Avermectin derivatives

• US 6,605,595 B1
• Filed: 02/11/2002
• Issued: 08/12/2003
• Est. Priority Date: 02/09/1999
• Status: Expired due to Term

• Current Assignee: Kitasato Institute (Kitasato University)
• Original Assignee: Kitasato Institute (Kitasato University)
• Inventors: Harder, Achim, von Samson-Himmelstjerna, Georg, Omura, Satoshi, Sunazuka, Toshiaki, Turberg, Andreas, Hansen, Olaf
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): REYES, HECTOR M
• Application Number:
  US09/890,824
• Time in Patent Office: 547 Days
• Field of Search: 514/30, 514/450, 549/264
• US Class Current: 514/30
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: C07H 17/08 Hetero rings containing eight or more ring members, e.g. erythromycins

Abstract

Avermectin derivatives represented by the general formula (I) or salts thereof:

wherein —X----Y— represents —CH═CH—, —CH₂—C(═O)—, —CH₂—CH₂—, or —CH₂—CH(R¹³)—; for example, 1) when —X----Y— represents —CH═CH—, R¹ represents (R¹¹)(R¹²)C [wherein R¹¹ represents a substituted or unsubstituted lower alkyl group; a formyl group; a lower alkoxylcarbonyl group etc.; and R¹² represents a hydrogen atom or a lower alkyl group]; when the bond between R² and a carbon atom at the 5-position is a single bond, R² represents a hydroxyl group or a tri(lower alkyl)silyloxy group; or R² forms a carbonyl group or a hydroxime group together with the carbon atom at the 5-position; 2) when —X----Y— represents —CH₂—C(═O)—, R¹ represents (R^11a)(R^12a)C [wherein R^11a represents a lower alkoxycarbonyl group, or —COOCH₂CH═CH₂; and R^12a represents a hydrogen atom]; and R² represents a hydroxyl group or a tri(lower alkyl)silyloxy group.

Claims

1. A compound represented by formula (I) or a salt thereof:

wherein —

X----Y—

represents —

CH═

CH—

, —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

, or —

CH²—

CH(R¹³)—

;

---- between R¹ and a carbon atom at the 4″

-position represents a single or double bond;

---- between R² and a carbon atom at the 5-position represents a single or double bond, with the provisos that

1) when —

X----Y—

represents —

CH═

CH— and

---- between R¹ and a carbon atom at the 4″

-position represents a double bond;

R¹ represents (R¹¹)(R¹²)C wherein R¹¹ represents a lower alkyl group (optionally substituted with from 1 to 3 members selected from the group consisting of a hydroxyl group, a halogen atom, an amino group, a hydroxyamino group, a mono(lower alkyl)amino group, a mono(lower alkoxy)amino group, an alkanoylamino group, an azide group, a heterocyclic group, a lower alkanoyloxy group, a heterocyclic carbonyloxy group where the heterocyclic moiety may be substituted with a halogen atom or a lower alkoxycarbonyl group, and a heterocyclic oxy group);

a formyl group;

a lower alkoxycarbonyl group, the alkyl moiety of which is optionally substituted with a heterocyclic group;

—

CH═

N—

OR³ wherein R³ represents a hydrogen atom or a lower alkyl group;

a lower alkenyloxycarbonyl group;

—

CH═

N—

NH—

CONH₂;

a cyano group;

—

COR⁴ wherein R⁴ represents a hydroxyl group or N(R⁵)(R⁶) wherein R⁵ and R⁶ form a nitrogen-containing heterocyclic group together with the adjacent nitrogen atom;

a vinyl group substituted with a lower alkenyloxycarbonyl group;

—

CO—

S—

CH₂—

CH₂—

NH—

CO—

R^x wherein R^x represents a lower alkyl group;

or —

CH═

CH—

COOH; and

R¹² represents a hydrogen atom, except that when R¹¹ represents a cyano group, R¹² represents a hydrogen atom or a lower alkyl group;

when ---- between R² and a carbon atom at the 5-position represents a single bond, R² represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; and

when ---- between R² and a carbon atom at the 5-position represents a double bond, R² forms a carbonyl group or a hydroxime group together with the carbon atom at the 5-position;

2) when —

X----Y—

represents —

CH₂—

C(═

O)—

, ---- between R¹ and a carbon atom at the 4″

-position represents a double bond;

R¹ represents (R^11a)R^12a)C wherein R^11a represents a lower alkoxycarbonyl group, the alkyl moiety of which is optionally may be substituted with a heterocyclic group, or —

COOCH₂CH═

CH₂; and

R^12a represents a hydrogen atom;

---- between R² and a carbon atom at the 5-position represents a single bond; and

R² represents a hydroxyl group, a lower alkoxy group, or a tri(lower alkyl)silyloxy group;

3) when —

X----Y—

represents —

CH₂—

CH₂—

,

R¹ 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 ---- between R¹ and a carbon atom at the 4″

-position represents a single bond, R¹ represents a carboxymethyl group or a cyanomethyl group;

---- between R² and a carbon atom at the 5-position represents a single bond; and

R² represents a hydroxyl group, a lower alkoxy group, or a tri(lower alkyl)silyloxy group;

4) when —

X----Y—

represents —

CH₂—

CH(R¹³)—

, and ---- between R¹ and a carbon atom at the 4″

-position represents a double bond;

R¹ 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;

R¹³ represents a hydroxyl group or a lower alkylcarbonyloxy group;

---- between R² and a carbon atom at the 5-position represents a single bond; and

R² represents a hydroxyl group, a lower alkoxy group or a tri(lower alkyl)silyloxy group.

2. The compound or the salt thereof according to claim 1 wherein —

X----Y—

is —

CH═

CH—

.

3. The compound or the salt thereof according to claim 2 wherein R¹¹ represents said optionally substituted lower alkyl group, a cyano group, or said —

COR⁴.

4. The compound or the salt thereof according to any one of claims 1 to 3 wherein R² is hydroxyl group or a tri(lower alkyl)silyloxy group.

5. The compound or the salt thereof according to claim 1 wherein —

X----Y—

is —

CH₂—

CH₂—

.

6. The compound or the salt thereof according to claim 5 wherein R^11b is a cyano group or a carboxyl group.

7. A medicament which comprises as an active ingredient the compound or the physiologically acceptable salt thereof according to claim 4.

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 or the physiologically acceptable salt thereof according to claim 4.

9. An agent for the therapeutic treatment of parasitosis which comprises as an active ingredient the compound or the physiologically acceptable salt thereof according to claim 4.