4"-and 4'-alkylthio avermectin derivatives

• US 5,208,222 A
• Filed: 03/28/1991
• Issued: 05/04/1993
• Est. Priority Date: 03/28/1991
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Meinke, Peter T., Mrozik, Helmut
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): OWENS, AMELIA A
• Application Number:
  US07/676,626
• Time in Patent Office: 768 Days
• Field of Search: 514/824, 514/450, 514/30, 549/264, 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 19/01 sharing oxygen

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'"'"'-α- and β-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.

Claims

1. A compound having the formula:

##STR8## wherein;

A at the 22,23 position represents

(1) a single bond and wherein R₁ is

(a) hydrogen,

(b) hydroxy, or

(c) oxo;

or

(2) a double bond and R₁ is absent;

R₂ is

(1) C_1-4 alkyl,

(2) substituted C_1-4 alkyl with 1 to 3 substituents selected from C_4-6 cycloalkyl, phenyl, and halo,

(3) alpha-branched C_3-8 alkyl,

(4) C_2-8 alkenyl,

(5) C_2-6 alkynyl,

(6) C_1-6 alkoxy C_1-6 alkyl,

(7) C_1-6 alkylthio C_1-6 alkyl,

(8) C_4-6 cycloalkyl or C_4-6 cycloalkenyl, either unsubstituted or substituted with 1 to 3 substitutents selected from

(a) methylene,

(b) halo, and

(c) C_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_1-4 alkyl, and

(b) halo, or

(10) phenyl, either substituted or unsubstituted with 1 to 3 substitutents selected from

(a) C_1-3 alkyl, and

(b) halo;

R₃ is

(1) hydroxy,

(2) C_1-6 alkoxy,

(3) C_2-6 alkanoyloxy,

(4) oxo, or

(5) oximino;

R₇ is hydrogen or C_1-6 alkyl, either straight chain or branched; and

R₄ is ##STR9## wherein;

R₅ is

(1) S(O)_n R₆ wherein n is 0, 1 or 2, or

(2) SCOR₆

wherein;

R₆ is

(1) hydrogen,

(2) C_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_1-3 alkoxy,

(d) phenoxy,

(e) C_1-3 alkylthio,

(f) C_1-3 alkylsulfinyl,

(g) C_1-3 alkylsulfonyl,

(h) amino,

(i) C_2-6 alkanoylamino,

(j) C_1-3 alkylamino,

(k) di(C_1-3 alkyl)amino,

(l) halo C_1-3 alkoxycarbonylamino,

(m) oxo,

(n) carboxy, and

(o) C_1-3 alkoxycarbonyl,

(3) C_2-8 alkanoyl either unsubstituted or substituted with 1-3 substitutents selected from

(a) halo,

(b) hydroxy,

(c) C_1-3 alkoxy,

(d) phenoxy,

(e) C_1-3 alkylthio,

(f) C_1-3 alkylsulfinyl,

(g) C_1-3 alkylsulfonyl,

(h) amino,

(i) C_2-6 alkanoylamino,

(j) C_1-3 alkylamino,

(k) di(C_1-3 alkyl)amino,

(l) halo C_1-3 alkoxycarbonylamino,

(m) oxo,

(n) carboxy, and

(o) C_1-3 alkoxycarbonyl,

(4) C_3-8 cycloalkyl either unsubstituted or substituted with 1-3 substitutents selected from

(a) halo,

(b) C_1-3 alkoxy,

(c) sulfonamido,

(d) amino,

(e) C_1-3 alkylamino,

(f) di(C_1-3 alkyl)amino, and

(g) C_2-6 alkanoylamino.

2. The compound of claim 1, wherein:

A at the 22,23 position represents

(1) a single bond and wherein R₁ is

(a) hydrogen, or

(b) hydroxy, or

(2) a double bond and R₁ is absent;

R₂ is

(1) alpha-branched C₃ -C₈ alkyl,

(2) alpha-branched C₃ -C₈ alkenyl,

(3) C4-6 cycloalkyl,

(4) C4-6 cycloalkenyl,

(5) phenyl, or

(6) p-fluoro-phenyl;

R₃ is

(1) hydroxy, or

(2) oximino;

R₇ is methyl; and

R₄ is ##STR10## wherein R₅ is

(1) S(O)_n R₆ wherein n is 0, 1 or 2, or

(2) SCOR₆ ;

wherein;

R₆ is

(1) hydrogen,

(2) C_1-4 alkyl either straight or branched chain and either unsubstituted or substituted with 1-3 substitutents selected from

(a) halo,

(b) hydroxy,

(c) C_1-3 alkoxy,

(d) C_1-3 alkylthio,

(e) C_1-3 alkylsulfonyl,

(f) amino,

(g) C_2-3 alkanoylamino,

(h) C_1-3 alkylamino,

(i) di(C_1-3 alkyl)amino,

(j) carboxy, and

(k) C_1-3 alkoxycarbonyl, or

(3) C_2-5 alkanoyl either unsubstituted or substituted with 1-3 substitutents selected from

(a) halo,

(b) hydroxy,

(c) C_1-3 alkoxy,

(d) C_1-3 alkylthio,

(e) C_1-3 alkylsulfinyl,

(f) C_1-3 alkylsulfonyl,

(g) amino,

(h) C_1-3 alkylamino,

(i) di(C_1-3 alkyl)amino.

3. The compound of claim 1, wherein:

A at the 22,23 position represents

(1) a single bond and wherein R₁ is

(a) hydrogen, or

(b) hydroxy, or

(2) a double bond and R₁ is absent;

R₂ is

(1) 2-propyl,

(2) 2-butyl,

(3) 2-buten-2-yl,

(4) 2-penten-2-yl,

(5) 4-methyl-2-penten-2-yl,

(6) cyclopentyl,

(7) cyclopentenyl,

(8) cyclohexyl,

(9) cyclohexenyl,

(10) phenyl, or

(11) p-fluoro-phenyl;

R₃ is

(1) hydroxy, or

(2) oximino;

R₇ is methyl; and

R₄ is ##STR11## wherein R₅ is

(1) S(O)_n R₆ wherein n is 0, 1, 2 or

(2) SCOR₆ ;

wherein

R₆ is C_1-3 alkyl either straight or branched chain and either unsubstituted or substituted with 1-3 substitutents selected from

(1) hydroxy,

(2) C_1-2 alkoxy,

(3) amino,

(4) acetylamino,

(5) C_1-2 alkylamino,

(6) dimethylamino, and

(7) halo.

4. The compound of claim 1 which is:

(a) 4"-deoxy-4"-epi-methylthio-avermectin B1a/B1b,

(b) 4"-deoxy-22,23-dihydro-4"-epi-methylthio-avermectin B1a/B1b,

(c) 4"-deoxy-4"-epi-methylsulfinyl-avermectin B1a/B1b,

(d) 4"-deoxy-4"-epi-methylsulfonyl-avermectin B1a/B1b,

(e) 4"-deoxy-4"-methylthio-avermectin B1a/B1b,

(f) 4"-deoxy-22,23-dihydro-4"-methylthio-avermectin B1a/B1b,

(g) 4"-deoxy-4"-methylsulfinyl-avermectin B1a/B1b,

(h) 4"-deoxy-4"-methylsulfonyl-avermectin B1a/B1b,

(i) 4"-deoxy-5-oximino-4"-epi-methylthio-avermectin B1a/B1b,

(j) 4"-deoxy-22,23-dihydro-5-oximino-4"-epi-methylthio-avermectin B1a/B1b,

(k) 4"-deoxy-5-oximino-4"-epi-methylsulfinyl-avermectin B1a/B1b,

(l) 4"-deoxy-5-oximino-4"-epi-methylsulfonyl-avermectin B1a/B1b,

(m) 4"-deoxy-5-oximino-4"-methylthio-avermectin B1a/B1b,

(n) 4"-deoxy-22,23-dihydro-5-oximino-4"-methylthio-avermectin B1a/B1b,

(o) 4"-deoxy-5-oximino-4"-methylsulfinyl-avermectin B1a/B1b,

(p) 4"-deoxy-5-oximino-4"-methylsulfonyl-avermectin B1a/B1b,

(q) 4"-deoxy-4"-(2-hydroxyethyl)thio-avermectin B1a/B1b,

(r) 4"-deoxy-4"-epi-(2-hydroxyethyl)thio-avermect in B1a/B1b,

(s) 4"-deoxy-5-oximino-4"-(2-hydroxyethyl)thio-avermectin B1a/B1b,

(t) 4"-deoxy-5-oximino-4"-(2-hydroxyethyl)-thio-avermectin B1a/B1b,

(u) 4"-deoxy-22,23-dihydro-4"-(2-hydroxyethyl)-thio-avermectin B1a/B1b,

(v) 4"-deoxy-22,23-dihydro-5-oximino-4"-(2-hydroxyethyl)thio-avermectin B1a/B1b,

(w) 4"-deoxy-22,23-dihydro-5-oximino-4"-epi-(2-hydroxyethyl)thio-avermectin B1a/B1b,

(x) 4"-deoxy-4"-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(y) 4"-deoxy-4"-epi-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(z) 4"-deoxy-5-oximino-4"-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(aa) 4"-deoxy-5-oximino-4"-epi-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(bb) 4"-deoxy-22,23-dihydro-4"-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(cc) 4"-deoxy-22,23-dihydro-4"-epi-(2-hydroxyethyl)-sulfinyl-avermectin B1a/B1b,

(dd) 4"deoxy-22,23-dihydro-5-oximino-4"-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(ee) 4"-deoxy-22,23-dihydro-5-oximino-4"-epi-(2-hydroxyethyl)sulfinyl-avermectin B1a/B1b,

(ff) 4"-deoxy-4"-(2-hydroxyethyl)sulfonyl-avermectin B1a/B1b,

(gg) 4"-deoxy-4"-epi-(2-hydroxyethyl)sulfonyl-avermectin B1a/B1b,

(hh) 4"-deoxy-5-oximino-4"-(2-hydroxyethyl)sulfonyl-avermectin B1a/B1b,

(ii) 4"-deoxy-5-oximino-4"-epi-(2-hydroxyethyl)sulfonyl-avermectin B1a/B1b,

(jj) 4"-deoxy-22,23-dihydro-4"-(2-hydroxyethyl)sulfonyl-avermectin B1a/B1b,

(kk) 4"-deoxy-22,23-dihydro-4"-epi-(2-hydroxyethyl)-sulfonyl-avermectin B1a/B1b,

(ll) 4"-deoxy-22,23-dihydro-5-oximino-4"-(2-hydroxyethyl)-sulfonyl-avermectin B1a/B1b,

(mm) 4"-deoxy-22,23-dihydro-5-oximino-4"-epi-(2-hydroxyethyl)-sulfonyl-avermectin B1a/B1b,

(nn) 4"-deoxy-4"-epi-methylthio-25-des-(2-butyl)-25-cyclohexyl-avermectin,

(oo) 4"-deoxy-4"-epi-methylthio-25-des-(2-butyl)-25-phenyl-avermectin,

(pp) 4"-deoxy-4"-epi-methylthio-25-des-(2-butyl)-25-[2-(4-methylpenten-2-yl)]-avermectin,

(qq) 4"-deoxy-4"-epi-(2-amino)ethylthio-25-des-(2-butyl)-25-cyclohexen-2-yl-avermectin,

(rr) 4"-deoxy-4"-epi-trifluoromethylthio-avermectin B1a/B1b, and

(ss) 4"-deoxy-4"-epi-2,2,2-trifluoroethylthio-avermectin B1a/B1b,

5. A protected derivative of a compound of claim 1 wherein R₃ is tert.-butyldimethylsilyloxy.

6. The compound of claim 5 which is

(a) 4"-deoxy-4"-trifluoromethanesulfonyl-5-O-tert.-butyldimethylsilyl-avermectin B1a/B1b.

7. A method for the therapeutic treatment of parasitic infections of animals or plants, which comprises topical, oral or parenteral treatment of the animal or topical treatment of the plant or the soil in which the plant grows with an effective amount of a compound of claim 1.

8. A composition useful for the therapeutic antiparasitic treatment of animals or plants which comprises an inert carrier and a compound of claim 1.