Thiazolidine derivatives and its use as antifungal agent

Details Thiazolidine derivatives and its use as antifungal agent Thiazolidine derivatives and its use as antifungal agent

2003-02-21

2004-05-25

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S183000

Reexamination Certificate

active

06740670

ABSTRACT:

The present invention relates to novel compounds, pharmaceutical compositions comprising novel compounds and novel compounds for use in medicine especially as antifungal agents. In addition, the invention provides compounds for the preparation of a medicament for use as an antifungal agent and methods of treating an individual susceptible to or suffering from an antifungal infection.
Fungal infections can affect animals including humans. These can include infections of the joints and skin. Some fungal infections occur as a result of opportunistic infection of a weakened or immune-suppressed individual. The incidence of life-threatening fungal infections has increased dramatically as the population of immunocompromised individuals (including cancer, organ transplant and AIDS patients) has increased. Present therapeutic options for the treatment of these infections are limited to two classes of compound: polyenes and azoles. The utility of polyenes is limited by nephrotoxicity and resistance is emerging to azoles. There is therefore a need for new anti-fungal compounds with novel mechanisms of action for use in treating or preventing such fungal infections.
WO94/29287 discloses arylidene-4-oxo-2-thioxo-3-thiazolidine carboxylic acids of the formula
and their use in the treatment of atherosclerosis, arteriosclerosis and the late effects of diabetes.
WO00/18747 discloses rhodanine carboxylic acid derivatives of the formula
for the treatment and prevention of metabolic bone disorders.
We have now found that certain thiazolidine derivatives exhibit antifungal activity.
The first aspect of the present invention provides a compound of formula I or a salt thereof
wherein X is O or S,
A and B are OR2 or Y—NR3R4
wherein when A is OR2, B is Y—NR3R4 and vice versa,
or when one of A or B is OR2, then the other can be CO
2
R7,
Y is CH
2
or C═O,
Q is (CH
2
)
m
—CH(R1)—(CH
2
)
n
,
R is OR6 or NHR7,
R1 is hydrogen, C
1
-C
6
branched or straight chain optionally substituted with hydroxyl, C
1
-C
3
alkylphenyl or phenyl,
R2 is hydrogen, C
1
-C
10
branched or straight chain alkyl or cycloalkyl, C
1
-C
10
branched or straight chain alkenyl, C
1
-C
10
branched or straight chain alkynyl, (CH
2
)
m
—(CF
2
)
n
CF
3
, (CH
2
)
n
—CH(R10)—(CH
2
)
q
-aryl or (CH2)
p
-aryl, where aryl is phenyl, pyridyl, thienyl or furyl;
wherein phenyl is optionally substituted by one or more substituents selected from F, Cl, Br, CF
3
, OCF
3
, OR6, C
1
-C
6
branched or straight chain alkyl, COR, CN, SO
2
R8, SONR8R9, and pyridyl, thienyl or furyl are optionally substituted by F, Cl, Br, CF
3
, OR6 or C1-C6 branched or straight chain alkyl,
R3 and R4 are independently hydrogen, C
1
-C
6
branched or straight chain alkyl, C(═O)R6, —CH(CH
2
OCOR8)-aryl or CH(R8)—(CH
2
)
p
-aryl where aryl is phenyl, pyridyl, thienyl or furyl wherein phenyl is optionally substituted by one or more substituents selected from F, Cl, Br, CF
3
, OCF
3
, OR6, C
1
-C
6
branched or straight chain alkyl, COR, CN, SO
2
R8 or phenyl,
R3 and R4 may be the same or different; taken together R3, R4 may form a 4-7 membered ring optionally incorporating an additional heteroatom, for example O, N or S wherein the ring may be optionally substituted at any position with (CH
2
)
p
-aryl where aryl is phenyl optionally substituted by one or more substituents selected from F, Cl, Br, CF
3
, OCF
3
, C
1
-C
6
branched or straight chain alkyl, COR, CN, SO2R8 or phenyl,
R5 is hydrogen, C
1
-C
6
branched or straight chain alkyl or phenyl optionally substituted by one or more substituents selected from F, Cl, Br, CF
3
, OCF
3
, OR6, C
1
-C
6
branched or straight chain alkyl, COR, CN or SO
2
R8,
R6 and R7 are independently hydrogen or C
1
-C
10
branched or straight chain alkyl or (CH
2
)
p
-phenyl
R8 is hydrogen or C
1
-C
3
alkyl.
R9 is C
1
-C
6
branched or straight chain alkyl or phenyl,
R10 is hydrogen, C
1
-C
10
branched or straight chain alkyl, (CH
2
)
p
-Aryl where aryl is phenyl optionally substituted by one or more substituents selected from F, Cl, Br, CF
3
, OCF
3
, C
1
-C
6
branched or straight chain alkyl, COR, CN, SO
2
R8,
and m, n and p are integers wherein m=0−3; n=0−2; p=0−3.
In a preferred embodiment compounds of formula I are provided in which:
X is O or S;
A and B are OR2 or Y—NR3R4
Wherein when A is OR2, B is Y—NR3R4 and vice versa,
or when one of A or B is OR2, then the other can be CO
2
R6;
Y is CH
2
or C═O;
Q is CH(R1);
R is OH;
R1 is hydrogen, C
1
-C
6
alkyl or C
1
-C
3
alkylphenyl;
R2 is hydrogen, C
1
-C
10
branched or straight chain alkyl, (CH
2
)
p
-phenyl, wherein phenyl is optionally substituted by one or more substituents selected from F and CF
3
;
R3 and R4 are independently hydrogen, C
1
-C
6
branched or straight chain alkyl, (CH
2
)
p
-phenyl, C(═O)C
1
-C
10
branched or straight chain alkyl, —CH(CR8)-phenyl —CH(CH
2
OCOR8)-phenyl, or R3 and R4 together form a morpholino, piperidinyl or piperazinyl group optionally substituted with (CH
2
)
p
-phenyl; and
R5 is hydrogen; and wherein p is an integer=0-3.
Preferred compounds of the invention include;
5-[[[3-(N-methyl-N-phenylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dibenzylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dipentylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-((S)-N-Benzyl-N-alpha-methylbenzylamino)carbonyl-4-(phenyl-methoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dibutylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N-Benzyl-N-butylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-((R)-N-alpha-methylbenzylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-((S)-N-methyl-N-alpha-methylbenzylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(Dipentylamino)carbonyl-4-methoxy]phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-((S)-N-Benzyl-N-alpha-methylbenzylamino)carbonyl-4-methoxy]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dipentylamino)carbonyl-4-[(2,4-difluorophenyl)-methoxy]]phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dipentylamino)carbonyl-4-(trifluorophenyl)-methoxy]phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[3-[(Dibenzylamino)methyl]-4-(phenylmethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[3-[(Dipentylamino)methyl]-4-(phenylmethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
(R)-5-[[[3-(N-&agr;-(Acetoxymethyl)benzyl-N-benzylamino)carbonyl-4-(phenylmethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[[3-(N,N-Dipentylamino)carbonyl-4-(2-phenylethoxy)]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid;
5-[[4-(2-Phenylethoxy)-3-[(N-phenyl-N-2-n-propyl-n-pentylcarbonyl)aminomethyl]-phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
The invention also extends to prodrugs of the aforementioned compounds. A prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug which is converted to the active ingredient or drug in the body. In addition, the invention extends to active derivatives of the aforementioned compounds.
Where a compound of the invention contains

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