WO1998034932A1 - Inhibiteurs de la vih integrase - Google Patents

Inhibiteurs de la vih integrase Download PDF

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Publication number
WO1998034932A1
WO1998034932A1 PCT/US1998/002292 US9802292W WO9834932A1 WO 1998034932 A1 WO1998034932 A1 WO 1998034932A1 US 9802292 W US9802292 W US 9802292W WO 9834932 A1 WO9834932 A1 WO 9834932A1
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WO
WIPO (PCT)
Prior art keywords
compound
aids
hiv
atcc
pharmaceutically acceptable
Prior art date
Application number
PCT/US1998/002292
Other languages
English (en)
Inventor
Gerald F. Bills
Russell B. Lingham
Ali Shafiee
Keith C. Silverman
Sheo Bux Singh
Deborah L. Zink
Fernando Pelaez
Ana M. Teran
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9707492.6A external-priority patent/GB9707492D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002280518A priority Critical patent/CA2280518A1/fr
Priority to US09/355,692 priority patent/US6403347B1/en
Priority to EP98904970A priority patent/EP1023281A4/fr
Priority to AU62710/98A priority patent/AU6271098A/en
Publication of WO1998034932A1 publication Critical patent/WO1998034932A1/fr

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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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • HIV HIV
  • LAV low immune deficiency syndrome
  • HTLV-III ARV
  • retrovirus replication A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid cells.
  • Integration is believed to occur in three stages: cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site; repair synthesis by host enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 227 (1985)].
  • Amino acid sequence homology provides evidence that the nol sequence encodes reverse transcriptase, an integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985). Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al, Nature 329, 351 (1987)].
  • antiviral compounds act as inhibitors of HIV and are effective agents in the treatment of HIV and similar diseases, e.g., azidothymidine or AZT.
  • Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase, probably by inhibiting strand transfer and cleavage activity.
  • the particular advantage of the present invention is specific inhibition of HIV integrase.
  • certain chaetochromins are potent inhibitors of HIV integrase. These compounds are useful for the treatment of AIDS or HIV infections.
  • This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • Compounds of formula I are defined as follows:
  • R1 is independently selected from:
  • a is represents a single bond or a double bond
  • Rl is independently selected from:
  • compositions useful for inhibiting HIV integrase comprising an effective amount of a compound of this invention.
  • Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC.
  • This invention also discloses the fungal culture MF6252 (ATCC 74396), Fusarium sp.
  • the present invention relates to the preparation of compounds of structural formula I comprising:
  • the compounds of structural formula I are preferably isolated by partitioning the fermentation extract between the organic solvent and water, followed by size exclusion chromatography and normal or reverse-phase chromatography.
  • variable e.g., X, Y, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the 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 integrase, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these purposes.
  • certain chaetochromins recovered from a fungal culture of MF6252 (ATCC 74396), identified as Fusarium sp. (Ascomycotina, Hypocreales), are useful for inhibiting HIV integrase.
  • the compounds of formula (I) are prepared by an aerobic fermentation procedure employing a novel fungal culture
  • MF6252 (ATCC 74396), identified as Fusarium sp., or a mutant thereof.
  • a mutant refers to an organism in which some gene on the genome is modified, leaving the gene or genes responsible for the organism's ability to produce the compounds of formula (I) in recoverable amounts functional and heritable.
  • ATCC Deposit of MF6252 (ATCC 74396). identified as Fusarium sp.
  • ATCC 74396 American Type Culture Collection
  • the culture access designation is 74396. This deposit will be maintained in the ATCC for at least 30 years and will be made available to the public upon the grant of a patent disclosing it. It should be understood that the availability of a deposit does not constitute a license to practice the subject invention in derogation of patent rights granted by government action.
  • Conidiophores, conidiogenous cells and conidia are of two different states; an Acremonium-like microconidial state which is the dominant form on SNA; and a macroconidial state which on SNA is restricted to pinnotes in the area immediately surrounding the inoculation point, on other media, e.g. potato-dextrose agar, the macroconidial form is produced throughout the colony.
  • Microconidial state Microconidiophores 25-70 ⁇ m long x 2.5-4 ⁇ m wide at the base, septate at the base, rarely 2- or 3-septate, mostly unbranched, tapered upward, straight to slightly geniculate, scattered to densely clustered on both the surface and aerial hyphae, terminating in a cylidrical to flared collarette, with slight periclinal thickening evident on some conidiogenesis cells, enteroblastic, phialidic. Microcondia for the most part distinct from macroconidia, 3.5-6 x 2-3 ⁇ m, narrowly ellipsoidal to allantoid.
  • Macroconidial state Macroconidiophores aggregated in pinnotes, consisting of penicillately branched fascicles of conidiogenous cells. Conidiogenous cells cylindrical or tapered apically, without collarettes, sometimes with slight periclinal thickenings at conidiogenous loci, with individual conidiogenous cells up to 35 ⁇ m long. Macroconidia 10-50 ⁇ m x 3.5-5 ⁇ m 1-6 septate, predominantly 3-septate, fusiform curved, with apical cell rounded, with slightly pedicellate foot cell, often the apical or subapical cells more curved than the more proximal cells. Chlamydospores and sclerotia not in observed in PDA or OA cultures incubated up to 5 weeks.
  • This fungus is assigned the anamorph genus Fusarium because it produces moist, f soid, curved, septate conidia with a pedicellate foot cell from phialidic conidiogenous cells.
  • This isolate possibly belongs in the Section Martiella of Fusarium (as defined by C. Booth. 1971. The genus Fusarium. Commonwealth Mycological Institute, Kew, U.K., pg. 44), due to its abundant Acremonium-like conidial state, penicillate macrocroconidial state, macroconidia with blunt rounded apices, pale to yellow or greenish yellow pigments, and moderate growth rate. The absence of chlamydospores has been noted in some species of the section Martiella e.g.
  • MF6252 (ATCC 74396), identified as Fusarium sp. is cultured on a solid medium, or in an aqueous nutrient medium containing sources of assimilable carbon and nitrogen.
  • the cultures can be grown under submerged aerobic conditions (e.g., shaking culture, submerged culture, etc.)
  • the aqueous medium is preferably maintained at a pH of about 6-8 at the initiation and termination (harvest) of the fermentation process.
  • the desired pH may be maintained by the use of a buffer such as morpholinoethane-sulfonic acid (MES), morpholinopropanesulfonic acid (MOPS), and the like, or by choice of nutrient materials which inherently possess buffering properties.
  • MES morpholinoethane-sulfonic acid
  • MOPS morpholinopropanesulfonic acid
  • the preferred source of carbon in the nutrient medium are carbohydrates such as glucose, xylose, galactose, glycerin, starch, sucrose, dextrin, and the like.
  • carbohydrates such as glucose, xylose, galactose, glycerin, starch, sucrose, dextrin, and the like.
  • Other cources which may be included are maltose, rhamnose, raffinose, arabinose, mannose, sodium succinate, and the like.
  • the preferred sources of nitrogen are yeast extract, meat extract, peptone, gluten meal, cottonseed meal, soybean meal and other vegetable meals (partially or totally defatted), casein hydrolysates, soybean hydrolysates, and yeast hydrolysates, corn steep liquor, dried yeast, wheat germ, feather meal, peanut powder, distiller's solubles, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e.g., ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea, amino acids, and the like.
  • ammonium salts e.g., ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea amino acids, and the like.
  • the carbon and nitrogen sources need not be used in their pure form, because less pure materials which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
  • the medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, cobalt salts, and the like.
  • a defoaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone may be added.
  • submerged aerobic cultural conditions is one method of culturing the cells.
  • a shaking or surface culture in a flask or bottle is employed.
  • the vegetative forms of the organism for inoculation in the production tanks in order to avoid growth lag in the process of production.
  • a vegetative inoculum of the organism by inoculating a relatively small quantity of culture medium with spores or mycelia of the organism produced in a "slant” and culturing said inoculated medium, also called the “seed medium”, and then to transfer the cultured vegetative inoculum aseptically to large tanks.
  • the fermentation medium in which the inoculum is produced, is generally autoclaved to sterilize the medium prior to inoculation.
  • the pH of the medium is generally adjusted to about 6-7 to the autoclaving step. Agitation and aeration of the culture mixture may be accomplished in a variety of ways.
  • Agitation may be provided by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermentor, by various pumping equipment, or by the passage of sterile air through the medium. Aeration may be effected by passing sterile air through the fermentation mixture.
  • the fermentation is usually conducted at a temperature between about 20°C and 30°C, preferably 22-25°C, for a period of about 14- 21 days, which may be varied according to fermentation conditions and scales.
  • Preferred culturing/production media for carrying out the fermentation include the media as set forth in the Examples.
  • the cells are harvested by conventional methods, e.g., centrifugation and filtration, and then extracted with the appropriate solvent, e.g., methylethylketone.
  • solvent e.g., methylethylketone
  • the product of the present invention can be recovered from the culture medium by conventional means which are commonly used for the recovery of other known substances.
  • the substances produced may be found in either or both the cultured mycelium and broth filtrate, and accordingly can be isolated and purified from the mycelium and the filtrate, which are obtained by filtering or centrifuging the cultured broth, by a conventional method such as concentration under reduced pressure, lyophilization, extraction with a conventional solvent, such as methylene chloride or methanol and the like, pH adjustment, treatment with a conventional resin (e.g., anion or cation exchange resin, non- ionic adsorption resin, etc.), treatment with a conventional adsorbent (e.g., activated charcoal, silicic acid, silica gel, cellulose, alumina, etc.), crystallization, recrystallization, and the like.
  • a conventional resin e.g., anion or cation exchange resin, non- ionic adsorption resin, etc.
  • a preferred method is extraction of cultured whole broth with methylethylketone, followed by filtration of the extract through filtering aid such as diatomaceous earth.
  • the methylethylketone layer of the filtrate was separated and concentrated to dryness initially by evaporating under reduced pressure followed by lyophilization.
  • the compounds were finally isolated either by solvent partitioning and crystallization or by preparative HPLC on reversed phase systems.
  • Compounds of formula (I) may be isolated from the aerobic fermentation of a culture of MF6252 (ATCC 74396), Fusarium sp..
  • a culture of MF6252 (ATCC 74396) is defined as substantially free of its natural soil contaminants and capable of forming compounds of structural formula (I) in recoverable amounts.
  • the culture employed in the present invention should be free from viable contaminating microorganisms deleterious to the production of the compound of structural formula (I).
  • a biologically pure culture of MF6252 (ATCC 74396) may also be employed.
  • the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)
  • 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.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results directly, or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
  • these compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally- acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally- acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-initiating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-initiating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses.
  • One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses.
  • Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
  • NC Kaposi's sarcoma, asymptomatic HFv 7 infection, less severe HIV disease, neurological involvement, in combination with other therapies.
  • Indinavir Merck (Rahway, NJ) AIDS, ARC, asymptomatic HIV positive, also in combination with AZT.
  • Granulocyte Hoeschst-Roussel AIDS Macrophage Colony (Sommerville, NJ) Stimulating Immunex Factor (Seattle, WA) Granulocyte Schering-Plough AIDS Macrophage Colony (Madison, NJ) AIDS, in combination Stimulating Factor w/AZT
  • Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
  • Granulocyte Amgen AIDS in combination Colony Stimulating (Thousand Oaks, CA) w/AZT Factor
  • Tumor Necrosis Genentech ARC in combination Factor: TNF (S. San Francisco, CA) w/gamma Interferon
  • Isethionate (IM & IV) (Rosemont, IL)
  • Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
  • Indinavir is generally administered at a dosage of 800 mg, three times a day.
  • Seed medium contained the following in g/L: corn steep liquor, 5 g; tomato paste, 40; oat flour, 10; glucose, 10; agar, 4; FeS ⁇ 4 » 7H2 ⁇ , 0.01; MnS ⁇ 4*4H2 ⁇ , 0.01; CuCl2*2H2 ⁇ , 0.00025; CaCl2, 0.001; H3BO3, 0.00056; (NH4)6Mo7 ⁇ 24*4H2 ⁇ , 0.00019; ZnS ⁇ 4*7H2 ⁇ , 0.002. The pH was adjusted to 6.8.
  • Production media contained the following in grams per liter: sucrose, 80; yellow corn meal, 50; yeast extract, 1.
  • FVM Frozen vegetative mycelia
  • the compounds were eluted from the column with a 60 minutes linear gradient of 50 to 90% aqueous acetonitrile containing 0.1% trifluoroacetic acid at a flow rate of 10 mL per minute.
  • the elution of the column was monitored by a in-line ultraviolet detection at 250 nm. Fractions eluting at 27 and 28 minutes were concentrated and subsequently lyophilized to give compound A and compound B, respectively, as yellow powders.
  • Natori Chem. Pharm. Bull, vol 35, pp 578-584, 1987 has same gross structure as A ([ ⁇ ]D +827) and B ([ ⁇ ]D -188) except for stereo-chemistry.
  • fraction eluting from 2500 mL to 3000 mL of elution volume of methanol were combined and concentrated to give fraction A; fractions from 3001 to 4100 mL elution volume of methanol gave fraction B and 4001 mL to 6000 mL gave fraction C.
  • fraction A A 75 mg portion of fraction A was dissolved in 0.5 mL acetonitrile and was chromatographed over a ZORBAX RX C-8 (22 x 250 mm) reverse phase column and eluted with a 60 minutes gradient of 40 to 60% aqueous acetonitrile containing 0.1% TFA at a flow rate of 10 mL per minute. The elution was detected by 210 nm in-line ultra violet light. The fractions eluting between 34 to 38 minutes were combined, concentrated under reduced pressure, and lyophilized to give compound C as a yellow powder.
  • Fraction B (1.0 g) was chromatographed on a silica gel column (3 x 20 cm). The column was packed in and washed with methylene chloride and the material was loaded in a 1:1 mixture of methylene chloride - acetone. Elution of the column with 4% methanol in methylene chloride containing 0.1 % acetic acid and concentration of the fractions gave compound B as yellow powder.
  • Fraction C (50 mg) was dissolved in 0.5 mL acetonitrile and was chromatographed on a similar ZORBAX RX C-8 column. Elution of the column at 10 mL per minute with a 80 minute step gradient of aqueous acetonitrile containing 0.1% TFA.
  • the gradient was as follows: 50% aqueous acetonitrile for 10 minute, 50 to 70% (10.01 to 70 minute) and 70 to 100% (70.01 to 80 minute). The fractions eluting between 46-47 minutes were combined, concentrated and lyophilized to give compound D as a yellow powder.
  • Compound C has 2,3-trans and 2',3'-cis stereochemistry.
  • Compound D has a 2,3-Cis stereochemistry.
  • CDCI3 at 75 MHz.
  • the compounds were eluted isocratically for 30 minutes with 60% aqueous acetonitrile containing 0.1% TFA followed by a gradient to 75% over 30 minutes. The flow rate was 10 mL per minute. Fractions eluting between 30 to 32, and 34 to 36 minutes were combined and lyophilized to give penta- (Compound F) and hexamethyl (Compound G) ethers, respectively, as yellow powders.
  • a microtiter assay for ligation of processed donor (HIV) DNA to unspecific, nicked host DNA was conducted according to Hazuda, D.J. et al, Nucl. Acids, Res. 2 , 1121 (1994), herein incorporated by reference for these purposes.
  • To assay inhibition of such strand transfer by HIV integrase the reaction was conducted with inhibition having various concentrations in the range of 0.75 to 100 ⁇ M. Representative results follow.
  • an oral composition of a compound of this invention 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

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Abstract

La présente invention a trait à des produits naturels tels que certaines chaétochromines. Ces composés sont utiles dans l'inhibition de la VIH intégrase, la prévention ou le traitement de l'infection par VIH et le traitement du SIDA, soit en tant que tels, soit comme sels pharmaceutiquement acceptables, comme ingrédients de composition pharmaceutique, en association ou non avec d'autres antiviraux, immunomodulateurs, antibiotiques ou vaccins. L'invention concerne également des procédés pour le traitement du SIDA et des procédés pour la prévention ou le traitement de l'infection par le VIH.
PCT/US1998/002292 1997-02-06 1998-02-03 Inhibiteurs de la vih integrase WO1998034932A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002280518A CA2280518A1 (fr) 1997-02-06 1998-02-03 Inhibiteurs de la vih integrase
US09/355,692 US6403347B1 (en) 1998-02-03 1998-02-03 HIV integrase inhibitors
EP98904970A EP1023281A4 (fr) 1997-02-06 1998-02-03 Inhibiteurs de la vih integrase
AU62710/98A AU6271098A (en) 1997-02-06 1998-02-03 Hiv integrase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3690297P 1997-02-06 1997-02-06
US60/036,902 1997-02-06
GBGB9707492.6A GB9707492D0 (en) 1997-04-14 1997-04-14 HIV integrase inhibitors
GB9707492.6 1997-04-14

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WO1998034932A1 true WO1998034932A1 (fr) 1998-08-13

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EP1186599A1 (fr) * 1999-06-02 2002-03-13 Shionogi & Co., Ltd. Nouveau procede de preparation de derives de propenone a substitution
EP1649282A2 (fr) * 2003-07-07 2006-04-26 David H. Wagner Methodes de prediction du developpement de maladies auto-immunes et traitement associe
AU2003205826B2 (en) * 2002-01-17 2007-04-26 The Secretary Of State For Defence Novel uses of polymers
US8283366B2 (en) 2010-01-22 2012-10-09 Ambrilia Biopharma, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
CN113717145A (zh) * 2021-09-18 2021-11-30 中国热带农业科学院热带作物品种资源研究所 双萘并r-吡喃酮类化合物及其在抗植物炭疽菌中的应用

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1186599A1 (fr) * 1999-06-02 2002-03-13 Shionogi & Co., Ltd. Nouveau procede de preparation de derives de propenone a substitution
EP1186599A4 (fr) * 1999-06-02 2003-02-26 Shionogi & Co Nouveau procede de preparation de derives de propenone a substitution
US6831177B1 (en) 1999-06-02 2004-12-14 Shionogi & Co., Ltd. Processes for the preparation of substituted propenone derivatives
AU2003205826B2 (en) * 2002-01-17 2007-04-26 The Secretary Of State For Defence Novel uses of polymers
EP1649282A2 (fr) * 2003-07-07 2006-04-26 David H. Wagner Methodes de prediction du developpement de maladies auto-immunes et traitement associe
EP1649282A4 (fr) * 2003-07-07 2007-08-29 Webb Waring Inst Methodes de prediction du developpement de maladies auto-immunes et traitement associe
US8283366B2 (en) 2010-01-22 2012-10-09 Ambrilia Biopharma, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
US8664248B2 (en) 2010-01-22 2014-03-04 Taimed Biologics, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
CN113717145A (zh) * 2021-09-18 2021-11-30 中国热带农业科学院热带作物品种资源研究所 双萘并r-吡喃酮类化合物及其在抗植物炭疽菌中的应用

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AU6271098A (en) 1998-08-26
CA2280518A1 (fr) 1998-08-13
EP1023281A4 (fr) 2000-08-02

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