Avermectin derivatives

Details Avermectin derivatives Avermectin derivatives

2002-02-11

2003-08-12

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S450000, C549S264000

Reexamination Certificate

active

06605595

ABSTRACT:

TECHNICAL FIELD
The present invention relates to avermectin derivatives having antiparasitic activity.
BACKGROUND ART
Avermectins are antiparasitic antibiotics produced by
Streptomyces avermitilis.
Four main ingredients (Ala, A2a, B1a and B2a) have been known, and among them, avermectin B1a is known to have potent activity (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 3-254678/1991).
Various derivatives have been synthesized so far to provide avermectin derivatives having higher activity. However, these derivatives fail to have fully satisfactory antiparasitic activity.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide avermectin derivatives having antiparasitic activity.
In order to find avermectin derivatives having higher antiparasitic activity, the inventors of the present invention synthesized various derivatives using avermectins B1a and B2a as starting materials. As a result, we succeeded in obtaining derivatives represented by the following general formula (I) which have high antiparasitic activity. The present invention was achieved on the basis of the findings.
The present invention thus provides compounds represented by the general formula (I) or salts thereof:
wherein —X----Y— represents —CH═CH—, —CH
2
—C(═O)—, —CH
2
—CH
2
—, or —CH
2
—CH(R
13
)—;
a line ---- between R
1
and a carbon atom at the 4″-position represents a single or double bond;
a line ---- between R
2
and a carbon atom at the 5-position represents a single or double bond;
1) when —X----Y— represents —CH═CH—,
the line ---- between R
1
and a carbon atom at the 4″-position represents a double bond;
R
1
represents (R
11
)(R
12
)C [wherein R
11
represents a substituted or unsubstituted lower alkyl group; a formyl group; a lower alkoxylcarbonyl group, the alkyl moiety of the said lower alkoxylcarbonyl group may be substituted with a heterocyclic group; —CH═N—OR
3
wherein R
3
represents a hydrogen atom or a lower alkyl group; a lower alkenyloxycarbonyl group; —CH═N—NH—CONH
2
; a cyano group; —COR
4
wherein R
4
represents a hydroxyl group or N(R
5
)(R
6
) wherein R
5
and R
6
form a nitrogen containing heterocyclic group together with the adjacent nitrogen atom; a vinyl group substituted with a lower alkenyloxycarbonyl group; —CO—S—CH
2
—CH
2
—NH—CO—R
x
wherein R
x
represents a lower alkyl group; or —CH═CH—COOH; and R
12
represents a hydrogen atom, or when R
11
represents a cyano group, R
12
represents a hydrogen atom or a lower alkyl group]; when the line ---- between R
2
and a carbon atom at the 5-position represents a single bond, R
2
represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; or when the line ---- between R
2
and a carbon atom at the 5-position represents a double bond, R
2
forms a carbonyl group or a hydroxime group {—C(═NOH)}, together with the carbon atom at the 5-position;
2) when —X----Y— represents —CH
2
—C(═O)—,
the line ---- between R
1
and a carbon atom at the 4″-position represents a double bond;
R
1
represents (R
11a
)(R
12a
)C [wherein R
11a
represents a lower alkoxycarbonyl group, the alkyl moiety of the said lower alkoxycarbonyl group may be substituted with a heterocyclic group, or —COOCH
2
CH═CH
2
; and R
12a
represents a hydrogen atom]; the line ---- between R
2
and a carbon atom at the 5-position represents a single bond; and R
2
represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group;
3) when —X----Y— represents —CH
2
—CH
2
—,
R
1
represents (R
11b
)(R
12b
)C [wherein R
11b
represents a cyano group, a carboxyl group, or a lower alkenyloxycarbonyl group; and R
12b
represents a hydrogen atom]; or when the line ---- between R
1
and a carbon atom at the 4″-position represents a single bond, R
1
may represent a carboxymethyl group or a cyanomethyl group; the line ---- between R
2
and a carbon atom at the 5-position represents a single bond; and R
2
represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group;
4) when —X----Y— represents —CH
2
—CH(R
13
)—,
the line ---- between R
1
and a carbon atom at the 4″-position represents a double bond;
R
1
represents (R
11c
)(R
12c
)C [wherein R
11c
represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group; and R
12c
represents a hydrogen atom]; R
13
represents a hydroxyl group or a lower alkylcabonyloxy group; the line ---- between R
2
and a carbon atom at the 5-position represents a single bond; and R
2
represents a hydroxyl group, a lower alkoxyl group or a tri(lower alkyl)silyloxy group.
Among the compounds of the general formula (I) according to the present invention, those wherein —X----Y— is —CH═CH— or the salts thereof are preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein —X----Y— represents —CH═CH—, and R
11
represents a substituted or unsubstituted lower alkyl group, a cyano group, or —COR
4
wherein R
4
has the same meaning as that defined above, or the salts thereof are also preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein R
2
is a hydroxyl group or a tri(lower alkyl)silyloxy group or the salts thereof are preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein —X----Y— represents —CH
2
—CH
2
— or the salts thereof are preferred. Among them, those wherein R
11b
represents a cyano group or a carboxyl group or the salts thereof are preferred.
According to another aspect of the present invention, there are provided medicaments which comprise as an active ingredient the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof. The medicaments can be administered as antiparasitics to a mammal including a human.
According to further aspects of the present invention, there are provided a use of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for therapeutic treatment of parasitosis which comprises the step of administering a therapeutically effective amount of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof to a mammal including a human.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter the compounds represented by the general formula (I) are referred to as the compounds (I). The compounds of other formula numbers are abbreviated in a similar manner.
In the compounds (I) of the present invention, —X----Y— represents —CH═CH—, —CH
2
—C(═O)—, —CH
2
—CH
2
—, or —CH
2
—CH(R
13
)— (in each formula, the carbon atom on the left side corresponds to X.).
In the compounds (I) of the present invention, the compounds, wherein R
2
is a hydroxyl group or a tri(lower alkyl)silyloxy group when —X----Y— represents —CH═CH— and the line ---- between R
2
and a carbon atom at the 5-position represents a single bond, are referred to as the compounds (Ia), and those wherein —X----Y— represents —CH═CH— and R
2
forms a carbonyl group or a hydroxime group together with the carbon atom at the 5-position are referred to as the compounds (Ic).
In the compounds (I) of the present invention, the compounds wherein —X----Y— represents —CH
2
—C(═O)—, the line ---- between R
2
and a carbon atom at the 5-position represents a single bond, and R
2
represents a hydroxyl group or a tri(lower alkyl)silyloxy group are referred to as the compounds (Ib).
In the compounds (I) of the present invention, the compounds wherein —X----Y— represents —CH
2
—CH
2
—, the line ---- between R
2
and a carbon atom at the 5-position represents a single bond, and R
2
represents a hydroxyl group or a tri(lower alkyl)silyloxy group are sometimes referred to particularly as “ivermectin deriv

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