Derivatives of 3'- and 3"-O-desmethyl avermectin compounds, compositions and methods of treating melmintic and parasitic infections

• US 5,169,839 A
• Filed: 05/11/1990
• Issued: 12/08/1992
• Est. Priority Date: 05/11/1990
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Mrozik, Helmut, Linn, Bruce O.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Peselev, Elli
• Application Number:
  US07/521,961
• Time in Patent Office: 942 Days
• Field of Search: 536/7.1, 574/30
• US Class Current: 514/30
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: C07H 19/01 sharing oxygen

Abstract

There are disclosed derivatives of avermectin compounds wherein one or both of the 13-oleandrose saccharide groups lack the methyl group of the 3'"'"'- or 3"-methoxy. Such compounds are potent anthelmintic and antiparasitic agents.

Claims

1. A compound having the formula:

##STR2## wherein the broken line at the 22,23 positions indicates that either a single or a double bond is present at the 22,23 position and that R₁ is present only when the broken line indicates a 22,23-single bond;

n is 0 or 1;

R₁ is hydrogen, hydroxy or a 23-oxo group;

R₂ is an α

-branched C₃ -C₈ alkyl, alkenyl, alkoxyalkyl or alkylthioalkyl;

a C₅ -C₈ cycloalkyl C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl or a C₅ -C₈ cycloalkenyl, each of which may be optionally substituted by methylene, or one or more C₁ -C₄ alkyl groups or halogen;

or a 3 to 6 membered oxygen or sulfur containing heterocycle which may be saturated or fully or partly unsaturated and which may be substituted by one or more C₁ -C₄ alkyl groups or halogen atoms;

R₃ is hydrogen, methyl, loweralkanoyl, loweralkoxycarbonyl, or triloweralkylsilyl;

R₄ and R₅ are independently hydrogen, methyl, loweralkanoyl, benzoyl, loweralkoxycarbonyl, phenoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkyl-carbamoyl or loweralkoxy loweralkyl, provided that both R₄ and R₅ are not simultaneously methyl; and

R₆, with the broken line indicating a single bond to R₆ is N-loweralkanoyl-N-loweralkylamino, loweralkoxycarbonylamino, triloweralkylsilyloxy, loweralkoxymethoxy, succinoyloxy or acetylglycyloxy;

or, when the broken line indicates a double bond to R₆, R₆ is, semicarbazono, loweralkanoyl hydrazono, benzoyl hydrazono, loweralkyl substituted benzoyl hydrazono or p-toluene sulfonylhydrazono.

2. The compounds of claim 1 wherein:

R₁ is hydrogen or hydroxy;

R₂ is an alpha-branched C₃ -C₈ alkyl or alkenyl group; and

R₃ is hydrogen or methyl;

R₄ and R₅ are independently hydrogen, methyl, loweralkanoyl, benzoyl, loweralkoxycarbonyl or loweralkoxyloweralkyl provided that both R₄ and R₅ are not simultaneously methyl; and

R₆, with the broken line indicating a single bond is, N-loweralkanoyl-N-loweralkylamino or loweralkoxymethoxy.

3. The compounds of claim 1 wherein

R₁ is hydrogen or hydroxy;

R₂ is 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-buten-2-yl, 2-penten-2-yl, 4-methyl-2-penten-2-yl, cyclohexyl, cylcopentyl, 3-thienyl, 3-furyl or 1-methylthioethyl;

R₃ is hydrogen;

R₄ and R₅ are independently hydrogen, methyl, loweralkanoyl, loweralkoxyloweralkyl, loweralkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl or N,N-diloweralkylcarbamoyl, provided that both R₄ and R₅ are not simultaneously methyl; and

;

R₆, with broken line indicating a single bond, is ethoxymethoxy;

succinoyloxy, or acetylglycyloxy.

4. The compounds of claim 1 wherein both R₄ and R₅ are other than hydrogen or methyl.

5. The compound of claim 3 which is 3'"'"',3"-bis-O-desmethyl-3'"'"',4"-di-O-methoxymethyl avermectin B1a/B1b.

6. The compound of claim 3 which is 3"-O-desmethyl-22,23-dihydro-4"-O-methoxymethyl avermectin B1a/B1b.

7. The compound of claim 3 which is 3"-acetylamino-3'"'"',3"-bis-O-desmethyl-3'"'"',4"-di-O-methoxymethyl avermectin B1a/B1b.

8. A method for the treatment of helmintic or parasitic infections in animals infected with helminths or parasites which comprises administering to such animals an effective amount of a compound of claim 1.

9. A method for the treatment of parasites of plants infected with parasites which comprises applying to such plants, to the soil in which they grow, or to the crops harvested therefrom, and effective amount of a compound of claim 1.

10. A composition useful for the treatment of parasitic diseases of plants or animals which comprises an inert carrier and an effective amount of a compound of claim 1.