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United States Patent (19) 11) Patent Number: 4,873,224 Linn Et Al

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United States Patent (19) 11) Patent Number: 4,873,224 Linn Et Al United States Patent (19) 11) Patent Number: 4,873,224 Linn et al. (45. Date of Patent: Oct. 10, 1989 54 AVERMECTIN DERIVATIVES Assistant Examiner-Elli Peselev 75) Inventors: Bruce O. Linn, Bridgewater; Helmut Attorney, Agent, or Firm-David L. Rose; Hesna J. Mrozik, Matawan, both of N.J. Pfeiffer 73) Assignee: Merck & Co., Inc., Rahway, N.J. 57 ABSTRACT 21 Appl. No.: 197,731 There are disclosed novel avermectin compounds wherein the 4' or 4 hydroxy group is oxidized to an 22 Filed: May 23, 1988 oxo group and replaced with a semicarbazone, carbo 51 Int. Cl........................ A61K 31/70; C07H 17/08 nyl- or sulfonyl-hydrazone, hydrazone, or oxime, and 52 U.S. Cl. ........................................ 514/30; 536/7.1 optionally reduced to the corresponding semicarbazide, 58 Field of Search ............................ 536/7.1; 514/30 carbonyl- or sulfonyl-hydrazide or hydrazine. The semicarbozones and hydrazones are prepared from the 56 References Cited 4' or 4 oxo compound using the corresponding semi U.S. PATENT DOCUMENTS carbazides or hydrazines. The compounds have utility 4,378,353 3/1983 Goegelman et al. ................ 536/7.1 as anti-parasitic agents and compounds for that use are also disclosed. The compounds are also highly potent OTHER PUBLICATIONS insecticides against agricultural pests. Compositions for Morrison et al., Organic Chemistry, 3rd ed., (1973) pp. such uses are also disclosed. 740-74. Primary Examiner-Johnnie R. Brown 13 Claims, No Drawings 4,873,224 1. 2 AVERMECTN DERVATIVES -continued R1 R2 R3 BACKGROUND OF THE INVENTION B2a. --OH sec-buty -OH 5 B2b --OH iso-propyl -OH The term avermectin (previously referred to as C 076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin produc The avermectin compounds are generally isolated as ing strain of Streptomyces avermitilis and derivatives mixtures of a and b components. Such compounds differ thereof. The morphological characteristics of the cul only in the nature of the R2 substituent and the minor ture are completely described in U.S. Pat. No. 10 structural differences have been found to have very 4,310,519. The avermectin compounds are a series of little effect on the isolation procedures, chemical reac macrollides, each of which is substituted thereon at the tivity and biological activity of such compounds. 13-position with a 4-(a-L-oleandrosyl)-a-L-oleandrose The terminal hydroxy group of the 13-position disac group. The avermectin compounds and the instant de charide substituent is situated at what is referred to as rivatives thereofhave a very high degree of anthelmin 15 the 4'-position. In U.S. Pat. No. 4,427,663 to Mrozik, tic and anti-parasitic activity. certain 4" derivatives of avermectin compounds are The avermectin series of compounds isolated from discussed, specifically 4'-amino compounds. Amino the fermentation broth have the following structures: and alkyl amino derivatives at the 4'-position are dis closed however the semicarbazones and hydrazones of 20 the instant invention are not suggested. SUMMARY OF THE INVENTION The instant invention is concerned with certain deriv atives of avermectin compounds wherein the 4'- 25 hydroxy group is oxidized to ketone and replaced by a semicarbazone, carbonyl or sulfonyl-hydrazone, hydra zone or oxime and optionally reduced to the corre sponding semicarbazide, carbonyl- or sulfonyl-hydra zide or hydrazine. Thus it is an object of the instant 30 invention to describe such 4'-substituted avermectin compounds. A further object is to describe processes for the preparation of such compounds. A still further object is to describe the uses of such compounds as anti parasitic agents and antibacterial agents. Still further 35 objects will become apparent from a reading of the following description. wherein R is the 4'-(a-1-oleandrosy)-a-1-oleandrose group of the structure: DESCRIPTION OF THE INVENTION The compounds of the instant invention have the CH3 CH3 following structural formula. CH3 CH3 O O 45 CHO R O O and wherein the broken line indicates a single or a dou ble bond; CH3O CH3O 50 R1 is hydrogen or hydroxy and is present only when said broken line indicates a signal bond; R2 is iso-propyl or sec-butyl; and R3 is methoxy or hydroxy. There are eight different avermectin natural product compounds and they are given the designations A1a, 55 Alb, A2a, A2b, Bla, B1b, B2a and B2b based upon the structure of the individual compounds. In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'(a-Loleandrosyl)-a-L-oleandrose): R R R3 Ala (22,23-Double Bond) sec-butyl -OCH3 A1b (22,23-Double Bond) iso-propyl -OCH3 65 CH3 A2a -OH sec-butyl -OCH3 A2B -OH iso-propyl -OCH3 Bia (22,23-Double Bond) sec-butyl * -OH B1 (22,23-Double Bond) iso-propyl -OH 4,873,224 4. wherein pholinyl, N-loweralkyl piperazinyl, N-(loweralkoxy m is 0 or l; phenyl)piperazinyl, N-(halophenyl)piperazinyl, or N R1 is (loweralkylphenyl)piperazinyl; or R1 is -NH-NRR' and R is loweralkyl, methoxyloweralkyl, diloweralk ylaminoloweralkyl, loweralkylphenyl, halophenyl, morpholinyl, carbonyl, N-loweralkyl piperazinyl car bonyl, M-(loweralkylphenyl)piperazinylcarbonyl; 10 R" is hydrogen or loweralkyl; RONE A is a double bond; B is a single bond or a double bond; wherein R2 is hydrogen n is 0 or 1; R3 is iso-propyl or sec-butyl or sec-butyl, R is hydrogen, amino, loweralkyl, mono- or di-lower 15 R4 is hydroxy alkyl amino, methoxy-loweralkylamino, diloweralk R5 and R5 are present only when B is a single bond ylamino-loweralkyl, diloweralkylamino-loweralk and are independently hydrogen or fluorine; ylamino, loweralkylphenyl, loweralkyl phenylamino, and the broken line indicates a single or a double loweralkoxyphenyl, loweralkoxyphenylamino, halo bond at the 22,23-position. phenyl, halophenylamino, sulfamylphenyl, sulfamyl 20 phenylamino, morpholinyl, N-loweralkyl piperazinyl, Further examples of preferred compounds of the N-(loweralkoxy-phenyl) piperazinyl, N-(halophenyl)- instant invention are wherein M=1, piperazinyl, benzimidazolylamino, pyrimidinylamino, R1 is thiazolylamino, benzothiazolyamino, or N (loweralkyl phenyl)piperazinyl; 25 R" is hydrogen or loweralkyl; X is carbonyl or sulfonyl; A is a double bond or an epoxide; and R is mono- or di lower alkyl amino, dilloweralk B is a single bond or a double bond; ylaminoloweralkylamino, loweralkylphenyl, halo R2 is hydrogen or hydroxy, 30 phenyl, N-loweralkyl piperazinyl, and N-(loweralkyl R3 is iso-propyl or sec butyl, phenyl)piperazinyl or R1 is R4 is hydroxy or methoxy, R5 and R6 are present only when B is a single bond and are independently hydrogen, hydroxy or halogen; and the broken line indicates a single or a double 35 and R is loweralkyl, or N-(loweralkylphenyl)- bond at the 22,23-position, provided that R2 is hydroxy piperazinyl carbonyl only when the broken line indicates a single bond. R" is hydrogen or loweralkyl; The term "loweralkyl' when used in the instant ap A is a double bond; plication is intended to represent those alkyl groups B is a double bond; either straight or branched chain which have from 1 to R2 is hydrogen 5 carbon atoms. Examples of such alkyl groups are R3 is iso propyl or sec-butyl, methyl, ethyl, propyl, iso propyl, butyl, sec-butyl, pen R4 is hydroxy, tyl, and the like. R5 and Ró are hydrogen; The term "loweralkoxy' is intended to include those and the broken line indicates a single or a double alkoxy groups of from 1 to 5 carbon atoms in either a 45 bond at the 22,23-position. straight or branched chain examples of such alkoxy Preferred compounds of the instant invention are groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, realized in the following specific compounds isopentoxy and the like. 4'-Oxoavermectin Bla/1b 4,4-dimethylsemicarbazone The term “loweralkanoyl' is intended to include those alkanoyl groups containing from 1 to 5 carbon 50 4'-Oxoavermectin B1a/B1b semicarbazone atoms in either a straight or branched chain. Examples 4'-Oxoavermectin B1a/B1b monosaccharide 4 methyl of such alkanoyl groups are formyl, acetyl, propionyl, semicarbazone butyryl, valeryl, and the like. 2,23-Dihydro-4'-oxo avermectin B1a/B1b semicarba The term "halogen' is intended to include those halo ZOle gen atoms fluorine, chlorine, bromine and iodine. 55 10, 11-Dihydro-10-fluoro 4'-oxoavermectin B1a/B1b. One aspect of the preferred compounds of this inven semicarbazone tion is realized in the above structural formula when 10, 11-Dihydro-4'oxoavermectin Bla/B1b semicarba 2One m is 1, 10, 11-Dihydro-10-fluoro 4'-oxoavermectin B1a/Blb R1 is 4,4-dimethylsemicarbazone 4'-Oxoavermectin Bla/lb 2-(morpholin-4-yl)car bonylhydrazone 4'-Oxoavermectin Bia/1b 4 (1H-benzimidazol-2- yl)semicarbazone and R is amino, loweralkyl, mono- or di lower alkyl 65 4'-Oxoavermectin B1a/1b 4 (thiazol-2-yl)semicarba amino, methoxyloweralkylamino, dilloweralk ZO8 ylaminoloweralkylamino, loweralkylphenyl, loweral 4'-Oxoavermectin Bla/lb 4-(benzothiazol 2 kyl phenylamino, halophenyl, halophenyl amino, mor yl)semicarbazone 4,873,224 9 -continued CH3 CH3 O O II - G RO-N= O O CH3 CH3O CH3O CH III wherein m, R, R, X, A, B, R2, R3, RA, R5 and Ró are as previously defined. In the first step of the foregoing reaction scheme, the usually complete in from 16 to 48 hours at 20 to 25 C. avermectin starting materials (I) which may be either and from 30 to 120 minutes at 80° C. The pH of the the naturally occurring products, the 22,23-dihydro reaction greater than 9 or less than 4 are to be avoided derivatives thereof or the monosaccharide derivative 25 since such conditions degrade the avermectin substrate. thereof, are oxidized at the 4'-position (or 4position) to The products, compound IV which are 4'-or 4'-oxo the corresponding keto compound (compound II).
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