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WO2011017395A1 - Composés chimiques - Google Patents

Composés chimiques Download PDF

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Publication number
WO2011017395A1
WO2011017395A1 PCT/US2010/044347 US2010044347W WO2011017395A1 WO 2011017395 A1 WO2011017395 A1 WO 2011017395A1 US 2010044347 W US2010044347 W US 2010044347W WO 2011017395 A1 WO2011017395 A1 WO 2011017395A1
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WO
WIPO (PCT)
Prior art keywords
compound
mammal
administering
formula
furan
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2010/044347
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English (en)
Inventor
Brian Alvin Johns
David P. Temelkoff
Emile Johann Velthuisen
Jason Gordon Weatherhead
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Filing date
Publication date
Application filed by GlaxoSmithKline LLC filed Critical GlaxoSmithKline LLC
Publication of WO2011017395A1 publication Critical patent/WO2011017395A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to highly functionalized 1 ,3-diamino-propan- 2-ols and pharmaceutically acceptable salts thereof. More specifically, the invention relates to highly functionalized 1 ,3-diamino-propan-2-ols that are derivatives of the HIV protease inhibitor darunavir.
  • Each element has a unique number of protons in the atoms nucleus.
  • the number of protons is called the atomic number and in a neutral state is equal to the number of electrons that surround the nucleus.
  • the mass number however is defined as the number of protons and neutrons contained within the nucleus of a given atom.
  • the molecular weight of an atom is equal to the number of protons and neutrons contained in that substance.
  • Isotopes are defined as atoms that contain the same number of protons (which define the element) and different numbers of neutrons. Some isotopes are unstable and decay to give off radioactivity, while others are stable and do not decay.
  • Hydrogen (H, 1 H, protio) is the simplest atom containing only a single proton and no neutrons (atomic number 1 , mass number 1 ).
  • Deuterium (D, 2 H, deutero) is a stable isotope of hydrogen that contains 1 proton and 1 neutron having an atomic number of 1 and a mass number of 2. Deuterium is present in a natural abundance of 0.015% .
  • Any carbon-hydrogen bond has a given energy resulting from vibrations in the molecule at a certain temperature. This energy is defined as the zero point energy.
  • a corresponding carbon-deuterium bond also has a zero point energy under the same conditions, however because of the greater mass of the deuterium (resulting from the extra neutron) the vibrations contribute to give a lower zero point energy relative to the hydrogen counterpart.
  • the difference in the C-H and C-D bond energies result in a different activation energy requirement to reach an identical transition state. This difference in energy gives rise to what is called a kinetic isotope effect. This small but often significant energy difference can lead to retarded reaction rates in the deuterium analogue when the bond is being broken in a rate limiting step during a chemical transformation.
  • Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs. Like other PIs, solubility and first pass metabolism were challenges during clinical investigations. To combat the first pass and other metabolism effects it is common to dose HIV protease inhibitors with the pharmacoenhancer ritonavir (RTV). Thus, the recommended oral dose of darunavir tablets is 600 mg (two 300 mg tablets) twice daily (BID) taken with ritonavir 100mg BID and with food.
  • RTV pharmacoenhancer ritonavir
  • the present invention addresses this issue by employing the deuterium isotope effect by making deuterium analogues of darunavir.
  • the invention will allow for reduced need for pharmacoenhancers or optionally remove the need altogether for co- dosing with the pharmacoenhancer.
  • Embodiments of the present invention feature newly discovered deuterated compounds which are protease inhibitors. Such compounds may be useful in the treatment of conditions related to infection with the human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • R 1 is independently selected from -D or -H, wherein at least one R 1 substituent is a deuterium atom;
  • R 2 is independently selected from -D or -H;
  • n 1-3;
  • x 1-2, or a pharmaceutically acceptable salt thereof.
  • each R 1 is independently selected from -D or -H, wherein the level of deuterium incorporation in each R 1 group substituted with -D is at least
  • n 1 , 2, or 3; and x is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • each R 1 and each R 2 is independently selected from -D or -H, wherein the level of deuterium incorporation in each R 1 group and each R 2 group substituted with -D is at least 50%;
  • n 1 , 2, or 3;
  • x is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • each R 1 and each R 2 is independently selected from -D or -H, wherein the level of deuterium incorporation in each R 1 group and each R 2 group substituted with -D is at least 70%;
  • n 1 , 2, or 3;
  • x is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a method of treating a mammal infected with a virus susceptible to HIV protease inhibition comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting HIV related aspartyl protease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a
  • a method of treating a mammal infected with protease resistant HIV comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a
  • a ninth aspect of the present invention there is provided a method of preventing development of protease resistant HIV in a mammal, comprising
  • a method of treating a mammal infected with a virus susceptible to HIV protease inhibition comprising administering to said mammal a long-acting parenteral composition, wherein the long- acting parenteral composition comprises a therapeutically effective amount of compound of formula (i), or a pharmaceutically acceptable salt thereof.
  • the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or further comprises at least one additional agent useful as a pharmacological enhancer.
  • a method of treating a mammal infected with a protease resistant HIV comprising administering to said mammal a long- acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of compound formula (I), or a pharmaceutically acceptable salt thereof.
  • the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.
  • a method of inhibiting HIV related aspartyl protease in a mammal comprising administering to said mammal a long-acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or wherein the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.
  • Still another particular embodiment provides a compound selected from the group consisting of: (3R,3aS,6aR)-Hexahydrofuro[2,3-6]furan-3-yl[(1 S,2R)-3-[[(4- aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-c/ 3 - carbamate trifluoroacetate salt,
  • a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • Particular related embodiments provide such compositions, wherein the long-acting parenteral
  • composition further comprises at least one additional agent useful in treating HIV infection; or at least two additional agents useful in treating HIV infection. Still more related particular embodiments provide a long-acting parenteral
  • compositions as described wherein the at least one additional agent is selected from the group consisting of GSK1349572, GSK1265744 and GSK1247303.
  • additional agent is selected from the group consisting of GSK1349572, GSK1265744 and GSK1247303.
  • Other related particular embodiments provide such a long-acting parenteral
  • composition wherein the at least one additional agent IDX-899.
  • additional agent is selected from the group consisting of GSK1349572, GSK1265744 and GSK1247303, and wherein the composition further comprises IDX-899.
  • Yet another embodiment provides a method of treating a mammal infected with a virus susceptible to HIV protease inhibition, comprising administering by parenteral injection to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and administering orally at least one agent useful as a pharmacoenhancer.
  • Another embodiment provides a method of treating a mammal infected with a virus susceptible to HIV protease inhibition, comprising: administering by parenteral injection to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and co-administering by parenteral injection at least one agent useful as a pharmacoenhancer.
  • treating a mammal infected with a virus susceptible to HIV protease inhibition further comprises inhibiting HIV related aspartyl protease in a mammal, treating protease resistant HIV in a mammal, or preventing development of protease resistant HIV in a mammal.
  • 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.
  • 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.
  • HIV refers to the human immunodeficiency virus. HIV is the causative agent for AIDS.
  • AIDS refers to acquired immunodeficiency syndrome. AIDS is a disease characterized by destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections.
  • D refers to a deuterium atom.
  • Deuterium (D, 2H, deutero) is a stable isotope of hydrogen that contains 1 proton and 1 neutron having an atomic number of 1 and a mass number of 2. Deuterium is present in a natural abundance of 0.015%.
  • Darunavir is an aspartyl protease inhibitor having a structure analogous to a compound of formula (I) wherein all of the R 1 groups are -H, shown below as the compound of formula (Ia):
  • deuterated darunavir means darunavir wherein at least one of the darunavir hydrogens is substituted with deuterium. That is, a compound of formula (I) wherein at least one R 1 is a deuterium.
  • enriched deuterated darunavir means darunavir wherein in each darunavir hydrogen substituted with deuterium the deuterium is incorporated at a level of at least 50%. That is, a compound of formula (I) wherein the level of incorporation of deuterium in each hydrogen substituted with deuterium is at least 50%.
  • H refers to a hydrogen atom.
  • Hydrogen (H, 1 H,) is a stable isotope of hydrogen that contains 1 proton having an atomic number of 1 and a mass number of 1. Also, unless otherwise stated when a particular R 1 is substituted with -H it is understood to have hydrogen and deuterium at their natural abundance isotopic composition.
  • the compounds of formula I are substantially enriched in deuterium to levels of 50% at the indicated positions.
  • the preferred level of deuterium incorporation at the indicated position is above 75%, 90%, 95% or 98% and approaching limits of quantitation for determining hydrogen (1 H) content. It will also be understood that compounds with multiple deuterium atoms incorporated will have isotopic mixtures dependent on the level of incorporation at each position.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 50%. In another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 75%. In still another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 90%. In a further embodiment, the level of deuterium incorporation in each R 1 group in the compound of formula (I) indicated as substituted with deuterium is at least 95%.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 98%. In a further embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium approaches 100% and is limited by the limits of quantitation for detecting hydrogen content.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 20%. In another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 25%. In still another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 30%. In a further embodiment, the level of deuterium incorporation in each R 1 group in the compound of formula (I) indicated as substituted with deuterium is at least 35%.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 40%. In a further embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 45%.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is greater than 0.015%. In another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 1%. In still another embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 3%. In a further embodiment, the level of deuterium incorporation in each R 1 group in the compound of formula (I) indicated as substituted with deuterium is at least 5%.
  • the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 10%. In a further embodiment, the level of deuterium incorporation in each R 1 group of the compound of formula (I) indicated as substituted with deuterium is at least 15%.
  • each deuterium substituted for hydrogen may be incorporated at any value of 50% or greater. That is, one deuterium substituted R 1 may have 60% deuterium incorporation whereas another deuterium substituted R 1 may have 80% deuterium incorporation and so on for other deuterium substituted R 1 groups.
  • Certain of 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 and/or diastereomerically enriched mixtures.
  • the individual isomers of the compounds of the present invention are also included within the scope of the invention, 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. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compounds of formula (I).
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
  • polygalacturonate potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate.
  • Other salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
  • formulations may include co-crystals of the compound of formula (1 ) with an alcohol such as ethanol, propanol, appropriate diols and the like.
  • compositions which include therapeutically effective amounts of the compound of formula (I) or salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the formula (I) or salt thereof are as described above.
  • 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 thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I), or salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Such a unit may contain, for example, 10Omg to 5g, 0.5mg to 1 g, 1 mg to 700mg, or 5mg to 10Omg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations 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 the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in 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 can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic 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 a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • Flavouring, preservative, dispersing and colouring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatine sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatine, 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 used in these dosage forms include 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 are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatine, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatine, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting 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 and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can 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 can 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
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can 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 formula (I) or salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) or salts thereof 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.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol,
  • polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • 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).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • 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 mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which 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 formulations 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.
  • 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 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 which 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 formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules 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.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the pharmaceutical formulation containing a compound of formula I or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) or salts thereof per se.
  • the compounds of formula (I) or salts thereof are believed to have activity in stopping or reducing the effects of HIV as a result of inhibition of aspartyl proteases.
  • a method of treating a mammal infected with a virus susceptible to protease inhibition including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a
  • the virus is HIV.
  • the protease is an aspartyl protease.
  • the protease is an HIV related aspartyl protease.
  • the mammal is a human.
  • a method of inhibiting HIV related aspartyl protease in a mammal including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.
  • a method of treating a mammal infected with a protease resistant HIV comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the mammal is a human. In one embodiment, the mammal is a human.
  • a method of preventing development of protease resistant HIV in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other therapeutic agents.
  • the compounds of the present invention and any 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 compounds 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.
  • administration in combination of a compound of the present invention and salts, solvates, or other 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 amounts of the compound(s) of formula (I) or salts thereof 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 present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • agents useful in the prevention or treatment of HIV 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, nevirapine, delavirdine, efavirenz, loviride, capravirine, TMC-278, TMC-125, etravirine, and similar agents;
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, raltegravir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542,
  • PRO-140 PRO-140, TNX-355, BMS-806, 5-Helix and similar agents;
  • lntegrase inhibitors such as L-870,810, elvitegravir, raltegravir and
  • GSK1349572 S/GSK1349572, GSK1265744, and GSK1247303 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; and other agents such as IDX-899.
  • 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. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the present invention may be used in combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV. Examples of such pharmacological enhancers (or pharmakinetic boosters) include, but are not limited to, ritonavir, GS-9350, and SPI-452.
  • Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1 [2-(1- methylethyl)-4-thiazolyl]-3,6-dioxo-8,1 1-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13- oic acid, 5-thiazolylmethyl ester, [5S-(5S * ,8R * ,10R * ,11 R * )] and is available from Abbott Laboratories of Abbott park, Illinois, as Norvir.
  • Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
  • Ritonavir also inhibits P450 mediated drug metabolism as well as the P-glycoprotein (Pgp) cell transport system thereby resulting increased concentrations of active compound within the organism.
  • GS-9350 is a compound being developed by Gilead Sciences of
  • SPI-452 is a compound being developed by Sequoia
  • a compound of formula (I) is used in combination with ritonavir.
  • the combination is an oral fixed dose combination.
  • the compound of formula (I) is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition.
  • the compound of formula (I) is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a compound of formula (I) is used in combination with GS-9350.
  • the combination is an oral fixed dose combination.
  • the compound of formula (I) is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition.
  • the compound of formula (I) is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • a compound of formula (I) is used in combination with SPI-452.
  • the combination is an oral fixed dose combination.
  • the compound of formula (I) is formulated as a long acting parenteral injection and SPI-452 is formulated as an oral composition.
  • the compound of formula (I) is formulated as a long acting parenteral injection and SPI-452 is formulated as an injectable composition.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative examples are set out below in the Working Examples.
  • ⁇ l_ microliter
  • psi pounds per square inch
  • Tr retention time
  • RP reverse phase
  • iodochloromethane in the presence of lithium diisopropylamide may result in the chloromethyl ketone 12.
  • Reduction of the ketone with subsequent epoxide formation could serve to provide a compound 13.
  • Ring opening as in Scheme 1 with isobutylamine followed by sulfonylation should serve to provide compound 14.
  • This material can be deprotected by treatment with acid followed by acylation with the p-nitrophenyl carbonate of the desired bis-tetrahydrofuran (5,5-PNP, 15). Finally, reduction of the nitro group could serve to provide 10.
  • a compound such as 12 could be subjected to reduction conditions that employ sodium borodeuteride to provide 16. This material can be converted to a compound of formula l-a using methods similar to those described in scheme 2 by way of example. [00139] Scheme 3
  • Dideuteroiodochloromethane could be employed as shown in scheme 4 to provide 17 which upon reduction will provide 18. This epoxide could be converted to a compound of formula l-b as depicted in scheme 2.
  • deuterium containing phenylalanine derivatives such as 20 through 23 could be employed to provide a compound of formula l-d through l-g as shown in schemes 6-9 respectively.
  • These starting compounds are available from modifications of literature methods known to one skilled in the art.
  • Schemes 12 and 13 show a known synthesis of the bis- tetrahydrofuran p-nitrophenyl carbonate shown in scheme 2 but the route is modified to incorporate a deuterium in each case using sodium borodeuteride in place of sodium borohydride or lithium aluminium deuteride from the known route.
  • a dideuterovalerolactone analogue 44 can be employed in a similar manner as shown above to provide an activated bis- tetrahydrofuran derivative 51 which can be coupled with amine 38 and the like to provide a compound of formula l-l (Scheme 14).
  • compound 65 can be oxidized using conditions known to one skilled in the art and subsequently reduced using a hydride reagent to form an enriched mixture containing 66 consisting of the desired stereochemistry. This step also provides an opportunity to introduce an additional deuterium if a deuteride reagent is used for the ketone reduction. In this case a compound of formula l-c would result. [00160] Scheme 16
  • Scheme 18 shows that, in a similar manner to that shown in scheme 15, the combination of the methods to produce bicyclic system 56 with lithium aluminium deuteride reduction of the ketone may produce trideutero analog 76 which can be elaborated to form a compound of formula l-o.
  • Example 1 (3R.3aS.6aRVHexahvdrofuror2.3-blfuran-3-yl r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate trifluoroacetate salt.
  • Example 2 (3R,3aS,6aR)-Hexahvdrofuror2,3-blfuran-3-yl-di- r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate trifluoroacetate salt.
  • the reaction was cooled to 0°C and additional pyridine (0.03 mL) and 4 nitrophenylchloroformate (73 mg) were added and stirring was continued at ambient temperature for 12 hours.
  • the reaction was diluted with water, the organic layer was washed with 1 N HCI, saturated sodium bicarbonate solution, and dried over sodium sulfate. Purification by silica-gel chromatography (0-100 % ethyl acetate/ hexanes) gave the title compound as a white solid (533 mg, 92%).
  • the title compound was prepared in a manner similar to that described in example 1 from 4-amino-N-[(2R,3S)-3- amino-2-hydroxy-4-phenylbutyl]-d3-N-(2-methylpropyl) benzenesulfonamide and (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-d1- 4-nitrophenyl carbonate and was isolated as an off-white solid after reverse phase chromatography as the trifluoroacetate salt.
  • Example 3 (3R.3aS.6aRVHexahvdrofuror2.3-blfuran-3-yl-d r r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate trifluoroacetate salt.
  • Tributyltin hydride (15.74 ml_, 59.4 mmol) and AIBN (0.077 g, 0.471 mmol) were combined in toluene (20 ml.) and heated to 104°C.
  • the solution was concentrated under reduced pressure, diluted with acetonitrile, concentrated again, and purified by silica-gel chromatography (0-100% EtOAc/hexanes) to give a clear oil (3.03 g, 50%).
  • 1 H NMR 400 MHz, CHLOROFORM- d) ⁇ 1.8-2.2 (m, 2 H), 3.3 (br s, 1 H), 4.9-5.1 (m, 2 H), 5.77 (m, 1 H).
  • Lithium aluminium deuteride (7.54 ml_, 1 M in diethyl ether) was added dropwise to a solution of rac-(3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one-d2 (2.18 g, 16.75 mmol) in dichloromethane (10 ml.) at 0 °C. After the addition was complete, the mixture was stirred 20 minutes and then quenched slowly with water (0.37 ml.)., 1 N Sodium hydroxide (0.37 ml.) and water (0.37 ml.) were added successively and the suspension was stirred 10 minutes and filtered through a pad of celite. The filter pad was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to give a colorless oil.
  • the reaction was stirred for 24 hours at 40 °C and then allowed to cool to ambient temperature, filtered through a fritted funnel, the filter was rinsed with water and dichloromethane, and the filtrate was extracted with dichloromethane.
  • the combined organics were washed with water until no undesired alcohol was present by TLC (1 :1 hexanes: ethyl acetate, KMnO 4 stain), dried over sodium sulfate and concentrated under reduced pressure and purified by silica-gel chromatography (0-100 % ethyl acetate/ hexanes gradient elution) to give a colorless oil (455 mg, 35 %).
  • the title compound was prepared in a manner similar to that described in example 1 from 4-amino-N-[(2R,3S)-3- amino-2-hydroxy-4-phenylbutyl]-d3-N-(2-methylpropyl) benzenesulfonamide and (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-d3-4-nitrophenyl carbonate and was isolated as an off-white solid after reverse phase chromatography as the trifluoroacetate salt.
  • Example 4 (3R.3aS.6aRVhexahvdrofuror2.3-blfuran-3-yl-d r r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate trifluoroacetate salt.
  • tetramethylethylenediamine (2.0 mL, 13.25 mmol) was treated by dropwise addition of n- butyllithium (30.9 mL, 77 mmol, 2.5M solution in hexanes). The mixture was stirred for 2 hours, cooled to -78° C and treated slowly with deuterium oxide (3 mL, 166 mmol). The cooling bath was allowed to expire on its own and the mixture was stirred overnight. The pale yellow solution was filtered over Celite to remove the precipitates, dried over sodium sulfate, and filtered.
  • Example 5 (3R.3aS.6aRVhexahvdrofuror2.3-blfuran-3-yl-d ⁇ - r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate.
  • the ice bath was allowed to expire and the mixture was stirred at ambient temperature until - ⁇ [(1 ,1-dimethylethyl)(dimethyl)silyl]oxy ⁇ butanal-d2 was consumed by GC.
  • the mixture was cooled to 0 °C and 1 N HCI (1.42 ml.) was added and the mixture was stirred for 2 days at ambient temperature or until complete by GC.
  • Pyridine (0.23 ml_, 2.78 mmol), toluene (6 vol.) and water (3.4 ml.) were added, and the mixture was stirred for 10 minutes and filtered through celite, the filter was washed with water and toluene.
  • Example 6 (3R.3aS.6aRVhexahvdrofuror2.3-blfuran-3-yl r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)-dR-aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate.
  • the crude amide product was dissolved in tetrahydrofuran (20 mL) and cooled to 0° C.
  • Lithium aluminum deuteride 14.95 mL, 14.95 mmol, 1 M solution in tetrahydrofuran
  • the mixture was cooled to ambient temperature and then to 0° C.
  • the mixture was treated with water (630 uL), 15% NaOH (630 uL) and water (1900 uL) with 5 minutes stirring after each addition.
  • the mixture was then diluted with ether and stirred vigorously at ambient temperature for 30 minutes.
  • Example 7 (3R.3aS.6aRVhexahvdrofuror2.3-blfuran-3-yl-d1- r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)-dR-aminol-2-hvdroxy-1- (phenylmethyDpropyli-dcj-carbamate.
  • Example 8 (3R,3aS,6aR)-hexahvdrofuror2,3-blfuran-3-yl-d3- r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)-dR-aminol-2-hvdroxy-1- (phenylmethyl)propyll-d3-carbamate.
  • Example 10 (3R,3aS,6aR)-Hexahydrofuror2,3-blfuran-3-yl-d fi - r(1S,2R)-3-rr(4-aminophenyl)sulfonyll(2-methylpropyl)-c/R-aminol-2-hvdroxy-1- (phenylmethyl)propyll-c/fi-carbamate.
  • cryopreserved hepatocytes could be of interest when using liver cells, cell fractions, purified enzymes or other preparations from various species including mouse, rat, dog, monkey and human.
  • in vitro systems that assess permeability and gut metabolism are also of particular interest. These may include but are not limited to MDCK and CACO-2 assays.
  • in vivo studies can also be of use to evaluate the compounds of formula I including orally administered pharmacokinetic studies originating from a solution, suspension or solid dosage form and bolus solution injection IV pharmacokinetic studies commonly employed to evaluate pharmaceutical agents. These include several common species such as mouse, rat, dog, monkey and mini-pigs.
  • Particle size reduction may include D50 values in the range of 10 micron to 0.1 micron.

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Abstract

La présente invention porte sur des 1,3-diamino-propan-2-ols hautement fonctionnalisés et sur des sels pharmaceutiquement acceptables de ceux-ci. Plus spécifiquement, l'invention porte sur des 1,3-diamino-propan-2-ols hautement fonctionnalisés qui sont des dérivés des inhibiteurs de protéase du VIH à base de darunavir.
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Cited By (3)

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WO2012151361A1 (fr) * 2011-05-03 2012-11-08 Concert Pharmaceuticals Inc. Dérivés de carbamoylpyridone
US11224597B2 (en) 2010-09-16 2022-01-18 Viiv Healthcare Company Pharmaceutical compositions

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120251826A1 (en) * 2009-09-17 2012-10-04 Siva Rama Prasad Vellanki Process for the preparation of darunavir
US8703980B2 (en) * 2009-09-17 2014-04-22 Siva Rama Prasad Vellanki Process for the preparation of darunavir
US11224597B2 (en) 2010-09-16 2022-01-18 Viiv Healthcare Company Pharmaceutical compositions
US12138264B2 (en) 2010-09-16 2024-11-12 Viiv Healthcare Company Pharmaceutical compositions
WO2012151361A1 (fr) * 2011-05-03 2012-11-08 Concert Pharmaceuticals Inc. Dérivés de carbamoylpyridone

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