US 5,208,222 AGranted

4"-and 4'-alkylthio avermectin derivatives

AssigneeMerck & Co., Inc.

InventorsPeter T. Meinke, Helmut Mrozik

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Abstract

Avermectin derivatives are disclosed wherein the 4"-hydroxy group is replaced by a substituted alkylthio or acylthio group or an iodo 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 from the 4"- and 4'-trifluoromethanesulfonyl avermectin derivatives with halo- or sulfur-containing nucleophiles. The 4"- and 4'-.alpha.- and .beta.-trifluoromethane sulfonates are prepared selectively and converted into 4"- or 4'-alkyl- or acylsulfides, or iodides using the appropriate sulfur-containing or iodine nucleophile. Substituted sulfoxy and sulfonyl substituents at the 4"- and 4'-positions are prepared from oxidation of the corresponding substituted sulfides. The new compounds are potent anti-parasitic agents; in particular, the compounds are anthelmintic, insecticidal and acaricidal agents.

A compound having the formula:

##STR8## wherein:
A at the 22,23 position represents
(1) a single bond and wherein R.sub.1 is
(a) hydrogen,
(b) hydroxy, or
(c) oxo;
or
(2) a double bond and R.sub.1 is absent;
R.sub.2 is
(1) C.sub.1-4 alkyl,
(2) substituted C.sub.1-4 alkyl with 1 to 3 substituents selected from C.sub.4-6 cycloalkyl, phenyl, and halo,
(3) alpha-branched C.sub.3-8 alkyl,
(4) C.sub.2-8 alkenyl,
(5) C.sub.2-6 alkynyl,
(6) C.sub.1-6 alkoxy C.sub.1-6 alkyl,
(7) C.sub.1-6 alkylthio C.sub.1-6 alkyl,
(8) C.sub.4-6 cycloalkyl or C.sub.4-6 cycloalkenyl, either unsubstituted or substituted with 1 to 3 substitutents selected from
(a) methylene,
(b) halo, and
(c) C.sub.1-4 alkyl,
(9) 3 to 6 membered nitrogen, oxygen or sulfur containing heterocycle containing one heteroatom saturated or unsaturated, connected through a carbon atom on the heterocycle to C-25 either unsubstituted or substituted with 1 to 3 substitutents selected from
(a) C.sub.1-4 alkyl, and
(b) halo, or
(10) phenyl, either substituted or unsubstituted with 1 to 3 substitutents selected from
(a) C.sub.1-3 alkyl, and
(b) halo;
R.sub.3 is
(1) hydroxy,
(2) C.sub.1-6 alkoxy,
(3) C.sub.2-6 alkanoyloxy,
(4) oxo, or
(5) oximino;
R.sub.7 is hydrogen or C.sub.1-6 alkyl, either straight chain or branched;
and
R.sub.4 is ##STR9## wherein:
R.sub.5 is
(1) S(O).sub.n R.sub.6 wherein n is 0, 1 or 2, or
(2) SCOR.sub.6
wherein:
R.sub.6 is
(1) hydrogen,
(2) C.sub.1-8 alkyl either straight or branched chain and either unsubstituted or substituted with 1-3 substitutents selected from
(a) halo,
(b) hydroxy,
(c) C.sub.1-3 alkoxy,
(d) phenoxy,
(e) C.sub.1-3 alkylthio,
(f) C.sub.1-3 alkylsulfinyl,
(g) C.sub.1-3 alkylsulfonyl,
(h) amino,
(i) C.sub.2-6 alkanoylamino,
(j) C.sub.1-3 alkylamino,
(k) di(C.sub.1-3 alkyl)amino,
(l) halo C.sub.1-3 alkoxycarbonylamino,
(m) oxo,
(n) carboxy, and
(o) C.sub.1-3 alkoxycarbonyl,
(3) C.sub.2-8 alkanoyl either unsubstituted or substituted with 1-3 substitutents selected from
(a) halo,
(b) hydroxy,
(c) C.sub.1-3 alkoxy,
(d) phenoxy,
(e) C.sub.1-3 alkylthio,
(f) C.sub.1-3 alkylsulfinyl,
(g) C.sub.1-3 alkylsulfonyl,
(h) amino,
(i) C.sub.2-6 alkanoylamino,
(j) C.sub.1-3 alkylamino,
(k) di(C.sub.1-3 alkyl)amino,
(l) halo C.sub.1-3 alkoxycarbonylamino,
(m) oxo,
(n) carboxy, and
(o) C.sub.1-3 alkoxycarbonyl,
(4) C.sub.3-8 cycloalkyl either unsubstituted or substituted with 1-3 substitutents selected from
(a) halo,
(b) C.sub.1-3 alkoxy,
(c) sulfonamido,
(d) amino,
(e) C.sub.1-3 alkylamino,
(f) di(C.sub.1-3 alkyl)amino, and
(g) C.sub.2-6 alkanoylamino.

78 more elements

Abstract

Claims8