Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-06
2002-04-23
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S397000, C514S383000, C544S366000, C544S370000, C548S266200, C548S268800, C548S311100, C548S315100
Reexamination Certificate
active
06376497
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation of International Application PCT/KR 00/00030, with an international filing date of Jan. 18, 2000, now abandoned.
1. Field of the Invention
The present invention relates to novel antifungal azole derivatives having a fluorinated vinyl group, a process for preparing same and an antifungal composition containing same as an active ingredient.
2. Description of the Prior Art
A number of antifungal compounds have been developed for treating diseases caused by fungal infection and examples by currently available antifungal drugs include such azole derivatives as Fluconazole of Pfizer (GB Pat. No. 2,099,818, U.S. Pat. No. 4,404,216), Itraconazole of Janssen (U.S. Pat. No. 4,267,179, EP Patent Publication No. 6,711) and Voriconazole of Pfizer (EP Patent Publication No. 440,372, U.S. Pat. No. 5,278.175).
However, a long-term use of the above drugs may cause side effects such as liver damage and there has emerged a renewed interest in developing a more active and less toxic antifungal drug, as an ever increasing number of people are afflicted with such diseases as AIDS (acquired immune deficiency syndrome), cancer and diabetes, and become vulnerable to fungal infection.
Recently, a number of new azole derivatives have been developed by Janssen (see German Patent No. 2,804,096, U.S. Pat. Nos. 4,144,346 and 4,223,036, and PCT Publication No. WO95/08,993), Schering (see PCT Publication No. WO95/17,407 and WO93/09,114), Takeda(see EP Publication No. 421,210) and YuhanCorporation(see PCT Publication No. WO95/025,107) however, these antifungal compounds exhibit lower antifungal activities and narrower antifungal spectra in comparison with the conventional drugs.
The present inventors have endeavored to develop compounds having high antifungal activity against a wide spectrum of pathogenic fungi; and have unexpectedly found that a new class of azole derivatives having a fluorinated vinyl group exhibit excellent antifungal activities and low toxicity.
SUMMARY OF THE INVENTION
Accordingly, it is aprimary object of the present invention to provide a novel compound which is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi including
Candida albicans
, Torulopsis, Cryptoccocus, Aspergillus, Trichophyton and Fluconazole-resistant
Candida alhicans
, and also in toxicity.
It is another object of the present invention to provide a process for the preparation of said compound.
It is a further object of the present invention to provide an antifungal composition containing said compound.
In accordance with one aspect of the present invention, there is provided a novel azole derivative of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X is CH or N;
Y is O,
R
1
and R
2
are each independently F or Cl;
R
3
is a thiophenyl, naphthyl, or phenyl group, the phenyl group being optionally substituted with one or more substituents selected from the group consisting of C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkoxy, methylenedioxy and halogen; and
R
4
is H or trifluoromethyl.
DETAILED DESCRIPTION OF THE INVENTION
Among the compounds of the present invention, preferred are those wherein YisO; R
3
isaphenyl groupoptionally substituted with one or more substituents selected from the group consisting of Cl, F and Br.
Further, another preferred are those wherein X is CH; Y is O; R
3
is methylphenyl; and R
4
is H.
The novel azole derivatives substituted carrying a fluorinated vinyl group of formula (I) of the present invention may be prepared by a process which comprises reacting a compound of formula (II) with a fluorinated vinyl compound of formula (III) in the presence of a base as shown in Reaction Scheme 1.
wherein, X, Y, R
1
, R
2
, R
3
and R
4
have the same meanings as defined in formula (I).
In the above reaction, the compounds of formulae (II) and (III) may be used in equimolar amounts, and the base, in 1 to 2 molar amount.
Further, the solvent which can be used in the present invention includes a typical organic solvent, e.g., benzene, toluene, tetrahydrofuran, acetone, acetonitrile, dichloromethane, dimethylformamide and dimethylsulfoxide and it also includes an organic solvent mixed with water.
The base which can be used in the present invention includes an inorganic base (e.g.: sodium hydride, potassium hydride, potassium t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate) and an organic base (e.g.: triethylamine and pyridine).
The reaction temperature may range from a room temperature to 100° C. and the progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC).
The compound of formula (II) is represented by the compounds of formulae (II-a), (II-b) and (II-c) depending on the definition of the substituent Y.
wherein, X, R
1
and R
2
have the same meanings as defined above.
A compound of formula (II-a) may be prepared by a conventional method(see Heeres, J. et al.,
J. Med. Chem
., 22(8), 1003(1979)) as shown in Reaction Scheme 2:
wherein, X, R
1
and R
2
have the same meanings as defined above.
In Reaction Scheme 2, i) the carbonyl group of a compound of formula (II-a-5) is protected to form a compound of formula (II-a-4); ii) the compound of formula (II-a-4) is brominated to form a compound of formula (II-a-3) (see Levene, P. A.,
Org. Syn. Coll
., 2, 88 (1943)); the compound of formula (II-a-3) is benzoylated and recrystallized to form a compound of formula (II-a-2) (see Wheeler, T. S.,
Org. Syn. Coll
., 4, 478(1943), and Szeja, W.,
Synthesis
., 821 (1979)); and the compound of formula (II-a-2) is subjected to a substitution reaction to form a compound of formula (II-a-1), which is, in turn, debenzoylated to form a compound of (II-a)(see Mashimo, K. et al.,
Tetrahedron
, 26, 803 (1970)).
Since the compound of formula (II-a) has two chiral carbons, it is obtained as a mixture of four stereoisomers, a cis- and trans-type diastereomers each of which is composed of two enantiomers. In the present invention, the cis type diastereomer is separated in one of the subsequent reaction steps to form a compound of formula (II-a).
For example, 2-bromomethyl-2-(2,4-dichlorophenyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane obtained from the reaction of 2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl methanol (i.e., the compound of formula (II-a-3) wherein R
1
and R
2
are Cl) with benzoyl chloride is subjected to recrystallization to separate the cis diastereomer having a melting point of 115° C. in the form of a colorless crystal which is used in the next reaction, as in Reaction Scheme 2.
Further, in case of 2-bromomethyl-2-(2,4-difluorophenyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane obtained from the reaction of 2-bromomethyl-2-(2,4-difluorophenyl)-1,3-dioxolan-2-yl methanol(i.e., the compound of formula (II-a-3) wherein R
1
and R
2
are F) with benzoyl chloride, it is converted into 2-(2,4-difluorophenyl)-2-(1H-1-imidazolyl-methyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane, which is subjected to recrystallization to separate the cis form(i.e., a compound of formula (II-a-1)) having a melting point of 136° C., as shown in the following Reaction Scheme 3.
wherein, X has the same meaning as defined above.
In the present invention, cis isomers of formulae (II-a) and (II-b) and (II-c) are used.
A compound of formula (II-b) may be prepared by the method described in Heeres, J. et al.,
J. Med. Chem
., 26 (4). 611 (1983), i.e., by the process shown in Reaction Scheme 4 which comprises the steps of conducting a sulfonation reaction of a compound of formula (II-a) (see Furst A. et al.,
Helv. Chem. Acta
. 30. 1454 (1947)), substitution and debenzylation (see Heathcock, C. H. et al.,
J. Amer. Chem. Soc
., 93. 1746 (1971)).
wherein, X, R
1
and R
2
have the same meanings as defined above.
An amine of formula (II-c) which can be used as a starting material in preparing the compound of formula (I) may be prepared by t
Han Sun-Young
Kim Bum-Tae
Pak Chwang-Siek
Anderson Kill & Olick PC
Bernhardt Emily
Korea Research Institute of Chemical Technology
LandOfFree
Antifungal azole derivatives having a fluorinated vinyl... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antifungal azole derivatives having a fluorinated vinyl..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antifungal azole derivatives having a fluorinated vinyl... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2922263