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AU2010200429A1 - Method of reducing or preventing blowfly strike - Google Patents

Method of reducing or preventing blowfly strike Download PDF

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Publication number
AU2010200429A1
AU2010200429A1 AU2010200429A AU2010200429A AU2010200429A1 AU 2010200429 A1 AU2010200429 A1 AU 2010200429A1 AU 2010200429 A AU2010200429 A AU 2010200429A AU 2010200429 A AU2010200429 A AU 2010200429A AU 2010200429 A1 AU2010200429 A1 AU 2010200429A1
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AU
Australia
Prior art keywords
alkyl
alkenyl
alkynyl
cio
nhc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2010200429A
Inventor
Victoria Anne Gordon
Paul Warren Reddell
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Ecobiotics Ltd
Original Assignee
Ecobiotics Ltd
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Filing date
Publication date
Priority claimed from AU2009900443A external-priority patent/AU2009900443A0/en
Application filed by Ecobiotics Ltd filed Critical Ecobiotics Ltd
Priority to AU2010200429A priority Critical patent/AU2010200429A1/en
Publication of AU2010200429A1 publication Critical patent/AU2010200429A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title ""Method of reducing or preventing blowfly strike" The following statement is a full description of this invention, including the best method of performing it known to me/us:- C:\NRLPortbl\DCC\AZB\2707916 DOC-4A)22010 METHOD OF REDUCING OR PREVENTING BLOWFLY STRIKE Field of the Invention 5 The present invention provides an alternative method to mulesing in subjects such as lambs or sheep to prevent fly strike. In particular, the present invention provides a method of chemical mulesing comprising locally administering a protein kinase C (PKC) activator to the breech area of a subject. Methods of decreasing skin wrinkling and reducing wool follicle density and causing a pro-inflammatory response in skin are also described. 10 Background of the Invention The practice of mulesing of lambs to prevent fly strike will be banned in Australia from 2010 on animal welfare grounds and is being phased out in other sheep producing nations 15 such as New Zealand. Mulesing is the surgical removal of strips of wool-bearing skin from around the breech of a sheep, generally skin is cut away from the perianal area down to the top of the hind limbs. As the wound heals, the skin is pulled tight reducing skin wrinkles and the number of wool 20 follicles in the area. Mulesing provides smooth scar tissue with minimal wool to get fouled by the urine and faeces of the sheep. This in turn reduces the likelihood that blow-flies will lay their eggs in the wool on the rear end of the sheep. Fly strike occurs when flies such as blow-flies, (eg: Lucilia cuprina), lay their eggs in the 25 fouled wool around a sheep's breech. When the maggots hatch they feed on the sheep's flesh causing discomfort to the sheep and if not quickly recognised and treated, the sheep can die a slow and painful death, often from septicaemia. It is thought that in Australia, up to 3,000,000 sheep could die each year from fly strike in the absence of mulesing. 30 The aim of mulesing is to reduce skin folds and wool density in the breech area of the sheep. It is thought that mulesing works by: C:WRPonbl\DCCAZBU707916_ 1.DOC-4A2/20 10 -2 1. Causing tightening of the skin and consequently decreasing the amount of skin wrinkling as the wound heals by contraction. Contraction of skin is a normal process in wound healing and involves healthy skin surrounding the 5 wound growing to cover the wound. 2. Creating a wound large enough to inhibit a complete healing by contraction leaving some of the wound to heal by epithelialisation. Sections of the wound healed by epithelialisation will contain no wool follicles. 3. Reducing the density of wool follicles in areas healed by contraction 10 because the surrounding skin and its embedded wool follicles has stretched to cover the wound. Alternatives to mulesing include regular mechanical removal of wool from around the breech area of the sheep (crutching) and regular monitoring of flocks of sheep to identify 15 instances of fly strike. These alternatives are labour intensive and are only practical for small flocks, not large flocks grazed on large properties. Other alternatives are being investigated but as yet, no widely applicable method has been identified. 20 It is predicted that the ceasing of mulesing will have a significant effect on the costs required to maintain a flock (Bell and Sackett, Sheep Updates, http://www.agric.wa.gov.au/content/AAP/SL/welf 02.pdf). In particular, increased labour costs are expected in shearing and crutching, particularly if more than one crutching per 25 year is required, and also for the application of chemicals used to prevent fly strike. Increased dag and wool stain is also expected and increased dag management will be required to prevent reduction in wool value. If more chemical fly control products are used, the timing of the use before shearing becomes important to reduce chemical residues in the wool. Bell and Sackett estimate that the cost of not mulesing will add about $1.47 to 30 the cost of each sheep, assuming no loss of stock from fly strike and that only one C:\NRPonb\DCC\AZB\2707916_L.DOC-4A)2I2210 -3 crutching of stock is required. A further 5% increase in the cost of shearing each sheep is also expected. Chemical methods equivalent to mulesing have the potential to accomplish the same 5 results without the pain and trauma associated with the physical removal of skin. Any chemical method would need to cause short-term and highly localised damage to the skin in the breech area of the treated animal with minimal discomfort and pain and result in rapid healing of the wound with tightening of the skin around the breech area and with no short-term or long-term side effects. The treatment would also need to be localised with 10 no chemical entering the blood stream of the animal and/or accumulating in the tissues of the animal, especially the muscle tissue or wool. It would also be advantageous if the chemical damaged keratinocytes in the basal hair follicles responsible for wool growth. Summary of the Invention 15 The present invention is predicted in part on the recognition that PKC activators cause localised cell death and induce localised pro-inflammatory responses that are followed by rapid skin renewal. PKC activators are also poorly mobile in serum and are therefore unlikely to cause systemic effects or form residues in tissues. Some PKC 20 activators inhibit keratinocytes and thereby block hair follicle activity. In a first aspect of the invention, there is provided a method of reducing or preventing fly strike in a subject comprising locally administering a pro-inflammatory amount of a PKC activator to the breech area of the subject. 25 In another aspect of the invention there is provided a method of decreasing skin wrinkling in the breech area of a subject comprising locally administering a pro inflammatory amount of a PKC activator to the breech area of the subject. 30 In yet another aspect of the invention there is provided a method of reducing wool follicle density in the breech area of a subject comprising locally administering a pro- C :WUonbl\DCCAZB\707916_.DOC-4A2/OI -4 inflammatory amount of a PKC activator to the breech area of the subject. In a further aspect of the invention there is provided a method of causing an inflammatory response in the skin of a subject comprising locally administering a pro 5 inflammatory amount of a PKC activator to the skin of the subject. In some embodiments the subject is a sheep, especially a lamb. In some embodiments, the sheep or lamb is a merino sheep or lamb. 10 Description of the Invention The present invention provides an alternative to mulesing but achieves similar effects by causing a pro-inflammatory response in the area of application and thereby reducing skin wrinkling, particularly in the breech area of the subject, and/or reducing 15 wool follicle density, particularly in the breech area of the subject. These effects reduce fouling of wool in the breech area of the subject and provide a breech environment that is less attractive to flies to lay their eggs resulting in a reduced incidence of fly strike. The method of the invention comprises locally administering a pro-inflammatory amount of a PKC activator to the breech area of the subject. 20 The PKC activator is applied locally to the skin, particularly in the breech area to induce localised cell death and pro-inflammatory responses that result in rapid skin renewal thereby providing smooth skin with in some cases reduced density of hair follicles. 25 In some embodiments, the treatment is performed on more than one, especially all, sheep in a flock and the treatment reduces the incidence of fly strike in a flock of sheep. In some embodiments the treatment is performed on a single sheep and reduces the risk of fly strike in that sheep. 30 C:\NRPonbl\DCC\AZB\27079163 DOC-A)2/2010 -5 The PKC activator may be any known PKC activator that produces a significant inflammatory response in the skin to cause scabbing and local inflammation to generate rapid skin renewal. Suitable natural product PKC activators and their synthetic analogues are described in Ma, D., Current Medicinal Chemistry, 2001, 8, 191-202. Suitable PKC 5 inhibitors include tigliaen-3-one compounds, teleocidins, phorbol esters, asplysiatoxins, ingenol esters, bryostatins and analogs thereof. In some embodiments, the PKC activator is a tigliaenone or a phorbol ester or an analogue thereof which is a compound of formula (I): 10 R2 R3 H R1 R4 R RR H R16 R6 ,16) HH H R15 R17 H R8R7 R1 R12 Ri R10R wherein R' is selected from hydrogen, -C 1 -Cio alkyl, -C 2 -Cio alkenyl and -C 2 -Cio alkynyl; 15 R 2 is selected from hydrogen, -Ci-Cio alkyl, -C 2 -Cio alkenyl and -C 2
-C
10 alkynyl;
R
3 is selected from -OH, -OCI-C 20 alkyl, -OC 2
-C
2 0 alkenyl, -OC 2
-C
2 0 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-C 20 alkyl, -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, 20 -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R 2 and R 3 taken together form a carbonyl group (=0); C \NRPonbI\DCC\AZB\2707916 I DOC-4A)2/200 -6
R
4 is selected from -OH, -OCI-C 20 alkyl, -OC 2
-C
20 alkenyl, -OC 2
-C
2 0 alkynyl, -Ocycloalkyl, -OC(O)C-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHC-C 2 0 alkyl, -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, 5 -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl;
R
5 and R6 are independently selected from hydrogen and -CI-Cio alkyl; R 7 and R 8 are hydrogen or taken together R7 and R8 form a double bond, -0-, -S- or 10 -NR' 8 -; R9 is selected from CI-C 20 alkyl, -C 2
-C
20 alkenyl, -C 2
-C
20 alkynyl, -OH, -OC-C 20 alkyl, -OC 2
-C
20 alkenyl, -OC 2
-C
20 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 2 0 alkyl, -OC(O)C 2 C 20 alkenyl, -OC(O)C 2
-C
2 0 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -NHCI-C 20 alkyl, -NHC 2
-C
20 alkenyl, -NHC 2
-C
20 alkynyl, 15 -NHcycloalkyl, -NHaryl, -NHheterocyclyl, -NHheteroaryl, -OC(O)NHCI-C 20 alkyl,
-OC(O)NHC
2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; 20 R10 and R" are independently selected from hydrogen, -Cr-C 6 alkyl,
-C
2
-C
6 alkenyl, -C 2
-C
6 alkynyl, -OH, -OC-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC 2
-C
6 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)C 2
-C
6 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl and -OC(O)heteroaryl or R10 and R" taken together form a carbonyl or thiocarbonyl group; 25 R1 2 is selected from hydrogen, -C-CIO alkyl, -C 2 -CIO alkenyl and -C 2 -CIO alkynyl;
R
1 3 is selected from hydrogen, -OH, -OC-C 2 0 alkyl, -OC 2
-C
2 0 alkenyl, -OC 2
-C
2 0 alkynyl, -Ocycloalkyl, -OC(O)C-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHC-C 20 alkyl, -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, 30 -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, C:\NRPotblWCC\AZB\2707916_1 DOC-4A'2/2010 -7 -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R1 2 and R 13 taken together form a carbonyl group;
R'
4 is selected from hydrogen, -OH, -OCI-C 20 alkyl, -0C 2
-C
20 alkenyl, -0C 2
-C
20 alkynyl, -Ocycloalkyl, -OC(O)CI-C 20 alkyl, -OC(0)C 2
-C
2 0 alkenyl, -OC(0)C 2
-C
2 0 alkynyl, 5 -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(0)NHCI-C 2 0 alkyl, -OC(0)NHC 2
-C
2 0 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 2 0 alkyl,
-OC(S)NHC
2
-C
2 0 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; 10 or R' 4 and R 15 together form =0 or =CH2; R 1 and Ri 6 are independently hydrogen or R 5 and R1 6 taken together form a 5 membered carbocyclic ring of the form: H
R
2 2 * R21>
R
20
R
19 15 wherein * indicates the carbon atoms bearing R 5 and R 16 ;
R'
9 and R 20 are independently selected from hydrogen, -OH, -OCi-CIO alkyl, -OC 2 CIO alkenyl, -0C 2 -CIO alkynyl, -Ocycloalkyl, -OC(O)CI-Cio alkyl, -OC(0)C 2 -Cio alkenyl, -OC(0)C 2 -CIO alkynyl, -OC(O)cycloalkyl, -OC(O)heterocyclyl, -OC(O)heteroaryl, 20 -OC(O)NHC-CIO alkyl, -OC(O)NHC 2 -Cjo alkenyl, -OC(O)NHC 2 -Co alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-CIO alkyl, -OC(S)NHC 2 -CIo alkenyl, -OC(S)NHC 2 -Cio alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or
R'
9 and R 20 taken together are =0, =S, =NH or =N(CI-C 6 alkyl); 25 R is hydrogen, -Cl-Cio alkyl, -C 2 -CIO alkenyl or -C 2 -CIO alkynyl;
R
22 and R 23 are each hydrogen, -CI-CIO alkyl, -C 2 -CIO alkenyl, -C 2
-C
0 alkynyl, -OH, -OCi-Cio alkyl, -0C 2 -CIO alkenyl, -0C 2 -CIo alkynyl, -Ocycloalkyl, -OC(O)Ci-CIO C:\NRPonbl\DCC\A.ZBU707916 1.DOC4A)2/2011) -8 alkyl, -OC(0)C 2 -Cio alkenyl, -OC(O)C 2 -Ci 0 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-Cjo alkyl, -OC(0)NHC 2
-C
10 alkenyl, -OC(0)NHC 2
-C
1 o alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHC 1
-C
10 alkyl, -OC(S)NHC 2
-C
10 5 alkenyl, -OC(S)NHC 2
-C
10 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, F, Cl, Br, I, -CN, -NO 2 or N(R")2, or R2 and R taken together form a double bond or are -0-, -S-, -NR'- or -CR 2 4 R"-; R1 7 is selected from hydrogen, -OH, -OCI-C 2 0 alkyl, -OC 2
-C
20 alkenyl, -OC 2
-C
20 alkynyl, -Ocycloalkyl, -OC(0)C 1
-C
20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
20 alkynyl, 10 -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-C 20 alkyl, -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 2 0 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; 15 R' 8 is selected from hydrogen and -C 1 -Cio alkyl;
R
2 4 and R 25 are independently selected from hydrogen, -Ci-C 1 o alkyl, -OH and -OCi-Clo alkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted; 20 a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. In one embodiment, the compound of formula (I) is a compound of formula (II) H Or-ma H R23 H R5O~R H R22 R6 R 21 OR' O OR O0 H ORd ORc C:\NRPonbl\DCC\AZB\2707916 1.DOC-4M2/2010 -9 wherein: R' is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl; R5 and R are each independently hydrogen or -CI-C 6 alkyl;
R
2 1 is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl; 5 R 22 and R 23 are each independently hydrogen, -CI-C 6 alkyl, -C 2
-C
6 alkenyl, -OH,
-OCI-C
6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, F, Cl, Br or I, or R 2 and R 23 taken together form a double bond or are -0-; Ra, Rb, Rc, Rd, Re and Rr are each independently selected from hydrogen, -C 1
-C
2 0 10 alkyl, -C 2
-C
20 alkenyl, -C 2
-C
20 alkynyl, -C(O)CI-C 20 alkyl, -C(O)C 2
-C
20 alkenyl, -C(O)C 2 C 2 0 alkynyl, -C(O)cycloalkyl, -C(O)aryl, -C(O)heterocyclyl, -C(O)heteroaryl, -C(O)NHCI
C
2 0 alkyl, -C(O)NHC 2
-C
20 alkenyl, -C(O)NHC 2
-C
2 0 alkynyl, -C(O)NHcycloalkyl, -C(O)NHaryl, -C(O)NHheterocyclyl, -C(O)NHheteroaryl, -C(S)NHCI-C 20 alkyl,
-C(S)NHC
2
-C
20 alkenyl, -C(S)NHC 2
-C
20 alkynyl, -C(S)NHcycloalkyl, -C(S)NHaryl, 15 -C(S)NHheterocyclyl and -C(S)NHheteroaryl; wherein each alkyl, alkenyl, aryl, heterocyclyl and heteroaryl group is optionally substituted; or a geometric isomer or stereoisomer, or a veterinary acceptable salt thereof. 20 In another embodiment, the compound of formula (I) is a compound of formula (III) R(2 R3 H R1 ORb R23 H R5 H ~ R 22 R6 H R21 OH H (lll O HOO R13 R 12 R"i R100R wherein: C:WRPortbl\DCCAZB\2707916 1.DOC4A)2/2010 - 10 R' is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl; R2 is hydrogen;
R
3 is hydroxy, -OCI-C 20 alkyl, -OC 2
-C
2 0 alkenyl, -OC(O)C-C 20 alkyl,
-OC(O)C
2
-C
20 alkenyl, -OC(O)aryl, -OC(O)heterocyclyl or -OC(O)heteroaryl; or R 2 and 5 R 3 taken together form a carbonyl group; R is hydrogen, -CI-C 2 0 alkyl, -C 2
-C
20 alkenyl, -C(O)CI-C 20 alkyl,
-C(O)C
2
-C
20 alkenyl, -C(O)aryl, -C(O)heterocyclyl or -C(O)heteroaryl;
R
5 and R 6 are each independently hydrogen or -CI-C 6 alkyl; R' is hydrogen, -CI-C 6 alkyl, -C 2
-C
6 alkenyl, -C(O)CI-C 6 alkyl, 10 -C(O)C 2
-C
6 alkenyl, -C(O)aryl, -C(O)heterocyclyl or -C(O)heteroaryl;
R'
0 and R" are independently selected from hydrogen, -OH, -OCI-C 6 alkyl and
-OC
2
-C
6 alkenyl or R'O and R" taken together form a carbonyl group; R1 2 is hydrogen;
R
3 is hydroxy, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 15 alkenyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl or R' 2 and R' 3 taken together form a carbonyl group;
R
2 1 is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl;
R
22 and R 23 are each independently hydrogen, -CI-C 6 alkyl, -C 2
-C
6 alkenyl, -OH,
-OCI-C
6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)aryl, 20 -OC(O)heterocyclyl, -OC(O)heteroaryl, F, Cl, Br or I, or R and R taken together form a double bond or are -0-; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; or a geometric isomer or stereoisomer thereof or a veterinary acceptable salt 25 thereof. In another embodiment, the compound of formula (I) is a compound of formula
(IV):
C:NPo.tbl\DCC\AZB\27079161 DOC-4A2/2010 H ORa H -11 R1 ORb R5 H R16 R6 R15 OR' H H R14 (IV) H H R11 R100R wherein: R' is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl;
R
5 and R 6 are each independently hydrogen or -CI-C 6 alkyl; 5 R' 0 and R" are each independently selected from hydrogen, -OH, -OCI-C 6 alkyl and -OC 2
-C
6 alkenyl or R' 0 and R" taken together form a carbonyl group;
R'
4 is selected from -OH, -OCI-C 2 0 alkyl, -OC 2
-C
20 alkenyl, -OC(O)CI-C 2 0 alkynyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
20 alkynyl, -OC(O) cycloalkyl, -OC(O) aryl, -OC(O) heterocyclyl, -OC(O) heteroaryl, -OC(O)NHC 1
-C
20 alkyl, 10 -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NH cycloalkyl, -OC(O)NH aryl, -OC(O)NH heterocyclyl, -OC(O)NH heteroaryl, -OC(S)NHC 2
-C
2 0 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHCI-C 20 alkynyl, -OC(S)NH cycloalkyl, -OC(S)NH aryl, -OC(S)NH heterocyclyl and -OC(S)NH heteroaryl; or R' 4 and R1 5 taken together form =0 or =CH2 15 R1 5 and R1 6 are independently selected from hydrogen or R 5 and Ri 6 taken together form a 5 membered carbocyclic ring of the form H
R
23 * R22 R21 R 0 wherein * indicates the carbon atoms bearing R 1 5 and R 1 6
;
C:NRPorb\DCC\AZB\27(7916 I DOC-4A)2/20) - 12
R
2 1 is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl;
R
22 and R 23 are each independently hydrogen, -CI-C 6 alkyl, -C 2
-C
6 alkenyl, -OH,
-OCI-C
6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)Ci-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, F, Cl, Br or I, or R 2 and R 23 taken together form a 5 double bond or are -0-; Ra, Rb, Rc and Rf are each independently selected from hydrogen, -Ci-C 2 0 alkyl,
-C
2
-C
20 alkenyl, -C 2
-C
2 0 alkynyl, -C(O)CI-C 20 alkyl, -C(O)C 2
-C
20 alkenyl, -C(O)C 2
-C
20 alkynyl, -C(O)cycloalkyl, -C(O)aryl, -C(O)heterocyclyl, -C(O)heteroaryl, -C(O)NHCI-C 20 alkyl, -C(O)NHC 2
-C
20 alkenyl, -C(O)NHC 2
-C
20 alkynyl, -C(O)NHcycloalkyl, 10 -C(O)NHaryl, -C(O)NHheterocyclyl, -C(O)NHheteroaryl, -C(S)NHCi-C 2 0 alkyl,
-C(S)NHC
2
-C
20 alkenyl, -C(S)NHC 2
-C
20 alkynyl, -C(S)NHcycloalkyl, -C(S)NHaryl, -C(S)NHheterocyclyl and -C(S)NHheteroaryl; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; 15 or a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. In preferred embodiments of formula (I) at least one of the following applies: R' is hydrogen or -CI-C 3 alkyl, especially hydrogen or methyl; 20 R 2 is hydrogen;
R
3 is -OH, -OCI-C 20 alkyl, -OC 2
-C
2 0 alkenyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, especially -OC(O)CI-CI 5 alkyl or -OC(O)C 2
-C
15 alkenyl, where each alkenyl group has one or more double bonds where the double bonds may be isolated or conjugated; 25 R 4 is -OH, -OCI-C 20 alkyl, -OC 2
-C
20 alkenyl, -OC(O)CI-C 20 alkyl or -OC(O)C 2
-C
20 alkenyl, especially -OC(O)CI-Cio alkyl or -OC(O)C 2
-C
1 o alkenyl;
R
5 and R 6 are each independently hydrogen or -CI-C 3 alkyl, especially hydrogen or methyl, more especially where both R 5 and R 6 are methyl;
R
7 and R 8 taken together form a double bond or -0-; 30 R9 is -OH, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl or -OC(O)C 2
-C
6 alkenyl, especially -OH or -OC(O)C I-C 3 alkyl; C:\.NRPorbl\DCC\AZB\2707916_ 1.DOC4A)2/2010 - 13 R10 and R" are independently selected from hydrogen, -OH, -OCi-C 3 alkyl, -OC 2 C 3 alkenyl or R' 0 and R" taken together form a carbonyl group, especially hydrogen, hydroxy or together a carbonyl group;
R
1 2 is hydrogen; 5 R1 3 is hydrogen, -OH, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl or
-OC(O)C
2
-C
6 alkenyl, especially hydrogen, -OH or -OC(O)CI-C 3 alkyl;
R'
4 is -OH or -OCi-C 3 alkyl, especially -OH, or R' 4 and R' 5 taken together form =0 or =CH 2 ; R1 5 and R1 6 are each independently hydrogen or taken together form a 5 membered 10 hydrocarbon ring of the form: H R23 R22 R 2 0 wherein * indicates carbon atoms bearing R 5 and R1 6 ;
R
7 is -OH or -OCI-C 3 alkyl, especially -OH; 15 R 2 1 is hydrogen or -C 1
-C
3 alkyl, especially hydrogen or methyl;
R
22 and R 2 3 are each hydrogen or R 22 and R 23 form a double bond or are -0-. In one particular embodiment, the compound of formula I is 12-tigloyl-13-(2 methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one (EBC-46): 20 C :NRPotbl\DCCAZB\2707916 1.DOC-4A2/2010 -14 0 0 0 OO 0 OH 0 OH O. In another embodiment, the compound of formula (1) is 12,13-di-(2 methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-tigliaen-3-one(EBC-47): 0 100 OHO O OH 0 OH 5 OH. In yet another particular embodiment, the compound of formula (I) is 12-(dodeca 2,4,6-trienoyl)-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3 one (EBC-59): 10 C:\NRPonbl\DCC\AZB\270)7916_l.DOC-4A2/2010 - 15 0 0 OH O OH 0 OH O. In still yet another particular embodiment, the compound of formula (I) is 12-(deca 2,4-dienoyl)-6,7-epoxy-4,5,9,2,13,20-hexahydroxy-I1 -tigliaen-3a-one (EBC-61): 5 O OH O OH O OH OH. In yet another embodiment, the compound of formula (I) is 12,13-di-(2 methylbutanoyl)-1,2-2H-l,2,6,7-diepoxy-6-carboxy-4,5,9,12,l3-pentahydroxy-tigliaen-3 10 one: C:NRPobl\DCC\AZB\27O7916 .DOC-4A]/2010 - 16 0 0 00 OH OH OH0 0 In still yet another embodiment, the compound of formula (I) is 12,13-di-(2 methylbutanoyl)-5,20-di-acetoyl-4,5,9,12,1 3,20-hexahydroxy-tigliaen-3-one: 5 0 0 O OH 0 O O- O OJI In yet another embodiment, the compound of formula (I) is 12-0 tetradecanoylphorbol- 13-acetate (TPA) 10 C 'NRPortbl\DCC\AZB\2707916_ IDOC-4A2/2010 -17 O
CH
3
(CH
2 )1 2 O C0 O CH3 CH3
CH
3 HH CH3 H H CH3 OH HO OH HOH In a further embodiment, the compound of formula (I) is O C3Hy O O C3H7 H3C- CH3 CH3 OHH HO 5 OH In yet a further embodiment, the compound of formula (I) is C:NRPonbl\DCC\AZB\2707916_l.DOC-4A)2/2010 -18 0 C3H7 O S O
C
3
H
7
CH
3
CH
3
CH
3 H OH H X/ OH wherein X is 0 or CH 2 . 5 In another embodiment, the compound of formula (I) is phorbol-12,13-didecanoate O O CH3(CH2)8 O (C 28 H CH3---- CH3 H CH3 CH3 H H OHH OO 0 OH O nH In some embodiments, the PKC activator is an ingenol compound of formula (V) 10 CANRPodbIlDCC\AZB\2707916J DOC-4)22010 - 19 R31 R32 H Rk H
R
30 0 R3 4 H H R46R47 H R45 H R44 R3 R43 R42 R36 R 41 R40 R39 R38R3 wherein
R
3 0 is selected from hydrogen, ky, -C 2
-C
2 alkeyl, a nyl 2 -C an -OH, alkynyl; 5 R3ky and R3 2 are each i n de p en dently selected from hydrogen, -CI-CIO alkyl, -CrCio alkenyl and -C 2 -Cio alkynyl; R and R34 are each independently selected from hydrogen, -Ci-CIO alkyl, -CCIO alkenyl and -CrClo alkynyl or R and R34 taken together are -C(R48O)(RN49Hk R 3s and R 36 are both hydrogen, or R 3 and R 36 taken together form a double bond, 10 -O-, -S- or -NR'O-; R 3 is selected from -C1-C20 alkyl, -C2-C20 alkenyl, -C2-C20 alkynyl, -OH, -OCi-C20 alkyl, -OC2-C20 alkenyl, -OC2-C20 alkynyl, -Ocycloalkyl, -OC(0)C I-C20 alkyl, -OC(0)C2 C20 alkenyl, -OC(0)C2-C20 alkynyl, -OC(O)cycloalkyl, -OC(0)aryl, -OC(0)heterocyclyl, -OC(O)heteroaryl, -NHCI-C20 alkyl, -NHCr-C20 alkenyl, -NHCr-C20 alkynyl, 15 -NHcycloalkyl, -NHaryl, -NHheterocyclyl, -NHheteroaryl, -OC(O)NHCi-C20 alkyl,
-OC(O)NHC
2
-C
20 alkenyl, -OC(O)NHC 2
-C
20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
2 0 alkenyl, -OC(S)NHC 2
-C
20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; 20 R 38 and R 39 are independently selected from hydrogen, -CI-C 6 alkyl,
-C
2
-C
6 alkenyl, -C 2
-C
6 alkynyl, -OH, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC 2
-C
6 alkynyl, -Ocycloalkyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)C 2
-C
6 alkynyl, C:\NRPorbl\DCC\AZB\2707916-1 DOC-4A2/2010 - 20 -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl and -OC(O)heteroaryl or R 3 8 and R 3 9 taken together form a carbonyl or thiocarbonyl group;
R
40 is selected from hydrogen, -CI-Cr 0 alkyl, -C 2 -CIo alkenyl and -C 2
-CI
0 alkynyl;
R
4 ' is selected from hydrogen, -OH, -OCI-C 20 alkyl, -0C 2
-C
2 O alkenyl, -OC 2
-C
2 0 5 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(0)C 2
-C
2 0 alkenyl, -OC(O)C 2
-C
2 0 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 20 alkyl, -OC(O)NHC 2
-C
2 0 alkenyl, -OC(O)NHC 2
-C
2 o alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 2 0 alkyl,
-OC(S)NHC
2
-C
20 alkenyl, -OC(S)NHC 2
-C
2 0 alkynyl, -OC(S)NHcycloalkyl, 10 -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R 4 0 and R 4 ' taken together form a carbonyl group;
R
42 is selected from hydrogen, -OH, -OCI-C 2 0 alkyl, -OC 2
-C
2 0 alkenyl, -OC 2
-C
20 alkynyl, -Ocycloalkyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl, -OC(O)C 2
-C
2 0 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 20 15 alkyl, -OC(O)NHC 2
-C
2 0 alkenyl, -OC(0)NHC 2
-C
2 0 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl,
-OC(S)NHC
2
-C
2 0 alkenyl, -OC(S)NHC 2
-C
2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl;
R
43 and R 44 are independently selected from hydrogen, -OH, -0CI-CI 0 alkyl, -OC 2 20 CIO alkenyl, -0C 2 -CIo alkynyl, -Ocycloalkyl, -OC(O)CI-Cio alkyl, -OC(O)C 2 -CIO alkenyl,
-OC(O)C
2
-CI
0 alkynyl, -OC(O)cycloalkyl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-CIO alkyl, -OC(0)NHC 2
-CI
0 alkenyl, -OC(O)NHC 2 -CIO alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-Cio alkyl, -OC(S)NHC 2
-C
1 o alkenyl, -OC(S)NHC 2
-CI
0 alkynyl, 25 -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, fluoro, chloro, bromo and iodo, or R 43 and R 44 taken together are =0, =S, =NH or =N(Cl
C
6 alkyl);
R
4 5 is hydrogen, -CI-C 1 o alkyl, -C 2 -C 10 alkenyl or -C 2
-C
10 alkynyl;
R
46 and R 47 are each hydrogen, -CI-CIO alkyl, -C 2 -Cio alkenyl, -C 2
-C
10 alkynyl, 30 -OH, -0CI-Ci 0 alkyl, -0C 2 -Cj 0 alkenyl, -0C 2
-C
0 alkynyl, -Ocycloalkyl, -OC(O)Ci-Co alkyl, -OC(O)C 2 -Cio alkenyl, -OC(O)C 2 -CIO alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, C:\NRPnrtbl\DCC\AZB\2707916_1 DOC-4A2/2010 -21 -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-Co alkyl, -OC(O)NHC 2 -CIo alkenyl, -OC(O)NHC 2 -CIO alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-Cio alkyl, -OC(S)NHC 2
-C
1 o alkenyl, -OC(S)NHC 2 -CIo alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, 5 -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, F, Cl, Br, I, -CN, -NO 2 or N(R" 0
)
2 , or R4 and R 47 taken together form a double bond or are -0-, -S-, -NR 0 - or -CRR s
R
48 and R 49 are each independently selected from hydrogen and -C 1
-C
1 o alkyl;
R
50 is hydrogen or -C 1 -Cio alkyl; R51 and R 5 2 are independently selected from hydrogen, -Cl-Cio alkyl, -OH and 10 -OCi-C oalkyl; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; or a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. 15 In one embodiment, the compound of formula (V) is a compound of formula (VI): H H H R33 H R 34 R30 0 R 47 H H R46 H R45 R 44H H R42 R41 |OR9 H R39 R38 (I wherein 20 R 30 is hydrogen, -C I-C6 alkyl or -C2-C6 alkenyl; C:NRPorbDCC\AZB\2707916_1 DOC-4A2201l - 22 R 3 3 and R 34 are independently selected from hydrogen and-CI-C 6 alkyl or R 33 and
R
3 4 taken together are -C(R 48)R49)- where R and R49 are independently selected from hydrogen and -CI-C 6 alkyl;
R
38 and R 39 are each independently selected from hydrogen, -OH, -OCI-C 6 alkyl 5 and -OC 2
-C
6 alkenyl or R 38 and R 39 taken together form a carbonyl group (=0);
R
4 1 and R 4 2 are independently selected from hydrogen, -OH, -OCI-C 20 alkyl, -OC 2 C 20 alkenyl, -OC(O)CI-C 20 alkynyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl,
-OC(O)C
2
-C
20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 2 0 alkyl, -OC(O)NHC 2
-C
20 alkenyl, -OC(O)NHC 2
-C
2 0 10 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHC 2
-C
2 0 alkyl, -OC(S)NHC 2
-C
20 alkenyl, -OC(S)NHCI
C
2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl;
R
44 is selected from -OH, -OCI-CIc alkyl, -OC 2 -CIo alkenyl, -OC 2 -CIO alkynyl, 15 Ocycloalkyl, -OC(O)CI-Cio alkyl, -OC(O)C 2 -Cio alkenyl, -OC(O)C 2 -Co alkynyl, -OC(O)cycloalkyl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 1 o alkyl,
-OC(O)NHC
2 -CIO alkenyl, -OC(O)NHC 2 -CIO alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-C 1 o alkyl,
-OC(S)NHC
2 -Cio alkenyl, -OC(S)NHC 2 -CIO alkynyl, -OC(S)NHcycloalkyl, 20 -OC(S)NHaryl, -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl and fluoro;
R
45 is hydrogen, -CI-C 6 alkyl or -C 2
-C
6 alkenyl;
R
46 and R 4 7 are each independently hydrogen, -CI-C 6 alkyl, -C 2
-C
6 alkenyl, -OH,
-OCI-C
6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O) aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, F, Cl, Br or I or R 46 and R 47 taken together form a 25 double bond; R9 is selected from hydrogen, -CI-C 20 alkyl, -C 2
-C
2 0 alkenyl, -C 2
-C
2 0 alkynyl, C(O)Ci-C 20 alkyl, -C(O)C 2
-C
20 alkenyl, -C(O)C 2
-C
2 0 alkynyl, -C(O)cycloalkyl, -C(O)aryl, -C(O)heterocyclyl, -C(O)heteroaryl, -C(O)NHCI-C 20 alkyl, -C(O)NHC 2
-C
20 alkenyl,
-C(O)NHC
2
-C
20 alkynyl, -C(O)NHcycloalkyl, -C(O)NHaryl, -C(O)NHheterocyclyl, 30 -C(O)NHheteroaryl, -C(S)NHCi-C 20 alkyl, -C(S)NHC 2
-C
2 0 alkenyl, -C(S)NHC 2
-C
20 alkynyl, -C(S)NHcycloalkyl, -C(S)NHaryl, -C(S)NHheterocyclyl and -C(S)NHheteroaryl; C:\NRPonbl\DCC\AZBU707916_ .DOC-4A)22010 -23 wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; or a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. 5 In particular embodiments of the PKC activators of formula (V) have one or more of the following:
R
30 is hydrogen or -CI-C 3 alkyl, especially hydrogen or methyl; R 3 and R 32 are independently hydrogen or -CI-C 3 alkyl, especially where one or 10 both are hydrogen;
R
33 and R 34 are independently hydrogen or -Ci-C 3 alkyl or taken together R 33 and R34 are -C(R 48
)(R
49 )- where R 48 and R 49 are independently hydrogen or -CI-C 3 alkyl, especially where R 33 and R 34 are both hydrogen or are -C(CH3)(CH3)-;
R
35 and R 36 are both hydrogen or taken together form a double bond or -0-; 15 especially where R 35 and R 36 taken together form a double bond;
R
3 1 is -OH, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl or , -OC(O)aryl, especially -OH, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl or -OC(O)phenyl, more especially -OH, -OC(O)phenyl or -OC(O)C(CH 3
)=CHCH
3 ;
R
3 8 and R 39 are independently selected from hydrogen, -OH, -OCI-C 3 alkyl, -OC 2 20 C 3 alkenyl or R 38 and R 39 taken together form a carbonyl group, especially where R 38 and
R
39 are hydrogen;
R
40 is hydrogen;
R
4 ' is hydrogen, -OH, -OCI-C 3 alkyl, -OC 2
-C
3 alkenyl, -OC(O)Ci-C 6 alkyl,
-OC(O)C
2
-C
6 alkenyl or -OC(O)aryl, especially hydrogen or -OH; 25 R 42 is hydrogen, -OH, -OCI-C 3 alkyl, -OC 2
-C
3 alkenyl, -OC(O)CI-C 6 alkyl,
-OC(O)C
2
-C
6 alkenyl or -OC(O)aryl, especially hydrogen or -OH;
R
43 is hydrogen;
R
44 is -OH, -OCi-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)Ci-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)aryl or fluoro, especially -OH, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, 30 -OC(O)aryl or fluoro, more especially -OH, fluoro, -OC(O)C(CH 3
)=CHCH
3 and -OC(O)phenyl; C:\NRPonbl\DCC\AZB\2707916 1.DOC-4A)2/2U10 - 24 R 45 is hydrogen or -CI-C 3 alkyl, especially hydrogen or methyl;
R
46 and R 4 7 are each hydrogen, or together form a double bond or -0- ; especially where R 46 and R 4 7 are both hydrogen or together form a double bond. 5 In one embodiment, the compound of formula (V) is ingenol 3-angelate: H CH3 H3C o CH3 100 H H3C H H O HO HO OH In another embodiment, the compound of formula (V) is ingenol 3-benzoate: 10 H CH3 H3C O CH3 H H3C H H O O HO HO
OH
C:NRPortbl\DCC\AZBU707916.DOC-3A2010 -25 In yet another embodiment, the compound of formula (V) is ingenol-3,20 dibenzoate: H CH3 H3C 0CH3 H3C H H 0 0 HO HO 5 In yet another embodiment, the compound of formula (V) is: H CH3 H3C CH3 100 H H HO HO HO OH 10 In a further embodiment, the compound of formula (V) is: C:NRPonbl\DCCA.ZBU07916 I.DOC-4M2/2O10 -26 H CH3 H3C O CH3 H H H F HO HO OH In yet a further embodiment, the compound of formula (V) is: 5 In still a further embodiment, the compound of formula (V) is: C:NRPorbl\DCC\AZB\27179 16 .DOC-4A1loi0 - 27 0 H 0 0 HO OH In yet another embodiment of the invention, the compound of formula (V) is: H3C H 0 0 HO HO OH 5 In some embodiments, the PKC activator is an indolactam or teleocidin compound or an analogue thereof having formula (VII): C:\NRPortbl\DCCAZBU7079 16 1.DOC-4A)2/20111 - 28 R 57 H H H N H
R
5 aa R5O R58b R55 R53 (VII) R54 wherein Z is -CH(R 5 9 )- or -N(R" 9 )-, where R 9 is selected from hydrogen or -CI-C 6 alkyl; 5 Y is absent and R 53 is hydrogen or Y together with R 53 are -NH-CH=Y'-,
-NH-CH
2
-Y
2 -, -O-CH=Y'- or -O-CH 2
-Y
2 - where Y' is -C- and Y 2 is -CH-;
R
5 4 is hydrogen, -Ci-C 2 0 alkyl, -C 2
-C
2 0 alkenyl, -C 2
-C
2 0 alkynyl, -C(O)C 1
-C
2 0 alkyl, -C(O)C 2
-C
20 alkenyl; -C(O)C 2
-C
20 alkynyl, -NHC(O)CI-C 20 alkyl, -NHC(O)C 2
-C
2 0 alkenyl or -NHC(O)C 2
-C
20 alkynyl; 10 R 55 is hydrogen, -CI-C 20 alkyl, -C 2
-C
20 alkenyl, -C 2
-C
2 0 alkynyl, or R 5 4 and R 5 ' taken together form a 5 or 6 membered carbocyclic ring optionally substituted with I to 4
-CI-C
6 alkyl or -C 2
-C
6 alkenyl groups;
R
56 is hydrogen, --- CI-C 20 alkyl, -C 2
-C
2 0 alkenyl, -C 2
-C
2 0 alkynyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl; -OC(O)C 2
-C
20 alkynyl, -NHC(O)Ci-C 2 0 alkyl, -NHC(O)C 2 15 C 20 alkenyl or -NHC(O)C 2
-C
20 alkynyl, or R 56 and R 59 taken together form a 5 membered saturated or unsaturated ring optionally substituted with 1 or 2 substituents selected from
-CI-C
6 alkyl or -C 2
-C
6 alkenyl;
R
57 is hydrogen or -CI-C 6 alkyl;
R
58 a is hydrogen or -CI-C 6 alkyl; 20 RS1b is -OH, -OCI-C 6 alkyl, -OC 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl or -OC(O)heteroaryl; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; C:\NRPortbW\CC\AZB\2707916_1. DO-C-4A2/20 10 -29 or a geometric isomer or stereoisomer thereof or a veterinary acceptable salt thereof. In some embodiments, the compound of formula (VII) is a compound of formula 5 (VIII):
R
57 H H H N H ZIY R 58a H OR58b R55 W R54 (VIII) wherein Z, R 57 , R 58 a and R 5 8 b are as defined in formula (VII); 10 W is -0- or -NH-;
R
5 4 is hydrogen, -C-C 20 alkyl, -C 2
-C
2 0 alkenyl, -C 2
-C
2 0 alkynyl, -C(0)CI-C 20 alkyl, -C(0)C 2
-C
20 alkenyl or -C(O)C 2
-C
20 alkynyl;
R
55 is hydrogen, -C 1
-C
20 alkyl, -C 2
-C
2 0 alkenyl, -C 2
-C
2 0 alkynyl, or R 54 and R 55 taken together form a 5 or 6 membered carbocyclic ring optionally substituted with I to 4 15 substituents selected from -Ci-C 20 alkyl or -C 2
-C
2 0 alkenyl groups; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; or a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. 20 In particular embodiments of the PKC activators of formula (VII) one or more of the following applies: C:WRPortbl\DCC\AZB\2707916-1 DOC-4A)21201m -30 Z is -CH 2 , -NH- or -N(CI-C 3 alkyl)-, especially -NH- or -N(Ci-C 3 alkyl)-, more especially -N(CH 3 )-;
R
5 3 is hydrogen and Y is absent or Y and R 5 3 taken together are -NH-CH=Y' or -O-CH=Yl where Y' is -C-; 5 R 54 is hydrogen or an -Ci-C 20 alkyl, -C 2
-C
20 alkenyl, -C 2
-C
2 0 alkynyl, -C(O)Ci-C 20 alkyl, -C(O)C 2
-C
2 0 alkenyl or -C(O)C 2
-C
20 alkynyl, particularly where the alkyl, alkenyl and alkynyl groups are unsubstituted; especially -Cj-Cio alkyl, -C 2 -Cio alkenyl, -C 2 -Cio alkynyl, -C(O)CI-Cio alkyl, -C(O)C 2 -Cio alkenyl or -C(O)C 2 -Cio alkynyl, more especially, n-hexyl, n-heptyl, n-octyl and n-octanoyl; 10 R 55 is hydrogen, -CI-C 20 alkyl, -C 2
-C
2 0 alkenyl, or-C 2
-C
20 alkynyl, especially hydrogen, -Cj-Cio alkyl, -C 2 -Cio alkenyl, or-C 2 -Cio alkynyl, more especially hydrogen; or R 54 and R 55 together form a 6 membered carbocyclic ring optionall substituted with I to 4 substituents selected from CI-C 6 alkyl and -CI-C 6 alkenyl;
R
56 is hydrogen, or together with R 59 forms a 5 membered unsaturated or saturated, 15 optionally substituted ring, especially hydrogen;
R
57 is -Ci-C 6 alkyl, especially -C 1
-C
3 alkyl, more especially isopropyl;
R
5 8a is hydrogen or -Ci-C 3 alkyl, especially hydrogen or methyl; Rssb is -OH, -OCI-C 6 alkyl, -C 2
-C
6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2
-C
6 alkenyl, -OC(O)aryl, especially -OH. 20 In one embodiment, the PKC activator of formula (VII) is 7-octyl-indolactam V: H H3C Y N N O H H O H N # H C8H17 C WRPortbl\DCC\AZB\2707916 I.DOC-4A2/21110 -31 In another embodiment, the PKC activator of formula (VII) is: H3C N HC N,,N OH HO H N C7H15 0 5 In yet another embodiment, the PKC activator of formula (VII) is: H H3C' N N N OH H V N H In a further embodiment, the PKC activator of formula (VII) is: C:\NRPorbl\DCC\AZB\2707916_-DOC-1)2/2010 - 32 H
H
3 C N N OH H 0 H 0
C
6
H
13 In another embodiment, the PKC activator of formula (VII) is: H H3C N N OH HO H 0 C6H13 5 In another embodiment, the PKC activator of formula (VII) is: N OH H O HN In yet another embodiment, the PKC activator of formula (VII) is: C\ NRPonblI\DCCAZB\2707916I.DOC42/2010 - 33 H N yN OH 0 Other PKC activators useful in the methods of the invention include bryostatins and their analogues as described by Ma, ibid and Wender et al. (US7,256,286 and US 5 6,624,189), the contents of which are incorporated herein by reference. Bryostatins are a class of marine natural products and have a typical structure as shown in formula (IX): 0 OAc 0 OH OH OH 0 0 MeO 2 C 0 co2Me 0 (IX) 10 These compounds are potent PKC activators, however their complex structure and low natural abundance have required suitable analogues to be prepared having the required PKC activating pharmacophores. Such compounds include compounds of formula (X) and formula (XI) as described and synthesised by Wender et al. (ibid): C:\NRPorbl\DCC\AZB\2 717916 1. DOC-4A12/20111 -34 L O z R90 R92 OH R91 (X) wherein 5 R 90 is H, -OH or -T-U-V-R 93 . T is -0-, -S-, -NH- or -N(CH 3 )-; U is absent or is selected from -C(O)-, -C(S)-, -S(0)- or -S(0)2-; V is absent or is selected from -0-, -S-, -NH- or -N(CH 3 )-, provided that V is absent when U is absent; 10 R 9 ' is =CR 94
R
9 s or R 9 ' is selected from R 9 6 or R9'
R
92 is hydrogen, -OH or R93 R93 in each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylaryl or -alkylheteroaryl; R94 and R 95 are independently hydrogen, -CO 2 R 93, -CONR 96
R
97 or R13 15 R 9 6 and R 97 are independently hydrogen, alkyl, alkenyl, alkynyl or
-(CH
2
)
1 -3CO 2
R
93 ; L is a straight or branched linear, cyclic or polycyclic moiety containing a continuous chain of from 6 to 14 chain atoms, which substantially maintains the relative distance between the Cl and C17 atoms and the directionality of the CIC2 and C16C17 20 bonds of naturally occurring bryostatin; and Z is -0- or -NH-; and veterinary acceptable salts thereof. In particular embodiments, the compounds of formula (X) are compounds of 25 formulae (XI-A), (XI-B), (XI-C) or (XI-D): C \NRPonbKDMCCAZBU2T77Y6- DOC-JA)2J20111 - 35 X 0 0R 9 0 R91 (XI-B) 5lo C:NRPortbI\DCC\AZB\2707916 1 DOC-4AJ2/2I1 -36 R 0 0 R9' (XI-C) 00 OR9 3H (C2)7 R90R92 OH R91 (XI-D) 5 wherein
R
90 , R 91 , R 92 , R 93 and Z are as defined in formula (X);
R
9 O is hydrogen or -OH;
R
99 is hydrogen, -OH or =0; Rico is selected from hydrogen, -OH, =0, R 93 , -(CH 2 )o-sOC(0)R 93 or 10 -(CH 2 )o.5CO 2 haloalkyl, provided that R 99 and R' 00 are not both =0;
R
0 1 is hydrogen or -OH or is absent; p is an integer of I to 3; and X is -CH 2 -, -0-, -S- or -NRi 0 2 - where R' 2 is -COH, -CO 2
R
93 or -SO 2
R
9 3
;
C:WRPonbl\DCCAZ8707916 I DOC-412/2010 -37 or a veterinary acceptable salt thereof. Other suitable PKC activators include aplysiatoxin analogues such as those of formula (XII): 0 ''0 OCH3 R71 R 70 5 OH OH (XII) wherein
R
70 is hydrogen or -OH; and
R
7 1 is hydrogen, fluorine, chlorine, bromine or iodine; 10 and tetrahydrofuran analogues of phorbol esters such as those of formula (XIII): R61 HO R62 (XIII) wherein
R
60 is selected from -OC(O)CI-C 20 alkyl, -OC(O)C 2
-C
20 alkenyl and -OC(O)C 2
-C
20 alkenyl; 15 R61 is selected from -Ci-C 6 alkylCOCi-C 6 alkyl, -CI-C 6 alkylCOC 2
-C
6 alkenyl, Ci
C
6 alkylCOC 2
-C
6 alkynyl, -CI-C 6 alkylCO 2 Ci-C 6 alkyl, -CI-C 6 alkyICO 2
C
2
-C
6 alkenyl or
-CI-C
6 alkylCO 2
C
2
-C
6 alkynyl; R62 is selected from -CI-C 6 alkylCOCI-C 6 alkyl, -CI-C 6 alkylCOC 2
-C
6 alkenyl, CI
C
6 alkylCOC 2
-C
6 alkynyl, -CI-C 6 alkylCO 2
CI-C
6 alkyl, -CI-C 6 alkylCO 2
C
2
-C
6 alkenyl or 20 -CI-C 6 alkylCO 2
C
2
-C
6 alkynyl; and C:\NRPorbIlCC\AZB\2707916 1 DOC-4AI 2010 - 38 - is a double or single bond; wherein each alkyl, alkenyl and alkynyl is optionally substituted; or a geometric isomer or stereoisomer thereof or a veterinary acceptable salt thereof. 5 Examples of such tetrahydrofuran analogues of phorbol esters include:
C
1 3
H
27 C 13
H
2 7 0 0 0 0 HO OCH3 HO
H
3 CO 0
C
13
H
27 0
OCH
3 HO:> 0 Other suitable PKC activators include 5, 6 and 7 membered lactams such as 10 compounds of formula (XIV) developed by Kozikowski et al. (US 5,962,504):
R
8 i
R
80 ,,- 0 N H OH (XIV) wherein
R
80 and R 8 1 are each independently -CI-CI 5 alkyl, -C 2
-C,
5 alkenyl, -C 2 -Ci 5 alkynyl, 15 -C 3
-C
8 cycloalkyl, -CI-Clo alkylC 3
-C
8 cycloalkyl, -C 2 -Ci 0 alkenylC 3
-C
8 cycloalkyl, -C 2 -CIo C:\NRPonbi\DCCAZB\2707916 LDOC4212010 -39 alkynylC 3
-C
8 cycloalkyl, -OCI-C 15 alkyl, -C(O)Ci-Ci 5 alkyl, -OC(O)CI-Ci 5 alkyl, aryl, heteroaryl, -CI-C 6 alkylaryl, -CI-C 6 alkylheteroaryl, -C 2 -Ci 5 alkenylaryl, -C 2
-CI
5 alkenylheteroaryl, -C 2 -Ci 5 alkynylaryl, -CI-C 15 alkynylheteroaryl, -OCI-Ci 5 alkylaryl, -OCi-C, 5 alkylheteroaryl, -C(O)CI-C, 5 alkylaryl, -C(O)Ci-Ci 5 alkylaryl, -OC(O)CI-C 1 5 5 alkylaryl, -OC(O)Ci-Ci 5 alkylheteroaryl; wherein R 8 0 and R 8 1 is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, -OH, -CF 3 , -OCF 3 , -CI-C 15 alkyl, -C 2 -Ci 5 alkenyl, -C 2 -Ci 5 alkynyl, -C 3
-C
8 cycloalkyl, -Ci-Co alkylC 3
-C
8 cycloalkyl, -C 2 -Co alkenylC 3 -Cs cycloalkyl, -C 2 -CIO 10 alkynylC 3 -Cs cycloalkyl, -OCi-Ci 5 alkyl, -C(O)Ci-Ci 5 alkyl, -OC(O)CI-C, 5 alkyl, -C(O)OH, -C(O)OCI-C 6 alkyl, -OC(O)OH, -OC(O)OC 1
-C
6 alkyl, -C(O)NRR, -OC(O)NRRk and -NR"'R" and wherein any aryl or heteroaryl of R 80 or R 8 is optionally substituted on a non-aromatic carbon by a divalent C 2
-C
7 alkylene chain to form a C 3
-C
8 spirocycloalkyl; 15 each Ri and Rk is independently hydrogen or -C-Cio alkyl, or Ri and Rk taken together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring; and each R m and R" is independently hydrogen, -Ci-Clo alkyl, -C(O)Ci-Co alkyl, phenyl, benzyl or phenylethyl, or R m and R" taken together with the nitrogen to which they 20 are attached are a 5-6 membered heterocyclic ring; or a veterinary acceptable salt thereof. In particular embodiments of the compounds of formula (XIV), R" 0 is -C,-C alkyl, -C 2
-C,
5 alkenyl, -C 2 -Ci 5 alkynyl, -C 3
-C
8 cycloalkyl, -Ci-Clo alkylC3-Cs cycloalkyl, 25 -C 2 -Cjo alkenylC 3 -Cs cycloalkyl, -C 2 -Cjo alkynylC 3 -Cs cycloalkyl, -OCI-C 15 alkyl, -C(O)CI-Cs alkyl, -OC(O)CI-Ci 5 alkyl, wherein R 80 is optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, nitro, cyano, -OH, -CF 3 , -OCF 3 , -C(O)NRR, -C(O)OH, -C(O)OCi-C 6 alkyl, -OC(O)NRRk and -NR m R" where R, Rk, R m and R" are as defined above, or R 80 is aryl, heteroaryl, -C 1
-C
6 alkylaryl, 30 Ci-C 6 alkylheteroaryl, -C 2
-C]
5 alkenylaryl, -C 2
-CI
5 alkenylheteroaryl, -C 2 -Ci 5 alkynylaryl, -Ci-Cs alkynylheteroaryl, wherein any aryl or heteroaryl of R 80 is optionally substituted C .WRPornb\DCCAZB\2707916_ LDOC-42A/2010 - 40 with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, -OH, -CF 3 , -OCF 3 , -CI-Ci 5 alkyl, -C 2 -CIs alkenyl, -C 2 C 15 alkynyl, -C 3
-C
8 cycloalkyl, -CI-Cio alkyIC 3 -Cs cycloalkyl, -C 2 -Cio alkenylC 3 -Cs cycloalkyl, -C 2 -Clo alkynylC 3 -Cs cycloalkyl, -OCI-CI 5 alkyl, -C(O)CI-Cs alkyl, 5 OC(O)CI-CIS alkyl, -C(O)OH, -C(O)OCI-C 6 alkyl, -OC(O)OH, -OC(O)OCi-C 6 alkyl, C(O)NRRk, -OC(O)NRjRk and -NR'R and wherein any aryl or heteroaryl of R 80 is optionally substituted on a non-aromatic carbon by a divalent C 2
-C
7 alkylene chain to form a C 3
-C
8 spirocycloalkyl; and R 8 1 is -C-Ci 5 alkyl, -C 2 -Ci 5 alkenyl, -C 2
-CI
5 alkynyl, -OCI
C
1 5 alkyl, -C(O)CI-Ci 5 alkyl, -OC(O)Ci-Ci 5 alkyl, wherein R is optionally substituted 10 with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, -OH, -CF 3 , -OCF 3 , -OCi-Cis alkyl, -C(O)Ci-Ci 5 alkyl, OC(O)CI-C 15 alkyl, -C(O)OH, --C(O)OCI-C 6 alkyl, -C(O)NRRk or -NR'R" wherein Ri, R , R' and R" are as defined above. 15 Other lactam PKC activators include compounds of formula (XV), (XVI) and (XVII): 0 NH R2N
R
82 OH (XV) wherein R 82 is -Ci-C 20 alkyl, especially -CIO-Ci 5 alkyl, more especially -Ci-Ci 4 20 alkyl; C:\NRPonbI\DCCAZB\270796_ I.DOC-4A12/12010 -41 H O C 3 HN R85 83 (XVI) wherein R 8 is hydrogen or -CI-C 1 o alkyl; 5 R 84 and R 85 are each independently -CI-C 1 o alkyl, especially -CI-C 6 alkyl; R88 R O N NH OH R86 (XVII) wherein
R
86 is hydrogen or -CI-C 15 alkyl; 10 R 87 is hydrogen or -CI-C 6 alkyl, especially -CI-C 3 alkyl; and
R
88 is -CI-C 6 alkyl, especially -CI-C 3 alkyl, more especially isopropyl. Other PKC activators that may be used in the present invention include dicoumarin compounds such as daphnoretin: 15 C:NRPonbl\DCC\AZB\2707916 L.DOC-4412/2010 -42 H3CO O O HO O O or compounds such as mezerein: 50 H H oH HO i HO 5 CH20H The term "alkyl" refers to optionally substituted linear and branched hydrocarbon groups having I to 20 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, -CI-C 6 alkyl which includes alkyl groups 10 having 1, 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl. 15 The term "alkenyl" refers to optionally substituted, unsaturated linear or branched hydrocarbons, having 2 to 20 carbon atoms and having at least one double bond. Where appropriate, the alkenyl group may have a specified number of carbon atoms, for example,
C
2
-C
6 alkenyl which includes alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear 20 or branched arrangements. Non-limiting examples of alkenyl groups include, ethenyl, C:\NRPrtbl\DCC\AZB27079161.DOC-4A)2/20i1 - 43 propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, hept-1,3-diene, hex 1,3-diene, non-1,3,5-triene and the like. The term "alkynyl" refers to optionally substituted unsaturated linear or branched 5 hydrocarbons, having 2 to 20 carbon atoms, having at least one triple bond. Where appropriate, the alkynyl group may have a specified number of carbon atoms, for example,
C
2
-C
6 alkynyl which includes alkynyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl and hexynyl. 10 The terms "cycloalkyl" and "carbocyclic" refer to optionally substituted saturated or unsaturated mono-cyclic, bicyclic or tricyclic hydrocarbon groups. Where appropriate, the cycloalkyl group may have a specified number of carbon atoms, for example, C 3
-C
6 cycloalkyl is a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Non-limiting examples 15 may include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cyclooctanyl and the like. "Aryl" means a C 6
-C
14 membered monocyclic, bicyclic or tricyclic carbocyclic ring system having up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples 20 of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. The aryl may comprise 1-3 benzene rings. If two or more aromatic or nonaromatic rings are present, then the rings may be fused together, so that adjacent rings share a common bond. 25 "Heterocyclic" or "heterocyclyl" refers to a non-aromatic ring having 3 to 8 atoms in the ring and of those atoms 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring selected from 3- to 7-membered alicyclic ring containing 0 to 4 heteroatoms, wherein said heteroatoms are independently selected from 0, N and S. Heterocyclic includes partially and fully saturated heterocyclic groups. Heterocyclic systems may be 30 attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated, which includes all forms of carbohydrate C:\NRPorfbIDCC\AZB\2707916_1.DOC-4A2/20 10 - 44 moieties. Non-limiting examples of heterocyclic include pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl, thiapinyl, imidazolinyl, thiomorpholinyl, and the like. 5 The term "heteroaryl" as used herein means a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1-4 heteroatoms, selected from sulfur, oxygen and nitrogen. Heteroaryl includes, but is not limited to, oxazolyl, thiazolyl, thienyl, furyl, 1-isobenzofuranyl, 10 pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl, indolizinyl, isoindolyl, indolyl, purinyl, phthalazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indoleninyl, 15 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[3,2-blpyridinyl, pyrido[4,3-b]pyridinyl, acridinyl, carbazolyl, quinaoxalinyl, pyrazolyl, benzotriazolyl, thiophenyl, isoquinolinyl, pyridinyl, tetrahydroquinolinyl, benzazepinyl, benzodioxanyl, benzoxepinyl, benzodiazepinyl, 20 benzothiazepinyl and benzothiepinyl and the like. The term "halo" as used herein refers to fluoro, chloro, bromo and iodo. Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group are 25 optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -CF 3 , -CO 2 R, -COR, -OR, -SR, -N(R) 2 , -NO 2 , -NROR, -ON(R) 2 , -SOR,
-SO
2 R, -SO 3 R, -SON(R) 2 , -SON(R) 2 , -SO 3
N(R)
2 , -P(R) 3 , -P(=O)(R) 3 , -OSi(R) 3 , -OB(R) 2 wherein R is selected from hydrogen, -CI-C 20 alkyl, -C 2
-C
20 alkenyl, -C 2
-C
20 alkynyl,
-C
3
-C
8 cycloalkyl, -C 6
-CI
4 aryl, -C 5
-C
14 heterocyclyl, -C 5
-C
1 4 heteroaryl, -alkylaryl, 30 alkylheteroaryl, -alkylheterocyclyl, -CI-Cio haloalkyl, -CI-Cla dihaloalkyl and -CI-Clo trihaloalkyl.
C:\NRPortbl\DCC\AZB\2707916 DOC-M4A)2/2010 -45 The term "veterinary acceptable salt" as used herein refer to salts which are toxicologically safe for local or topical administration to an animal. The veterinary acceptable salts may be selected from the group including, but not limited to, alkali and 5 alkali earth, ammonium, aluminium, iron, amine, glucosamine, chloride, sulphate, sulphonate, bisulphate, nitrate, citrate, tartrate, bitarate, phosphate, carbonate, bicarbonate, malate, maleate, napsylate, fumarate, succinate, acetate, benzoate, terephthalate, pamoate, pectinate and s-methyl methionine salts, piperazine and the like. 10 It will also be recognised that compounds of formula (I) possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres e.g., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such 15 isomers may be obtained by isolation from natural sources, by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution. The compounds may exist as geometrical isomers. The compounds may be in substantially pure cis (Z) or trans (E) forms or mixtures thereof. 20 The compounds of formula (I) may be obtained by isolation from a plant or plant part, or by derivatisation of the isolated compound, or by derivatisation of a related compound. One or more compounds of formula (I) to formula (IV), may be extracted from a 25 plant or plant part. In some embodiments, the compound is a tigliaenone compound and the plant is of the genus Fontainea or Hylandia, such as the species is Fontainea pancheri, Fontainea australis, Fontainea borealis, Fontainea fugax, Fontainea oraria, Fontainea picrosperma, 30 Fontainea rostrata, Fontainea subpapuana, Fontainea venosa or Hylandia dockrillii, especially Fontainea picrosperma, Fontainea venosa or Hylandia dockrillii.
C:WRPonbl\DCC\AZB\27417916 1. DOC-4A)2/20 10 - 46 The parts of the plant may include fruit, seed, bark, leaf, flower, roots and wood. In particular embodiments, the extract is obtained from the seed, bark and/or 5 flowers. For example, the biomass obtained from seeds, leaves, flowers and bark of the plant is subject to initial solvent extraction, for example with a polar solvent such as methanol. The initial extraction is then concentrated and diluted with water and subject to 10 extraction with a second solvent, for example, ethyl acetate. The solvent samples from the second extraction are pooled and subject to separation by preparative HPLC fractionation. The fractions are analysed by analytical HPLC and pooled according to the retention time of compounds found in the samples. The pooled fractions are weighed, bioassayed and analysed by analytical HPLC. Further fractionation using one or more preparative HPLC 15 is performed to isolate specific compounds. Each compound is bioassayed and its structure identified by UV, NMR and mass spectrometric techniques. Other PKC activating compounds of formula (I) may be obtained by derivatising compounds isolated from plants or parts of plants, especially from the genus Fontainea, 20 especially from the species Fontainea picrosperma, especially the seeds, bark and/or flowers of Fontainea picrosperma. In some embodiments, the compound of formula (I) is a phorbol compound and the compound is extracted from plants of the order Euphorbiales and family Euphorbiaceae. 25 The most common source of phorbol is from croton oil obtained from the seeds of Croton tiglium. Phorbol may be esterified by means known in the art, such as acylation, particularly at the C12 and/or C13 hydroxy groups. Some phorbol derivatives with PKC activating activity may be prepared by 30 synthetic methods. For example, some phorbol ester derivatives lacking an A-ring have been synthesised by Wender and co-workers (Wender P. A., et al, Org. Lett., 1999, 1009].
C:\NRPonbl\DCC\AZB\2707916I DOC-4A)2/2010 - 47 Ingenol compounds such as those of formula (V) may be isolated from plants of the Euphorbiaceae family. total synthesis of ingenol has also been completed [Winkler et al., J. Am. Chem. Soc., 2002, 124, 9726; Tanino et al., J. Am. Chem. Soc., 2003, 125, 1498]. 5 The teleocidin compounds may be isolated from microorganisms such as Streptomyces, particularly Streptomyces mediocidicus, by methods known in the art. Compounds such as indolactam V are able to be synthesised by methods known in the art [Kogan et al., Tetrahedron, 1990, 46, 6623]. Kozikowski and Ma have synthesised 10 benzofuran derivatives of inolactam V [Kozikowski et al., J. Am. Chem. Soc., 1995, 117, 6666; Kozikowski et al., Bioorg. Chem. Med. Lett., 1994, 5, 637; Kozikowski et al., Pure Appl. Chem., 1994, 66, 2087]. Other lactam compounds that have PKC activating activity have been synthsised. 15 For example, 5 membered lactams with PKC activating activity have been synthesised by Kozikowski et al. (US 5,962,504), 6 membered 2-piperazinones have been designed and prepared by Endo et al. [Bioorg. Med. Chem. Lett., 1997, 7, 2997] and 7 membered lactones have been prepared by Ma and co-workers [Ma and Tang, Tet. Lett., 1998, 39, 7369; Ma et al., J. Org. Chem., 1999, 64, 6366]. 20 Bryostatins are a class of marine natural products isolated from a species of bryozoan, Bugula neritina by known methods. Structurally simplified bryostatin analogues have been prepared by Wender and co-workers [US 7,256,286; US 6,624,1890. 25 Asplysiostatins are also compounds isolated from marine organisms. They were first isolated in the 1970s from the digestive gland of the sea hare Stylocheilus longicauda [Kato and Scheuer, J. Am. Chem. Soc., 1974, 96, 2245; Entzeroth et al., J. Org. Chem., 1985, 50, 1255]. Some simplified analogues with PKC activating activity have also been synthesised [Nakamura et al. Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 9672; Park et al. J. 30 Am. Chem. Soc., 1987, 109, 6205].
C.NRPonbI\DCC\AZB\2707916_ IDOC-402/20 10 -48 Daphnoretin is a dicoumarin compound isolated from the plant Wikstroemia indica C. A. Mey [Chen et al. J. Taiwan. Pharm. Assoc., 1981, 33, 28-29]. Mezerein is isolated from the plant Daphne mezereum and is commercially available. 5 Derivatives of the natural compounds can be obtained by techniques known in the art. For example, hydroxy groups may be oxidised, to ketones, aldehydes or carboxylic acids by exposure to oxidising agents such as chromic acid, Jones' reagent, KMnO 4 , peracids such as mCPBA (metachloroperbenzoic acid) or dioxiranes such as dimethyldioxirane (DMDO) and methyl(trifluoromethyl)dioxirane (TFDO). Oxidising 10 agents may be chosen such that other functional groups in the molecule are or are not also oxidised. For example, a primary alcohol may be selectively oxidised to an aldehyde or carboxylic acid in the presence of secondary alcohols using reagents such as RuCl 2 (PPh 3
)
3 benzene. Secondary alcohols may be selectively oxidised to ketones in the presence of a primary alcohol using C1 2 -pyridine or NaBrO 3 -ceric-ammonium nitrate. Alcohols may be 15 oxidised in the presence of double and triple bonds and without epimerisation at adjacent stereocentres using Jones' reagent with our without Celite (or ammonium chloride). Alternatively, reagents chosen may be less selective resulting in oxidation at more than one functional group. 20 Hydroxy groups may also be derivatised by etherification or acylation. For example, ethers may be prepared by formation of an alkoxide ion in the presence of base and reacting the alkoxide with an appropriate alkylhalide, alkenylhalide, alkynylhalide or arylhalide. Similarly acylation may be achieved by formation of an alkoxide ion and reaction with an appropriate carboxylic acid or activated carboxylic acid (such as an 25 anhydride). Hydroxy groups may be derivatised to provide carbamates or thiocarbamates by reaction with isocyanates or isothiocyanates. 30 Carboxylic acids can be converted to thioesters or thioamides using Lawesson's reagent.
C:\NRPorbl\DCC\AZD2707916 DOC-4A)2/2010 - 49 Acyl groups may be hydrolysed to provide alcohols by acid or base hydrolysis as known in the art and those alcohols can be derivatised further as above. 5 Ketones may be reduced to secondary alcohols by reducing agents such as lithium aluminium hydride and other metal hydrides without reducing double bonds, including a-unsaturated ketones. Double bonds and triple bonds may be reduced to single bonds using catalytic 10 reduction, for example, H 2 /Pd. Double bonds may also be oxidised to epoxides using oxidising agents such as per acids, for example mCPBA or dioxiranes, such as DMDO and TFDO. Double bonds may also be subject to addition reactions to introduce substituents such as halo groups, hydroxy or alkoxy groups and amines. 15 A person skilled in the art would be able to determine suitable conditions for obtaining derivatives of isolated compounds, for example, by reference to texts relating to synthetic methodology, examples of which are Smith M.B. and March J., March's Advanced Organic Chemistry, Fifth Edition, John Wiley & Sons Inc., 2001 and Larock R.C., Comprehensive Organic Transformations, VCH Publishers Ltd., 1989. Furthermore, 20 selective manipulations of functional groups may require protection of other functional groups. Suitable protecting groups to prevent unwanted side reactions are provided in Green and Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons Inc., 3 rd Edition, 1999. 25 A full description of the isolation and extraction of the tigliaenone compounds of formula (I) together with the chemical characterization of some compounds of formula (I) is provided in WO 2007/0700985, the entire contents of which are incorporated by reference. 30 As used herein, "fly strike" refers to flies laying their eggs in the wool of a subject resulting in a maggot infestation in the subject. The flies may be any of the flies from the C:NFRorbl\DCC\AZB2707916_1.DOC-4)2/210 - 50 diptera family that cause fly strike, including those from the families Oestroidea (botflies), Calliphoridae (blowflies), Sarcophagidae (fleshflies), Anisopodidae, Piophilidae, Stratiomyidae and Syriphidae. In particular embodiments, the flies are from the family Calliphoridae including subfamilies Auchermeromyiinae, Calliphorinae, Luciliinae, 5 Melanomyinae and Polleniinae, including blue bottles, clusterfles and green bottles especially from the subfamily the Luciliinae. In a particular embodiment, the blow fly is Lucilia cuprina. The subject is any animal that is at risk of fly strike around the breech. In 10 particular embodiments the subject is a wool producing animal such as a sheep, llama or alpaca. The sheep may be a lamb or an adult sheep especially a lamb. In some embodiments, the sheep has a high density wool coat and/or skin folds or wrinkling in its breech area. The sheep may be a merino sheep including strains such as Peppin Merino, Saxon Merino, South Australian Merino and Spanish Merino, or the sheep may be a 15 Corriedale, a Polwarth, a Perendale, a Turidale, a Drysdale, a Border Leicester, a Romney, a Poll Dorset, a Southdown, a Dorset Horn, a Lincoln, a Cheviot, a Shropshire, a Suffolk, a South Suffolk, a Ryland, a Hampshire Down, a Wiltshire Horn or a cross breed of these sheep. In particular embodiments, the sheep is a merino sheep or a sheep cross bred to have merino characteristics such as a high density wool coat. 20 In some embodiments, the PKC activator causes inflammation and damage to the skin around the breech of the subject and upon healing results in tightening of the skin area and a reduction in skin wrinkling and a reduction in a density of wool follicles. 25 In some embodiments, the PKC activator further inhibits or inactivates keratinocytes resulting in a reduction in or total lack of active wool follicles in the treated breech area. In the methods of the invention, the PKC activator is administered locally to the 30 breech area. Administration may be any kind of administration that provides a localised effect. In some embodiments, the PKC activator is administered by topical application or C.NRPonbr\DCC\AZB707916_1DOC-4A2/2110 -51 intradermal application for example, by subcutaneous injection. Topical application may be achieved using a cream or gel or a patch and the application may occur by wiping the breach area with the PKC activator formulation with a cloth, a roller or brush. 5 Although it may be possible to apply the PKC activator in neat form in a localised manner, it is convenient to present the PKC activator in a veterinary composition containing veterinary acceptable carriers and excipients. Suitable carriers and excipients are those used for compositions for localised administration. 10 Suitable formulations for localised administration include solutions, suspensions, gels, dispersions, aerosols, creams and ointments. Suitably, the veterinary composition comprises a veterinary acceptable excipient or an acceptable excipient. By "veterinary acceptable excipient" is meant a solid or liquid 15 filler, diluent or encapsulating substance that may be safely used. Depending upon the particular means of administration, a variety of carriers, well known in the art may be used. These carriers or excipients may be selected from a group including sugars, starches, cellulose and its derivates, malt, gelatine, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and 20 pyrogen-free water. The compositions of the invention may be presented in multiple dose formulations or in discrete units. The composition contains a predetermined amount of PKC activator, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non 25 aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion or as a solution or suspension in a cream or gel. Such compositions may be prepared by any of the method of veterinary pharmacy but all methods include the step of bringing into association one or more pharmaceutically active compounds of the invention with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by 30 uniformly and intimately admixing the PKC activators with liquid carriers or finely divided solid carriers or both.
C :W bPob\DCC\AZB\2707916 I.DC-4/22U10 -52 Liquid form preparations for localised administration include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, subcutaneous injection liquid preparations can be formulated as solutions in 5 aqueous polyethylene glycol solution. The PKC activators may thus be formulated for subcutaneous or intradermal administration (e.g. by injection, for example bolus injection) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose 10 containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, 15 pyrogen-free water, before use. For topical administration to the epidermis the PKC activators may be formulated as ointments, creams, gels or lotions. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or 20 gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Gels may also be formed by mixing a solution of the active ingredient with a 25 gelling agent such as natural gums, starches, pectins, agar-agar and gelatins including alginates, agar, carrgeenan, locust bean gum, pectin and gelatin. In some embodiments, the gel is an isopropanol-based gel. The PKC inhibitor may also be administered as an atomised or aerosol spray. In 30 such cases, a liquid formulation may be pumped through a spray nozzle or a liquid composition may be provided in a pressurised pack with a suitable propellent such as a C:\NRPonb\DCC\AZB\2707916.1 DOC-4A2/201( -53 chlorofluorocarbon (CFC). Suitable CFC's include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. The dosage of the active compound may be controlled by use of a metered valve. 5 The PKC activators may be applied topically to the breech area of the subject. This may be achieved by any means of topical application, for example, by rubbing a cream, lotion or ointment or gel onto the breech area, by spraying a liquid formulation onto the breech area, by painting or rolling a liquid formulation onto the breech area or by injecting an injectable formulation such as a solution, dispersion or emulsion under the skin of the 10 breech area by intradermal or subcutaneous injection. In some embodiments, a single injection may be sufficient. In other embodiments, multiple injections may be used to cause a sufficient area of cell damage. In some embodiments, the breech area of the subject is shaved or shorn before 15 topical application to expose the skin of the breech area. The PKC activator is applied in a pro-inflammatory amount effective to cause an inflammatory response on the skin which preferably subsequently forms a scab (eschar) which heals. An effective amount may be determined by a veterinarian or a farmer to 20 obtain the required amount of scar tissue and the required reduction in wool density. Suitable amounts will fall within a broad range depending on the size of the breech area to be treated, and the age of the animal being treated, and the mode of administration. Suitable pro-inflammatory amounts may also depend on the type of compound used. For example, some compounds have greater PKC activating activity than others. The greater 25 the PKC activating activity, the lower the pro-inflammatory amount will be. Effective pro inflammatory amounts may be in the range of 20 pg/cm 2 to 20 mg/cm 2 . Administration by intradermal injection may allow lower dosages to be used, for example 20 pg/cm2 to 1 mg/cm 2, especially 20 pg/cm 2 to 600 pg/cm 2, 25 pg/cm2 to 500 pg/cm 2 , 30 pg/cm 2 to 400 pg/cm 2 , especially about 40 pg to about 600 pg/cm 2. Topical administration in a cream, 30 ointment, lotion, gel or spray may require higher dosages, for example 250 pg/cm 2 to 20 mg/cm 2. The upper end of this range may be required if only mild inflammation is C :WRPonb\DCC\&ZB2707916-IDOC.M220O - 54 observed upon application of lower amounts In some embodiments, the breech area may be washed before application occurs. For example, the breech area may be washed with soap or detergent. Washing the breech 5 area may be useful if the wool in the surrounding area has appreciable amounts of lanolin. In a further aspect of the invention there is provided a method of causing an inflammatory response in the skin of a subject comprising locally administering a pro inflammatory amount of a PKC activator to the skin of the subject. 10 In another aspect of the invention there is provided a use of a PKC activator in the manufacture of a veterinary medicament for reducing or preventing fly strike in a subject, for decreasing skin wrinkling in the breech area of a subject or for reducing wool follicle density in the breech area of a subject, wherein the veterinary medicament is formulated 15 for localised administration. In particular embodiments, the PKC inhibitor is 12-tigloyl-13-(2-methylbutanoyl) 6,7-epoxy-4,5,9,12,13,20-hexahydroxy- I -tigliaen-3 -one (EBC-46), 12-0 tetradecanoylphorbol- 13-acetate, 3-ingenol angelate, 3-ingenol benzoate, 3,20-ingenol 20 dibenzoate, phorbol-12,13-didecanoate or 7-octyl-indolactam V. Brief description of the Figures Figure 1 is a photographic representation of the back of a mouse 12 days after 25 treatment with ethanol carrier (right hand mouse) or with EBC-46 (left hand mouse). Figure 2 is a photographic representation of the back of a mouse treated with EBC 46, 33 days after application. Good wound healing was observed and skin tightening of the skin around the wound was observed. 30 Figure 3 is a photographic representation showing the effect of six concentrations C:NRkPorbI\DCC\AZB\27079i6_I.DOC-42/20 10 - 55 of topically applied EBC-46 on the skin of a sheep 12 days after treatment. Figure 4 is a photographic representation showing the effect of three higher concentrations of topically applied EBC-46 on the skin of a sheep. Crusting of the skin 5 surface was observed in all three samples. Figure 5 provides photographic representations comparing skin histology from a single sheep. Upper images (a) are biopsies from the control or untreated areas of the sheep. Lower images (b) are biopsies from areas treated with EBC-46. The biopsies from 10 the areas treated with EBC-46 showed subdermal disruption and lack of normal wool follicle development. The left hand images are at lower magnification than the right hand images and both images are of the same area. Figure 6 provides photographic representations showing the effect of 100 Ig of 15 TPA on the back of a mouse at day three after administration (Figure 6a) and at 27 days after administration (Figure 6b). Figure 7 provides photographic representations showing the effect of 50 Ig of Ingenol-3-angelate on the back of a mouse at day three after administration (Figure 7a) and 20 at 27 days after administration (Figure 7b). Figure 8 provides photographic representations showing the effect of 50 ptg of (-) 7-octyl-indolactam V on the back of a mouse at day three after administration (Figure 8a) and at 27 days after administration (Figure 8b). 25 The invention will now be described by reference to the following non-limiting examples.
C:NRPonblDCCAZB\2707916_I.DOC-4A)2/2O10 - 56 EXAMPLES Example 1: Effect of topical application of EBC-46 on normal skin of mice. 5 To assess the effect of EBC-46 on healthy skin of mice, 40pL of 5 mg/mL EBC-46 in ethanol was applied to an area of skin on the shaved back of a 7 month old C57BL/6 mouse. The control treatment involved application of 40 pL of ethanol to an equivalent area of skin on the back of a second mouse. 10 Within 24 hours of application, EBC-46 had caused a mild inflammatory response and reddening on the area of treated skin with no apparent discomfort to the animal. By seven days, a scab (eschar) had formed over the treated area and this was followed by rapid and uneventful healing with no complications (see Figures 1 & 2). Localised skin tightening was evident in the treated area over the course of the healing process. 15 Example 2: Effect of topical application of EBC-46 on skin of mature sheep. An initial dose escalation study examined the effect of topical application of 6 concentrations of EBC-46 (in isopropanol gel) onto the surface of skin of mature sheep 20 that had been clipped to remove the wool and expose the application site. Aim To test the effect of EBC-46 as a chemical alternative to mulesing, a pilot dose escalation study in sheep was performed to address four major questions: 25 e Does EBC-46 produce cell death and a controlled localised inflammatory response in healthy skin of sheep similar to that observed in mice? * What level of trauma (if any) does this cause the treated animals? * Does EBC-46 block hair follicle activity and regrowth in sheep? * Does skin regrowth after treatment have other features (speed of healing, skin 30 tightness) consistent with efficacy as a chemical mulesing agent? C:\NRPortbl\DCC\AZB\2707916_L DOC-42/20 10 -57 The protocol for the pilot experiment with six sheep was as follows: e Early in the day, each sheep was shaved at one location on the flank and one on the breech. Each shaved area was approximately 10cm x 5cm (or equivalent). e 200ptL of each of the pre-formulated gels #1 to #6 (supplied by EcoBiotics) was 5 applied individually over an area of about 3mm x 3mm in each site. Higher dosages #7 and #8 were prepared in the event that only mild inflammation was observed. e The application sites were photographed at 6 and 24 hrs after application and on subsequent days as significant changes in appearance occurred. 10 9 The sheep were observed for as long as necessary to determine the extent of the wool regrowth. " After several weeks a skin biopsy was taken to compare hair follicle densities. Doses for use in this study are: 15 Gel Amount of EBC-46 Concentration of EBC-46 in gel Amount EBC-46 per cm2 of skin (ig/200pL) (mg/mL) (pg/cm 2 #1: 0, Vehicle only 0 0 20 #2: 375 1.85 375 #3: 750 3.75 750 #4: 1500 7.5 1500 #5: 3000 15 3000 #6: 6000 30 6000 25 #7: 12000 60 12000 #8 18000 90 18000 There was a clear effect of increasing concentration of EBC-46 on skin of the treated sheep. Even at the highest concentration there was no severe reaction to EBC-46, but a 30 crusty scab developed which was increasingly obvious in the three highest treatment concentrations (numbers 4 to 6 in Figure 3). Because surface lanolin and a thick epidermal layer may have been preventing effective intradermal penetration of EBC-46, two more concentrated treatments of EBC-46 (#7 and 35 #8) were applied topically and compared with the highest previous treatment. In all three C:\NRPornbl\DCC\AZB\2707916_LDOC-4A)22010 - 58 treatments there was consistent crusting on the skin surface (Figure 4). Histological assessment of biopsies taken from sheep treated with the higher concentrations of EBC-46 and compared with untreated controls revealed: 5 e marked diffuse crusting and hyperplasia in the epidermis; e mild to marked dermal fibrosis in the subdermis; e mild to marked disruption of the hair follicles; and, e cystic dilation and other changes in the sweat glands. Figure 5 illustrates these effects in biopsies taken from a single sheep. 10 Results from the topical studies with mature sheep show that EBC-46 has strong potential to produce effects that are desirable in a chemical that could be used as an alternative to mulesing. A limitation in these studies was the apparent low penetration of the topically applied drug into the subdermal layers of skin (which consequently required relatively high 15 concentrations to achieve desirable effects). Intradermal delivery is likely to be much more effective and produce the desired effects at lower concentrations of the chemical. Example 3: Effect of intradermal application of EBC-46 on skin of mature sheep. 20 A second pilot study was undertaken to observe the effect of intradermal injection of EBC 46 at two concentrations (40 and 120 tg EBC-46 /cm 2 ) on wound development and healing in two mature sheep. EBC-46 Stock Solutions 25 #1 = PEG 400 (carrier) only #6 = 30 pg/pL (30mg/mL) EBC-46 in PEG 400 Preparation of Treatment Solutions Prepare: 30 * 0.4 pg/pL solution of EBC-46 by diluting Stock #6 seventy-five times with Stock #1.
C:WRPortbl\DCC\AZB\2717916_1 .OC-4A1/2010 - 59 1.2 pgL solution of EBC-46 by diluting Stock #6 twenty-five times with Stock #1. Treatments 5 1. Control: Carrier (Stock #1) only 2. EBC-46 dose 1: 40 pg EBC-46 per injection site (cm 2 ) = 100 pL of 0.4 pg/pL EBC-46 3. EBC-46 dose 2: 120 pg EBC-46 per injection site (cm 2 )= 100 pL of 1.2 pg/pL EBC-46 10 Design * 2 sheep * 2 to 3 treatment areas/ sheep * 3 treatments applied in each treatment area 15 Treatment Application e Each treatment was applied over separate 5 x 5 cm area in each treatment area * Treatments were delivered as multiple injections each of 100 pL of drug (or PEG control), with individual injection sites evenly spaced on approx. 1 cm 2 grid 20 e Injections were delivered in a tuberculin syringe with 29 gauge needle Observations * Occurrence & severity of inflammation at 24 hours post treatment * Occurrence & nature of scabbing at 2 to 5 days post treatment 25 e Progress of wound healing e Any wound healing complications e.g. impaired healing (such as infection, dehiscence, necrosis, haematoma), seroma formation, etc For scoring acute local reactions, the scale developed by Theon et al 1993 (JAVMA 202: 30 261-267) might be useful: 0 = no change from condition before treatment C.\NRPonbl\DCC\AZB\2707916 1 DOC-4t2/20 10 - 60 1 = tenderness, bright erythema, slight oedema 2 = moderate oedema lasting < 3 days, focal ulceration /crusting 3 = moderate oedema lasting > 3 days, patchy ulceration/ crusting over <50% of the treatment field 5 4 = pitting oedema, ulceration/crusting over > 50% of the treatment field, or necrosis. Results from initial injections showed that only the higher concentration produced oedema, crusting and cardboard-like scab on the treated area. There was no apparent discomfort, pain or tenderness associated with these treatments. Subsequently, two higher rates (360 10 and 600 pg EBC-46 /cm 2 ) were used for injection of new areas. In both cases there was more erythematous reaction, localised swelling and full skin thickness necrosis consistent with the higher doses delivered, but nothing demonstrably painful to the treated animals. In some cases there was also a well developed reaction in the subdermal layers laterally beyond the area of injection. Areas treated with these higher doses, and their surrounds, 15 resolved within two weeks to have tightly adhering scabs. Any systemic effect in the sheep seems to be minimal and treatment and resolution does not appear to be painful or cause discomfort. Conclusions 20 e EBC-46 has been demonstrated to have the desired effects (wound formation, healing process, lack of pain or any apparent systemic effects) and shows the potential of it and other PKC activators as a chemical alternatives to mulesing " Results in adult sheep are likely to significantly over-estimate the amount of drug required to produce the desired effect compared to the thinner skin on the breech of 25 lambs * Optimising the delivery using needleless or similar injection technologies is likely to further significantly reduce the amount of drug required C \NRPonbr\DCC\AZBU707916I..DOC-4A)2/2010 -61 Example 4: Preparation of Gel formulation containing EBC-46 Method Manufacture of the Isopropanol Gel 5 Ingredients: Final Concentrations A. Glycerin 5% Cyclomethicone 0.5% B. Isopropyl alcohol 25% C. Carbomer 0.3% 10 D. Propyl alcohol 25% E. Water 43.7% F. Ethanolamine to pH 6.5 Procedure: 15 Dispense ingredients C in E and dissolve at 40 'C, then add ingredient D. Dissolve ingredient A in ingredient B. Mix ingredients A and C solution, add ingredient E up to 100%, adjust pH with ingredient F. Check pH with pH meter. The gel is stored in a sterile container at room temperature and can be stored at room 20 temperature for a maximum of 2 years. Discard at anytime if gel becomes liquid. Preparation of Compound in Isopropanol Gel 1. Aliquot the required mass of EBC46 for the procedure into a 1.5 mL screw cap microcentrifuge tube. 25 2. Resuspend compound in 100% acetone by vortexing and brief centrifugation, so that the final concentration of acetone in the gel will be 3 % (v/v) (e.g. For a 1 pg/pL final solution, resuspend 500 4g of compound in 15 pL of 100% acetone). 3. Add required volume of isopropanol gel and mix well using a sterile spatula (e.g. For a 1 pg/pL final solution of 500 ptg resuspended in 15 pL of 100% acetone, add 30 485 pL of isopropanol gel). If product is no longer a gel discard.
C \NRPonb\DCCAZB2707916_I.DOC-4AI2/2OI - 62 Example 5: Action of protein kinase C activators on the normal skin of mice Aims To compare the ability of protein kinase C activators of diverse structure to: * cause local inflammation on the skin of mice, 5 * followed by long term shrinkage of the skin in a manner potentially applicable to the mulesing of sheep. Background Based on the data obtained for EBC-46 showing its potential application for chemical 10 mulesing of sheep, other protein kinase C-activating compounds were examined on normal mouse skin. Materials and Methods Three known PKC activators were used. The PKC activators and stock solutions were 15 TPA (10 mg/mL in ethanol), 3-ingenol angelate (5 mg/mL in ethanol) and 7-octyl indolactam V (5 mg/mL in ethanol). The compounds were applied on Day 0 to the shaved hindquarters of 4-month-old C57BL/6 male mice by slowly running 10 uL of the above solutions onto each hindquarter. 20 Mice were photographed at days 1, 3, 7, 14, and 27. Results The three compounds, TPA, 3-ingenol angelate and 7-octylindolactam V, caused visible inflammation within 3 days, followed by scabbing at 7 days (Table 1). By 27 days healing 25 was complete, with scar formation and contraction of adjacent skin. The Day 1 and Day 27 photographs are shown in Figures 6-8.
C:\4RPortb\DCC\AZBU707916_I DOC-4A)2/2)10 -63 Table 1. Action of PKC activators on normal mouse skin PKC Dose Day of photograph activator Per 3 7 14 27 site (ug) TPA 100 DSCN5090* DSCN5105 DSCN5114 DSCN5124 Inflammation Right hand Right hand Sites healed, across the mouse mouse with 2 scars on application Scabs on Healing nearly each side sites application complete Figure 6b Figure 6a sites showing contraction of skin Ingenol 3- 50 DSCN5087 DSCN5102 DSCN5113 DSCN5120 angelate Left hand Left hand Left hand Sites healed, mouse mouse mouse with 2 scars Inflammation Scab formed Healing nearly near base of across the across the complete, skin the tail application application being Figure 7b sites sites contracted Figure 7a (-)-7-octyl- 50 DSCN5087 DSCN5105 DSCN5114 DSCN5122 indolactam V Right hand Left hand Left hand Sites healed, mouse mouse mouse with 2 scars on Inflammation Scabs on Healing nearly each side across the application complete Figure 8b application sites showing sites contraction of Figure 8a skin * photograph number C:\NRPo,1bi\DCC\AZB12707916 I.DOC4Am2/210 -64 Conclusion Three diverse structures with strong PKC activating ability, a phorbol ester (TPA), an ingenol ester and an indolactam, all gave the same desired response on mouse skin as 5 EBC-46: inflammation followed by healing and apparent skin contraction at the site of application. The outcome is therefore a general property of potent PKC activators.

Claims (19)

1. A method of reducing or preventing fly strike in a subject comprising locally administering a PKC activator to the breech area of a subject. 5
2. A method of decreasing skin wrinkling in the breech area of a subject comprising locally administering a PKC activator to the breech area of the subject.
3. A method of reducing wool follicle density in the breech area of a subject 10 comprising locally administering a PKC activator to the breech area of the subject.
4. A method of causing an inflammatory response in the skin of a subject comprising locally administering a pro-inflammatory amount of a PKC activator to the skin of the subject. 15
5. A method according to any one of claims I to 4 wherein the PKC activator is a compound of formula (I): R2 R3 H 1 R4 R R5 H R16 R6 H H R15 R17 i(k) Ra R 13 R1 20 R11 R10R wherein R' is selected from hydrogen, -Ci-Cio alkyl, -C2-Cio alkenyl and -C2-C10 alkynyl; C:\NRPorbl\DCC\AZB\2707916_1.DOC-4A)2/2010 - 66 R 2 is selected from hydrogen, -CI-Clo alkyl, -C 2 -C 1 o alkenyl and -C 2 -CIO alkynyl; R 3 is selected from -OH, -OCI-C 2 0 alkyl, -OC 2 -C 2 0 alkenyl, -OC 2 -C 20 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2 -C 2 0 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 20 5 alkyl, -OC(O)NHC 2 -C 20 alkenyl, -OC(O)NHC 2 -C 20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, -OC(S)NHC 2 -C 2 0 alkenyl, -OC(S)NHC 2 -C 2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R 2 and R 3 taken together form a carbonyl group (=0); 10 R4 is selected from -OH, -OCI-C 20 alkyl, -OC 2 -C 20 alkenyl, -OC 2 -C 20 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2 -C 20 alkenyl, -OC(O)C 2 -C 2 0 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-C 2 0 alkyl, -OC(O)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 2 0 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, 15 -OC(S)NHC 2 -C 2 0 alkenyl, -OC(S)NHC 2 -C 2 o alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; R 5 and R 6 are independently selected from hydrogen and -CI-C 1 o alkyl; R and R are hydrogen or taken together R7 and R form a double bond, -0-, -S- or 18 -NR -; 20 R 9 is selected from CI-C 20 alkyl, -C 2 -C 2 0 alkenyl, -C 2 -C 2 0 alkynyl, -OH, -OCI-C 2 0 alkyl, -OC 2 -C 2 0 alkenyl, -OC 2 -C 2 0 alkynyl, -Ocycloalkyl, -OC(O)CI-C 2 0 alkyl, -OC(O)C 2 C 20 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -NHCI-C 20 alkyl, -NHC 2 -C 20 alkenyl, -NHC 2 -C 20 alkynyl, -NHcycloalkyl, -NHaryl, -NHheterocyclyl, -NHheteroaryl, -OC(O)NHCI-C 20 alkyl, 25 -OC(O)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 2 o alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, -OC(S)NHC 2 -C 2 0 alkenyl, -OC(S)NHC 2 -C 20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; R' 0 and R" are independently selected from hydrogen, -CI-C 6 alkyl, 30 -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OH, -OCI-C 6 alkyl, -OC 2 -C 6 alkenyl, -OC 2 -C 6 alkynyl, -Ocycloalkyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2 -C 6 alkenyl, -OC(O)C 2 -C 6 alkynyl, C:\NRPortbI\DCC\AZB707916 LDOC-4A2/2010 - 67 -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl and -OC(O)heteroaryl or R' and R" taken together form a carbonyl or thiocarbonyl group; R1 2 is selected from hydrogen, -CI-Cio alkyl, -C 2 -Cio alkenyl and -C 2 -Ci 0 alkynyl; R1 3 is selected from hydrogen, -OH, -OCI-C 20 alkyl, -0C 2 -C 20 alkenyl, -0C 2 -C 2 0 5 alkynyl, -Ocycloalkyl, -OC(O)CI-C 20 alkyl, -OC(0)C 2 -C 20 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 20 alkyl, -OC(0)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 2 o alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-C 20 alkyl, -OC(S)NHC 2 -C 20 alkenyl, -OC(S)NHC 2 -C 20 alkynyl, -OC(S)NHcycloalkyl, 10 -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R1 2 and R" taken together form a carbonyl group; R' 4 is selected from hydrogen, -OH, -OCI-C 20 alkyl, -OC 2 -C 20 alkenyl, -OC 2 -C 20 alkynyl, -Ocycloalkyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2 -C 20 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCi-C 20 15 alkyl, -OC(O)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 2 0 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, -OC(S)NHC 2 -C 2 0 alkenyl, -OC(S)NHC 2 -C 20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; or R' 4 and R1 5 together form =0 or =CH2; 20 R's and Ri 6 are independently hydrogen or R 1 5 and Ri 6 taken together form a 5 membered carbocyclic ring of the form: H R 22 * R 21 R 20 R 19 25 wherein * indicates the carbon atoms bearing R' 5 and R' 6 . R' 9 and R 20 are independently selected from hydrogen, -OH, -OCI-Co alkyl, -OC 2 CIO alkenyl, -OC 2 -CIo alkynyl, -Ocycloalkyl, -OC(O)Ci-CIO alkyl, -OC(O)C 2 -Cjo alkenyl, C:\NRPorbl\DCCAZB\2707916_LDOC-4AJ22010 -68 -OC(O)C 2 -CIO alkynyl, -OC(O)cycloalkyl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-Cro alkyl, -OC(O)NHC 2 -CIO alkenyl, -OC(O)NHC 2 -CIO alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-CIO alkyl, -OC(S)NHC 2 -Co alkenyl, -OC(S)NHC 2 -Cjo alkynyl, 5 -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R' 9 and R 2 0 taken together are =0, =S, =NH or =N(Ci-C 6 alkyl); R 2 1 is hydrogen, -CI-CIO alkyl, -C 2 -CIo alkenyl or -C 2 -Cio alkynyl; R 22 and R 23 are each hydrogen, -Ci-CIO alkyl, -C 2 -Cio alkenyl, -C 2 -Cio alkynyl, -OH, -OCI-CIO alkyl, -OC 2 -CIO alkenyl, -OC 2 -CIo alkynyl, -Ocycloalkyl, -OC(O)Ci-CIo 10 alkyl, -OC(O)C 2 -C 10 alkenyl, -OC(O)C 2 -C 10 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-Cio alkyl, -OC(O)NHC 2 -CIO alkenyl, -OC(O)NHC 2 -CIo alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-CIO alkyl, -OC(S)NHC 2 -Cio alkenyl, -OC(S)NHC 2 -CIO alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, 15 -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, F, Cl, Br, I, -CN, -NO 2 or N(R'") 2 , or R2 and R 23 taken together form a double bond or are -0-, -S-, -NR"- or -CRR24R-; R 7 is selected from hydrogen, -OH, -OCI-C 20 alkyl, -OC 2 -C 20 alkenyl, -OC 2 -C 2 0 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2 -C 2 0 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 2 0 20 alkyl, -OC(O)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 20 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-C 20 alkyl, -OC(S)NHC 2 -C 2 o alkenyl, -OC(S)NHC 2 -C 2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; R1 8 is selected from hydrogen and -CI-CIO alkyl; 25 R 24 and R 25 are independently selected from hydrogen, -CI-Cio alkyl, -OH and -OCI-C 10 alkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted; a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt thereof. 30
6. A method according to claim 4 wherein the PKC activator is 12-tigloyl-13-(2- C:\NRPortbI\DCC\AZB\2707916 1.DOC-4A)2120 10 -69 methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy- 1 -tigliaen-3-one, 12-0 tetradecanoylphorbol- 13-acetate or phorbol-12,13-didecanoate
7. A method according to any one of claims 1 to 4 wherein the PKC activator is a 5 compound of formula (V) R31 R32 H Ra H R 30 0 R3 4 H H R 46R47 H R45 H 5 44 R43 R42 R 36 hd R41 R40 R39 R38 R37 wherein 10 R 3 0 is selected from hydrogen, -Ci-Cio alkyl, -C 2 -CIO alkenyl and -C 2 -C1 alkynyl; R3k and R3 2 are each independently selected from hydrogen, -CI-CIO alkyl, -C2-CIO alkenyl and -C 2 -C1a alkynyl; R 3 and R 3 are each independently selected from hydrogen, -CI-CIO alkyl, -C2-CIO alkenyl and -C2-CIO alkynyl or R 3 and R 3 taken together are -C(R 48)(R 49)_ 15 R 3 and R 36 are both hydrogen, or R 35 and R 36 taken together form a double bond, -O-, -S- or -NR'O-;, R 3 is selected from -CI-C20 alkyl, -C2-C20 alkenyl, -C2-C20 alkynyl, -OH, -OCi-C20 alkyl, -OC2-C20 alkenyl, -OC2-C20 alkynyl, -Ocycloalkyl, -OC(O)C I-C2a alkyl, -OC(0)C2 C20 alkenyl, -OC(0)C2-C20 alkynyl, -OC(O)cycloalkyl, -OC(0)aryl, -OC(0)heterocyclyl, 20 -OC(O)heteroaryl, -NHCI-C 20 alkyl, -NHC 2 -C 20 alkenyl, -NHC 2 -C 20 alkynyl, -NHcycloalkyl, -NHaryl, -NHheterocyclyl, -NHheteroaryl, -OC(O)NHCi-C 20 alkyl, -OC(O)NHC 2 -C 2 0 alkenyl, -OC(O)NHC 2 -C 20 alkynyl, -OC(O)NHcycloalkyl, C:ANRPorbr\DCC\AZB\2707916_ .DOC-4A2/2 10 -70 -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, -OC(S)NHC 2 -C 20 alkenyl, -OC(S)NHC 2 -C 2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; R 38 and R 39 are independently selected from hydrogen, -Ci-C 6 alkyl, 5 -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OH, -OCI-C 6 alkyl, -OC 2 -C 6 alkenyl, -OC 2 -C 6 alkynyl, -Ocycloalkyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2 -C 6 alkenyl, -OC(O)C 2 -C 6 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl and -OC(O)heteroaryl or R 38 and R 39 taken together form a carbonyl or thiocarbonyl group; R 40 is selected from hydrogen, -Ci-CIO alkyl, -C 2 -Cio alkenyl and -C 2 -CIO alkynyl; 10 R 4 ' is selected from hydrogen, -OH, -OCI-C 20 alkyl, -OC 2 -C 20 alkenyl, -OC 2 -C 2 0 alkynyl, -Ocycloalkyl, -OC(O)Ci-C 20 alkyl, -OC(O)C 2 -C 20 alkenyl, -OC(O)C 2 -C 20 alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 20 alkyl, -OC(O)NHC 2 -C 20 alkenyl, -OC(O)NHC 2 -C 2 0 alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, 15 -OC(S)NHC 2 -C 20 alkenyl, -OC(S)NHC 2 -C 2 0 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl or R 40 and R 4 ' taken together form a carbonyl group; R 42 is selected from hydrogen, -OH, -OCi-C 20 alkyl, -OC 2 -C 20 alkenyl, -OC 2 -C 20 alkynyl, -Ocycloalkyl, -OC(O)C i-C 20 alkyl, -OC(O)C 2 -C 20 alkenyl, -OC(O)C 2 -C 20 alkynyl, 20 -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-C 2 0 alkyl, -OC(O)NHC 2 -C 20 alkenyl, -OC(O)NHC 2 -C 2 o alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCI-C 20 alkyl, -OC(S)NHC 2 -C 2 0 alkenyl, -OC(S)NHC 2 -C 20 alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl and -OC(S)NHheteroaryl; 25 R 43 and R 44 are independently selected from hydrogen, -OH, -OCI-CIO alkyl, -OC 2 C 1 o alkenyl, -OC 2 -Co alkynyl, -Ocycloalkyl, -OC(O)CI-Cio alkyl, -OC(O)C 2 -Cio alkenyl, -OC(O)C 2 -CIO alkynyl, -OC(O)cycloalkyl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-Clo alkyl, -OC(O)NHC 2 -Cio alkenyl, -OC(O)NHC 2 -Cio alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, 30 -OC(S)NHCI-Cio alkyl, -OC(S)NHC 2 -CIO alkenyl, -OC(S)NHC 2 -Cio alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, C.\NRPortbl\DCC\A2B\2707916_l.DOC-422/10110 -71 fluoro, chloro, bromo and iodo, or R 43 and R 44 taken together are =0, =S, =NH or =N(Ci C 6 alkyl); R 4 5 is hydrogen, -Ci-Cio alkyl, -C 2 -CIO alkenyl or -C 2 -C 10 alkynyl; R 46 and R 4 7 are each hydrogen, -CI-CIO alkyl, -C 2 -CIO alkenyl, -C 2 -Clo alkynyl, 5 -OH, -OCi-CIO alkyl, -OC 2 -CIo alkenyl, -OC 2 -CIo alkynyl, -Ocycloalkyl, -OC(O)CI-CIo alkyl, -OC(O)C 2 -Cio alkenyl, -OC(O)C 2 -CIO alkynyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl, -OC(O)heteroaryl, -OC(O)NHCI-Cio alkyl, -OC(O)NHC 2 -CIO alkenyl, -OC(O)NHC 2 -Cio alkynyl, -OC(O)NHcycloalkyl, -OC(O)NHaryl, -OC(O)NHheterocyclyl, -OC(O)NHheteroaryl, -OC(S)NHCi-Cio alkyl, -OC(S)NHC 2 -CIO 10 alkenyl, -OC(S)NHC 2 -Cio alkynyl, -OC(S)NHcycloalkyl, -OC(S)NHaryl, -OC(S)NHheterocyclyl, -OC(S)NHheteroaryl, F, Cl, Br, I, -CN, -NO 2 or N(R")2, or R16 and R 4 7 taken together form a double bond or are -0-, -S-, -NR" 0 - or -CR 5 'Rs 2 R 4 8 and R 4 9 are each independently selected from hydrogen and -Ci-CIO alkyl; R 50 is hydrogen or -CI-Cio alkyl; 15 R 5 ' and R 52 are independently selected from hydrogen, -CI-Cia alkyl, -OH and -OCI-Cio alkyl; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; or a geometric isomer or stereoisomer thereof, or a veterinary acceptable salt 20 thereof.
8. A method according to claim 7 wherein the compound is selected from 3-ingenol angelate, 3-ingenol benzoate and 3,20-ingenol dibenzoate. 25
9. A method according to any one of claims 1 to 4 wherein the PKC activator is an indolactam or teleocidin compound or an analogue thereof having formula (VII): C \NRPortb4\DCCAZBU7(7916_I.DOC-4M2/lO - 72 R 57 H H H N H ZIY R5aa R56 OR 58 b R#6 R53 (VII) R54 wherein Z is -CH(R" 9 )- or -N(R")-, where R 59 is selected from hydrogen or -CI-C 6 alkyl; 5 Y is absent and R 53 is hydrogen or Y together with R 53 are -NH-CH=Y'-, -NH-CH 2 -Y 2 -, -O-CH=Y - or -O-CH 2 -Y 2 - where Y' is -C- and Y2 is -CH-; R 54 is hydrogen, -CI-C 20 alkyl, -C 2 -C 2 0 alkenyl, -C 2 -C 2 0 alkynyl, -C(O)CI-C 2 0 alkyl, -C(O)C 2 -C 2 0 alkenyl; -C(O)C 2 -C 20 alkynyl, -NHC(O)CI-C 20 alkyl, -NHC(O)C 2 -C 20 alkenyl or -NHC(O)C 2 -C 2 0 alkynyl; 10 R 55 is hydrogen, -C 1 -C 20 alkyl, -C 2 -C 2 0 alkenyl, -C 2 -C 2 0 alkynyl, or R 54 and R 5 5 taken together form a 5 or 6 membered carbocyclic ring optionally substituted with 1 to 4 -CI-C 6 alkyl or -C 2 -C 6 alkenyl groups; R 56 is hydrogen, -C-C 2 0 alkyl, -C 2 -C 2 0 alkenyl, -C 2 -C 2 0 alkynyl, -OC(O)CI-C 20 alkyl, -OC(O)C 2 -C 2 0 alkenyl; -OC(O)C 2 -C 20 alkynyl, -NHC(O)CI-C 20 alkyl, -NHC(O)C 2 15 C 20 alkenyl or -NHC(O)C 2 -C 20 alkynyl, or R 56 and R 59 taken together form a 5 membered saturated or unsaturated ring optionally substituted with I or 2 substituents selected from -CI-C 6 alkyl or -C 2 -C 6 alkenyl; R 57 is hydrogen or -Ci-C 6 alkyl; Rssa is hydrogen or -C 1 -C 6 alkyl; 20 R S8 is -OH, -OCI-C 6 alkyl, -OC 2 -C 6 alkenyl, -OC(O)CI-C 6 alkyl, -OC(O)C 2 -C 6 alkenyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heterocyclyl or -OC(O)heteroaryl; wherein each alkyl, alkenyl, aryl, heterocyclyl or heteroaryl is optionally substituted; C:\NRPonbl\DCC\AZB\2707916_LDOC-4A)2/20IU -73 or a geometric isomer or stereoisomer thereof or a veterinary acceptable salt thereof.
10. A method according to claim 9 wherein the PKC activator is 7-octyl-indolactam V. 5
11. A method according to any one of claims I to 4 wherein the PKC activator is a compound of formula (X): LO R91 (X) 10 wherein R 9 0 is H, -OH or -T-U-V-R 93 . T is -0-, -S-, -NH- or -N(CH3)-; U is absent or is selected from -C(O)-, -C(S)-, -S(0)- or -S(0)2-; 15 V is absent or is selected from -0-, -S-, -NH- or -N(CH 3 )-, provided that V is absent when U is absent; R 9 ' is =C R 9 5 or R 9 ' is selected from R 96 or R 92 is hydrogen, -OH or R93 R 93 in each instance is independently selected from hydrogen, alkyl, alkenyl, 20 alkynyl, aryl, heteroaryl, -alkylaryl or -alkylheteroaryl; R 94 and R 95 are independently hydrogen, -CO 2 R 93, -CONR96R97 or R9' R 96 and R 97 are independently hydrogen, alkyl, alkenyl, alkynyl or -(CH 2 )1- 3 CO 2 R 93 ; L is a straight or branched linear, cyclic or polycyclic moiety containing a 25 continuous chain of from 6 to 14 chain atoms, which substantially maintains the relative C:\NRPortb\DCCAZB\2707916 IDOC-4A)22010 -74 distance between the Cl and C17 atoms and the directionality of the C1C2 and C16C17 bonds of naturally occurring bryostatin; and Z is -0- or -NH-; and veterinary acceptable salts thereof. 5
12. A method according to any one of claims I to 4 wherein the PKC activator is a tetrahydrofuran analogues of phorbol esters such as those of formula (XIII): HOR1 R62 (XIII) wherein 10 R 60 is selected from -OC(O)CI-C 20 alkyl, -OC(O)C 2 -C 20 alkenyl and -OC(O)C 2 -C 20 alkenyl; R61 is selected from -CI-C 6 alkylCOCI-C 6 alkyl, -CI-C 6 alkylCOC 2 -C 6 alkenyl, C 1 C 6 alkylCOC 2 -C 6 alkynyl, -Ci-C 6 alkylCO 2 Ci-C 6 alkyl, -Ci-C 6 alkylCO 2 C 2 -C 6 alkenyl or -CI-C 6 alkylCO 2 C 2 -C 6 alkynyl; 15 R 62 is selected from -Ci-C 6 alkylCOCi-C 6 alkyl, -CI-C 6 alkylCOC 2 -C 6 alkenyl, C 1 C 6 alkylCOC 2 -C 6 alkynyl, -CI-C 6 alkylCO 2 Ci-C 6 alkyl, -CI-C 6 alkylCO 2 C 2 -C 6 alkenyl or -CI-C 6 alkylCO 2 C 2 -C 6 alkynyl; and - is a double or single bond; wherein each alkyl, alkenyl and alkynyl is optionally substituted; 20 or a geometric isomer or stereoisomer thereof or a veterinary acceptable salt thereof.
13. A method according to any one of claims I to 4 wherein the PKC activator is a lactam of formula (XIV): C:N'RPonbl\DCC\AZB\27079I6I DOC-4A)2/21 - 75 R 81 R 80 0 N H OH (XIV) wherein R 0 and R 8 1 are each independently -CI-C 15 alkyl, -C 2 -C 15 alkenyl, -C 2 -C 15 alkynyl, 5 -C 3 -C 8 cycloalkyl, -Ci-Cio alkylC 3 -C 8 cycloalkyl, -C 2 -CIO alkenylC 3 -Cs cycloalkyl, -C 2 -C 1 O alkynylC 3 -C8 cycloalkyl, -OCI-Ci 5 alkyl, -C(O)CI-Ci 5 alkyl, -OC(O)CI-CI 5 alkyl, aryl, heteroaryl, -CI-C 6 alkylaryl, -CI-C 6 alkylheteroaryl, -C 2 -CI 5 alkenylaryl, -C 2 -Ci 5 alkenylheteroaryl, -C 2 -CI 5 alkynylaryl, -CI-CI 5 alkynylheteroaryl, -OCI-Ci 5 alkylaryl, -OCI-C 1 5 alkylheteroaryl, -C(O)CI-Cis alkylaryl, -C(O)CI-CI 5 alkylaryl, -OC(O)CI-CI 5 10 alkylaryl, -OC(O)Ci-CI 5 alkylheteroaryl; wherein R 80 and R ' is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, -OH, -CF 3 , -OCF 3 , -CI-C 5 alkyl, -C 2 -CI 5 alkenyl, -C 2 -CIS alkynyl, -C 3 -C 8 cycloalkyl, -CI-CIo alkylC 3 -C 8 cycloalkyl, -C 2 -CIo alkenylC 3 -C 8 cycloalkyl, -C 2 -C 10 15 alkynylC 3 -Cs cycloalkyl, -OCi-Ci 5 alkyl, -C(O)CI-CI 5 alkyl, -OC(O)CI-C 5 alkyl, -C(O)OH, -C(0)OCi-C 6 alkyl, -OC(O)OH, -OC(O)OCI-C 6 alkyl, -C(O)NRR, -OC(O)NRRk and -NR m R" and wherein any aryl or heteroaryl of R 80 or R 8 1 is optionally substituted on a non-aromatic carbon by a divalent C 2 -C 7 alkylene chain to form a C3-Cs spirocycloalkyl; 20 each R and Rk is independently hydrogen or -CI-CIO alkyl, or R and Rk taken together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring; and each R' and R" is independently hydrogen, -CI-Cio alkyl, -C(O)CI-CIO alkyl, phenyl, benzyl or phenylethyl, or R m and R" taken together with the nitrogen to which they 25 are attached are a 5-6 membered heterocyclic ring; or a veterinary acceptable salt thereof. C:\NRWonbI\DCCAZB\2 707916 L DOC-4A2/20)10 -76
14. A method according to any one of claims I to 4 wherein the PKC activator is a lactam of formula (XV), (XVI) and (XVII): 0 NH RSN R 82 OH (XV) 5 wherein R 82 is -CI-C 20 alkyl, especially -CIO-CI 5 alkyl, more especially -CI-CI 4 alkyl; HO H3 R84 HN R85 O H R83 (XVI) 10 wherein R 8 is hydrogen or -CI-C 10 alkyl; R84 and R 85 are each independently -CI-C 1 o alkyl, especially -CI-C 6 alkyl; C:\NRPorbI\DCC\AZB\2717916_1.DOC4A)2/20 I0 - 77 R 88 N NH OH R86 (XVII) wherein R 86 is hydrogen or -CI-C 15 alkyl; R 8 is hydrogen or -CI-C 6 alkyl, especially -CI-C 3 alkyl; and 5 R 88 is -CI-C 6 alkyl, especially -CI-C 3 alkyl, more especially isopropyl.
15. A method according to any one of claims 1 to 4 wherein the PKC activator is an aplysiastatin compound of formula (XII): O O OCH3 R71 R 7 OHO OH OH (XII) 10 wherein R 70 is hydrogen or -OH; and R 71 is hydrogen, fluorine, chlorine, bromine or iodine; Daphnoretin or mezerein. 15
16. A method according to any one of claims I to 4 wherein the subject is a sheep. C:WRPonbIDCCAZB\27(17916_ .DOC-4A)2/010 - 78
17. A method according to any one of claims 1 to 4 wherein the subject is a merino sheep or a sheep bred to have merino characteristics. 5
18. A method according to any one of claims I to 4 wherein the subject is a lamb.
19. A method according to any one of claims 1 to 4 wherein the administration is by topical administration or intradermal injection.
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JP2014507393A (en) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド 3-acyl-inogenol II
JP2014507396A (en) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド Ingenol-3-acylate I
JP2014512331A (en) * 2010-12-22 2014-05-22 レオ・ラボラトリーズ・リミテッド Ingenol-3-acylate III and ingenol-3-carbamate
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US9388124B2 (en) 2010-12-22 2016-07-12 Leo Laboratories Limited Ingenol-3-acylates I
JP2014507396A (en) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド Ingenol-3-acylate I
JP2014512331A (en) * 2010-12-22 2014-05-22 レオ・ラボラトリーズ・リミテッド Ingenol-3-acylate III and ingenol-3-carbamate
US9708286B2 (en) 2010-12-22 2017-07-18 Leo Laboratories Limited Ingenol-3-acylates III and ingenol-3-carbamates
US9656945B2 (en) 2010-12-22 2017-05-23 Leo Laboratories Limited 3-acyl-ingenols II
JP2014507393A (en) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド 3-acyl-inogenol II
JP2016029081A (en) * 2010-12-22 2016-03-03 レオ・ラボラトリーズ・リミテッドＬｅｏ Ｌａｂｏｒａｔｏｒｉｅｓ Ｌｉｍｉｔｅｄ Ingenol-3-acylates iii and ingenol-3-carbamates
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