Avermectin derivatives

Abstract

A compound represented by the general formula (I) or a salt thereof: wherein, —X Y— represents —CH═CH—, —CH 2 —CH 2 — or the like, between R 1 and the carbon atom at 4′-position represents a single bond or a double bond, between R 2 and the carbon atom at 5-position represents a single bond or a double bond, and for example, 1) when —X Y— represents —CH═CH— or —CH 2 —CH 2 —, and between R 1 and the carbon atom at 4′-position represents a double bond, R 1 represents ═C(R 11 )(R 12 ) (wherein R 11 represents a lower alkyl group or the like and R 12 represents a hydrogen atom or the like) or the like, and R 2 represents a hydroxyl group or the like, or R 2 may be combined together with the carbon atom at 5-position to form a carbonyl group, and 2) when —X Y— represents —CH═CH— or —CH 2 —CH 2 —, and between R 1 and the carbon atom at 4′-position represents a single bond, R 1 represents —OCH(R 1a )(R 1b ) (wherein R 1a represents a lower alkyl or the like and R 1b represents a hydrogen atom or the like) or the like, and R 2 represents a hydroxyl group or the like.

What is claimed is:  
     
         1 . A compound represented by the general formula (I) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein, —X Y— represents —CH═CH—, —CH 2 —C(═O)—, —CH 2 —CH 2 —, or —CH 2 —CH(R 13 S)— (wherein R 13  represents a hydroxyl group or a lower alkylcarbonyloxy group, 
   between R 1  and the carbon atom at 4′-position represents a single bond or a double bond,  
   between R 2  and the carbon atom at 5-position represents a single bond or a double bond, and 
 1) when —X Y— represents —CH═CH— or —CH 2 —CH 2 , and  between R 1  and the carbon atom at 4′-position represents a double bond,    
 R 1  represents ═C(R 11 )(R 12 ) <wherein R 11  represents a substituted or unsubstituted lower alkyl group, a formyl group, a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), —CH═N—OR 2  (wherein R 3  represents a hydrogen atom or a lower alkyl group), a lower alkenylcarbonyl group, —CH═N—NH—CONH 2 , a cyano group, —COR 4  (wherein R 4  represents a hydroxyl group, a lower alkenyloxy group ,or —N(R 5 )(R 6 ) (wherein R 5  and R 6  are combined together with the adjacent nitrogen atom to form a nitrogen-containing heterocyclic group)), 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, provided that when R 11  represents a cyano group, R 12  represents a hydrogen atom or a lower alkyl group>, or is combined together with the carbon atom at 4′-position to form a carbonyl group, and  
 when  between R 2  and the carbon atom at 5-position represents a single bond, R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group, and  
 when  between R 2  and the carbon atom at 5-position represents a double bond, R 2  is combined together with the carbon atom at 5-position to form a carbonyl group or a hydroxime group (—C(═NOH)—); 
 2) when —X Y— represents —CH═CH— or —CH 2 —CH 2 —, and  between R 1  and the carbon atom at 4′-position represents a single bond,  
 
 R 1  represents a hydroxyl group, —OCH(R 1a )(R 1b ) <wherein R 1a  represents a substituted or unsubstituted lower alkyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), —CH═N—OR 7  (wherein R 7  represents a hydrogen atom or a lower alkyl group), a lower alkenyloxycarbonyl group, —CH═N—NH—CONH 2 , a cyano group, —COR 8  {(wherein R 8  represents an arylalkyloxy group (wherein the aryl group may contain one or more heteroatoms as ring-constituting atoms) or —N(R 9 )(R 10 ) (wherein R 9  and R 10  are combined together with the adjacent nitrogen atom to form a nitrogen-containing heterocyclic group)}, a vinyl group substituted with a lower alkenyloxycarbonyl group, —CO—S—CH 2 —CH 2 —NH—CO—R Y  (wherein R Y  represents a lower alkyl group), —CH═CH—COOH, or a substituted or unsubstituted aryl group, and R 1b  represents a hydrogen atom, provided that when R 1a  represents a carboxyl group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), R 1b  may further represents a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), a carboxyl group, a cyano group, or an aryl group>, a carboxymethyl group, or a cyanomethyl group, and  
 when  between R 2  and the carbon atom at 5-position represents a single bond, R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group, and  
 when  between R 2  and the carbon atom at 5-position represents a double bond, R 2  is combined together with the carbon atom at 5-position to form a carbonyl group or a hydroxime group (—C(═NOH)—);  
 3) when —X Y— represents —CH 2 —C(═O)—, and between R 1  and the carbon atom at 4′-position represents a double bond,  
 R 1  represents ═C(R 11a )(R 12a ) (wherein R 11a  represents a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group) or —COOCH 2 CH═CH 2 , and R 12a  represents a hydrogen atom), or is combined together with the carbon atom at 4′-position to form carbonyl group,  
   between R 2  and the carbon atom at 5-position represents a single bond, and R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group;  
 4) when —X Y— represents —CH 2 —C(═O)—, and  between R 1  and the carbon atom at 4′-position represents a single bond,  
 R 1  represents —OCH(R 1aa )(R 1ba ) <wherein R 1aa  represents a substituted or unsubstituted lower alkyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), —CH═N—OR 7a  (wherein R 7a  represents a hydrogen atom or a lower alkyl group), a lower alkenyloxycarbonyl group, —CH═N—NH—CONH 2 , a cyano group, —COR 6a  {wherein R 6a  represents an arylalkyloxy group (wherein the aryl group may contain one or more heteroatoms as ring-constituting atoms), or —N(R 9a )(R 10a ) (wherein R 9a  and R 10a  are combined together with the adjacent nitrogen atom to form a nitrogen-containing heterocyclic group)}, a vinyl group substituted with a lower alkenyloxycarbonyl group, —CO—S—CH 2 —CH 2 —NH—CO—R Ya  (wherein R Ya  represents a lower alkyl group), —CH═CH—COOH, or a substituted or unsubstituted aryl group, and R 1ba  represents a hydrogen atom, provided that when R 1aa  represents a carboxyl group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), R 1ba  may further represents a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), a carboxyl group, a cyano group, or an aryl group>, and  
 when  between R 2  and the carbon atom at 5-position represents a single bond, R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group, and  
 when  between R 2  and the carbon atom at 5-position represents a double bond, R 2  is combined together with the carbon atom at 5-position to form a carbonyl group or a hydroxime group (—C(═NOH)—); 
 5) when —X Y— represents —CH 2 —CH(R 13 )— (wherein R 18  has the same meaning as that defined above), and  between R 1  and the carbon atom at 4′-position represents a double bond,  
 
 R 1  represents ═C(R 11b )(R 12b ) (wherein R 11b  represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group, or a lower alkenyloxycarbonyl group, or is combined togethrer with the carbon atom at 4′-position to form a carbonyl group, and R 12b  represents a hydrogen atom),  
   between R 2  and the carbon atom at 5-position represents a single bond, and R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group; and 
 6) when —X Y— represents —CH 2 —CH(R 13 )— (wherein R 13  has the same meaning as that defined above), and  between R 1  and the carbon atom at 4′-position represents a single bond,    
 R 1  represents —OCH(R 1ab )(R 1bb ) <wherein R 1ab  represents a substituted or unsubstituted lower alkyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), —CH═N—OR 7b  (wherein R 7b  represents a hydrogen atom or a lower alkyl group), a lower alkenyloxycarbonyl group, —CH═N—NH—CONH 2 , a cyano group, —COR 8b  }wherein R 8b  represents an arylalkyloxy group (wherein the aryl group may contain one or more heteroatoms as ring-constituting atoms), or —N(R 9b )(R 10b ) (wherein R 9b  and R 10b  are combined together with the adjacent nitrogen atom to form a nitrogen-containing heterocyclic group)}, a vinyl group substituted with a low r alkenyloxycarbonyl group, —CO—S—CH 2 —CH 2 —NH—CO—R Yb  (wherein R Yb  represents a lower alkyl group), —CH═CH—COOH, or a substituted or unsubstituted aryl group, and R 1bb  represents a hydrogen atom, provided that when R 1ab  represents a carboxyl group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), R 1bb  may further represents a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group), a carboxyl group, a cyano group, or an aryl group>, and  
 when  between R 2  and the carbon atom at 5-position represents a single bond, R 2  represents a hydroxyl group, a lower alkoxyl group, or a lower alkenyloxycarbonyloxy group, and  
 when  between R 2  and the carbon atom at 5-position represents a double bond, R 2  is combined together with the carbon atom at 6-position to form a carbonyl group or a hydroxime group (—C(═NOH)—)  
 
     
     
         2 . The compound or the salt according to  claim 1 , wherein —X Y— is —CH═CH—.  
     
     
         3 . The compound or the salt according to  claim 1 , wherein —X Y— is —CH 2 —CH 2 —.  
     
     
         4 . The compound or the salt according to any one of  claims 1  to  3 , wherein R 11  is a substituted or unsubstituted lower alkyl group, a formyl group, a lower alkoxycarbonyl group, a lower alknenylcarbonyl group, a cyano group, or —COR 4  (wherein R 4  has the same meaning as that defined above).  
     
     
         5 . The compound or the salt according to any one of  claims 1  to  3 , wherein R 1  is a hydroxyl group or —OCH 2 R 1ac  {wherein R 1ac  represents a substituted or unsubstituted lower alkyl group, a carboxyl group, or a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group)}.  
     
     
         6 . The compound or the salt according to any one of  claims 1  to  5 , wherein R 2  is a hydroxyl group or a lower alkenyloxycarbonyloxy group.  
     
     
         7 . A medicament which comprises the compound according to any one of  claims 1  to  6  or a physiologically acceptable salt thereof as an active ingredient.  
     
     
         8 . A method for therapeutic treatment of parasitosis which comprises the step of administering to a mammal including a human a therapeutically effective amount of the compound according to any one of  claims 1  to  6  or a physiologically acceptable salt thereof.  
     
     
         9 . A medicament for therapeutic treatment of parasitosis which comprises the compound according to any one of  claims 1  to  6  or a physiologically acceptable salt thereof as an active ingredient.  
     
     
         10 . Use of the compound according to any one of  claims 1  to  6  or a physiologically acceptable salt thereof for manufacture of an antiparasitic agent.