Sesterterpene derivatives exhibiting antifungal activities

Details Sesterterpene derivatives exhibiting antifungal activities Sesterterpene derivatives exhibiting antifungal activities

2001-01-30

2001-10-16

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S453000

Reexamination Certificate

active

06303797

ABSTRACT:

TECHNICAL FIELD
This invention is useful in the field of pharmaceuticals, and more specifically relates to a novel antifungal agent.
BACKGROUND ART
In the field of antifungal agents, many compounds have already been put to practical use as pharmaceuticals. For example, flucytosine is known to be a less poisonous antifungal agent since it is specifically taken into certain species of fungi and exerts its antifungal activity, but it has the disadvantages that the species of fungi on which it is effective are limited and moreover, it should be used, at present, together with another antifungal agent because of early emergence of resistant fungi [Shinkin, Shinkin-sho, Kagaku Ryoho (Fungi, Fungous Diseases and Chemotherapy) written by Kazuo IWATA, pages 129-130 (1994), Soft Science Co.] (hereinafter, referred to as Reference A). Amphotericin B is an antifungal agent having a strong antifungal activity and capable of exerting the effect on wide species of fungi, but has the disadvantage that it has strong toxicity because it also acts on human cell membrane sterols (Reference A, pages 156-157). In view of the disadvantages of flucytosine and amphotericin B, azole-type antifungal agents such as miconazole, fluconazole and itraconazole, exerting their antifungal activities by inhibiting the ergosterol synthesis pathway of fungi, are now generally used. However, as a result of frequent use of these various azole-type antifungal agents in treatment and prophylaxis of fungous diseases, the problem of emergence of fungi resistant to azole-type antifungal agents arose (Reference A, pages 123-135). Since azole-type antifungal agents are the same in their action mechanisms and have similar chemical structures, the emergence of fungi resistant thereto caused the serious problem that, on fungi which acquired resistance to one of azole-type antifungal agents, other azole-type antifungal agents cannot exert a sufficient effect [Denning D W. et al., European Journal of Clinical Microbiology & Infectious Disease, volume 16, No. 4, pages 261-280, 1997].
Compounds analogous to the compounds of the invention in structure are disclosed in an international application published based on Patent Cooperation Treaty (International Publication No. WO97/19186, International Publication Date: May 29, 1997) and an European published patent application corresponding thereto, EP 0877091 A1, and it is disclosed therein that the compounds have novel structures and exert an excellent antifungal activity on some fungi. However, the compounds are poor in extent of chemical structure since they are secondary metabolites of microorganisms, and in the international application, only such limited compounds are disclosed that in the general formula [I], not only Y
1
is limited to a group represented by O—CO, but R
1
is limited to a C
7
-C
9
alkyl group or a C
7
aralkyl group and the substituent of R
1
is almost always a hydroxyl group.
Namely, in compounds of the general formula [1] of the invention, compounds wherein Y
1
is other than O—CO, specifically Y
1
represents an oxygen atom, NH, O—SO
2
, NH—CO, O—CO—NH, O—CS—NH, NH—SO
2
, NH—CO—NH or NH—CS—NH, or compounds wherein even when Y
1
is O—CO, R
1
is other than a C
7
-C
9
alkyl group or a C
7
aralkyl group, specifically R
1
represents a C
1
-C
5
alkyl group, a C
2
-C
10
alkenyl group, a C
3
-C
6
alkynyl group, a C
6
-C
12
aryl group, a C
8
-C
15
aralkyl group, a C
9
-C
15
arylalkenyl group, a C
9
-C
15
arylalkynyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
16
alkyl group, a C
1
-C
16
alkylcarbonyl group, a C
1
-C
16
alkoxycarbonyl group, a C
6
-C
12
arylcarbonyl group or a heterocyclic group; or a C
1
-C
5
alkyl group, a C
2
-C
10
alkenyl group, a C
3
-C
6
alkynyl group, a C
6
-C
12
aryl group, a C
7
-C
15
aralkyl group, a C
9
-C
15
arylalkenyl group, a C
9
-C
15
arylalkynyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
16
alkyl group, a C
1
-C
16
alkylcarbonyl group, a C
1
-C
16
alkoxycarbonyl group, a C
6
-C
12
arylcarbonyl group or a heterocyclic group, each having 1 to 5 substituents selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a C
1
-C
16
alkyl group (excluding the case where R
1
is a C
1
-C
5
alkyl group), a C
1
-C
16
alkoxy group, a C
1
-C
16
alkylcarbonyloxy group, an amino group, a mono-C
1
-C
16
alkylamino group, a di-C
1
-C
16
alkylamino group, a carboxyl group, a C
1
-C
16
alkoxycarbonyl group, an aminocarbonyl group, a sulfo group, a C
6
-C
12
aryloxy group, a C
7
-C
15
aralkyloxy group and a hetersocyclic group, are novel compounds not disclosed in literatures, and these compounds and their use are not specifically disclosed nor suggested. Further, it cannot readily be conceived by a person skilled in the art that the compounds of the invention exert good antifungal activity on fungi against which the effects of the above compounds could not be exerted.
DISCLOSURE OF INVENTION
The effects of existing antifungal agents on various kinds of harmful fungi are not always sufficient, and emergence of fungi resistant to these antifungal agents, especially fungi resistant to azole-type antifungal agents being frequently used gets to be clinically a large problem. Thus, development of medicaments effective on harmful fungi and resistant fugi against which these existing antifungal agents cannot sufficiently exert their effects has been desired, and this invention aims to provide novel antifungal agent capable of meeting the desire, and it is the problem to be solved by the invention to provide a medicament exerting an antifungal effect on not only various fungi but also resistant fungi.
The present inventors have intensely studied for solving the problem, and as a result, they found that a compound represented by the general formula [I], or a pharmacologically acceptable salt or ester thereof has an excellent antifungal activity, and completed the invention. More specifically, the invention relates to a compound represented by the formula [I]
wherein Y
1
represents an oxygen atom, or a group represented by NH, O—CO, O—SO
2
, NH—CO, O—CO—NH, O—CS—NH, NH—SO
2
, NH—CO—NH or NH—CS—NH,
R
1
represents a group selected from the group consisting of, each unsubstituted, a C
1
-C
16
alkyl group, a C
2
-C
10
alkenyl group, a C
3
-C
6
alkynyl group, a C
6
-C
12
aryl group, a C
7
-C
15
aralkyl group, a C
9
-C
15
arylalkenyl group, a C
9
-C
15
arylalkynyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
16
alkyl group, a C
1
-C
16
alkylcarbonyl group, a C
1
-C
16
alkoxycarbonyl group, a C
6
-C
12
arylcarbonyl group and a heterocyclic group; or a group selected from the group consisting of a C
1
-C
16
alkyl group, a C
2
-C
10
alkenyl group, a C
3
-C
6
alkynyl group, a C
6
-C
12
aryl group, a C
7
-C
15
aralkyl group, a C
9
-C
15
arylalkenyl group, a C
9
-C
15
arylalkynyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
16
alkyl group, a C
1
-C
16
alkylcarbonyl group, a C
1
-C
16
alkoxycarbonyl group, a C
6
-C
12
arylcarbonyl group and a heterocyclic group, each having 1 to 5 substituents selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a C
1
-C
16
alkyl group (excluding the case where R
1
is a C
1
-C
16
alkyl group), a C
1
-C
16
alkoxy group, a C
1
-C
16
alkylcarbonyloxy group, an amino group, a mono-C
1
-C
16
alkylamino group, a di-C
1
-C
16
alkylamino group, a carboxyl group, a C
1
-C
16
alkoxycarbonyl group, an aminocarbonyl group, a sulfo group, a C
6
-C
12
aryloxy group, a C
7
-C
15
aralkyloxy group, a C
1
-C
16
alkylcarbonyl group, a C
1
-C
16
alkoxycarbonyl group, a C
6
-C
12
arylcarbonyl group and a heterocyclic group;
with the proviso that when Y
1
represents O—CO, R
1
does not represent a 2,4-dimethylhexyl group, a 2-hydroxy-2,4-dimethylhexyl group, a 1,2-dihydroxy-2,4-dimethylhexyl group, a 1-hydroxy-3,5-dimethylheptyl group, a 1,2-dihydroxy-5-methylheptyl group, a 1,2-di

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