Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
  • C07D239/80—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
• This virus was previously known as LAV, HTLV-III, or ARV.
• a common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
• Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313. 277 (1985)].
• Amino acid sequence homology provides evidence that the rjoi sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al, EMBO J. 4, 1267 (1985); Power, M.D. et ah, Science, 231, 1567 (1986); Pearl, L.H. et al., Nature 329, 351 (1987)].
• Compounds of formula I as herein defined, are disclosed. These compounds are useful in the inhibition of HIV reverse transcriptase (and its resistant varieties), the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
• This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV reverse transcriptase and its resistant varieties, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
• Compounds of formula I are defined as follows:
• G when present is halo, nitro, or cyano; n is 0-4;
• Ri is C3_5cycloalkyI, C2_5alkynyl, C2_4alkenyl, or cyano;
• R2 is C2_5alkynyl substituted with one or more of A, or
• C2_5alkenyl substituted with one or more of A wherein A is i) halo, ii) hydroxy, iii) amino, iv) cyano, v) nitro, vi) azido, vii) C3_gcycloalkyl, viii) C j _4alkoxy, unsubstituted or substituted with one or more of halo, ix) di-(C ⁇ _4alkyl)amino, x) C j _4alkylamino, xi) aryl, unsubstituted or substituted with one or more of D, wherein D is amino, nitro, cyano, or xii) aryloxy, unsubstituted or substituted with one or more of D; xiii) heterocycle, unsubstituted or substituted with one or more of D; xiv) heterocycle oxy; or xv) C2_5alkenyl; x
• any terminal alkynyl carbon is not substituted with any substituent selected from the group consisting of halo, hydroxy, amino, cyano, nitro, azido, C j _4alkoxy unsubstituted or substituted with one or more of halo, di-(C ⁇ _4alkyl)amino, C ⁇ alkylamino, aryloxy unsubstituted or substituted with one or more of D, or heterocycle oxy; or a pharmaceutically acceptable salt thereof.
• R 2 i IS C2_5 alkynyl substituted with halo, hydroxy, amino, cyano, nitro, azido, C3_g cycloalkyl, C j _4 alkoxy, di-(C ⁇ _4alkyl)amino, C j _4alkylamino, phenyl,
• R3 IS H or C ⁇ _ 3 alkyl
• Preferred compounds include
• Compound 26 has (S) stereochemistry at the 4-position, with the structure:
• the compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as racemates, racemic mixtures or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
• any variable e.g., G, R R R- etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkenyl” is intended to cover both branched- and straight-chain alkyl groups with at least one carbon-carbon double bond; “alkynyl” is intended to cover both branched- and straight-chain alkyl groups with at least one carbon-carbon triple bond.
• Halogen or “halo” as used herein, means fluoro, chloro, bromo and iodo.
• aryl is intended to mean phenyl, naphthyl, tetrahydronaphthyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
• heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
• heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiper- azinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimi
• the compounds of the present invention can be synthesized by the following methods.
• Method A The characteristic feature of Method A is R-metal addition to a dihydroquinazoline in the presence of magnesium ions and other good Lewis acids. Method A is further illustrated by Examples 24-29.
• Method B involves a cross-coupling reaction in the presence of palladium (II) chloridetriphenylphosphine couplex as a catalyst, to give aryl and heterocyclic substitutions of the 4-acetylene group.
• Example 35 illustrates the Method.
• Method C depicts another method of obtaining substituted 4-acetylene derivatives.
• a tetrahydropyran derivative 9 is formed by R-metal addition as in Method A, followed by reaction with an alcohol in the presence of pyridinium paratoluene sulfonate (PPTS) to form the corresponding alcohol intermediate jJL, wherein R ⁇ is CH3.
• PPTS pyridinium paratoluene sulfonate
• Method D is suitable for halo substituted 4-alkynyl derivatives.
• the penultimate hydroxy derivative JJ. is formed as in Method C, followed by reaction with the florinating agent diethylamino- sulfurtrifluoride (DAST). Deprotection may then be desired. Chlorination is a side reaction. Method D is specifically illustrated by Examples 11-14.
• the compounds of the present inventions are useful in the inhibition of HIV reverse transcriptase, the prevention of treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
• Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
• the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
• the particular advantage of the compounds of this mvention is their potent inhibition against HIV reverse transcriptase rendered resistant to other antivirals, such as L-697,661, which is 3- ([(4,7-dichloro-l,3-benzoxazol-2-yl)methyl]-amino)-5-ethyl-6-methyl- pyridin-2(lH)-one; or L-696,229, which is 3-[2-(l,3-benzoxazol-2- yl)ethyl]-5-ethyl-6-methyl-pyridin-2(lH)-one; or AZT.
• L-697,661 which is 3- ([(4,7-dichloro-l,3-benzoxazol-2-yl)methyl]-amino)-5-ethyl-6-methyl- pyridin-2(lH)-one
• L-696,229 which is 3-[2-(l,3-benzoxazol-2- yl)ethyl]
• the compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.
• the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
• the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV reverse transcriptase, e.g., by competitive inhibition.
• the compounds of this invention are commercial products to be sold for these purposes.
• the compounds of the present invention may be a ⁇ nostired orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
• a method of treating and a pharmaceutical composition for treating HIV infection and AIDS involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically- effective amount of a compound of the present invention.
• compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
• these compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
• these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
• compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally- acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• suitable non-toxic, parenterally- acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
• a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
• the compounds of this invention can be administered orally to humans in a dosage range of 0.1 to 100 mg/kg body weight in divided doses.
• One preferred dosage range is 0.1 to 10 mg/kg body weight orally in divided doses.
• Another preferred dosage range is 0.1 to 20 mg/kg body weight orally in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
• the present invention is also directed to combinations of the HIV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS.
• the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following Table C.
• Drug Name Manufacturer Indication is also directed to combinations of the HIV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS.
• the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following Table C.
• Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL)
• Granulocyte Amgen AIDS in combination Colony (Thousand Oaks, CA) w/AZT Stimulating Factor Fluconazole Pfizer cryptococcal
• the compound L-735,524 is an HTV protease inhibitor with the chemical name N- (2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(l- (4-(3-pyridyl-methyl)-2(S)-N , -(t-butylcarboxamido)-piperazinyl))- pentaneamide.
• Example 1 was dissolved in 5 mL of dry DMF and treated with 25 mg
• Example 2 was treated with a solution of 2.5 mL of trifluoroacetic acid in 3.5 mL of methylene chloride for 3 h under Ar. The solvents were removed by rotary evaporation and the residue partitioned between CHCI3 and 10% Na2C03. The organic layer was dried over Na2S ⁇ 4 and the solvents removed to give 47 mg of a yellow oil which was chromatographed on 5 g fine Si ⁇ 2 using 98:2 CHCI3-CH3OH to afford 33 mg of the title compound which solidified upon lyophilization from dioxane: mp ll9-121°C,
• Example 6 The product from Example 6 (4.22 g, 0.85 mmol) was dissoved in 75 mL of ethanol and treated with 214 mg (852 mmol) of pyridinium p-toluenesulfonate at 60°C under Ar for 5 h, followed by 17 h at room temp. The reaction mixture was concentrated and the residue partitioned between EtOAc and 10% NaHC03. The organic layer was washed with 10% NaHC03, water, brine, dried over Na2S ⁇ 4 and solvents removed to give 3.73 g (quant.) of an off-white solid which was used in subsequent reactions without further purification.
• Example 8 in 1 mL of mo ⁇ holine was stirred at room temp, under Ar for Ih, then stored in the freezer for 56 h.
• the solvent was removed by rotary evaporation, and the residue partitioned between water and
• Example 10 was treated by the procedure of Example 7 to afford 61 mg (97%) of the title compound which was used without further purification in the subsequent reaction.
• Example 15 was treated by the procedure of Example 13 to give 7 mg
• Example 7 was treated by the procedure of Example 13 to give 29 mg
• Example 1 A quantity of 300 mg (0.88 mmol) of 6-chloro-4- cyclopropyl-l-(4-methyoxybenzyl)-quinazolin-2(lH)-one (of Example 1, Step C) was treated with 3-ethynyl-pyridine (prepared according to Sakamoto et. al., Synthesis, No. 1, p. 312, 1983) by the procedure of Example 23 to afford 187 mg of a yellow solid. A quantity of 100 mg of this material was treated by the procedure of Example 3 to provide 68 mg (39%) of the title compound as a colorless foam.
• Example 3 to provide 33 mg (29%) of the title compound as a solid: mp 245°C (dec);
• Step C) was treated with 5-ethynyl-pyrimidine (prepared according to Sakamoto et. al., supra) according to the procedure of Example 23 to afford 125 mg of a yellow solid, mp 165-167°C, which was then treated by the procedure of Example 3 to provide 49 mg (18%) of the title compound as a solid: mp 255-256°C (dec);
• Example 23 was treated by the procedure of Example 2 to afford 78 mg of an oil which was then treated according to the procedure of Example
• Step C) was treated with (trimethylsilyl)acetylene according to the procedure of Example 23 to afford approximately 7 g of an oil which was dissolved in 200 mL of THF and stirred vigorously with 150 mL of
• Example 8 was treated with 5 mL of dimethylamine (condensed at
• Example 31 A mixture of 70 mg (0.28 mmol) of 6-Chloro-4- cyclopropyl-3,4-dihydro-4-ethynylquinazolin-2(lH)-one (Example 31), was coupled with iodobenzene according to the methods of Example 32 to provide 50 mg of the title compound as a colorless solid: mp 193-
• Example 3 was methylated according to Example 2 to give 200 mg of an oil. Treatment of this oil with TFA according to Example 3 provided 20 mg of the title compound as a colorless solid: mp 123-
• Example 7 was deprotected by treatment with TFA according to
• Example 3 to give 200 mg (82%) of the title compound as a colorless solid.
• An analytical sample was obtained by crystallization from hexane: mp 76-80°C.
• Example 8 and 99.7 mg (1.05 mmol) of 2-hydroxypyridine was treated according to the procedure of Example 21 to give 34 mg (71%) of the title compound as a colorless solid: mp 130-132°C,
• Example 31 A mixture of 60 mg (0.24 mmol) of 6-chloro-4- cyclopropyl-3,4-dihydro-4-ethynylquinazolin-2(lH)-one (Example 31), was coupled with 2-iodonitrobenzene according to the procedure of Example 32 to provide 32 mg of the title compound as a colorless solid: mp 181-182°C(dec);
• Example 39 in 1.0 mL of dimethoxyethane was treated with 0.4 mL of
• the assay measures the inco ⁇ oration of tritiated deoxyguanosine monophosphate by recombinant HTV reverse transcriptase (HIV RTR) (or other RT) into acid-precipitable cDNA at the Km values of dGTP and poly r(C) » oligo d(G)i2-l - Th e inhibitors of the present invention inhibit this inco ⁇ oration.
• HTV RTR HTV reverse transcriptase
• the assays were carried out in 55 mM Tris (pH 8.2)-30 mM KC1-30 mM MgCl 2 -l mM dithiothreitol-20 ⁇ g of rC:dG 12 _i8
• a 17 RT was employed in the assay.
• A17 RT is resistant to various aminopyridones, as described in Nunberg, J.H. et al, J. Virol. 65, 4887 (1991).
• the mixture was incubated overnight at 37°C in 5% CO2 atmosphere.
• MT-4 cells (50,000 per well) in a 96-weli microtiter cell culture plate. Incubation was continued for 3 days at 37°C in 5% CO2 atmosphere.
• the settled cells were resuspended and 125 ⁇ l harvested into a separate microtiter plate. The supernatant was assayed for HTV p24 antigen.
• the concentration of HIV p24 antigen was measured by an enzyme immunoassay, described as follows. Ahquots of p24 antigen to be measured were added to microwells coated with a monoclonal antibody specific for HIV core antigen. The microwells were washed at this point, and at other appropriate steps that follow. Biotinylated HIV- specific antibody was then added, followed by conjugated strepavidin- horseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to the concentration of HIV p24 antigen.
• Pairwise combinations of inhibitors were found to exhibit markedly enhanced inhibition of virus spread, in comparison to each inhibitor alone, or in comparison to merely additive inhibition of each inhibitor.
• the pairwise combination of 372 and ddl was found to exhibit markedly enhanced inhibition of virus spread, in comparison to 372 alone or ddl, or in comparison to the sum of 372 inhibitor and ddl inhibition.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Communicable Diseases (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Virology (AREA)
• Oncology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=27128564

Family Applications (2)

Family Applications After (1)

Country Status (15)

Families Citing this family (13)

Family Cites Families (2)

• 1993
  • 1993-04-28 WO PCT/US1993/003975 patent/WO1993022292A1/en not_active Application Discontinuation
  • 1993-04-28 AU AU42204/93A patent/AU4220493A/en not_active Abandoned
  • 1993-04-28 HU HU9403187A patent/HUT71401A/hu unknown
  • 1993-04-28 EP EP93910860A patent/EP0639184A1/en not_active Withdrawn
  • 1993-04-28 CZ CZ942724A patent/CZ272494A3/cs unknown
  • 1993-04-28 KR KR1019940703948A patent/KR950701322A/ko not_active Application Discontinuation
  • 1993-04-29 EP EP93201232A patent/EP0569083A1/en not_active Withdrawn
  • 1993-04-29 IL IL105551A patent/IL105551A0/xx unknown
  • 1993-04-29 CA CA002095194A patent/CA2095194A1/en not_active Abandoned
  • 1993-05-05 HR HR930857A patent/HRP930857A2/hr not_active Application Discontinuation
  • 1993-05-06 MX MX9302681A patent/MX9302681A/es unknown
  • 1993-05-06 AU AU38413/93A patent/AU3841393A/en not_active Abandoned
  • 1993-05-06 CN CN93107074A patent/CN1085550A/zh active Pending
  • 1993-05-07 SI SI9300244A patent/SI9300244A/sl unknown
  • 1993-05-07 JP JP5107015A patent/JPH0813805B2/ja not_active Expired - Lifetime
• 1994
  • 1994-10-31 BG BG99149A patent/BG99149A/xx unknown
  • 1994-11-04 FI FI945199A patent/FI945199A/fi unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events