AU2009245870A1 - Combinations of an avermectin or milbemycin with 3-aryl-4-hydroxyfuranones - Google Patents

Description

S&F Ref: 932330 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Wyeth LLC, of Five Giralda Farms, Madison, New of Applicant : Jersey, 07940, United States of America Actual Inventor(s): Thomas Gerard Cullen Robert Alan Pollet Daniel Wayne Smith Daniel Howard Cohen Zhenpeng Xi Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Combinations of an avermectin or milbemycin with 3 aryl-4-hydroxyfuranones The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(2432554 1) COMBINATIONS OF AN AVERMECTIN OR MILBEMYCIN WITH 3-ARYL-4 HYDROXYFURANONES RELATED APPLICATION This application claims benefit of US provisional patent application No. 61/121575 5 entitled "Combinations of an Avermectin or Milbemycin with 3-aryl-4-hydroxyfuranones" filed 11 December 2008, the entire contents of which is incorporated herein by reference. TECHNICAL FIELD The invention relates to combinations of an avermectin or a milbemycin such as 10 moxidectin, with 3-aryl-4-hydroxyfuranones, and to methods for using the combination in veterinary applications, including the control of one or more helminthes, such as cestodes and nematodes, and the treatment of conditions related thereto, such as helminthiasis in an animal. 15 BACKGROUND OF THE INVENTION Moxidectin is a second-generation endectocide of the milbemycin family of macrocyclic lactone compounds. The compound is registered and marketed in various formulations for the control of internal and external parasites in farm livestock and companion animals, including horses. A 2% oral gel formulation (EQUEST, QUEST) for horses is marketed worldwide. The 20 product is highly effective against a broad-spectrum of internal parasites found in horses and ponies. Modern ecto- and endoparasiticidal agents, such as moxidectin, have a wide margin of safety, considerable activity against immature or larval stages of parasites and a broad 25 spectrum of activity. Nonetheless, the usefulness of any endoparasiticidal agent is limited by the inherent efficacy of the drug itself, its mechanism of action, its pharmacokinetic properties, features relating to the host animal, features relating to the target parasites and the form of administration. 30 Moreover, although these and other insecticidal and miticidal agents have been developed in order to control various pests such as helminthes, such as cestodes and nematodes, pests which have acquired resistance against various agents have been appearing as a result of the repeated use of these agents. Resistance development in certain pest families may be favored by a high mutation rate and frequent inbreeding, due to minimal 35 migration, as well as a pest's ability to deposit large numbers of eggs and produce large numbers of generations which themselves require only a few days for development. Therefore, in order to prevent and control the damage against such pests, development of a new insecticidal and miticidal agent which shows a high effect against pests which have acquired resistance against the conventional miticidal agents is highly desirable. To obtain an insecticidal and miticidal composition which shows no cross-resistance 5 with existing insecticidal and miticidal agents, has no toxicity problems and has little negative impact on the environment, is extremely difficult. Therefore, a means to delay or prevent the development of resistant strains of pest species is always being sought. In order to apply an effective agent as long as possible, a rotational application of agents with different mechanisms of action is adopted for good pest management practice. However, this approach 10 does not necessarily give satisfactory pest control. Therefore, after a resistance problem has occurred, a countermeasure to resistance by combining insecticidal and miticidal agents has been studied. However, a high synergistic action has not always been found. Therefore, it is an object of this invention to provide an insecticidal and miticidal 15 composition which demonstrates a high controlling effect against pests such as helminthes, such as cestodes and nematodes, which have acquired resistance against previously used agents. SUMMARY OF THE INVENTION 20 In a broad aspect, the present invention provides a method for the control of one or more helminthes, such as cestodes and nematodes, and the treatment of conditions related to one or more helminthes, such as helminthiasis, in an animal, comprising administering to the animal effective amounts of an avermectin, or a milbemycin such as moxidectin, and a compound of formula I 0 R, RO R2 25 (I) wherein R is H, COR 4 or a C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

1 is phenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , 30 S0 2

R

5 , NR 6

SO

2

R

7 , NR 8

COR

9 , NR 1 0

R

1 1 , C-C 6 haloalkyl or a C-C 6 alkyl,

C

3

-C

6 cycloalkyl, C 2 -Cealkenyl or C 2 -Cralkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2

R

5 , NR 6

SO

2

R

7 , NR 8 CORq, NR 0

R

11 , C-C 6 haloalkyl or a Cr-C 6 alkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted, 5 naphthyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2

R

5 , NR 6

SO

2

R

7 , NR 8

COR

9 , NR 1 aR 1 , CrCO 6 haloalkyl or a C-C 6 alkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted, or heteroaryl optionally substituted with one, two or three halogen, CN, OR 3 , 10 COR 4 , SO 2

R

5 , NR 6

SO

2

R

7 , NR 8

COR

9 , NR 1 oR 1 , CrCO 6 haloalkyl or a C

C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or 0 2

-C

6 alkynyl group each optionally substituted;

R

2 is phenyl optionally substituted with one, two or three halogen, CN, OR 12 ,

COR

1 3 , S0 2

R

14 , NR 1 5

SO

2

R

1 6 , NR 1 7

COR

1 8 , NR 19

R

20 , Cr 1

C

6 haloalkyl or a Cr 1

C

6 alkyl, C3 15 C 6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl or heteroaryl group each optionally substituted; biphenyl optionally substituted with one, two or three halogen, CN, OR 12 ,

COR

1 3 , S0 2

R

14 , NR 15 S0 2

R

1 6 , NR 1 7

COR

1 8 , NR 19

R

20 , Cr 1

C

6 haloalkyl or a

C-C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each 20 optionally substituted; naphthyl optionally substituted with one, two or three halogen, CN, OR 12 ,

COR

13 , S0 2

R

14 , NR 1 5 S0 2

R

16 , NR 1 7

COR

1 8 , NR 19

R

20 , Cr-C 6 haloalkyl or a

C-C

6 alkyl, C 3

-C

6 cycloalkyl, C 2 -Cealkenyl or C 2

-C

6 alkynyl group each optionally substituted; 25 heteroaryl optionally substituted with one, two or three halogen, CN, OR 12 ,

COR

13 , SO 2

R

14 , NR 1 5

SO

2

R

16 , NR 1 7

COR

1 8 , NR 1 9

R

20 , Cr 1

C

6 haloalkyl or a CrC 6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, phenyl or heteroaryl group each optionally substituted; or

C

3

-C

6 cycloalkyl optionally substituted with one, two or three halogen, CN, OR 12 , 30 COR 1 3 , S0 2

R

14 , NR 1 5

SO

2

R

16 , NR 17

COR

1 8 , NR 19

R

20 , O 1

-C

6 haloalkyl or a Cr 1

C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted;

R

3 , R 4 , R 9 , R 12 , R 1 3 and R 1 8 are each independently H, Cr 1

C

6 haloalkyl, or a CrC 6 alkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group 35 each optionally substituted;

R

5 , R 7 , R 14 and R 1 6 are each independently a Cr-C 6 alkyl, C 3

-C

6 cycloalkyl,

C

2

-C

6 alkenyl, C 2

-C

6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

6 , R 8 , R 1 5 and R 17 are each independently H or an optionally substituted

C

1

-C

6 alkyl group; and 5 R 10 , R 11 , R 19 and R 20 are each independently H, C-C 6 haloalkyl, or a C 1

-C

6 alkyl, C3

C

6 cycloalkyl, 0 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 1 and R 11 or R 1 and R 20 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7 membered ring optionally containing one or two additional heteroatoms 10 selected from N, 0 or S; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof. The invention is also directed to a composition comprising effective amounts of an 15 avermectin or a milbemycin such as moxidectin and a compound of formula 1, for the control of one or more helminthes, such as cestodes and nematodes, and the treatment of conditions related thereto, in an animal. Also provided is the use of an avermectin or a milbemycin such as moxidectin and a 20 compound of formula I in the preparation of a medicament for the control of one or more helminthes, such as cestodes and nematodes, and the treatment of conditions related thereto, in an animal. DETAILED DESCRIPTION OF THE INVENTION 25 Compounds of formula I are disclosed in U.S. patent publication 2005-0054721A1 incorporated by reference herein in its entirety. As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term aryl designates a carbocyclic aromatic ring system such as phenyl, naphthyl, 30 anthracenyl or the like. The term heteroaryl, as used herein, designates a 5- to 10-membered aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, 0 or S. Such heteroaryl ring systems include pyrrolyl, azolyl, diazolyl, triazolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzodioxolyl, benzisoxazolyl or the like. The term haloalkyl as 35 used herein designates CnH 2 n.

1 group having from one to 2n+1 halogen atoms which may be the same or different.

As used herein, when terms such as C1-C6 alkyl, C3-C6 cycloalkyl, aryl or heteroaryl are designated as being "optionally substituted", the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their 5 structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl, cycloheteroalkyl or cycloalkyl groups, preferably 10 halogen atoms, C1-C4 alkyl, halo(C 1

-C

4 )alkyl or halo(C 1 -C4)alkoxy groups. Typically, 0-3 substituents, preferably 1 or 2, the same or different, may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched, and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms. 15 Pharmaceutically acceptable salts may be any salt formed by a compound of formula I and a pharmaceutically acceptable base such as organic or inorganic bases, e.g. alkali metal salts, (i.e., sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts, dialkylammonium or trialkylammonium salts or the like. 20 Compounds of formula I may exist as one or more stereoisomers or in enolic tautomeric forms. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Tautomers include enols or ketones. One skilled in the art will appreciate that one stereoisomer or tautomer may be more active or may exhibit 25 beneficial effects when enriched relative to the other stereoisomer(s) or tautomer or when separated from the other stereoisomer(s) or tautomer. Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers or tautomers. Accordingly, the compositions and methods of the present invention employ compounds of formula 1, the stereoisomers thereof, the tautomers thereof and the pharmaceutically acceptable salts 30 thereof. The compounds of formula I may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form. In one embodiment of the compound of formula 1, R is H, COR 4 or a C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl 35 or heteroaryl group each optionally substituted;

R

1 is phenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2

R

5 , NR 6

SO

2

R

7 , NR 8

COR

9 , NR 10

R

11 , C 1

-C

6 haloalkyl or a C 1

-C

6 alkyl, 0 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2

R

5 , NR6SO 2

R

7 , NR 8 CORg, NR 1 aR, 1 , Cr 1

C

6 haloalkyl or a Cr 1

C

6 alkyl, 5 C 3

-C

6 cycloalkyl, 0 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted, or naphthyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2

R

5 , NR 6

SO

2

R

7 , NR 8 CORg, NR 10

R

1 , 0 1

-C

6 haloalkyl or a Cr 1

C

6 alkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally 10 substituted, or heteroaryl optionally substituted with one, two or three halogen, CN, OR 3 ,

COR

4 , SO 2

R

5 , NR 6

SO

2

R

7 , NR8CORg, NR 1 aR 1 , Cr-C 6 haloalkyl or a C

C

6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl group each optionally substituted; 15 R 2 is a phenyl or biphenyl group substituted with one or two halogen, CN or

CF

3 groups;_or heteroaryl optionally substituted with one, two or three halogen, CN, OR 12 ,

COR

1 3 , S0 2

R

1 4 , NR 15

SO

2

R

1 6 , NR 1 7

COR

1 8 , NR 1 9

R

20 , Cr 1

C

6 haloalkyl or a Cr 1

C

6 alkyl, C 3

-C

6 cycloalkyl, O 2

-C

6 alkenyl, C 2

-C

6 alkynyl, phenyl or 20 heteroaryl group each optionally substituted;

R

3 , R 4 , Rg, R 1 2 , R 13 and R 1 8 are each independently H, Cr 1

C

6 haloalkyl, or a 1 -Cralkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

5 , R 7 , R 1 4 and R 1 6 are each independently a Cr-C 6 alkyl, C 3

-C

6 cycloalkyl, 25 C 2

-C

6 alkenyl, C 2

-C

6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

6 , R 8 , R 1 5 and R 1 7 are each independently H or an optionally substituted

C-C

6 alkyl group; and

R

1 0 , R 11 , R 1 9 and R 2 0 are each independently H, Cr 1

C

6 haloalkyl, or a Cr 1

C

6 alkyl, C3 30 C 6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 1 0 and R 11 or R 1 and R 2 0 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7 membered ring optionally containing one or two additional heteroatoms selected from N, 0 or S. 35 In another embodiment of the compound of formula 1, R is H, COR 4 or a 0-C 6 alkyl, C 3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

1 is a phenyl or biphenyl group substituted with one or two halogen, CN or CF 3 groups; 5 R 2 is an optionally substituted phenyl or biphenyl group;

R

3 , R 4 , R 9 , R 1 2 , R 13 and R 1 8 are each independently H, C-C 6 haloalkyl, or a C-C 6 alkyl,

C

3

-C

6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

5 , R 7 , R 1 4 and R 16 are each independently a C-C 6 alkyl, C 3

-C

6 cycloalkyl, 10 C 2

-C

6 alkenyl, C 2

-C

6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted;

R

6 , R 8 , R 1 5 and R 17 are each independently H or an optionally substituted

C

1

-C

6 alkyl group; and

R

1 0 , R 11 , R 1 and R 20 are each independently H, C-C 6 haloalkyl, or a C-C 6 alkyl, C3 15 C 6 cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 10 and R 11 or R 1 and R 2 0 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two additional heteroatoms selected from N, 0 or S. 20 In another embodiment of the compound of formula 1, R 1 is phenyl substituted with one or two halogen, CN or C-C 6 haloalkyl groups. In another embodiment, R 1 is an optionally substituted biphenyl group. In another embodiment, R 1 is pyridyl optionally with phenyl that is optionally substituted with halogen. Examples of compounds of formula I suitable for use in the invention, include, but are 25 not limited to the following: (5Z)-5-[(3',5'-dichloro-1,1'-biphenyl-3-yl)methylene]-3-(3,5-dichlorophenyl)-4 hydroxyfuran-2(5H)-one; (5Z)-5-[(3',4'-dichloro-1,1'-biphenyl-2-yl)methylene]-3-(3,4-dichlorophenyl)-4 hydroxyfuran-2(5H)-one; 30 5-[(Z)-[1,1'biphenyl]-4-ylmethylidene]-3-(3-chlorophenyl)-4-hydroxy-2(5H) furanone; (5E)-5-[2'-chloro-2-methyl- 1, 1'-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl) 4-hydroxyfuran-2(5H)-one; (5Z)-3-(3,5-d ichlorophenyl)-4-hyd roxy-5-{[2-methoxy-2'-(trifluoromethyl)- 1, l1'-biphenyl-4-yI]methylene~furan-2(5H)-one; (5Z)-3-(3,5-dichlorophenyl)-5-[2,2'-dimethyl-1, 1'-biphenyl-4-yI)methylene]-4 hydroxyfuran-2(5H )-one; 5-{[2-chloro-3-(trifluoromethyl )phenyl]methylene}-3-(3-fluoro-4-bi phenyl )-4 5 hydroxyfuran-2(5H)-one; 3-(3-fluoro-4-biphenyl)-5-{[2-fluoro-5-(trifluoromethyl)phenyl]methylene}-4 hydroxyfuran-2(5H )-one; (5Z)-3-(3,5-d ichiorop he nyl )-4-hyd roxy-5-{[2-methyl-2'-(trifl uorom ethyl )- 1, 1' biphenyl-4-yI]methylene)furan-2(5H)-one; 10 (5Z)-5-(3-(benzyloxy)benzylidene]-3-(3, 5-dichlorophenyl)-4-hydroxyfuran-2(5H) one; (5Z)-5-[(2'-acetyl-2-methyl-1, 1 -biphenyl-4-ylmethylene]-3-(3,5-dichloro-phenyl) 4-hydroxyfuran-2(5H)-one; 1-()l l'-biphenyl]-4-ylmethylidene]-3-(3,4-dichlorophenyl)-4-hydroxy-2(5H) 15 furanone; 1-Z-l l'-biphenyl]-4ylmethylidene]-3-(3,5-dichlorophenyl)-4-hydroxy-2(5H) furanone; 3-(2-fluoro[1, 1'-biphenyl]-4-yI)-4-hydroxy-5-{(Z)-[3-(trifluoromethyl)phenyl] methylidene)furan-2(5H )-one; 20 5-[(Z)-[1, 1'-biphenyl]-4-ylmethylidene]-3-[3,5-bis(trifluoromethyl)phenyl]-4 hydroxy-2(5H )-furanone; (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-( 1 -naphthylmethylene)furan-2(5H)-one; 5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4 hydroxyfuran-2(5H )-one; 25 5-{[2-chloro-5-(trifluoromethyl )phenyl]methylene}-3-(4'-ethoxy-4-biphenyl )-4 hydroxyfuran-2(5H)-one; (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{(4-methoxy-1 -naphthyl)methylene] furan-2(5H)-one; (5Z)-3-(3-ch lo rophenyl)-4-hyd roxy-5-{[2-methyl-2'-(trifl uorom ethyl)- 1, 1 '-biphenyl 30 4-yI]methylenelfuran-2(5H)-one; (5Z)-5-[(3'-4'-dichloro-1, 1'-biphenyl-3-yI)methylene]-3-(3,4-dichlorophenyl)-4 hydroxyfuran-2(5H)-one; a stereoisomer thereof; a tautomer thereof; or a pharmaceutically acceptable salt thereof. The compounds of formula I may be conveniently prepared using conventional 5 synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I may be prepared by reacting a 3-bromo-4-alkoxy- furanone of formula II with an aldehyde of formula III to give the 5-hydroxyalkyl-furanone of formula IV; dehydrating the formula IV hydroxyalkylfuranone to give the corresponding 5 methylenefuranone of formula V; reacting the formula V compound with a boronic acid 10 derivative of formula VI to give the 3-arylfuranone of formula VII; and hydrolyzing the formula VII compound to the desired 4-hydroxyfuranone of formula 1. Alternatively, the formula 11 compound may be reacted with tributyl tin chloride to give the compound of formula VII. The formula VII compound may then be sequentially reacted with the aldehyde of formula III and dehydrated to give the compound of formula X; and said 15 formula X compound may be reacted with an aryl halide of formula XI to give the 4-alkoxy compound of formula VII. The formula VII compound may then be hydrolyzed as described hereinabove to give the desired compound of formula 1. The reactions are shown in flow diagram I below wherein R represents C-C 6 alkyl, Hal represents Cl, Br or I and DMF designates dimethyl formamide.

Flow Diagram I B Br R2CHO RO RO (II) HO R2 Bu 3 SnCI Bu 3 Sn 0 dehydrate RO (VIII) O I Br

R

2 CHO (III) RO Bu 3 Sn 0 O )I(V)

R

2 RO HO R2

RIB(OH)

2 (VI) (IX) I dehydration Bu 3 Sn O RI-Hal R O S0 4 .(XI), RO RO R2 R2 R2 (VII) (X) 1) LiBr, DMF 2) H 3 0* 0 HO 1 R2 (I) 5 Further suitable methods for preparing compounds of formula I are disclosed in U.S. patent publication 2005-0054721A1.

The avermectin or milbemycin may be, for example, milbemycin D, avermectin, ivermectin, abamectin, doramectin, moxidectin and combinations thereof. In a preferred embodiment, the milbemycin is moxidectin. 5 The helminthes that may be treated by the composition of the invention and/or in accordance with the method of the invention may be cestodes and nematodes. A helminth may be an endo- or ecto-parasite, or may be carried by an insect which acts as a vehicle or carrier. 10 For the preparation of the insecticidal and miticidal composition of the invention, it is suitable to formulate as a wettable powder, aqueous concentrate, emulsion, liquid concentrate, sol (flowable agent), powder, aerosol, or the like, by conventional methods such as admixing the milbemycin or avermectin and one or more compounds of formula I with a suitable carrier and auxiliaries, such as emulsifiers, surfactants, dispersants, stabilizers, 15 suspending agents, penetrants, and the like. In this embodiment of the invention, solid carriers suitable for use in the ecto- or endoparasiticidal composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, 20 compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid, which is in admixture with the active components of the composition of the invention. In tablets, the composition of the invention may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets may contain 25 up to 99% by weight of the composition of the invention. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. 30 Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. The active components of the composition of the invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Liquid compositions may 35 contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, surfactants, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), dimethyl sulfoxide, alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate or 5 isopropyl myristate. Ecto- or endoparasiticidal compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Inventive compositions suitable for oral administration may be in either liquid or solid 10 composition form. In one embodiment, the composition of the invention is syringable. An ecto- or endoparasiticidal composition of the invention may be in the form of a pill, tablet, bolus, implant, capsule or drench, containing sufficient amounts of the active components of the composition of the invention to provide the treated animal with about 0.01 15 mg/kg to 100 mg/kg of animal body weight per day of each active component. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/or builders such as starch, lactose, talc, magnesium stearate, vegetable gums or the like. These unit dosage formulations may be varied according to the kind and size of the animal to be treated, the severity or type of 20 infection encountered, the weight of the host animal, or the like. For a parenteral composition, the active components of the composition of the invention compound may be dispersed in a physiologically acceptable solvent for subcutaneous injection or may be dispersed in a fat or wax or mixture thereof containing an 25 oil, buffer, surfactant, stabilizer, preservative and salt. Components useful in these preparations include carbowax, aluminum monostearate gel, diethyl succinate, soya oil, glyercal dioleate, saline and capric/caprylic triglycerides. The composition of the invention may also be applied topically to the larger animals 30 such as swine, sheep, cattle and horses and companion animals such as dogs and cats in the form of aqueous dips or sprays. For this inventive composition, the composition may be generally prepared as a wettable powder, emulsifiable concentrate, aqueous flowable or the like, which is mixed with water at the site of treatment, or may be a pre-formulated pour-on or spot-on solution or suspension. The composition may be applied topically to the hide, skin or 35 hair of the animal. Sprays or dips usually contain about 0.5 ppm to 5000 ppm and preferably about 1 ppm to 3000 ppm of the compound.

The content of the total active ingredients of the composition of the invention, expressed as weight/weight %, is preferably in the range of about 1-90% for wettable powder, aqueous concentrate, emulsion, liquid concentrate and sol formulations. The preferable content of total active ingredients is about 0.5-10% for powder formulations and about 0.01 5 2% for aerosol formulations. Carriers suitable for use in the insecticidal and miticidal compositions of the invention may be any solid or liquid carrier which is commonly used for an agrohorticultural composition. Various surfactants, stabilizers and other auxiliary ingredients may be used according to the 10 necessity. In commercially useful formulations, the composition of the invention may also be present in a mixture with other active agents, for example various insecticidal, miticidal, fungicidal and herbicidal agents, plant growth regulators, repellants, attractants, synergists and fertilizers and fragrances, in order to expand its applicability. 15 The ratio of an avermectin or milbemycin, such as moxidectin, to the compound of Formula I in the insecticidal and miticidal composition of the invention is about 1 weight part of an avermectin or milbemycin to about 0.01-100 weight parts, preferably about 1-20 weight parts, of a compound(s) of formula 1. 20 In one embodiment, moxidectin technical material, moxidectin technical concentrate, or a combination thereof is used in the composition. Moxidectin technical material includes between about 0.3 and 0.6% of the antioxidant BHT. This technical material or concentrate can be stored for a suitable length of time in order that commercial products can be prepared which include the active material. For example, the Fort Dodge Animal Health products 25 CYDECTIN@ and VETDECTIN@ liquid compositions in New Zealand are solutions prepared using moxidectin technical material or moxidectin technical concentrate. Both these commercial products have excellent stability. Both CYDECTIN@ and VETDECTIN@ include as active material, moxidectin, stabilized 30 by the BHT originally present in the technical material or concentrate of moxidectin used to produce the commercial product. As will be clear to persons skilled in the art, where compositions according to the present invention are to be used or be prepared for use, in veterinary medicine, they may also 35 contain additional carriers, stabilizing agents, buffering agents, preservatives or other excipients as will be well known in the art.

The active ingredients of the composition of the present invention typically can be utilized as fine particles of 10-50 microns in size, with it being highly preferred that the avermectin or milbemycin and the compound of formula I is micronized so that 90% of the particles are less than 10 microns in size. This maximizes the absorption of the active 5 ingredients, and achieves a suitable blood level to enable the desired level of therapeutic activity. Carriers suitable for use in the compositions of the invention may be any solid or liquid carrier which is commonly used for an agrohorticultural composition. Various surfactants, 10 stabilizers and other auxiliary ingredients may be used according to the necessity. In commercially useful formulations, the compositions of the invention may also be present in a mixture with other active agents, for example various insecticidal, miticidal, fungicidal and herbicidal agents, plant growth regulators, repellants, attractants, synergists and fertilizers and fragrances, in order to expand its applicability. 15 In one embodiment, compositions of the invention may include a benzimidazole compound or a salt thereof. Benzimidazoles suitable for use in the composition include thiabendazole, cambendazole, parbendazole, mebendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiophanate, febantel, netobimin, 20 triclabendazole, salts thereof, and combinations thereof. In one preferred embodiment, the benzimidazole compound is oxibendazole, albendazole, fenbendazole, mebendazole, triclabendazole or a salt thereof or combination thereof. In another embodiment, the benzimidazole anthelmintic is triclabendazole or a salt thereof. Triclabendazole is highly effective against liver fluke at all stages of their life cycle. 25 In one embodiment, a benzimidazole compound or a salt thereof may be present in the composition in an amount of about 10% to about 40% w/v. In general, amounts of about 15 25% w/v, of a benzimidazole compound, such as triclabendazole, are preferred. 30 In one embodiment, closantel or an organic amine salt of closantel may be present in the composition. Suitable organic amine salts include, but are not limited to, alkanol amine salts such as ethanolamine, diethanolamine, methylpropanol amine, or the like; N-methyl glucamine, piperidine, piperazine, triethylamine, methyl amine, a-methylbenzyl amine, or the like. Typically, such salts are prepared by contacting closantel with a solution of the organic 35 amine. Organic amine salts are generally described, for instance, in U.S. Patent No. 4,005,218. In general, amounts of about 5% w/v to 60% w/v of closantel or an organic amine salt thereof are suitable for use in the present invention.

In one embodiment, the composition of the present invention includes pyrantel, which is a tetrahydropyrimidine. Pyrantel may be present in the composition in an amount of about 0-15% w/v. In another embodiment, the composition includes an imidothiazole, such as levamisole 5 or tetramisole or a salt thereof. In general, suitable amounts of levamisole or tetramisole or a salt thereof are in the range of about 0-30% %w/v. In a further embodiment, the composition includes praziquantel. Praziquantel has high efficacy against cestode parasites. Praziquantel may be present in the composition in an 10 amount of about 2-20% w/v. The compositions may include other classes of anthelmintics, such as cyclooctadepsipeptides or oxindole alkaloids. In one embodiment, the composition includes emodepside or paraherquamide. 15 The compositions of the invention may be aqueous compositions in which the active components may be solubilized in the water of the composition by using one or more particular organic solvents and one or more surfactants as solubilizers. Generally, such solvents and surfactants are selected for their ability to solubilize the particular active 20 component or components in minimal amounts, as well as for their compatibility with the particular active component or components. Accordingly, in one embodiment the composition according to the invention includes sufficient amounts of one or more organic solvents and one or more surfactants to enable 25 dissolution of the active component or components. Suitable organic solvents include, but are not limited to, glycols, glycol ethers, glycol ether acetate, C-C 8 alkyl pyrrolidones, lactone solvents (e.g., butyrolactone, y-hexalactone), aliphatic hydrocarbons, aromatic hydrocarbons, and combinations thereof. The preferred alilphatic hydrocarbons are those with a boiling point between 30 and 320 0 C, such as hexane, heptane and pentane. The preferred aromatic 30 hydrocarbons are those with a boiling point between 100 and 240*C, such as toluene and xylene. Preferred solvents are, for instance, propylene glycol, glycerol formal, glycerine and polyethylene glycol, with propylene glycol and polyethylene glycol, especially polyethylene glycol 6000 being highly preferred. In one embodiment, the compositions are used as pour-on compositions, wherein the compositions of the invention may include solvents having the 35 ability to effectively penetrate the skin, thereby making the active agents more likely to be systemically absorbed by the animal.

A surfactant may be selected from non-ionic, cationic, anionic or amphoteric surfactants. Preferred surfactants are the non-ionic surface active agents such as polyoxyethylated vegetable oils, polyoxyethylene sorbitan monoisostearate, polyoxyethylene sorbitan monostearate and polyoxyethyene sorbitan monooleate (also known as polysorbate 5 80, and sold under the trademark Tween 80). Optionally, but usually, buffering systems can be utilized to maintain the pH of the composition of the invention at optimally between 6.0 and 6.8. Preferred are buffer combinations such as sodium phosphate dibasic dodecahydrate and sodium phosphate monobasic dihydrate. In the manufacturing process where very large commercial quantities 10 are being prepared, the use of an antifoam agent such as Antifoam 9020 is also highly preferred. The compositions of the present invention may also contain suitable antimicrobial agents to protect against bacteria, yeast and mould contamination. As examples of 15 antimicrobial preservatives there may be mentioned methyl-, ethyl-, propyl- and butyl parabens, benzyl alcohol, sodium edetate, or combinations thereof. A stabilizing agent may be added to the composition. Stabilizing agents may be present in the composition in amounts of about 0-5% w/v, and preferably 0-2% w/v. 20 Suitable stabilizing agents include, but are not limited to, C 1

.

12 alkyl gallate; C1.6 alkyl hydroxybenzoate or a salt thereof; benzyl hydroxytoluene; a quinone or a salt thereof; nordihydroguaiaretic acid; a tocopherol; dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sufoxylate; sodium thiosulfate; thioglycolic acid; thiourea; 25 ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin, isoascorbic acid; ethylene diamine tetra-acetic acid or a salt thereof; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and combinations thereof. In one embodiment, the stabilizing agent is butylated hydroxytoluene (BHT). 30 In another embodiment, the present invention provides a modified composition which includes selenium. Selenium is an important additive for the treatment of "white muscle disease" a degenerative condition of the heart. In some areas, food stocks are selenium deficient. The composition may be modified with small quantities of selenium, e.g., up to around 0.1%. The selenium can be added in by any suitable method. One particularly 35 suitable method is by the use of sodium selenate.

Helminthiasis may be related to one or more helminthes carried by an insect acting as a carrier of the one or more helminthes. Ectoparasitic insects which may be controlled, ameliorated or treated by the animal health method of invention include Diptera, Muscidae or Siphonsptera, in particular, Diptera: Muscidae such as Musca autumnalis (face flies), 5 Haemtobia irritans (horn flies) Stomoxys calcitrans (stable flies), heel flies, tsetse flies, blow flies, fleas, lice, face flies, horn flies or the like. Said insects are breeders of filth and vectors of disease and are serious ectoparasitic pests of important agronomic animals such as cattle, horses and sheep. Further, Diptera: Hippoboscidae (louse flies) such as Melophagus ovinus (sheep ked), which is a serious parasite of sheep are problematic in animal production. 10 Among the Phthiraptera families known to be ectoparasites of animals are: Trichodectidae such as Bovicola bovis (important cattle-biting louse), B. ovis (sheep-biting louse) or B. equi (horsebiting louse); Haematopinidae such as Haematopinus suis (hog louse), or H. asini (horse sucking louse); Linognathidae such as Linognathus stenopsis (goat sucking 15 louse) or L. vitali (long-nosed cattle louse); or the like. One of the Siphon6ptera, families known to infest companion animals is pulicidae such as archaeopsyllniae (cat and dog fleas), spilopsyllinae (rabbit fleas), or the like. Endoparasitic infections which may be controlled, ameliorated or treated by the 20 method of the invention include those Helminthiasis infections caused by the class Nematoda, commonly known as nematodes or roundworms. Nematodes cause serious damage to the walls and tissues of the organs in which they reside, including the intestinal tract, heart, lungs and blood vessels, and are a primary cause of anemia. If left untreated they may result in death to the infected host. The nematodes most commonly found to be the infecting agents of 25 warm-blooded animals include Haemonchus, Ostertagia, Cooperia, Drofilaria, Oesphagastomum, Nematodirus and Dictyocaulus. Animals suitable for use in the method of invention are all warm-blooded animals susceptible to ecto- or endoparasitic infection or infestation including farm animals or 30 companion animals or humans. Examples of animals suitable for use in the methods of the invention include cattle, sheep, swine, horses, poultry such as chickens, turkeys, geese and ducks; rabbits, goats, dogs, cats, gerbils, birds, camels, water buffalos, donkeys, fallow deer, reindeer, minks, chinchillas, and raccoons. 35 The composition of the invention may be administered to the target homeothermic animal orally, topically or parenterally, preferably orally or topically. For example, the composition of the invention may be administered to said animal in or with their drinking water or as a feed additive or in the form of a pill, tablet, bolus, implant, capsule or drench. The formula I compound may also be administered topically by applying said compound to the skin, hide or hair of the homeothermic animal. Parenteral administration, i.e., intramural, intramuscular or subcutaneous injection is also suitable for the inventive method. 5 In addition to helminthic infection, the present method of invention is also useful for the control of endoparasitic arthropod infestations such as cattle grub. The method of invention is also effective against infection caused by nematodes such as, T. colubriformis, H. contortus, or the like. 10 Advantageously, the insecticidal and miticidal composition of the invention shows simultaneous control of troublesome pests such as leafroller moths (Tortricidae), Carposinidae, leafminer moths (Lyonetiidae), plant bugs (Pentatomidae), aphids (Aphididae), leafhoppers (Deltociphalidae), thrips (Thripidae), aphids (Aphididae), diamond back moths 15 (Plutella xylostella), Mamestra brassicae, leaf beetles (Chrysomelidae), whiteflies (Aleyrodidae) on important agronomic crops such as fruit trees, for example citrus, apple and pear; tea plants; vegetables and the like. In one embodiment, by combining the known therapeutic range of an avermectin or 20 milbemycin, such as moxidectin, with the compound of formula 1, a composition is provided with dual efficacy, for example in the convenient dosage form of an oral drench, or as another example as a pour-on composition, and possessing the necessary chemical and physical stability in storage and use. 25 The composition of the invention may be an aqueous composition in which the avermectin or milbemycin and the compound of formula I of the present composition may be solubilized in the water of the composition by using one or more particular organic solvents and one or more surfactants as solubilizers. Generally, such solvents and surfactants are selected for their ability to solubilize the particular avermectin or milbemycin and compound of 30 formula I in minimal amounts, as well as for their compatibility with these active ingredients. Accordingly, in one embodiment the composition according to the invention includes sufficient amounts of one or more organic solvents and one or more surfactants to enable dissolution of the avermectin or milbemycin and compound of formula 1. Preferred solvents for solubilizing abamectin, moxidectin and ivermectin, are, for instance, propylene glycol, glycerol formal, 35 glycerine and polyethylene glycol, with propylene glycol and polyethylene glycol, especially polyethylene glycol 6000 being highly preferred. Preferred surfactants are the non-ionic surface active agents such as polyoxyethylated vegetable oils, polyoxyethylene sorbitan monoisostearate, polyoxyethylene sorbitan monostearate and polyoxyethyene sorbitan monooleate (also known as polysorbate 80, and sold under the trademark Tween 80). As discussed further below, when the composition is used as a pour-on composition, the composition of the invention may include solvents having the ability to effectively penetrate the 5 skin, thereby making the active agents more likely to be systemically absorbed by the animal. Oral drench compositions In one embodiment, the composition comprising effective amounts of an avermectin or milbemycin, such as moxidectin, and a compound of formula I is used as an oral drench. In 10 an example of this embodiment, the oral drench further comprises a non-surfactant rheology modifier. In a further embodiment, the non-surfactant rheology modifier is an inorganic rheology modifier. It preferably contains one or more of the following components silicon dioxide, magnesium oxide, alginates, cellulose or mixtures thereof. 15 Depending upon the particular rheology modifier used, the amount used in the present invention may vary from about 0.2 to about 2% by weight/volume. Stability and viscosity are to some extent competing interests. It is advantageous to provide both chemical and physical stability as well as suitable rheology for using the 20 composition as an oral drench. It is therefore helpful to provide a quantity of the non surfactant rheology modifier sufficient to maintain the composition of the invention in a form that is suitable for use as an oral drench. Oral drenches are typically administered via a drenching gun, which requires that the composition be neither too thin nor too viscous. Various rheology modifiers may be used. However, it is preferable that the rheology modifier 25 has desirable effects on the chemical stability of the active agents of the composition whilst maintaining a physically stable composition. The rheology modifier may be present in an amount that varies according to the desired viscosity of the resulting composition. For example, the rheology modifier may be 30 present between an amount such that the viscosity of the composition containing the rheology modifier is no less than 5% greater than the viscosity of the composition in the absence of the rheology modifier, and an amount such that the viscosity of the composition is less than or equal to 2000 centipoises, or for example less than or equal to 1500 centipoises, or for example less than or equal to 1000 centipoises, or for example less than or equal to 500 35 centipoises. As will be understood by persons skilled in the art, providing such a composition with dual efficacy in a suitable dosage form which is also physically and chemically stable in storage and use is a complex problem. Making a high viscosity composition may provide physical stability but may cause difficulties with dosage. Chemical stability of the composition is also vital and accordingly, it is preferable that the rheology modifier has minimal effect on the chemical stability of the composition. 5 In still a further aspect the present invention provides a method of treating a mammal comprising providing an efficacious dose of the aforementioned composition. Pour-on compositions 10 In another embodiment, the composition comprising effective amounts of an avermectin or milbemycin, such as moxidectin, and a compound of formula I is used as a pour-on composition. The term "pour-on composition" and the like as used herein is intended to mean a composition wherein a particularly preferred route of administration is pour-on administration. Typically, "pour-on" compositions are referred to as such because they are 15 poured-on the animal's back, usually from the withers to the tailhead of animals. Animals suitable for treatment in the method include: swine, cattle, sheep, horses, goats, camels, water buffalos, donkeys, fallow deer, reindeer, or the like, preferably swine, cattle, horses or sheep. 20 In this embodiment, it is advantageous to have liquid compositions which contain the active components and which are easily administered to the animal by being poured on the backs of animals. Liquid compositions may be in the form of a solution or a suspension. When formulating compositions such as anthelminthic compositions, it is necessary 25 that the compositions maintain both the chemical activity of the active compounds, as well as the physical stability of the composition. This allows for the compositions to be prepared well in advance of their intended use, and to also have a useful shelf life as a commercial product. The liquid composition of the invention in the form of a pour-on may include solvents 30 having the ability to effectively penetrate the skin, thereby making the active agents more likely to be systemically absorbed by the animal. Preferably, a suitable pour-on composition has a low freezing point and low surface tension to help with administration as a pour-on, and is highly water repellant to inhibit wash off from the animal during rain or other water exposure. The solvent may be a water-immiscible solvent, such as a lactone solvent which 35 may be, for example, y-hexalactone, butyrolactone, 6-hexalactone, y-dodecalactone, 6 nonalactone, 6-decalactone, y-decalactone, and 6- dodecalactone and other alkyl lactones and combinations thereof.

The liquid composition of the invention in the form of a pour-on may include an oil component, such as an essential oil selected from, but not limited to, the following: 1,8-cineole (also known as Eucalyptol), 1,4-cineole, Euganol, limonene oil, Tea Tree oil, citronellol and combinations thereof. In one embodiment, the essential oil component is 1,8-cineole. 5 The liquid composition of the invention in the form of a pour-on may include emulsifiers or surfactants such as polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mono-, di- and triglycerides and combinations thereof. Nonionic surfactants 10 may be preferable. The surfactant may also be a mixture of mono-, di-, and triglycerides and mono- and di-fatty acid esters of polyethylene glycol. For example, a suitable surfactant is Labrasol@ (Gattefosse, Saint-Priest, France), which is composed mainly of PEG esters and glycerides with medium acyl chains. Labrasol@ is also known as PEG-8 caprylic/capric glycerides. Another suitable surfactant is PEG-6 caprylic/capric glycerides. Other surfactants 15 suitable for use in the compositions are those such as polyethylene glycol monolaurate, polyethylene glycol dilaurate, polyethylene glycol monooleate, polyethylene glycol dioleate or glycerin polyethylene glycol coconut oil. In actual practice, the composition of the invention may be administered in dose rates 20 of mg of active ingredient per kg of body weight of the host animal. Dose rates suitable for use in the method of invention will vary depending upon the mode of administration, the species and health of the host animal, the target parasite, the degree of infection or infestation, the breeding habitat, the potency of the additional parasiticidal compound, and the like. 25 As will be clear to persons skilled in the art, where compositions according to the present invention are to be used, or are to be prepared for use, in veterinary medicine, they may also contain additional carriers, stabilizing agents, buffering agents, preservatives or other excipients well know in the art. 30 The present invention will now be described with reference to the following examples. These are the embodiments of the present invention and should in no way be considered limiting. 35 Example 1: Caenorhabditis elegans screening The effectiveness of a composition comprising moxidectin and the compound of formula la, shown below N CI C HO-.... N O O Ia was tested against C. elegans, a non-parasitic nematode, at varying concentrations of moxidectin and the compound of formula la in DMSO/methanol 1:1. The results are shown in 5 Table 1 below. In the table, "9" indicates no movement of C. Elegans at 4 hours after treatment; "8" indicates no movement of C. Elegans at 24 hours after treatment; "7" indicates slowed movement of C. Elegans at 24 hours after treatment; "0" indicates no effect. The test concentration of active agents ranged from 0.004 to 1 ppm for moxidectin and from 0.01 to 2.5 ppm for the compound of formula Ia. The C. elegans culture volume was of 100 10 microliters/well. Table 1: evaluation of effectiveness of composition comprising moxidectin and the compound of formula Ia against C. elegans. Columns: concentrations (ppm) of the compound of formula Ia, increasing from left to right. Rows: concentrations (ppm) of moxidectin, 15 decreasing from top to bottom. 0 0.01 0.03 0.09 0.27 0.83 2.5 1 9 9 9 9 9 9 9 0.3 9 9 9 9 9 9 9 0.1 8 8 8 7 7 7 9 0.04 7 7 7 7 7 7 9 0.01 0 0 0 0 7 7 9 0.004 0 0 0 0 7 7 9 0 0 0 0 0 7 7 9 Example 2: T. colubriformis Larval Development Assay ("LDA") The effectiveness of a composition comprising moxidectin and the compound of formula Ia 20 was tested in a development assay of T. colubriformis larvae, a parasitic nematode, at varying concentrations of moxidectin and the compound of formula Ia in DMSO. The results are shown in Table 2 below. In the table, "5" indicates that eggs were not hatched; "4" indicates that the larvae were dead at an early stage (L1 or L2); "3" indicates that the larvae were alive, including slow-moving larvae, at an early stage (L1 or L2); "2" indicates that the larvae were dead at a more advanced stage (L3); "1" indicates that the larvae were alive, including slow 5 moving, at a more advanced stage (L3); and "0" indicates no effect. The test concentration of active agents ranged from 0.001 M to 0.33 ppm for moxidectin and from 0.01 to 2.5 ppm for the compound of formula Ia. Table 2: evaluation of effectiveness of composition comprising moxidectin and the 10 compound of formula Ia in a T. colubriformis LDA. Columns: concentrations (ppm) of the compound of formula Ia, increasing from left to right. Rows: concentrations (ppm) of moxidectin, increasing from top to bottom. 0.01 0.03 0.09 0.27 0.83 2.5 0.33 2 1 1 1 1 2 0.11 1 1 1 1 1 4 0.37 1 1 1 3 3 4 0.012 2 3 3 3 4 4 0.004 0 0 1 1 3 4 0.001 0 1 1 1 1 4 0 0 0 1 1 1 4 EXAMPLES 3 AND 4 - ORAL DRENCH COMPOSITIONS 15 In the following examples, moxidectin can be supplied via a moxidectin technical concentrate in benzyl alcohol (30%) [MTC] or moxidectin technical [90%] material (MTM). Examples 3 and 4 are oral drench formulations using moxidectin technical concentrate and moxidectin technical material respectively. In both examples, 0.70 %wt/vol of a non 20 surfactant rheology modifier is used and preferably BHT (butylated hydroxy toluene) is added in a quantity of 10%w/v.

Example 3 ORAL DRENCH OF MOXIDECTIN AND COMPOUND OF FORMULA IA Raw Material Batch Size 1000 L Amount % Ingredient mg/mL Exces Description Potency Requirements s Moxidectin 1.00 5.0 Moxidectin Technical Concentrate 30% w/v g .345 .45 Compound 50 5.0 Compound of formula la 100% of formula la .25 2.5 Antifoam 9020 .070 .70 Polysorbate 80 USP or equivalent 0.000 00.0 Butylated Hydroxytoluene NF or equivalent .250 .5 Disodium Edetate USP or equivalent .200 .0 Propylene Glycol USP or equivalent 0.000 00.0 Polyethylene Glycol 6000 NF or equivalent .000 0.0 Polyoxyethylene 40 stearate NF or equivalent .500 5.0 Sodium Phosphate Dibasic Dodecahydrate USP or equivalent .950 .50 Sodium Phosphate Monobasic Dihydrate USP or equivalent .620 .20 Benzyl Alcohol NF or equivalent .000 0.00 non-surfactant rheology modifier 0.70 .00 Purified Water USP or equivalent 0.11 01.1 Total 05.0 050.0 *Adjust pH if outside the range of 6.0 - 6.8 with 10% Sodium Hydroxide solution or 20% 5 Phosphoric acid solution. The non-surfactant rheology modifier is combined with an amount of water equivalent to 20% w/ non-surfactant rheology modifier, mixed until fully dispersed, and then heated to 70-80 0

C.

To this is then added the polyethylene glycol 6000, polyoxyethylene 40 stearate and butylated hydroxytoluene, with mixing until homogenous. The buffering agents are then added, with further mixing, and to the resultant mixture is added polysorbate 80, antifoam 9020, followed by a solution of the Compound of formula la in propylene glycol. When mixing is complete, 5 the moxidectin is added, followed by the remainder of water to make volume. The pH is adjusted to the range 6.0-6.8 before filling into packaging.

EXAMPLE 4 ORAL DRENCH OF MOXIDECTIN AND COMPOUND OF FORMULA IA Raw Material Ingredient Amount Excess Description Potency Requirement mg/mL s %w/v Moxidectin 1.00 5.0 Moxidectin Technical 90% 0.1167 Material Compound 50 5.0 Compound of formula 100% 5.25 of formula la la Antifoam 9020 0.070 Polysorbate 80 USP 10.000 or equivalent Butylated 0.250 Hydroxytoluene NF or equivalent Disodium Edetate 0.200 USP or equivalent Propylene Glycol USP 10.000 or equivalent Polyethylene Glycol 3.000 6000 NF or equivalent Polyoxyethylene 40 2.500 stearate NF or equivalent Sodium Phosphate 0.950 Dibasic Dodecahydrate USP or equivalent Sodium Phosphate 0.620 Monobasic Dihydrate USP or equivalent Benzyl Alcohol NF or 1.228 equivalent non-surfactant rheology 0.70 modifier Purified Water USP or 70.11 equivalent Total 105.0 *Adjust pH if outside the range of 6.0 - 6.8 with 10% Sodium Hydroxide solution or 20% Phosphoric acid solution. The above ingredients are mixed in the same order as those of Example 3. 5 EXAMPLE 5- POUR-ON COMPOSITIONS Example 5 a) Process of Preparing Anthelminthic Compositions A pour-on veterinary anthelminthic composition may be prepared according to the following procedure. Labrasol (a surfactant) is added to a mixing tank and the surfactant 10 was heated to about 600C. Thereafter, a compound of formula I such as the compound of formula la is added to the heated surfactant. Heating was discontinued once a solution formed. The solution is then allowed to cool to about 40*C, after which time Eucalyptol (an essential oil) is added to the mixing tank with continued mixing. The solution is allowed to cool to about 300C at which point y-hexalactone is added with continued mixing. A stabilizer, such 15 as butylated hydroxytoluene (BHT), is then added to the mixing vessel and mixed until dissolved. Thereafter, moxidectin is added and mixed until dissolved. The resulting solution is filtered through a 2 p filter cartridge (Pall Corporation, East Hills, NY) and packaged into bottles suitable for pour-on veterinary applications. 20 While the foregoing describes one preferred embodiment of the process, it is well within the contemplation of the present invention that the components may be added in a different order. For example, in another embodiment, the lactone solvent is added first to the mixing tank, followed by the addition of the essential oil with continued mixing. Thereafter, a compound of formula I such as the compound of formula la is added, followed by the 25 surfactant. Heat may be applied to facilitate the formation of a solution at one or more steps during the process. Subsequently, the solution is allowed to cool to about 25-30*C, and the stabilizer is then added and mixed until dissolved. Moxidectin, or another suitable anthelminthic agent, is then added and mixed until dissolved. The resulting composition is filtered and packaged similar to as described above.

Example 5 b) Pour-On Veterinary Composition Table I below illustrates various embodiments of anthelminthic compositions representative of the present invention. These compositions are suitable for administration as 5 a pour-on in homeothermic animals, such as cattle, deer and/or sheep. In a preferred embodiment of Table I, the compound of formula I is the compound of formula Ia. Table I. Embodiments of Anthelminthic Compositions COMPONENT Composition A Composition B Composition C Composition D (% w/v) (% w/v) (% w/v) (% w/v) Compound of 25.0 25.0 20.0 20.0 formula Ia Moxidectin 0.42 0.42 0.5 0.5 BHT 0.5 0.5 0.5 0.5 y-hexalactone q.s. ad 34.0 q.s. ad 34.0 1,8-Cineole 7.0 q.s. ad 7.0 q.s. ad PEG400 45.0 --- 45.0 laurate Labrasol ---- 45.0 ---- 45.0 10 It will be understood that the present invention can be embodied in forms other than described above without departing from the spirit or scope of the inventive idea. The foregoing examples are in no way limiting of the scope of the present invention, which is defined by the claims appended herein.

Claims (35)

1. A method for the control of one or more helminthes and the treatment of a condition related to one or more helminthes, in an animal, comprising administering to the animal effective amounts of (a) an avermectin or a 5 milbemycin and (b) a compound of formula I 0 Ri RO R2 wherein R is H, COR4 or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; 10 R 1 is phenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2 R 5 , NR 6 SO 2 R 7 , NR 8 COR 9 , NR 1 aR 1 , 0 1 -C 6 haloalkyl or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or 0 2 -C 6 alkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , 15 S0 2 R 5 , NR6SO 2 R 7 , NR 8 COR 9 , NR 10 R 1 , Cr 1 C 6 haloalkyl or a CrC 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted, naphthyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , SO 2 R 5 , NR 6 SO 2 R 7 , NR 8 COR 9 , NR 10 R 11 , C-C 6 haloalkyl or a C-C 6 alkyl, 20 C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted, or heteroaryl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , SO 2 R 5 , NR6SO 2 R 7 , NR 8 COR 9 , NR 1 OR 1 , Cr 1 C 6 haloalkyl or a Cr1 C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each 25 optionally substituted; R 2 is phenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , S0 2 R 14 , NR 15 SO 2 R 1 6 , NR 1 7 COR 1 8 , NR 1 9 R 2 0 , CO-CO 6 haloalkyl or a Cr C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or heteroaryl group each optionally substituted; 30 biphenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 S0 2 R 16 , NR 1 7 COR 1 8 , NR 1 9 R 2 0 , CrCO 6 haloalkyl or a Cr 1 C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; naphthyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 S0 2 R 1 6 , NR 17 COR 1 8 , NR 1 9 R 20 , C-C 6 haloalkyl or a Cl-C 6 alkyl, 0 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; 5 heteroaryl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 S0 2 R 1 6 , NR 17 COR 1 8 , NR 1 9 R 20 , C-C 6 haloalkyl or a Cl-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or heteroaryl group each optionally substituted; or C 3 -C 6 cycloalkyl optionally substituted with one, two or three halogen, CN, OR 12 , 10 COR 13 , S0 2 R 14 , NR 15 SO 2 R 1 6 , NR 17 COR 1 8 , NR 1 9 R 20 , 0 1 -C 6 haloalkyl or a C-C 6 alkyl, 0 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl or O 2 -C 6 alkynyl group each optionally substituted; R 3 , R 4 , R 9 , R 1 2 , R 13 and R 18 are each independently H, C-C 6 haloalkyl, or a 0 1 -C 6 alkyl, O 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl, 0 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group 15 each optionally substituted; R 5 , R 7 , R 14 and R 16 are each independently a C-C 6 alkyl, C 3 -C 6 cycloalkyl, O 2 -C 6 alkenyl, 0 2 -C 6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted; Rr, R8, R 1 5 and R 17 are each independently H or an optionally substituted 20 C-C 6 alkyl group; and R 10 , Rij, R 1 and R 20 are each independently H, C-C 6 haloalkyl, or a O 1 -C 6 alkyl, C3 C 6 cycloalkyl, 0 2 -C 6 alkenyl, 0 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 10 and R 11 or R 19 and R 20 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7 25 membered ring optionally containing one or two additional heteroatoms selected from N, 0 or S; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method is a method for the control of cestodes, and for the treatment of conditions related to one or more cestodes. 30

3. The method of claim 1, wherein the method is a method for the control of nematodes and for the treatment of conditions related to one or more nematodes.

4. The method of any of claims 1, 2 or 3, wherein the condition is helminthiasis,

5. The method of claim 4, wherein the helminthiasis is related to one or more helminthes carried by an insect acting as a carrier of the one or more helminthes.

6. The method of claim 5, wherein the insect an insect is selected from the group 5 consisting of Diptera, Muscidae and Siphon6ptera.

7. The method of claim 5, wherein the insect an insect is selected from the group consisting of heel flies, tsetse flies, blow flies, fleas; lice; blow flies; face flies and horn flies.

8. The method of claim 3, wherein the nematode is a nematode selected from the 10 group consisting of Haemonchus, Ostertagia, Cooperia, Drofilaria, Oesphagastomum, Nematodirus and Dictyocaulus.

9. The method of any of claims 1 to 8, wherein the animal is selected from the group consisting of cattle, sheep, swine, horses, poultry, rabbits, goats, dogs, cats, gerbils, birds, camels, water buffalos, donkeys, fallow deer, reindeer, 15 minks, chinchillas, raccoons, and humans.

10. The method of any of claims 1 to 9, wherein (a) is a milbemycin.

11. The method of claim 10, wherein the milbemycin is moxidectin.

12. An ecto- or endoparasiticidal composition which comprises effective amounts of (a) an avermectin or a milbemycin and (b) a compound of formula 1 20 0 RI 1 0 RO (I) wherein R is H, COR 4 or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; 25 R 1 is phenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2 R 5 , NR 6 SO 2 R 7 , NRaCOR 9 , NR 1 oR 11 , C-C 6 haloalkyl or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -Cealkenyl or C 2 -Cralkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , 30 SO 2 R 5 , NReSO 2 R 7 , NR 8 COR 9 , NR 1 aR 1 , C-C 6 haloalkyl or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted, naphthyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , SO 2 R 5 , NR 0 SO 2 R 7 , NR 8 COR 9 , NR 1 oR 1 , C-C 6 haloalkyl or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted, or 5 heteroaryl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , SO 2 R 5 , NR6SO 2 R 7 , NRCOR 9 , NR 10 R 11 , 0 1 -C 6 haloalkyl or a C C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; R 2 is phenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , 10 SO 2 R 14 , NR 15 S0 2 R 1 6 , NR 17 COR 1 8 , NR 19 R 20 , 0 1 -C 6 haloalkyl or a C C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or heteroaryl group each optionally substituted; biphenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR

13 , SO 2 R 14 , NR 15 SO 2 R 16 , NR 1 7 COR 1 8 , NR 1 9 R 20 , C-C 6 haloalkyl or a 15 C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; naphthyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 S0 2 R 1 6 , NR 17 COR 1 8 , NR 19 R 2 0 , C 1 -C 6 haloalkyl or a 0 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each 20 optionally substituted; heteroaryl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 SO 2 R 16 , NR17COR 1 8 , NR 19 R 20 , Cl-C 6 haloalkyl or a Cl-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or heteroaryl group each optionally substituted; or 25 C 3 -C 6 cycloalkyl optionally substituted with one, two or three halogen, CN, OR 1 2 , COR 13 , SO 2 R 14 , NR 1 5 SO 2 R 16 , NR 17 COR 1 8 , NR 19 R 20 , Cr 1 C 6 haloalkyl or a C-C 6 alkyl, 0 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; R 3 , R 4 , R 9 , R 12 , R 13 and R 1 8 are each independently H, C-C 6 haloalkyl, or a O 1 -C 6 alkyl, 30 O 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl, 0 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; R 5 , R 7 , R 14 and R 1 6 are each independently a Cr 1 C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, O 2 -C 6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted; 35 R 6 , R 8 , R 1 5 and R 17 are each independently H or an optionally substituted Cr-C 6 alkyl group; and R 1 0 , R 11 , R 1 9 and R 20 are each independently H, C 1 -C 6 haloalkyl, or a C 1 -Cralkyl, C 3 Cecycloalkyl, C 2 -Cealkenyl, C 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 1 0 and R 11 or R 1 9 and R 20 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7 5 membered ring optionally containing one or two additional heteroatoms selected from N, 0 or S; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof. 10 13. The composition of claim 12, wherein the composition is in the form of an oral drench.

14. The composition of claim 13, further comprising a non-surfactant rheology modifier.

15. The composition of claim 14, wherein the rheology modifier is an inorganic 15 rheology modifier.

16. The composition according to claim 14 or claim 15 wherein the rheology modifier is present in an amount of 0.2 - 2% w/v.

17. The composition of claim 12, wherein the composition is in the form of a pour on. 20

18. The composition of claim 17, wherein the composition comprises a water immiscible solvent.

19. The composition of claim 18, wherein the water-immiscible solvent is a lactone solvent.

20. The composition of claim 19, wherein the lactone solvent is y-hexalactone, 25 butyrolactone, 6-hexalactone, y-dodecalactone, 6-nonalactone, 6-decalactone, y-decalactone, and 6- dodecalactone and other alkyl lactones and combinations thereof.

21. The composition of any of claims 17 to 20, wherein the composition comprises an oil component. 30

22. The composition of claim 21, wherein the oil component is an essential oil.

23. The composition of claim 22, wherein the essential oil is selected from the group consisting of 1,8-cineole, 1, 4-cineole, Euganol, limonene oil, Tea Tree oil, citronellol and combinations thereof.

24. The composition of any of claims 17 to 23, wherein the composition comprises 35 a surfactant.

25. The composition of claim 24, wherein the surfactant is selected from the group consisting of polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mono-, di- and triglycerides and combinations thereof.

26. The composition of claim 24, wherein the surfactant comprises PEG esters and glycerides with medium acyl chains. 5

27. The composition of claim 12, wherein (a) is a milbemycin.

28. The composition of claim 27, wherein the milbemycin is moxidectin.

29. The composition of claim 12, wherein the avermectin or milbemycin and the compound of formula I are present in a total amount of 0.5-10% by weight.

30. The composition of claim 17, wherein (a) is a milbemycin. 10

31. The composition of claim 30, wherein the milbemycin is moxidectin.

32. The composition of claim 17, wherein the avermectin or milbemycin and the compound of formula I are present in a total amount of 0.5-10% by weight.

33. A composition according to any one of claims 12 to 32 including up to around 0.1% selenium. 15

34. A composition according to any one of claims 12 to 33 including sufficient amounts of one or more organic solvents and one or more surfactants.

35. Use of (a) an avermectin or a milbemycin and (b) a compound of formula I 0 RI RO R2 (0) in the preparation of a medicament for the control of one or more helminthes and the 20 treatment of a condition related to one or more helminthes, in an animal, wherein: R is H, COR 4 or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; R 1 is phenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , 25 SO 2 R5, NR 6 SO 2 R 7 , NRCOR 9 , NR 1 oR 11 , C-C 6 haloalkyl or a C-C 6 alkyl, C 3 -Cecycloalkyl, C 2 -C 6 alkenyl or C 2 -Cralkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2 R 5 , NR6SO 2 R 7 , NR 8 COR 9 , NR 10 R 11 , C-C 6 haloalkyl or a C-C 6 alkyl, 30 C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted, naphthyl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2 R 5 , NR 6 SO 2 R 7 , NR8COR 9 , NR 10 R 1 , 0 1 -C 6 haloalkyl or a C-C 6 alkyl, C 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl or 0 2 -C 6 alkynyl group each optionally substituted, or 5 heteroaryl optionally substituted with one, two or three halogen, CN, OR 3 , COR 4 , S0 2 R 5 , NR 6 SO 2 R 7 , NR 8 COR 9 , NR 10 Rj 1 , C-C 6 haloalkyl or a C C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; R 2 is phenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , 10 S0 2 R 14 , NR 15 SO 2 R 1 6 , NR1 7 COR 1 8 , NR 19 R 20 , 0 1 -C 6 haloalkyl or a C Cealkyl, C 3 -Cecycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or heteroaryl group each optionally substituted; biphenyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , S0 2 R 14 , NR 1 5 S0 2 R 1 r, NR 17 COR 1 8, NR 1 9 R 20 , C-C 6 haloalkyl or a 15 C-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -Cealkenyl or C 2 -C 6 alkynyl group each optionally substituted; naphthyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , S0 2 R 14 , NR 15 SO 2 R 1 6 , NR 1 7 COR 1 8 , NR 19 R 2 0 , C-C 6 haloalkyl or a Cl-C 6 alkyl, 0 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each 20 optionally substituted; heteroaryl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 SO 2 R 16 , NR 1 7 COR 1 8 , NR 1 9 R 2 0 , C-C 6 haloalkyl or a 0 1 -C 6 alkyl, 0 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or heteroaryl group each optionally substituted; or 25 C 3 -C 6 cycloalkyl optionally substituted with one, two or three halogen, CN, OR 12 , COR 13 , SO 2 R 14 , NR 15 SO 2 R 1 6 , NR 1 7 COR 1 8 , NR 19 R 2 0 , 0 1 -C 6 haloalkyl or a Cl-C 6 alkyl, 0 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group each optionally substituted; R 3 , R 4 , R 9 , R 1 2 , R 13 and R 1 8 are each independently H, C-C 6 haloalkyl, or a 0 1 -C 6 alkyl, 30 C 3 -C 6 cycloalkyl, 0 2 -C 6 alkenyl, 0 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; R 5 , R 7 , R 1 4 and R 1 6 are each independently a 0 1 -C 6 alkyl, 0 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, 0 2 -C 6 alkyl, benzyl, aryl or heteroaryl group each optionally substituted; 35 R 0 , R 8 , R 1 5 and R 17 are each independently H or an optionally substituted Cj-C 6 alkyl group; and R 1 o, R 11 , R 1 and R 20 are each independently H, C 1 -C 6 haloalkyl, or a C 1 -C 6 alkyl, C3 C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R 10 and R 11 or R 19 and R 20 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7 5 membered ring optionally containing one or two additional heteroatoms selected from N, 0 or S; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof. Dated 7 December, 2009 10 Wyeth LLC Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON