alkyl of 1 to a carbon atoms, optionally suostislated with one of the groups (a) C 1 -C 4 alkoxy; 5) NR ⁵ R ⁷ c) cycloalkyl of 3 to 5 carbon atoms, d) aryl or heterocyclic radical, e) HO, f) -SCO1 ^ ⁵ * or g) -0 (0) NR ⁵ R ^7, 2) aryl or heterocyclic radical, 3) halogen atom, (4) 0R ^S , 5) NR ^S R ⁷ , ·· ··· * - 357 b) CN, 7) 20 ₂ 3) CS \ 9) -S (O) - R ^Sa , ® A 7 10) -C (O) NR R or L1) cycloalkyl of 3 to 3 carbon atoms, m means 0, 1 or; n means 0.1, 2.3 i P means 0, i, 2, 3 q means 1 or 2, r · means 0 to 5 per! that V is an atom ' WITH means 0 or 1 OF means 0 or 1 a at means 4 or 5, and 0 in the case, provided that when t = 1, the substituent (R ⁸ ) -VA ¹ (CR ^1a ) A ⁸ (CR ^1a ) - represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. .