Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D277/82—Nitrogen atoms

Definitions

• This invention relates to 1- (benzothiazol-2-yl) -4- (1- phenylmethyl) piperazines and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases . Description of the Related Art
• neuroleptics The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors.
• neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain.
• EPS extrapyramidal side effects
• tardive dyskinesias which are attributed to blockade of D2 receptors in the striatal region of the brain.
• the dopamine D4 receptor subtype has recently been identified
• Selective D 4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics .
• Rl and R2 are the same or different and represent hydrogen
• Ci-Cg alkyl Ci-Cg alkoxy
• Ci-C ⁇ alkylthio halogen, Ci-Cg alkyl, Ci-Cg alkoxy, Ci-C ⁇ alkylthio
• Ar represents aryl or heteroaryl, each of which is optionally substituted with R 3 , R 4 and/or R 6 ;
• R 7 , R 8 , R 9 , and R 10 are the same or different and represent hydrogen or alkyl;
• R 3 , R 4 , and R 6 independently represent hydrogen, halogen, hydroxy, C1-C6 alkyl, alkoxy, perfluoro alkyl ,
• R 3 , R 4 , and R 6 are methoxy, no two methoxy groups may be positioned ortho to each other on the phenyl ring; or or R 3 and R 4 together with the atoms to which they are attached represent a ring having 5-7 atoms; R5 represents hydrogen or C1-C6 alkyl.
• Dopamine D 4 receptors are concentrated in the limbic system (Science, 265 : 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders.
• Compounds of the present invention demonstrate high affinity and selectivity in binding to the D 4 receptor subtype. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine- mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D 4 receptors .
• Compounds of this invention are also useful in the treatment of depression, memory- impairment or Alzheimer's disease by modulation of D 4 receptors since they exist selectively in areas known to control emotion and cognitive functions .
• the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents.
• the compounds of the invention are useful in treatment of depression, memory- impairment or Alzheimer's disease.
• the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents .
• the invention provides pharmaceutical compositions comprising compounds of Formula I.
• the invention provides intermediates useful in the preparation of compounds of Formula I. DETAILED DESCRIPTION OF THE INVENTION As noted above, this invention provides compounds of Formula I which interact with dopamine subtypes.
• Preferred compounds of Formula I are those where R x and R 2 are hydrogen. More preferred compounds of Formula I are those wherein R ⁇ and R 2 are hydrogen and Ar is not unsubstituted phenyl, i.e., phenyl substituted with at least one non-hydrogen substituent. Particularly preferred compounds of Formula I are those where Ar is phenyl or naphthyl, each of which is optionally substituted with up to three of the groups listed above. In these particularly preferred compounds, when Ar is phenyl and R x and R 2 are hydrogen, R3 , R4 , and R 6 may not all be
• R 7 , R 8 , R 9 , and R 10 are hydrogen or C 1 -C 2 alkyl.
• no two methoxy groups may be methoxy groups positioned ortho to each other; more preferably no methoxy group may be positioned ortho to another methoxy group or to an ethoxy group. Even more preferably, when Ar is phenyl and two or three of R 3 , R 4 , and R 6 are methoxy or ethoxy, no methoxy or ethoxy group may be in an ortho position on the phenyl ring with respect to another methoxy or ethoxy group.
• Highly preferred compounds of the invention include those where one and only one of R 3 , R 4 , and R 6 is alkoxy when Ar is phenyl
• More preferred compounds of Formula I are those where Ar is
• Preferred compounds of the invention include those of Formula II :
• R3 and R4 are the same or different and represent hydrogen
• R4 are hydrogen simultaneously;
• R5 represents hydrogen or C1-C6 alkyl.
• Preferred compounds of Formula II include those where R 5 is hydrogen.
• Other preferred compounds of Formula II include those where R 5 is hydrogen, and R 3 is halogen or alkyl. More preferred compounds of Formula II are where R 4 is halogen, R 5 is hydrogen, and R 3 is halogen or C ⁇ C g alkyl.
• Particularly preferred compounds of Formula II are those where R x and R 2 are hydrogen, R 4 is halogen, R 5 is hydrogen, and R 3 is halogen or C- L -Cg alkyl.
• a highly preferred group of compounds are those where R 4 is halogen in the meta position of the phenyl ring, R 5 is hydrogen, and R 3 is halogen or C ⁇ C g alkyl.
• Rl and R2 are the same or different and represent hydrogen
• R 6 represents hydrogen, halogen, hydroxy, C1-C6 alkyl
• R 5 represents hydrogen or C1-C6 alkyl.
• Preferred compounds of Formula III include those where R 5 is hydrogen.
• Other preferred compounds of Formula III include those where R 5 is hydrogen, and R 6 is hydrogen, halogen or alkyl. More preferred compounds of Formula III are where R 6 is hydrogen.
• Particularly preferred compounds of Formula III are those where R 17 R 2 , and R 5 are hydrogen.
• the invention also provides intermediates useful in preparing compounds of Formula I . These intermediates have Formulae IV and V.
• R x and R 2 are defined as above for Formula I; and Z is a leaving group, such as halogen.
• Preferred compounds of Formula IV are where R ⁇ and R 2 are hydrogen, methyl or ethyl; and Z is chloro.
• R 1 , R 2 , and R 7 -R 10 are defined as above for Formula I.
• Preferred compounds of Formula V are where R x and R 2 are hydrogen.
• Particularly preferred compounds of Formula V are those where R 1# R 2 , and R 7 -R 10 are hydrogen, methyl, or ethyl.
• the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
• These compounds can be, for example, racemates or optically active forms.
• the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
• Representative compounds of the present invention include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
• Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n -COOH where n is 0-4, and the like.
• acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n -COOH where n is 0-4, and the like.
• acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,
• the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
• acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I .
• the invention is not limited to any one of the specific tautomers.
• the invention includes all tautomeric forms of a compound.
• C 1 -C 6 alkyl or “lower alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl , isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl , 2-pentyl, isopentyl, neopentyl , hexyl , 2-hexyl, 3-hexyl, and 3- methylpentyl .
• Preferred C1-C6 alkyl groups are methyl, ethyl,
• C- L -Cg alkoxy or “lower alkoxy” in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy .
• halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
• aryl or “Ar” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl) , or multiple condensed rings in which at least one is aromatic, (e.g., 1, 2 , 3 , 4-tetrahydronaphthyl, naphthyl , anthryl, or phenanthryl) , which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl , lower acyloxy, aryl, heteroaryl, and hydroxy.
• Preferred Ar groups are phenyl and 2- naphthyl .
• aryl or “Ar” is also meant heteroaryl groups where heteroaryl is defined as 5, 6, or 7 membered aromatic ring systems having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.
• heteroaryl groups are pyridyl , pyrimidinyl , pyrrolyl , pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl , quinolinyl, isoquinolinyl , thiazolyl, and thienyl, which can optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl , lower acyloxy, aryl, heteroaryl, and hydroxy.
• R 3 and R 4 may be connected together to form another ring with the atoms to which they are attached on the parent aryl or heteroaryl group.
• R 3 and R 4 may represent an alkylene, alkenylene, alkyleneoxy, alkylenedioxy, alkyleneazo, or alkylenediazo chain that together with the atoms to which they are attached form a ring having 5-7 atoms.
• Ar may be an optionally substituted naphthyl group or a bicyclic oxygen-containing group of the formula
• heterocyclic oxygen containing ring has a total of from 5 to 7 ring members, the heterocyclic ring being saturated or unsaturated, and optionally substituted.
• Ar may be a bicyclic nitrogen- containing group of the formula
• E is methylene or nitrogen and the heterocyclic oxygen containing ring has a total of from 5 to 7 ring members, the heterocyclic ring being saturated or unsaturated, and optionally substituted.
• bicyclic nitrogen-containing groups are :
• the invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders.
• the selective interaction of compounds of the invention with dopamine receptors results in the pharmacological activity of these compounds.
• the compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier.
• One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
• compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example ethyl, or n-propyl p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
• flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
• sweetening agents such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol , sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono-or diglycerides .
• fatty acids such as oleic acid find use in the preparation of injectables.
• the compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• Compounds of general formula I may be administered parenterally in a sterile medium.
• the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
• adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
• Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
• a 2-chlorobenzothiazole IV may be condensed with an appropriately substituted piperazine to provide a 1- (benzothiaol-2-yl) piperazine V.
• Piperazine V may then be reductively alkylated with an arylaldehyde VI using, for example, sodium cyanoborohydride to provide a 1- (benzothiaol-2-yl) -4- (1-phenylmethyl) piperazine of Formula I.
• Formula 1 represents a leaving group, e.g., a halide.
• a 1- (benzothiaol-2- yl) piperazine V may be alkylated using an appropriate arylmethyl compound VII where X is a halide, sulphonate ester or the like to provide a 1- (benzothiaol-2-yl) -4- (1- phenylmethyl) piperazine of Formula 1.
• Example 3 The following compounds are prepared essentially according to the methods set forth above in Examples 1 and 2 :
• the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer at 4° C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl . Incubations are carried out at 48 °C and contain 0.4 ml of
• nM 3 H-YM 09151-2 (Nemonapride, cis-5-Chloro- 2-methoxy-4- (methylamino) -N- (2-methyl-2- (phenylmethyl) -3- pyrroli-dinyl) benzamide) and the compound of interest in a total incubation of 1.0 ml.
• Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding.
• Binding characteristics for representative compounds of the invention for the D 2 and D 4 receptor subtypes are shown in Table 2 for rat striatal homogenates . Table 2 Compound Number 1 D 4 Ki (nM) D 2 Ki (nM)
• the binding constants of compounds of Formula I for the D 4 receptor generally range from about 5 nanomolar (nM) to about 100 nanomolar (nM) .
• These compounds typically have binding constants for the D 2 receptor of from about 500 nM to at least 4000 nM.
• the compounds of the invention are generally at least about 5 time more selective for the D 4 receptor than the D 2 receptor.
• these compounds are at least 10, and more preferably at least 20-50, times more selective for the D 4 receptor than the D 2 receptor.
• these compounds are at least 100 times more selective for the D 4 receptor than the D 2 receptor.

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• 1999
  • 1999-06-25 WO PCT/US1999/014427 patent/WO2000000482A1/en not_active Application Discontinuation
  • 1999-06-25 AU AU48326/99A patent/AU4832699A/en not_active Abandoned
  • 1999-06-25 EP EP99931915A patent/EP1089990A1/de not_active Withdrawn
  • 1999-06-25 CA CA002336150A patent/CA2336150A1/en not_active Abandoned
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