Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-05
2001-10-09
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S204000, C548S205000
Reexamination Certificate
active
06300353
ABSTRACT:
The present invention relates to novel azoles of general formula I,
wherein:
R
14
, R
15
are each independently hydrogen or fluorine,
T is a group of the formula:
wherein
R
9
is pyrrolidinyl or a group A—NH—B—,
A is hydrogen or straight-chain or branched C
1
-C
5
alkyl;
B is straight-chain or branched C
1
-C
4
alkylene, —CH
2
—CONH—CH
2
or —CH
2
CH
2
CH
2
—CH(NH
2
); and
X
−
is a pharmaceutically acceptable anion.
The present invention further relates to processes for the manufacture of said azoles, pharmaceutical compositions, particularly antifungal compositions, containing said azoles, and the use of these azoles for the production of medicaments for the treatment of fungal infections.
SUMMARY
Several azoles are currently used for systemic mycoses. However, none of them fully satisfies the requirements of the clinical setting, particularly with regard to: broad antifungal spectrum including aspergillus fumigatus; less drug-drug interaction; and appropriate plasma half-life for once a day treatment. Other clinical requirements which are not fulfilled by the azoles currently in use are: efficacy against major systemic mycoses including disseminated aspergillosis; safety; and oral or parenteral formulations. Particularly, the demand for a parenterally administered azoles is increasing for the treatment of serious systemic mycoses. Most of the azoles on the market, as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.
The novel azoles of formula I have less metabolic interaction liability which is a clear clinical advantage. Those azoles of formula I, wherein T is a group T
1
, are water soluble compounds useful for the treatment of systemic mycoses and suitable for both oral and particularly parenteral administration. Thus, the invention also relates to a method for the therapy of fungal infections and mycoses, which comprises administering to the infected organism an effective amount of the novel azole compounds.
DETAILED DESCRIPTION
The novel azoles of the present invention have the formula
wherein
R
14
, R
15
are each independently hydrogen or fluorine,
T is a group of the formula:
wherein
R
9
is pyrrolidinyl or a group A—NH—B—,
A is hydrogen or straight-chain or branched C
1
-C
5
alkyl;
B is straight-chain or branched C
1
-C
4
alkylene, —CH
2
—CONH—CH
2
or —CH
2
CH
2
CH
2
—CH(NH
2
); and
X
−
is a pharmaceutically acceptable anion;
and pharmaceutically acceptable salts of said compounds, and hydrates and solvates of the compounds of formula I and the salts thereof.
Where T is T
1
in the above formula I, the azoles of the invention have the formula
wherein
R
9
is pyrrolidinyl or a group A—NH—B—,
A is hydrogen or straight-chain or branched C
1
-C
5
alkyl;
B is straight-chain or branched C
1
-C
4
alkylene, —CH
2
—CONH—CH
2
or —CH
2
CH
2
CH
2
—CH(NH
2
); and
R
14
and R
15
are each independently hydrogen or fluorine.
Where T is T
2
in the above formula I, the azoles of the invention have the formula
wherein R
14
and R
15
are each independently hydrogen or fluorine.
Preferred compounds of formula I (I′ or II) are those wherein R
14
and R
15
are both H or F; or R
14
is H and R
15
is F.
Also preferred among the compounds of formula I′ are those wherein R
9
is 2-pyrrolidinyl, aminomethyl, (methylamino)methyl or (ethylamino)methyl.
The anion X
−
can be derived from a pharmaceutically acceptable inorganic acid, and thus is a chloride, bromide, sulfate or the like. The anion X
−
can also be derived from an organic acid, e.g. an aliphatic, aromatic or araliphatic carboxylic acid or sulfonic acid, and thus is an acetoxy, trifluoroacetoxy, mesyloxy or the like anion.
Examples of preferred azole compounds of the formula (I′) are:
1-[(2R,3R)-3-[4-(4-cyanophenyl)-thiazol-2-yl]-2-(2,4,5-trifluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)-benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)-benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-{4-cyanophenyl)thiazol-2-yl)]-2-(3-fluorophenyl)-2-hydroxybutyl]-3-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)-benzyl]-1H-1,2,4-triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
(2R,3R)-4-(4-aminoacetoxy-3,5-dimethylbenzyl)-1-[3-[4-(4-cyanophenyl)thiazol-2yl]-2-(2,4,5-trifluorophenyl)-2-hydroxynutyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
(2R,3R)-4-(4-aminoacetoxy-3,5-dimethylbenzyl)-1-[3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
(2R,3R)-4-(4-aminoacetoxy-3,5-dimethylbenzyl)-1-[3-[4-(4-cyanophenyl)-thiazol-2-yl]-2-(3-fluorophenyl)-2-hydroxybutyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4,5-trifluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(3-fluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
(2R,3R)-1-[3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4,5-trifluorophenyl)-2-hydroxybutyl]-4-[4-[(ethylamino)-acetoxy]-3,5-dimethylbenzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
(2R,3R)-1-[3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[4-[(ethylamino)-acetoxy]-3,5-dimethylbenzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluoroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(3-fluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(ethylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide, and particularly its trifluroacetic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4,5-trifluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium chloride, and particularly its hydrochloric acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1 ,2,4]triazol-4-ium chloride, and particularly its hydrochloric acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(3-fluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium chloride, and particularly its hydrochloric acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4,5-trifluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide hydrobromic acid salt,
1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[3,5-dimethyl-4-[(methylamino)acetoxy]benzyl]-1H-[1,2,4]triazol-4-ium bromide hydrobro
Hayase Tadakatsu
Ichihara Shigeyasu
Isshiki Yoshiaki
Liu Pingli
Ohwada Jun
Basilea Pharmaceutica AG, a Swiss Company
Gerstl Robert
Johnston George W.
Tramaloni Dennis P.
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