AU702254B2

AU702254B2 - Di-tert-butylphenol compounds useful as anti-inflammatory agents

Info

Publication number: AU702254B2
Application number: AU13722/95A
Authority: AU
Inventors: Thomas Tod Hudec; Maurice Edward Loomans; Joel Ira Shulman
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1993-12-17
Filing date: 1994-12-16
Publication date: 1999-02-18
Anticipated expiration: 2014-12-16
Also published as: HU9601656D0; AU1372295A; NZ277986A; JPH09506624A; BR9408334A; NO962535L; CZ285436B6; CA2179009A1; CN1137752A; EP0734256A1; CZ175596A3; NO962535D0; WO1995016443A1; SK76996A3; PL315061A1; HUT74507A

Description

1 -Ui I WO 95/16443 PCT/US94/14405 DI-TERT-BUTYLPHENOL COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS TECHNICAL FIELD The subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted di-tert-butylphenol compounds.

BACKGROUND OF THE INVENTION Di-tert-butylphenol compounds are a class of compounds known for their use as stabilizers for plastics, oils and fats; see, U.S.

Patent No. 3,711,544 issued to Engelhardt, Fruhstorfer, Hesse, Dennler Baumer on January 16, 1973.

Certain di-tert-butylphenol compounds and other compounds structurally related thereto have been found to have significant antiinflammatory and/or analgesic activity. Such compounds, processes for making them, and uses for them are disclosed in the following references: U.S. Patent Nos. 3,784,701 issued to Tomcufcik, Grassing Sloboda on January 8, 1974; 3,917,672 issued to Schmidt on November 4, 1975; 4,124,725 issued to Moore on November 7, 1978; 4,130,666 issued to Moore on December 19, 1978; 4,165,383 issued to Moore on August 21, 1979; 4,172,082 issued to Moore on October 23, 1979; 4,357,345 issued to Moore on November 2, 1982; 4,418,074 issued to Moore on November 29, 1983; 4,440,784 issued to Katsumi, Kondo, Yamashita, Hidaka, Hosoe, Ariki, Yamashita Watanobe on April 3, 1984; 4,535,165 issued to Moore on August 13, 1985; 4,677,113 issued to Bell Moore on June 30, 1987; 4,708,966 issued to Loomans, Matthews Miller on November 24, 1987; 4,714,776 issued to Bell Moore on December 22, 1987; 4,833,155 issued to Muchowski, Greenhouse, Young Murthy on May 23, 1989; 4,968,710 issued to Rustad on November 6, 1990; 4,982,006 issued to Hudec on January 1, 1991; 5,086,064 issued to Capris, Conner Sircar on February 4, 1992; 5,102,897 issued to Boschelli, Conner, Kostlan, Kramer, Mullican Sircar on April 7 1992; European Patent Application No. 0,212,848 of Riker Laboratories, published WO 95/16443 PCTIUS94/14405 2 March 4, 1987; PCT Patent Application Nos. WO 83/01774 and WO 83/91775 of Riker Laboratories, both published May 26, 1983; WO 93/07865 of The Procter Gamble Company, published April 29, 1993; Kaffenberger, T.H. Eichhold M.J. Doyle, "Determination of Tebufelone (A New Anti-Inflammatory Drug) Strength and Stability in Bulk Drug, Dosage Formulations and Feed Admixtures by Reversed- Phase High-Performance Liquid Chromatography", Journal of Chromatographv, Vol. 505 (1990), pp. 349-356. Such compounds are also disclosed and reviewed in Batt, "5-Lipoxygenase Inhibitors and Their Anti-inflammatory Activities", Progress in Medicinal Chemistry, Vol 29 (1992), pp. 1-15, 45-50, and references disclosed therein.

Although a number of di-tert-butylphenol compounds have been demonstrated to exhibit anti-inflammatory activity, many such compounds exhibit little or no anti-inflammatory activity. Thus it is generally not possible to predict whether such compounds have substantial anti-inflammatory activity without testing for the activity.

It is an object of the subject invention to provide compounds which have effective anti-inflammatory, analgesic and/or anti-oxidant activity.

It is a further object of the subject invention to provide such compounds which cause few adverse side effects.

It is also an object of the subject invention to provide methods for treating inflammation and/or pain using the subject compounds.

SUMMARY OF THE INVENTION The subject invention involves compositions comprising compounds having the structure:

(CH

3 3

C

HO C(O)-CHR- (CH2)n-C(0)-(CH2)m-CH 3

(CH

3 3

C

wherein n is an integer from 1 to about 5, m is an integer from 0 to about 3, -R is hydrogen or straight or branched chain C 1

-C

3 alkanyl; and a pharmaceutically-acceptable carrier. The subject invention also I j involves methods for treating diseases characterized by inflammation and/or pain, such as rheumatoid arthritis and osteoarthritis, in humans c "u an MMMMM- 4 WO 95/16443 PCT/US94/14405 3 or lower animals by administration of a safe and effective amount of these compounds to the human or lower animal in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION The subject invention involves particular di-tert-butylphenol compounds having the following structure:

(CH

3 3

C

HO C (O)-CHR- (CH2)n-C(O)-(CH2)m--CH 3

(CH

3 3

C

In the above structure, n is an integer of from 1 to about 5, preferably from 1 to 4, more preferably 1 or 2 or 3, most preferably 2. In the above structure, m is an integer of from 0 to about 3, preferably from 0 to 2, more preferably 0 or 1, most preferably 0.

In the above structure, -R is hydrogen or straight or branched chain alkanyl having from 1 to about 3 carbon atoms. -R is preferably .1 hydrogen, methyl or ethyl, most preferably hydrogen.

Preferred compounds useful in the subject invention include: 4-(1,5-dioxohexyl)-2,6-di-tert-butylphenol and 4-(1,4-dioxopentyl)-2,6di-tert-butylphenyl.

In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. The anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response. Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test. Analgesic activity may be tested in art-known models such as the phenylbenzoquinoneinduced writhing test in mice, and the Randall Selitto test in rats.

Another useful art-known test is the rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.

WO 95/16443 PCT/US94/14405 4 These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U.S. Patent No. 4,130,666 issued to Moore on December 19, 1978; U.S. Patent No. 4,431,656 issued February 14, 1984 to Katsumi, et al.; U.S. Patent No. 4,440,784 issued to Katsumi, et al. on April 3, 1984; Japanese Patent Application 85/54315 of Katsumi, et al., published March 28, 1985; European Patent Application No. 0,059,090 of Yamanuchi Pharmaceutical Company Ltd., published September 1, 1982; Opas, R.J. Bonney J.L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse r.ars Inflamed by Arachadonic Acid", The Journal of Investigative Dermatology, Vol. 84, No. 4 (1985), pp. 253-256; Swingle, KF., R.L.

Bell G.G.I. Moore, "Anti-inflammatory Activity of Antioxidants", Anti- i inflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K.D.

Rainsford, ed., CRC Press, Inc., (1985), pp. 105-126; Adamkiewicz, W.B. Rice J.D. McColl, "Antiphlogistic Effect of Trypsin in Normal and in Adrenalectomized Rats", Canadian Journal of Biochemistry Physiology, Vol. 33 (1955), pp. 332-339; Sellye, H., "Further Studies Concerning the Participation of the Adrenal Crtex in the Pathogenesis of Arthritis", British Medical Journal, Vol. 2 (1949), pp. 1129-1135; and Winter, E.A. Risley G.W. Nuss, "Carrageenan-lnduced Edema in Hind Paw of the Rats as an Assay for Antiinflammatory Drugs" Proceedings of Society of Experimental Biology and Medicine, Vol. 111 (1962), pp. 544-547; Otterness, M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatory Drugs, Chapter 3, J. G. Lombardino, ed., John Wiley Sons, Inc. (1985), pp. 111-252. Hitchens, J. S. Goldstein, L. Shemano J. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally- Induced Pain", Arch. Int. Pharmacodyn., Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. T. M. Twomey, "The Analgetic Properties of Piroxicam in Animals and Correlation with Experimentally Determined Plasma Levels", Agents and Actions, Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. O. J. J. Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", Arch. Int.

Pharmacodyn.. Vol. 111, No. 4 (1957), pp. 409-419; Winter, C. A. L.

Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs",

-I

WO 95/16443 PCT/US94/14405 J. Pharmacol. Exp. Ther., Vol. 148, No. 3 (1965), pp. 373-379; the disclosure of all these references are incorporated herein by reference.

Many anti-inflammatory drugs, particularly non-steroidal antiinflammatory drugs (NSAIDs) cause undesirable gastrointestinal side effects, especially when dosed perorally; such side effects may include ulcers and erosions. These side effects, which are often asymptomatic, can become serious enough to require hospitalization and can even be lethal. Compounds of the subject invention generally cause fewer such gastrointestinal side effects compared to other NSAIDs, even compared to many other di-tert-butylphenol derivatives.

Certain NSAIDs, including certain di-tert-butylphenol derivatives, when dosed systemically, cause an undesirable increase in systemic levels of certain liver enzymes. Compounds of the subject invention generally cause less of such liver enzyme side effects compared to other di-tert-butylphenol compounds.

Compounds useful in the subject invention can be made using the following general reaction scheme: R O O R 00- RT OH 0 R'MgX R (CH

(CHH

2 )no ether 0 anhydride akyl Grignard O R CF 3 C(O)OC(O)CF3 O(CH) R neat orwith solvert -R toluene, dichloromethane) di-t-butylphenol Another reaction scheme can be used when m is 0, as depicted by Example 1.

1 Y WO 95/16443 PCT/US94/14405 6 Example 1 Preparation of 4-(1,5-dioxohexvl)-2,6-di-tert-butylphenol 0 SCI H+ C-78o to 25 o 0 To a solution of 2.06 g (10.0 mmol) of 2,6-di-t-butylphenol and 1.17 g (10.0 mmol) of 4-hexynoyl chloride in 20 mL of dichloromethane is added, at -78 0 C, 2.30 mL (20.0 mmol) of stannic chloride. The mixture is stirred at -78°C for 30 minutes, and then let warm to room temperature and stirred for an additional 30 minutes. The reaction is added slowly to 1N HCI at 0 C, and after stirring for 5 minutes, layers are allowed to form and are separated. The aqueous portion is extracted with ether, and the combined organic phase is washed with sat. NaHCO 3 and sat. NaCI, and then dried (MgSO 4 Flash chromatography (20% EtOAc/hex, Rf=0.25) affords 2.23 g of product as a dark brown viscous oil. Further purification is achieved by recrystallization from hexane/benzene to afford 1.85 g of pure 4-(1,5dioxohexyl)-2,6-di-tert-butylphenol, mp 100.5-101 C.

Compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceuticallyacceptable carrier. As used herein, "safe and effective amount" means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement. A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.

Compositions of the subject invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably

U

WO 95/16443 PCTIUS94/14405 7 from about 20% to about 80%, and most preferably from about 40% to I |about In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, it is preferably injected non-intravenously; the preferred pharmaceutically-acceptable carrier is 35 sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4. Such injectable compositions preferably cop rise from about 1% to about 50% of the WO 95/16443 PCTIUS94/14405 8 subject compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose.

Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like. Topical compositions preferably contain from about 1% to about of an emollient, more preferably from about 5% to about 25% of an emollient. Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.

The preferred mode of administering the subject compound is perorally. The preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about mg to about 600 mg. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration 0I are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.

Many of the subject compounds are hydrophobic. If it is desired to provide an aqueous-based composition or a composition soluble in or miscible with aqueous media, a solubilizing agent may be included in the composition. Non-limiting examples of such solubilizing agents include polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene (35) castor oil.

Particularly preferred oral composition carriers suitable for compositions of the subject invention are disclosed in pending U.S.

Patent Application Serial Nos. 07/732,951 of Kelm Bruns, filed July 19, 1991, entitled "Pharmaceutical Compositions of Tebufelone", and 07/885,932 of Kelm Dobrozsi, filed May 19, 1992, entitled "Solid Dispersion Compositions of Tebufelone", hereby incorporated herein by reference.

Another aspect of the subject invention is methods for treatinn or preventing diseases characterized by inflammation by administeringa WO 95/16443 PCT/US94/14405 9 safe and effective amount of a subject compound to a human or lower animal in need of such treatment. The term "diseases characterized by inflammation", as used herein, means conditions which are known to involve inflammation, and may include conditions such as arthritis rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus, erythematosus and gout), as well as the presence of inflammation whether or not it is associated with an identifiable disease. Diseases characterized by inflammation further may include inflammation in the oral cavity inflammation associated with gingivitis or periodontal disease); inflammation in the gastrointestinal tract, inflammation associated with ulcers and irritable bowel disease); inflammation associated with dermatological diseases psoriasis, acne, and other skin inflammation); and inflammation associated with the respiratory tract asthma, bronchitis, and allergies).

Another aspect of the subject invention is methods for treating or preventing pain by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. Pain which can be treated or prevented by administering the subject compounds may include peripheral pain, menstrual pain, dental pain, and lower back pain.

Another aspect of the subject invention is methods for protecting against free radical damage resulting from oxidative stress and ischemic conditions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. Such treatment may inciude protecting against ischemic heart disease, atherosclerosis, stroke, and ischemic cell damage of heart.

The preferred mode of administration of the subject compounds is peroral, but other known methods of administration are contemplated as well, dermatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like). Ocular administration and inhalation are also included.

Thus specific modes of administration include, without limitation, WO 95/16443 PCTIUS94/14405 peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration.

Preferred doses of the subject compounds range from about 0.2 mg/kg to about 70 mg/kg, more preferably from about 0.5 mg/kg to about 12 mg/kg. Preferred injectable doses comprise from about 0.1 mg/kg to about 10 mg/kg of the subject compound. Preferred topical doses comprise from about 1 mg/cm 2 to about 200 mg/cm 2 of the subject compound applied to the skin surface. Preferred peroral doses comprise from about 0.5 mg/kg to about 25 mg/kg of the subject compound. Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily.

The following nonlimiting examples illustrate the subject invention.

Example 2 Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient Quantity (mg per tablet) 4-(1,5-dioxohexyl)- 2,6-di-tert-butylphenol) 200 Microcrystalline Cellulose 100 Sodium Starch Glycollate Magnesium Stearate 3 When administered orally two times daily, the above composition significantly reduces the inflammation in a patient suffering from rheumatoid arthritis. A significant benefit is also achieved by twice daily administration of this composition to a patient suffering from osteoarthritis.

Example 3 A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows: Ingredient Quantity (ma per capsule) 4-(1,4-dioxopentyl)- 2,6-di-tert-butylphenol 200 j Lactose To fill to volume of capsule UUL11 The above capsule administered orally once a day substantially reduces the -symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.

While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention, It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

"Comprises/comprising" when used In this specification is taken to specify the presence of stated features, integers, steps or components b~ut does not preclude the presence or addition of one or more other features, integers, steps.

components or groups thereof.

Claims

7. JW. 199 i:W WATERMARK 613 9819 6010 NO, 1588 P, 9 9 9 4 «e 99*0 9 *9 *9. 9* 9* 99 9 99 «°m o 12 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A pharmaceutical composition including: a safe and effective amount of a compound having the structure: (CH 3 )zC HO Q -C(O)-CHR- (CH 2 )n-C(O)-(CH2)m-CH3 (C H) 3 C wherein n is an integer from 1 to 5, m is an integer from 0 to 3; and R is hydrogen or straight or branched chain C 1 -C 3 alkanyl; and a pharmaceutically-acceptable carrier. 2. A pharmaceutical composition in dosage from 5 mg to 3500 mg, of a compound having the structure: (CH 3 3 C HO (O)-CHR- (CH 2 )n-C(O)-(CH2)m-CH3 (CH 3 3 C wherein n is an integer from 1 to 5; m is an integer from 0 to 3; and R is hydrogen or straight or branched chain C 1 -C 3 alkanyl; and a pharmaceutically-acceptable carrier. 3. The composition of Claim 2 wherein dosage is from 25 mg to 600 mg. 4. The composition of Claim 2 or 3 wherein n is 1 or 2. The composition of any one of Claims 2 to 4 wherein m is 0 or 1. 6. The composition of any one of Claims 2 to 5 wherein R is hydrogen. 6. The composition of any one of Claims 2 to 5 wherein R is hydrogen. Ri^1 1 'I 7. JAN, 1999 17:52 WATERMARK 13 9 9 1 13 7. The composition of any one of Claims 1 to 6 wherein n is 2 and m is 0.
8. Use of the compound having the structure: (CH 3 3 C (CHg)C wherein n is an integer from 1 to 5, m is an integer from 0 to 3, and R is hydrogen or straight or branched chain CI-Cs alkyl, in the treatment of a disease characterised by inflammation.
9. Use of a compound for manufacture of a medicament for treating a disease characterised by inflammation, te compound having the structure: (CH3)3C. HO (O)-CHR- (CH2)n-C(O)-(CH)m-CH (CH 3 3 C wherein n is an integer from 1 to 5, m is an integer from 0 to 3, and R is hydrogen or straight or branched chain Ci-Ca alkyl. c 10. The use of Claim 8 or 9 wherein n is from 1 to 4: m is from 0 to 2; R is hydrogen; and from 0.2 mg/kg to 70 mg/kg of the compound is administered to a human from 1 to 6 times per day.
11. The use of Claim 10 wherein n is from 1 or 2; m is from 0 of 1; R is hydrogen; and from 0.5 mg/kg to 12 mg.kg, of the compound is administered to a human from 1 to 4 times, per day.
12. The use of any one of Claims 8 to 11 wherein the disease is rheumatoid arthritis or osteoarhritis. 1, JAN.19 175 WATERMARK 613 9819 6010 NO, 1588 P. 14
13. Use of the compound having the structure: (C H 3 )3C Ho Q C(O)-CHR-(CH 2 )n-C(0h-(CH2)mC-H3 (CH 3 )3C wherein n is an integer from 1 to 5. m is an integer from 0 to 3, and R is hydrogen or straight or branched chain C 1 -C 3 alkyl, in the treatment of pain.
14. Use of a compound for manufacture of a medicament for treating pain, the compound having the structure: (C H,) 3 C HO C H 2 )m-CH 3 (CH 3 3 C wherein n is an integer from 1 to 5, m is an integer from 0 to 3, and R is hydrogen or straight or branched chain C 1 .C 3 alkyl. woo: The use of Claim 13 or 14 wherein n is from I to 4; rn is from 0 to 2; R is hydrogen; and from 0.2 mg/kg to 70 mg/kg, of the compound is administered to a human from 1 to 6 times per day,
16. The use of Claim 15 wherein n is from 1 to 2; m is from 0 or 1; R3 is hydrogen; and from 0.5 mg/kg to 12 mg/kg, of the compound is administered to a human from 1 to 4 times per day. DATED ihis 71h day of January, 1999 THE PROCTER GAMBLE COMPANY WATERMARK PATENT &TRADEMARK ATTORNEYS 290 BUR WOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA LCG/JGC:BA VAX DOC 024 AU I372295.WPC