Class of piperazino substituted thiazoles

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C544S367000

Reexamination Certificate

active

06281217

ABSTRACT:

This invention relates to a novel class of substituted azoles and, more specifically, diaryl substituted thiazoles, diaryl substituted thiadiazoles and diaryl substituted oxadiazoles, compounds which are useful in the treatment of fungal infections in mammals including humans. These compounds are active against a broad spectrum of fungi such as
Candida albicans, Candida parpsilosis, Candida tropicalis, Candida Krusei, Cryptococcus neoformans, Aspergillus fumigatus
and
Torulopsis glabrata
. Moreover, compounds within this series are also active against Fluconazole resistant strains and isolates.
BACKGROUND OF THE INVENTION
Opportunistic fungal infections are responsible for increased morbidity and mortality among patients suffering from AIDS and other immunocompromised diseases including infections resulting from neutropenia, cancer chemotherapy and organ transplantation (Annals N.Y. Acad. Sc., 544:1-3).
Moreover, until recently, the treatment of deep seated fungal infections has lagged behind the treatment of bacterial infections and only a few systemic agents are available for combatting these invasive pathogens.
Current therapy provides for administering polyenes such as amphotericin B, allylamines such as Naftafin and Terbinafin and azoles such as Fluconazole, Itraconazole and Ketoconazole. Amphotericin B, once the treatment of choice, is no longer favored due to the acute and chronic toxicities associated with its use.
Also, antifungal azoles are fungistatic, not fungicidal, and this has resulted in azole resistant fungi, that is, fungi strains and isolates which are resistant to treatment with Fluconazole and other known antifungal agents (New Engl. J. Med., 1944, 330: 263-272.)
KNOWN PRIOR ART
Azole compounds in which hydroxy and/or carboxy groups comprise the molecular structure are known to be useful in combatting pathogenic fungi.
For example, British Patent No. 2,099,818 and U.S. Pat. No. 4,404,216 disclose Fluconazole
a triazole derivative which has played an important role in protecting against a variety of fungi.
Also, DE-4124942 discloses azoles of the following structure having antithrombotic and fibrinogen-binding activities:
wherein: one of X
1
-X
5
=Q
1
-Q
3
, a second=Q
4
-Q
6
, a third=S, SO, N, R
1
N, R
2
C, (R
2
)
2
C, a fourth=O, S, N, SO
2
, R
2
C, CO, and a fifth=R
2
C, (R
2
)
2
C, N; A=cyano, (substituted) phenylene, pyridinylene, pyrazinylene, triazinylene, C=(substituted) phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, triazinylene, cycloalkylene) cycloalkylene; D=(substituted) alkylene, alkeylene, etc.; E=bond, alkylene, etc., F=carboxy, (substituted) alkoxycarbonyl; R
1
=H, alkyl, aralkyl, aryl, heteroaryl; R=H, Cl, Br, alkyl, aralkyl, aryl, heteroaryl, alkoxy, R
1
O
2
C, (R
1
)
2
N, etc. These compounds are said to have antithrombotic and fibrinogen-binding activity. The closest example is 4-(4-amidinophenyl)-2-[4-(2-carboxyethyl)phenyl]thiazole.
WO-9209586 (EP 0 513387 A1) discloses thiazole derivatives represented by the following structure useful as superoxide radical inhibitors:
wherein:
R
1
is substituted phenyl, pyridyl, thienyl, carbostyril, pyrazyl, pyrrolyl, quinolyl, 3,4-dihydrocarbostyril;
R
2
is hydrogen, halo, alkyl, phenyl, alkoxycarbonyl, alkylamino, and the like;
X is sulfur or oxygen;
R
3
is Q (supra) wherein R is hydroxyl, carboxylic acid, alkyl, alkenyl and m is 0-2 or, R
3
may be T (supra), wherein R
4
is hydrogen or alkyl and R is aminoalkyl.
The structure activity relationship (SAR) of the above series has been published in the J. Med. Chem. 1995, 38, 353-358 where the following general structure is shown:
WO-9324472 (EP 0 600092 A1) discloses compounds of the following structure as an active oxygen inhibitor:
wherein:
R
1
is Ph which may be substituted by 1 to 3 alkoxy groups; and
R
2
is a substituted pyridylcarbonyl which may be substituted by alkoxycarbonyl, carboxyl, a 5 to 15 membered mono-, di-, or tricyclic heterocyclic ring residue having 1 to 3 N, O or S, atoms, or a phenylmoiety of the formula:
 wherein, R
3
represents carboxyl, lower alkoxycarbonyl, hydroxyl substituted lower alkyl, lower alkoxy, tri-lower alkyl-substituted silyloxy, hydroxy, or hydrogen; R
4
represents hydrogen, lower alkenyl or lower alkyl: R
5
represents an amino-lower alkoxycarbonyl which may be substituted further by lower alkyl, amino-lower alkoxy, or lower alkoxy or the like.
U.S. Pat. No. 4,791,200 describes compounds of the following structure useful as antisecretory agents:
wherein:
R is C1 to C4 alkyl, phenyl, phenyl substituted by CF
3
, halo selected from I, Br or Cl, C1-C3 alkyl, alkoxy, acetamido, nitro, cyano, alkyamino or dialkylamino having 1-4 carbons or pyridyl.
R
1
is H or C1-C4 alkyl,
R
2
is H, C1-C4 alkyl, C1-C3 alkoxy or, Cl Br or I,
R
3
or R
4
are —O—(CH
2
)
m
—NR
5
R
6
wherein m=1-3.
Patel and Colah in Bull Haff Instt. (1977), 5, 72-74 disclose p-(2-substituted-4-thiazolyl)phenylacetic acid and p-(2-substituted-4-thiazolyl)phenoxyacetic acids useful in treating tuberculosis and fungi:
wherein R
1
is CH
2
COOH or OCH
2
COOH; and
Ar is phenyl, substituted phenyl or benzyl and the like.
Kirke et al in Bull. Haffkine Inst., (1977), 5, 75-7, and (1974), 2, 28-31 disclose a series of thiazolyl-phenoxyacetic acids and derivatives having in vitro antiluberculosis and antifungal activity against
T. rubrum
and
T. mentagrophytes.
Anne et al in Antimicrob. Agents Chemother., (1980), 18(2), 231-9 disclose diaryloxadiazole derivatives having only very weak activity against
Candida albican
(MIC
50
>60 &mgr;g/ml) as, for example:
SUMMARY OF THE INVENTION
This invention relates to diaryl substituted azoles and pharmaceutically acceptable salts thereof useful as antifungal agents.
This invention also includes methods for preparing said azoles and antifungal compositions containing these compounds or a pharmaceutically acceptable salt thereof as the active ingredient.
The azoles of this invention are compounds of the general formula:
wherein:
Ar is phenyl, thienyl, pyridyl substituted with R
1
R
2
where R
1
, R
2
are independently hydrogen or halogen such as F, Cl, Br and I; alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxyl, cyano, nitro, COOH, aminocarbonyl or aminosulfonyl, alkylamino, diakylamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl, alkylamino, dialkylamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl or, taken together, R
1
, R
2
may form a ring —O—(CH
2
)
n
—O— wherein n=1,2.
R
3
, R
4
are independently hydrogen, C1-C16 alkyl which may optionally be substituted with amino, dialkylamino, hydroxy, cyano, carboxy; alkenyl, alkynyl, acyl or, taken together, R
3
and R
4
may be —(CH
2
)m—Q—(CH
2
)m′— where m′=m=2, Q=CH
2
, O, S(O)
n
, n=0-2, NR
7
wherein R
7
is C1-C3 alkyl with the proviso that when Q is CH
2
, m′ can also be 1.
R
5
is H, halogen as defined above, OR, OH, NO
2
, NH
2
or NHCOR where R is lower alkyl, alkyl or aryl, and the like.
X is N, O or S;
Y is N or S, with the proviso when X=O or S, Y must be N;
Z is N or CR
8
, where R
8
is hydrogen, halogen such as Cl, Br or I, lower alkyl or alkoxycarbonyl, with the proviso that X, Y and Z cannot all be N at the same time.
V is N, O or S, and when V is N, it may also be combined with R
3
and R
4
to form a heterocycle such as pyrrole, imidazol-1,2,4,-triazole, 1,3,4-triazole and pyrazole, and when V is O or S, R
3
and R
4
combine to form a single substituent having the definition of R
4
alone; and
P is an integer having a value of 1-3.
Specifically, this invention relates to thiazoles of the formula:
wherein: R
1
, R
2
, R
3
, R
4
, R
5
, p and V are each as defined above in formula (I) and R
6
is hydrogen, halogen, carboxy, alkoxy carbonyl, lower alkyl, hydroxy and lower alkoxy and the nontoxic pharmacologically acceptable salts thereof.
This invention also relates to thiadiazoles of the follo

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