COMPOSES AZOLE COMME AGENTS THERAPEUTIQUES POUR TRAITER DES INFECTIONS MYCOSIQUES

AZOLE COMPOUNDS AS THERAPEUTIC AGENTS FOR FUNGAL INFECTIONS

Abrégé français

L'invention concerne des dérivés de composés azole substitués de manière spéciale qui possèdent une activité antimycosique accrue par comparaison avec des composés connus tels que le fluconazole et l'itraconazole, ainsi que des procédés de préparation de ces dérivés. L'invention concerne aussi des compositions pharmaceutiques contenant ces composés, et leur utilisation pour traiter et/ou prévenir des infections mycosiques chez des mammifères, de préférence des êtres humains.

Abrégé anglais

The present invention relates to the derivatives of specially substituted
azole compounds which have improved antifungal activity as compared to known
compounds such as fluconazole and itraconazole and the processes for the
preparation thereof. This invention also relates to pharmaceutical
compositions containing the compounds of the present invention and their use
in treating and/or preventing fungal infections in mammals, preferably humans.

Revendications

WE CLAIM:
1. A compound of Formula IA
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-,
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with ~ 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of

halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl ;
X1, X2, Y1, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl.
2. A compound of Formula IB
<IMG>
81

and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-,
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
82

R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl ;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
B is selected from oxygen and sulphur atoms; and
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoro-
83

methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l)
tetra-
fluoropropyl and (m) tetrafluoropropoxyl.
3. A compound of Formula II
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-,
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
84~

amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted; and
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (p) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoro-
methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l)
tetra-
fluoropropyl and (m) tetrafluoropropoxyl;
85

B is selected from oxygen and sulphur atoms; and
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl.
4. A compound of Formula III
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides,
prodrugs or metabolites, wherein
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
86

R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl;
87

X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl; and
B is selected from oxygen and sulphur atoms.
5. A compound is selected from the group consisting of:
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone (Compound No. 1)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl)-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl]-3-(2H,4H)-
1,2,4-triazolone (Compound No. 2)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl)-3-
(2H,4H)-1,2,4-triazolone (Compound No. 3)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 4)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl)-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4-
triazolone (Compound No. 5)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(1-phenylpiperazinyl)phenyl}-3-(2H,4H)-1,2,4-
triazolone (Compound No. 6)
88

- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 7)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 8)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 9)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 10)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone (Compound No. 11)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone (Compound No. 12)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone(Compound No. 13)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 14)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 15)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 16)
89

- 2-([1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl)-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl]-
3-
(2H,4H)-1,2,4-triazolone (Compound No. 17)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl}-
3-
(2H,4H)-1,2,4-triazolone (Compound No. 18)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl)-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 19)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-1,2,4-triazolone (Compound No. 20)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-
3-
(2H,4H)-1,2,4-triazolone (Compound No. 21)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-
3-
(2H,4H)-1,2,4-triazolone (Compound No. 22)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl)-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl)-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 23)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl)propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl)-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 24)
- 2-([1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-
5-
methyl-1,2,4-triazolone (Compound No. 25)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl)-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-
5-
methyl-1,2,4-triazolone (Compound No. 26)
90

- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl}-
3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 27)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl)-
3-(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 28)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 29)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 30)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
5-
methyl-1,2,4-triazolone (Compound No. 31)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-
5-
methyl-1,2,4-triazolone (Compound No. 32)
- 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 33)
- 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl-3-
(2H,4H)-5-methyl-1,2,4-triazolone (Compound No. 34)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
methoxyphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-5-methyl-1,2,4-triazolone
(Compound No. 35)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
(Compound No. 36)
91

- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 37)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-diaminophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 38)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
methylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone (Compound
No. 39)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 40)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 41)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 42)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 43)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
hydroxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 44)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[1-
phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound No. 45)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
(Compound No. 46)
92

- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 47)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(5-
chloro-2-methylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
(Compound No. 48)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3-
chloro-4-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 49)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-dichlorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
(Compound No. 50)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3-
trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 51)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-difluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 52)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3-
chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 53)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 54)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3,4-difluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 55)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 56)
93

- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone (Compound
No. 57).
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
chloro- 4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 58)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
methoxy- 5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 59)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
ethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone (Compound
No.60).
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 61)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2-
fluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone (Compound
No. 62)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(1,2,3-trifluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 63)
- 3-{4-[4-(p-tolylaminothiocarbonylamino)piperazinyl]phenoxy)-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 64)
- 3-{4-[4-(isopropylaminothiocarbonylamino)piperazinyl]phenoxy)-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 65)
- 3-{4-[4-(4-chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)-propan-2-ol (Compound No. 66)
- 3-{4-[4-(4-chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 67)
- 3-{4-[4-(1-napthyl thioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 68)
94

- 3-{4-[4-(1-hapthyl thioureido)piperazinyl]phenoxy]-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 69)
- 3-{4-[4-(4-trifluoromethylphenyl thioureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 70)
- 3-{4-[4-(4-methoxyphenylureido)piperazinyl]phenoxy]-2-(2,4-difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 71)
- 3-{4-[4-(2,4-dichlorophenylureido)piperazinyl]phenoxy)-2-(2,4-
difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (Compound No. 72)
- 3-{4-[4-(4-chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 73)
- 3-{4-[4-(4-chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-2-ethoxy-3-propylamine (Compound No.
74)
- 3-{4-[4-N-(4-Chlorophenyl)-N-(methylureido)-piperazinyl ]-phenoxy)-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-2-methoxypropane (Compound No. 75)
- 3-{4-[4-(4-aminophenylureido)piperazinyl]phenoxy)-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)-propan-2-ol. (Compound No. 76)
- [1R2R/1S2S] 1-{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy}-2-(2,4-
difluorophenyl)-1-methyl-3-(1H-1,2,4-triazolyl)-propan-2-ol (Compound No.
77)
- [1R2S/1S2R] 1-{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy)2-(2,4-
difluorophenyl)-1-methyl -3-(1H-1,2,4-triazolyl)-propan-2-ol (Compound No.
78)
- 1-{4-[4-(4-Trifluoromethylphenylureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-methyl-3-(1H-1,2,4-triazol-1-yl)-propan-2-ol (Compound No.
79)
- 3-{4-[4-(Phenylureido)-piperazinyl ]-phenoxy}-2-(2,4-difluorophenyl)-1-(1H-
1,2,4-triazol-1-yl)-propan-2-ol(Compound No. 80)
- 2-(2,4-Difluorophenyl)-3-{4-(thioureidophenyl)N-methyl-N-phenyl}-1-(1H-
1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 81)
95

- 2-(2,4-Difluorophenyl)-3-{4-(isopropylthioureido)N-methyl-N-phenyl}-1-(1H-
1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 82)
- 3-{N-[4-(p-Tolylthioureido)-phenyl]- N-methyl-2-(2,4-difluorophenyl)-1-(1H-
1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 83)
- 3-{N-[4-(p-Fluorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 84)
- 3-{N-[4-(p-Nitrophenyltureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 85)
- 3-{N-[4-(p-Chlorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 86)
- 3-{N-[4-(Carboxymethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 87)
- 3-{N-[4-(2-Methoxy-2-oxoethyl)-phenyltureido)-phenyl]- N-methyl-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 88)
- 3-{N-[4-(p-Chlorophenylthiouredo)-phenyltureido)-phenyl]- N-methyl-2-(2,4--
difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 89)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(isopropylthiouredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 90)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
chlorophenyluredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 91)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
chlorophenylthiouredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 92)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
(2-methoxy-2-oxoethyl)phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone (Compound No. 93)
- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
(carboxyethyl)-phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
(Compound No. 94)
96

- 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
(2-hydroxyethyl)phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone(Compound No. 95)
6. A pharmaceutical composition comprising the compound of claim 1 to 5 and a
pharmaceutical acceptable carrier.
7. A pharmaceutical composition comprising a pharmaceutically effective
amount of compound according to claim 1 to 5 or a physiologically acceptable
acid addition salt thereof with a pharmaceutically acceptable carrier for
treating fungal infection.
8. A method of treating or preventing fungal infection in mammals comprising
administering to said animal a compound of Formula IA
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-,
97

R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl; and
98

X1, X2, Y1, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl.
9. A method of treating or preventing fungal infection in an animal comprising
administering to said animal a compound of Formula IB
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
99

R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
B is selected from oxygen and sulphur atoms; and
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
100

which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (I) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl.
10. A method of treating or preventing fungal infection in an animal
comprising
administering to said animal a compound of Formula II
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
101

X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
102

amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j), formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoro-
methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l)
tetra-
fluoropropyl and (m) tetrafluoropropoxyl;
B is selected from. oxygen and sulphur atoms; and
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl.
103

11. A method of treating or preventing fungal infection in an animal
comprising
administering to said animal a compound of Formula III
<IMG>
and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites, wherein
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
104

amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl;
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-;
105

Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1 ) halogen (2)
nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl; and
B is selected from oxygen and sulphur atoms.
12. A method of treating or preventing fungal infection in an animal
comprising the
step of administering to said animal the pharmaceutical composition
according to claims 6 and 7.
13. A process for preparing a compound of Formula IA
<IMG>
wherein X is selected from the group consisting of CH2, CO, CS, SO2 and -
N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
106

(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl; and
X1, X2, Y1, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl;
which comprises reacting 1-[2-(2,4-disubstituted phenyl)-2,3-epoxy derivative
of 1,2,4-triazole of Formula IV
107

<IMG>
wherein X, R and R1 are the same as defined above with triazol-3-one
derivatives of Formula V
<IMG>
wherein R2, R3, X1, X2, Y, Y1, Y2 and Z have the same meanings as defined
above, in the presence of sodium hydride to afford the desired compound of
Formula IA.
14. A process for preparing a compound of Formula IA
<IMG>
108

wherein X is selected from the group consisting of CH2, CO, CS, SO2 and -
N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl; and
109

X1, X2, Y1, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl;
which comprises reacting epoxide derivative of Formula VI
<IMG>
with 1,2,4-triazole to afford a compound of Formula IA.
15. A process for preparing a compound of Formula IB,
<IMG>
wherein X is selected from the group consisting of CH2, CO, CS, SO2 and -
N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
110

amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently selected from the group consisting of (1)
hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of
halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) SO2R' wherein R' is hydrogen, alkyl or aryl
and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl;
R3 is selected from the group consisting of C1-C4 alkyl group, halogen,
hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2R' wherein R' is
hydrogen, alkyl or aryl;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
B is selected from oxygen and sulphur atoms; and
111

R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl,
which comprises reacting a compound of Formula ID
<IMG>
112

wherein X, R, R1,R2, R3 and Y have the same meanings as defined above,
with a compound of Formula R5 - N = C = B wherein R5 and B are the same
as defined above to give a compound of Formula IC
<IMG>
which on reaction with R4Z, gives a compound of Formula IB wherein X, R,
R1, R2, R3, R4, R5,Y and B have the same meanings as defined above and Z
is any halogen atom.
16. A process for preparing a compound of Formula II
<IMG>
wherein X is selected from the group consisting of CH2, CO, CS, SO2 and -
N=N-;
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
113

selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
114

amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoro-
methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l)
tetra-
fluoropropyl and (m) tetrafluoropropoxyl;
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl; and,
B is selected from oxygen and sulphur atoms;
which comprises reacting a compound of Formula VII
<IMG>
with a compound R5-N=C=B, wherein R, R1, R5, X and Y have the same
meanings as defined above, to give a compound of Formula VIII
115

<IMG>
and which further comprises reacting the compound of Formula VIII with R4Z,
wherein R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl
group which is unsubstituted or substituted and Z is any halogen atom, to
obtain a compound of Formula II.
17. A process for the preparation of a compound of Formula III
<IMG>
wherein
R is selected from the group consisting of (1) C1-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy
(7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl
(12)
116

triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl
(17)
imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
117

trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (I)
tetrafluoropropyl and (m) tetrafluoropropoxyl,
X is selected from the group consisting of CH2, CO, CS, SO2 and -N=N-,
Y is a phenyl group which is unsubstituted or substituted with substituents
each independently selected from the group consisting of (1) halogen (2) nitro
(3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4
alkoxy and (8) SO2R' wherein R' is hydrogen, alkyl or aryl; and,
B is selected from oxygen and sulphur atoms,
which comprises reacting a compound of Formula IX
<IMG>
with a compound of Formula B=C=N-R5, to give the desired compound of
Formula III.
118

18. A process for preparing a compound of Formula IA wherein X=CH2, R=F,
<IMG>
and wherein
R2 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy, and
X1, X2, Y2, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl,
119

which involves the reaction of triazol-3-one derivatives of Formula V wherein
R3 =H, Y= C6 H4 -,
<IMG>
wherein R2, X1, X2, Y1, Y2 and Z are the same as defined above, with the
compound of Formula IV wherein R=F, R1=H, X=CH2
<IMG>
in the presence of sodium hydride.
19. A process for the preparation of triazol-3-one derivatives of Formula V
wherein R3 =H, Y= C6 H4 -
<IMG>
comprising reacting the substituted phenyl piperazine of Formula XIV
120

<IMG>
wherein X1, X2, Y1, Y2 and Z are independently selected from the group
consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted
aryl,
C1-C4 alkyl, C1-C4 alkoxy, carboxyl or protected carboxyl, with 4-
chloronitrobenzene to give the corresponding nitroaryl compound of Formula
XV
<IMG>
which on catalytic reduction affords the anilino derivative of Formula XVI
<IMG>
acylating the compound of Formula XVI with phenyl chloroformate to afford
phenyl carbamate derivatives of Formula XVII
121

<IMG>
reacting the carbamate derivative of Formula XVII, with hydrazine hydrate,
forming semicarbazide derivative of Formula XVIII
<IMG>
and cyclizing the compound of Formula XVIII with formamidine derivatives to
form triazol-3-one derivatives of Formula V.
20. A process for preparing a compound of Formula IA wherein X=CH2, R=F, R1=
CH3, Y=C6H4-, R3=H
<IMG>
wherein
122

R2 is selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl
group
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7)
SO2R' wherein R' is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy, and
X1, X2, Y1, Y2 and Z are independently selected from the group consisting of
halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4
alkyl,
C1-C4 alkoxy, carboxyl or protected carboxyl,
comprising reacting the 1, 3-difluorobenzene of Formula X
<IMG>
with racemic (~) 2-chloropropionyl chloride of Formula XIX
<IMG>
to form a compound (~) 2-chloro-2-methyl-2', 4'-difluoroacetophenone of
Formula
XX
123

<IMG>
which on condensation with the intermediate of Formula V wherein R3=H,
Y=C6H4- and R2, X1, X2, Y1,Y2 and Z are as defined herein
<IMG>
in the presence of sodium hydride, forms the compound of Formula XXI
<IMG>
which is then epoxidized with trimethylsulphoxonium iodide (TMSI) in DMSO
to give an epoxide derivative of Formula VI wherein X=CH2, R=F, R1=CH3,
Y=C6H4-, R3=H,
124

<IMG>
which on condensation with 1,2,4-triazole forms the compound of Formula IA.
21. A process for preparing compounds of Formula II wherein X=CH2, R=F, R1=H,
y=C6H4-
<IMG>
and wherein
R4 is selected from the group consisting of hydrogen, C1 - C4 alkyl group
which is unsubstituted or substituted;
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
125

each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoro-
methoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l)
tetra-
fluoropropyl and (m) tetrafluoropropoxyl; and
B is selected from oxygen and sulphur atoms,
by reacting 2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazolyl)-1-[4-(piprazinyl)
phenoxy]-propan-2-ol of Formula VII wherein X=CH2, R=F, R1=H, Y=C6H4-
<IMG>
126

with the compound of Formula B=C=N-R5, to form a compound of Formula
VIII wherein X=CH2, R=F, R1=H, Y=C6H4-
<IMG>
wherein R5 and B are as defined herein; and
further reacting the compound of Formula VIII with R4Z wherein R4 is selected
from the group consisting of hydrogen, C1 - C4 alkyl group which is
unsubstituted or substituted, in the presence of sodium hydride to give the
required compound of Formula II.
22. A process for preparing a compound of Formula II wherein X=CH2, R=F,
R1=CH3, R4=H, y-C6H4-
<IMG>
wherein
127

R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl, and
B is selected from oxygen and sulphur atom,
which comprises treatment of 2,4-difluoro-.alpha.-methyl-phenacyl chloride of
Formula XXII,
128

<IMG>
with 1-acetyl-4-hydroxyphenylpiperazine of Formula XXIII,
<IMG>
to form 2-[4-(4-acetylpiperazine)phenoxy]-2-methyl-2',4'-difluoroacetophen-
one of Formula XXIV,
<IMG>
which on treatment with trimethyl sulphoxonium iodide forms the corre-
sponding epoxide of Formula XXV,
129

<IMG>
which is then reacted with 1,2,4-triazole to yield a compound of Formula
XXVI,
<IMG>
which on hydrolysis gives a compound of Formula VII wherein X=CH2, R=F,
R1=CH3 Y=C6H4
<IMG>
130

and reacting the compound of Formula VII with R5-N=C=B gives the
compound of Formula II.
23. A process for preparing a compound of Formula III wherein X=CH2, R=F,
R1=H, Y=C6H4-
<IMG>
wherein
B is selected from oxygen and sulphur atoms, and
R5 is selected from the group (1) hydrogen, (2) C1- C4 alkyl group which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents
each independently selected from the group consisting of (a) C1-C4 alkyl
which is unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and
amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy
(g) C1-C4 alkoxycarbonyl amino (h) phenyloxy or naphthyloxy carbonylamino
(i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n)
amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2
and (u)
131

OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6
substituents selected from (a) C1 - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-
C4 alkyl) halo, (d) C1-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k)
tetrafluoroethoxyl (l)
tetrafluoropropyl and (m) tetrafluoropropoxyl,
comprising reacting 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triaz-
ole of Formula IV wherein R=F, X=CH2, R1=H
<IMG>
with N-methyl-4-nitroaniline of Formula XXVII gives 2-(2,4-difluorophenyl)-2-
hydroxy-3-(1H,1,2,4-triazol-1-yl)-1-propylamino-1N, -methyl-4-nitrobenzene of
Formula XXVIII
<IMG>
132

which on reduction gives 2-(2,4-diflurophenyl)2-hydroxy-3-(1H-1,2,4-triazol-1-
yl)-1-propylamino-1H methyl 4-aniline of Formula IX wherein X=CH2, R=F,
R1=H, Y=C6H4-
<IMG>
which on reaction with B=C=N-R5 gives the compound of Formula III.
133

Description

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
AZOLE COMPOUNDS AS
THERAPEUTIC AGENTS FOR FUNGAL INFECTIONS
Field of the Invention
The present invention relates to the derivatives of specially substituted
azole compounds which have improved antifungal activity as compared to known
compounds such as fluconazole and itraconazole and the processes for the
preparation thereof. This invention also relates to pharmaceutical
compositions
containing the compounds of the present invention and their use in treating
and/or preventing fungal infections in mammals; preferably humans.
Background of the Invention
Life-threatening, systemic fungal infections continue to be a significant
problem in health care today. In particular, patients who become "immuno-
compromised: as a result of diabetes, cancer, prolonged steroid therapy, organ
transplantation antirejection therapy, the acquired immune deficiency syndrome
(AIDS) or other physiologically or immunologically compromising syndromes, are
especially susceptible to opportunistic fungal infections. Most of these
infections
are caused by opportunistic pathogens, like species of Candida and Aspergillus
and Cryptococcus neoformans. During the last 20 years, the incidence of sepsis
fungal infection caused by candida species has increased significantly in
debilitated and immuno-compromised patients. In addition, the more aggressive
and frequently used broad spectrum antibiotic, antineoplastic and
immunosuppressive chemotherapies have also augmented fungal infections.
CONFIRMATION COPY

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Cryptococcosis is a leading cause of morbidity among AIDS patients. The
incidence of life threatening cryptococcal infection among these patients have
been estimated to vary from 10 to 30%. During initial therapy, 10 to 20% of
these
patients die and 30 to 60% patients succumb within a year. Amphoteracin B has
changed disseminated cryptococcosis from uniformly fatal infection to curable
infection but since Amphoteracin B penetrates the central nervous system
poorly,
interventricular injection may have to be administered for successful
management of severe cases of patients with cryptococcal meningitis. Invasive
aspergil(osis has also become a leading cause of death, mainly among patients
suffering from acute leukaemia or after a)logenic bone marrow transfusion and
after cytotoxic treatment of these conditions. It also occurs in patients with
condition such as AIDS and chronic granulomatous disease. At present, only
Amphoteracin B and itraconazole are available for treatment of aspergillosis.
Inspite of their activity in-vifro, the effect of these drugs in-vivo against
Aspergillus
fumigatus remains low and as a consequence mortality from invasive
aspergillosis remains high.
In addition, the emergence of fluconazo(e -resistant isolates of pathogenic
yeasts, particularly in HIV-positive patients, and the general nature of
treating
fungal infections caused by Aspergillus species, are of growing concerns among
infections disease specialists. The precise incidence of infections caused by
Aspergillus species is difFicult to determine due to lack of accurate,
reliable
diagnostic methodologies and poor diagnosis. The majority of Aspergillus
infections in AIDS patients occur in late stage disease when immune cell
functions are minimal. Impaired neutrophil and macrophage function is related
to
2

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
increased infection rates with Aspergillus species. The most common species of
Aspergillus causing disease in AIDS patients are A. fumigatus (83%), A. flavus
(9%), A. niger (5%) and A. terreus (3%).
Within the available drugs to treat fungal infections, the azole class
appears to be most promising. This class of compounds inhibits the
biosynthesis
of ergosterol in fungi, which is the main constituent of fungal cell membrane.
Of
the various representative antifungals, early azoles used were miconazole,
clotrimazole and tioconazole, which were potent against a wide range of fungi
pathogenic to human. However, their in-vitro activity was not well exhibited
in in-
vivo models due to poor oral bioavailability and metabolic vulnerability.
Ketoconazole was the first drug that could be used against systemic fungal
infection and successfully delivered through oral route. However, it was still
quite
susceptible to metabolic inactivation and also caused impotence and
gynacomastia probably due to its activity against human cytochrome P450
enzymes.
Fluconazole is the current drug of choice for treatment of severe infections
caused by Candida species and C. neoformans. However, fluconazole has only
weak activity against isolates of Aspergillus species [minimum inhibitory
concen-
tration (MIC) values of 400 ~.g/ml], since the drug has low potency (IC5o =
4.8 p,M)
against lanosterol 14a - demethylase, the target enzyme in the fungus.
Itraconazole, another triazole antifungal compound, generally is more active
than
fluconazole in the treatment of aspergillosis, but its activity in the clinic
remains
mixed as it showed variable oral availability, low solubility and caused
ovarian
cancer in animals. This may be due to its high protein binding properties.
3

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Thus, the antifungals available in the market suffer with drawbacks such
as, toxicity, narrow spectrum of activity and fungistatic profile rather
fungicidal.
Some of them also exhibit drug-drug interactions and, as a result, therapy
becomes very complex. In view of the high incidence of fungal infections in
immunocompromised patients and the recent trends for the steady increase of
the populations of such patients, demands for new antifungal agents with broad
spectrum of activity and good pharmacokinetic properties has increased. Thus,
the continuing demand for safe and effective broad spectrum antifungal agent
with favourable pharmacokinetic properties has spurred both the design and
development of new systemically active antifungal triazoles. The development
of
earlier compounds which were referred to as second generation triazoles and
which included SCH 39304 (Genaconazole), SCH42427 (Saperaconazole) and'
BAY R 8783 (Electrazole) had to be discontinued as a result of safety
concerns.
Another promising second generation triazole, D0870, a derivative of
fluconazole,
exhibited significant variations in plasma pharmacokinetics besides having
weak
antiaspergillus activity. Other fluconazole derivatives in different stages of
development include voriconazole and ER 30346 (BMS 207147). Voriconazole
also shows non-linear pharmacokinetics besides some concern regarding its
ocular toxicity, while ER 30346's anti-aspergillus activity, both in vitro and
in vivo,
is at best, only equal to itraconazole's activity. SCH 56592, is a
hydroxylated
analogue of itraconazole with potent in-vitro and in-vivo activity, but is
undetectable even when the serum drug concentration after several days of
treatment are 25 to 100 times above the MIC for the most resistant C.
neoformans. Thus, the potent activity of SCH 56592 for C.neoformans is
partially
negated by its low concentration at the site of infection to the central
nervous
4

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
system. The above azole candidates are discussed in the following
publications:
SCH 56592; Antimicrob. Agents Chemother, 40, 1910 (1996); 36t" Interscience
conference Antimicrob Agents Chemother, September, 1996, New Orleans, Abst.
F87-F102; TAK-187; 36t" Interscience conference Antimicrob Agents Chemother,
September, 1996, New Orleans, Abst. F74; EP 567892; ER-30346: Drugis of the
Future, 21, 20 (1996).
Various compounds having thiol, sulphone, sulphonamides, N-di-
substituted sulphonamides, triazoles and tetrazoles of the second asymmetric
centre of fluconazole with various side chains have been covered in U.S.
Patent
Nos. 5,466,820; 5,371,181 and 5,371,101 assigned to Takeda. But none of them
satisfies the above-described medical needs completely, either being weak in
spectrum, potency, safety or having undesired pharmacokinetics.
Despite the therapeutic success of fluconazole and itraconazole, there
remains a significant need for improved, broad spectrum, better tolerated,
less
toxic, .more potent antifungal compounds with minimal potential for
development
of resistance among target fungi.
SUMMARY OF THE INVENTION
The present invention relates to new substituted azole compounds which
can be utilized to treat and/or prevent the fungal infections in mammals,
preferably in humans.
5

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
The first aspect of the present invention provides compounds of Formula
IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites,
XI Y~
N
_.. IN Y- ~ ~ ~ Z
NJ
Xz Yz
FORMULA IA
wherein X is selected from the group consisting of CH2, CO, CS, S02 and
-N=N-;
R is selected from the group consisting of (1 ) C~-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C~-C4 alkoxy and
amino (2) C~-C4 alkoxy, (3) halogen (4) formyl, (5) carboxyl (6) C~-C4
acyloxy, (7) phenyl or substituted phenyl, (8) hydroxy, (9) vitro (10) amino
(11 ) furyl, (12) triazolyl, (13) thienyl, (14) piperazinyl (15) morpholinyl
(16)
thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl;
R~ and R2 are each independently (1 ) hydrogen, (2) C~-C4 alkyl group
which is unsubstituted or substituted by 1-3 substituents each
~ independently selected from the group consisting of halogen, hydroxy, C~-
C4 alkoxy and amino; (3) vitro, (4) amino (5) cyano, (6) carboxyl or
6

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
protected carboxyl (7) S02R' wherein R' is alkyl or aryl and (8) C~-C4
a I koxy;
Y is a phenyl group which is unsubstituted or substituted by substituents
each independently selected from the group consisting of (1 ) halogen (2)
nitro, (3) amino, (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy
(7) C~-C4 alkoxy and (8) S02R' wherein R' is hydrogen alkyl or aryl;
R3 is selected from the group consisting of C~-C4 alkyl group, halogen,
hydroxy, C~-C4 alkoxy, nitro, amino, cyano, carboxyl and S02R' wherein R'
is hydrogen, alkyl or aryl; and
X~, X2, Y~, Y2 and Z are independently selected from the group consisting
of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C~-C4
alkyl, C~-C4 alkoxy, carboxyl or protected carboxyl.
When R~ is other than hydrogen, Formula IA has two asymmetric centres
and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention
relates to the mixture of enantiomers as well as individual isomers and the
most
preferred isomer in this situation is RR.
According to the second aspect of the present invention, there are
provided compounds of Formula IB, and its pharmaceutically acceptable salts,
enantiomers, diastereomers, N-oxides, prodrugs or metabolites,
R3
~1V~ Y- ~~N ~
F ~ ~R
s

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
wherein X, R, R~, R2, Y and R3 are the same as defined earlier,
R4 is selected from the group consisting of hydrogen, C~-C4 alkyl group
which is unsubstituted or substituted, B is selected from oxygen and
sulphur atoms; and
R5 is selected from the group, (1 ) hydrogen, (2) C~-C4 alkyl group which is
unsubstituted or substituted by 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C~-C4 alkoxy and
amino (3) phenyl which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of (a)
C~-C4 alkyl which is unsubstituted or substituted with 1-3 substituted each
independently selected from the group consisting of halogen, hydroxy, C~-
C4 alkoxy and amino (b) C~-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl
(f) C~-C4 alkoxy (g) C~-C4 alkoxycarboxyl amino (h) phenyl or naphthyl
oxycarbonyl amino (i) semicarbazido (j) formamido (k) thioformamide (I)
hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl
(s)
imidazolyl (t) CF3 and (u) OCF3 (4) naphthyl or naphthyl (C~-C4 alkyl) which
may be substituted with 1-6 substituents selected from (a) C~-C5 alkyl
which is unsubstituted or substituted with 1-3 substituents each
independently selected from the group consisting of halogen, hydroxy, C~-
C4 alkoxy and amino (b) halogen, (c) (C~-C4 alkyl) halo (d) C~-C4 alkoxy (e)
8

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j)
tetrafluoroethyl (k) tetrafluoroethoxyl (I) tetrafluoropropyl and (m)
tetrafluoropropoxyl.
When R~ is other than hydrogen, Formula IA has two asymmetric centres
and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention
relates to the mixture of enantiomers as well as individual isomers and the
most
preferred isomer in this situation is RR.
According to the third aspect of the present invention there are provided
compounds of Formula II and its pharmaceutically acceptable salts,
enantiomers,
diastereomers, N-oxides, prodrugs or metabolites,
R1 B
Nw ~X O~
- N O-Y-N N~~
F ~ Rs
N /
R
FORMULA 1I
wherein X, R, R~, R4, R5, B and Y have the same meanings as defined
earlier.
When R~ is other than hydrogen, Formula II has two asymmetric centres
and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention
relates to the mixture of enantiomers as well as individual isomers and the
most
preferred isomer in this situation is RR.
9

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
The fourth aspect of the present invention provides compounds of Formula
III and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-
oxides, prodrugs or metabolites,
B
/' ~--~N\ RS
H H
N 3
R
FoRMUi~ ~
wherein X, R, R~, Y, B and R5 have the same meanings as defined above.
When R~ is other than hydrogen, Formula III has two asymmetric centres
and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention
relates to the mixture of enantiomers as well as individual isomers and the
most
preferred in this situation is RR.
Pharmaceutically acceptable, non-toxic, acid addition salts of the
compounds of the present invention of Formulae IA, 1 B, I I and I II may be
formed
with inorganic or organic acids, by methods well known in the art.
It is further object of the invention to provide compositions containing the
novel compounds of the present invention in the treatment of fungal
infections.
The present invention also includes within its scope prodrugs of the
compounds of Formulae lA, IB, ll and III. In general, such prodrugs will be
functional derivatives of these compounds which readily get converted in vivo
into

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
defined compounds. Conventional procedures for the selection and preparation
of suitable prodrugs are known.
The invention also includes pharmaceutically acceptable salts, enantio-
mers, diastereomers, N-oxides, prodrugs, metabolites of the above formulae in
combination with pharmaceutically acceptable carriers and optional excipients.
Other advantages of the invention will be set forth in the description which
follows, and in part will be apparent from the description, or may be learned
by
the practice of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In order to achieve the above mentioned aspects and in accordance with
the purpose of the invention as embodied and described herein, there are
provided processes for the syntheses of compounds of Formulae IA,1 B, II and
III,
wherein R, R~, R2, R3, R4, R5,X, Y, X~, Y~, , X2 ,Y2 , Z and B are the same as
defined earlier. The compounds of Formulae IA,1 B, II and III of the present
invention may be prepared by following the reaction sequences as depicted
below in schemes IA, IB to IX.
11

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME IA
0
Rt Xw ~ N Yt Xt ~ O iH
~--N
F N~ Z ~ ~ N N-Z' N ~ N
~,
yz Xz Rz
R
FORMULA V
FORMULA IV
NaH
Xt Yi
N-Y- ~ ~ ~ Z
\ Rz Xz y2
R
FORMULA IA
In Scheme IA there is provided a process for preparing a compound of
Formula IA, as shown above, wherein
X is selected from the group consisting CH2, CO, CS, S02 and -N=N-,
R is selected from the group consisting of (1 ) C~-C4 alkyl which is
unsubstituted or substituted with 1-3 substituents each independently
selected from the group consisting of halogen, hydroxy, C~-C4 alkoxy and
amino (2) C~-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C~-C4
acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino
12

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
(11 ) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16)
thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl,
R~ and R2 are each independently selected from the group consisting of (1 )
hydrogen, (2) C~-C4 alkyl group which is unsubstituted or substituted by 1-
3 substituents each independently selected from the group consisting of
halogen, hydroxy, C~-C4 alkoxy and amino (3) vitro (4) amino (5) cyano (6)
carboxyl or protected carboxyl (7) S02R' wherein R' is hydrogen, alkyl or
aryl and (8) C~-C4 alkoxy, Y is a phenyl group which is unsubstituted or
substituted by substituents each independently selected from the group
consisting of (1 ) halogen (2) vitro (3) amino (4) cyano (5) carboxyl or
protected carboxyl (6) hydroxy (7) C~-C4 alkoxy and (8) S02R' wherein R'
is hydrogen, alkyl or aryl,
R3 is selected from the group consisting of C~-C4 alkyl group, halogen,
hydroxy, C~-C4 alkoxy, vitro, amino, cyano, carboxyl and S02R' wherein R'
is hydrogen, alkyl or aryl; and
X~, X2, Y~, Y2 and Z are independently selected from the group consisting
of halogen, vitro, cyano, amino, sulphonyl, aryl or substituted aryl C~-C4
alkyl, C~-C4 alkoxy, carboxyl or protected carboxyl.
Also, when R~ is other than hydrogen, Formula I has two asymmetric
centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this
invention relates to the mixture of enantiomers as well as individual isomers
and
the most preferred isomer in this situation is RR, which comprises reacting 1-
[2-
(2,4-disubstituted phenyl)-2,3-epoxy derivative of 1,2,4-triazole of Formula
IV,
wherein X, R and R~, are the same as defined above, with triazol-3-one
13

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
derivatives of Formula V, wherein R2,, R3, X~, X2, Y, Y~, Y2 and Z have the
same
meanings, as defined above, in the presence of sodium hydride to afford the
desired compound of Formula IA, wherein X, X~,X~, Y~, Y2, Z, R, R~, R2 and R3
have the same meanings as defined above.
SCHEME IB
R3
Y-N NH
FORMULA ID
B=C=N-R s
R3 B
/~~ \ ~ H
s ~N N-Y- ~~N
_J , U ~R
s
~R
2
FORMULA IC
RaZ
~ B
Y-N ~N~
Rs
R
FORMULA IB
14

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
In Scheme IB there is provided a process for preparing a compound of
Formula IB, wherein X, R, R~, R2 ,R~ and Y are the same as defined above, R4
is
selected from the group hydrogen, C~ - C4 alkyl group which is unsubstituted
or
substituted, B is selected from oxygen and sulphur atoms, R5 is selected from
the
group (1 ) hydrogen, (2) C~- C4 alkyl group which is unsubstituted or
substituted
by 1-3 substituents each independently selected from the group consisting of
halogen, hydroxy, C~-C4 alkoxy and amino, (3) phenyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of (a) C~-C4 alkyl which is unsubstituted or substituted with 1-3
substituents each independently selected from the group consisting of halogen,
hydroxy, C~-C4 alkoxy and amino (b) C~-C4 alkoxy, (c) halogen, (d) formyl (e)
carboxyl (f) C~-C4 acyloxy (g) C~-C4 alkoxycarbonyl amino (h) phenyl or
naphthyl-
oxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (I)
hydroxy
(m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl(r) oxazolyl (s)
imidazolyl (t) CF2
and (u) OCF3 (4) naphthyl or naphthyl (C~-C4 alkyl) which may be substituted
with
1-6 substituents selected from (a) C~ - C5 alkyl which is unsubstituted or
substituted with 1-3 substituents each independently selected from the group
consisting of halogen, hydroxy, C~-C4 alkoxy and amino, (b) halogen (c) (C~-C4
alkyl) halo, (d) C~-C4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h)
trifluoromethoxyl
(i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (I)
tetrafluoropropyl and
(m) tetrafluoropropoxyl.
Also, when R~ is other than hydrogen, Formula I has two asymmetric
centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this
invention relates to the mixture of enantiomers as well as individual isomers
and

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
the most preferred isomer in this situation is RR, which comprises reacting a
compound of Formula ID wherein X, R, R~,R~, R3 and Y have the same meanings
as defined earlier, with a compound of Formula R5 - N = C = B wherein R5 and B
are the same as defined earlier to give a compound of Formula IC, which on
reaction with R4Z wherein R4 is the same as defined above and Z is any halogen
atom, gives a compound of Formula IB wherein X, R, R~, R2, R3, R4, R5, Y and B
have the same meanings as defined earlier.
SCHEME II
~ X, Y'
Y-N N ~ ~ Z
F
Xz Y2
Fo~ur~ m
1 ~~J
Xl YI
~NwN~ Y- ~ ~ ~ Z
N~ F
X2 Y2
Fo~m.a r~
In Scheme II, there is provided a process for preparing a compound of
Formula IA, wherein X, R, R~, R2, R3, Y, X~, X2, Y~, Y2 and Z are the same as
defined above, also when R~ is other than hydrogen, Formula I has two
16

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
asymmertric centres and there are four possible enantiomers i.e. RR, RS, SR
and SS, this invention relates to the mixture of enantiomers as well as
individual
isomers and the most preferred isomer in this situation is RR, which comprises
reacting epoxide derivative of Formula VI, wherein X, R, R~, R2, R3, X~, X2,
Y, Y~,
Y2 and Z are the same as defined above with 1,2,4-triazole to afford a
compound
of Formula IA.
SCHEME III
OH RI
/ \N/x O-Y ~ fi
F
FORMULA ViI
R
Rs-N--C=B
OH R~ B
~~~Rs
lei' H
F
\
R FORMULA VIII
R4Z
B
/ O-Z'- ~~N~Rs
FORMULA II
17

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
There is provided a process for preparing a compound of Formula II,
wherein X, R, R~, R4, R5, Y and B have the same meanings as defined earlier,
also when R~ is other than hydrogen, Formula II has two asymmetric centres and
there are four possible enantiomers i.e. RR, RS, SR and SS, this invention
relates to the mixture of enantiomers as well as individual isomers and the
most
preferred isomer in this situation is RR, which comprises reacting a compound
of
Formula VII, wherein R, R~, X and Y are same as defined earlier with a
compound R5-N=C=B, wherein R5 and B are the same defined earlier to give a
compound of Formula VIII, wherein R, R~, R5, X, Y and B have the same
meanings as defined earlier. The compound of Formula VIII, on reaction with
R4Z, wherein R4 is C~-C4 alkyl and Z is any halogen atom, gives a compound of
Formula II, wherein R, R~, R4, R5, X, Y and B are the same as defined earlier.
SCHEME IV
~N~ ~X
I~ ~ I~
F~
R
FORMULA IX
B~~Rs
N~ ~X ~R~
.- F ~~H ~H
R
FORMULA III
18

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
In scheme IV there is provided a process for the preparation of a
compound of Formula III, wherein R, R~, R5, X, Y and B are the same as defined
above, also when R~ is other than hydrogen, Formula III has two asymmetric
centres and there are four possible enantiomers i.e. RR, RS, SR and SS , this
invention relates to the mixture of enantiomers as well as individual isomers
and
the most preferred isomer in this situation is RR, which comprises reacting a
compound of Formula IX with a compound of Formula B=C=N-R5 wherein B and
R5 are the same as defined earlier, to give the desired compound of Formula
III.
19

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME V
F
O CI O N N
Cl A2~3 ~N
+ Cl~ ~ / F 1,2,4-Triawle F TMSI
\ /
O
\ \
F
~J F F
FORMULA X FORMULA XI FORMULA XII FORMULA XIII FORMULA N
(R--F, X--CHz, Rt=H)
Yi XI Y~ Xt
CI ~ ~ NOp
Z ~ ~ Z ~ ~ ~ ~ ~ NOz Reduction
KzCOc
Yz ?Cz Y2 Xz
FORMULA XIV FORMULA XV
y1 XI Yt Xt O
O ~ NHZNHZ . H20
Z ~ ~ ~ ~ ~ ~z CI~ Z ~ ~ T ~ ~ ~ ~ OPiW
yz Xz yz Xz
FORMULA XVI FORMULA XVII
15 yt Xt O R C~rrH ~ ~H
z ~ N
NHz Z ~ ~ ~ -IL-N I
Z ~ ~ N N ~ ~ NH NHNHz ~ / N
U
Y X~ Yz Xz Rz
FORMULA XVIII FORMULA V (R3=H, Y--C6Hq-)
20 X N y Xt ~ O H
Rt w ~N + Z ~ ~ ~ -Y- ~ N
Yz - Xz
R FORMULA V (R3=H, Y=C6Hq )
FORMULA N
(R--F, Rt=H, X=CH,) NaH I'1
XI ~ Z
25 R3 ~ ~ Y
z
NJ Xz
so
(X=CH 2, R--F, R ,=H, Y--C sHd-, R3=I~

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
In Scheme V 1,3-difluorobenzene of Formula X, on treatment with
chloroacetyl chloride of Formula XI, in the presence of a Lewis acid catalyst
such
as aluminium trichloride gives a-choro-2, 4-difluoroacetophenone of Formula
Xll.
This compound of Formula XIl is further reacted with 1,2,4-triazole to obtain
2-
(1 H-1,2,4-triazol-1-yl)-2'-4'-difluoroacetophenone of Formula XIII. This
compound of Formula XIII is further reacted with trimethyl sulphoxonium iodide
(TMSI) to afford 1-[2-(2,4-difluorophenyl)-2, 3-epoxypropyl]-1H-1,2,4-triazole
of
Formula IV (R=F, X=CH2, R~=H). The procedure as described in US Patent
4,404,216 is followed to prepare compound of Formula IV.
The triazol-3-one derivatives of Formula V (R3 = H, Y=C6 H4 -), wherein R2,
X~, X2, Y~ , Y2 and Z are the same as defined earlier, are prepared by
reacting
substituted phenyl piperazine of Formula XIV, wherein X~, X2, Y~, Y2 and Z are
the same as defined earlier, is reacted with 4-chforonitrobenzene to give the
corresponding nitroaryl compound of Formula XV, which on catalytic reduction
affords the anilino derivative of Formula XVI. The compound of Formula XVI, is
acylated with phenyl chloroformate to afford phenyl carbamate derivatives of
Formula XVII. Reaction of these carbamate derivative of Formula XVII, with
hydrazine hydrate yields semicarbazide derivative of Formula XVIII, which on
cyclization with formamidine derivatives gives the triazol-3-one derivatives
of
Formula V(R3 = H, Y=C6 H4 -). The reaction of compound of Formula V, with the
compound of Formula IV (R=F, R~=H, X=CH2) is carried out in the presence of
sodium hydride to afford the desired compound of Formula IA (X=CH2, R=F,
R~=H, Y=C6H4-, R3=H), wherein R2, X~, X2, Y~, Y2 and Z are the same as defined
earlier.
21

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME VI
F ~ CH3 Yi x, R3 0I1
AICI3 ~ * Z ~ ~ N N-1'-N~NH
+ H3 COCI ~ ~ ~ ~--i '
\ Yp ~ Rz
F
FORMULA V
F \ (R3 = H> ~'= CsHa )
FORMULA X FORMULA XIX
NaH
F
FORMULA XX
Xt Yt
~ /
F
XZ y2
......_..Y.. ... ~
xt Ii
Y ~ / \
xZ .Y
Z
FORMULA VI ( X CHZ, R--F, R,=CH3, Y--C~H4 , R3=H)
N~ R3 Xt Yt
N
N Y-N N / \ Z
Xz y2
FORMULA IA
(X CH z; R--F, R , = CH 3> Y-- C 6Hd-, R3=H)
The compounds of Formula IA (X=CHI, R=F, R~= CH3, Y=C6H4-, R3=H)
wherein R2, X~, Y~,X2, Y2 and Z have the same meanings as defined earlier, are
synthesized following the reaction sequence embodied in Scheme VI. Thus, 1, 3-
difiuorobenzene of Formula X is reacted with racemic (~) 2-chioropropionyl
22

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
chloride of Formula XIX to give a compound (~) 2-chloro-2-methyl-2', 4'-
difluoro-
acetophenone of Formula XX. The intermediate of Formula V which in turn is
prepared by following the reaction sequence as described in Scheme V wherein
R2, X~, X2, Y~, Y2 and Z have the same usual meanings, is condensed with (~)2-
chloro-2-methyl-2', 4'-difluoroacetophenone of Formula XX in the presence of
sodium hydride to afford compound of Formula XXI, wherein R2, X~, X2, Y~,Y~
and
Z have the same meanings as defined earlier. The compound of Formula XXI is
epoxidized with trimethylsulphoxonium iodide (TMSI) in dimethylsulfoxide
(DMSO) to give an epoxide derivative of Formula VI (X=CH2, R=F, R~=CH3,
Y=C6H4-, R3=H), which is then condensed with 1,2,4-triazole to give a compound
of Formula IA (X=CH2, R=F, R~= CH3, Y=C6H4-, R3=H), wherein R~, X~, Y~, X2, Y2
and Z are the same as defined earlier.
23

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME VII
_~_
Y ~N H
B=C=N-R s
FORMULA VII (X=CH2, R--F, Rl=H, Y--C6H4 ) _
B
1 0 ~y ~ -I~ i -RS NaH
H Ra Z
FORMULA VIII (X--CH2, R--F, Rl=H, Y--C6H4 )
/~ II
Y- ~ -C- I -Rs
FORMULA II (X=CH2, R=F, Rl=H, Y--C6H4 )
The compounds of Formula II (X=CH2, R=F, R~=H, Y=C6H4-) wherein R4,
R5, and B have the same meanings as defined earlier, are synthesized by
following the reaction sequence as depicted above in Scheme VII. Thus, 2-(2,4-
difluorophenyl)-3-(1H-1, 2,4-triazolyl)-1-[4-(piprazinyl) phenoxy]-propan-2-of
of
Formula VII (X=CH2, R=F, R~=H, Y=C6H4-) (prepared by the process as disclosed
in US Patent No. 5,023,258, assigned to Pfizer) on treatment with the compound
of Formula B=C=N-R5, wherein B and R5 are. the same as defined earlier gives a
compound of Formula VIII (X=CH2, R=F, R~=H, Y=C6H4-) wherein R5 and B are
24

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
the same as defined earlier. This compound of Formula VIII (X=CH2, R=F, R~=H,
Y=C6H4-) is further reacted with R4Z in the presence of sodium hydride gives
the
required compound of Formula II (X=CH2, R=F, R~=H, Y=C6H4-), wherein R4, R5
and B are the same as defined earlier.

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME VIII
CH3
O O
CI ~ ~ K=CO,/DMF
+ HO O N N' _CH3 +
60°C
F FORMULA X3QII
FORMULA XHII
O
CH3 O ~N~CH3
O ~ ~~ ~CHs)a SOI
O U ~3 DMSO~
F
FORMULA XXIV FORMULA XXV
'~~ ~ / \~ NaOHlDioxane-Hz0
~lN~ / NaH 7 DMF N~ ~ ~3
~N ~ F
FORMULA XXVI
~~.
XJ O-Y ~ -H Rs - N=C=B
F
0
R FORMULA VII (X=CH2, R=F, Ri=CH3, Y=C6Ha')
B
,Y- ~~ i -RS
FORMULA II (X=CH2, R=F, R~=CH3, RQ=H, Y--C6H4- )
In Scheme VIII, 2-chloro-methyl-2',4'-difluoroacetophenone of Formula
XXII, on treatment with 1-acetyl-4-hydroxyphenylpiperazine of Formula XXIII,
26

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
gives 2-[4-(4-acetylpiperazine)phenoxy]-2-methyl-2',4'-difluoroacetophenone of
,
Formula XXIV in the presence of potassium carbonate in dimethylformamide,
which on treatment with trimethyl sulphoxonium iodide (TMSI) in DMSO gives the
corresponding epoxide of Formula XXV. This compound of Formula XXV is
reacted with 1,2,4-triazole to yield a compound of Formula XXVI, which in turn
on
hydrolysis with sodium hydroxide in dioxane gives a compound of Formula VII
(X=CH2, R=F, R~=CH3, Y=C6H4-). The compound of Formula VII on reaction with
R5-N=C=B gives a compound of Formula II (X=CH2, R=F, R~=CH3, R4=H)
wherein R5 and B have the same meanings as defined earlier.
27

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
SCHEME IX
Pd(C)
~ NOZ
H i 1--( ( ) r--NO., Na~ HCOONHq
~+
~ 80°C
3
FORMULA IV FORMULA XXVII FORMULA XXVIII
(R--F, X=CH2, R~=H)
~H B=C=N-R s
3
FORMULA IX (X=CH~, R--F, Rl=H, Y--C6Hq-)
B
I I
t-N-C-N-RS
H I
H
FORMULA III (X--CH2, R--F, R~=H, Y--C6H4 )
In Scheme IX 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole
of Formula IV (R=F, X=CH2, R~=H) on treatment with N-methyl-4-nitroaniline of
Formula XXVII gives 3-[N-Methyl-N-(4-nitrophenyl)]-2-(2,4-difluorophenyl)-1-(1
H-
1,2,4-triazolyl)-propan-3-amino-2-of of Formula XXVIII which on reduction with
palladium on charcoal gives 3-[N-Methyl-N-(4-aminophenyl)]-2-(2,4-difluoro
phenyl)-1-(1 H-1,2,4-triazolyl)-propane-3-amino-2-of of Formula IX, (X=CH2,
R=F,
R~=H, Y=C6H4-) which on reaction with B=C=N-R5 gives a compound of Formula
III (X=CH2, R=F, R~=H, Y=C6H4-) wherein B and R5 are the same as defined
earlier.
28

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
In the above schemes where specific acids, bases, solvents, catalysts,
oxidising agents, reducing agents etc. are mentioned, it is to be understood
that
the other acids, bases, solvents, catalysts, oxidising agents, reducing agents
etc.
may be used. Similarly, the reaction temperature and duration of the reaction
may be adjusted according to the need.
An illustrative list of particular compounds according to the invention and
capable of being produced by Schemes IA, IB to IX include:
Compound
No. Chemical Name
1. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-~4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
2. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
3. 2-([1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-yl)
propyl}-4-~4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
4. 2-~[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-
y1) propyl}-4-(4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
5. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4-triazolone
6. 2-~[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(1-phenylpiperazinyl) phenyl}-3-(2H,4H)-1,2,4-triazolone
7. 2-{[1 R2R/1 S2S]-2-(2,4-Difl uorophenyl )-2-hydroxy-1-methyl-3-( 1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
8. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
29

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
9. 2-f [1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-
triazolone
10. 2-{[1 R2S11 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-
triazolone
11. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1
yl) propyl}-4-f4-[4-(4-fluorophenyl)-1-piperazinyi]phenyl}-3-(2H,4H)-1,2,4
triazolone
12. 2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
13. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
14. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-f4-[4-(4-methoxyphenyi)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
15. 2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-
triazolone
16. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-
triazolone
17. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-~4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone
18. 2-{[1 R2S11 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone
19. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-( 1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
20. 2-{[1 R2S11 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
21. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hyd roxy-1-methyl-3-( 1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone
22. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hyd roxy-1-methyl-3-( 1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone
23. 2-{[1 R2R11 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
24. 2-{[1R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
25. 2-{[1 R2R11 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-5-methyl-
1,2,4-triazolone
26. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-
1,2,4-triazolone
27. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl~-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
5-
methyl-1,2,4-triazolone
28. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl~-4-{4-[4-(2-methoxy-5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
5-
methyl-1,2,4-triazolone
29. 2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
30. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl~-4-{4-[4-(3,5-dichlorophenyl)-1-piperaziny!]phenyl-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
31. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-
1,2,4-
triazolone
32. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-
1,2,4-
triazolone
31

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
33. 2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
34. 2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1=methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2,4-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-
methyl-
1,2,4-triazolone
35. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
36. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
37. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3,4-
dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
38. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2,4-
diaminophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
39. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
40. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2,4-
dinitrophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
41. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
42. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
43. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
44. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
hydroxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
45. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-[4-
[1-
phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
46. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
47. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
48. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(5-
chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
49. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3-
chloro-4-methylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
32

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
50. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2,4-
dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
51. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3
trifluoromethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
52. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2,4
difiuorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazoione
53. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3
chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
54. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(2,4-
dimethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
55. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3,4-
difluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
56. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(3,4-
dimethylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
57. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(3-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
58. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(2-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
59. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4- (2-
methoxy-5-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
60. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(2-ethylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
61. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(3,5-dichlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
62. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(2-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
63. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-
{4-[4-(2,3;4-trifluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
64. 3-{4-[4-(p-Tolylthioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1 H-1,2,4
triazol-1-yl)-propan-2-ol.
65. 3-{4-[4-(Isopropylaminothiocarbonylamino)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
66. 3-{4-[4-(4-Chlorophenylthioureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-
(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
67. 3-{4-[4-(4-Chlorophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-
1-(1 H-
1,2,4-triazol-1-yl)-propan-2-ol.
33

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
68. 3-{4-(4-(1-Napthylthioureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazol-1-yl)-propan-2-ol.
69. 3-{4-[4-( 1-Napthylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-(
1 H-1,2,4-
triazol-1-yl)-propan-2-ol.
70. 3-{4-[4-(4-Trifluoromethylphenyl thioureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
71. 3-{4-[4-(4-Methoxyphenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-
1-
(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
72. 3-{4-[4-(2,4-Dichlorophenylureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-
(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
73. 3-{4-[4-(4-Chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazolyl)-propan-3-amino-2-of
74. 3-{4-[4-(4-Chlorophenyl-N-ethylureido)-piperazinyl ]-phenoxy)-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazolyl)-2-ethoxy-3-propane.
75. 3-{4-[4-N-(4-Chlorophenyl)-N-(methylureido)-piperazinyl]-phenoxy}-2-(2,4-
difluorophenyl)-1-( 1 H-1,2,4-triazolyl)-2-methoxypropane.
76. 3-{4-[4-(4-Aminophenylureido)piperazinyl]phenoxy}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazol-1-yl)-propan-2-ol.
77. [1 R2R/1 S2S] 1-{4-(4-(4-Chlorophenylureido)-piperazinyl ]-phenoxy}-2-(2,4-
difluorophenyl)-1-methyl -3-(1H-1,2,4-triazolyl)-propan-2-of
78. [1 R2S/1 S2R] 1-{4-[4-(4-Chlorophenylureido)-piperazinyl ]-phenoxy}2-(2,4-
difluorophenyl)-1-methyl -3-(1 H-1,2,4-triazolyl)-propan-2-of
79. 1-{4-[4-(4-Trifluoromethylphenylureido)piperazinyl]phenoxy}-2-(2,4-
difluorophenyl)-1-methyl-3-(1 H-1,2,4-triazol-1-yl)-propan-2-ol.
80. 3-{4-[4-(Phenylureido)-piperazinyl ]-phenoxy}-2-(2,4-difluorophenyl)-1-(1H-
1,2,4-
triazol-1-yl)-propan-2-ol.
81. 3-{N-[4-(Phenylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-(1
H-1,2,4-
triazolyl)-propan-3-amino-2-of
82. 3-{N-[4-(Isopropylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazolyl)-propan-3-amino-2-of
83. 3-{N-[4-(p-Tolylthioureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-(1
H-1,2,4-
triazolyl)-propan-3-amino-2-of
84. 3-{N-[4-(p-Fluorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazolyl)-propan-3-amino-2-of
85. 3-{N-[4-(p-Nitrophenyltureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazolyl)-propan-3-amino-2-of
34

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
86. 3-(N-[4-(p-Chlorophenylureido)-phenyl]- N-methyl}-2-(2,4-difluorophenyl)-1-
(1 H-
1,2,4-triazolyl)-propan-3-amino-2-of
87. 3-{N-[4-(Carboxymethyl)-phenyltureido)-phenyl]- N-methyl-2-(2,4-
difluorophenyl)-
1-( 1 H-1,2,4-triazolyl)-propan-3-ami no-2-of
88. 3-(N-[4-(2-Methoxy-2-oxoethyl)-phenyltureido)-phenyl]- N-methyl}-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazolyl)-propan-3-amino-2-of
89. 3-~N-[4-(p-Chlorophenylthiouredo)-phenyltureido)-phenyl]- N-methyl}-2-(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazolyl)-propan-3-amino-2-of
90. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-
(isopropylthiouredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
91. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-(4-
[4-(4
chlorophenyluredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
92. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-(4-
[4-(4-
chlorophenylthiouredio)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
93. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-f4-
[4-(4-(2-
methoxy-2-oxoethyl)phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
94. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-(4-
[4-(4
(carboxyethyl)-phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
95. 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-
[4-(4-(2-
hydroxyethyl)phenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
Preferred group of compounds belonging to the compounds of Formulae
IA, IB, II and III of the present invention are exemplified in Table I to
Table IV
though the present invention is not limited to the compounds given there.

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
TABLE I FORMULA IA (X=CH2, R=F, Y=C6H4-, R3=H)
A. LIST OF a-METHYL ANALOGUES
Compound R~ R2 X~ Y~ Z Y2 X2 Comments m.p
No. * (~C)
1 CH3 H H H CI H H RR, SS 192-196
2 CH3 H H H CI H H (RS, SR) 220-222
3 CH3 H N02 H N02 H H (RR, SS) 155-160
4 CH3 H N02 H N02 H H (RS, SR) 153-155
CH3 H H H H H H RR, SS 212-214
6 CH3 H H H H H H (RS, SR 205-207
7 CH3 H H CI CI H H RR, SS 102-105
8 CH3 H H CI CI H H RS, SR 233-240
9 CH3 H H CF3H H H (RR, SS) 182-186
CH3 H H CF3H H H (RS, SR) 170-172
11 CH3 H H H F H H RR, SS 174-177
12 CH3 H H H F H H RS, SR 218-219
13 CH3 H H H oCH3 H H RR, SS 180-185
14 CH3 H H H oCH3 H H RS, SR 106-111
CH3 H H CI F H H RR, SS 148-150
16 CH3 H H CI F H H RS, SR 194-197
17 CH3 H H CI CH3 H H (RR, SS 156-158
18 CH3 H H CI CH3 H H RS, SR 148-150
19 CH3 H CH3 H CH3 H H RR, SS 201-202
CH3 H CH3 H CH3 H H RS, SR 92-94
21 CH3 H CH3 H H CI H RR, SS Foam
22 CH3 H CH3 H H CI H RS, SR Foam
23 CH3 H H CH3CH3 H H RR, SS Gummy
24 CH3 H H CH3CH3 H H RS, SR Gumm
CH3 H F H H H H RR, SS Gumm
26 CH3 H F H H H H RS, SR 179-181
27 CH3 H oCH3 H H F H RR, SS 83-85
28 CH3 H oCH3 H H F H RS, SR 90-93
29 CH3 H H CI H CI H RR, SS 188-191
CH3 H H CI H CI H RS, SR 207-210
31 CH3 H C2H5 H H H H RR, SS 142-145
32 CH3 H C2H5 H H H H RS, SR 177-178
33 CH3 H CI H CI H H RR, SS Foam
34 CH3 H CI H CI H H RS, SR Foam
36

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
B. LIST OF non- a-METHYL ANALOGUES
Compound R~ [~2 ~(~ y~ Z, y2 X~ m.p
No. ~C
35 H CH3 ocH3 H H H H 144-149
36 H CH3 H H F H H 188-189
37 H H H CI CI H H 194-196
38 H H N H N H H 215-222
Hz Hz
39 H H H H CH3 H H 146-148
40 H H N02 H N02 H H 120-123
41 H H H H oCH3 H H 183-186
42 H H ocH3 H H H H 95-97
43 H H H H F H H 173-177
44 H H H H OH H H 246-248
45 H H H H H H H 170-172
46 H CH3 H H CI H H 88-94
47 H H H H CI H H 207-208
48 H H CH3 H H CI H 82-87
49 H H H H CH3 CI H 189-201
50 H H CI H CI H H 97-99
51 H H H CF3H H H 166-168
52 H H F H F H H 157-158
53 H H H CI F H H 182-85
54 H H CH3 H CH3 H H 76-77
55 H H H F F H H 117-118
56 H H H CH3CH3 H H 136-137
57 H H H CI H H H 177-78
58 H H CI H F H H Oil
59 H H ocH3 H H F H Gummy
~60 H H C2H5 H H H H 148-150
61 H H H CI H CI H 222-225
62 H H F H H H H 74-76
63 H H ~ F F H H 186-187
F
37

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
TABLE - II (FORMULA II)
(X = CH2, R= F, Y= CgHq,-)
Compound R4 B R1 Rq. R5 m,p.oC MIC
No. (ug/ml)
(A.fmnigatus
s 1008)
64 H S H H ~ 192-1943.12
~ I
65 H S H H 75-78 >12.5
-CH(CH3)z
66 H S H H ~ ~ Ci 138 >12.5
67 H O H H 136-1376.25
v i
68 H S H H ~ , 109-111>12.5
69 H O H H . ~ 138-139>12.5
70 H S H H 150-151>12.5
~F
71 H O H H Gummy > 12.5
~,
72 H O H H .-~ ~I Gummy >12.5
CI
73 H O H C2H5~-~ ~, Gummy >12.5
74 C2H5 O H C2H5~-~ ~, Gummy >12.5
75 CH3 O H CH3 \ ~ ~~ Gummy >12.5
76 H O H H ~ ~ N,~ Gummy > I 2. 5
77 H O CH3 H ~~~ 106-1082
w
78 H O CH3 H ~~ 105-1070.5
~i
79 H O CH3 H ~ , Gummy 8
CFA
80 H S H H ~ 154-156>12.5
~i
38

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
TABLE - III (FORMULA III)
(X = CH2, R= F, Y= CgHq.-)
Compound B R1 RS m,p,oC MIC (ug/ml)
No. (A. unzigatus s
1008)
81 S H ~ 147-150 >12.5
~i
82 S H -CH(CH3)Z 76 >12.5
83 S H ~ 174 >12.5
Ha
84 O H ~F 160-164 >12.5
w
85 O H ~ 87-88 >12.5
~ NOi
86 O H ~ 174-176 >12.5
~ Ci
87 O H Gummy >12.5
CHiCOOH
88 O H Gummy >12.5
CHiCOOCH
89 S H ~ ~ C, 162-164 >12.5
TABLE - IV (FORMULA IB)
(X = CH2, R= F, Y= C6Hq,-, R~, R2, R3 and Rq,=H)
Compoun B RI RS m,p,oC MIC (ug/ml)
d No. (A. unzigatus
s 1008)
90 S H -CH(CH3)Z Gummy >12.5
solid
91 O H ~ ~ C, 149-153 >12.5
92 S H ~ ~ ~, 142-144 >12.5
93 O H ~ , CH~COOC~,66-69 >12.5
94 O H _ 235-239 >12.5
CHiCOOH
95 O H ~ ~ CH~.CH~.OH114-115 >12.5
39

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
All compounds mentioned in the above list as well as the compounds
mentioned in formulae IA, IB, II and III with a variety of substituents were
prepared using the methods described earlier depending upon whether they are
mixtures of a-methylated isomers, mixtures of non a-methylated isomers or pure
RR isomers.
The examples mentioned below demonstrate the general synthetic
procedure as well as the specific preparation for the preferred compound. The
examples are given to illustrate the details of the invention and should not
be
constrained to limit the scope of the present invention.
Most of the compounds were characterized using NMR, IR and were
purified by chromatography. Crude products were subjected to column
chromatographic purification using silica gel (100 -200 or 60-120 mesh) as
stationary phase.
EXAMPLE 1
Preparation of 2-~2-[(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-
yl)propyl]~-4-~[4-[4-(substituted/unsubstituted phenyl)-1-
piperazinyl]phenyl]~-3-(2H, 4H)-1,2,-substituted triazol-4-one.
Step 1: Preparation of 2-chloro-2', 4'-difluoro acetophenone.
Into the solution of 1,3-difluorobenzene in 1,2-dicholoroethane (DCE) was
added anhydrous aluminium chloride (1.2 molar equivalent of 1,3-
difluorobenzene) at 25-30°C and stirred for 30 minutes. The reaction
mixture was
then cooled to 0°C and chloroacetyl chloride (1.1 molar equivalent of
1,3-

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
difluorobenzene), in DCE, was then added into it over a period of 30-60 min
keeping the reaction temperature below 20°C. After the addition was
over, the
reaction mixture was stirred at 25-30°C for 5-7 hours. The reaction
mixture was
then diluted with DCE and poured into dil. hydrochloric acid (5%) at 0-
5°C. The
mixture was then extracted with DCE. The combined organic layer was washed
successively with 5% aq. sodium bicarbonate solution and water. Evaporating
DCE from the organic layer under reduced pressure gave an oil which on
triturating with n-Hexane gave the title compound as white crystalline
material
(Yield 75% of theory).
Step 2: Preparation of 2-(1 H,2,4-triazol-1-yl)-2',4'-difiuoro acetophenone
The product obtained in Step -1 was reacted with 1,2,4-triazole (1.2 molar
equivalent) in the presence of sodium bicarbonate as base and toluene as
solvent under refluxing condition. After the reaction was over, the reaction
mixture was poured into crushed ice and extracted with toluene. The combined
organic layer was then washed with water and concentrated under reduced
pressure to give brown semisolid compound which was recrystallized from ethyl
acetate - hexane mixture to give light yellow solid compound which was then
used as such in the next step.
Step 3: Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropylj-1H-1,2,4-
triazole
Step 2 product was dissolved in toluene, followed by the addition of
trimethylsulfoxonium iodide (TMSI), cetramide and 20% aq. sodium hydroxide
solution. This mixture was then heated at 60° C for 4 hrs. After the
reaction was
41

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
over, it was diluted with toluene and poured into chilled water. The organic
layer
was washed with water and concentrated under reduced pressure to give light
brown oil which was used after column chromatographic purification (silica
gel) in
the next step.
Step 4: Preparation of 1-(substituted phenyl)-4-(4-nitrophenyi) piperazine.
Substituted phenyl piperazine was reacted with 4-chloronitrobenzene (1.1
molar equivalent of phenyl piperazine) in dimethylsulphoxide [DMSO] (5 times)
using anhydrous potassium carbonate (1.5 molar equivalent) at a temperature
135-1400 C for 6 to 8 hrs. The reaction mixture was poured into crushed ice
and
the compound was isolated either as a solid or by extracting with chlorinated
organic solvent. After drying under vacuum at 30-35°C for 6-8 hrs, the
compound
was used as such for next step.
Step 5: Preparation of 1-(substituted phenyl)-4-(4-aminophenyl)piperazine
The nitro compound was then reduced to amine by two methods:
Method 1: The compound of Step 4 was dissolved in methanol and
Palladium on charcoal (wet, 10% w/w) was added under nitrogen followed by the
addition of ammonium formate (5 molar equivalent). The reaction mixture was
then stirred at a temperature ranging from 45 to 70 oC until the reaction went
to
completion. After the reaction was over, the reaction mixture was then cooled
to
25-30°C and filtered. The filtrate was then concentrated under reduced
pressure
to give a residue which was again dissolved in dichloroethane and washed with
water. The organic layer on concentration gave the desired product.
42

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Method 2: The compound of Step 4 was refluxed in ethyl acetate in the
presence of 5.0 molar equivalent stannous chloride dihydrate for 6-8 hrs.
After
completion of the reaction, the reaction mixture was poured into 10% aq.
sodium
bicarbonate and extracted with ethyl acetate. The combined organic layer was
then washed with water dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give the desired product.
Step 6: Preparation of [4-(4-(substitutedlunsubstituted phenyl) -1-
piperazinyl]
phenyl carbamate
The amine obtained from Step 5 was dissolved in a mixture of
dichloroethane (DCE) and pyridine and cooled to 5°C. A solution of
phenylchloroformate (1.4 molar equivalent) in DCE was added into the solution
of
amine at such a rate that reaction temperature remained below 35oC. After the
addition was over, reaction mixture was stirred at 25-30°C for 3-5
hours. Solvent
was evaporated off under reduced pressure to give brownish residue which on
triturating with n-hexane gave brown solid. It was then obtained was washed
with
5% aq. solution of sodium bicarbonate and water. It was then dried under
vacuum at 40 oC for 3 to 5 hrs to give the corresponding carbamate.
Step 7: Preparation of N-[4-[(4-substituted phenyl) 1-
piperazinyl]phenyl]hydrazine
carboxamide. ,
The carbamate obtained in Step 6 was stirred in 1,4-dioxane followed by
the addition of hydrazine hydrate (2.5 molar equivalent 98%) at room
temperature. After refluxing the reaction mixture for 4 to 6 hrs, solvent was
evaporated off to give solid residue which was triturated with 10% methanol in
,..
43

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
diethyl ether, filtered the separated solid and dried under vacuum at 35 -40oC
for
4 to 6 hrs to give corresponding semicarbazide.
Step 8: 4-(4-Substituted phenyl)-1-piperazin]phenyl-3H-1,2,4-triazol-3-ones.
The semicarbazide so obtained was dissolved in dry dimethylformamide
(DMF) followed by the addition of formamidine acetate (4.5 molar equivalent).
After heating at 120 - 130°C for 3 to 5 hrs, reaction mixture was
poured into
chilled saturated aq. solution of sodium bicarbonate with stirring. Solid so
obtained was filtered, washed with water and dried under vacuum at 40°C
for 7
hrs. to give corresponding triazolone.
Step 9: Preparation of 2-[(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-
yl)-
propyl]-4-[4-[4-su bstituted phenyl-1-piperazinyl]phenyl]-3-(2H,4H)-1,2,3-
substituted triazol-4-one.
Hexane washed sodium hydride (0.015 mg, 1.0 mmol) was added into a
stirred solution of compound obtained from Step -8 (0.4g, 1.12 mmol) in
dimethyl
formamide (DMF) (10 ml) maintaining nitrogen atmosphere. After stirring at 25-
30°C, a solution of the compound obtained from Step 3 (1.68mmol) in DMF
was
added drop-wise into the reaction mixture at 40oC, temperature was raised to
80oC and maintained at this temperature for about 4 hr. After the reaction was
over, reaction mixture was cooled to 35-40°C, poured it into chilled
water (50 ml)
and extracted with ethyl acetate (3x 100m1). The combined organic layer was
washed with water (4x50m1), dried over anhydrous sodium sulphate and
concentrated under vacuum to give an oily residue (0.3 gm). The oil was
purified
by column chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate
44

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
(1:1 ) followed by ethyl acetate or by crystallisation from suitable solvent
to give
the required compound.
EXAMPLE 2
Preparation of 2-{[1 R,2R/1 S,2S/1 R,2S/1 S,2R]2-[(2,4-Difluorophenyl)-2-
hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]}-4-{[4-[4-substituted
/unsubstituted)phenyl-1-piperazinyl]phenyl]~- 3- (2H, 4H)-1, 2, 3- substituted
triazol -4-one.
Step 1: Preparation of 2-chloro-2-methyl-2',4'-difluoro acetophenone
Into the solution of 1,3-Difluorobenzene in 1,2-dicholoroethane (DCE) was
added anhydrous aluminium chloride (1.2 mol eqnt.) at 25-30°C and
stirred for 30
minutes. The reaction mixture was then cooled to 0°C and (~) 2-
chloropropionyl
chloride (1.1 molar equivalent), diluted in DCE , was then added into it over
a
period of 30-60 min keeping the reaction temperature below 20oC. After the
addition was over, reaction mixture was stirred at room temperature for 5-7
hours. For workup, reaction mixture was diluted with DCE and poured into
chilled
aq. hydrochloric acid solution (5%). The mixture was extracted with DCE and
the
combined organic layer was washed with 5% aq. sodium bicarbonate solution
and water. The solvent was evaporated off under reduced pressure to afFord an
oil.

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Step 2: Preparation of 2-~[4-[4-[4-(substituted/unsubstituted phenyl)piperazin-
yl]phenyl-(2H,4H)-1,2,4-triazol-3-one-2-yl])-2(R/S)-methyl-2',4'-
difluoroacetophenone
Hexane washed sodium hydride (1.2 molar equivalent) was added into a
stirred solution of compound of Formula XII (1.0 molar equivalent) in
dimethylsulphoxide (DMSO) maintained under nitrogen atmosphere. After
stirring at 25-30°C for 1 hr, a solution of the compound of Formula XIV
(2 molar
equivalent) in DMSO was added dropwise into the reaction mixture at about
15°C. The reaction mixture was then stirred at 25-30°C for 2 hrs
and slowly the
temperature was raised to 60 oC and maintained this temperature for 3-4 hrs.
After the reaction was over, reaction mixture was cooled to 25-30°C,
poured into
chilled water and extracted with ethyl acetate. The combined organic layer was
washed with water, dried over anhydrous sodium sulphate and concentrated to
give an oily residue under vacuum. The crude product was purified by column
chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate (1:1 )
followed by using ethyl acetate to give the required compound.
Step 3: Preparation of 2-~[1 (R/S)-methyl-2-(2',4'-difluorophenyl)-2,3-epoxy
propyl]-4-[4-(substituted phenyl)piperazinyl]phenyl]}-3-{2H,4H)-1,2,4-
substituted
thiazolone.
Hexane washed sodium hydride was stirred in DMSO followed by the
addition of trimethylsulfoxonium iodide (TMSI) at 15 oC. The reaction mixture
was stirred at 25-30°C under nitrogen atmosphere for 1-2 hrs. A
solution of the
compound obtained in Step 2 in DMSO was added into the above mixture at 25-
30°C and then heated to 80 to 90 oC for 1-2 hrs. Due to the generation
of
46

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
second chiral center in the molecules two pairs of diasteromers were formed
which were detected both by TLC as well as by HPLC methods. After the
reaction was over the reaction mixture was cooled to 25-30°C, poured
into chilled
brine and extracted with ethyl acetate. The combined organic layer was washed
with water, dried over sodium sulfate and concentrated under vacuum to give
either an oil or a fluffy solid which was then used as such for the next step.
Step 4: Preparation of 2-{[1 R,2R11 S,2S/1 R,2S/1 S,2R]2-[(2,4-Difiuoro
phenyl)-2-
hydroxy-3-methyl-3-(1-H-1,2,4-triazol-1-yl)propyl]~-4-~4-[4-
(substituted/unsubstituted phenyl)-1-piperazinyl]phenyl]~-3-(2H,4H)-1,2,3-
substituted triazol-4-one].
1,2,4-Triazole was stirred with sodium hydride in dimethylformamide
(DMF) at 25-30°C for about 1 hr. The solution of epoxide obtained from
step-3 in
DMF was then added into this reaction mixture at 25-30°C and
stirred the
reaction mixture at 100oC. After the reaction was over the reaction mixture
was
cooled to 25-30°C, poured into chilled brine and extracted with ethyl
acetate. The
combined organic layer was washed with water, dried over anhydrous sodium
sulfate and concentrated under vacuum to give either an oil or a fluffy solid.
Compound so obtained was actually a mixture of four isomers showing two spots
on TLC. The mixtures of diastereomers was then separated by preparative
HPLC.
47

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
EXAMPLE 3
Preparation of 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-
yl)propyl]-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone
5-Chloro-2-methyl-phenylpiperazine (20.0g) was reacted with 4-
chloronitrobenzene (16.0g) in dimethylsulphoxide (DMSO) (110m1) in the
presence of anhydrous potassium carbonate (19.9g) at a temperature of 135-
140°C for 8 hours. After the reaction was over (TLC monitoring), the
reaction
mixture was poured into crushed ice and the compound was isolated as an
orange solid. After drying under vacuum at 25-30°C for 6-8 hours, the
nitro
compound (29.0g, orange solid; m.p. 146-150°C) was used as such for the
next
step.
The nitro compound (18.0g) was refluxed in ethyl acetate (150m1) in the
presence of stannous chloride dihydrate (55.5g) for 8 hours. After completion
of
the reaction, the reaction mixture was poured into 10°l° aqueous
sodium
bicarbonate (500m1) and extracted with ethyl acetate (3 x 150m1). The combined
organic layer was washed with water (3 x 100m1) and then dried over anhydrous
sodium sulfate. The organic layer was concentrated under vacuum to give the
desired amine (15.3g, brown oil; yield:93%).
The amine (15.0g) was dissolved in a mixture of dichloroethane (DCE)
(80m1) and pyridine (30m1). The reaction mixture was cooled to about
15°C. A
solution of phenylchloroformate (11.67g) in DCE (10m1) was added into the
solution of amine at such a rate that reaction temperature remained below
20°C.
After the addition was over, reaction mixture was stirred at 25-30°C
for about 3
48

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
hours. Solvent was evaporated off under reduced pressure to give brownish
residue which on triturating with n-hexane (150m1) gave brown solid. Solid was
washed with n-hexane (2x100m1), 5% aq. solution of sodium bicarbonate (2 x
1 OOmI) and distilled water (2x150m1) followed by drying under vacuum at
40°C for
5 hours to give 10gm of corresponding carbamate (Yield 86%) m.p.201-
205°C.
The carbamate (18.0g) was stirred in 1,4-dioxane (130m1) followed by the
addition of hydrazine hydrate (98%) (5.32g) at 25-30°C. After refluxing
the
reaction mixture for 4 hours, solvent was evaporated off to give solid residue
which was triturated with 10% methanol in diethyl ether (150m1). The separated
solid was filtered, washed and dried under vacuum at 35°C for 4 to 6
hours to
give corresponding semicarbazide (15.5g) mp 177-182°C.
The semicarbazide (5.0g) was stirred in dry DMF (25m1) followed by the
addition of formamidine acetate (6.5g). After heating at 120°C for 3 to
5 hours,
the reaction mixture was poured into a chilled saturated aq. solution of
sodium
bicarbonate (100m1) with stirring. Solid so obtained was filtered, washed with
water (3 x 50m1) and dried under vacuum at 40°C for 5 hours to give
corresponding triazolone derivative (4.3g, 84%) as a brown amorphous solid; mp
258-262°C.
Hexane washed sodium hydride (0.057g, 60% suspension in oil) was
added into a stirred suspension of the above triazolone intermediate (0.5g) in
DMF (10m1) maintained under nitrogen atmorphere. After stirring at 25-
30°C, a
solution of the epoxide interemdiate (0.481gm) in DMF (5m1) was added dropwise
into the reaction mixture at 40°C. Temperature was then raised to
80°C and
49

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
maintained for about 4 hr. Reaction mixture then was cooled to 25-30°C,
poured
into chilled water (50m1) and extracted with ethyl acetate (3 x 100m1). The
combined organic layer was washed with water (4x50m1), dried over anhydrous
sodium sulphate and concentrated under vacuum to give an oily residue (0.3gm).
The oily residue was subjected to column chromatography (silica gel 100-
200mesh) using hexane-ethyl acetate (1:1, 300m1) followed by ethyl acetate
(500m1) to give the required compound. (0.481 gm, 57%) mp 82-91°C.
EXAMPLE 4
2-~(1 R2RI1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-yl) propyl}-4-~4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-
3-(2H,4H)-1,2,4-triazolone (Compound No. 21)
2-~[1 R2SI1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl~-
3-(2H,4H)-1,2,4-triazolone (Compound No. 22)
Step 1: Preparation of 2-{4-[4-[4-(2-methyl-5-chlorophenyl)piperazinyl]phenyl~-
(2H,4H)-1,2,4-triazol-3-one-2-yl}-2(R/S)-methyl-2,4-difluoroacetophenone.
Hexane washed sodium hydride (0.311g) was added into a stirred solution
of triazolone intermediate (4-[4-(2-methyl-5-chlorophenyl)-1-
piperazinyl]phenyl-1-
(3-(2H,4H)-1,2,4 triazolone (2.5g) in DMSO (25m1) maintained under nitrogen
atmosphere. After stirring at 25-30°C for 1 hour, a solution of the
intermediate of
Formula XIV (2.77g) in DMSO (5m1) was added dropwise into the above reaction
mixture at 15°C. The reaction mixture was then stirred at 25-
30°C for 2 hours,
slowly the temperature was raised to 60°C and maintained for 3-4 hours.
Reaction mixture was cooled to 25-30°C, poured into chilled brine
(150m1) and

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
extracted with ethyl acetate (3 x 100m1). The combined organic layer was
washed with water (4 x 50m1), dried over anhydrous sodium sulphate and
concentrated to an oily residue under vacuum. The crude oil was subjected to
column chromatography (silica gel 100-200mesh) using hexane -ethyl acetate
(1:1 ) followed by ethyl acetate to give required compound in pure form
(2.6gm;
71 %) mp 125-128°C.
Step 2: Preparation of 2-[1-(R/S)-methyl-2-(2'-4'-difluorophenyl)-2,3-epoxy-
propyl]-4-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]phenyl]~-3-(2H,4H)-1,2,4-
triazolone.
Hexane washed sodium hydride (0.128g) was stirred in DMSO (15m1)
followed by the addition of trimethylsulfoxonium iodide (TMSI) (0.736g) at
15°C.
The reaction mixture was stirred at 25-30°C under nitrogen atmosphere
for 1 hr.
A solution of Step 1 product (0.9g) in DMSO (5m1) was added into the above
reaction mixture at 25-30°C and then heated to 80 to 90°C for
about 1 hr. Due to
generation of second chiral centre in the molecule, two pairs of diastereomers
were formed which were detected by the TLC and by HPLC analyses. After the
reaction was over, the reaction mixture was cooled to 25-30°C, poured
into
chilled brine and extracted with ethyl acetate (3 x 75m1). The combined
organic
layer was the washed with water (2 x 50m1), dried over sodium sulfate and
concentrated under vacuum to give an oil (0.93gm, 100%) which was then used
as such immediately for next step.
51

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Step 3: 2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-
1,2,4-
triazol-1-yl) propyl)-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-
3-
(2H,4H)-1,2,4-triazolone (Compound No. 21)
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone (Compound No. 22)
1,2,4-Triazole (0.232g) was stirred with anhydrous potassium carbonate
(0.465g) in DMF (10m1) at 25-30°C for 1-2 hours. A solution of epoxide
obtained
from Step-2 (0.925g) in. DMF (3.0m1) was then added into the above mixture at
25-30°C followed by heating the reaction mixture at 90 to 100°C
for 1 hr. After
the reaction was over, reaction mixture was cooled to 25-30°C, poured
into
chilled brine (70.0m1) and extracted with ethyl acetate (3 x 75m1). The
combined
organic layer was washed with water (2x250m1), dried over sodium sulfate and
concentrated under vacuum to give an oil. Compound obtained actually was a
mixture of two pairs of diastereomers showing two spots on TLC (Ethyl
acetate).
The mixture of diastereomers (0.613g, 59%) was then separated by column
chromatography to get compound no.21 ) (faster moving spot on TLC) (35mg),
compound no.22 (slower moving spot on TLC) and 550mg of mixture of the two
spots.
52

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
EXAMPLE 5
Preparation of 3-[4-(4-Chlorophenylthioureido)N-methyl-N-phenyl]-2-(2,4-
difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-of (Compound No.
89)
Step 1: Preparation of 3-[N-methyl-N-(4-nitrophenyl))-2-(2,4-difluorophenyl)-1-
(1 H-1,2,4-triazolyl)- propan-3-amino-2-ol.
Into a stirred suspension of sodium hydride (42 mg) in dry
dimethylformamide (DMF) (5.0 ml) was added N-methyl-p-nitroaniline (1.5 gm) at
5-10oC. The resulting suspension was stirred at 30oC for 1 hour followed by
the
addition of a solution of epoxide (Formula IV) in DMF (2.0 ml) at 5-10oC.
Reaction mixture was then stirred at 30oC for 30 min, heated to 60-65oC for 12
hrs and was cooled to 30oC. Poured the reaction mixture into ice-water mixture
and extracted with dichloromethane (3x100 ml). The combined organic layer was
washed with DM water (2 x 70 ml), dried over sodium sulphate and concentrated
under reduced pressure to give a yellow solid (2.1 g, m.p. 248-50oC).
Step 2: Preparation of 3-[N-methyl-N-(4-aminophenyl)]-2-(2,4-difluorophenyl)-1-
(1 H-1,2,4-triazolyl)- propane-3-amino-2-ol.
Into a stirred solution of Step 1 product in methanol was added palladium
on carbon (10%) (50% w/w) (0.5 g) under nitrogen atmosphere. The suspension
was then cooled to 10oC followed by the addition of ammonium formate (1.2 g)
in
portions over a period of 15 min. The reaction mixture was then heated to
reflux
and stirred at reflux for 5 hours. Reaction mixture was cooled to 30oC and
filtered through a celite pad. The combined filtrate was concentrated under
53

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
vacuum to give a yellow semi-solid which was redissolved in dichloromethane
(200 ml). The organic layer was washed with DM water (3 x 100 ml), dried over
sodium sulfate and concentrated under reduced pressure to give semi-solid
amine which was subjected to next step without further purification.
Step 3: Preparation of 3-[4-(4-Chlorophenylthioureido)N-methyl-N-phenyl]-2-
(2,4-
difluorophenyl)-1-(1 H-1,2,4-triazolyl)-propari-3-amino-2-of (Compound No. 89)
Dissolved the amine (Step-II product) (400 mg) in anhydrous acetonitrile (5
ml) and added p-chlorophenyl isothiocyanate (227 mg, 1.2 eqm) to it. Stirred
for
4 hours at 25-30°C and the solvent was evaporated off to afford residue
which
was purified using column chromatography (Yield: 200 mg, 34%).
EXAMPLE 6
Preparation of 3-~4-[4-N-(4-chlorophenyl)-N-(methylureido)-piperazinyl ]-
phenoxy~-2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazolyl)-2-methoxypropane
(Compound No. 75)
Dissolved the amine of Formula VII (prepared by following the process as
described in US Patent No. 5,023,258) (9 g) in anhydrous acetonitrile (50 ml)
and
added p-chlorophenyl isocyanate (4 g) to it. Stirred the reaction mixture for
1 hr
at 25-30°C and evaporated the solvent to afford crude oil which was
purified
using column chromatography (Yield: 8.3 g, 75%).
54

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
EXAMPLE 7
Preparation of [1R2R/1S2S] 1-~4-[4-(4-chlorophenylureido)-piperazinyl ]-
phenoxy}-2-(2,4-difluorophenyl)-1-methyl -3-(1H-1,2,4-triazolyl)-propan-2-of
(Compound No. 77) and
[1 R2S/1 S2R] 1-{4-[4-(4-chlorophenylureido)-piperazinyl ]-phenoxy~-2-(2,4-
difluorophenyl)-1-methyl -3-(1H-1,2,4-triazolyl)-propan-2-of (Compound No.
78)
Step 1: Preparation of 2-(4-[4-acetyl-1-piperazinyl]-phenyl]-2(R/S)-methyl-2,4-
difluoroacetophenone
A solution of 2-chloro-2(R/S)-methyl-2,4-difluoroacetophenone(10.5 g) (1.5
molar equivalent) in dry dimethylformamide (DMF) was added into a stirred
suspension of 1-acetyl-4-hydroxyphenylpiperazine (8.0 g) and potassium
carbonate (12.16 g) in dimethylformamide (DMF) at 5-10oC. Reaction mixture
was then stirred at 30oC for 20 min, heated to 60oC and stirred at 60°C
for about
5 hrs. Reaction mixture then was cooled to 25-30°C, poured into ice-
water
mixture and extracted with ethyl acetate (3 x 200 ml). The combined organic
layer was washed with water (3 x 100 ml), dried over sodium sulfate and
concentrated under reduced pressure to get foamy product (8.0 g; 71 %).
Step 2: Preparation of 1-(RlS)-methyl-2,3-epoxypropyl-2-(4-[(4-
acetylpiperazinyl)] phenoxy}-2-(2',4'- difluorobenzene)
Into a stirred suspension of sodium hydride (1.97 g) in dry
dimethylsulphoxide (DMSO) under nitrogen atmosphere was added
trimethylsulfoxomium iodide (9.075 g) at 10-15oC. The foaming suspension was

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
stirred at 30oC for 1 hr followed by the addition of a solution of Step-I
product (8.0
g) in DMSO at 10-15oC over a period of 10 min. Reaction mixture was then
heated to 90oC and stirred at 90°C for about 4 hours. Cooled the
reaction
mixture, poured it into ice-water mixture and extracted with ethyl acetate (3
x 200
ml). The combined organic layer was then washed with water (3x150 ml), dried
over sodium sulphate and concentrated under reduced pressure to give foamy
product (7.0 g; 85%).
Step 3: Preparation of 1-~4-[4-Acetylpiperazinyl)-phenyl]-2-(2,4-
difluorophenyl)-
1 (R/S)- methyl-3-(1 H-1,2,4- triazolyl)-propane-2-ol)]
Into a stirred suspension of sodium hydride(1.67 g) in dry
dimethylformamide (DMF), was added 1,2,4-triazole (2.4 g) under nitrogen
atmosphere and stirred at 30oC for 1 hour. A solution of Step 2 product (7.0
g) in
DMF was then added into the above suspension at 30oC followed by heating to
80-85oC and stirred at 80-85°C for 8 hrs. Reaction mixture was then
cooled to
30oC, poured into ice-water mixture and the suspension was extracted with
ethyl
acetate (3x200 ml). The combined organic extract was washed with DM water (3
x 150 ml), dried over sodium sulfate and concentrated under reduced pressure
to
give semisolid compound (6.0 g, 73%).
Step 4: Preparation of 1-[4-(4-(piperazinyl)phenoxy]-2-(2,4-difluorophenyl)-
1 (R/S)-methyl-3-(1 H-1,2,4-triazolyl)- propan-2-of
Step 3 product (6.0 g) was dissolved in 1,4-dioxane (50 ml) followed by the
addition of a solution of sodium hydroxide (1.0 g) in water (50 ml). Heated
the
56

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
reaction mixture to reflux, stirred it at reflux for about 5 hrs and
concentrated
under reduced pressure to give a brown semi-solid residue. This brown semi
solid was redissolved in ethyl acetate (200 ml), washed with DM water (2x100
ml), dried over sodium sulphate and concentrated to get a pure brown semi-
solid
(4.5 g; 81 %).
Step 5: Preparation of [1 R2R/1 S2S) 1-f4-[4-(4-chlorophenylureido)-
piperaziny]-
phenoxy}-2-(2,4- difluorophenyl)-1-methyl-3-(1 H-1,2,4-triazolyl)-propan-2-ol.
(Compound No. 77) and
[1 R2R/1 S2S]-1-~4-[4-(4-chlorophenylureido)-piperazinyl]-phenoxy}-2-(2,4-
difluorophenyl)-1-methyl-3-(1H-1,2,4-triazolyl)propane-2-ol. (Compound No.
78).
Dissolved the amine obtained as Step 4 product (Formula VII) (800 mg) in
anhydrous acetonitrile (5 ml) followed by the addition of p-chlorophenyl
isocyanate (3.44 mg). The reaction mixture so obtained was stirred for 1 hour
at
room temperature and after the reaction was over, the solvent was evaporated
off
to give brown semi solid residue which was purified using column
chromatography. The two spots observed on TLC were separated by preparative
HPLC (Upper spot, 50mg, 30%, compound No. 77; Lower spot, 25mg, 20%,
Compound No. 78)
57

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
EXAMPLE 8
Preparation of 2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-
yi)propyl]-4-~4-[4-(4-chlorophenyluredio)-1-piperazinyi]phenyl}-3-(2H,4H)-
1,2,4-triazolone (Compound No. 91)
Dissolved the starting amine of Formula VII (following the method as
described in US Patent No. 5,371,101 ) in anhydrous acetonitrile and added p-
chlorophenyl isocyanate (1.2 moler equivalent) to it and stirred for 1 hr at
25-
x
30°C. After completion of the reaction, the solvent was evaporated off
to obtain a
crude product which was purified using column chromatography.
Assignment of RR/SS was done on the basis of ~HNMR analysis.
An illustrative list of some of the compounds of the invention which were
synthesized by one or more of the above described methods is given below along
with their 'HNMR data. All 'HNMR spectra were recorded on Brucker AMX 300
NMR machines (300 MHZ) using °CDC13 as a solvent and TMS as an
internal
standard unless otherwise specified. All values are given in ppm.
Symbols in the examples have the following meanings. Thus, s singlet;
d:doublet; tariplet; q:quartet; dd: double doublet; m:multiplet; br:broad; J:
coupling
constant:
Compound No. 1:
2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hyd roxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-(4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
NMR(CDC13):- 8 7.96(s, 1 H; Ar-H), 7.72-7.67 (d, 2H; J = 14.7 Hz; Ar-H), 7.60-
7.52
(q, 1 H; Ar-H), 7.45-7.42 (d, 2H; J = 9.0 Hz; Ar-H), 7.26-7.23 (d, 2H; J = 9.0
Hz;
58

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Ar-H), 7.06-7.03 (d, 2H; J = 9.0 Hz; Ar-H), 6.91-6.88(d, 2H; J = 9.0 Hz; Ar-
H),
6.83-6.77(m, 2H; Ar-H), 5.56 (s, 1 H; OH, D20 ex.), 5.12-5.05(q, 1 H; -
CH.CH3),
5.03-4.98 (d, 1 H; J = 15.0 Hz; triazole-CHI), 4.38-4.33 (d, 1 H; J = 15.0 Hz;
triazole-CH2), 3.39-3.37 (d, 8H; piperazine-CHI ) & 1.31-1.28(d, 3H; J = 7.2
Hz;
CH.CH3)ppm.
Compound No. 2:
2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-~4-[4-(4-chlorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-
triazolone
NMR(CDC13):- ~ 8.09(s, 1 H; Ar-H), 7.68 (s, 1 H; Ar-H), 7.39(s, 1 H; Ar-H),
7.36-7.30
(m, 1 H; Ar-H), 7.26-7.22 (m, 3H; Ar-H), 7.16-7.13 (d, 2H; J = 9.0 Hz; Ar-H),
6.97-
6.94(d, 2H; J = 9.0 Hz; Ar-H), 6.89-6.87(d, 2H; J = 9.0 Hz; Ar-H), 6.77-
6.63(m,
2H; Ar-H),6.04(s, 1 H;Ar-H), 5.29 (s, 1 H; OH, D20 ex.), 5.11-5.04(q, 1 H; -
CH.CH3),
4.92-4.88 (d, 1 H; J = 15.0 Hz; triazole-CHz), 4.63-4.59 (d, 1 H; J = 15.0 Hz;
triazole-CH2), 3.34-3.28 (q, 8H; piperazine-CH2 ) & 1.64-1.61 (d, 3H; J = 7.2
Hz; -
CH.CH3)ppm.
Compound No. 3:
2-{[1R2R/1S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-
yl) propyl~-4-{4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-
triazolone
NMR(CDCI3):- 8 8.81-8.80(d, 1 H; Ar-H), 8.40-8.36(dd, 1 H; Ar-H),8.03(s,1 H;Ar-
H),
7.79-7.75 (d, 2H; Ar-H), 7.65-7.62(q, 1 H; Ar-H), 7.54-7.51 (d, 2H; Ar-H),
7.25-
7.22 (d, 1 H; Ar-H), 7.09-7.07 (d, 2H; J = 9.0 Hz; Ar-H), 6.91-6.85(m, 2H; Ar-
H),
5.60 (s, 1 H; OH, Dz0 ex.), 5.17-5.05(qd, 2H; -CH.CH3 & triazole-CHI), 4.46-
4.41
(d, 1 H; J = 15.0 Hz; triazole-CHz), 3.54-3.53 (d, 8H; piperazine-CH2 ) & 1.37-
1.35(d, 3H; J = 7.2 Hz; -CH.CH3)ppm.
59

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Compound No. 4:
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-~4-[4-(2,4-dinitrophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-
triazolone
NMR(CDCI3):- 8 8.73-8.72(d, 1 H; Ar-H), 8.32-8.28(dd, 1 H; Ar-H),8.08(s, 1 H;
Ar-
H),7.68 (s, 1 H; Ar-H), 7.41 (s, 1 H; Ar-H), 7.35-7.32 (m, 1 H; Ar-H), 7.18-
7.13 (m,
3H; Ar-H), 6.76-6.74(d, 2H; J = 9.0 Hz; Ar-H), 6.73-6.63(m, 2H; Ar-H), 5.99
(s,
1 H; OH, DSO ex.), 5.09-5.07(q, 1 H; -CH.CH3), 4.93-4.88 (d, 1 H; J = 15.0 Hz;
triazole-CH2), 4.64-4.59 (d, 1 H; J = 15.0 Hz; triazole-CHZ), 3.46-3.39 (q,
8H;piperazine-CH2 ) & 1.64-1.61 (d, 3H; J = 7.2 Hz; -CH.CH3) ppm.
Compound No. 5:
2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-[4-(1-phenylpiperazinyl)phenyl]-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- b 7.96(s, 1 H; Ar-H), 7.72-7.67 (d, 2H; J = 13.5 Hz; Ar-H), 7.60-
7.52
(q, 1 H; Ar-H), 7.44-7.41 (d, 2H; J = 9.0 Hz; Ar-H), 7.33-7.26 (m, 3H; Ar-H),
7.07-
6.97 (m, 4H; Ar-H), 6.93-6.88(m,1 H; Ar-H), 6,84-6.77(m, 2H; Ar-H), 5.56 (s, 1
H;
OH, DSO ex.), 5.12-4.98(qd, 2H; -CH.CH3triazole-CHZ), 4.38-4.33 (d, 1 H; J =
15.0
Hz; triazole-CH2), 3.38-3.37 (d, 8H; piperazine-CH2 ) & 1.30-1.28(d, 3H; J =
6.9
Hz; -CH.CH3) ppm.
Compound No. 6:
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl)-4-~4-[4-(1-phenylpiperazinyl) phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- b 8.09 (s, 1 H; Ar-H), 7.68 (s, 1 H; Ar-H), 7.39 (s, 1 H; Ar-H),
7.36-
7.26 (m, 3H; Ar-H), 7.15-7.12 (d, 2H; J = 9.0 Hz; Ar-H), 6.97-6.87 (m, 5H; Ar-
H),
6.77-6.64 (m, 2H; Ar-H), 6.05 (s, 1 H; OH, DSO ex.), 5.09-5.07 (q, 2H; -CH.CH3
triazole-CH2), 4.91-4.87 (d, 1 H; J = 15.0 Hz; triazole-CH2), 4.63-4.58 (d, 1
H; J =
15.0 Hz; triazole-CH2), 3.34 (s, 8H; piperazine-CH2 ) & 1.63-1.61 (d, 3H; J =
6.9
Hz; -CH.CH3) ppm.

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Compound No. 7:
2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl~-4-~4-[4-(3,4-dichlorophenyl)-1-piperzinyl]phenyl-3-(2H,4H)-1,2,4-
triazolone
NMR(CDC13):- 8 7.96(s, 1 H; Ar-H), 7.71-7.67 (d, 2H; J = 13.5 Hz; Ar-H), 7.61-
7.52
(q, 1 H; Ar-H), 7.45-7.42 (d, 2H; J = 9.0 Hz; Ar-H), 7.33-7.30 (d, 1 H; J =
8.7 Hz;
Ar-H), 7.06-7.01 (m, 3H; Ar-H), 6.84-6.77(m,3H; Ar-H), 5.56 (s, 1 H; OH, D20
ex.),
5.12-5.05(q, 1 H; -CH.CH3), 5.03-4.98 (d, 1 H; J = 15.0 Hz; triazole-CH2),
4.38
4.34 (d, 1 H; J = 15.0 Hz; triazole-CHI), 3.39-3.37 (d, 8H; piperazine-CH2 ) &
1.30
1.28(d, 3H; J = 7.2 Hz; -CH.CH3)ppm.
Compound No. 8:
2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl~-4-~4-[4-(3,4-dichlorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-
triazolone
NMR(CDCI3):- 8 8.08 (s, 1 H; Ar-H), 7.67 (s, 1 H; Ar-H), 7.39-7.25 (m, 3H; Ar-
H),
7.15-7.12 (d, 2H; J = 9.0 Hz; Ar-H), 6.99-6.93 (m, 3H; Ar-H), 6.79-6.65 (m,
3H;
Ar-H), 6.01 (s, 1 H; OH, DSO ex.), 5.10-5.05 (q, 1 H; -CH.CH3), 4.91-4.87 (d,
1 H; J
= 15.0 Hz; triazole-CH2), 4.62-4.58 (d, 1 H; J = 15.0 Hz; triazole-CHZ), 3.31
(s, 8H;
piperazine-CH2 ) & 1.63-1.60 (d, 3H; J = 7.2 Hz; -CH.CH3) ppm.
Compound No. 9:
2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1
yl) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-
1,2,4
triazolone NMR(CDCI3):- 7.99(s, 1 H; Ar-H), 7.74-7.70 (d, 2H; J = 14.7 Hz; Ar
H), 7.62-7.54 (q, 1 H; Ar-H), 7.48-7.39 (m, 3H; Ar-H), 7.19-7.07 (m, 5H; Ar-
H),
6.85-6.79(m, 2H; Ar-H), 5.59 (s, 1 H; OH, D20 ex.), 5.15-5.01 (qd, 1 H; -
CH.CH3 &
triazole-CH2), 4.40-4.35 (d, 1 H; J = 15.0 Hz; triazole-CH2), 3.43 (s, 8H;
piperazine-CH2-) & 1.32-1.30(d, 3H; J = 7.2 Hz; -CH.CH3) ppm.
61

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Compound No. 10:
2-{[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-
1,2,4-triazolone NMR(CDC13):- b 8.12(s, 1 H; Ar-H), 7.71 (s, 1 H; Ar-H), 7.43-
7.32
(m, 3H; Ar-H), 7.15-7.11 (m, 5H; Ar-H), 7.00-6.97(d, 2H;Ar-H), 6.78-6.66 (m,
2H;
Ar-H), 6.06 (s, 1 H; OH, D20 ex.), 5.13-5.07(q, 1 H; -CH.CH3~, 4.95-4.90 (d, 1
H; J
= 15.0 Hz; triazole-CH2),4.65-4.61 (d, 1 H; J = 15.0 Hz; triazole-CH2), 3.39
(s, 8H;
piperazine-CHz ) & 1.66-1.64(d, 3H; J = 9.6 Hz; -CH.CH3) ppm.
Compound No. 11:
2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-
triazolone NMR(CDCI3):- 7.96.09 (s, 1 H; Ar-H), 7.72 (s, 1 H; Ar-H), 7.67 (s,
1 H;
Ar-H), 7.55-7.57 (m, 1 H; Ar-H), 7.41-7.44 (d, 2H; Ar-H), 6.77-7.07 (m, 8H; Ar-
H),
5.57 (S, 1 H; OH, D20 ex.), 5.10-5.17 (q, 1 H; J = 7 Hz; -CH), 4.98-5.03 (d, 1
H; J
= 14.7 Hz, -CH), 4.33-4.37 (d, 1 H; J = 14.7~Hz; triazole-CH2), 3.38-3.40 (m,
4H; 2
x -CH2), 3.25-3.29 (m, 4H; 2 x CH2-) & 1.28 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 12:
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1
yl) propyl~-4-{4-[4-(4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4
triazolone
NMR(CDC13):- b 8.09 (s, 1 H; Ar-H), 7.68 (s, 1 H; Ar-H), 6.60-7.40 (m, 12H; Ar-
H),
6.02 (S, 1 H; OH, D20 ex.), 5.04-5.11 (q, 1 H; J = 7 Hz; -CH), 4.87-4.92 (d, 1
H; J =
14.7 Hz, -CH), 4.58-4.63 (d, 1 H; J = 14.7 Hz; triazole-CHz), 3.33-3.44 (m,
4H; 2 x
-CH2), 3.23-3.25 (m, 4H; 2 x CH2 ) & 1.28 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 13:
2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-
triazolone
62

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
NMR(CDCI3):- 8 7.97 (s, 1 H; Ar-H), 7.74 (s, 1 H; Ar-H), 7.67 (s, 1 H; Ar-H),
7.60-
7.51 (m, 1 H; Ar-H), 7.44-7.41 (d, 2H; Ar-H), 7.28 (s, 1 H; Ar-H), 7.07-7.04
(d, 2H;
Ar-H),6.98-6.95 (m, 2H; Ar-H), 6.89-6.86 (m, 2H; Ar-H),6.82-6.77 (m, 2H; Ar-
H),5.59 (S, 1 H; OH, D20 ex.), 5.10-4.99 (q, 1 H; J = 7 Hz; -CH), 4.37-4.33
(d, 1 H;
J = 14.7 Hz, -CH), 3.79(s, 3H; OCH3), 3.41-3.38 (t, 4H; 2 x -CHz), 3.25-3.22
(t,
4H; 2 x CH2 ) & 1.30-1.25 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 15:
2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone NMR(CDC13):- ( s, 1 H; Ar-H), 7.73-7.69(d, 2H; Ar-H), 7.62-
7.53(m, 1 H; Ar-H), 7.46-7.43(d, 2H; Ar-H), 7.10-7.05(t, 3H; Ar-H),7.00-6.98
(m,
1 H; Ar-H), 6.85-6.79(m, 3H; Ar-H),5.57 (s, 1 H; OH, D20 ex.), 5.14-5.00 (m,
2H; J
= 7 Hz; -CH), 4.39-4.35 (d, 1 H; J = 14.7 Hz, -CH), 3.40-3.38 (d, 4H; 2 x -
CH2),
3.30-3.29 (d, 4H; 2 x CH2-) & 1.32-1.30(d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 16:
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-~4-[4-(3-chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone NMR(CDC13):- 88.02(s, 1 H; Ar-H), 7.61 (s, 1 H; Ar-H), 7.37
(s, 1 H;
Ar-H), 7.33-7.23 (m, 1 H; Ar-H), 7.09-7.06(d, 2H; Ar-H), 6.98-6. 956(t, 1 H;
Ar-H),
6.90-6. 87(d, 3H; Ar-H),6.76-6.57 (m, 3H; Ar-H),5.96 (s, 1 H; OH, D20 ex.),
5.05-
4.98(q, 1 H; J = 7 Hz; -CH-CH3), 4.87-4.81 (d, 1 H; J = 14.7 Hz, -CH), 4.57-
4.52
(d, 1 H; J = 14.7 Hz, -CH), 3.27-3.25 (t, 4H; 2 x -CH2), 3.19-3.18 (t, 4H; 2 x
CHI )
& 1.57-1.55(d, J = 7 Hz; 3H; CH3)
Compound No. 17:
2-~[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(3-chloro-4-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone NMR(CDCI3):- 7.98 (s, 1 H; Ar-H), 7.74-7.69(d, 2H; Ar-H),
7.62-
7.53(q, 1 H; Ar-H), 7.46-7.43(d, 2H; Ar-H), 7.16-7.13(d, 1 H; Ar-H), 7.08-
7.05(d,
63

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
2H; Ar-H), 6.98-7.97 (m, 1 H; Ar-H),6.86-7.98 (m, 3H; Ar-H), 5.59 (s, 1 H; OH,
D20
ex.), 5.14-5.00 (m, 2H; J = 7 Hz; -CH), 4.39-4.35 (d, 1 H; J = 14.7 Hz, -CH),
3.40-
3.38 (d, 4H; 2 x -CH2), 3.33-3.32 (d, 4H; 2 x CH2-) , 2.31 (s, 3H; Ar-CH3) &
1.32-
1.29 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 19:
2-{[1 R2R/1 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
NMR(CDCI3):- 8 7.48 (s, 1 H; Ar-H), 7.74 (s, 1 H; Ar-H), 7.69 (s, 1 H; Ar-H),
7.53-
7.61 (m, 1 H; Ar-H), 7.42-7.45 (m, 2H; Ar-H), 6.47-7.08 (m, 5H; Ar-H), 6.78-
6.85
(m, 2H, Ar-H), 5.60 (s, 1 H; OH, D20 ex.), 5.07-5.14 (q, 1 H; J = 7 Hz; -CH),
5.00-
5.05 (d, 1 H; J = 14 Hz, -CH), 4.34-4.39 (d, 1 H; J = 14 Hz; triazole-CH2),
3.37-
3.40 (m, 4H; 2 x -CH2), 3.05-3.09 (m, 4H; 2 x CHz ), 2.33 (s, 3H, CH3), 2.30
(s,
3H, CH3) & 1.29-1.32 (d, J = 7 Hz; 3H; CH3) ppm
Compound No. 20:
2-~[1 R2S/1S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-triazol-
1-
yl) propyl}-4-{4-[4-(2,4-dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-
triazolone
NMR(CDC13):- 8 8.08 (s, 1 H; Ar-H), 7.67 (s, 1 H; Ar-H), 7.31-7.39 (m, 2H; Ar-
H),
6.94-7.14 (m, 7H; Ar-H), 6.63-6.76 (m, ZH, Ar-H), 6.06 (s, 1 H; OH, D20 ex.),
5.04-
5.11 (q, 1 H; J = 7 Hz; -CH), 4.87-4.92 (d, 1 H; J = 15 Hz, -CH), 4.58-4.63
(d, 1 H;
J = 15 Hz; triazole-CHZ), 3.31-3.34 (m, 4H; 2 x -CH2), 3.02-3.03 (m, 4H; 2 x
CHI
), 2.29 (s, 3H, -CH3), 2.28 (s, 3H, CH3) & 1.61-1.63 (d, J = 7 Hz; 3H; CH3)
ppm
Compound No. 21:
2-{[1 R2R11 S2S]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
y1) propyl}-4-~4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone NMR(CDC13):- 88.03(s, 1 H; Ar-H), 7.78-7.73(d, 2H; Ar-H),
7.62-
7.60(q, 1 H; Ar-H), 7.50-7.47(d, 2H; Ar-H), 7.19-7.03(m, 5H; Ar-H), 6.89-6.82
(m,
64

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
2H; Ar-H), 5.58 (s, 1 H; OH, D20 ex.), 5.16-5.04 (m, 2H; J = 7 Hz; -CH), 4.43-
4.39
(d, 1 H; J = 14.7 Hz, -CH), 3.45-3.41 (d, 4H;2 x-CH2), 3.13-3.10 (d, 4H; 2 x
CH2 ),
2.35(s, 3H; Ar-CH3) & 1.36-1.33 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 22:
2-~[1 R2S/1 S2R]-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1 H-1,2,4-
triazol-1-
yl) propyl}-4-{4-[4-(5-chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-
1,2,4-triazolone NMR(CDCI3):- 88.15(s, 1 H; Ar-H), 7.74 (s, 1 H; Ar-H), 7.46-
7.39(m, 1 H; Ar-H), 7.31 (s, 1 H; Ar-H), 7.21-7.15(t, 3H; Ar-H), 7.05-6.99(m,
4H; Ar-
H), 6.79-7.72 (m, 2H; Ar-H), 6.12 (s, 1 H; OH, D20 ex.), 5.15-5.13 (q, 1 H; J
= 7
Hz; -CH-CH3), 4.98-4.93 (d, 1 H; J = 14.7 Hz, -CH), 4.69-4.64 (d, 1 H; J =
14.7 Hz,
-CH), 3.40-3.37 (t, 4H; 2 x -CH2), 3.10-3.07 (d, 4H; 2 x CHI ), 2.33(s, 3H; Ar-
CH3)
& 1.69-1.67 (d, J = 7 Hz; 3H; CH3) ppm.
Compound No. 35:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yf)propyl]-4-~4-[4-
(2-
methoxyphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-5-methyl-1,2,4-triazolone
NMR(CDC13):- 8 8.16 (s, 1 H; Ar-H), 7.81 (s, 1 H; Ar-H), 7.60-7.57 (m, 1 H; Ar-
H),
7.02-6.79 (m, 9H; Ar-H), 6.10 (s, 1 H; OH; D2O ex.), 4.70 (s, 2H; triazolone-
CH2),
4.55-4.50 (d, 1 H; J = 14.7 Hz; triazole-CH2), 4.18-4.13 (d,1 H; J = 15.0 Hz;
triazole-CH2), 3.89 (s, 3H; o-OCH3 ), 3.41 (s, 4H; piperazine-CHI ),3.21 (s,
4H;
piperazine-CH2 ) & 2.04(s, 3H; triazolone-CH3) ppm.
Compound No. 36:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
NMR(CDC13 DMSO-ds):- b 8.19 (s, 1 H; Ar-H), 7.77 (s, 1 H; Ar-H), 7.60-7.52 (m,
1 H; Ar-H), 7.42 (s, 1 H; Ar-H), 7.32-7.30 (d, 1 H; J = 8.7 Hz; Ar-H), 7.08-
7.29 (m,
9H; Ar-H), 6.86-6.79 (m, 2H; Ar-H), 6.09 (s, 1 H; OH, D20 ex.), 4.72 (s, 2H;
triazolone-CH2), 4.50-4.60 (d, 1 H; J =14.7 Hz;triazole-CH2), 4.19-4.15 (d, 1
H; J =

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
14.7 Hz; triazole-CH2), 3.39-3.33 (br, 4H;piperazine-CH2 ), 3.26 (s, 4H;
piperazine-CH2 ) & 2.04 (s, 3H; triazolne-CH3) ppm.
Compound No. 37:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(3,4-
dichlorophenyl)-1-piperazinyl]phenyl]~-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- b 8.16 (s, 1 H; Ar-H), 7.83 (s, 1 H; Ar-H), 7.59-7.56 (m, 1 H; Ar-
H),
7.49 (s, 1 H; Ar-H), 7.32-7.26 (m, 4H; Ar-H), 6.99-6.97 (d, 3H; Ar-H), 6.85-
6.76 (m,
3H; Ar-H), 4.70 (s, 2H; triazolone-CHI), 4.63-4.58 (d, 1 H; J = 14.7 Hz;
triazole-
CH2), 4.21-4.16 (d, 1H; J = 14.7 Hz; triazole-CHz), & 3.33 (s, 8H; piperazine-
CHZ ) ppm.
Compound No. 38:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-
diaminophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- b 8.19 (s, 1 H; Ar-H), 7.85 (s, 1 H; Ar-H), 7.63-7.55 (m, 1 H; Ar-
H),
7.51 (s, 1 H; Ar-H), 7.28-7.25 (d, 3H; Ar-H), 7.01-6.98 (d, 2H; Ar-H), 6.89-
6.80 (m,
3H; Ar-H), 6.15-6.10 (m,br, 2H; Ar-H), 4.72 (s, 2H; triazolone-CH2), 4.65-4.60
(d,
1 H; J = 15.0 Hz; triazole-CHz), 4.23-4.18 (d, 1 H; J = 15.0 Hz; triazole-
CH2), 3.34
(s, br, 4H; piperazine-CH2 ~ , & 3.02-3.00 (d, 4H; piperazine-CHZ )ppm.
Compound No. 39:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
methylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- b 8.18 (s, 1 H; Ar-H), 7.85 (s, 1 H; Ar-H), 7.64-7.55 (q, 1 H; Ar-
H),
7.50 (s, 1 H; Ar-H), 7.29-7.27 (t, 3H; Ar-H), 7.14-7.11 (d, 2H; Ar-H), 7.03-
6.99 (d,
2H; Ar-H), 6.93-6.80 (m, 4H; Ar-H), 5.95 (s, 1 H; OH, D20 ex.), 4.72 (s, 2H;
triazolone-CHz), 4.66-4.61 (d, 1 H; J = 15.0 Hz; triazole-CH2), 4.23-4.17 (d,
1 H; J
- 14.7 Hz; triazole-CHz), 3.38-3.36 (d, 4H; piperazine-CH2 ), 3.31-3.29(d, 4H;
piperazine-CH2 ) & 2.31 (s, 3H; triazolne-CH3) ppm.
66

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Compound No. 40:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-
dinitrophenyl.)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- b 8.74-8.73 (d, 1 H; Ar-H), 8.33-8.29 (m, 1 H; Ar-H), 8.17 (s, 1
H; Ar-
H), 7.82 (s, 1 H; Ar-H), 7.60-7.53 (m, 2H; Ar-H), 7.32-7.29 (d, 3H; Ar-H),
7.19-7.16
(d, 1 H; Ar-H), 6.98-6.95 (d, 2H; Ar-H), 6.85-6.79 (m, 2H; Ar-H), 5.90 (s, 1
H; OH,
D20 ex.), 4.72 (s, 2H; triazolone-CH2), 4.62-4.57 (d, 1 H; J = 14.7 Hz;
triazole-
CH2), 4.22-4.18 (d, 1 H; J = 14.7 Hz; triazole-CH2), 3.46-3.43(d, 8H;
piperazine-
CHz ) ppm
Compound No. 41:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(4-
methoxyphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- 8 8.19 (s, 1 H; Ar-H), 7.86 (s, 1 H; Ar-H), 7.65-7.57 (q, 1 H; Ar-
H),
7.51 (s, 1 H; Ar-H), 7.31-7.28 (m, 2H; Ar-H), 7.04-6.81 (m, 8H; Ar-H), 5.96
(s, 1 H;
OH, D20 ex.), 4.73 (s, 2H; triazolone-CH2), 4.66-4.61 (d, 1 H; J = 15.0 Hz;
triazole-CH2), 4.24-4.19 (d, 1 H; J = 15.0 Hz; triazole-CHI), 3.81 (s, 3H, -
OCH3),
3.40-3.37 (d, 4H;J piperazine-CHI ), & 3.26-3.23 (d, 4H; piperazine-CH2 ) ppm.
Compound No. 42:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(2-
methoxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- 8 8.19 (s, 1 H; Ar-H), 7.85 (s, 1 H; Ar-H), 7.64-7.55 (q, 1 H; Ar-
H),
7.50 (s, 1 H; Ar-H), 7.29-7.26 (t, 2H, Ar-H), 7.09-6.80 (m, 8H;Ar-H), 4.72 (s,
2H;
triazolone-CH2), 4.66-4.61 (d, 1 H; J = 15.0 Hz; triazole-CH2), 4.23-4.18 (d,
1 H; J
= 14.7 Hz; triazole-CH2), 3.91 (s, 3H, -OCH3), 3.43-3.39 (t, 4H; piperazine-
CH2 ),
& 3.25-3.22 (t, 4H; piperazine-CHz-) ppm.
Compound No. 43:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-{'4-[4-
(4-
fluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
67

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
NMR(CDCI3):- 8 8.17 (s, 1 H; Ar-H), 7.84 (s, 1 H; Ar-H), 7.59-7.57 (q, 1 H; Ar-
H),
7.49 (s, 1 H; Ar-H), 7.29-7.26 (t, 2H; Ar-H), 7.03-6.79 (s, 8H; Ar-H), 5.93
(s, 1 H;
OH, D20 ex.), 4.71 (s, 2H; triazolone-CH2), 4.64-4.59 (d, 1 H; J = 14.7 Hz;
triazole-CHI), 4.21-4.17 (d, 1 H; J = 14.7 Hz; triazole-CH2), 3.38-3.34 (t,
4H;
piperazine-CH2 ), & 3.27-3.24 (t, 4H; piperazine-CHI ) ppm.
Compound No. 44:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(4-
hydroxyphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- b 8.86 (s, 1 H; Ar-H), 8.32-8.27 (d, 2H; Ar-H), 7.72 (s, 1 H; Ar-
H),
7.44-7.41 (d, 2H; Ar-H), 7.33-7.30 (q, 1 H; Ar-H), 7.18-7.14 (t, 1 H; Ar-H),
7.10-
7.07 (d, 2H; Ar-H), 6.94-6.84 (m, 3H; Ar-H), 6.69-6.66 (d, 2H; Ar-H), 6.19 (s,
1 H;
OH, D20 ex), 4.83-4.77 (d, 1 H; J = 14.4 Hz; triazole-CH2), 4.66-4.62 (d, 1 H;
J =
14.4 Hz; triazole-CHI), 4.20 (s, 2H; triazolone-CHI), 3.35-3.32 (merging with
DMSO-d6 signal)(s, 4H; piperazine-CH2 ), & 3.11-3.09(d, 4H; piperazine-CHI )
ppm.
Compound No. 45:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-( 1 H-1,2,4-triazol-1-yl)propyl]-4-[4-[1-
phenylpiperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDC13):- 8 8.19(s, 1
H;
Ar-H), 7.85 (s, 1 H; Ar-H), 7.64-7.56 (s, 1 H; Ar-H), 7.50 (s, 1 H; Ar-H),
7.35-7.27
(m, 5H; Ar-H), 7.03-6.80 (m, 7H; Ar-H), 5.95 (s, 1 H; OH, D20 ex.), 4.72 (s,
2H;
triazolone-CHz), 4.66-4.61 (d, 1 H; J = 14.7 Hz; triazole-CHI), 4.23-4.18 (d,
1 H; J
= 14.7 Hz; triazole-CH2), & 3.37(s, 8H; piperazine-CH2 ) ppm.
Compound No. 46:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
- chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-5-methyl-1,2,4-triazolone
NMR(CDCI3):-88.17 (s, 1 H;Ar-H), 7.81 (s, 1 H;Ar-H), 7.58-7.55 (m, 1 H;Ar-H),
7.32-
7.26 (m, 2H;Ar-H), 7.06-6.78 (m, 9H;Ar-H), 6.06 (s, 1 H; OH, DSO ex.), 4.70
(s,
2H; triazolone-CH2), 4.54-4.49 (d, 1 H; J = 14.7 Hz; triazole-CHI), 4.19-4.14
(d,
68

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
1 H; J = 14.7 Hz; triazole-CH2), 3.37-3.33 (t, 8H; piperazine-CHZ-), & 2.03
(s, 3H;
triazolone-CH3) ppm.
Compound No. 47:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(4-
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- s 8.17 (s, 1 H; Ar-H), 7.83 (s, 1 H; Ar-H), 7.62-7.54 (m, 1 H; Ar-
H),
7.50 (s, 1 H; Ar-H), 7.29-7.23 (m, 4H; Ar-H), 7.01-6.98 (d, 2H; Ar-H), 6.91-
6.79 (m,
8H; Ar-H), 5.96 (s, 1 H; OH, DSO ex.), 4.72 (s, 2H; triazolone-CHz), 4.63-4.59
(d,
1 H; J = 14.7 Hz; triazoie-CHI), & 4.22-4.17 (d, 1 H; J = 14.7 Hz; triazole-
CH2), &
3.37-3.30 (q, 8H; piperazine-CHI ) ppm.
Compound No. 48:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(5-
chloro-2-methylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- 8 8.28 (s, 1 H; Ar-H), 7.90 (s, 1 H; Ar-H), 7.66-7.58 (m, 1 H; Ar-
H),
7.53 (s, 1 H; Ar-H), 7.32-7.29 (t, 2H; Ar-H), 7.29-7.26(d, 2H; Ar-H), 7.16-
7.14 (d,
1 H; Ar-H), 7.04-7.02(d, 4H, Ar-H), 6.89-6.82(m, 2H, Ar-H),5.96(br, 1 H; OH,
DSO
ex.), 4.74 (s, 2H; triazolone-CH2), 4.67-4.62 (d, 1 H; J = 14.7 Hz; triazole-
CHI), &
4.26-4.20 (d, 1 H; J = 14.7 Hz; triazole-CHI), 3.40-3.33(m, 4H; piperazine-CH2
) ,
3.10-3.07 (m, 4H; piperazine-CH2-) ppm.
Compound No. 49:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(3-
chloro-4-methylphenyl)-1-piperazinyl]phenyl-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- 8 8.20 (s, 1 H; Ar-H), 7.87 (s, 1 H; Ar-H), 7.65-7.58 (q, 1 H; Ar-
H),
7.52 (s, 1 H; Ar-H), 7.31-7.29 (d, 2H; Ar-H), 7.16-7.14(d, 2H; Ar-H),7.04-6.98
(m,
3H; Ar-H), 6.88-6.80 (m, 3H; Ar-H), 5.96(s, 1 H; OH, DSO ex.), 4.74 (s, 2H;
triazolone-CH2), 4.67-4.62 (d, 1 H; J = 14.7 Hz; triazole-CHI), & 4.24-4.17
(d, 1 H;
J = 14.7 Hz; triazole-CH2), & 3.3-3.33 (m, 8H; piperazine-CH2 ) ppm.
69

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Compound No. 50:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4
dichiorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDC13):
8.19 (s, 1 H; Ar-H), 7.86 (s, 1 H; Ar-H), 7.65-7.56 (m, 1 H; Ar-H), 7.51 (s, 1
H; Ar
H)', 7.43-7.42(d, 1 H; Ar-H),7.31-7.23 (m, 3H; Ar-H), 7.03-7.01 (d, 3H; Ar-H),
6.88-
6.81 (m, 2H; Ar-H), 5.93 (s, 1 H; OH, D20 ex.), 4.73 (s, 2H; triazolone-CH2),
4.66-
4.61 (d, 1 H; J = 14.7 Hz; triazole-CH2), & 4.24-4.19 (d, 1 H; J = 14.7 Hz;
triazole-
CH2), 3.42-3.39 (m, 4H; piperazine-CH2-) , 3.22-3.18 (m, 4H; piperazine-CH2-)
ppm.
Compound No. 51:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(3-
trifluoromethylphenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- 8 8.16 (s, 1 H; Ar-H), 7.83 (s, 1 H; Ar-H), 7.62-7.57 (q, 1 H; Ar-
H),
7.49 (s, 1 H; Ar-H), 7.40-7.35 (t, 1 H; Ar-H), 7.29-7.26(d, 2H; Ar-H), 7.15-
7.09(m,
3H; Ar-H),7.01-6.98 (d, 2H; Ar-H), 6.84-6.78 (m, 2H; Ar-H), 5.90(s, 1 H; OH,
DSO
ex.), 4.70 (s, 2H; triazolone-CHI), 4.63-4.58 (d, 1 H; J = 14.7 Hz; triazole-
CH2), &
4.21-4.16 (d, 1 H; J = 14.7 Hz; triazoie-CHI), & 3.37 (s, 8H; piperazine-CH2 )
ppm.
Compound No. 52:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-{4-[4-
(2,4-
difluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone NMR(CDCI3):-
8.16 (s, 1 H; Ar-H), 7.83 (s, 1 H; Ar-H), 7.62-6.78 (m, 11 H; Ar-H), 5.90 (s,
1 H,
OH), 4.70 (s, 2H; triazolone-CH2), 4.63 (d, 1 H; J = 14.9 Hz; triazole-CH2-),
4.19
(d, 1 H; J = 14.9 Hz; triazole-CH2-), 3.35 (bm, 4H; piperazine-CH2), 3.16 (bm,
4H;
piperazine -CH2) ppm
Compound No. 53:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propy!]-4-{4-[4-
(3-
chloro-4-fluorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- 8.17(s, 1 H; Ar-H), 7.84(s, 1 H; Ar-H), 7.62-7.54 (m, 1 H; Ar-H),

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
7.49 (s, 1 H; Ar-H), 7.29-7.26 (m, 2H; Ar-H), 7.08-6.95 (m, 4H; Ar-H),6.83-
6.98(m,
3H; Ar-H), 5.90 (s, 1 H; OH, D20 ex.), 4.71 (s, 2H; triazolone-CH2), 4.63-4.59
(d,
1 H; J = 14.8 Hz; triazole-CH2), 4.21-4.16 (d, 1 H; J = 14.8 Hz; triazole-
CH2),
3.35-3.34 (d, 4H; 2 x piperazine-CH2-) & 3.27-3.26 (d, 4H; 2 x piperazine-CH2-
)
ppm.
Compound No. 54:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(2,4
dimethylphenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDC13):
8.16 (s, 1 H; Ar-H), 7.82 (s, 1 H; Ar-H), 7.59-7.57 (m, 1 H; Ar-H), 7.48 (s, 1
H; Ar
H), 7.24-7.27 (m, 3H; Ar-H), 7.02-6.78 (m, 7H; Ar-H), 5.93 (s, 1 H; OH, D20
ex.),
4.63-4.70 (s, 2H; triazolone-CH2), 4.47-4.58 (d, 1 H; J = 15 Hz; triazole-
CH2),
4.21-4.16 (d, 1 H; J = 15 Hz; triazole-CH2), 3.35-3.32 (m, 4H; 2 x piperazine-
CH2-
3.04-3.01 (m, 4H; 2 x piperazine-CH2-) 2.30 (s, 3H; CHg) & 2.28 (s, 3H, CH3)
' ppm.
Compound No. 57:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(3
chlorophenyl)-1-piperazinyl]phenyl}-3-(2H,4H)-1,2,4-triazolone NMR(CDCI3):
8.16 (s, 1 H; Ar-H), 7.83 (s, 1 H; Ar-H), 7.59-7.57 (q, 1 H; Ar-H), 7.49 (s, 1
H; Ar
H), 7.29-7.26(d, 2H; Ar-H), 7.22-7.17(t, 1 H; Ar-H),7.00-6.97 (d, 2H; Ar-H),
6.92-
6.91 (m, 1 H; Ar-H),6.87-6.78 (m, 4H; Ar-H), 5.90(s, 1 H; OH, D20 ex.), 4.70
(s,
2H; triazolone-CH2), 4.63-4.58 (d, 1 H; J = 14.7 Hz; triazole-CH2), & 4.21-
4.16 (d,
1 H; J = 14.7 Hz; triazole-CH2), & 3.34 (s, 8H; piperazine-CH2-) ppm.
Compound No. 58:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1,2,4-triazo!-1-yl)propyl]-4-~4-[4-
(2-
chloro-4-fluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
NMR(CDC13):- 8 8.18(s, 1 H; Ar-H), 7.84(s, 1 H; Ar-H), 7.59-7.57 (m, 1 H; Ar-
H),
7.49 (s, 1 H; Ar-H), 7.29-6.79 (m, 9H; Ar-H), 5.92 (s, 1 H; OH, DSO ex.), 4.71
(s,
2H; triazolone-CH2), 4.64-4.59 (d, 1 H; J = 14.8 Hz; triazole-CHI), 4.22-4.17
(d,
71

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
1 H; J = 14.8 Hz; triazole-CH2), 3.38-3.35 (t, 4H; 2 x piperazine-CHZ-) & 3.23-
3.20
(t, 4H; 2 x piperazine-CH2 ) ppm.
Compound No. 59:
2-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-~4-[4-
(2-
methoxy-5-fluorophenyl)-1-piperazinyl]phenyl)-3-(2H,4H)-1,2,4-triazolone
NMR(CDCI3):- b 8.19(s, 1 H; Ar-H), 7.85(s, 1 H; Ar-H), 7.60-7.57 (m, 1 H; Ar-
H),
7.50 (s, 1 H; Ar-H), 7.29-7.26 (m, 3H; Ar-H),7.02-6.99 (d, 2H; Ar-H), 6.85-
6.78 (m,
3H; Ar-H),6.72-6.68(m, 2H; Ar-H),5.95 (s, 1 H; OH, DSO ex.), 4.72 (s, 2H;
triazolone-CH2), 4.65-4.60 (d, 1 H; J = 14.8 Hz; triazole-CHz), 4.22-4.17 (d,
1 H; J
= 14.8 Hz; triazole-CHI), 3.87(s,3H;OCH3), 3.41-3.38 (d, 4H; 2 x piperazine-
CHI )
& 3.22-3.21 (d, 4H; 2 x piperazine-CH2 ) ppm.
PHARMACOLOGICAL ACTIVITY
Compounds of the Formulae IA, IB, II and III as shown herein, and their
salts are useful in the curative or prophylactic treatment of fungal
infections in
animals, including humans. For example, they are useful in treating topical
fungal infection in man caused by, among other organisms, species of candida,
Trichophyton, Microsporum or Epidermophyton in mucosal infections caused by
C. albicans (e.g., thrush and vaginal candidiasis). They can also be used in
the
treatment of systemic fungal infections caused by, for example, species of
Candida (e.g., Candida albicans), Cryptococcus neoformans or Aspergillus
fumigatus.
The compounds of the present invention have been found to have
unexpectedly good activity against clinically important Aspergillus species
fungi.
72

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
The in vitro evaluation of the antifungal activity of the compounds can be
performed by determining the minimum inhibitory concentration (MIC) which is
the concentration of the test compound in Rosewell Park Memorial Institute
~RPMI) 1640 liquid medium buffered with (3-[Morphoiinojpropanesulphonic acid)
MOPS to ~H7, at which there is significant inhibition of the particular fungi
In
practice the National Committee for Clinical Laboratory Standard (NCCLS) M27A
document for Candida and Cryptococcus and M38P for Aspergillus was used to
determine the MIC against yeast and filamentous fungi with suitable
modifications
for dermatophytes. Two quality control strains were included each time the MIC
were determined and readings recorded only when the QC results fell into the
acceptable range. After MIC results had been recorded, 100 p1 from each of the
well showing no growth was spread over Sabouraud Dextrose Acv ar (SDA) to
determine the minimum fungicidal concentration.
The in vivo evaluation of the compound can be carried out at a series of
dose levels by oral or I.V. injection to mice which are inoculated I.V. with
the
minimum lethal dose of Candida albicans, Cryptococcus neoformans or
Aspergillus fumigates by the tail vein. Activity is based on the survival of a
treated group of mice after the death of an untreated group of mice. For
Aspergillus and Cryptococcus infections target organs were cultured after
treatment to document the number of mice cured of the infection for further
assessment of activity.
For human use, the antifungal compounds of the formula and their salts
can be administered alone, but will generally be administered in admixture
with a
pharmaceutical carrier selected with regard to the intended route of
73

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
administration and standard pharmaceutical practice. For example, they can be
administered orally in the form of tablets containing such excipients as
starch or
lactose, or in capsules or ovules either alone or in admixture with
excipients, or in
the form of elixirs, solutions or suspensions containing flavouring or
colouring
agents. They can be injected parenterally, for example, intravenously,
intramuscularly or subcutaneously. For parenteral administration, they are
best
used in the form of a sterile aqueous solution which may contain other
substances, for example, enough salts or glucose to make the solution isotonic
with blood.
The solubility of a compound of the Formulae IA, IB, II and III in an
aqueous medium may be improved by complexation with a hydroxyalkyl
derivative of a cyclodextrin in the preparation of an appropriate
pharmaceutical
composition.
For oral and parenteral administration to human patients, the daily dosage
level of the antifungal compounds of the Formulae IA, IB, II and III and their
salts
will be from 0.01 to 20 mg/kg (in single or divided doses) when administered
by
either the oral or parenteral routes. Thus tablets or capsules of the compound
will contain from 5 mg to 0.5 gm of active compound for administration one,
two
or more at a time, as appropriate. The physician in any event will determine
the
actual dosage which will be most suitable for an individual patient and it
will vary
with age, weight and response of the particular patient. The above dosages are
exemplary of the average case, there can, of course, be individual instances,
where higher or lower dosage ranges are required and such are within the scope
of this invention.
74

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Alternatively, the antifungal compound or Formulae IA, IB, II and III can be
administered in the form of a suppository or pessary, or they may be applied
topically in the form of a lotion, solution, cream, ointment or dusting
powder. For
example, they can be incorporated into a cream consisting of an aqueous
emulsion of polyethylene glycols or liquid paraffin, or they can be
incorporated, at
a concentration between 1 and 10 % into an ointment consisting of a white wax
or white soft paraffin base together with such stabilizers and preservatives
as
may be required.
Cryptococcosis is a leading cause of morbidity and mortality among AIDS
patients. In many patients Cryptococcosis is the first indication of AIDS. The
incidences of life-threatening cryptococcal infection among patients with AIDS
has been estimated to vary from 10 - 30 %. During initial therapy, 10 - 20 %
of
these patients die and 30 - 60 % patients succumb within 12 months (Powderly
WG: Cryptococcus meningitis and AIDS Clin. Infect. Dis. 1993; 17: 837 - 842).
Amphotericin B has changed disseminated cryptococcosis from uniformly
fatal infection to curable infection, but since Amphotericin B penetrates the
central nervous system poorly, intraventricular injection may have to be
administered for successful management of severe cases of Cryptococcal
meningitis. Fluconazole has excellent pharmacokinetics in CSF and perForms
equally well in patients with Cryptococcal meningitis. However, there is a
trend
towards earlier deaths and longer period before sterilisation of the CSF
(NIAID
[National Institute of Allergy and Infection Disease] Mycoses study group and
AIDS clinical trials group: comparison of Amphotericin B and Fluconazole in
the

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
treatment of acute AIDS associated Cryptococcus meningitis (N Engl J Med
1992; 326: 83 - 89).
Invasive aspergillosis has become a leading cause of death, mainly
among patients suffering from acute leukaemia or after allogenic bone marrow
transfusion and after cytotoxic treatment of these conditions. It also occurs
in
patients with conditions such as AIDS and chronic granulomatous disease. At
present, only Amphotericin B and Itraconazole are available for treatment of
aspergillosis. In spite of their activity in vitro, the effect of these drugs
in vivo
against Aspergillus fumigatus remains low and as a consequence mortality from
invasive aspergillosis remains high.
In vitro activity:
Compounds of this invention have potent in vitro activity against a wide
range of fungal pathogens tested. They are active against all species of
Candida, Histoplasma capsulatum, Cryptococcus neoformans, dermatophytes,
Aspergillus fumigatus and A. flavus. The action on many of these strains,
especially against Cryptococcus and Aspergillus is fungicidal in vitro.
76

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Table containing the biological evaluation of these compounds
Candida C.krusei C.parap-CandidaC. H. C. A.
albicans silosisfropicalisglabratacapsul-neoformans
fumigatu
o. Q. ATCC 90030 afum s 1008
C.
A 26 1.549Y'~~'~9766-1 I M
Q. 106
C
1 <0.03 0.12 0.12 0.25 0.12<0.03 <0.03 0.25 0.06 <0.03<0.030.12
2 <0.03 1.00 0.25 2.00 1.00<0.03 <0.03 0.50 <0.03<0.03<0.03>16
3 <0.03 0.12 0.50 1.00 0.50<0.03 <0.03 0.25 <0.03<0.03<0.030.25
4 <0.03 4.00 >16 >16 >16 0.25 <0.03 2.00 0.50 0.25 1.00 >16
<0.03 2.00 0.12 0.50 0,12<0.03 <0.03 1.00 <0.03<0.03<0.030.50
6 <0.03 2.00 8.00 >16 16.00.125 <0.03 >16 0.12 0.25 2.00 >16
7 <0.03 0.25 0.12 0.25 0.12<0.03 <0.03 0.12 0.12 <0.03<0.030.25
8 <0.03 >16 > 16 >16 > 1.00 >16 >16 2.00 16.0016.00>16
16
9 <0.03 0.25 0.25 0.50 0.12<0.03 <0.03 0.25 0.06 <0.03<0.030.50
<0.03 0.50 1.00 >16 1.00<0.03 <0.03 0.50 0.06 0.06 <0.03>16
11 <0.03 0.06 0.12 0.25 0.12<0.03 <0.03 0.25 <0.03<0.03<0.030.25
12 <0.03 4.00 8.00 >16 8,000.06 <0.03 4.00 <0.030.12 0.25 >16
13 <0.03 0.12 0.25 0.50 0.12<0.03 <0.03 0.50 0.06 <0.03<0.030.25
14 <0.03 2.00 2.00 >16 16.00.06 <0.03 2.00 0.12 0.50 <0.03>16
<0.03 1.00 0.25 0.50 0.25<0.03 <0.03 0.50 0.12 <0.03<0.030.50
16 <0.03 4.00 1.00 >16 1.000.06 <0.03 0.50 0.50 0.12 0.12 >16
17 <0.03 0.25 0.25 0.50 0.50<0.03 <0.03 0.50 0.25 <0.03<0.030.25
18 <0.03 2.00 1.00 >16 2,000.25 <0.03 1.00 0.25 0.12 0.25 >16
19 <0.03 1.00 1.00 >16 0.500.06 <0.03 >16 0.50 <0.03<0.03>16
<0.03 8.00 2.00 >16 2.000.12 <0.03 2.00 0.50 0.25 0.25 >16
21 <0.03 0.25 0.25 0.50 0.250.06 <0.03 0.50 0.12 <0.03<0.031.00
22 <0.03 2.00 1.00 8.00 1.000.25 <0.03 1.00 >16 0.12 0.06 >16
23 <0.03 0.25 0.50 0.50 0.25<0.03 <0.03 0.50 0.06 <0.03<0.031.00
24 <0.03 2.00 16.00 >16 16.00.25 <0.03 2.00 0.25 0.50 1.00 >16
<0.03 0.06 0.12 0.12 0.06<0.03 <0.03 0.12 0.06 <0.03<0.030.50
26 <0.03 0.25 1.00 2.00 0.50<0.03 <0.03 1.00 0.12 <0.03<0.038.00
27 <0.03 1.00 0.50 2.00 0.50<0.03 <0.03 1.00 <0.03<0.03<0.03>16
28 <0.03 8.00 4.00 >16 16.00.25 <0.03 4.00 2.00 0.25 1.00 >16
29 <0.03 0.25 0.25 0.50 0.25<0.03 <0.03 0.50 0.25 <0.03<0.030.50
<0.03 0.50 1.00 8.00 1.000.12 <0.03 1.00 0.50 0.12 0.25 >16
31 <0.03 >16 0.12 0.50 0.12<0.03 <0.03 0.50 0.06 <0.03<0.031.00
32 <0.03 >16 4.00 >16 4.000.50 <0.03 2.00 0.25 0.50 0.50 >16
33 <0.03 0.13 0.13 0.25 0.06<0.03 <0.03 0.25 0.12 <0.03<0.030.50
34 <0.03 1.00 1.00 2.00 1.000.25 <0.03 0.50 0.12 0.25 <0.03>1677
<0.02 1.56 3.12 12.503.120.20 <0.02 12.50 0.20 0.80 3.12 >12.5
36 <0.02 0.20 0.40 3.12 1.56<0.02 <0.02 3.12 <0.020.20 0.40 >12.5
37 <0.03 0.06 0.06 0.25 0.06<0.03 <0.03 0.12 <0.03<0.03<0.03>16
38 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16 >16
39 <0.02 0.10 0.02 0.80 0.10<0.02 6.25 0.10 0.05 <0.020.05 6.25
<0.02 0.40 0.40 6.25 1.560.05 1.56 0.80 0.05 0.05 0.20 1.56
41 <0.02 0.05 0.10 1.56 0.40<0.02 3.12 0.80 <0.020.10 0.40 6.25
42 0.05 0.40 12.50 3.12 1.56<0.02 12.50 1.56 0.05 0.20 0.80 >12.5
43 <0.02 <0.020.05 1.56 0.20<0.02 12.50 0.40 <0.020.05 0.05 >12.5
44 >12.5 >12,51.56 >12.56.250.20 6.25 6.25 1.56 1.56 3.12 >12.5
<0.02 0.05 0.05 0.80 0.10<0.02 3.12 0.10 3.12 <0.020.10 >12.5
46 <0.02 0.40 0.40 3.12 0.80<0.02 0.05 6.25 0.10 0.05 0.40 >12.5
47 <0.02 0.20 0.20 1.56 1.56<0.02 <0.02 3.12 0.05 <0.020.40 3.12
48 <0.03 0.50 0.50 1.00 0.500.12 <0.03 1.00 0.25 <0.030.06 >16
49 <0.03 <0.03<0.03 0.25 0.06<0.03 <0.03 0.25 <0.03<0.03<0.034.00
<0.03 0.12 0.12 0.50 0.25<0.03 <0.03 0.50 <0.03<0.03<0.032.00
77

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
Candida C.krusei C.parap-CandidaC. N. C. A.
albicans neoformans
silosistropicalisglabratacapsui- fumigatu
No. Q. ATCC 90030 atom s 1008
C.
A 26 1.549Y-01-19766-1Q. I M
C 106
51 <0.03 0.25 0.25 1.00 0.250.06 <0.03 1.00 <0.03<0.03 <0.03>16
52 <0.03 0.06 0.12 4.00 0.50<0.03 <0.03 1.00 <0.03<0.03 <0.03>16
53 <0.03 0.06 <0.03 0.50 0.12<0.03 <0.03 0.50 <0.03<0.03 <0.034.00
54 <0.03 8.00 0.12 0.50 0.12<0.03 <0.03 1.00 0.06 <0.03 <0.032.00
55 <0.03 0.03 0.03 1.00 0.12<0.03 <0.03 0.25 0.004<0.03 0.02 >16
56 <0.03 0.06 0.03 1.00 0.25<0.03 <0.03 0.25 0.004<0.03 0.03 >16
57 <0.03 0.25 0.12 0.50 0.25<0.03 <0.03 0.25 0.06 <0.03 <0.03>16
58 <0.03 0.03 0.03 1.00 0.25<0.03 <0.03 0.25 0.004<0.03 <0.032.00
59 <0.03 1.00 0.50 4.00 1.00<0.03 <0.03 1.00 <0.03<0.03 0.12 >16
60 <0.03 >16 0.25 1.00 0.25<0.03 <0.03 0.50 <0.03<0.03 <0.03>16
61 <0.03 0.25 0.12 0.50 0.25<0.03 <0.03 0.50 <0.03<0.03 <0.03>16
62 <0.03 4.00 0.50 2.00 0.50<0.03 <0.03 1.00 <0.03<0.03 0.12 16.00
63 <0.03 0.06 0.12 8.00 0.25<0.03 <0.03 0.50 <0.03<0.03 <0.03>16
In vivo activity:
Compounds of this invention have enhanced antifungal activity against the
important fungal pathogens of men and animals.
a) Anti candida activity:
A single oral dose of 12.5 mg / kg bw. (0.25 mg per mouse) is adequate to
offer significant protection to mice infected via the tail vein by lethal dose
of C. albicans A-26.
1o Summary of single dose studies with azoles in systemic
infection with Candida albicans A-26
Exam 1e Mean survival days
1 cd) 12.1
1 10.5
Sham treated 3.5
78

CA 02402345 2002-09-06
WO 01/66551 PCT/IBO1/00300
b) Anti cryptococcal activity:-
The compounds of this invention cross the blood brain barrier to excert
their potent anti cryptococcal activity in the brain. In an animal model
where lethal infection (1 million cells of C. neoformans) were injected into
the cranium of the animal, oral dosing with 25 mg/kg bw. BID for ~ days
reduced the count by 4 logs, causing 99.99 % reduction in the fungal load.
c) Anti Aspergillus activity:-
Doses as low as 6.25 mg / kg bw. significantly increased the survival of
mice infected via the tail vein with lethal dose of Aspergillus fumigatus
conidia.
d) Anti Dermatophyte activity:-
Single local application of the drug had significant effect on Trichophyton
menfagrophyfe infection of guinea pig skin.
79