WO2007121416A2 - Composés chimiques - Google Patents

Composés chimiques Download PDF

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Publication number
WO2007121416A2
WO2007121416A2 PCT/US2007/066734 US2007066734W WO2007121416A2 WO 2007121416 A2 WO2007121416 A2 WO 2007121416A2 US 2007066734 W US2007066734 W US 2007066734W WO 2007121416 A2 WO2007121416 A2 WO 2007121416A2
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WO
WIPO (PCT)
Prior art keywords
compound
oxy
chloro
inhibitors
similar agents
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Application number
PCT/US2007/066734
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English (en)
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WO2007121416A3 (fr
Inventor
Christopher Joseph Aquino
George Andrew Freeman
Michael Tolar Martin
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Smithkline Beecham Corporation
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Publication of WO2007121416A2 publication Critical patent/WO2007121416A2/fr
Publication of WO2007121416A3 publication Critical patent/WO2007121416A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • 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

Definitions

  • the present invention relates to a compound that is a non-nucleoside reverse transcriptase inhibitor, and to processes for the preparation and use of the same.
  • the treatment of human immunodeficiency virus infection is disclosed which includes the administration of a benzophenone derivative.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase.
  • Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
  • NNRTIs Non-nucleoside reverse transcriptase inhibitors
  • the NNRTIs interact with a specific site of HIV-I reverse transcriptase that is closely associated with, but distinct from, the NRTI binding site.
  • NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site (E. De Clercq, // Famaco 54, 26-45, 1999). Failure of long-term efficacy of NNRTIs is often associated with the emergence of drug-resistant virus strains (J. Balzarini, Biochemical Pharmacology, VoI 58, 1-27, 1999).
  • WO 02/070470, WO 01/17982, and US 2006/0025480 disclosed certain benzophenones as non-nucleoside reverse transcriptase inhibitors. We have now discovered that the compounds of the present invention are useful as inhibitors of both wild type and mutant variants of HIV reverse transcriptase.
  • the present invention features a compound of formula (I)
  • the present invention also features a compound of formula (IA)
  • the present invention features a compound of formula (IB)
  • the present invention features pharmaceutical compositions comprising a compound of the present invention.
  • the present invention features a compound of the present invention for use in medical therapy, for example, the treatment of viral infections and associated conditions, such as HIV infections and associated conditions.
  • the present invention also features the use of a compound of the present invention in the manufacture of a medicament for use in the treatment of viral infections and associated conditions, for example, in the treatment of HIV infections and associated conditions.
  • the present invention features a method for the treatment of viral infections and associated conditions, for example, HIV infections and associated conditions, comprising the administration of a compound of the present invention.
  • treatment refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable ester, salt of an ester, ether, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing directly or indirectly a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs, and salts thereof are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal, for example, by allowing an orally administered compound to be more readily absorbed into the blood, or which enhance delivery of the parent compound to a biological compartment, for example, the brain or lymphatic system, relative to the parent species.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • the biological or medical response may be considered a prophylactic response or a treatment response.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • the present invention features a compound of formula (I)
  • the compound has the name 2-( ⁇ 4- chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl ⁇ oxy)-N- ⁇ 4-[(2,3-dihydroxy-3- methylbutyl)oxy]-3-fluoro-2-methylphenyl ⁇ acetamide.
  • the present invention also features a compound of formula (IA)
  • the compound has the name 2-( ⁇ 4- chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl ⁇ oxy)-N-(4- ⁇ [(25)-2,3-dihydroxy-3- methylbutyl]oxy ⁇ -3-fluoro-2-methylphenyl)acetamide.
  • the present invention further features a compound of formula (IB)
  • the compound has the name 2-( ⁇ 4- chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl ⁇ oxy)-N-(4- ⁇ [(2i?)-2,3-dihydroxy-3- methylbutyl]oxy ⁇ -3-fluoro-2-methylphenyl)acetamide.
  • Compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms and unsolvated forms are encompassed within the scope of the present invention.
  • Compounds of the present invention may exist in a mixture of forms and/or solvates or as a mixture of amorphous material and one or more forms and/or solvates. In general, all physical forms are intended to be within the scope of the present invention. Forms may be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • Esters of the compounds of the present invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, Ci_4alkyl, or Ci_4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonate esters, such as alkyl- or aralkylsulfonate esters, such as alkyl- or aralkylsulfon
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • Ethers of the compounds of the present invention include, but are not limited to methyl, ethyl, butyl and the like.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of the present invention) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • compositions that include effective amounts of a compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the present invention are as herein described.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical composition including admixing a compound of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the composition, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of the present invention for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day. The actual amount per day would usually be from 0.3 to 3,000 mg.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the present invention, depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal) route.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component may be combined with an oral, nontoxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents may also be present.
  • Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the mixture before the encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture.
  • binders examples include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets may be formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture may be wet- granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials
  • the powder mixture may be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules may be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention may also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material,
  • Oral fluids such as solutions, syrups, and elixirs may be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups may be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs may be prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions may be formulated generally by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like may also be added.
  • dosage unit compositions for oral administration may be microencapsulated.
  • the composition may also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers may include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • PVP polyvinylpyrrolidone
  • pyran copolymer polyhydroxypropylmethacrylamide-phenol
  • polyhydroxyethyl-aspartamidephenol polyhydroxyethyl-aspartamidephenol
  • polyethyleneoxidepolylysine substituted with palmitoyl residues may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or am
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
  • Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the compositions may be applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraff ⁇ nic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
  • compositions adapted for nasal administration where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit- dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question.
  • compositions suitable for oral administration may include flavoring or coloring agents.
  • a compound according to the invention for use in medical therapy particularly for the treatment of viral infections such as an HIV infection.
  • Compounds according to the invention have been shown to be active against HIV infections, although these compounds may be active against HBV infections as well.
  • the compound according to the invention is particularly suited to the treatment of HIV infections and associated conditions.
  • Reference herein to treatment extends to treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.
  • ARC AIDS related complex
  • Kaposi's sarcoma Kaposi's sarcoma
  • AIDS dementia AIDS dementia
  • the present invention provides a method of treatment of HIV mutant viruses that exhibit NNRTI drug resistance by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable derivative thereof to a mammal, in particular a human.
  • the compounds of the present invention may be used to treat wild-type HIV-I as well as several resistance mutations, for example, K103N, LlOOI, or Y181C.
  • the present invention provides a method for the treatment of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • a further aspect of the invention includes a method for the treatment of the symptoms or effects of an HBV infection.
  • the compounds of the present invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the compounds of the present invention and any pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other therapeutic agents.
  • the compounds of the present invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and any pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • the compounds may be used in combination with any other pharmaceutical composition where such combined therapy may be useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and/or immunoregulatory diseases.
  • the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • agents include: Nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleoside reverse transcriptase inhibitors (including an agent having anti- oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, and similar agents
  • Protease inhibitors such as saquinavir, r
  • Entry inhibitors such as enfuvirtide (T-20), T- 1249, PRO-542, PRO- 140, TNX- 355, BMS-806, 5-Helix and similar agents;
  • Integrase inhibitors such as L-870,180 and similar agents
  • Budding inhibitors such as PA-344 and PA-457, and similar agents
  • CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
  • the scope of combinations of the compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then the specific compounds of the invention are prepared in the working Examples. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention.
  • the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecif ⁇ c synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), incorporated by reference with regard to stereochemistry.
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • CDCI3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • SiO 2 silicon
  • DMSO dimethylsulfoxide
  • EtOAc ethyl acetate
  • atm atmosphere
  • HCl hydrochloric acid
  • CHCI3 chloroform
  • MsCl methanesulphonyl chloride
  • sat'd saturated
  • DCE (1,2-dichloroethane); Ps (polymer supported); EDCI (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride);
  • TES triethylsilane
  • TBAF tetrabutylammonium fluoride
  • CSA camphor sulfonic acid
  • n-BuLi n-butyllithium
  • TBDPSCl tert-butyldiphenyl silylchloride
  • HOAc acetic acid
  • AcCl acetyl chloride
  • DIBAL-H diisobutyl aluminium hydride
  • MgSO 4 magnesium sulfate
  • NaHCO 3 sodium bicarbonate
  • IPA isopropyl alcohol
  • Rt retention time
  • ACN acetonitrile
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • MgSO 4 magnesium sulfate
  • NaHCO 3 sodium bicarbonate
  • Pd/C palladium on carbon
  • DCM dichloromethane
  • Eq equivalents
  • IPA isopropyl alcohol
  • Rt retention time
  • SFC supercritical fluid chromatography
  • N normal
  • mCPBA metal-chloroperoxybenzoic acid
  • Step A l,2-difluoro-3-methyl-4-nitrobenzene (intermediate 1)
  • WO2002028825(A2) was combined with copper(I) oxide (4.58g, 32mmol, 0.2eq) in 50OmL acetonitrile and heated at reflux Ih.
  • the reaction mixture was filtered through celite and the filtrate was concentrated to a green oil. This residue was dissolved in diethyl ether and filtered through celite a second time. The filtrate was concentrated to dryness and the crude product purified by vacuum distillation (79-90 0 C, 2-5mm Hg) to give the title compound (28.0g) as a light yellow oil which crystallized on standing.
  • Step B (45)-2,2-dimethyl-4- ⁇ l-methyl-l-[(phenylmethyl)oxy]ethyl ⁇ -l,3-dioxolane (intermediate 2)
  • Step C (2S)-3-methyl-3-[(phenylmethyl)oxy]-l,2-butanediol (intermediate 3)
  • Step D (2S)- l-[(2-fluoro-3-methyl-4-nitrophenyl)oxy]-3-methyl-3-[(phenylmethyl)oxy]- 2-butanol (intermediate 4)
  • (2S)-3-methyl-3-[(phenylmethyl)oxy]-l,2-butanediol (58.9g crude, intermediate 3) and l,2-difluoro-3-methyl-4-nitrobenzene (42.6g, 219mmol, intermediate 1) were combined in 73OmL benzene and treated with 73OmL 6N NaOH and benzyltriethylammonium chloride (2.5Og, l lmmol, 0.05eq) with vigorous mechanical stirring at 60 0 C for 16h.
  • the phases were separated and the aqueous phase extracted twice with EtOAc.
  • the organic phases were combined, dried over MgSO 4 , filtered, and the filtrate concentrated to dryness.
  • Step E (2S)- l-[(4-amino-2-fluoro-3-methylphenyl)oxy]-3-methyl-2,3-butanediol (intermediate 5)
  • Step G 2-( ⁇ 4-chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl ⁇ oxy)-N-(4- ⁇ [(2S)-2,3- dihydroxy-3-methylbutyl]oxy ⁇ -3-fluoro-2-methylphenyl)acetamide
  • Example 2 was prepared via the method of Procedure 1 with the following exception: 2- [(4i?)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-propanol was used in place of 2-[(4S)-2,2- dimethyl-l,3-dioxolan-4-yl]-2-propanol in step B. 2-[(4i?)-2,2-dimethyl-l,3-dioxolan-4- yl]-2-propanol was in turn prepared according to the method of Schrotter et. al.
  • Step A 2-fluoro-3-methyl-4-nitrophenol (intermediate 7)
  • Step B 2-fluoro-3-methyl-l-[(3-methyl-2-buten-l-yl)oxy]-4-nitrobenzene (intermediate 8)
  • Step C l-[(2-fluoro-3-methyl-4-nitrophenyl)oxy]-3-methyl-2,3-butanediol (intermediate 9)
  • Step D l-[(4-amino-2-fluoro-3-methylphenyl)oxy]-3-methyl-2,3-butanediol (intermediate 10)
  • Step E 2-( ⁇ 4-chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl ⁇ oxy)-/V- ⁇ 4-[(2,3- dihydroxy-3-methylbutyl)oxy] -3-fluoro-2-methylphenyl ⁇ acetamide
  • reaction mixture was purified on silica gel eluting with 50 to 100% EtOAc in hexanes. Appropriate fractions were collected and concentrated and the residue dissolved in EtOAc and washed with equal portions of 0.1 N HCl, water and brine. The organic layer was dried over MgSO 4 and concentrated to give the title compound (77 mg, 0.13 mmol, 79%) as a white solid.
  • the second half of the catalyst, ligand, and PMHS was charged by adding a slurry of 1,1- bis(diphenylphosphino)ferrocene (DPPF, 0.01 wt, 0.0065 equiv) and palladium acetate (.0031 wt, .005 equiv.) in DME (0.15 vol) and washed into reactor with additional DME (0.05 vol).
  • PMHS O.Olwt, 0.06 equiv
  • DME 0.1 vol
  • the reaction was allowed to heat at approximately 8O 0 C for an additional two hours at which point remaining starting material is ⁇ 1% by standard LC method.
  • the HeLa cell assay was performed according to a modifcation of Kimpton J. and Emerman M., Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated ⁇ -galactosidase gene, J. Virol. 66:2232-2239 (1992), in which HIV-I infection is detected by the activation of an HIV-LTR driven ⁇ -galactosidase reporter that is integrated into the genome of a CD4 + HeLa cell line. Quantitation of ⁇ -galactosidase is achieved by measuring the activation of a chemiluminescent substrate (Applied Biosystems). The concentration of each compound required to inhibit 50% (IC 50 ) of the HIV-I induced ⁇ -galactosidase signal, relative to untreated controls, was determined for each isogenic, recombinant virus.
  • Hygromycin B (GibcoBRL #1687-010)
  • PBS Phosphate Buffered Saline
  • DMSO Dimethyl Sulfoxide
  • DMSO Gal-Screen Reporter Gene Assay System
  • HeLa-CD4-LTR- ⁇ -gal cells are propagated in DMEM containing 10% fetal bovine serum + 0.2 mg/ml geneticin + 0.1 mg/ml hygromycin B. Cells are split by standard trypsinization when confluency reaches 80% (roughly every 2 to 3 days).
  • DNA encoding the HIV-I reverse transcriptase was subcloned from a M13 phage into a general shuttle vector, pBCSK+, as a -1.65 kbp EcoRI/Hindlll ended DNA fragment.
  • the HIV DNA insert of the resulting plasmid, pRT2 was completely sequenced on both strands prior to use in site directed mutagenesis experiments. Specific amino acid replacements were made using Stratagene Quick Change reagents and mutagenic oligonucleotides from Oligos. Following mutagenesis, the entire mutant RT coding sequence was verified by sequencing both DNA strands.
  • Each mutant RT coding sequence was crossed into the RT-deleted HIV-I viral DNA backbone by in vivo homologous recombination.
  • Transfected cell cultures were expanded and monitored until syncitia formation and CPE were extensive.
  • Virus was harvested by clear spin of the culture supernatants and frozen at - 80 0 C as primary stock. Recombinant progeny virus was sequenced in the RT region to confirm the mutant genotype.
  • Virus stocks were further expanded by infection of MT4 cells, harvested and stored as frozen aliquots. Stocks were titered in HeLa MAGI cells for assay.
  • HIV-I virus stocks were titered in the HeLa-CD4-LTR- ⁇ -gal assay system to establish the appropriate infecting dose.
  • the endpoint for this assay is relative light units (RLUs), and titer is recorded as RLUs/ml.
  • Virus stocks are diluted (serial 1 :2) into DMEM containing 10% FBS plus 25ug/ml DEAE-dextran and assayed as described in the "Experimental Protocol" section below without test compound.
  • a "multiplicity of infection” defined as infectious units per cell is usually not calculated but is typically «1.0. Relationship of RLUs/ml to other measures of infectivity such as HeLa PFU/ml or MT4 TCID50/ml may not be consistent from lot to lot or strain to strain and should be determined for each lot.
  • Test compounds are titrated into DMEM + 10% FBS + 0.135% DMSO (0.1% final). The final volume of titrated compound in each well should be at least 150ul and DMSO should be at 0.135% (0.1% final) including the no compound controls.
  • Raw data are transformed into percent of control by the following formula: (raw signal in each well / average raw signal for the two no compound controls in the same row)* 100. Percent of control is plotted vs. compound concentration using either Robsage or Robofit programs (GSK).

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Abstract

L'invention concerne un composé étant un inhibiteur de transcriptase inverse non nucléosidique, et des procédés de préparation et d'utilisation de ce composé. L'invention concerne plus précisément des procédés d'utilisation d'un tel composé dans le traitement d'infections virales d'immunodéficience humaines.
PCT/US2007/066734 2006-04-17 2007-04-17 Composés chimiques WO2007121416A2 (fr)

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Publication number Priority date Publication date Assignee Title
US6995283B2 (en) * 2001-03-02 2006-02-07 Smithkline Beecham Corporation Benzophenones as inhibitors of reverse transcriptase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6995283B2 (en) * 2001-03-02 2006-02-07 Smithkline Beecham Corporation Benzophenones as inhibitors of reverse transcriptase

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