OA10223A - New antiparasitic agents related to the milbemycins and avermectins - Google Patents

Claims (13)

1. WO 94/15944 - 54 - PCT/EP94/00095

   £1·&ΙΜ£ A compound of formula (I) 010223

   wherein the broken line at the 22-23 position represents 20 an optional bond and either this bond is présent and Rx isabsent or this bond is absent and R1 is H, OH, oxo oroximino optionally substituted by a C^-C, alkyl group, R3is a Οχ-Οβ alkyl, C2-C, alkenyl or 03-Οβ cycloalkyl group,or a 3- to 6- membered heterocyclic ring containing a 25 sulphur or oxygen atom, said ring being saturated or fully or partially unsaturated and optionally substitutedby one or more Οχ-Ο4 alkyl groups or halogen atoms, R3 is H or OH, and R4 is H or a group capable of being hydrolysed in vivo toyield a compound in which R* is H, R5 is OH, optionally substituted with a group capable ofbeing hydrolysed in vivo to yield a compound in which R5is OH, and R6 is H or θ!-θ4 alkyl or R6 is H and R5 isamino, optionally substituted with at least one group 25 selected from Οχ-Οβ alkyl and acyl groups.

   -TTC \VO 94/15944 PCT/EP94/00095 •4

   10 15 20 25 010223 2. A. compound according to Claim 1, in which said groups capable of being hydrolysed in vivo are independently substituted or unsubstituted C3-C. alkanoyl,aroyl, carbamoyl, C3-Ce alkoxycarbonyl, dicarboxylic acidor amino acid group.
2. 3. A compound according to Claim 2, in which said groupcapable of being hydrolysed in vivo is an acetyl,butylcarbonyl, £.-butyloxycarbonyl, benzoyl,methylpiperazinecarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, formylphenylcarbamoyl, N-(4-diethylaminomethylphenyl) -carbamoyl, N- (4-methyl-l-piperazin-methylphenyl)-carbamoyl, N- (3-pyridylcarbonyl)-carbamoyl, N-(3-pyridyl)-carbamoyl, allylcarbamoyl,succinoyl, methoxysuccinoyl, 4-methylpiperazinesuccinoyl,pyrid-4-ylaminosuccinoyl, lysinyl or a N, Nl-bis(9- f luoreny lmethoxycarbony1 ) lys inyl group.
3. 4. A compound according to Claim 1, 2 or 3 in which R2 is an alkyl or cycloalkyl group. ' — —··
4. 5. A compound according to Claim'4, in which Ra iscyclohexyl, isopropyl or sec-butyl.
5. 6. A compound according to any preceding claim, inwhich R’ is H and the optional bond at the 22-23 positionis présent or this optional bond is absent and Rx is H orOH.
6. 7. A compound according to claim 1 which R3 and R4are H. 30 _ 8. Any one of the following compounds: 5-oximino-22,23-dihydroavermectin Bla monosaccharide,5-oximino-22,23-dihydro-25-cyclohexylavermectin B1monosaccharide, 5-oximino-25-cyclohexylavermectin B2 monosaccharide,5-oximino-25-cyclohexylavermectin B1 monosacccharide,4‘-epi-5-oximino-25-cyclohexyl-22,23-dihydroavermectinmonosaccharide, 4a-hydroxy-5-oximino-25-cyclohexyl-22,23- dihydroavermectin B1 monosaccharide, 5-oximino-25-(4-tetrahydropyranyl)-22,23- /

   35 \VO 94/15944 PCT/EP94/00095 56 - 10 010223 20 25 30 dihydroavennectin B1 monosacccharide. 4 ' -0-Acetyl-5-oximino-25-cyclohexyl-22,23- dihydroavermectin B1 monosaccharide, 4 ‘ -me thy1-5-oximino-25-cyclohexy1-22,2 3-dihydroavermect inBl monosaccharide, 4' -acetylamino-4’ -deoxy-5-oximino-22,23-dihydro-25-cyciohexylavermectin B1 monosaccharide,5-oximino-23-oxo-25-cyclohexylavermectin B2monosaccharide, 5-oximino-23-methoximino-25-cyclohexylavermectin B2monosaccharide, 4'-0-succinoyl-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 4‘-O-(3-methoxycarbonylpropanoyl)-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 4'-O- (3-(4-methylpiperazin-l-yl)carbonylpropanoyl)-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Blmonosaccharide, ' . _„ 4'-O- (3-(pyrid-4-ylamino)carbonylpropanoyl)-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 4‘-O- (Ν,Ν’-bis- (9-fluorenylmethoxycarbonyl)lysinyl)-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Blmonosaccharide, 4’-0-lysinyl-5-oximino-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 5- (trimethylacetyloximino)-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 5- (benzoyloximino)-25-cyclohexyl-22,23-dihydroavermectinBl monosaccharide, 5- (N-methylcarbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 5- (N, N-dimethylcarbamoyloximino) -25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 5- ( 4-methylpiperazinyl-l-carbonyloximino)-25-cyclohexy1-22,23-dihydroavermectin Bl monosaccharide, 5- (χ,-butyloxycarbonyloximino)-25-cyclohexyl-22,23-dihydroavermectin Bl monosaccharide, 35

   if* A 010223 5-(N-(4-formylphenyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide, 5-(N-(4-(diethy1aminornethyl)phenyl)-carbamoyloximino)-25-cyclohexyl -22,23-dihydroavermectin B1 monosaccharide, 5 5-(N-(4-(4-methyl-l-piperazinyl-methyl)phenyl)- carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectinB1 monosaccharide, 5-(N-(3-pyridylcarbonyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide, IC 5-(N-(3-pyridyl)-carbamoyloximino)-25-cyclohexyl-22,23- dihydroavermectin B1 monosaccharide, 5-(N-allylcarbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide.
7. 9. A pharmaceutical or veterinary composition, Ί5 comprising a compound according to any preceding claim and a pharmaceutically acceptable carrier or excipient.
8. 10. A compound according to any one of daims 1 to8 for use in animal or human medicine.
9. 11. A compound according to any one of claims 1 to 2q 8, for use as an antiparasitic agent.
10. 12. Use of a compound according to any one ofclaims 1 to 8 for making a médicament for treatment orprophylaxie of flea infestations.
11. 13. Médicament for the treatment or prophylaxis of25, parasitic infections, which comprises an effective amount of a compound according to any one of claims 1 to 8.
12. 14. An intermediate compound useful notably forpreparing the compounds of formula I according to claim 1,said intermediate compound corresponding to formula III. 50 55

    WO 94/15944 PCT/EP94/00095 010223 wherein the broken line, R1, Ra, R3 and R4 are as definedin claim 1, or R5 is α-oleandrosyloxy and R* is H.
13. 15. A process for preparing a compound of formula (I) :

    20 wherein the broken line at the 22-23 position représente an optional bond and either this bond is présent and R* isabsent or this bond is absent and R1 is H, OH, oxo oroximino optionally substituted by a Cx-Ca alkyl group, R3is a Cx-Ce alkyl, C2-C, alkenyl or C3-C„ cycloalkyl group, 25 or a 3- to 6- membered heterocyclic ring containing a sulphur or oxygen atom, said ring being saturated orfully or partially unsaturated and which may optionallybe substituted by one or more Cx-C4 alkyl groups orhalogen atoms, 30 R3 is H or OH, R4 is H or a group capable of being hydrolysed in vivo toyield a compound in which R4 is H, Rs is OH, optionally substituted with a group capable ofbeing hydrolysed in vivo to yield a compound in which Rs .. .'1 35 is OH, and R® is H or Ci-C^ alkyl or R6 is H and R5 is amino, optionally substituted with at least one groupselected from Cj-Co alkyl and acyl groups. - ,· ' ' · l·'. ,'x

    WO 94/15944 5g PCT/EP94/00095 010223 which comprises the steps (1) of oxidising a compound offormula (II):

    wherein the broken line, R1, R3, R’ and R® 'are as definedabove and Rs is as defined above or R? is 2-a- A ’ . 4 20 oleandrosyloxy and Re is H to yield a compound of formula (III):

    WO 94/15944 PCT/EP94/00095 -60’ 01 0223 and (ii) allowing the compound of formula (III) to reactwith a compound of formula R4-O-NH3 where R4 is as definedabove and where R5 is s-oleandrosyloxy, hydrolysing the compound 5 obtained to yield a compound of formula (I), and (iii) if necessary replacing group R4 when the latteris H with said group capable of being hydrolysed in vivoto yield a compound in which R4 is H, if necessary, the process further comprising one or more 10 of the following steps before or after steps (i), (ii) and (iii), (iv) substituting group Rs when the latter is OH with saidgroup capable of being hydrolysed in vivo to yield acompound in which Rs is OH, 15 (v) oxidising group R1 when the latter is OH to oxo, (vi) reacting the compound obtained from step (v) withhydroxylamine optionally substituted by a Cj-C, alkylgroup to yield a compound in which R1 is optionally "substituted oxo, , ·- ·;,·►·" -y 20 (vii) hydrogenating the compound to reduce a double bond at the 22-23 position to a single bond, · *-· (viii) oxidising a compound in which R3 is H to a compoundin which R3 is OH, (ix) oxidising a compound in which R5 is OH and R* is H to 2 5 a compound in which Rs is oxo and Re is absent, and either: (x) reducing the compound obtained from (IX) to produce acompound in which R5 is an epi-OH group, or (xi) reacting the compound obtained from (IX) with a 30 Grignard reagent to. yield a compound in which R® is OH and R6 is alkyl, or (xii) subjecting the compound obtained from (IX) toreductive amination to yield a compound in which R5 is anamino or alkylamine group, and if necessary acylating the 35 compound obtained, any free OH groups being protected if necessary during any of the above steps. Λ-- 8 * 8 liti ta