Avermectin derivatives

• US 5,023,241 A
• Filed: 07/31/1989
• Issued: 06/11/1991
• Est. Priority Date: 07/31/1989
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Mrozik, Helmut, Linn, Bruce O.
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US07/387,207
• Time in Patent Office: 680 Days
• Field of Search: 514/30, 536/7.1
• US Class Current: 514/30
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: C07H 17/08 Hetero rings containing eight or more ring members, e.g. erythromycins

Abstract

Novel avermectin derivatives are disclosed, wherein the 4"-hydroxy group is replaced by a substituted acylamino or benzoylamino group. These avermectin derivatives can be further derivatized at the 5- and 23-positions as ketoximes or O-substituted ketoximes. The 4"-substituted avermectin derivatives are prepared by the acylation of the known 4"-aminoavermectins with acylating reagents. The new compounds are potent anti-parasitic agents, in particular, the compounds are anthelmintic, insecticidal and acaricidal agents.

Claims

1. A compound having the formula:

##STR8## wherein A at the 22,23 position represents a single bond and wherein R₁ is hydrogen or hydroxy or oxo, or A represents a double bond and R₁ is absent;

R₂ is methyl, ethyl, an alpha-branched C₃ -C₈ alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group;

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

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

R₃ is hydroxy, loweralkoxy, loweralkanoyloxy, oxo or oxime;

R₄ is ##STR9## where R₅ is NR₆ R₇, R₆ is substituted loweralkanoyl, wherein the substituent is halogen, hydroxy, loweralkoxy, phenoxy, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, amino, loweralkanoylamino, loweralkylamino, haloloweralkoxycarbonylamino, oxo, carboxy or lower alkoxycarbonyl;

or R₆ is cycloloweralkanoyl, or benzoyl, or substituted benzoyl, wherein the substituent is halogen, loweralkoxy, sulfonamido, amino, loweralkylamino, diloweralkylamino or loweralkanoylamino;

or R₆ is nicotinoyl;

R₇ is hydrogen, loweralkyl, substituted loweralkyl where the substituent is phenyl, hydroxy, loweralkoxy, amino, loweralkylamino, loweralkanoylamino, methylthio, methylsulfonyl or methylsulfinyl;

or R₅ = ##STR10## R₅ =--NH--CO--NR₈ R₉, R₈, R₉ and R₁₀ are independently hydrogen or loweralkyl;

or R₅ =--NH--CN.

2. A compound of claim 1, wherein A at the 22,23 position represents a single bond and wherein R₁ is hydrogen or hydroxy, or A represents a double bond and R₁ is absent;

R₂ iso-propyl, sec-butyl, or an alpha-branched C₃ -C₈ alkenyl group; and

R₃ is hydroxy or oxime;

R₄ is ##STR11## where R₅ is NR₆ R₇, R₆ is substituted loweralkanoyl, where the substituent is halogen, hydroxy, loweralkoxy, phenoxy, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, amino, loweralkanoylamino, loweralkylamino, haloloweralkoxycarbonylamino, oxo, carboxy or loweralkoxycarbonyl;

or R₆ is cycloloweralkanoyl, or benzoyl, or substituted benzoyl, wherein the substituent is halogen, loweralkoxy, sulfonamido, amino, loweralkylamino, diloweralkylamino or loweralkanoylamino;

or R₆ is nicotinoyl;

R₇ is hydrogen, loweralkyl, substituted loweralkyl where the substituent is phenyl, hydroxy, loweralkoxy, amino, loweralkylamino, loweralkanoylamino, methylthio, methylsulfonyl or methylsulfinyl;

or R₅ =--NH--CO--NR₈ R₉,

where R₈ and R₉ and R₁₀ are independently hydrogen or loweralkyl.

3. A compound of claim 1,

wherein A at the 22,23 position represents a single bond and

wherein R₁ is hydrogen or hydroxy, or A represents a double bond and R₁ is absent;

R₂ is 2-propyl, 2-butyl, 2-buten-2-yl, 2-penten-2-yl, or 4-methyl-2-penten-2-yl;

R₃ is hydroxy;

R₄ is ##STR12## where R₅ is NR₆ R₇, R₆ is substituted loweralkanoyl, where the substituent is halogen, hydroxy, loweralkoxy, phenoxy, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, amino, loweralkanoylamino, loweralkylamino, haloloweralkoxycarbonylamino, oxo, carboxy or loweralkoxycarbonyl;

or R₆ is cycloloweralkanoyl, or benzoyl, or substituted benzoyl, wherein the substituent is halogen, loweralkoxy, sulfonamido, amino, loweralkylamino, diloweralkylamino or loweralkanoylamino;

or R₆ is nicotinoyl;

R₇ is hydrogen, loweralkyl, substituted loweralkyl where the substituent is phenyl;

or R₅ =--NH--CO--NR₈ R₉,

where R₈ and R₉ and R₁₀ are independently hydrogen or loweralkyl.

4. The compound of claim 1, which is 4"-deoxy-4"-epi-methoxyacetylaminoavermectin B1a/B1b.

5. The compound of claim 1, which is 4"-deoxy-22,23-dihydro-4"-epi-(N-methoxyacetyl-N-methylamino)avermectin B1a/B1b.

6. The compound of claim 1, which is 4"-deoxy-4"-epi-methylthioacetylaminoavermectin B1a/B1b.

7. The compound of claim 1, which is 4"-epi-(N-acetylglycylamino)-4"-deoxyavermectin B1a/B1b.

8. The compound of claim 1, which is 4"-deoxy-4"-epi-phenoxyacetylaminoavermectin B2a/B2b.

9. The compound of claim 1, which is 4"-deoxy-4"-epi-nicotinoylamino-4"-avermectin B1a/B1b.

10. The compound of claim 1, which is 4"-deoxy-4"-epi-methoxycarbonylaminoavermectin B1a/B1b.

11. The compound of claim 1, which is 4"-deoxy-4"-epi-methylthioacetylaminoavermectin B1a/B1b monosaccharide.

12. A method for the treatment of parasitic infections of animals, which comprises treating the infected animal with an effective amount of a compound of claim 1.

13. A method for the treatment of parasitic infections of plants, which comprises treating the infected plant, or the soil in which the infected plant grows, with an effective amount of a compound of claim 1.

14. A composition useful for the treatment of animals or plants infected with parasites, which comprises an inert carrier and an effective amount of a compound of claim 1.