WO1997040825A1 - Inhibiteurs de la protease du vih utiles dans le traitement du sida - Google Patents

Inhibiteurs de la protease du vih utiles dans le traitement du sida Download PDF

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Publication number
WO1997040825A1
WO1997040825A1 PCT/US1997/006595 US9706595W WO9740825A1 WO 1997040825 A1 WO1997040825 A1 WO 1997040825A1 US 9706595 W US9706595 W US 9706595W WO 9740825 A1 WO9740825 A1 WO 9740825A1
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Prior art keywords
compound
substituted
unsubstituted
4alkyl
hiv
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PCT/US1997/006595
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English (en)
Inventor
Randall W. Hungate
Byeong Moon Kim
Joseph P. Vacca
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Merck & Co., Inc.
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Filing date
Publication date
Priority claimed from GBGB9613488.7A external-priority patent/GB9613488D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97923431A priority Critical patent/EP0912170A4/fr
Priority to AU29238/97A priority patent/AU711713B2/en
Priority to JP9538974A priority patent/JP2000509389A/ja
Publication of WO1997040825A1 publication Critical patent/WO1997040825A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • 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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV.
  • HIV human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a viral ly encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad.
  • norbornene derivatives of peptide analogs are potent HIV protease inhibitors.
  • R and R 1 are independently
  • R2 is a) hydrogen; b) Phenyl unsubstituted or substituted with one or more of -OH or C 1-3 alkoxy; c) C5-7cycloalkyl, unsubstituted or substituted with one or more of -OH or Cl -3alkoxy; or d) C 1 -4 alkyl; and
  • R 3 is -CH2NR 5 R 6 , or
  • -Cl -4alkyl oxo, amino or halo
  • aryl unsubstituted or substituted with one or more of -Cl -4alkyl, Cl -4 alkoxy, nitro, oxo, amino, amido, carboxy, hydroxy, halo, or aryl
  • Cl -4alkyl unsubstituted or substituted once with aryl or 5- to 7-membered heterocycle; or d) C3-5cycloaLkyl, unsubstituted or substituted at the 3-position with Cl -4alkyl
  • R 5 is a) -V-R4; wherein V is -C(0)-Q-, or -S02-Q-, wherein Q is absent, -0-, or -NH-; and
  • R° is a) hydrogen, or b) -Cl -4alkyl unsubstituted or substituted with one or more of i) halo, ii) hydroxy, iii) Cl-3alkoxy, iv) aryl unsubstituted or substituted with one or more of Cl -4alkyl, Cl -4alkoxy, nitro, amino, amido, carboxy, hydroxy, halo or aryl; v) -W-aryl or W-benzyl, wherein W is -0-, -S-, or -NH-; or vi) heterocycle, unsubstituted or substituted with one or more of Cl -4alkyl, hydroxy or halo; vii) carboxyl; c) -C3_5cycloalkyl, unsubstituted or substituted at the 3- position with Cl -4alkyl; or d) aryl unsubstituted or substituted with one or more of C l
  • Preferred compounds of the present invention include the following:
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heterocycle, R, R l , R ⁇ , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, mo ⁇ holinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimid
  • the pharmaceutically-acceptable salts of the compounds of Formulas I or II include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen -containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • Schemes 1 -6 for preparing the novel compounds of this invention are presented below.
  • the Schemes are not limited by any particular substituents employed in the schemes for illustrative pu ⁇ oses.
  • the examples specifically illustrate the application of the following schemes to specific compounds.
  • Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or l -ethyl-3-(3-dimethyl- aminopropyl) carbodiimide.
  • Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester.
  • solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
  • the acid moiety in Compound 9 was converted to the corresponding acid chloride (10) and the acid chloride was subsequently coupled to various amines to provide amide 11.
  • the ethyl ester moiety in Compound 11 was hydrolyzed to the corresponding acid 12 by treating with LiOH in DME- water.
  • Scheme 5 shows the synthesis of the norbornene- hydroxyethylsulfonamide class of inhibitors.
  • Isobutylamine was coupled to arenesulfonyl chloride to give Compound 22.
  • the sulfonamide group of Compound 22 was alkylated by first deprotonating with nBuLi followed by addition of proper alkylating agent such as epichlorohydrin.
  • the epoxide moiety in Compound 23 was opened by an azide group and the corresponding azidoalcohol (Compound 24) was reduced to the amine 25.
  • the amine 25 was then coupled to norbornenyl acid (Compound 12) using HOBT and EDC as coupling reagents to furnish Compound 26.
  • Various amides at the norbornenyl side chain were prepared.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these pu ⁇ oses.
  • the compounds of the present invention are useful in the inhibition of HIV protease the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS.
  • HIV human immunodeficiency virus
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • a method of treating and a pharmaceutical composition for treating HIV infection and AIDS involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
  • these compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non -toxic, parenteral ly- acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non -toxic, parenteral ly- acceptable diluents or solvents such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • Dosage levels of the order of 0.02 to 5.0 or 10.0 grams- per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher.
  • infection by HIV is effectively treated by the administration of from 1.0 to 50 milligrams of the compound per kilogram of body weight from one to four times per day.
  • dosages of 100- 400 mg every six hours are administered orally to each patient.
  • the present invention is also directed to combinations of the HIV protease inhibitory compounds with one or more agents useful in the treatment of AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre- exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
  • Interferon Beta (Almeda, CA) sarcoma, ARC
  • Ganciclovir (Palo Alto, CA) peripheral CMV retinitis
  • Ribavirin (Costa Mesa, CA) positive, LAS, ARC
  • TNF S. San Francisco, w/gamma Interferon CA
  • Isethionate (IM & IV) (Rosemont, IL)
  • Preferred combinations are simultaneous or alternating treatments of an inhibitor of HIV protease and a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddl.
  • Preferred inhibitors of HIV protease are Compounds A-D, most preferred are compounds E and F. Assav for Inhibition of Microbial Expressed HIV Protease
  • Lithium hydroxide monohydrate (906 mg, 21.6 mmol) was added to a solution of 3 in dioxane (20 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated, diluted with ethyl acetate, and washed with I N HCl (2 x 25 mL). The organic layer was dried (Na2S ⁇ 4) and concentrated to give 4 (2.5 g) as a white solid which was used crude.
  • the solution was concentrated, diluted with ethyl acetate, and washed with saturated NaHC ⁇ 3 (2 x 25 mL), and brine ( 1 x 25 mL).
  • the organic layer was dried (Na2S ⁇ 4) and concentrated.
  • the resulting white solid was purified by flash chromatography (10% hexane/ ethyl acetate) to give the less polar single diastereomer of 6 (70 mg), mixture of diastereomers of 6 (875 mg), and the more polar single diastereomer of 6 (85 mg), all as white solids.

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Abstract

Des analogues de peptides contenant du norbornène sont des inhibiteurs de la protéase du VIH. Ces composés, utiles dans la prévention ou le traitement d'une infection par le VIH et dans le traitement du sida, se présentent sous forme de composés, de sels acceptables en pharmacologie ou d'ingrédients de compositions pharmaceutiques, séparément ou en combinaison avec d'autres antiviraux, immunomodulateurs, antibiotiques ou vaccins. Des méthodes permettant de traiter le sida et de prévenir ou de traiter une infection par le VIH sont également décrites.
PCT/US1997/006595 1996-05-02 1997-04-29 Inhibiteurs de la protease du vih utiles dans le traitement du sida WO1997040825A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97923431A EP0912170A4 (fr) 1996-05-02 1997-04-29 Inhibiteurs de la protease du vih utiles dans le traitement du sida
AU29238/97A AU711713B2 (en) 1996-05-02 1997-04-29 HIV protease inhibitors useful for the treatment of AIDS
JP9538974A JP2000509389A (ja) 1996-05-02 1997-04-29 Ａｉｄｓの治療に有効なｈｉｖプロテアーゼインヒビター

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1668596P 1996-05-02 1996-05-02
US60/016,685 1996-05-02
GBGB9613488.7A GB9613488D0 (en) 1996-06-27 1996-06-27 HIV protease inhibitors useful in the treatment of aids
GB9613488.7 1996-06-27

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WO1997040825A1 true WO1997040825A1 (fr) 1997-11-06

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AU (1) AU711713B2 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
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US9688689B2 (en) 2014-05-13 2017-06-27 Novartis Ag Compounds and compositions for inducing chondrogenesis
US9701727B2 (en) 2011-06-29 2017-07-11 The Trustees Of Columbia University In The City Of New York Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction

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JP2007023254A (ja) * 2005-06-14 2007-02-01 Fujifilm Corp 硬化促進剤、熱硬化性樹脂組成物、感光性組成物及び感光性フィルム、並びに、永久パターン及びその形成方法
EP2640699B1 (fr) * 2010-11-17 2015-10-07 Actelion Pharmaceuticals Ltd. Dérivés d'esters de spiro[2.4]heptane pontés

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IL89900A0 (en) * 1988-04-12 1989-12-15 Merck & Co Inc Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them
US5413999A (en) * 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
CA2084800A1 (fr) * 1991-12-16 1993-06-17 Joseph P. Vacca Inhibiteurs du vih protease presentant un anneau lactame interne

Non-Patent Citations (2)

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Title
CHEMICAL ABSTRACTS, 126:37109, May 1997, MILSTEIN SAM J., "Diamide-Dicarboxylic Acid Microspheres". *
See also references of EP0912170A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9701727B2 (en) 2011-06-29 2017-07-11 The Trustees Of Columbia University In The City Of New York Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction
US9688689B2 (en) 2014-05-13 2017-06-27 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10188638B2 (en) 2014-05-13 2019-01-29 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10383863B2 (en) 2014-05-13 2019-08-20 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10660881B2 (en) 2014-05-13 2020-05-26 Novartis Ag Compounds and compositions for inducing chondrogenesis
US11510912B2 (en) 2014-05-13 2022-11-29 Novartis Ag Compounds and compositions for inducing chondrogenesis

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AU2923897A (en) 1997-11-19
EP0912170A1 (fr) 1999-05-06
CA2252918A1 (fr) 1997-11-06
AU711713B2 (en) 1999-10-21
EP0912170A4 (fr) 2003-04-09
JP2000509389A (ja) 2000-07-25

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