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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/32—Antioestrogens

Definitions

• the present invention relates to a compound.
• the present invention relates to a compound and to a pharmaceutical composition comprising the compound.
• the present invention also relates to the use of that compound in the field of medicine.
• oestrogens are the major mitogens involved in promoting the growth of tumours in endocrine-dependent tissues, such as the breast and endometrium.
• plasma oestrogen concentrations are similar in women with or without breast cancer, breast tumour oestrone and oestradiol levels are significantly higher than in normal breast tissue or blood.
• In situ synthesis of oestrogen is thought to make an important contribution to the high levels of oestrogens in tumours and therefore specific inhibitors of oestrogen biosynthesis are of potential value for the treatment of endocrine-dependent tumours.
• PCT/GB92/01587 teaches novel steroid sulphatase inhibitors and pharmaceutical compositions containing them for use in the treatment of oestrone dependent tumours, especially breast cancer.
• These steroid sulphatase inhibitors are sulphamate esters. Examples of such inhibitors are sulphamate ester derivatives of steroids.
• steroids have the general fo ⁇ nula of:
• PCT/GB92/01587 is oestrone-3-sulphamate (otherwise known as "EMATE"), Wahich has the following structure:
• EMATE is a potent El-STS inhibitor as it displays more than 99% inhibition of El-STS activity in intact MCF-7 cells at 0J ⁇ M. EMATE also inhibits the El-STS enzyme in a time- and concentration-dependent manner, indicating that it acts as an active site-directed inactivator.
• EMATE was originally designed for the inhibition of El-STS, it also inhibits dehydroepiandrosterone sulphatase (DHA-STS), which is an enzyme that is believed to have a pivotal role in regulating the biosynthesis of the oestrogenic steroid androstenediol.
• DHA-STS dehydroepiandrosterone sulphatase
• EMATE is also active in vivo as almost complete inhibition of rat liver El-STS (99%) and DHA-STS (99%) activities resulted when it is administered either orally or subcutaneously.
• EMATE has been shown to have a memory enhancing effect in rats.
• Studies in mice have suggested an association between DHA-STS activity and the regulation of part of the immune response. It is thought that this may also occur in humans.
• the bridging O-atom of the sulphamate moiety in EMATE is important for inhibitory activity.
• the present invention seeks to provide novel compounds suitable for the inhibition of El- STS but preferably wherein those compounds also have an oestrogenic effect.
• a key advantage of the present invention is that the sulphamate compounds of the present invention can act as El-STS inhibitors.
• the compounds of the present invention can be used as oestrogenic compounds.
• the compounds are potent oestrogenic compounds. More preferably some of the compounds are highly oestrogenic compounds.
• the present invention therefore provides sulphamate compounds which are both steroid sulphatase inhibitors and oestrogenic.
• the compounds of the present invention are also advantageous in that they may be orally active.
• the sulphamate compounds of the present invention are believed to be useful for the treatment of breast cancer.
• the sulphamate compounds of the present invention are useful for the treatment of non-malignant conditions, such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
• the sulphamate compounds of the present invention are also believed to have therapeutic uses other than for the treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases and ho ⁇ none replacement therapy.
• the sulphamate compounds of the present invention are also believed to be useful for birth control etc.
• ring components may be fused together or joined via one or more suitable spacer groups.
• the present invention also encompasses combinations thereof.
• sulphamate as used herein includes an ester of sulphamic acid, or an ester of an N-substituted derivative of sulphamic acid, or a salt thereof.
• the sulphamate group has the formula:
• each of Rj and R 2 is independently selected from H or a hydrocarbyl group.
• hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen. A non-limiting example of a hydrocarbyl group is an acyl group.
• the hydrocarbyl group is a hydrocarbon group.
• hydrocarbon means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group.
• hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
• Ri and R 2 are independently selected from H or alkyl, cycloalkyl, alkenyl and aryl, or together represent alkylene, wherein the or each alkyl or cycloalkyl or alkenyl or optionally contain one or more hetero atoms or groups.
• the N-substituted compounds of this invention may contain one or two N-alkyl, N-alkenyl, N-cycloalkyl or N-aryl substituents, preferably containing or each containing a maximum of 10 carbon atoms.
• R t and/or R 2 is alkyl
• the preferred values are those where R ! and R 2 are each independently selected from lower alkyl groups containing from 1 to 5 carbon atoms, that is to say methyl, ethyl, propyl etc.
• Rj and R 2 are both methyl.
• R ⁇ and/or R 2 is aryl
• typical values are phenyl and tolyl (-PhCH 3 ; o-, m- or p-).
• Rj and R 2 represent cycloalkyl
• typical values are cyclopropyl, cyclopentyl, cyclohexyl etc.
• R;. and R 2 typically represent an alkylene group providing a chain of 4 to 6 carbon atoms, optionally interrupted by one or more hetero atoms or groups, e.g. -0- or -NH- to provide a 5-, 6- or 7- membered heterocycle, e.g. morpholino, pyrrolidino or piperidino.
• alkyl, cycloalkyl, alkenyl and aryl we include substituted groups containing as substituents therein one or more groups which do not interfere with the sulphatase inhibitory activity of the compound in question.
• exemplary non-interfering substituents include hydroxy, amino, halo, alkoxy, alkyl and aryl.
• At least one of Rj and R 2 is H.
• the polycyclic compound can comprise at least two ring components, or least three ring components, or least four ring components.
• the polycyclic compound comprises four ring components.
• the polycyclic compound will contain, inclusive of all substituents, no more than 50 about carbon atoms, more usually no more than about 30 to 40 carbon atoms.
• Preferred polycyclic compounds are those that are based on steroidal ring structures, that is to say a cyclopentanophenanthrene skeleton.
• a preferred polyclic compound of the present invention has a structure similar to a steroidal structure but wherein an oxime group is attached to or is part of the D ring.
• ring D 1 represents the combination of a ring and the oxime group (i.e. the oxime group is part of or is attached to the ring component).
• the ring of D 1 may be substituted or unsubstituted, saturated or unsaturated.
• the rings A, B and C - which are similar to those of a steroidal nucleus - may be substituted or unsubstituted, saturated or unsaturated.
• a preferred example of D 1 has the formula:
• )- symbols represent the ring of D 1 being joined to the remainder of the steroidal structural formula; and X represents H or a suitable substiment.
• a suitable substituent is a hydrocarbyl group.
• D 1 SUBSTTTUTE SHEET (RULE 26) A further preferred example of D 1 has the formula:
• )- symbols represent the ring of D 1 being joined to the remainder of the steroidal structural formula; and X represents H or a suitable substiment.
• X represents H or a suitable substiment.
• a suitable substituent is a hydrocarbyl group. Here the indicated Me group is vertical.
• the ring of D 1 may be substituted with suitable groups - such as alkyl, hydroxy, halo etc.
• suitable groups - such as alkyl, hydroxy, halo etc.
• the ring atoms of D 1 that are not associated with neighbouring ring(s) are unsubstituted.
• these ring atoms are indicated below as 1 and 2 for the above presented preferred formula:
• the oxime group can be of either geometrical isomeric form.
• the oxime group can be the syn isomer.
• the oxime group is the anti isomer.
• the above presented formulae for D 1 show the anti isomeric structure.
• the present invention encompasses compounds that have geometrical isomers.
• the compounds may be present in just one isomeric form or in combinations thereof.
• the compound is present as at least the anti isomer.
• the compound is present only as the anti isomer.
• suitable preferred steroidal nuclei rings A-C for the rings A-C of the compounds of the present invention include rings A-C of oestrone and dehydroepiandrosterone .
• Preferred steroidal nuclei having suitable rings A-C for the rings A-C of the compounds of the present invention are:
• oestrones and substituted oestrones viz: oestrones
• dehydroepiandrosterones and substi ted dehydroepiandrosterones viz: dehydroepiandrosterones
• the ring system .ABCD 1 may contain a variety of non-interfering substituents.
• the ring system ABCD 1 may contain one or more of hydroxy, alkyl especially lower (C r C 6 ) alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and other pentyl isomers, and n-hexyl and other hexyl isomers, alkoxy especially lower (C r C 6 ) alkoxy, e.g. methoxy, ethoxy, propoxy etc., alkinyl, e.g. ethinyl, or halogen, e.g. fluoro substituents.
• the polyclic compound may not contain or be based on a steroid nucleus.
• the polyclic compound may contain or be based on a non- steroidal ring system - such as diethylstilboestrol, stilboestrol and other ring systems.
• the at least one sulphamate group is attached to any one or more of the ring components.
• the polycyclic compound has a steroidal structore and wherein the sulphamate group is attached to the A ring.
• the sulphamate group is attached to the 3 position of the A ring.
• a preferred compound has the formula:
• R denotes a sulphamate group as described above.
• Me group is vertical.
• R is die above-mentioned preferred formula for the sulphamate group.
• the oxime group can be of either geometrical isomer form.
• the oxime group can be the syn isomer.
• the oxime group is the anti isomer.
• a more preferred compound has the formula:
• R denotes a sulphamate group as described above.
• R is the above-mentioned preferred formula for the sulphamate group.
• Rj and R 2 is H.
• the oxime group can be of either geometrical isomer form.
• the oxime group can be the syn isomer.
• the oxime group is the anti isomer.
• sulphamate group of the compound of the present invention were to be replaced with a sulphate group to foim a sulphate compound then that sulphate compound would be hydroly sable by an enzyme having steroid sulphatase (E.C. 3J.6.2) activity - i.e. when incubated with steroid sulphatase EC 3 J.6.2 at pH 7.4 and 37 °C.
• E.C. 3J.6.2 enzyme having steroid sulphatase
• sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sulphatase (E.C. 3J.6.2) activity and would yield a K m value of less than 50mmoles when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37 ⁇ C.
• E.C. 3J.6.2 enzyme having steroid sulphatase
• sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sulphatase (E.C. 3J.6.2) activity and would yield a K m value of less than 50 ⁇ moles when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37°C.
• E.C. 3J.6.2 enzyme having steroid sulphatase
• the compound of the present invention is not hydrolysable by an enzyme having steroid sulphatase (E.C. 3J.6.2) activity.
• the sulphamate compounds of the present invention may be prepared by reacting an appropriate alcohol with the appropriate sulfamoyl chloride, R ⁇ NSO ⁇ l. Preferred conditions for carrying out the reaction are as follows.
• the alcohol is derivatised, as appropriate, prior to reaction with the sulfamoyl chloride.
• functional groups in the alcohol may be protected in known manner and the protecting group or groups removed at the end of the reaction.
• the steroid sulphatase inhibitors of this invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, adjuvants, excipients, diluents etc. and usually for parenteral administration.
• Approximate effective dose rates are in the range 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70Kg) body weight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day. They may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days.
• the compounds may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose.
• the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg.
• Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the
• the steroid sulphatase inhibitors of this invention may be used in combination therapies, either with another sulphatase inhibitor, or, for example, in combination with an aromatase inhibitor, such as for example, 4-hydroxyandrostenedione (4-OHA).
• an aromatase inhibitor such as for example, 4-hydroxyandrostenedione (4-OHA).
• the subject is preferably a mammal, more preferably a human.
• the human is a woman.
• the present invention provides novel compounds for use as steroid sulphatase inhibitors, and pharmaceutical compositions containing them.
• the compounds also have a oestrogenic activity - particularly when compared with EMATE.
• the present invention provides novel compounds having steroid sulphatase inhibitory activity which, in some cases, have extremely .high activity levels.
• the present invention provides novel compounds having oestrogenic activity which, in some cases, have extremely high activity levels.
• SUBSTTTUTE SHEET (RULE 26) (iv) a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or the salt, admixed with a pharmaceutically acceptable diluent, carrier or excipient;
• the pharmaceutically acceptable salts of the compounds of/for use in the present invention include suitable acid addition or base salts thereof.
• suitable pharmaceutical salts see Berge et al, J Pharm Sci, ( ⁇ 6, 1-19 (1977).
• suitable acid addition salts are formed from acids which form non- toxic salts.
• suitable examples of such salts are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
• suitable base salts are formed from bases which form non-toxic salts. Suitable examples thereof are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, N-benzyl-N-(2-phenylethyl)amine, 1 -adamantylamine and diethanolamine salts.
• the present invention also covers pharmaceutical compositions comprising the compounds of the present invention.
• the compounds of the present invention including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates
• they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice.
• the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
• SUBSTTTUTE SHEET (RULE 26) Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
• a physician will determine the dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
• the compounds of /for use in the present invention can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
• An alternative means of transdermal administration is by use of a skin patch.
• they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, such as at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
• compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
• excipients such as starch or lactose
• capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
• compositions can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
• the compositions will comprise a suitable carrier or diluent.
• compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
• compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
• the daily dosage level of the compounds of the present invention and their pharmaceutically acceptable salts and solvates may typically be from 10 to 500 mg (in single or divided doses).
• tablets or capsules may contain from 5 to 100 mg of active compound for administration singly, or two or more at a time, as appropriate.
• the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. It is to be noted that whilst the above-mentioned dosages are exemplary of the average case there can, of course, be individual instances where higher or lower dosage ranges are merited and such dose ranges are within the scope of this invention.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent, excipient or carrier.
• the invention further provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament.
• the present invention also provides a veterinary formulation comprising a compound of the present invention, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, together with a veterinarily acceptable diluent, excipient or carrier.
• a compound of the present invention or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity is typically administered as a suitably acceptable formulation in accordance with normal veterinary practice and the
• SUBSTTTUTE SHEET (RULE 26) veterinary surgeon will determine the dosing regimen .and route of administration which will be most appropriate for a particular animal. However, as with human treatment, it may be possible to administer the compound alone for veterinary treatments.
• the present invention provides a compound of the present invention, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, or a veterinary formulation containing any of the foregoing, for use as an animal medicament.
• Steroid sulphatase (Steroid sulphatase is defmed as: Steryl Sulphatase EC 3J.6.2.) activity was measured in vitro using intact MCF-7 human breast cancer cells. This hormone dependent cell line is widely used to study the control of human breast cancer cell growth. It possesses significant steroid sulphatase activity (Maclndoe et al. Endocrinology, 123, 1281-1287 (1988); Purohit & Reed, Int. J. Cancer, 50, 901-905 (1992)) and is available in the U.S.A. from the American Type Culture Collection (ATCC) and in the U.K. (e.g. from The Imperial Cancer Research Fund).
• ATCC American Type Culture Collection
• MEM Minimal Essential Medium
• HEPES Flow Laboratories, Irvine, Scotland
• 5% foetal bovine serum 20 mM HEPES
• 2 mM glutamine 2 mM glutamine
• non-essential amino acids 0.075% sodium bicarbonate.
• Up to 30 replicate 25 cm 2 tissue cultore flasks were seeded with approximately 1 x 10 5 cells/flask using the above medium. Cells were grown to 80% confluency and medium was changed every third day.
• SUBSTTTUTE SHEET (RULE 26) Intact monolayers of MCF-7 cells in triplicate 25 cm tissue cultore flasl s were washed with Earle's Balanced Salt Solution (EBSS from ICN Flow, High Wycombe, U.K.) and incubated for 3-4 hours at 37°C with 5 pmol (7 x 10 5 dpm) [6,7- 3 H]oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in se.rum-free MEM (2.5 ml) together with oestrone-3-sulphamate (11 concentrations: 0; lfM; O.OlpM; O.lpM; lpM; O.OlnM; O.lnM; InM; O.OlmM; O.lmM; ImM).
• EBSS Earle's Balanced Salt Solution
• the mass of oestrone-3 -sulphate hydro lysed was calculated from the 3 H counts obtained (corrected for the volumes of the medium and organic phase used, and for recovery of [ 14 C]oestrone added) and the specific activity of the substrate.
• Each batch of experiments included incubations of microsomes prepared from a sulphatase-positive human placenta (positive control) and flasks without cells (to assess apparent non-enzymatic hydrolysis of the substrate).
• the number of cell nuclei per flask was determined using a Coulter Counter after treating the cell monolayers with Zaponin.
• One flask in each batch was used to assess cell membrane status and viability using the Trypan Blue exclusion method (Phillips, H.J. (1973) In: Tissue culture and applications, [eds: Kruse, D.F. & Patterson, M.K.]; pp. 406-408; Academic Press, New York).
• Results for steroid sulphatase activity are expressed as the mean ⁇ 1 S.D. of the total product (oestrone + oestradiol) formed during the incubation period (20 hours) calculated for 10 cells and, for values showing statistical significance, as a percentage reduction (inhibition) over incubations containing no oestrone-3 -sulphamate. Unpaired Student's t- test was used to test the statistical significance of results.
• Incubations (1 ml) were carried out using a protein concentration of 100 mg/ml, substrate concentration of 20 mM [6, 7- 3 H]oestrone-3 -sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) and an incubation time of 20 minutes at 37°C.
• Eight concentrations of the compounds to be tested may be employed: 0 (i.e. control); 0.05mM; OJmM; 0.2mM; 0.4mM; 0.6mM; 0.8mM; l.OmM.
• Compounds according to the present invention such as Compound 2 (such as at levels of 0J mg/Kg/day for five days) are admimstered orally to rats with another group of animals
• SUBSTTTUTE SHEET (RULE 26) receiving vehicle only (propylene glycol). At the end of the stody uteri are obtained and weighed with the results being expressed as uterine weight/ whole body weight x 100.
• CHN analysis for oestrone o.xime was alright, but by considering a .small methanol content (from the cryst ⁇ ilUzation solvent), which involved in hydrogen bonding to the molecule as X-ray shows, then the CHN values are veiy close.
• Ace. MS: m/z (FAB) + 365.15451 C I 8 H 25 N 2 O 4 S

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• 1997
  • 1997-12-04 GB GB9725749A patent/GB2331987B/en not_active Expired - Fee Related
• 1998
  • 1998-12-03 AU AU13458/99A patent/AU1345899A/en not_active Abandoned
  • 1998-12-03 DE DE69841374T patent/DE69841374D1/de not_active Expired - Lifetime
  • 1998-12-03 ES ES98957034T patent/ES2337427T3/es not_active Expired - Lifetime
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  • 1998-12-03 JP JP2000522921A patent/JP2001524525A/ja active Pending
  • 1998-12-03 AT AT98957034T patent/ATE451107T1/de not_active IP Right Cessation
• 2000
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