Merck + Co., Inc.

Helmut H Mrozik

Michael H Fisher

Bruce O Linn

Peter T Meinke

Thomas L Shih

Peter Kulsa

Matthew J Wyvratt

Peter J Sinclair

William R Schoen

Timothy A Blizzard

Lin Chu

John C Chabala

Dale R Hoff

Frank S Waksmunski

Burton G Christensen

Edward F Rogers

Todd K Jones

George E Albers-Schonberg

John G MacConnell

August J Kempf

Gaye Marino

Philip Eskola

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 avermect 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.

24-and 25-substituted avermectin and milbemycin derivatives

There are disclosed certain novel compounds identified as heterocyclic-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such heterocyclic-fused lactams as the active ingredient thereof are also disclosed.

Heterocyclic-fused lactams promote release of growth hormone

Avermectin derivatives are disclosed which incorporate two fluorine atoms at the 4' monosaccharide position, the 4' disaccharide position or the 23 position. Avermectin aglycone derivatives are also disclosed which incorporate two fluorine atoms at position 13 or 23. These difluoro avermectin analogs are derived from corresponding ketones and enones which in turn are prepared by chemical modification of naturally occurring avermectins. These compounds are used as antiparisitic, insecticidal and antihelmintic agents in humans and animals and compositions containing such compounds as the active ingredient thereof are also disclosed.

Avermectin difluoro derivatives

There are disclosed certain novel compounds identified as benzo-fused lactams ##STR1## which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. The compounds are prepared by substitution of an amino-lactam with a substituted amide function. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.

Benzo-fused lactams promote release of growth hormone

Avermectin compounds are substituted at the 4a-position: the 4a-methyl group is first derivatized with a hydroxy group which is then substituted with a variety of alkyl, alkoxy alkyl, or polyalkoxy alkyl groups and derivatives thereof. The compounds are potent antiparasitic and anthelmintic agents and compositions for such uses are also disclosed.

4.alpha.-substituted avermectin derivatives

Avermectin analogs are prepared where the 23-position ring carbon atom is deleted and replaced by an oxygen atom. The compounds are prepared by opening the outer spiroketal ring to gain access to the 23-position atom, substituting the ring-opened compounds with a substituent containing the oxygen atom in the appropriate position and closing the ring to prepare the desired compounds. The compounds are potent anthelmintic agents and methods and compositions including such 23-nor-23-oxa compounds are also disclosed.

23-nor-23-oxa avermectin analogs are active anthelmintic agents

Avermectin compounds are substituted at the 4', 4' or 13-postion hydroxy group with an alkylthioalkyl group and are optionally substituted at the other reactive positions of the avermectin molecule. The compounds are prepared by reacting protected avermectins, avermectin monosaccharides or avermectin aglycones with dialkylsulfoxides. The compounds are potent antiparasitic agents and compositions for such uses are also disclosed.

Alkylthio alkyl avermectins are active antiparasitic agents

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.

4'-and 4'-alkylthio avermectin derivatives

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.

Derivatives of 3'- and 3'-O-desmethyl avermectin compounds, compositions

Avermectin analogs are prepared where the 23-position ring carbon atom is deleted and replaced by a sulfur atom. The compounds are prepared by opening the outer spiroketal ring to gain access to the 23-position atom, substituting the ring-opened compounds with a substituent containing the sulfur atom in the appropriate position and closing the ring to prepare the desired compounds. The compounds are potent anthelmintic agents and methods and compositions including such 23-nor-23-thia compounds are also disclosed.

23-nor-23-thia avermectin analogs are active anthelmintic agents

There are disclosed novel avermectin derivatives wherein the outer oleandrose ring of avermectin or avermectin monosaccharide is homologated by addition of diazomethane to 4'- or 4'-oxo-avermectin to afford the perhydrooxepine derivatives. The homologated avermectins can then be further derivatized to afford additional novel avermectins. The new compounds are potent antiparasitic agents, in particular, the compounds are anthelmintic, insecticidal and acaricidal agents.

Avermectin derivatives

There are disclosed avermectin derivatives in which position 13 of the avermectins has been inverted from the normal (alpha) stereoschemistry to the epimeric 13-beta stereochemistry. The synthetic 13-epi analogs are derived from the corresponding aglycones which in turn are prepared by chemical modification of naturally occurring avermectins. The compounds are active antiparasitic agents and compositions for that use are disclosed.

13-epi-avermectin derivatives useful as antiparasitic agents

There are disclosed novel avermectin derivatives wherein the outer oleandrose ring of avermectin or avermectin monosaccharide is homologated by addition of diazomethane to 4'- or 4'-oxo-avermectin to afford the oleandrose 4'- or 4'-spiro-epoxide. The homologated avermectins can then be further derivatized to afford additional novel avermectins. The new compounds are potent antiparasitic agents, in particular, the compounds are anthelmintic, insecticidal and acaricidal agents.

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Matawan, NJ, United States of America

Helmut H Mrozik