Antiparasitic agents related to the milbemycins and avermectins

• US 5,981,500 A
• Filed: 05/09/1997
• Issued: 11/09/1999
• Est. Priority Date: 01/12/1994
• Status: Expired due to Term

• Current Assignee: ZOETIS LLC (Zoetis Incorporated)
• Original Assignee: Pfizer Inc.
• Inventors: Perry, David Austen, Pacey, Michael Stephen, Bishop, Bernard Frank
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US08/853,686
• Time in Patent Office: 914 Days
• Field of Search: 536/7.1, 514/30, 514/27, 514/28
• US Class Current: 514/30
• CPC Class Codes: C07H 19/01 sharing oxygen

Abstract

A 5-oximino-25-substituted avermectin B1 or B2 monosaccharide of formula I herein has use in the treatment of parasitic infections in animals and humans. The compounds may be prepared from corresponding 5-keto substituted derivatives.

Claims

1. A compound of formula (I) ##STR5## wherein the broken line at the 22-23 position represents an optional bond and either this bond is present and R¹ is absent or this bond is absent and R¹ is H or OH;

R² is a C₁ -C₈ alkyl, or C₃ -C₈ cycloalkyl group;

R³ is H;

R⁴ is H or a group capable of being hydrolyzed in vivo to yield a compound in which R⁴ is H;

R⁵ is OH; and

R⁶ is H.

2. A compound according to claim 1, in which said group capable of being hydrolyzed in vivo is an acetyl, t-butylcarbonyl, t-butyloxycarbonyl, benzoyl, methylpiperazinecarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, formylphenylcarbamoyl, N-(4-diethylaminomethylphenyl)-carbamoyl, N-(4-methyl-1-piperazin-methylphenyl)-carbamoyl, N-(3-pyridylcarbonyl)-carbamoyl, N-(3-pyridyl)-carbamoyl or allylcarbamoyl, succinoyl, methoxysuccinoyl, 4-methylpiperazinesuccinoyl, pyrid-4-ylaminosuccinoyl, lysinyl or a N, N -bis(9-fluorenylmethoxy-carbonyl)lysinyl group.

3. A compound according to claim 1, in which R is cyclohexyl.

4. A compound according to claim 1, in which the optional bond at the 22-23 position is absent and R¹ is H.

7. A pharmaceutical or veterinary composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

8. A method of treatment of parasitic infections in an animal or human, which comprises administering to said animal or human an effective amount of a compound according to claim 1.

5. 5-Oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide.

6. A compound selected from the group consisting of:

5-oximino-22,23-dihydroavermectin B1 a monosaccharide;

5-oximino-25-cyclohexylavermectin B2 monosaccharide;

5-oximino-25-cyclohexylavermectin B1 monosaccharide;

5-(trimethylacetyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(benzoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

p1 5-(N-methylcarbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N,N-dimethylcarbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(4-methylpiperazinyl-1-carbonyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(t-butyloxycarbonyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N-(4-formylphenyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N-(4-(diethylaminomethyl)phenyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N-(4-(4-methyl-1-piperazinyl-methyl)phenyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N-(3-pyridylcarbonyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide;

5-(N-(3-pyridyl)-carbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide; and

5-(N-allylcarbamoyloximino)-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide.

9. A process for preparing a compound of Formula I ##STR6## wherein the broken line at the 22-23 position represents an optional bond and either this bond is present and R¹ is absent or this bond is absent and R¹ is H or OH;

R² is a C₁ -C₈ alkyl, or C₃ -C₈ cycloalkyl group;

R³ is H;

R⁴ is H or a group capable of being hydrolyzed in vivo to yield a compound in which R⁴ is H;

R⁵ is OH; and

R⁶ is H;

which comprises the steps of (1) oxidizing a compound of formula II ##STR7## wherein the broken line, R¹, R², R³ and R⁶ are as defined above and R⁵ is as defined above or R⁵ is L-α

-oleandrosyloxy and R⁶ is H to yield a compound of formula III ##STR8## and (2) allowing the compound of formula (III) to react with a compound of formula R⁴ --O--NH₂ where R⁴ is as defined above, and, where R⁵ is α

-oleandrosyloxy, hydrolyzing the compound obtained to yield a compound of formula (I).

10. A process according to claim 9 wherein group R⁴ when H is replaced with said group capable of being hydrolyzed in vivo to yield a compound in which R⁴ is H.

11. A process according to claim 9 wherein the compound of formula I obtained has a double bond at the 22-23 position and said compound is hydrogenated to reduce the double bond at the 22-23 position to a single bond.