WO1999033815A1 - Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors - Google Patents
Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors Download PDFInfo
- Publication number
- WO1999033815A1 WO1999033815A1 PCT/US1998/004595 US9804595W WO9933815A1 WO 1999033815 A1 WO1999033815 A1 WO 1999033815A1 US 9804595 W US9804595 W US 9804595W WO 9933815 A1 WO9933815 A1 WO 9933815A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- optionally substituted
- compound
- compound according
- independently selected
- Prior art date
Links
- 0 C[C@@](*)(C(N[C@@](Cc1ccccc1)[C@](*)CN(*)S(*)(=O)=O)=O)N* Chemical compound C[C@@](*)(C(N[C@@](Cc1ccccc1)[C@](*)CN(*)S(*)(=O)=O)=O)N* 0.000 description 4
- FFWAQFXCJUHCDZ-UHFFFAOYSA-N C(C1)C11COCC1 Chemical compound C(C1)C11COCC1 FFWAQFXCJUHCDZ-UHFFFAOYSA-N 0.000 description 2
- LJPCNSSTRWGCMZ-YFKPBYRVSA-N C[C@@H]1COCC1 Chemical compound C[C@@H]1COCC1 LJPCNSSTRWGCMZ-YFKPBYRVSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N C#Cc1ccccc1 Chemical compound C#Cc1ccccc1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 1
- LGMUWAWUEYMTDQ-HTWCLWFGSA-N CC(C)CN(C[C@@H](COP(O)(O)=O)[C@H](Cc1ccccc1)NC(OC1COCC1)=O)S(c(cc1)ccc1N)(=O)=O Chemical compound CC(C)CN(C[C@@H](COP(O)(O)=O)[C@H](Cc1ccccc1)NC(OC1COCC1)=O)S(c(cc1)ccc1N)(=O)=O LGMUWAWUEYMTDQ-HTWCLWFGSA-N 0.000 description 1
- KEOSGJGQCXMEHM-VQTJNVASSA-N CC(C)CN(C[C@H]([C@H](Cc1ccccc1)NC(O)=O)OP(O)(O)=O)S(c(cc1)ccc1N)(=O)=O Chemical compound CC(C)CN(C[C@H]([C@H](Cc1ccccc1)NC(O)=O)OP(O)(O)=O)S(c(cc1)ccc1N)(=O)=O KEOSGJGQCXMEHM-VQTJNVASSA-N 0.000 description 1
- QSTVMWWSIFJZKK-VQTJNVASSA-N CC(C)CN(C[C@H]([C@H](Cc1ccccc1)NN=O)O)Sc1ccccc1 Chemical compound CC(C)CN(C[C@H]([C@H](Cc1ccccc1)NN=O)O)Sc1ccccc1 QSTVMWWSIFJZKK-VQTJNVASSA-N 0.000 description 1
- CXXHUNVNOPNZGD-RYUDHWBXSA-N CC(C)CNCC[C@H](C)NC(O[C@@H]1COCC1)=O Chemical compound CC(C)CNCC[C@H](C)NC(O[C@@H]1COCC1)=O CXXHUNVNOPNZGD-RYUDHWBXSA-N 0.000 description 1
- CVDZKWIGNKYDIU-UHFFFAOYSA-N O=[S+]c1cc[n]cc1 Chemical compound O=[S+]c1cc[n]cc1 CVDZKWIGNKYDIU-UHFFFAOYSA-N 0.000 description 1
- XDPCNPCKDGQBAN-BYPYZUCNSA-N O[C@@H]1COCC1 Chemical compound O[C@@H]1COCC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
Definitions
- the present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors.
- this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient.
- This invention also relates to pharmaceutical compositions comprising these prodrugs.
- the prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.
- Aspartyl protease inhibitors are considered the most effective current drug in the fight against HIV infection. These inhibitors, however, require certain physicochemical properties in order to achieve good potency against the enzyme. One of these properties is high hydrophobicity. Unfortunately, this property results in poor aqueous solubility and low oral bioavailability.
- United States Patent 5,585,397 describes a class of sulfonamide compounds that are inhibitors of the aspartyl protease enzyme. These compounds illustrate the drawbacks concomitant to pharmaceutical compositions comprising hydrophobic aspartyl protease inhibitors.
- VX-478 (4-amino-N- ( (2-syn, 3S) -2-hydroxy-4- phenyl-2 ( (S) -tetrahydrofuran-3-yl-oxycarbonylamino) - butyl -N-isobutyl-benzenesulfonamide) is an aspartyl protease inhibitor disclosed in the v 397 patent. It has a relatively low aqueous solubility.
- VX-478 produces an upper limit of 150 mg of VX-478 in each capsule. Given a therapeutic dose of 2400 mg/day of VX- 478, this formulation would require a patient to consume 16 capsules per day. Such a high pill burden would likely result in poor patient compliance, thus producing sub-optimal therapeutic benefit of the drug. The high pill burden is also a deterrent to increasing the amount of the drug administered per day to a patient. Another drawback of the pill burden and the concomitant patient compliance problem is in the treatment of children infected with HIV.
- these "solution" formulations such as the mesylate formulation, are at a saturation solubility of VX-478. This creates the real potential of having the drug crystallize out of solution under various storage and/or shipping conditions. This, in turn, would likely result in a loss of some of the oral bioavailability achieved with VX-478.
- One way of overcoming these problems is to develop a standard solid dosage form, such as a tablet or a capsule or a suspension form. Unfortunately, such solid dosage forms have much lower oral bioavailability of the drug.
- the present invention provides novel prodrugs of a class of sulfonamide compounds that are inhibitors of aspartyl protease, in particular, HIV aspartyl protease. These prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo .
- the present invention also provides pharmaceutical compositions comprising these prodrugs and methods of treating HIV infection in mammals using these prodrugs and the pharmaceutical compositions thereof.
- prodrugs can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
- This novel class of sulfonamides is represented by formula I :
- A is selected from H; Ht ; -R 1 -Ht; -R 1 -C ⁇ -C 6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R 2 ) 2 ; -R 1 -C 2 -C 6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht , -O-Ht, -NR 2 -CO-N (R 2 ) 2 or -CO-N(R 2 ) 2 ; or R 7 ; each R 1 is independently selected from -C(O)-, - S(0) 2 -, -C(0)-C(0)-, -O-C(O)-, -0-S(0) 2 , -NR 2 -S(0) 2 -, -NR 2
- each R 2 is independently selected from H, or C r C 4 alkyl optionally substituted with Q;
- B when present, is -N (R 2 ) -C (R 3 ) 2 -C (O) - ;
- each x is independently 0 or 1;
- each R 3 is independently selected from H, Ht , C ⁇ -C 6 alkyl, C
- D and D' are independently selected from Q; Ci- C 6 alkyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, -OR 2 , -R 3 , -O-Q or Q; C 2 -C 4 alkenyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, - OR 2 , -R 3 , -0-Q or Q; C 3 -C 6 cycloalkyl, which is optionally substituted with or fused to Q; or C 5 -C 6 cycloalkenyl, which is optionally substituted with or fused to Q; each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(0) n or N(R 2 ) ; where
- E is selected from Ht ; O-Ht; Ht-Ht; -O-R 3 ; -N(R 2 ) (R 3 ) ; Ci-C ⁇ alkyl, which is optionally substituted with one or more groups selected from R 4 or Ht ; C 2 -C 6 alkenyl, which is optionally substituted with one or more groups selected from R 4 or Ht ; C 3 -C 6 saturated carbocycle, which is optionally substituted with one or more groups selected from R 4 or Ht ; or C 5 -C 6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R 4 or Ht ; each R 4 is independently selected from -OR 2 , -SR 2 , -C(0)-NHR 2 , -S(0) 2 -NHR 2 , halo, -NR 2 -C (O) -R 2 , -N(R 2 ) 2 or -CN; each R 7 is independently selected from
- M' is H, C ⁇ -Ci 2 -alkyl, C 2 -C X2 -alkenyl , or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from 0, S, S (O) , S (0 2 ) , or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6 is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , N(R 2 ) 3 , -R 2 OH, -CN, -C0 2 R 2 , -C(0)-N(R 2 ) 2 , -S (0) 2 -N (R 2 ) 2 , -N(R 2 ) -C(0) -R 2 , -C(0)R 2 , -S(0) n -R 2 , -
- Z is CH 2 , 0, S, N(R 2 ) 2 , or, when M is absent, H;
- Y is P or S
- X is 0 or S
- R 9 is C(R 2 ) 2 , 0 or N(R 2 ) ; and wherein when Y is S, Z is not S; and
- R 6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C ⁇ -C alkyl, 0-C ! -C 4 alkyl or 0C(0)C ⁇ -C 4 alkyl. It is a also an object of this invention to provide pharmaceutical compositions comprising the sulfonamide prodrugs of formula I and methods for their use as prodrugs of HIV aspartyl protease inhibitors .
- the terms "-S0 2 -" and “-S(0) 2 -” as used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S) , and not a sulfinate ester.
- the stereochemistry of OR 7 is defined relative to D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compounds of formula XI, XV, XXII, XXIII and XXXI) .
- aryl refers to a carbocyclic aromatic radical containing the specified number of carbon atoms.
- heterocyclic refers to a stable 5-7 membered monocycle or 8-11 membered bicyclic heterocycle which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic.
- Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- nitrogen and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
- the heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable structure.
- Preferred heterocycles defined above include, for example, benzimidazolyl, imidazolyl, imidazolinoyl , imidazolidinyl , quinolyl , isoquinolyl, indolyl , pyridyl, pyrrolyl , pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, ⁇ - carbolinyl, tetrazolyl, thiazolidinyl , benzofuranoyl , thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl , oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl ,
- HIV protease and “HIV aspartyl protease” are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
- pharmaceutically effective amount refers to an amount effective in treating HIV infection in a patient.
- prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient.
- patient refers to a mammal, including a human.
- pharmaceutically acceptable carrier or adjuvant refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- acids examples include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
- Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N- (C 1 - 4 alkyl) 4+ salts.
- alkali metal e.g., sodium
- alkaline earth metal e.g., magnesium
- ammonium e.g., sodium
- N- (C 1 - 4 alkyl) 4+ salts thiocarbamates
- the compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers . All such isomeric forms of these compounds are expressly included in the present invention.
- Each stereogenic carbon may be of the R or S configuration.
- the explicitly shown hydroxyl is also preferred to be syn to D, in the extended zigzag conformation between the nitrogens shown in compounds of formula I .
- stable refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- the compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrox- yethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, pers
- This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.
- the basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
- novel sulfonamides of this invention are those of formula I :
- A is selected from H; Ht; -R 1 -Ht; -R 1 -C ⁇ -C e alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R) 2 ; -R 1 -C 2 -C 6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R 2 ) 2 ; or
- each R 1 is independently selected from -C(O)-, - S(0) 2 -, -C(0)-C(0)-, -O-C(O)-, -0-S(0) 2 , -NR -S(0) 2 -, -NR 2 - C(0)- or -NR -C(0) -C(0) -; each Ht is independently selected from C 3 -C 7 cycloalkyl; C 5 -C 7 cycloalkenyl; C 6 -C 10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R 2 ), 0, S and S(0) n ; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, -OR 2 , SR 2 , -R 2 , - N(R 2 ) (R 2 ), -R 2
- each R 2 is independently selected from H, or Ci- C alkyl optionally substituted with Q;
- G when present, is selected from H, R 7 or C ⁇ -C 4 alkyl, or, when G is C ⁇ -C 4 alkyl, G and R 7 are bound to one another either directly or through a C ⁇ -C 3 linker to form a heterocyclic ring; or when G is not present (i.e., when x in (G) x is 0) , then the nitrogen to which G is attached is bound directly to the R 7 group in -OR 7 with the concomitant displacement of one -ZM- group from R 7 ;
- D and D 1 are independently selected from Q; Ci- C 6 alkyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, -OR 2 , -R 3 ,
- each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ) ; wherein Q is optionally substituted with one or more groups selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , -N(R 2 ) -C(O) -R
- each R 4 is independently selected from -OR 2 , -SR 2 , -C(0)-NHR 2 , -S(0) 2 -NHR 2 , halo, -NR 2 -C (O) -R 2 , -N(R 2 ) 2 or -CN; each R 7 is independently selected from ZM
- each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R 2 ) 4 , C ⁇ -C 12 -alkyl , C 2 - C ⁇ 2 -alkenyl, or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group, other than the -CH 2 that is bound to Z, is optionally replaced by a heteroatom group selected from 0, S, S(0), S(0 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R s is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , N(R 2 ) 2 , N(R 2 ) 3 , R 2 0H, -CN, -C0 2 R 2 , -C (O) -N (R 2 ) 2 , S(0) 2 - N(R 2 ) 2 , N(R 2 )
- M' is H, C ⁇ -C ⁇ 2 -alkyl, C 2 -C ⁇ 2 -alkenyl , or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S (O) , S(0 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6 is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , N(R 2 ) 3 , -ROH, -CN, -C0 2 R 2 , -C(0)-N(R 2 ) 2 , -S (O) 2 -N (R 2 ) 2 , -N(R 2 ) -C(0)-R 2 , -C(0)R 2 , -S(0) n -R 2 , -OCF 3
- Z is CH 2 , 0, S, N(R 2 ) 2 , or, when M is not present, H.
- Y is P or S
- X is 0 or S
- R 9 is C(R 2 ) 2 , 0 or N(R 2 and wherein when Y is
- R R 66 iiss aa 55-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ) ; and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C ! -C 4 alkyl, 0-C x -C 4 alkyl or 0-C(0)-C ⁇ -C 4 alkyl.
- At least one R 7 is selected from:
- component M or M' in the formulae set forth herein will have either a covalent, a covalent/ zwitterionic, or an ionic association with either Z or R 9 depending upon the actual choice for M or M' .
- M or M' is hydrogen, alkyl, alkenyl, or R 6
- M or M' is covalently bound to R 9 or Z .
- M is a mono- or bivalent metal or other charged species (i.e., NH 4 + )
- Z When x is 0 in (M) x , Z may be a charged species. When that occurs, the other M may be oppositely charged to produce a 0 net charge on the molecule. Alternatively, the counter ion may located elsewhere in the molecule.
- the compounds of this invention are those represented by formulas XXII, XXIII or XXXI:
- A is selected from 3-tetrahydrofuryl-O-C (0) - , 3- (1, 5-dioxane) -0-C (0) - , or 3-hydroxy-hexahydrofura [2 , 3-b] - furanyl-0-C (0) - ;
- D' is C 1 -C 4 alkyl which is optionally substituted with one or more groups selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -R 3 , -0-Q and Q;
- E is Cs-Cio aryl optionally substituted with one or more substituents selected from oxo, -OR 2 , SR 2 , -R 2 , - N(R 2 ) 2 , -R 2 -OH, -CN, -C0 2 R 2 , -C (0) -N (R 2 ) 2 , -S (0) 2 -N (R 2 ) 2 , -N(R 2 )-C(0)-R 2 , -C(0)-R 2 , -S(0) n -R 2 , -OCF 3 , -S(0) n -Q, methylenedioxy, " -N (R 2 ) -S (0) 2 (R 2 ) , halo, -CF 3 , -N0 2 , Q, -0Q, -OR 7 , -SR 7 , -R 7 , -N(R 2 ) (R 7 ) or -N(R
- Ht insofar as it is defined as part of R 3 , is defined as above except for the exclusion of heterocycles ; and all other variables are as defined for formula I .
- Even more preferred are compounds of formula XXII, wherein A is 3-tetrahydrofuryl-O-C (0) - ; G is hydrogen; D' is isobutyl; E is phenyl substituted with N(R 7 ) 2 ; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C 1 -C 4 alkyl or -N(R 2 ) 4 ; and each M' is H or C ! -C 4 alkyl.
- E is a 5 -membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH 3 , R 4 , or Ht; and all other variables are as defined for formula I .
- R 7 in -OR 7 is -PO (OM) 2 or C (0) CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 and both R 7 in -N (R 7 ) 2 are H , wherein M is H , Li , Na , K or C ⁇ - C 4 alkyl ; or wherein R 7 in -OR 7 is C (0) CH 2 OCH 2 CH 2 OCH 3 , one R 7 in -N (R 7 ) 2 is C (0) CH 2 OCH 2 CH 2 OCH 3 and the other is H .
- R 3 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 5 -C 6 cycloalkyl, C 5 -
- D' is C x -C 3 alkyl or C 3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -0-Q and Q (with all other variables being defined as above for compounds of formula I) .
- R 7 is -PO(OM) 2 or -C(0)-M'.
- R 3 is independently C ! -C 6 alkyl which may be optionally substituted with a substituent selected from the group consisting of -OR 2 , -C(0)-NH-R 2 , -S (0) n N (R 2 ) (R 2 ) , Ht , -CN, -SR 2 , -C0 2 R 2 or -NR 2 -C(0) -R 2 ; and D' is C ⁇ -C 4 alkyl, which may be optionally substituted with a group selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -0-Q; and E is Ht, Ht-Ht and -NR 2 R 3 .
- the invention provides compounds of the following formulae:
- United States patent 5,585,397 discloses the synthesis of compounds of formula: wherein A, B, n, D, D' , and E are as defined above.
- Prodrugs of formula (I) of the present invention can be readily synthesized from the '397 compounds using conventional techniques.
- One of skill in the art would be well aware of conventional synthetic reagents to convert the -OH group of the ⁇ 397 compounds to a desired -OR 7 functionality of the present invention, wherein R 7 is as defined above.
- the relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds .
- VX-478 a compound disclosed in the ⁇ 397 patent, can be readily converted to the corresponding bis-phosphate ester derivative, as shown below:
- compositions of the present invention may be readily prepared using known techniques.
- disodium salt of the mono-phosphate ester shown above can be prepared as shown below:
- the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system
- the prodrugs of this invention increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- the first mechanism involves the enzymatic or chemical transformation of the prodrug species into the active form.
- the second mechanism involves the enzymatic or chemical cleavage of a functionality on the prodrug to produce the active compound.
- the chemical or enzymatic transformation can involve to transfer of a functional group (i.e., R 7 ) from one heteroatom within the molecule to another heteroatom. This transfer is demonstrated in the chemical reactions shown below:
- the cleavage mechanism is demonstrated by the reaction below where a phosphate ester-containing prodrug is converted into the active form of the drug by removal of the phosphate group.
- the prodrugs of the present invention are characterized by unexpectedly high aqueous solubility. This solubility facilitates administration of higher doses of the prodrug, resulting in a greater drug load per unit dosage.
- the prodrugs of the present invention are also characterized by facile hydrolytic cleavage to release the active aspartyl protease inhibitor in vivo .
- the high aqueous solubility and the facile in vivo metabolism result in a greater bioavailability of the drug. As a result, the pill burden on a patient is significantly reduced.
- the prodrugs of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
- a prodrug of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally- infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
- the prodrugs of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time.
- the prodrugs may be employed in such vaccines either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of protease inhibitors in vaccines.
- a prodrug of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against HIV infection.
- the novel protease inhibitors of this invention can be administered as agents for treating or preventing HIV infection in a mammal.
- the prodrugs of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV.
- the co- administered anti -viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA.
- Anti-HIV agents targeting such early life cycle events include, didanosine (ddl) , alcitabine (ddC) , d4T, zidovudine (AZT) , polysulfated polysaccharides, sT4 (soluble CD4) , ganiclovir, dideoxycytidine, trisodium phosphonoformate, eflor- nithine, ribavirin, acyclovir, alpha interferon and tri- menotrexate.
- non-nucleoside inhibitors of reverse transcriptase such as TIBO or nevirapine may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase .
- Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication.
- the use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
- These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents.
- These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
- These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
- prodrugs act synergistically in preventing the replication of HIV in human T cells.
- Preferred combination therapies include the administration of a prodrug of this invention with AZT, ddl, ddC or d4T.
- the prodrugs of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species .
- HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species .
- prodrugs of this invention we prefer administering the prodrugs of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
- retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
- retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
- the prodrugs of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) ; and antibiotics (e.g., pentamidine isethiorate) to prevent or combat infection and disease associated with HIV infections, such as AIDS and ARC.
- immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO
- antibiotics e.g., pentamidine isethiorate
- prodrugs of this invention When the prodrugs of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient.
- pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of a prodrug of this invention and another therapeutic or prophylactic agent.
- this invention focuses on the use of the prodrugs disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, as well as other AIDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, but are not limited to, HTLV-I and HTLV-II.
- the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors.
- compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
- Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat .
- compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection.
- the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial , intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
- suitable vehicles and solvents that may be employed are mannitol, 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 and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
- the pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added .
- compositions of this invention may also be administered in the form of suppositories for rectal administration.
- These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
- suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
- Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
- the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water.
- the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
- compositions of this invention may be administered by nasal aerosol or inhalation.
- Such 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.
- Dosage levels of between about .01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- 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.
- a typical preparation will contain from about 5% to about 95% active compound (w/w) .
- such preparations contain from about 20% to about 80% active compound.
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- 13C (CDC13) : 155.2 152.2, 149.9, 145.6, 135.9, +129.0, +128.8, +128.5, +127.2, +125.4, +124.4, +121.8, +78.1, +75.8, -73.1, -66.9, -56.5, +52.7, -48.2, -35.9, -35.9, 32.6, -+26.4, +19.9, +19.8.
- 13C (d3-acetonitrile) : 157.1, 157.0, 153.2, 139.6 , +130.3 , +130.2, +129.2, +127.2, 126.2, +114.2, +76.0, +75.4, - 73.6, -67.4, -58.2, +54.9, -50.2, -41.6, -39.8, -35.9, - 33.4, +27.3, +23.1, +20.4, +20.2.
- 13C (DMSO): 169.3, 155.8, 153.1, 138.0, 129.1, 129.0, 128.1, 126.3, 122.6, 112.8, 94.3, 75.6, 74.6, 72.4, 66.1, 57.8, 52.7, 52.0, 49.3, 38.4, 34.7, 32.2, 29.1, 26.6, 21.4, 20.1, 20.0.
- Example 12 1H-NMR (CDC13) : 0.78 (6H,dd), 1.9 (2H,m), 2.1 (lH,m), 2.3 (3H,s), 2.9 (8H,m), 2.9 (2H,m), 3.15 (lH,m), 3.35 (lH,m), 3.5 (lH,m) , 3.75 (4H,m), 4.06 (2H,s), 4.15 (2H,m), 4.9 (lH,dd), 5.05 (lH,bs), 5.2 (lH,bs), 6.63 (2H,d), 7.2 (5H,m), 7.55 (2H,d), 8.0 (2H,m). ESMSP: 676 (MH+) .
- Example 26 N-diacylated Prodrugs
- the general procedure for N, O-diacylated compounds followed the protocol outlined in Example 20, above, except that a five fold excess of reagents was used relative to the starting material .
- 227 can be synthesized directly from 197.
- 197 was dissolved in pyridine (300mL) .
- the resulting solution was concentrated in vacuo to about 150 ml at 50-55°C.
- the solution was then cooled under N 2 to 5°C, and treated with POCl 3 (6.5 ml, 1.24 equiv.) over 2 minutes.
- the cooling bath was removed and the reaction stirred at ambient temperature for 2.5 hrs .
- the solution was then cooled to 5°C and water (300 ml) was added over 30 minutes.
- the resulting mixture was extracted with 4- methylpentan-2-one (MIBK, 2 x 150 ml) .
- MIBK 4- methylpentan-2-one
- the combined extracts were washed with 2N HCl (2 x 250 ml) .
- the acid washes were back extracted with MIBK (60 ml) , then the combined MIBK solutions were treated with 2N HCl (150 ml) .
- the two phase mixture was stirred rapidly and heated to 50°C for 2 hours.
- the reaction mixture was cooled to 20°C, the phases were separated and the MIBK solution was washed with brine (150 ml) .
- the product, 227 was isolated by drying the solution with magnesium sulfate, filtering of the drying agent and concentrating in vacuo at 40°C to give the product as a pale yellow foam (31 g, 90% yield) .
- the solution was evaporated en vacuo to 100 ml then lyophilized to yield the TEA salt (1.5 TEA equivalents) .
- the TEA salt was (5.8 g) was dissolved in 200 ml water, 300 ml of 1 N HCl was added and the mixture was extracted with EtOAc (3 x
- 13C (DMSO): 156.2, 150.1, 145.7, 140.0, +129.7, +129.2, +128.5, +126.3, +125.0, +71.8, -60.0, +56.2, -56.0, -51.8, -36.0, +26.3, +20.3, +20.1, +14.6.
- a dose of 50 mg / Kg of compound 229 is equal to 40 mg/ Kg of VX-478. no compound 229 was detected in plasma at 15 min. ( first data point ).
- Compound 229 229 VX-478 vehicle solid capsule methyl 22% cellulose in 5% TPGS/PEG EtOH/water 400/PG
Priority Applications (22)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ505776A NZ505776A (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
AU65466/98A AU755087B2 (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
EEP200000385A EE04466B1 (et) | 1997-12-24 | 1998-03-09 | Sulfoonamiidi derivaadid kui aspartüülproteaasi inhibiitorid |
YU39800A RS52483B (en) | 1997-12-24 | 1998-03-09 | SULFONAMIDE DERIVATIVES AS ASPARTYL PROTEASE INHIBITOR PRO-DRUGS |
IL13694198A IL136941A0 (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives and pharmaceutical compositions containing the same |
HU0101831A HU229596B1 (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
APAP/P/2000/001850A AP1172A (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors. |
SK966-2000A SK287123B6 (sk) | 1997-12-24 | 1998-03-09 | Deriváty sulfónamidov a farmaceutický prostriedok, ktorý ich obsahuje |
MEP-820/08A MEP82008A (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
EA200000703A EA003509B1 (ru) | 1997-12-24 | 1998-03-09 | Сульфонамидные производные в качестве пролекарств, ингибиторов аспартилпротеаз |
PL342113A PL202845B1 (pl) | 1997-12-24 | 1998-03-09 | Pochodne sulfonamidowe, zawierające je kompozycje farmaceutyczne i zastosowanie pochodnych sulfonamidowych |
BR9814480-4A BR9814480A (pt) | 1997-12-24 | 1998-03-09 | Derivados de sulfonamida como pró-drogas de inibidores de aspartil protease |
UA2000074456A UA72733C2 (en) | 1997-12-24 | 1998-09-03 | Sulfonamide derivatives as precursors of aspartyl protease inhibitors |
IS5546A IS2817B (is) | 1997-12-24 | 2000-06-22 | Súlfonamíðafleiður sem forlyf fyrir tálma við aspartýlprótínkljúfum |
IL136941A IL136941A (en) | 1997-12-24 | 2000-06-22 | History of sulfonamides and pharmaceutical preparations containing them |
US09/602,494 US6559137B1 (en) | 1997-12-24 | 2000-06-23 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
NO20003304A NO326265B1 (no) | 1997-12-24 | 2000-06-23 | Sulfonamid-derivater som medisinforloper av aspartylproteaseinhibitorer |
US10/370,171 US6838474B2 (en) | 1997-12-24 | 2003-02-19 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
US10/958,223 US7592368B2 (en) | 1997-12-24 | 2004-10-04 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
NO2009008C NO2009008I2 (US06559137-20030506-C00112.png) | 1997-12-24 | 2009-04-22 | |
US12/504,243 US20100124543A1 (en) | 1997-12-24 | 2009-07-16 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
HUS1400042C HUS1400042I1 (hu) | 1997-12-24 | 2014-07-18 | Szulfonamid-származékok mint aszpartil-proteáz inhibitorok prodrugjai |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/998,050 US6436989B1 (en) | 1997-12-24 | 1997-12-24 | Prodrugs of aspartyl protease inhibitors |
US08/998,050 | 1997-12-24 |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/998,050 Continuation-In-Part US6436989B1 (en) | 1997-12-24 | 1997-12-24 | Prodrugs of aspartyl protease inhibitors |
US08/998,050 Continuation US6436989B1 (en) | 1997-12-24 | 1997-12-24 | Prodrugs of aspartyl protease inhibitors |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/602,494 Continuation US6559137B1 (en) | 1997-12-24 | 2000-06-23 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999033815A1 true WO1999033815A1 (en) | 1999-07-08 |
Family
ID=25544691
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/004595 WO1999033815A1 (en) | 1997-12-24 | 1998-03-09 | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors |
Country Status (43)
Cited By (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000004033A1 (en) * | 1998-07-18 | 2000-01-27 | Glaxo Group Limited | Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate |
WO2001000635A2 (en) * | 1999-06-24 | 2001-01-04 | Glaxo Group Limited | Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
WO2003048120A2 (en) | 2001-11-30 | 2003-06-12 | Osi Pharmaceuticals, Inc. | 2-aryl pyrrologpyrimidines for a1 and a3 receptors |
WO2003049746A2 (en) * | 2001-12-12 | 2003-06-19 | Tibotec Pharmaceuticals Ltd. | Combination of cytochome p450 dependent protease inhibitors |
US6664252B2 (en) | 1999-12-02 | 2003-12-16 | Osi Pharmaceuticals, Inc. | 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof |
US6673802B2 (en) | 2000-12-01 | 2004-01-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US6680324B2 (en) | 2000-12-01 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US6680322B2 (en) | 1999-12-02 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US6686366B1 (en) | 1998-06-02 | 2004-02-03 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US6800633B2 (en) | 1998-06-02 | 2004-10-05 | Osi Pharmaceuticals, Inc. | Pyrrolo[2,3d]pyrimidine compositions and their use |
US6878716B1 (en) | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
WO2005061450A2 (en) * | 2003-12-11 | 2005-07-07 | Abbott Laboratories | Hiv protease inhibiting sulfonamides |
WO2006024488A2 (en) | 2004-08-30 | 2006-03-09 | Interstitial Therapeutics | Medical stent provided with inhibitors of atp synthesis |
WO2006058905A1 (en) | 2004-12-01 | 2006-06-08 | Devgen Nv | 5-CARBOXAMIDO SUBSTITUTED THIAZOLE DERIVATIVES THAT INTERACT WITH ION CHANNELS, IN PARTICULAR WITH ION CHANNELS FROM THE Kv FAMILY |
US7160890B2 (en) | 1999-12-02 | 2007-01-09 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US7199148B2 (en) | 2002-08-14 | 2007-04-03 | Tibotec Pharmaceuticals Ltd | Broadspectrum substituted oxindole sulfonamide HIV protease inhibitors |
WO2007045496A1 (en) | 2005-10-21 | 2007-04-26 | Universiteit Antwerpen | Novel urokinase inhibitors |
US7244752B2 (en) | 2001-04-09 | 2007-07-17 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors |
US7300924B2 (en) | 2003-04-25 | 2007-11-27 | Gilead Sciences, Inc. | Anti-infective phosphonate analogs |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
US7417055B2 (en) | 2003-04-25 | 2008-08-26 | Gilead Sciences, Inc. | Kinase inhibitory phosphonate analogs |
US7427636B2 (en) | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
US7429565B2 (en) | 2003-04-25 | 2008-09-30 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7432272B2 (en) | 2003-12-22 | 2008-10-07 | Gilead Sciences, Inc. | Antiviral analogs |
US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
US7462636B2 (en) | 2002-05-17 | 2008-12-09 | Tibotec Pharmaceuticals Ltd | Broadspectrum substituted benzisoxazole sulfonamide HIV protease inhibitors |
US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7501407B2 (en) | 2001-12-20 | 2009-03-10 | Osi Pharmaceuticals, Inc. | Pyrimidine A2B selective antagonist compounds, their synthesis and use |
WO2009052970A2 (en) | 2007-10-26 | 2009-04-30 | Bayer Schering Pharma Aktiengesellschaft | Compounds for use in imaging, diagnosing, and/or treatment of diseases of the central nervous system or of tumors |
EP2100900A1 (en) | 2008-03-07 | 2009-09-16 | Universitätsspital Basel | Bombesin analog peptide antagonist conjugates |
WO2009112439A1 (en) | 2008-03-10 | 2009-09-17 | Janssen Pharmaceutica Nv | 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors |
EP2116236A1 (en) | 2008-04-21 | 2009-11-11 | Université de Mons-Hainaut | Bisbenzamidine derivatives for use as antioxidant |
US7622490B2 (en) | 2001-05-11 | 2009-11-24 | Tibotec Pharmaceuticals, Ltd. | Broadspecturm 2-amino-benzoxazole sulfonamide HIV protease inhibitors |
US7645754B2 (en) | 2001-12-20 | 2010-01-12 | Osi Pharmaceuticals, Inc. | Pyrrolopyrimidine A2B selective antagonist compounds, their synthesis and use |
US7645747B2 (en) | 2003-04-25 | 2010-01-12 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US7649015B2 (en) | 2002-04-26 | 2010-01-19 | Gilead Sciences, Inc. | Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds |
US7659404B2 (en) | 2001-02-14 | 2010-02-09 | Tibotec Pharmaceuticals Ltd. | Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors |
EP2165709A3 (en) * | 2004-08-02 | 2010-06-23 | Ambrilia Biopharma Inc. | Lysine based compounds |
US7763641B2 (en) | 2001-12-21 | 2010-07-27 | Tibotec Pharmaceuticals Ltd. | Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors |
US7803836B2 (en) | 2005-11-28 | 2010-09-28 | Tibotec Pharmaceuticals Ltd. | Aminophenylsulfonamide derivatives as HIV protease inhibitor |
EP2279759A2 (en) | 2006-09-08 | 2011-02-02 | Bayer Schering Pharma Aktiengesellschaft | Compounds and methods for 18F labeled agents |
WO2011061590A1 (en) | 2009-11-17 | 2011-05-26 | Hetero Research Foundation | Novel carboxamide derivatives as hiv inhibitors |
WO2011061295A1 (en) | 2009-11-19 | 2011-05-26 | Blue Medical Devices Bv | Narrow profile composition-releasing expandable medical balloon catheter |
US8008297B2 (en) | 2004-08-02 | 2011-08-30 | Ambrilia Biopharma Inc. | Lysine based compounds |
WO2011114212A1 (en) * | 2010-03-19 | 2011-09-22 | Lupin Limited | Ammonium, calcium and tris salts of fosamprenavir |
WO2011141515A1 (en) | 2010-05-14 | 2011-11-17 | Bayer Pharma Aktiengesellschaft | Diagnostic agents for amyloid beta imaging |
US8084494B2 (en) | 2005-11-28 | 2011-12-27 | Tibotec Pharmaceuticals Ltd. | Substituted aminophenylsulfonamide compounds as HIV protease inhibitor |
US8143421B2 (en) | 2002-03-12 | 2012-03-27 | Tibotec Pharmaceuticals Ltd. | Broadspectrum substituted benzimidazole sulfonamide HIV protease inhibitors |
WO2012062847A1 (en) | 2010-11-10 | 2012-05-18 | Protea Biopharma N.V. | Use of 2',5'-oligoadenylate derivative compounds |
US8193227B2 (en) | 2003-12-11 | 2012-06-05 | Abbott Laboratories | HIV protease inhibiting compounds |
EP2460408A1 (en) | 2004-12-17 | 2012-06-06 | deVGen N.V. | Nematicidal compositions |
US8227450B2 (en) | 2005-11-30 | 2012-07-24 | Ambrilia Biopharma Inc. | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
US8318731B2 (en) | 2007-07-27 | 2012-11-27 | Janssen Pharmaceutica Nv | Pyrrolopyrimidines |
US8410300B2 (en) | 2006-09-21 | 2013-04-02 | Taimed Biologics, Inc. | Protease inhibitors |
US8492377B2 (en) | 2006-07-13 | 2013-07-23 | Janssen Pharmaceutica Nv | MTKI quinazoline derivatives |
US8557854B2 (en) | 2005-04-15 | 2013-10-15 | Janssen R&D Ireland | Use of a sulfonamide compound for improving the pharmacokinetics of a drug |
EP2700396A2 (en) | 2012-06-20 | 2014-02-26 | Sylphar Nv | Strip for the delivery of oral care compositions |
US8691224B2 (en) | 2005-11-30 | 2014-04-08 | Abbvie Inc. | Anti-Aβ globulomer 5F7 antibodies |
US8772272B2 (en) | 2003-12-18 | 2014-07-08 | Janssen Pharmaceutica Nv | Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents |
US8785648B1 (en) | 2010-08-10 | 2014-07-22 | The Regents Of The University Of California | PKC-epsilon inhibitors |
US8877190B2 (en) | 2006-11-30 | 2014-11-04 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
US8895004B2 (en) | 2007-02-27 | 2014-11-25 | AbbVie Deutschland GmbH & Co. KG | Method for the treatment of amyloidoses |
US8951986B2 (en) | 2008-07-08 | 2015-02-10 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
US8987419B2 (en) | 2010-04-15 | 2015-03-24 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9107956B2 (en) | 2007-03-12 | 2015-08-18 | Nektar Therapeutics | Oligomer-protease inhibitor conjugates |
US9176150B2 (en) | 2003-01-31 | 2015-11-03 | AbbVie Deutschland GmbH & Co. KG | Amyloid beta(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US9227990B2 (en) | 2012-10-29 | 2016-01-05 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
WO2016003450A1 (en) | 2014-07-01 | 2016-01-07 | The Regents Of The University Of California | Pkc-epsilon inhibitors |
WO2016083490A1 (en) | 2014-11-27 | 2016-06-02 | Remynd Nv | Compounds for the treatment of amyloid-associated diseases |
US9457035B2 (en) | 2004-07-27 | 2016-10-04 | Gilead Sciences, Inc. | Antiviral compounds |
WO2016176437A1 (en) | 2015-04-28 | 2016-11-03 | Newsouth Innovations Pty Limited | Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity |
US9688691B2 (en) | 2004-12-08 | 2017-06-27 | Janssen Pharmaceutica Nv | Macrocyclic quinazole derivatives and their use as MTKI |
US9877981B2 (en) | 2012-10-09 | 2018-01-30 | President And Fellows Of Harvard College | NAD biosynthesis and precursors for the treatment and prevention of cancer and proliferation |
WO2018206760A1 (en) | 2017-05-11 | 2018-11-15 | Remynd N.V. | Compounds for the treatment of epilepsy, neurodegenerative disorders and other cns disorders |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US10851125B2 (en) | 2017-08-01 | 2020-12-01 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate |
WO2021170600A1 (en) | 2020-02-24 | 2021-09-02 | Katholieke Universiteit Leuven | Pyrrolopyridine and imidazopyridine antiviral compounds |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
WO2022136486A1 (en) | 2020-12-22 | 2022-06-30 | Luxembourg Institute Of Health (Lih) | Conolidine analogues as selective ackr3 modulators for the treatment of cancer and cardiovascular diseases |
WO2022184898A1 (en) | 2021-03-04 | 2022-09-09 | Universiteit Antwerpen | Quinazolin-4-one and thieno[2,3-d]pyrimidin-4-one inhibitors of erbb4 (her4) for use in the treatment of cancer |
WO2022253785A2 (en) | 2021-05-31 | 2022-12-08 | Universität Heidelberg | Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof |
WO2023021132A1 (en) | 2021-08-18 | 2023-02-23 | Katholieke Universiteit Leuven | 6-substituted- and 6,7-disubstituted-7-deazapurine ribonucleoside analogues |
WO2023046900A1 (en) | 2021-09-23 | 2023-03-30 | Katholieke Universiteit Leuven | Ribonucleoside analogues against -sars-cov-2 |
WO2023241799A1 (en) | 2022-06-15 | 2023-12-21 | Université Libre de Bruxelles | Flavanols for use in the treatment of retroviral infections |
WO2024062043A1 (en) | 2022-09-21 | 2024-03-28 | Universiteit Antwerpen | Substituted phenothiazines as ferroptosis inhibitors |
Families Citing this family (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040122000A1 (en) * | 1981-01-07 | 2004-06-24 | Vertex Pharmaceuticals Incorporated. | Inhibitors of aspartyl protease |
UA59384C2 (uk) * | 1996-12-20 | 2003-09-15 | Пфайзер, Інк. | Похідні сульфонамідів та амідів як агоністи простагландину, фармацевтична композиція та способи лікування на їх основі |
US6436989B1 (en) * | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
AU6329599A (en) * | 1998-09-28 | 2000-04-17 | Glaxo Group Limited | Antiviral combinations comprising (s)-2-ethyl -7-fluoro -3-oxo-3, 4-dihydro -2h-quinoxaline -1-carboxylic acid isopropyl ester |
US7576084B2 (en) * | 2001-10-12 | 2009-08-18 | Choongwae Pharma Corporation | Reverse-turn mimetics and method relating thereto |
US7157489B2 (en) * | 2002-03-12 | 2007-01-02 | The Board Of Trustees Of The University Of Illinois | HIV protease inhibitors |
CA2425031A1 (en) * | 2003-04-01 | 2004-10-01 | Smithkline Beecham Corporation | Pharmaceutical compositions |
EA200600221A1 (ru) | 2003-07-09 | 2006-06-30 | Пэрэтек Фамэсьютикэлс, Инк. | Замещённые соединения тетрациклина (варианты), фармацевтическая композиция и способ лечения чувствительного к тетрациклину состояния у субъекта |
EP2292590A3 (en) * | 2003-07-09 | 2012-05-02 | Paratek Pharmaceuticals, Inc. | Prodrugs of 9-aminomethyl tetracycline compounds |
US20050119163A1 (en) * | 2003-09-18 | 2005-06-02 | The Government Of The United States Of America, As Represented By The Secretary, | SH2 domain binding inhibitors |
US7834043B2 (en) * | 2003-12-11 | 2010-11-16 | Abbott Laboratories | HIV protease inhibiting compounds |
PL1699455T3 (pl) * | 2003-12-15 | 2013-10-31 | Merck Sharp & Dohme | Heterocykliczne inhibitory proteaz aspartylowych |
US7718633B2 (en) | 2004-07-06 | 2010-05-18 | Abbott Laboratories | Prodrugs of HIV protease inhibitors |
RU2416616C2 (ru) * | 2005-01-19 | 2011-04-20 | Райджел Фармасьютикалз, Инк. | Пролекарства соединений 2,4-пиримидиндиамина и их применения |
EP1855672A4 (en) * | 2005-03-11 | 2011-11-30 | Glaxosmithkline Llc | HIV PROTEASE INHIBITORS |
CA2606025A1 (en) | 2005-04-27 | 2006-11-02 | Ambrilia Biopharma Inc. | Method for improving pharmacokinetics of protease inhibitors and protease inhibitor precursors |
AU2006330277B2 (en) * | 2005-12-27 | 2011-10-06 | Otsuka Pharmaceutical Co., Ltd. | Water-soluble benzoazepine compound and its pharmaceutical composition |
US9095620B2 (en) * | 2008-03-12 | 2015-08-04 | Nektar Therapeutics | Reagents |
KR101687841B1 (ko) | 2008-12-09 | 2016-12-19 | 길리애드 사이언시즈, 인코포레이티드 | 톨-유사 수용체의 조절제 |
US20120135965A1 (en) * | 2009-05-20 | 2012-05-31 | Ranbaxy Laboratories Limited | Amorphous fosamprenavir calcium |
JP2012530069A (ja) | 2009-06-12 | 2012-11-29 | ネクター セラピューティックス | プロテアーゼ阻害剤、水溶性非ペプチドオリゴマーおよび親油性部分を含む共有結合体 |
US9085592B2 (en) | 2009-09-16 | 2015-07-21 | Ranbaxy Laboratories Limited | Process for the preparation of fosamprenavir calcium |
WO2011085130A1 (en) | 2010-01-07 | 2011-07-14 | Pliva Hrvatska D.O.O. | Solid state forms of fosamprenavir calcium salt and process for preparation thereof |
DK3494972T3 (da) | 2010-01-27 | 2024-01-29 | Viiv Healthcare Co | Kombinationer af dolutegravir og lamivudin til behandling af HIV-infektion |
US20110223131A1 (en) | 2010-02-24 | 2011-09-15 | Gilead Sciences, Inc. | Antiviral compounds |
US20110224443A1 (en) * | 2010-03-15 | 2011-09-15 | Venkata Naga Brahmeshwara Rao Mandava | Preparation of fosamprenavir calcium |
US20130211108A1 (en) | 2010-06-18 | 2013-08-15 | Mylan Laboratories Ltd | Novel process for the preparation of (3s)-tetrahydrofuran-3-yl (is, 2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-(phosphonooxy) propylcarbamate and its pharmaceutically acceptable salts |
EP2614055A2 (en) * | 2010-09-10 | 2013-07-17 | Lupin Limited | Process for preparation of substantially pure fosamprenavir calcium and its intermediates |
WO2012085625A1 (en) | 2010-12-21 | 2012-06-28 | Lupin Limited | Process for the preparation of fosamprenavir calcium and intermediate used in its preparation |
US8993786B2 (en) * | 2011-02-10 | 2015-03-31 | Mylan Laboratories Ltd. | Crystalline fosamprenavir calcium and process for the preparation thereof |
MX360782B (es) | 2011-06-21 | 2018-11-16 | Alnylam Pharmaceuticals Inc | Composiciones de arni similares a angiopoyetina 3 (angptl3) y metodos para su uso. |
EP3597750B1 (en) | 2011-06-23 | 2022-05-04 | Alnylam Pharmaceuticals, Inc. | Serpina1 sirnas: compositions of matter and methods of treatment |
US9309213B2 (en) | 2011-07-11 | 2016-04-12 | Purdue Research Foundation | C-3 substituted bicyclooctane based HIV protease inhibitors |
WO2013011485A1 (en) | 2011-07-20 | 2013-01-24 | Ranbaxy Laboratories Limited | Process for the preparation of sulfonamides useful as retroviral protease inhibitors |
WO2013105118A1 (en) | 2012-01-10 | 2013-07-18 | Council Of Scientific & Industrial Research | A process for synthesis of syn azido epoxide and its use as intermediate the synthesis of amprenavir & saquinavir |
US9127274B2 (en) | 2012-04-26 | 2015-09-08 | Alnylam Pharmaceuticals, Inc. | Serpinc1 iRNA compositions and methods of use thereof |
ES2657608T3 (es) | 2012-12-05 | 2018-03-06 | Alnylam Pharmaceuticals, Inc. | Composiciones de arni de pcsk9 y métodos de uso de las mismas |
RS56663B1 (sr) | 2013-03-14 | 2018-03-30 | Alnylam Pharmaceuticals Inc | Irnk sastavi komponente komplementa c5 i metode za njihovu upotrebu |
SG10201804472YA (en) | 2013-05-22 | 2018-07-30 | Alnylam Pharmaceuticals Inc | SERPINA1 iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
AU2014268529C1 (en) | 2013-05-22 | 2020-10-01 | Alnylam Pharmaceuticals, Inc. | TMPRSS6 iRNA compositions and methods of use thereof |
CA3107872A1 (en) | 2013-12-12 | 2015-06-18 | Alnylam Pharmaceuticals, Inc. | Complement component irna compositions and methods of use thereof |
EP3960860A3 (en) | 2014-02-11 | 2022-06-08 | Alnylam Pharmaceuticals, Inc. | Ketohexokinase (khk) irna compositions and methods of use thereof |
WO2015175510A1 (en) | 2014-05-12 | 2015-11-19 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for treating a serpinc1-associated disorder |
CN112852809A (zh) | 2014-05-22 | 2021-05-28 | 阿尔尼拉姆医药品有限公司 | 血管紧张素原(AGT)iRNA组合物及其使用方法 |
WO2016001907A1 (en) | 2014-07-02 | 2016-01-07 | Prendergast Patrick T | Mogroside iv and mogroside v as agonist/stimulator/un-blocking agent for toll-like receptor 4 and adjuvant for use in human/animal vaccine and to stimulate immunity against disease agents. |
NZ728072A (en) | 2014-07-11 | 2018-06-29 | Gilead Sciences Inc | Modulators of toll-like receptors for the treatment of hiv |
EP3191591A1 (en) | 2014-09-12 | 2017-07-19 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting complement component c5 and methods of use thereof |
WO2016061487A1 (en) | 2014-10-17 | 2016-04-21 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting aminolevulinic acid synthase-1 (alas1) and uses thereof |
US9738664B2 (en) | 2014-10-29 | 2017-08-22 | Wisconsin Alumni Research Foundation | Boronic acid inhibitors of HIV protease |
EP3904519A1 (en) | 2014-10-30 | 2021-11-03 | Genzyme Corporation | Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof |
CA2968114A1 (en) | 2014-11-17 | 2016-05-26 | Alnylam Pharmaceuticals, Inc. | Apolipoprotein c3 (apoc3) irna compositions and methods of use thereof |
EP3256587A2 (en) | 2015-02-13 | 2017-12-20 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
WO2016168286A1 (en) | 2015-04-13 | 2016-10-20 | Alnylam Pharmaceuticals, Inc. | Angiopoietin-like 3 (angptl3) irna compositions and methods of use thereof |
TWI727948B (zh) | 2015-05-06 | 2021-05-21 | 美商阿尼拉製藥公司 | 第十二因子(哈格曼因子)(F12)、激肽釋放素B、血漿(夫列契因子)1(KLKB1)及激肽原1(KNG1)iRNA組成物及其使用方法 |
WO2016205323A1 (en) | 2015-06-18 | 2016-12-22 | Alnylam Pharmaceuticals, Inc. | Polynucleotde agents targeting hydroxyacid oxidase (glycolate oxidase, hao1) and methods of use thereof |
EP3350328A1 (en) | 2015-09-14 | 2018-07-25 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting patatin-like phospholipase domain containing 3 (pnpla3) and methods of use thereof |
CA2997955A1 (en) | 2015-09-15 | 2017-03-23 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
SG11201804729RA (en) | 2015-12-07 | 2018-07-30 | Genzyme Corp | Methods and compositions for treating a serpinc1-associated disorder |
JP2018536689A (ja) | 2015-12-10 | 2018-12-13 | アルナイラム ファーマシューティカルズ, インコーポレイテッドAlnylam Pharmaceuticals, Inc. | ステロール調節エレメント結合タンパク質(SREBP)シャペロン(SCAP)iRNA組成物およびその使用方法 |
EP3469083A1 (en) | 2016-06-10 | 2019-04-17 | Alnylam Pharmaceuticals, Inc. | COMPLEMENT COMPONENT C5 iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) |
TWI788312B (zh) | 2016-11-23 | 2023-01-01 | 美商阿尼拉製藥公司 | 絲胺酸蛋白酶抑制因子A1 iRNA組成物及其使用方法 |
WO2018112320A1 (en) | 2016-12-16 | 2018-06-21 | Alnylam Pharmaceuticals, Inc. | Methods for treating or preventing ttr-associated diseases using transthyretin (ttr) irna compositions |
US11564921B2 (en) | 2017-07-21 | 2023-01-31 | Viiv Healthcare Company | Regimens for treating HIV infections and AIDS |
WO2019089922A1 (en) | 2017-11-01 | 2019-05-09 | Alnylam Pharmaceuticals, Inc. | Complement component c3 irna compositions and methods of use thereof |
AR114551A1 (es) | 2018-08-13 | 2020-09-16 | Alnylam Pharmaceuticals Inc | COMPOSICIONES DE AGENTES DE ARNhd CONTRA EL VIRUS DE HEPATITIS B (HBV) Y MÉTODOS PARA SU USO |
MX2021008628A (es) | 2019-01-16 | 2021-11-17 | Genzyme Corp | Composiciones de arni para serpinc1 y metodos de uso de las mismas. |
WO2021154941A1 (en) | 2020-01-31 | 2021-08-05 | Alnylam Pharmaceuticals, Inc. | Complement component c5 irna compositions for use in the treatment of amyotrophic lateral sclerosis (als) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994005639A1 (en) * | 1992-09-08 | 1994-03-17 | Vertex Pharmaceuticals Incorporated | Sulfonamide inhibitors of hiv-aspartyl protease |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3743722A (en) | 1971-07-14 | 1973-07-03 | Abbott Lab | Anti-coagulant isolation |
FR2459235A1 (fr) | 1979-06-14 | 1981-01-09 | Sanofi Sa | Nouveaux derives de sulfonyl-aniline, leur procede de preparation et leur application therapeutique |
JPS5946252A (ja) | 1982-09-09 | 1984-03-15 | Dainippon Ink & Chem Inc | 含フツ素アミノカルボキシレ−トおよびその製法 |
JPS5948449A (ja) | 1982-09-13 | 1984-03-19 | Dainippon Ink & Chem Inc | 直鎖状含フツ素アニオン化合物およびその製造方法 |
JPS6171830A (ja) | 1984-09-17 | 1986-04-12 | Dainippon Ink & Chem Inc | 界面活性剤組成物 |
US4616088A (en) | 1984-10-29 | 1986-10-07 | E. R. Squibb & Sons, Inc. | Amino acid ester and amide renin inhibitor |
US4629724A (en) | 1984-12-03 | 1986-12-16 | E. R. Squibb & Sons, Inc. | Amino acid ester and amide renin inhibitors |
DE3635907A1 (de) | 1986-10-22 | 1988-04-28 | Merck Patent Gmbh | Hydroxy-aminosaeurederivate |
CH676988A5 (US06559137-20030506-C00112.png) | 1987-01-21 | 1991-03-28 | Sandoz Ag | |
CA1340588C (en) | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
IL91780A (en) | 1988-10-04 | 1995-08-31 | Abbott Lab | History of the amine of the xenon-preventing xanine acid, the process for their preparation and the pharmaceutical preparations containing them |
WO1990007329A1 (en) | 1989-01-06 | 1990-07-12 | The Regents Of The University Of California | Selection method for pharmacologically active compounds |
US5151438A (en) | 1989-05-23 | 1992-09-29 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5354866A (en) * | 1989-05-23 | 1994-10-11 | Abbott Laboratories | Retroviral protease inhibiting compounds |
IE902295A1 (en) | 1989-07-07 | 1991-01-16 | Abbott Lab | Amino acid analog cck antagonists |
GB8927913D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Amino acid derivatives |
JPH07502970A (ja) | 1990-06-01 | 1995-03-30 | ザ・デュポン・メルク・ファーマシュウティカル・カンパニー | 1,4―ジアミノ―2,3―ジヒドロキシブタン類 |
TW225540B (US06559137-20030506-C00112.png) | 1990-06-28 | 1994-06-21 | Shionogi & Co | |
CA2096408C (en) | 1990-11-19 | 2005-02-08 | Gary Anthony Decrescenzo | Retroviral protease inhibitors |
EP0558657B1 (en) | 1990-11-19 | 1997-01-08 | Monsanto Company | Retroviral protease inhibitors |
ES2059296T3 (es) | 1990-11-19 | 1996-07-16 | Monsanto Co | Inhibidores de proteasas retrovirales. |
ES2243959T3 (es) | 1990-11-19 | 2005-12-01 | Monsanto Company | Inhibidores de proteasas retrovirales. |
IE20010533A1 (en) | 1990-11-20 | 2003-03-05 | Abbott Lab | Intermediates for preparing retroviral protease inhibiting compounds |
IL103613A (en) | 1991-11-08 | 1999-05-09 | Merck & Co Inc | VIH protease inhibitors, and the process of preparing intermediates and pharmaceutical preparations containing them. |
CA2131182C (en) | 1992-05-20 | 2005-04-26 | John S. Ng | Method for making intermediates useful in synthesis of retroviral protease inhibitors |
EP1447398A1 (en) | 1992-05-21 | 2004-08-18 | Monsanto Company | Retroviral protease inhibitors |
CA2140928C (en) | 1992-08-25 | 2008-01-29 | Michael L. Vazquez | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
DK0656887T3 (da) | 1992-08-25 | 1999-07-05 | Searle & Co | Hydroxyethylaminosulfonamider til anvendelse som inhibitorer af retrovirale proteaser |
US5463104A (en) | 1992-08-25 | 1995-10-31 | G. D. Searle & Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
DE59309867D1 (de) * | 1992-09-03 | 1999-12-16 | Boehringer Ingelheim Pharma | Neue aminosäurederivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende pharmazeutische zusammensetzungen |
US5783701A (en) | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
US5723490A (en) * | 1992-09-08 | 1998-03-03 | Vertex Pharmaceuticals Incorporated | THF-containing sulfonamide inhibitors of aspartyl protease |
TW372972B (en) | 1992-10-23 | 1999-11-01 | Novartis Ag | Antiretroviral acyl compounds |
US6156768A (en) | 1992-10-30 | 2000-12-05 | G. D. Searle & Co. | Alpha- and beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors |
ES2196436T3 (es) | 1992-10-30 | 2003-12-16 | Searle & Co | Acidos sulfonilalcanoilamino-hidroxietilamino-sulfamicos utiles como inhibidores de proteasas retrovirales. |
US5484926A (en) | 1993-10-07 | 1996-01-16 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
WO1994018192A1 (en) | 1993-02-12 | 1994-08-18 | Merck & Co., Inc. | Piperazine derivatives as hiv protease inhibitors |
TW281669B (US06559137-20030506-C00112.png) | 1993-02-17 | 1996-07-21 | Chugai Pharmaceutical Co Ltd | |
DE69415326T2 (de) | 1993-08-24 | 1999-06-02 | Searle & Co | Hydroxyaminosulfonamide verwendbar als inhibitoren retroviraler proteasen |
IL110898A0 (en) | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
IL111584A0 (en) | 1993-11-18 | 1995-01-24 | Merck & Co Inc | Prodrugs of an inhibitor of hiv protease and pharmaceutical compositions containing them |
US5527829A (en) | 1994-05-23 | 1996-06-18 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
DE19506742A1 (de) | 1995-02-27 | 1996-08-29 | Bayer Ag | Verwendung von Chinoxalinen in Kombination mit Protease-Inhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen |
US5691372A (en) | 1995-04-19 | 1997-11-25 | Vertex Pharmaceuticals Incorporated | Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease |
US5750493A (en) | 1995-08-30 | 1998-05-12 | Raymond F. Schinazi | Method to improve the biological and antiviral activity of protease inhibitors |
US5646180A (en) | 1995-12-05 | 1997-07-08 | Vertex Pharmaceuticals Incorporated | Treatment of the CNS effects of HIV |
US6180634B1 (en) | 1997-11-13 | 2001-01-30 | Merck & Co., Inc. | Combination therapy for the treatment of AIDS |
ID25551A (id) * | 1997-12-24 | 2000-10-12 | Vertex Pharma | Bahan baku obat penghambat protease aspartil |
US6436989B1 (en) * | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
TWI260322B (en) * | 1999-02-12 | 2006-08-21 | Vertex Pharma | Inhibitors of aspartyl protease |
-
1997
- 1997-12-24 US US08/998,050 patent/US6436989B1/en not_active Expired - Lifetime
-
1998
- 1998-03-09 RS YU39800A patent/RS52483B/en unknown
- 1998-03-09 CN CNA2009101453192A patent/CN101565412A/zh active Pending
- 1998-03-09 AU AU65466/98A patent/AU755087B2/en not_active Expired
- 1998-03-09 PL PL342113A patent/PL202845B1/pl unknown
- 1998-03-09 SK SK966-2000A patent/SK287123B6/sk not_active IP Right Cessation
- 1998-03-09 TR TR2000/02615T patent/TR200002615T2/xx unknown
- 1998-03-09 NZ NZ505776A patent/NZ505776A/xx not_active IP Right Cessation
- 1998-03-09 WO PCT/US1998/004595 patent/WO1999033815A1/en active Application Filing
- 1998-03-09 IL IL13694198A patent/IL136941A0/xx active IP Right Review Request
- 1998-03-09 AP APAP/P/2000/001850A patent/AP1172A/en active
- 1998-03-09 ME MEP-820/08A patent/MEP82008A/xx unknown
- 1998-03-09 KR KR10-2000-7007113A patent/KR100520737B1/ko not_active IP Right Cessation
- 1998-03-09 BR BR9814480-4A patent/BR9814480A/pt not_active Application Discontinuation
- 1998-03-09 HU HU0101831A patent/HU229596B1/hu active Protection Beyond IP Right Term
- 1998-03-09 EA EA200000703A patent/EA003509B1/ru not_active IP Right Cessation
- 1998-03-09 EE EEP200000385A patent/EE04466B1/xx unknown
- 1998-03-09 CZ CZ20002363A patent/CZ301653B6/cs not_active IP Right Cessation
- 1998-03-09 ID IDW20001413A patent/ID24962A/id unknown
- 1998-03-09 CN CNB988132338A patent/CN100503589C/zh not_active Expired - Lifetime
- 1998-03-10 SI SI9830903T patent/SI0933372T1/sl unknown
- 1998-03-10 EP EP98104292A patent/EP0933372B1/en not_active Expired - Lifetime
- 1998-03-10 EP EP07024817A patent/EP1944300A3/en not_active Withdrawn
- 1998-03-10 DE DE69838903T patent/DE69838903T2/de not_active Expired - Lifetime
- 1998-03-10 PT PT98104292T patent/PT933372E/pt unknown
- 1998-03-10 CA CA002231700A patent/CA2231700C/en not_active Expired - Lifetime
- 1998-03-10 AT AT98104292T patent/ATE382042T1/de active
- 1998-03-10 JP JP05870598A patent/JP3736964B2/ja not_active Expired - Lifetime
- 1998-03-10 ES ES98104292T patent/ES2299193T3/es not_active Expired - Lifetime
- 1998-03-10 DE DE122008000021C patent/DE122008000021I2/de active Active
- 1998-03-10 DK DK98104292T patent/DK0933372T3/da active
- 1998-09-03 UA UA2000074456A patent/UA72733C2/uk unknown
- 1998-12-22 MY MYPI98005827A patent/MY131525A/en unknown
- 1998-12-22 TW TW087121460A patent/TW486474B/zh not_active IP Right Cessation
- 1998-12-23 ZA ZA9811830A patent/ZA9811830B/xx unknown
- 1998-12-23 AR ARP980106679A patent/AR017965A1/es active IP Right Grant
- 1998-12-23 CO CO98076458A patent/CO4990992A1/es unknown
- 1998-12-23 PE PE1998001275A patent/PE20000048A1/es not_active IP Right Cessation
-
2000
- 2000-02-03 HK HK00100695A patent/HK1021737A1/xx not_active IP Right Cessation
- 2000-06-22 IL IL136941A patent/IL136941A/en not_active IP Right Cessation
- 2000-06-22 IS IS5546A patent/IS2817B/is unknown
- 2000-06-23 NO NO20003304A patent/NO326265B1/no not_active IP Right Cessation
- 2000-06-23 OA OA1200000187A patent/OA11468A/en unknown
- 2000-06-23 US US09/602,494 patent/US6559137B1/en not_active Expired - Lifetime
- 2000-07-24 BG BG104631A patent/BG64869B1/bg unknown
-
2003
- 2003-02-19 US US10/370,171 patent/US6838474B2/en not_active Expired - Lifetime
-
2004
- 2004-10-04 US US10/958,223 patent/US7592368B2/en not_active Expired - Fee Related
-
2005
- 2005-07-13 JP JP2005205007A patent/JP4282639B2/ja not_active Expired - Lifetime
-
2008
- 2008-03-26 NL NL300339C patent/NL300339I2/nl unknown
- 2008-04-02 LU LU91426C patent/LU91426I2/fr unknown
- 2008-04-17 FR FR08C0015C patent/FR08C0015I2/fr active Active
-
2009
- 2009-01-27 JP JP2009016033A patent/JP2009102400A/ja not_active Withdrawn
- 2009-04-22 NO NO2009008C patent/NO2009008I2/no not_active IP Right Cessation
- 2009-07-16 US US12/504,243 patent/US20100124543A1/en not_active Abandoned
-
2014
- 2014-07-18 HU HUS1400042C patent/HUS1400042I1/hu unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994005639A1 (en) * | 1992-09-08 | 1994-03-17 | Vertex Pharmaceuticals Incorporated | Sulfonamide inhibitors of hiv-aspartyl protease |
Cited By (132)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6686366B1 (en) | 1998-06-02 | 2004-02-03 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US7429574B2 (en) | 1998-06-02 | 2008-09-30 | Osi Pharmaceuticals, Inc. | 4-heterocyclo-pyrrolo[2,3d] pyrimidine compositions and their use |
US6878716B1 (en) | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
US6800633B2 (en) | 1998-06-02 | 2004-10-05 | Osi Pharmaceuticals, Inc. | Pyrrolo[2,3d]pyrimidine compositions and their use |
EP1240903A2 (en) * | 1998-07-18 | 2002-09-18 | Glaxo Group Limited | Combination of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate with ritonavir |
EP1240903A3 (en) * | 1998-07-18 | 2003-02-12 | Glaxo Group Limited | Combination of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate with ritonavir |
WO2000004033A1 (en) * | 1998-07-18 | 2000-01-27 | Glaxo Group Limited | Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate |
WO2001000635A2 (en) * | 1999-06-24 | 2001-01-04 | Glaxo Group Limited | Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
WO2001000635A3 (en) * | 1999-06-24 | 2003-04-17 | Glaxo Group Ltd | Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
US7160890B2 (en) | 1999-12-02 | 2007-01-09 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US6664252B2 (en) | 1999-12-02 | 2003-12-16 | Osi Pharmaceuticals, Inc. | 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof |
US6680322B2 (en) | 1999-12-02 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US7598252B2 (en) | 2000-12-01 | 2009-10-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A, receptors and uses thereof |
US6680324B2 (en) | 2000-12-01 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US6673802B2 (en) | 2000-12-01 | 2004-01-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US7659404B2 (en) | 2001-02-14 | 2010-02-09 | Tibotec Pharmaceuticals Ltd. | Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors |
US7595334B2 (en) | 2001-04-09 | 2009-09-29 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors |
US7244752B2 (en) | 2001-04-09 | 2007-07-17 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors |
US7622490B2 (en) | 2001-05-11 | 2009-11-24 | Tibotec Pharmaceuticals, Ltd. | Broadspecturm 2-amino-benzoxazole sulfonamide HIV protease inhibitors |
US7863306B2 (en) | 2001-05-11 | 2011-01-04 | Tibotec Pharmaceuticals Ltd | Broadspectrum 2-amino-benzoxazole sulfonamide HIV protease inhibitors |
WO2003048120A2 (en) | 2001-11-30 | 2003-06-12 | Osi Pharmaceuticals, Inc. | 2-aryl pyrrologpyrimidines for a1 and a3 receptors |
EP2050751A1 (en) | 2001-11-30 | 2009-04-22 | OSI Pharmaceuticals, Inc. | Compounds specific to adenosine A1 and A3 receptors and uses thereof |
US7504407B2 (en) | 2001-11-30 | 2009-03-17 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 and A3 receptors and uses thereof |
WO2003049746A3 (en) * | 2001-12-12 | 2003-12-31 | Tibotec Pharm Ltd | Combination of cytochome p450 dependent protease inhibitors |
WO2003049746A2 (en) * | 2001-12-12 | 2003-06-19 | Tibotec Pharmaceuticals Ltd. | Combination of cytochome p450 dependent protease inhibitors |
US7501407B2 (en) | 2001-12-20 | 2009-03-10 | Osi Pharmaceuticals, Inc. | Pyrimidine A2B selective antagonist compounds, their synthesis and use |
US7645754B2 (en) | 2001-12-20 | 2010-01-12 | Osi Pharmaceuticals, Inc. | Pyrrolopyrimidine A2B selective antagonist compounds, their synthesis and use |
US7763641B2 (en) | 2001-12-21 | 2010-07-27 | Tibotec Pharmaceuticals Ltd. | Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors |
US8143421B2 (en) | 2002-03-12 | 2012-03-27 | Tibotec Pharmaceuticals Ltd. | Broadspectrum substituted benzimidazole sulfonamide HIV protease inhibitors |
US7649015B2 (en) | 2002-04-26 | 2010-01-19 | Gilead Sciences, Inc. | Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds |
US7462636B2 (en) | 2002-05-17 | 2008-12-09 | Tibotec Pharmaceuticals Ltd | Broadspectrum substituted benzisoxazole sulfonamide HIV protease inhibitors |
US7199148B2 (en) | 2002-08-14 | 2007-04-03 | Tibotec Pharmaceuticals Ltd | Broadspectrum substituted oxindole sulfonamide HIV protease inhibitors |
US9176150B2 (en) | 2003-01-31 | 2015-11-03 | AbbVie Deutschland GmbH & Co. KG | Amyloid beta(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US10464976B2 (en) | 2003-01-31 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7300924B2 (en) | 2003-04-25 | 2007-11-27 | Gilead Sciences, Inc. | Anti-infective phosphonate analogs |
US7427636B2 (en) | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
US7429565B2 (en) | 2003-04-25 | 2008-09-30 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
US9139604B2 (en) | 2003-04-25 | 2015-09-22 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7645747B2 (en) | 2003-04-25 | 2010-01-12 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US8871785B2 (en) | 2003-04-25 | 2014-10-28 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US8022083B2 (en) | 2003-04-25 | 2011-09-20 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7417055B2 (en) | 2003-04-25 | 2008-08-26 | Gilead Sciences, Inc. | Kinase inhibitory phosphonate analogs |
US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
EP2216334A1 (en) * | 2003-12-11 | 2010-08-11 | Abbott Laboratories | Hiv protease inhibiting sulfonamides |
EP2264032A3 (en) * | 2003-12-11 | 2011-03-23 | Abbott Laboratories | Hiv protease inhibiting sulfonamides |
WO2005061450A2 (en) * | 2003-12-11 | 2005-07-07 | Abbott Laboratories | Hiv protease inhibiting sulfonamides |
WO2005061450A3 (en) * | 2003-12-11 | 2005-10-20 | Abbott Lab | Hiv protease inhibiting sulfonamides |
US8193227B2 (en) | 2003-12-11 | 2012-06-05 | Abbott Laboratories | HIV protease inhibiting compounds |
US8653141B2 (en) | 2003-12-11 | 2014-02-18 | Abbvie Inc. | HIV protease inhibiting compounds |
US8772272B2 (en) | 2003-12-18 | 2014-07-08 | Janssen Pharmaceutica Nv | Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents |
US8933067B2 (en) | 2003-12-18 | 2015-01-13 | Janssen Pharmaceutica Nv | Pyrido and pyrimidopyrimidine derivatives as anti-profilerative agents |
US7432272B2 (en) | 2003-12-22 | 2008-10-07 | Gilead Sciences, Inc. | Antiviral analogs |
US9457035B2 (en) | 2004-07-27 | 2016-10-04 | Gilead Sciences, Inc. | Antiviral compounds |
US9579332B2 (en) | 2004-07-27 | 2017-02-28 | Gilead Sciences, Inc. | Phosphonate analogs of HIV inhibitor compounds |
US8008297B2 (en) | 2004-08-02 | 2011-08-30 | Ambrilia Biopharma Inc. | Lysine based compounds |
EP2165709A3 (en) * | 2004-08-02 | 2010-06-23 | Ambrilia Biopharma Inc. | Lysine based compounds |
WO2006024488A2 (en) | 2004-08-30 | 2006-03-09 | Interstitial Therapeutics | Medical stent provided with inhibitors of atp synthesis |
WO2006058905A1 (en) | 2004-12-01 | 2006-06-08 | Devgen Nv | 5-CARBOXAMIDO SUBSTITUTED THIAZOLE DERIVATIVES THAT INTERACT WITH ION CHANNELS, IN PARTICULAR WITH ION CHANNELS FROM THE Kv FAMILY |
US10208062B2 (en) | 2004-12-08 | 2019-02-19 | Janssen Pharmaceutica Nv | Macrocyclic quinazole derivatives and their use as MTKI |
US9688691B2 (en) | 2004-12-08 | 2017-06-27 | Janssen Pharmaceutica Nv | Macrocyclic quinazole derivatives and their use as MTKI |
EP2460408A1 (en) | 2004-12-17 | 2012-06-06 | deVGen N.V. | Nematicidal compositions |
US8557854B2 (en) | 2005-04-15 | 2013-10-15 | Janssen R&D Ireland | Use of a sulfonamide compound for improving the pharmacokinetics of a drug |
WO2007045496A1 (en) | 2005-10-21 | 2007-04-26 | Universiteit Antwerpen | Novel urokinase inhibitors |
US8084494B2 (en) | 2005-11-28 | 2011-12-27 | Tibotec Pharmaceuticals Ltd. | Substituted aminophenylsulfonamide compounds as HIV protease inhibitor |
US7803836B2 (en) | 2005-11-28 | 2010-09-28 | Tibotec Pharmaceuticals Ltd. | Aminophenylsulfonamide derivatives as HIV protease inhibitor |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US8691224B2 (en) | 2005-11-30 | 2014-04-08 | Abbvie Inc. | Anti-Aβ globulomer 5F7 antibodies |
US8227450B2 (en) | 2005-11-30 | 2012-07-24 | Ambrilia Biopharma Inc. | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
US10538581B2 (en) | 2005-11-30 | 2020-01-21 | Abbvie Inc. | Anti-Aβ globulomer 4D10 antibodies |
US9540432B2 (en) | 2005-11-30 | 2017-01-10 | AbbVie Deutschland GmbH & Co. KG | Anti-Aβ globulomer 7C6 antibodies |
US8580995B2 (en) | 2005-11-30 | 2013-11-12 | Taimed Biologics, Inc. | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
US10323084B2 (en) | 2005-11-30 | 2019-06-18 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US8492377B2 (en) | 2006-07-13 | 2013-07-23 | Janssen Pharmaceutica Nv | MTKI quinazoline derivatives |
EP2289564A2 (en) | 2006-09-08 | 2011-03-02 | Bayer Schering Pharma Aktiengesellschaft | Derivatives of aniline as precursors for F18-labeling |
EP2455105A2 (en) | 2006-09-08 | 2012-05-23 | Bayer Pharma Aktiengesellschaft | Bombesin analogues |
EP3056509A1 (en) | 2006-09-08 | 2016-08-17 | Piramal Imaging SA | Bombesin analogues for use in diagnosis |
EP2279759A2 (en) | 2006-09-08 | 2011-02-02 | Bayer Schering Pharma Aktiengesellschaft | Compounds and methods for 18F labeled agents |
US8742158B2 (en) | 2006-09-21 | 2014-06-03 | TaiMed Biologies, Inc. | Protease inhibitors |
US8410300B2 (en) | 2006-09-21 | 2013-04-02 | Taimed Biologics, Inc. | Protease inhibitors |
US9394360B2 (en) | 2006-11-30 | 2016-07-19 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
US9359430B2 (en) | 2006-11-30 | 2016-06-07 | Abbvie Inc. | Abeta conformer selective anti-Abeta globulomer monoclonal antibodies |
US9951125B2 (en) | 2006-11-30 | 2018-04-24 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
US8877190B2 (en) | 2006-11-30 | 2014-11-04 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
US8895004B2 (en) | 2007-02-27 | 2014-11-25 | AbbVie Deutschland GmbH & Co. KG | Method for the treatment of amyloidoses |
US9107956B2 (en) | 2007-03-12 | 2015-08-18 | Nektar Therapeutics | Oligomer-protease inhibitor conjugates |
US8318731B2 (en) | 2007-07-27 | 2012-11-27 | Janssen Pharmaceutica Nv | Pyrrolopyrimidines |
EP2374779A1 (en) | 2007-10-26 | 2011-10-12 | Bayer Pharma Aktiengesellschaft | Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors |
EP2388245A1 (en) | 2007-10-26 | 2011-11-23 | Bayer Pharma AG | Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors |
WO2009052970A2 (en) | 2007-10-26 | 2009-04-30 | Bayer Schering Pharma Aktiengesellschaft | Compounds for use in imaging, diagnosing, and/or treatment of diseases of the central nervous system or of tumors |
EP2100900A1 (en) | 2008-03-07 | 2009-09-16 | Universitätsspital Basel | Bombesin analog peptide antagonist conjugates |
WO2009112439A1 (en) | 2008-03-10 | 2009-09-17 | Janssen Pharmaceutica Nv | 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors |
US8609836B2 (en) | 2008-03-10 | 2013-12-17 | Janssen Pharmaceutica Nv | 4-aryl-2-anilino-pyrimidines |
US8318929B2 (en) | 2008-03-10 | 2012-11-27 | Janssen Pharmaceutica Nv | 4-aryl-2-anilino-pyrimidines |
EP2116236A1 (en) | 2008-04-21 | 2009-11-11 | Université de Mons-Hainaut | Bisbenzamidine derivatives for use as antioxidant |
US8951986B2 (en) | 2008-07-08 | 2015-02-10 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
US9381206B2 (en) | 2008-07-08 | 2016-07-05 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
US9783568B2 (en) | 2008-07-08 | 2017-10-10 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
WO2011061590A1 (en) | 2009-11-17 | 2011-05-26 | Hetero Research Foundation | Novel carboxamide derivatives as hiv inhibitors |
WO2011061295A1 (en) | 2009-11-19 | 2011-05-26 | Blue Medical Devices Bv | Narrow profile composition-releasing expandable medical balloon catheter |
WO2011114212A1 (en) * | 2010-03-19 | 2011-09-22 | Lupin Limited | Ammonium, calcium and tris salts of fosamprenavir |
US9822171B2 (en) | 2010-04-15 | 2017-11-21 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US8987419B2 (en) | 2010-04-15 | 2015-03-24 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
WO2011141515A1 (en) | 2010-05-14 | 2011-11-17 | Bayer Pharma Aktiengesellschaft | Diagnostic agents for amyloid beta imaging |
US9376423B2 (en) | 2010-08-10 | 2016-06-28 | The Regents Of The University Of California | PKC-epsilon inhibitors |
US8785648B1 (en) | 2010-08-10 | 2014-07-22 | The Regents Of The University Of California | PKC-epsilon inhibitors |
US10047121B2 (en) | 2010-08-14 | 2018-08-14 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
WO2012062847A1 (en) | 2010-11-10 | 2012-05-18 | Protea Biopharma N.V. | Use of 2',5'-oligoadenylate derivative compounds |
EP2700396A2 (en) | 2012-06-20 | 2014-02-26 | Sylphar Nv | Strip for the delivery of oral care compositions |
US9877981B2 (en) | 2012-10-09 | 2018-01-30 | President And Fellows Of Harvard College | NAD biosynthesis and precursors for the treatment and prevention of cancer and proliferation |
US9227990B2 (en) | 2012-10-29 | 2016-01-05 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
WO2016003450A1 (en) | 2014-07-01 | 2016-01-07 | The Regents Of The University Of California | Pkc-epsilon inhibitors |
WO2016083490A1 (en) | 2014-11-27 | 2016-06-02 | Remynd Nv | Compounds for the treatment of amyloid-associated diseases |
WO2016176437A1 (en) | 2015-04-28 | 2016-11-03 | Newsouth Innovations Pty Limited | Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity |
WO2018206760A1 (en) | 2017-05-11 | 2018-11-15 | Remynd N.V. | Compounds for the treatment of epilepsy, neurodegenerative disorders and other cns disorders |
US11548881B2 (en) | 2017-05-11 | 2023-01-10 | Remynd N.V. | Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders |
US11939324B2 (en) | 2017-05-11 | 2024-03-26 | Remynd N.V. | Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders |
US10851125B2 (en) | 2017-08-01 | 2020-12-01 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate |
WO2021170600A1 (en) | 2020-02-24 | 2021-09-02 | Katholieke Universiteit Leuven | Pyrrolopyridine and imidazopyridine antiviral compounds |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
WO2022136486A1 (en) | 2020-12-22 | 2022-06-30 | Luxembourg Institute Of Health (Lih) | Conolidine analogues as selective ackr3 modulators for the treatment of cancer and cardiovascular diseases |
WO2022184898A1 (en) | 2021-03-04 | 2022-09-09 | Universiteit Antwerpen | Quinazolin-4-one and thieno[2,3-d]pyrimidin-4-one inhibitors of erbb4 (her4) for use in the treatment of cancer |
WO2022253785A2 (en) | 2021-05-31 | 2022-12-08 | Universität Heidelberg | Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof |
WO2023021132A1 (en) | 2021-08-18 | 2023-02-23 | Katholieke Universiteit Leuven | 6-substituted- and 6,7-disubstituted-7-deazapurine ribonucleoside analogues |
WO2023046900A1 (en) | 2021-09-23 | 2023-03-30 | Katholieke Universiteit Leuven | Ribonucleoside analogues against -sars-cov-2 |
WO2023241799A1 (en) | 2022-06-15 | 2023-12-21 | Université Libre de Bruxelles | Flavanols for use in the treatment of retroviral infections |
WO2024062043A1 (en) | 2022-09-21 | 2024-03-28 | Universiteit Antwerpen | Substituted phenothiazines as ferroptosis inhibitors |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0933372B1 (en) | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors | |
EP1042280A2 (en) | Prodrugs of aspartyl protease inhibitors | |
WO1999033792A2 (en) | Prodrugs os aspartyl protease inhibitors | |
CA2560071C (en) | Lysine based compounds | |
MXPA00006315A (en) | Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors | |
RU2379312C2 (ru) | Соединения на основе лизина, фармацевтическая композиция, содержащая эти соединения, применение указанных соединений для лечения или профилактики вич инфекции | |
MXPA00006316A (es) | Profarmacos de inhibidores de aspartil proteasa | |
CZ20002364A3 (cs) | Deriváty sulfonamidů a farmaceutický prostředek, který je obsahuje | |
NZ552853A (en) | Lysine based compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 136941 Country of ref document: IL Ref document number: P-398/00 Country of ref document: YU Ref document number: 98813233.8 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: PV2000-2363 Country of ref document: CZ Ref document number: 9662000 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2000/006315 Country of ref document: MX Ref document number: 09602494 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020007007113 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 65466/98 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 505776 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200000703 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000/02615 Country of ref document: TR |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2000-2363 Country of ref document: CZ |
|
122 | Ep: pct application non-entry in european phase | ||
WWP | Wipo information: published in national office |
Ref document number: 1020007007113 Country of ref document: KR |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWG | Wipo information: grant in national office |
Ref document number: 65466/98 Country of ref document: AU |
|
WWG | Wipo information: grant in national office |
Ref document number: 1020007007113 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV2006-602 Country of ref document: CZ |