Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

• This invention relates to novel enantiomerically pure compounds of formula (I) useful in treating disorders which are characterized by an increased profileration and/or abnormal differentiation of normal, preneoplastic or neoplastic epithelial cells. These compounds are particularly useful in the field of dermatology. Also disclosed are compositions containing said novel compounds as well as methods of using the mentioned compounds to treat the mentioned disorders.
• the dextrorotatory compounds of formula (I) are useful for the manufacture of a medicine for treating keratinization disorders. Further the present invention provides methods of preparing the present novel compounds.
• novel compounds subject to the present invention are the dextrorotatory isomer of the compound liarozole and the pharmaceutically acceptable acid addition salts thereof.
• Liarozole is a racemic mixture, i.e. a mixture of its optical isomers, and is specifically mentioned as compound 28 in EP-0,371,559. Said patent application mentions the use of compounds like liarozole in the treatment of epithelial disorders.
• EP-0,260,744 describes the use of compounds like liarozole for inhibiting or lowering androgen formation.
• EP-0,371,559 and EP-0,260,744 recognize that compounds like liarozole have stereochemically isomeric forms, no example of an enantiomerically pure form is given of liarozole.
• Chemically liarozole is ( ⁇ )-5-[3-chlorophenyl]-lH-imidazol-l-ylmethyl]-lH-benz- imidazole, and is represented by formula (I). As can be seen from the chemical structure, liarozole has one stereogenic center (indicated with an asterisk in formula (I)).
• the subject of this invention is the enantiomerically pure dextrorotatory isomer or (+)-isomer of liarozole. Said isomer will hereinafter be referred to as (+)-liarozole.
• (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is iaevorotatory and with (+) or d meaning that the compound is dextrorotatory.
• the optically active isomers having an opposite sign of optical rotation are called enantiomers.
• Said enantiomers are identical except that they are mirror images of one another.
• a 1: 1 -mixture of such enantiomers is called a racemic mixture.
• Stereochemical purity is of importance in the field of pharmaceuticals since the respective enantiomers may have a different potency or may have a different activity.
• the enantiomer of a beneficial isomer may even be deleterious rather that simply inert. Several examples of such differences are known in the art.
• enantiomerically pure means that the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment the term “enantiomerically pure” means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.
• optical rotation of chemical substances is dependent upon experimental parameters.
• the values shown in the experimental part hereinunder are specific rotations and the experimental conditions such as temperature, the wavelength of the plane polarized light used, the solvent as well as the concentration of the sample are indicated in the conventional way.
• the optical rotation may vary (it may even change sign!) when for instance an acid addition salt is formed.
• the sign of the optical rotation of the base fo ⁇ n is intended under the given experimental conditions shown hereinunder.
• the intermediate with the same absolute configuration of the stereocenter as the desired enantiomer of the final product will be designated with the prefix (B) before the reference number.
• the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
• the latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,
• 2-oxopropanoic ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butene- dioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricar- boxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
• salt form can be converted by treatment with alkali into the free base form.
• addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
• Preferred pharmaceutically acceptable acids are hydrochloric acid and (E)-2-butenedioic acid.
• Enantiomerically pure (+)-liarozole may be prepared by reacting an enantiomerically pure intermediate diamine of formula (B)-(II) with formic acid or a functional derivative thereof.
• Said functional derivative of formic acid is meant to comprise the halide, anhydride, amide and ester, including the ortho and imino ester form thereof. Also methanimidamide or an acid addition salt thereof can be used as cyclizing agent.
• the enantiomerically pure intermediate diamine of formula (B)-(II) may be prepared by reducing an intermediate of formula (B)-(i ⁇ ) by a standard nitro-to-amine reduction reaction.
• the desired enantiomer of the intermediate of formula (B)-(]H) can be prepared by fractional crystallization of a racemic mixture of the intermediate of formula (HI) with an enantiomerically pure chiral acid.
• Preferred chiral acid for the above fractional crystallization is 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid (i.e. 10-camphorsulfonic acid).
• Appropriate solvents for carrying out said fractional crystallization are water, ketones, e.g. 2-propane, 2-butanone; alcohols, e.g. methanol, ethanol, 2-propanol. Mixtures of ketones and water are very suitable for the above fractional crystallization. Preferably a mixture of 2-propanone and water is used.
• the ratio of water/2-propanone by volume may vary from 1/10 to 1/2. Preferred range of said ratio is 1/5 to 1/3.
• fractional crystallizations are suitably carried out below room temperature, preferably below 5°C.
• (+)-isomer of the compound of formula (I) may be prepared by cyclizing an intermediate of formula (B)-(IV) following procedures as described above for the cyclization of intermediates of formula (B)-(II) and desulfurating the thus obtained intermediate of formula (B)-(V).
• R represents Ci ⁇ alkyl, wherein Ci- ⁇ alkyl means a straight or branch chained saturated hydrocarbon radicals having 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl.
• R is methyl.
• the intermediates of formula (B)-(IV) may be prepared by reacting an intermediate of formula (B)-(VI) with a reagent of formula (VII), alkylating the thus formed thiourea derivative of formula (B)-(VIII) subsequently cyclizing the intermediate of formula
• the enantiomerically pure intermediate of formula (B)-(VI) can be prepared by art- known resolution techniques, e.g. by chromatography using chiral stationary phases or by forming diastereomeric compounds such as forming an amide with an enantiomerically pure chiral acid, e.g. ⁇ -hydroxybenzeneacetic acid (mandelic acid), or by forming diastereomeric salt forms using enantiomerically pure chiral acid.
• Liarozole has retinoid mimetic effects in vivo and in vitro. This means that the compound is thought to inhibit retinoic acid (RA) catabolism, so that increased retinoic acid (RA) levels lead to pronounced RA effects at the tissue or cell level. Liarozole has also been shown to be a potent inhibitor of androgen biosynthesis. Preclinical and clinical studies are ongoing showing the utility of liarozole in the field of oncology and dermatology.
• (+)-liarozole shows increased retinoic mimetic activity when compared with racemic liarozole or with the enantiomerically pure leavorotat ⁇ ry isomer of liarozole, hereinafter referred to as (-)-liarozole. More in particular, (+)-liarozole is a stronger inhibitor of the retinoic acid metabolism in human skin epidermis and human tongue squamous carcinoma cells (SCC25). Moreover, the increased effectiveness of (+)-liarozole as a retinoic mimetic, especially in the field of dermatology, can be evidenced by the test "Induction of Pinnal Epidermal Hyperplasia in Hairless Mice".
• (+)-liarozole The effect of retinoic acid at the level of normal human keratinocytes is also more potentiated by (+)-liarozole. Furthermore, it has been found from toxicity tests that, unexpectedly, the use of (+)-liarozole is more suitable, when compared to (-)-liarozole, for the manufacture of a medicament for treating keratinization disorders.
• the increased retinoic mimetic activity of (+)-liarozole is described in more detail in the experimental part hereinafter. From the above, it can be conceived that by administering an effective amount of (+)-liarozole it is possible to accomplish a more "targeted” dermatological therapy.
• a more "targeted” dermatological therapy means that by using the (+)-isomer of liarozole, the compound is used which has a higher retinoic mimetic activity.
• (+)-liarozole and its pharmaceutically acceptable acid addition salts in the method of the present invention is based on their useful property to delay the catabolism of retinoids, such as, all-tr ⁇ /w-retinoic acid, 13-cw-retinoic acid and their derivatives. The latter results in more sustained/ higher tissue concentrations of retinoids and improved control of differentiation and growth of various cell types.
• This action of (+)-liarozole is also called retinoic mimetic activity because administering (+)-liarozole causes the same effect as if retinoid would be administered.
• (+)-liarozole can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic epithelial cells.
• (+)-Liarozole and its pharmaceutically acceptable acid addition salts is therefore useful in a method of treating disorders which are characterized by an increased proliferation and or abnormal differentiation of epithelial cells.
• (+)-Liarozole shows activity on cells of which the growth and differentiation is not substantially mediated by or insensitive to the actions of androgens or estrogens, in particular on cells of which the growth and differentiation is sensitive to the actions of retinoids.
• Special uses include the ability to cure and/or reduce a variety of disorders of keratinization such as, for example, rosacea, acne, psoriasis, ichthyosis, warts, callosites, acanthosis nigricans, lichen planus, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, precancerous skin conditions, such as, actinic keratoses, and keloids, epidermolytic hyperkeratosis, Darter's disease, pityriasis rubra pilaris, congenital ichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, melasma, hyperpigmentation.
• (+)-Liarozole and its pharmaceutically acceptable acid addition salts is useful for the manufacture of a medicine for treating keratinization disorders.
• an effective amount to treat disorders which are characterized by an excessive proliferation and/or abnormal differentiation of tissues would be from 0.001 mg/kg to 20 mg/kg body weight and more preferably from 0.01 mg kg to 10 mg kg body weight.
• compositions there may be cited all compositions usually employed for systemically or topically administering drugs.
• an effective amount of the particular compound, optionally in acid-addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
• any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represents the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
• Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
• Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
• the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
• compositions usually employed for topically administering drugs e.g., creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders, liquid or semi-liquid formulation and the like.
• Application of said compositions may be by aerosol e.g. with a propellent such as nitrogen carbon dioxide, a fireon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab.
• a propellent such as nitrogen carbon dioxide, a fireon
• a propellent such as a pump spray
• drops lotions
• a semisolid such as a thickened composition which can be applied by a swab.
• semisold compositions such as salves, creams, pastes, gellies, ointments and the like will conveniently be used.
• Dosage unit form as used in the specification and claims herein refers to physically discreate units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powders packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
• compositions of the cosmetic type, such as toilet waters, packs, lotions, skin milks or milky lotions.
• Said preparations contain, besides the active ingredient, components usually employed in such preparations.
• components usually employed in such preparations.
• further ingredients may be incorporated in the compositions, e.g. antiinflamatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, or other anti-acne agents.
• compositions which comprise an inert carrier, an effective amount of (+)-liarozole or an acid addition salt form thereof and an effective amount of a retinoic acid, a derivative thereof, in particular retinol, or a stereochemically isomeric form thereof.
• retinoic acids and (+)-liarozole act in a synergistic manner. Indeed, the combined effect of both substances is greater than the sum of their respective effects when administered separately.
• the above described retinoic acid containing compositions are particularly useful for treating acne or for retarding the effects of aging of the skin and generally improve the quality of the skin, particularly human facial skin.
• a pharmaceutical or cosmetical composition containing retinoic acid or a derivative thereof as the active ingredient in intimate admixture with a dermatologically acceptable carrier can be prepared according to conventional compounding techniques, such as those known for topical application of retinoic acid and its derivatives optionally in admixture with cyclodextrines or derivatives thereof known in the art.
• compositions for topical application are in form of a cream, ointment or lotion comprising from 0.001 to 0.5% (particularly from 0.01 to 0.1%) all- rr ⁇ /tf-retinoic acid, 13-cw-retinoic acid or a derivative thereof, in particular retinol, and from 0.1 to 5% of a (+)-liarozole or a dermatologically acceptable acid addition salt thereof, in a semi-solid or liquid diluent or carrier.
• These preferred compositions should preferably be non-irritating and as far as possible they should be odorless and non-toxic.
• the composition usually contain, besides water or an organic solvent, several of certain organic emollients, emulsifiers for the aqueous and/or non aqueous phases of the compositions, wetting agents preservatives and agents that facilitate the penetration and remainence of the active agents in the skin.
• the retinoic acid containing compositions of the invention are applied topically to the area to be treated or protected, at regular intervals, as needed, generally about 7 to about 21 times per week. The duration of the treatment will depend upon the nature and severity of the condition to be treated as well as the frequency of application of the composition.
• Example 1 A heterogeneous mixture of ( ⁇ )-4-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-2- nitrobenzenamine (the preparation of which is described in EP-371,559) (500 g) in
• Example 2 a) A mixture of (4-amino-3-nitrophenyl) (3-chlorophenyl)methanone (50 g), formamide (375 ml) and formic acid (63 ml) was sti ⁇ ed and refluxed for 17 hours. After cooling, the mixture was poured on ice. The precipitate was filtered off and dried, yielding 55 g (99.4%) of ( ⁇ )-N-[(4-amino-3-nitrophenyl) (3-chlorophenyl)methyl]formamide (interm. 3). b) A mixture of intermediate (3) (50.7 g), hydrochloric acid 6N (350 ml) and 2-propanol (70 ml) was stirred and refluxed for 17 hours.
• Example 7 Retinoic acid metabolism in human tongue squamous carcinoma cells.
• Human tongue squamous carcinoma cells (SCC25) were seeded in 6- well plates and grown for 4 days at 37 °C.
• the medium used consisted of a 1:1 mixture of Hans' F12 and Dulbecco's modified Eagle's medium supplemented with hydrocortisone and fetal calf serum. After 4 days of growth, the medium was replaced by a keratinocyte serum free medium and the confluent cells were further incubated for 3 days. The medium was refreshed 16 hours before the onset of the experiment.
• test compound and/or 2 ⁇ l DMSO were added to the media before the reaction was initiated by the addition of 1 ⁇ Ci [1 l,12-3H]-retinoic acid. After 3 hours of incubation at 37 °C, the medium plus the cells were extracted and [1 l,12-3__T]-retinoic ac ⁇ as analyzed by HPLC as described by Van Wauwe et al., J. Pharmacol. Exp. Ther. (1992), 261 : 773-779. The results of this test showed that compound No. 2, i.e.
• the HC1 salt of (+)-liarozole inhibited the hydroxylation of retinoic acid in human tongue squamous carcinoma cells with an IC50 value of 1.0 ⁇ M, the HC1 salt of racemic liarozole had an IC50 value of 2.9 ⁇ M and the HC1 salt of (-)-liarozole was almost inactive.
• Example 8 Induction of Pinnal Epidermal Hyperplasia in Hairless Mice
• One of the cutaneous effects of retinoids is their potent ability to induce epidermal hyperplasia in vivo (Conner, Models in dermatology 1987, Vol. 3 Karger, Basel, 1987, p. 23-28). Therefore, liarozole and both its stereochemically isomers were compared with all-tr ⁇ tts-retinoic acid for their ability to induce epidermal hyperplasia in hairless mice.
• mice On day 15, the animals were killed and ear tissue was collected from which 2 ⁇ m thick sections were prepared for morphological analysis. The thickness of the total viable epidermis was measured and the epidermis of placebo treated mice consisted of a thin epithelium. In contrast, the epidermis of animals treated with RA or a test compound was hyperplastic. The results are presented in Table 1.
• Example 9 Toxicological test. Dogs were administered daily and for one month an oral dose of the test compounds, compound No. 2 and the HC1 salt of (-)-liarozole. At a dose of 10 mg/kg/day, the concentrations in most dog tissues for compound No. 2 were at least a tenfold lower than for the HC1 salt of (-)-liarozole.
• compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention.
• Active ingredient as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
• Example 13 Film-coated tablets -Prep.arati.on..Q tabtet.co ⁇ e
• the wet powder mixture was sieved, dried and sieved again.
• the whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient
• Example 14 Injectable solution
• Example 15 Suppositories 3 g A.I. was dissolved in a solution of 3 g 2,3-dihydroxy-butanedioic acid in 25 ml polyethylene glycol 400. 12 G surfactant (SPAN ®) and triglycerides (Witepsol 555 ®) q.s. ad 300 g were molten together. The latter mixture was mixed well with the former solution. The thus obtained mixture was poured into moulds at a temperature of 37 ⁇ 38°C to form 100 suppositories each containing 30 mg of the active ingredient
• Example 16 2% cream
• 75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearate and 10 mg isopropyl myristate are introduced into a doublewall jacketed vessel and heated until the mixture has completely molten.
• This mixture is added to a separately prepared mixture of purified water, 200 mg propylene glycol and 15 mg polysorbate 60 having a temperature of 70 to 75°C while using a homogenizer for liquids.
• the resulting emulsion is allowed to cool to below 25°C while continuously mixing.
• a solution of 20 mg A.I., 1 mg polysorbate 80 and purified water and a solution of 2 mg sodium sulfite anhydrous in purified water are next added to the emulsion while continuously mixing.
• the cream, 1 g of the A.I. is homogenized and filled into suitable tubes.
• Example 17 2% topical gel
• Example 18 2% topical cream
• Example 19 2% liposome formulation A mixture of 2 g A.I. microfine, 20 g phosphatidyl choline, 5 g cholesterol and 10 g ethyl alcohol is stirred and heated at 55-60°C until complete dissolution and is added to a solution of 0.2 g methyl paraben, 0.02 g propyl paraben, 0.15 g disodium edetate and 0.3 g sodium chloride in purified water while homogenizing. 0.15 g Hydroxypropyl- methylcellulose in purified water ad 100 g is added and the mixing is continued until swelling is complete.
• Example 20 2% liposome formulation
• a mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 g ethyl alcohol is stirred and heated at 40°C until complete dissolution.
• 2 g A.I. microfine is dissolved in purified water by mixing while heating at 40°C.
• the alcoholic solution is added slowly to the aqueous solution while homogenizing during 10 minutes.
• 1.5 g Hydroxypropyl- methylcellulose in purified water is added while mixing until swelling is complete.
• the resulting solution is adjusted to pH 5.0 with sodium hydroxide 1 N and diluted with the rest of the purified water ad 100 g.

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• 1995
  • 1995-02-10 TW TW084101153A patent/TW401415B/zh active
  • 1995-02-10 SG SG1996002813A patent/SG52325A1/en unknown
  • 1995-02-10 WO PCT/EP1995/000490 patent/WO1995022540A1/en not_active Application Discontinuation
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  • 1995-02-10 AU AU15787/95A patent/AU689206B2/en not_active Expired - Fee Related
  • 1995-02-10 EP EP95907662A patent/EP0745077A1/de not_active Withdrawn
  • 1995-02-10 CA CA002182583A patent/CA2182583A1/en not_active Abandoned
  • 1995-02-17 IL IL11268895A patent/IL112688A0/xx unknown
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