EP1490042A2 - Utilisation d'antagonistes de ltb4 dans la medecine animale - Google Patents

Utilisation d'antagonistes de ltb4 dans la medecine animale

Info

Publication number
EP1490042A2
EP1490042A2 EP03708263A EP03708263A EP1490042A2 EP 1490042 A2 EP1490042 A2 EP 1490042A2 EP 03708263 A EP03708263 A EP 03708263A EP 03708263 A EP03708263 A EP 03708263A EP 1490042 A2 EP1490042 A2 EP 1490042A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
formula
alkoxy
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.)
Withdrawn
Application number
EP03708263A
Other languages
German (de)
English (en)
Inventor
Franz Birke
Kandace Matzek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1490042A2 publication Critical patent/EP1490042A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of an LTB 4 antagonist or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of respiratory diseases in companion and farm animals.
  • LTB 4 antagonists are compounds with pharmacologically valuable properties. LTB 4 antagonists are used in human medicine in the treatment of arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion injury / ischaemia, cystic fibrosis, atherosclerosis and multiple sclerosis.
  • LTB 4 antagonists are known, for example, from International Patent Applications WO 93/16036, WO 94/11341, WO 96/02497, WO 97/21670, WO 98/11062, WO 98/11119, WO 01/25186, WO 01/51457 and US Pat WO 02/34715.
  • Respiratory diseases especially chronic diseases in companion animals and livestock usually have other causes than asthma or chronic obstructive pulmonary diseases in humans. Because of these breathing pathological illnesses, the yields and benefits fall sharply, especially in farm animals or sports animals, thus leading to high economic losses.
  • the drugs used so far such as beta-mimetics or steroids, lead to long waiting times in animals that are used for meat production, and to exclusions from competitions for suspected doping in animals used in sports. In addition, these drugs sometimes have low potency and / or unwanted side effects.
  • the invention thus relates to the use of an LTB antagonist or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of respiratory disorders in companion animals and livestock.
  • A is a group of the formula
  • PHE represents an optionally substituted by one or two C_-C 6 alkyl groups 1,4-phenylene group, preferably a by ortho in
  • A is a group of the formula preferably the formula
  • Ri is H, OH, CN, CORIO, or CHO, preferably H or COOR 10;
  • R 2 is H, Br, Cl, F, CF 3, CHF 2, OH, HSO 3 -O, dC 6 alkyl, dC 6 alkoxy, C 5 -C 7 -
  • R 4 is H or dC 6 alkyl, preferably H
  • R 5 is C 1 -C 4 -alkyl, CF 3 , CH 2 OH, COOH or COO (C 1 -C 4 -alkyl), preferably
  • R 6 is H, C 1 -C 4 -alkyl or CF 3 , preferably C 1 -C 4 -alkyl, in particular methyl;
  • R 7 is CH 2 OH, COOH, COO (C 1 -C 4 -alkyl), CONR 8 R 9 or CH 2 NR 8 R 9 ;
  • R 8 is H, C 1 -C 6 -alkyl, phenyl, phenyl (C 1 -C 6 -alkyl), COR 10 , COOR 10 , CHO, CONH 2 ,
  • CONHR 10 SO 2 - (C 1 -C 6 -alkyl), SO 2 -phenyl, where the phenyl group may be monosubstituted or disubstituted by Cl, F, CF 3 , C 1 -C 4 -alkyl, OH and / or C 1 -C 4 -alkoxy , preferably C 1 -C 4 -alkyl, in particular isopropyl;
  • R 9 is H or C 1 -C 6 -alkyl, preferably H or C 1 -C 4 -alkyl, in particular isopropyl; or R 8 and R 9 taken together represent a C 4 -C 6 -alkylene group;
  • R 10 is Ci-C ö alkyl, Cs-C 7 cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl (C ⁇ - C 6 alkyl), preferably dC 4 alkyl wherein those listed in the radicals R 2 and R 10 Aryl groups are phenyl or naphthyl, the heteroaryl groups are pyrrole, pyrazole, imidazole, furanyl, thienyl, pyridine or pyrimidine and each one or more times by Cl, F, CF 3 , dC 4 - alkyl, OH, HSO 3 -O - or dC 4 -alkoxy, preferably substituted by OH or HSO 3
  • Another object of the invention are pharmaceutical preparations containing at least one LTB 4 antagonist of formula I and at least one beta
  • Mimetic or at least one steroid are Mimetic or at least one steroid.
  • the invention further provides a ready-to-use two-component system, wherein (a) a component contains at least one LTB 4 antagonist of the formula I; and
  • the other component contains at least one beta-mimetic or at least one steroid.
  • LTB 4 antagonists of the formula IA are particularly preferred.
  • A is a group of the formula
  • Phenylene group stands; or A is a group of the formula
  • R. COOR I Q means; R 2 CF 3 , CHF 2 , OH, HSO 3 -O-, C 1-6 -alkyl, C 1 -C 6 -alkoxy, CONR 8 R 9 or
  • R 3 is H or dC 6 -alkoxy
  • R 4 is H;
  • R 5 is dC 4 alkyl;
  • R 6 is dC alkyl
  • R 8 is H, C 1 -C 6 -alkyl, phenyl, phenyl (C 1 -C 6 -alkyl), COR JO , COOR 10 , CHO, CONH 2 ,
  • R 9 is H or dC 6 -alkyl
  • Rio Ci-C ⁇ -alkyl wherein the aryl groups listed in the radical R 2 are phenyl and may each be substituted by OH, HSO 3 -O- or -CC 4 alkoxy, and their pharmacologically acceptable acid addition salts, glycosides and
  • the respective active compound of the formula I or IA can be present in the formulation according to the invention in the form of a physiologically tolerated acid addition salt.
  • physiologically acceptable acid addition salts according to the invention pharmaceutically acceptable salts are understood, which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. If appropriate, mixtures of the abovementioned acids can also be used for the preparation of the salts.
  • the salts of the formula I are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate and methanesulfonate.
  • the salts are particularly preferably selected from hydrochloride, hydrobromide and fumarate.
  • the active ingredient may optionally be in the form of a hydrate. According to the invention, however, the compound of the formula I is preferably added in the form of the free base and in the anhydrous form of the tablet.
  • Particularly preferred compounds of the formula I are those of the formulas IA1 to IA8, in particular IA1:
  • the compounds of formula I wherein R ! other than hydrogen are usually prodrugs which are converted in vivo to the corresponding compounds of formula I wherein Ri is hydrogen. From the compound IA, for example, the compound of the formula IA1 is formed in vivo.
  • the particular active ingredient is used in crystalline, unmilled or ground form, in particular in jet-ground form, in which the particle size distribution is within the following limits: D ⁇ 0 ⁇ 3 microns, D 50 3 to 8 microns, D 90 ⁇ 8 to 30 microns ,
  • D 10 , D 5 o and D 90 in microns are the particle size ranges within one
  • Passage total of 10% by volume, 50% by volume or 90% by volume of the measured particles (cumulative volume distribution) is achieved.
  • livestock usually stands for such animals, which are of economic interest, for the production of food or wool or for the performance of work, preferably kept on farms. These are predominantly paired mammals, such as cattle, sheep and goats or pigs.
  • the particular active ingredient is usually administered orally, preferably as a tablet, granules, suspension or as a feed additive.
  • the LTB antagonist preferably the compound of the formula I, in particular IA according to the invention, is from 0.2 to 95% by weight, preferably from 0.7 to 60% by weight, particularly preferably from about 5 to 50% by weight contain.
  • the proportion of the free base of I is particularly preferably between 6 and 40% by weight, based on the total mass of the dosage form.
  • the pharmaceutical formulation according to the invention also contains at least one adjuvant as filler / dry binder.
  • carbohydrates such as lactose or mannose, in particular finely divided lactose or sugar alcohols such as mannitol, sorbitol or xylitol, in particular mannitol as adjuvant, are of particular importance.
  • These adjuvants have proven to be particularly advantageous in the formulation according to the invention.
  • a preferred aspect of the present invention therefore relates to a tablet containing at least one compound of the formula I which, in addition to the active ingredient and the wetting agent, contains lactose, in particular finely divided lactose, particularly preferably lactose monohydrate or mannitol as adjuvant.
  • the dosage form according to the invention may contain, in addition to lactose, a wetting agent and the active ingredient, further auxiliaries or fillers. According to the invention, it is possible with preference to use those compounds which can function as binders.
  • Binder above and below refers to those auxiliaries which are suitable for binding other components together. Binders preferred according to the invention are selected from the group consisting of:
  • Powder cellulose, especially microcrystalline cellulose and / or copovidone, are preferably present as binders. Most preferred is a mixture of microcrystalline cellulose and a copolymer of vinylpyrrolidone and vinyl acetate, namely Copovidone VA 64, wherein the ratio of vinylpyrrolidone to vinyl acetate is about 3: 2 (m / m).
  • the tablet according to the invention has a weight ratio of microcrystalline cellulose to Copovidone VA 64 of 20: 1 to 1: 1, preferably 15: 1 to 2: 1, in particular about 10: 1 to 3: 1. Because of this particularly preferred binder combination of microcrystalline cellulose and copovidone tablets with increased bioavailability of the compounds of formula I are obtained.
  • the dosage form according to the invention may also contain, as further constituents, flow regulators and lubricants.
  • flow regulators and lubricants for example, silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and Glyceroltribehenat.
  • Magnesium stearate is preferably used according to the invention. If the above-mentioned flow or flow regulators or lubricants are used, their proportion by weight, based on the total mass of the tablet according to the invention, is preferably in a range of about 0.1-10% by weight, preferably about 0.5-5% by weight. more preferably between 0.6 and 1.5% by weight.
  • the dosage form according to the invention may contain one or more synthetic or natural, pharmaceutically acceptable dyes, preferably indigo carmine. If the above-mentioned dyes are used, their proportion by weight, based on the total mass of the tablet according to the invention, is from 0.01 to 0.5% by weight.
  • the dosage form according to the invention may contain one or more synthetic or natural, pharmaceutically acceptable odorants or flavorings.
  • the nature of these odorants and flavorings depends on the species of the animal to be treated. If the aforementioned odorants or flavoring agents are used, their proportion by weight, based on the total mass of the tablet according to the invention, is from 0.01 to 0.5% by weight.
  • the dosage form according to the invention can be prepared by mixing the ingredients directly, compressing and pelleting, or by granulating, compressing and pelleting.
  • the LTB antagonist in a daily dose range especially in connection with the feeding, from 0.1 to 20 mg kg, preferably from 0.5 to 8.0 mg / kg,
  • a horse warmblood mare, 12 years old has the following symptoms due to chronic bronchitis: coughing, breathlessness, lethargy.
  • This horse is for 20 days, daily once 10 g of the compound of formula IA1 in the form of a methylcellulose (thiol) suspension, with the feed (oats) administered.
  • the LTB 4 antagonist of formula IA1 was well tolerated without any evidence of side effects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes de LTB4 pour la production d'un médicament destiné au traitement ou à la prévention de maladies respiratoires chez les animaux de compagnie et le bétail de rapport.
EP03708263A 2002-03-26 2003-03-24 Utilisation d'antagonistes de ltb4 dans la medecine animale Withdrawn EP1490042A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10213350 2002-03-26
DE10213350A DE10213350A1 (de) 2002-03-26 2002-03-26 Verwendung von LTB¶4¶Antagonisten in der Tiermedizin
PCT/EP2003/003021 WO2003080037A2 (fr) 2002-03-26 2003-03-24 Utilisation d'antagonistes de ltb4 dans la medecine animale

Publications (1)

Publication Number Publication Date
EP1490042A2 true EP1490042A2 (fr) 2004-12-29

Family

ID=28050833

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03708263A Withdrawn EP1490042A2 (fr) 2002-03-26 2003-03-24 Utilisation d'antagonistes de ltb4 dans la medecine animale

Country Status (10)

Country Link
EP (1) EP1490042A2 (fr)
JP (1) JP2005529085A (fr)
AR (1) AR039141A1 (fr)
AU (1) AU2003212375A1 (fr)
CA (1) CA2480032A1 (fr)
DE (1) DE10213350A1 (fr)
PE (1) PE20030947A1 (fr)
TW (1) TW200407109A (fr)
UY (1) UY27731A1 (fr)
WO (1) WO2003080037A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110869362A (zh) 2017-05-12 2020-03-06 国立研究开发法人理化学研究所 A类gpcr结合性化合物改性体

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5246965A (en) * 1991-06-11 1993-09-21 Ciba-Geigy Arylethers, their manufacture and methods of treatment
CZ280133B6 (cs) * 1991-11-25 1995-11-15 Eli Lilly And Company Substituovaný fenylfenolleukotrienový antagonist a farmaceutický prostředek, který ho obsahuje
DE19636689A1 (de) * 1996-09-10 1998-03-12 Boehringer Ingelheim Kg Neue Benzamidinderivate
US6291531B1 (en) * 1999-10-07 2001-09-18 Boehringer Ingelheim Pharma Kg LTB4 antagonist, processes for the preparation thereof and its use as a pharmaceutical composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03080037A2 *

Also Published As

Publication number Publication date
AU2003212375A1 (en) 2003-10-08
JP2005529085A (ja) 2005-09-29
WO2003080037A3 (fr) 2004-06-10
DE10213350A1 (de) 2003-10-16
CA2480032A1 (fr) 2003-10-02
TW200407109A (en) 2004-05-16
UY27731A1 (es) 2003-10-31
PE20030947A1 (es) 2004-01-13
AR039141A1 (es) 2005-02-09
WO2003080037A2 (fr) 2003-10-02

Similar Documents

Publication Publication Date Title
DE60026144T2 (de) Benzamidformulierung mit histon-deacetylase-inhibitoraktivität
DE69912790T2 (de) Farnesyl protein transferase inhibitoren zur behandlung von arthropathien
DE60211937T2 (de) Verwendung von flibanserin bei der behandung von störungen des sexuellen verlangens
EP1750700B1 (fr) Preparation liquide destinee a la medecine veterinaire, procede de fabrication et utilisation de ladite preparation
EP2477660B1 (fr) Composition pharmaceutique renfermant les agents actifs metformine et sitagliptine ou vildagliptine
EP2269647A2 (fr) Compositions médicamenteuses à base de composés à action anticholinergiques et de betamimétiques
DE102004011512A1 (de) Pharmazeutische Zubereitung enthaltend Pimobendan
DE60307258T2 (de) Salze von Tolterodin
EP1812002B1 (fr) Traitement de mastites
DE60101559T2 (de) Benutzung von comt-inhibitoren als analgetika
EP1682144B1 (fr) Formulations pharmaceutiques aromatisees presentant des proprietes pharmaceutiques ameliorees
EP2432452B1 (fr) Une solution pharmaceutique à boire contenant telmisartan
DE60030654T2 (de) Verwendung von Lasofoxifen
DE2360332C2 (de) Die Verwendung von 1-Carnitin oder einem 1-Carnitinderivat oder eines Salzes davon bei der Behandlung spezieller Lungenkrankheiten
DE102007052070A1 (de) Candesartancilexetil
EP2934490B1 (fr) Comprimés présentant une appétence améliorée et une stabilité au stockage satisfaisante
DE69907387T2 (de) Verwendung von Hydantoin-Derivaten zur Herstellung eines Medikaments zur Behandlung von refraktärer Vasculitis.
WO2003080037A2 (fr) Utilisation d'antagonistes de ltb4 dans la medecine animale
DE19815411A1 (de) Thermogenese stimulierend wirksame Arzneimittel
DE3528481A1 (de) Neues pharmazeutisches praeparat
DE2605243A1 (de) Pyrazolessigsaeurehaltiges arzneimittel
US20030225004A1 (en) Use of LTB4 antagonists in veterinary medicine
DE60311134T2 (de) Oromukosale formulierung und herstellungsverfahren dafür
DE2823268A1 (de) Blutdrucksenkendes mittel
DE2551591A1 (de) 4-(4-diphenylyl)-butylamine und pharmazeutische zusammensetzungen

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

17P Request for examination filed

Effective date: 20041210

17Q First examination report despatched

Effective date: 20050428

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060527