Nova Patents
EP0428286A2

24- and 25-substituted avermectin and milbemycin derivatives.

Abstract

Novel avermectin and milbemycin derivatives are disclosed, where the C-24 and C-25 carbon atoms are substituted by hydrogen, alkyl, alkenyl, substituted alkyl or substituted alkenyl groups. These compounds can be further substituted at the 4˝-, 5-, 13-, and 23-­positions. The new C-24 and C-25 substituted avermectin and milbemycin derivatives are prepared by cleavage of known and suitably protected avermectin and milbemycin compounds. The new compounds are potent anti-parasitic agents, in particular, the compounds are anthelmintic, insecticidal and acaricidal agents.

EP0428286A2, drawing sheet 1
Sheet 1 of 17

Term

Term ended

Projected expiry passed 29 October 2010, 15.9 years ago.

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11 claims: 2 independent, 9 dependent

  1. 1
    A compound having the formula:where A and B are single or double bonds, provided that only one of A and B is a double bond at any one time;R₁ = H, OH, loweralkanoyloxy, oxo, or halogen, when A is a single bond;or: R₁ is absent when A is a double bond;R₂ = OCO-lower alkyl or OSi-tri-lower alkyl, provided one of A or B is a double bond;or: R₂ = H, OH, oxo, NOH, NOCH₃ or halogen, provided R₁ is OH and A and B are single bonds;R₃ = H, lower alkyl, cycloloweralkyl, or loweralkoxyloweralkyl;R₄ = H, lower alkyl, OH, OCO-loweralkyl, O-loweralkyl or halogen, provided A is a single or double bond and B is a single bond;R₅ = H, phenyl, optionally substituted phenyl wherein the substituents are from 1 to 3 of loweralkyl, loweralkoxy, halogen, amino, or loweralkanoylamino, heteroaryl such as pyrrolyl, pyridyl, or optionally substituted pyrrolyl, pyridyl wherein the substituents are from 1 to 3 of loweralkyl, loweralkoxy, halogen, amino, or loweralkanoylamino;or: R₅ = H, CH₃, C₂H₅, a C₃-C₁₂ straight or branch chained alkyl, alkenyl, alkynyl, loweralkoxyalkyl or loweralkylthioalkyl 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;a C₅-C₈ cycloalkyl substituted C₁-C₄ group;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 halogen atoms;furyl or thienyl groups;provided neither R₃ or R₄ are methyl groups;R₆ is hydroxy, loweralkyloxy, oxo, or oxime;R₇ is hydrogen, hydroxy, loweralkoxy, loweralkanoyloxy, oxymethyleneoxyloweralkylloweralkoxy, halogen or wherein R₈ is attached to C-4˝ or C-4′ by a single bond and is hydroxy, loweralkanoyloxy, loweralkoxy, amino, N-loweralkylamino, N,N-diloweralkylamino, N-­ loweralkanoylamino, N-loweralkyl -N-loweralkanoylamino;or R₈ is attached to C-4˝ or C-4′ by a double bond and is oxo, semicarbazido, N-­loweralkylsemicarbazido, N,N-loweralkylsemicarbazido, loweralkanoylhydrazido, benzoylhydrazido, or loweralkylbenzoylhydrazido.
  2. 7
    A process for the preparation of compounds of Claim 1, which comprises reacting a suitably protected avermectin degradation product containing a 21,21-O,22,23-bis-seco-­21-methoxy-22-oxo structure with a suitably protected substituted 3-­hydroxyalkanetriphenylphosphine salt in a Wittig reaction, and cyclizing this intermediate to the dioxaspirane ring system of the avermectins containing novel C-24 and C-25 substituents.
  3. 8
    A method for the treatment of parasitic infections of plants, which comprise treating the infected plant, or the soil in which the infected plant grows with an effective amount of a compound of Claim 1.
  4. 9
    The use of a compound of Claim 1 for the preparation of a medicament useful for the treatment of parasitic infections of animals.
  5. 10
    A composition useful for the treatment of animals or plants infected with parasites, which comprises an inert carrier and a compound of Claim 1.
  6. 11
    A compound having the formula:where R is loweralkyl;R₆ is hydroxy, loweralkyloxy, oxo, or oxime;R₇ is hydrogen, hydroxy, loweralkoxy, loweralkanoyloxy, oxymethyleneoxyloweralkylloweralkoxy, halogen or wherein R₈ is attached to C-4˝ or C-4′ by a single bond and is hydroxy, loweralkanoyloxy, loweralkoxy, amino, N-loweralkylamino, N,N-loweralkylamino, N-­loweralkanoylamino, N-loweralkyl -N-loweralkanoylamino;or R₈ is attached to C-4˝ or C-4′ by a double bond and is oxo, semicarbazido, N-­loweralkylsemicarbazido, N,N-diloweralkylsemicarbazido, loweralkanoylhydrazido, benzoylhydrazido, or loweralkylbenzoylhydrazido. R₆ is hydroxy, loweralkyloxy, oxo, or oxime;R₇ is hydrogen, hydroxy, loweralkoxy, loweralkanoyloxy, oxymethyleneoxyloweralkylloweralkoxy, halogen or wherein R₈ is attached to C-4˝ or C-4′ by a single bond and is hydroxy, loweralkanoyloxy, loweralkoxy, amino, N-loweralkylamino, N,N-diloweralkylamino, N-­loweralkanoylamino, N-loweralkyl -N-loweralkanoylamino;or R₈ is attached to C-4˝ or C-4′ by a double bond and is oxo, semicarbazido, N-­loweralkylsemicarbazido, N,N-diloweralkylsemicarbazido, loweralkanoylhydrazido, benzoylhydrazido, a loweralkylbenzoylhydrazido.
Independent claims6