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WO2009111893A1 - Composés de pyrimidine substitués et leurs utilisations en tant que médiateurs d'ifnar - Google Patents

Composés de pyrimidine substitués et leurs utilisations en tant que médiateurs d'ifnar Download PDF

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WO2009111893A1
WO2009111893A1 PCT/CA2009/000325 CA2009000325W WO2009111893A1 WO 2009111893 A1 WO2009111893 A1 WO 2009111893A1 CA 2009000325 W CA2009000325 W CA 2009000325W WO 2009111893 A1 WO2009111893 A1 WO 2009111893A1
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ifnar
compounds
compound
application
formula
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Lakshmi Premakanth Kotra
Eleanor Naomi Fish
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University Health Network
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University Health Network
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to a series of substituted pyrimidines compounds and their use as ligands for the interferon ⁇ receptor (IFNAR).
  • IFNAR interferon ⁇ receptor
  • the application further relates to the use of the pyrimidine compounds for the treatment of diseases which benefit from either inhibition of IFNAR such as autoimmune diseases e.g. systemic lupus erythematosus, or activation of IFNAR, such as virus infections and malignancies.
  • autoimmune diseases e.g. systemic lupus erythematosus
  • activation of IFNAR such as virus infections and malignancies.
  • Interferons are a family of biologically active proteins classified as types 1, 2 and 3.
  • Type 1 IFNs mediate diverse biological effects, including antiviral, and antiproliferative responses, and several cell type-restricted responses of immunological relevance such as maturation and differentiation of dendritic cells and modulation of B, T and NK cell responses.
  • 2 IFNs have widespread clinical application as therapeutic agents for the treatment of viral infections, especially in the context of hepatitis B and C (HBV and HCV) infections.
  • IFNs are clinically useful against a variety of solid tumors and hematological malignancies, including chronic myelogenous leukemia (CML), multiple myeloma and hairy cell leukemia, and for the treatment of multiple sclerosis.
  • CML chronic myelogenous leukemia
  • multiple myeloma multiple myeloma
  • hairy cell leukemia and for the treatment of multiple sclerosis.
  • Deregulation of IFNs is implicated in certain autoimmune diseases such as systemic lupus erythematosus (SLE). 6 ' 7 ' 8
  • Type 1 IFNs comprise a family of homologous helical bundle cytokines that in humans include 14 IFN- ⁇ subtypes, and single IFN- ⁇ , IFN-K and IFN- ⁇ subtypes. There is >50% sequence homology amongst all type-1 IFNs.
  • IFNs ⁇ , ⁇ , K, and ⁇ activate the IFN receptor, IFNAR, engaging the two subunits of this receptor, IFNAR- 1 and IFNAR-2. Each of these subunits possesses a separate ligand-binding domain and a functional ligand-receptor complex.
  • IFNs Due to the important roles that IFNs play: (i) in protection from viral infections, ii) in cancer and (iii) in certain autoimmune diseases, and in light of the understanding that the potency of a particular IFN resides in the nature of the ligand-receptor interaction for individual IFNs, 11 it is important to develop small molecule IFN mimetics, focusing on receptor interactive domains.
  • the present application provides a series of nonpeptidic pyrimidine based molecules that mimic targeted regions on the surface of the IFN molecule. These compounds bind to specific interactive subdomains in either IFNAR-I or IFNAR-2 and compete for and block the binding of IFN to the complete extracellular pocket described by IFNAR. As such, these molecules are characterized as antagonists for IFN-IFNAR interactions. IFNAR antagonists will have potential utility in the treatment of diseases where IFN is implicated in pathogenesis, such as autoimmune diseases, including systemic lupus erythematosus (SLE). Accordingly, the present application includes a compound of Formula I,
  • X is selected from O, S and CH 2 ; n and o are independently is selected from 0, 1 and 2; m and p are independently selected from 2, 3 and 4; and
  • R 1 , R 2 , R 3 and R 4 are independently selected from H and C 1- 4alkyl, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • X is S and in another embodiment X is O.
  • R 1 , R 2 , R 3 and R 4 are each methyl.
  • n and o are 0 and m and p are 2.
  • the present application includes a method of treating or preventing diseases or disorders which benefit from inhibition of IFNAR comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • the present application includes a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the prevention or treatment of diseases which benefit from the inhibition of IFNAR, as well as a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the preparation of a medicament for the prevention or treatment of diseases which benefit from the inhibition of IFNAR.
  • a pharmaceutical composition comprising one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, and a pharmaceutically acceptable carrier.
  • diseases which benefit from inhibition of IFNAR include, for example, autoimmune diseases such as lupus erythematosus (SLE).
  • SLE lupus erythematosus
  • the compounds of the application are also predicted to activate the IFNAR receptor upon binding. Accordingly another aspect of the present application includes a method of treating or preventing diseases or disorders which benefit from activation of IFNAR comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • the present application includes a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the prevention or treatment of diseases which benefit from the activation of IFNAR, as well as a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the preparation of a medicament for the prevention or treatment of diseases which benefit from the activation of IFNAR.
  • diseases which benefit from activation of IFNAR include, for example, virus infections and cell proliferative disorders.
  • Figure 1 shows the antagonistic effects of IFN mimetics on IFN-inducible STATl phosphorylation.
  • Daudi cells were either left untreated or treated with IFN alfacon-1 in the absence or in the presence of compounds Ia and Ib, 3 and 4, for 15 mins.
  • Daudi cells were either left untreated (-) (lane 1) or treated with IFN alfacon-1 (+) (lane 2) in the presence of compound Ia (lane 3) or Ib (lane 4) for 15 mins, as indicated.
  • Nuclear extracts were prepared, mixed with radiolabeled pIRE, resolved by native agarose gel electrophoresis, then the pIRE-bound STAT complexes visualized by autoradiography as shown.
  • C 1-4 alkyl as used herein means straight and/or branched chain, saturated alkyl radicals containing from one to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, and the like.
  • solvate means a compound of Formula I, or a salt or prodrug of a compound of Formula I, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • compound(s) of the application means compound(s) of Formula I, and/or salts, solvates and/or prodrugs thereof (including mixtures thereof).
  • pharmaceutically acceptable salt means an acid addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compound of the application, or any of its intermediates.
  • basic compounds of the application that form an acid addition salt include, for example, where the R 1 , R 2 , R 3 and/or R 4 is H or Ci -4 alkyl.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-
  • tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of the compounds of the application are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • non-pharmaceutically acceptable acid addition salts e.g. oxalates
  • oxalates are used, for example, in the isolation of the compounds of the application, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • IFNAR activity is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another conditions. More specifically, inhibition of IFNAR as used herein refers to binding or interaction of a compound at subdomains in either IFNAR-I or IFNAR-2 that compete and block the binding of IFN to the complete extracellular pocket described by IFNAR. Molecules which interact with IFNAR in this manner may be referred to "IFNAR antagonists" or “IFNAR inhibitors”.
  • To "activate” a function or activity, such as IFNAR activity is to increase the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another conditions.
  • activation of IFNAR refers to binding or interaction of a compound at subdomains in either IFNAR-I or IFNAR-2 that results in the triggering of a response by the receptor. Typically the response is the same action evoked by the binding of IFN.
  • Molecules which interact with IFNAR in this manner may be referred to "IFNAR agonists" or "IFNAR activators”.
  • viral infection refers to the detrimental colonization of a host organism by one or more foreign viruses.
  • the infecting virus seeks to utilize the host's resources in order to multiply (usually at the expense of the host) and interferes with the normal functioning of the host and can lead to chronic wounds, gangrene, loss of an infected limb, disease and even death.
  • viral infections include, but are not limited to, hepatitis B (HBV), and hepatitis C (HCV), influenza virus, SARS CoV, HIV and any other virus
  • cell proliferative disorder means any disease wherein a cell type increases in numbers in an undersirable manner and includes cancers and other malignancies.
  • autoimmune disease refers to any disease or disorder in which the body's immune system attacks the tissues of the body.
  • the tissues being attacked include connective tissue, nerves, muscles, endocrine system, digestive system or other tissues of the body.
  • Specific autoimmune disease include systemic lupus erythematosus (SLE) and the like.
  • a cell as used herein includes a plurality of cells. Administering a compound to a cell includes in vivo, ex vivo and in vitro treatment.
  • cell death includes all forms of cell death including necrosis and apoptosis.
  • a "therapeutically effective amount", “effective amount” or a “sufficient amount” of one or more compounds of the application is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of inhibiting IFNAR, for example, it is an amount of the one or more compounds sufficient to achieve such an inhibition in IFNAR activity as compared to the response obtained without administration of the compound.
  • therapeutically effective amounts of the one or more compounds of the present application are used to treat, modulate, attenuate, reverse, or affect any disease which benefits from inhibition or activation of IFNAR in a mammal.
  • diseases include but are not limited to autoimmune diseases such as SLE, virus infections and cancers and hematologoical malignancies.
  • An "effective amount" is intended to mean that amount of the one or more compounds that is sufficient to treat, prevent or inhibit the disease.
  • a "therapeutically effective amount" of one or more compounds of the present application is an amount which prevents, inhibits, suppresses or reduces the disease (e.g., as determined by clinical symptoms) in a subject as compared to a control.
  • a therapeutically effective amount of one or more compounds of the application is readily determined by one of ordinary skill by routine methods known in the art.
  • a "treatment” or “prevention” regime of a subject with a therapeutically effective amount of one or more compounds of the application consists of a single administration, or alternatively comprises a series of applications.
  • the one or more compounds of the application are administered at least once a week.
  • the one or more compounds are administered to the patient from about one time per week to about six times daily, suitably about one time per week to about 4 times daily, more suitably about one time per week to about once daily, for a given treatment.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the one or more compounds of the application, or a combination thereof.
  • the effective dosage of the one or more compounds used for the treatment or prophylaxis increases or decreases over the course of a particular treatment or prophylaxis regime. Changes in dosage result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required.
  • the compounds of the present application are administered before, during or after manifestation of the disease benefiting from inhibition of IFNAR.
  • administered contemporaneously means that two substances are administered to a subject such that they are both biologically active in the subject at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and include, for example, administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens are routine for one skilled in the art.
  • two substances are administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment also means prolonging survival as compared to expected survival if not receiving treatment.
  • “Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
  • prevention or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease which benefits from inhibition or activation of IFNAR.
  • subject or “patient” or synonym thereto, as used herein includes all members of the animal kingdom, especially mammals, including human.
  • the subject or patient is suitably a human.
  • X is selected from O, S and CH 2 ; n and o are independently is selected from O, 1 and 2; m and p are independently selected from 2, 3 and 4; and
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group selected from H and
  • Ci- 4 alkyl and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • a compound according of Formula I wherein X is S, in a further embodiment X is O.
  • R 1 , R 2 , R 3 and R 4 are each methyl.
  • n and o are 0 and m and p are 2.
  • the compound of Formula I is 2- ( ⁇ 4-[2- ⁇ [2-dimethylamino)ethyl]thio ⁇ -6-(2-furyl)pyrimidin-4-yl]phenyl ⁇ thio)-N,N- dimethyl ethanamine (compound Ia) or 2- ⁇ [4-(4- ⁇ [2-
  • a pharmaceutical composition comprising a compound selected from one or more compounds of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present application includes novel substituted pyrimidine compounds of Formula I as defined above, accordingly the present application covers all uses of the compounds of Formula I, and pharmaceutically acceptable salts, solvates and prodrugs thereof, including uses in methods of therapy and diagnosis.
  • a method of treating or preventing diseases which benefit from inhibition of IFNAR comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I, and pharmaceutically acceptable salts, solvates, and prodrugs thereof:
  • X is selected from O, S and CH 2 ; n and o are independently is selected from 0, 1 and 2; m and p are independently selected from 2, 3 and 4; and
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group selected from H and
  • the present application includes a method of treating or preventing diseases or disorders which benefit from inhibition of IFNAR, comprising administering to a subject in need thereof an IFNAR inhibitory effective amount of one or more compounds selected from a compound of Formula I as defined above and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • the present application includes a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the prevention or treatment of a disease which benefits from inhibition of IFNAR, as well as a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the preparation of a medicament for the prevention or treatment of diseases which benefit from inhibition of IFNAR.
  • a pharmaceutical composition for the treatment or prevention of a disease which benefits from in the inhibition of IFNAR comprising an IFNAR inhibitory amount of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present application also includes the methods and uses as defined above wherein the diseases which benefit from inhibition of IFNAR include autoimmune diseases such as SLE.
  • the present application includes a method of treating or preventing diseases or disorders which benefit from activation of IFNAR, comprising administering to a subject in need thereof an IFNAR activating effective amount of one or more compounds selected from a compound of Formula I as described above and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • the present application includes a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the prevention or treatment of a disease which benefits from activation of IFNAR, as well as a use of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, for the preparation of a medicament for the prevention or treatment of diseases which benefit from activation of IFNAR.
  • the one or more compounds of Formula I are those in which X is S. In a further embodiment, the one or more compounds of Formula I are those in which, X is O. In still another embodiment of the application, the one or more compounds of Formula I are those in which, R 1 , R 2 , R 3 and R 4 are each methyl. In yet another embodiment, the one or more compounds of Formula I are those in which n and o are 0 and m and p are 2.
  • the one ore more compounds of Formula I are selected from 2-( ⁇ 4-[2- ⁇ [2- dimethylamino)ethyl]thio ⁇ -6-(2-furyl)pyrimidin-4-yl]pheny 1 ⁇ thio)-N,N-dimethyl ethanamine (compound Ia) and 2- ⁇ [4-(4- ⁇ [2-(dimethylamino)ethyl]thio ⁇ phenyl)-6-(2- thienyl)pyrimidine-2-yl]thio ⁇ -N,N-dimethyl ethanamine (compound Ib), and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • a pharmaceutical composition for the treatment or prevention of a disease which benefits from in the activation of IFNAR comprising an IFNAR activating amount of one or more compounds selected from a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, and a pharmaceutically acceptable carrier or diluent.
  • diseases which benefit from activation of IFNAR include, for example, virus infections, cell proliferative disorders, cancers and hematological malignancies.
  • the compounds of the application are suitably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • the compositions containing the compounds of the application are prepared by known methods for the preparation of pharmaceutically acceptable compositions which are administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle.
  • Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999.
  • compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • the compounds of Formula I are used pharmaceutically in the form of the free base, in the form of salts, solvates and as prodrugs. All forms are within the scope of the application.
  • acid addition salts are formed with the compounds of the application for use as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for example, when the salt is formed only for the purposes of purification and identification. All salts that can be formed with the compounds of the application are therefore within the scope of the present application.
  • the described compounds of the application are administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the application are administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration.
  • parenteral administration is by continuous infusion over a selected period of time.
  • the compounds of the application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they are enclosed in hard or soft shell gelatin capsules, or they are compressed into tablets, or it they are incorporated directly with the food of the diet.
  • the compounds of the application are incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the compounds of the application are also administered parenterally.
  • solutions of the compounds of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • a person skilled in the art would know how to prepare suitable formulations. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which take the form, for example, of a cartridge or refill for use with an atomizing device.
  • the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser
  • a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • the aerosol dosage forms take the form of a pump-atomizer.
  • Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • the compounds of the application are administered to an animal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the compounds of the application are also used alone or contemporaneously with other agents that inhibit IFNAR activity or in combination with other types of treatment (which may or may not modulate IFNAR) for treating diseases or conditions that benefit from an inhibition of IFNAR.
  • IV. Methods of Preparing Compounds of the Application are also used alone or contemporaneously with other agents that inhibit IFNAR activity or in combination with other types of treatment (which may or may not modulate IFNAR) for treating diseases or conditions that benefit from an inhibition of IFNAR.
  • the compounds of the application are prepared by processes analogous to those established in the art.
  • compounds of Formula 1 were synthesized according to Scheme 1. Either a furan (when X is O) or thiophene (when X is S) was added to 2- chloropyrimidine after activation with n-butyl lithium. The crude products were subjected to oxidation by the treatment with DDQ to yield the intermediate (b).
  • Compounds of the chemical structure (c) were obtained by nucleophilic substitution of chloride on compound (b) by N,N-(dialkylamino)ethanethiol in the presence of metallic sodium.
  • a person skilled in the art would appreciate that other suitable leaving groups could be used in place of chloro.
  • Pyrimidine starting materials and reagents are commercially available or are prepared using methods known in the art.
  • the chemistries outlined above are modified, for instance by use of protective groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This is, for example, achieved by means of conventional protecting groups, for example as described in "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999.
  • a desired compound salt is achieved using standard techniques.
  • the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
  • solvates of the compounds of the application will vary depending on the compound and the solvate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent.
  • the solvate is typically dried or azeotroped under ambient conditions.
  • Prodrugs of the compounds of Formula I are, for example, conventional esters formed with an available amino group.
  • available amino groups are acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
  • inert solvent e.g. an acid chloride in pyridine.
  • Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 8 -C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.
  • the present application includes radiolabeled forms of the compounds of the application, for example, compounds of the application labeled by incorporation within the structure 3 H, 11 C or 14 C or a radioactive halogen such as 125 I and 18 F.
  • a radiolabeled compound of the application is prepared, for example, using standard methods known in the art.
  • tritium is incorporated into a compound of the application using standard techniques, for example by hydrogenation of a suitable precursor to a compound of the application using tritium gas and a catalyst.
  • a compound of the application containing radioactive iodo is prepared from the corresponding trialkyltin (suitably trimethyltin) derivative using standard iodination conditions, such as [ 125 I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide.
  • standard iodination conditions such as [ 125 I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide.
  • the trialkyltin compound is, for example, prepared from the corresponding non-radioactive halo, suitably iodo, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50-100 0 C.
  • a compound of the application containing a radioactive fluorine is, for example, prepared by reaction of K[ 18 F]/K222 with a suitable precursor compound, such as a compound of Formula I comprising a suitable leaving group, for example a tosyl group, that is displaced with the 18 F anion.
  • a suitable precursor compound such as a compound of Formula I comprising a suitable leaving group, for example a tosyl group, that is displaced with the 18 F anion.
  • NMR spectra were recorded on a Varian spectrometer (300 or 400 MHz forlH; 75 or 100 MHz for 13C). Chemical shifts are reported in ⁇ ppm using tetramethylsilane as the reference. Mass spectra were determined in a Q-Star mass spectrometer using either ESI or EI technique. Purity of the compounds were established using Waters Delta 600 HPLC (Symmetry® C 18, 3.5 ⁇ m, 4.6 x 75 mm column), equipped with a 600 Controller, and a 996 Photodiode Array detector using isocratic conditions (15 min; 0.5 mL/min flow rate; 60 to 100% 0.1% acetic acid in water/0-40% methanol). All solvents for HPLC were obtained from commercial sources and filtered through waters membranes 47 mm GHP 0.45 ⁇ m (Pall Corporation) and degassed with helium. Samples for HPLC were filtered through Waters Acrodisc Syringe Filters.
  • reaction mixture was treated with DDQ (5 mmol) in THF (6 mL), stirred at room temperature for 25 min, and cooled in an ice bath.
  • the reaction mixture was treated with hexanes (6 mL) and then with a cold solution of NaOH (3 M, 5 mL, 15 mmol) and stirred for 5 min.
  • the organic layer was separated, washed with brine and dried with anhyd Na 2 SO 4 . Solvent was evaporated to dryness and the residue was purified by column chromatography (Hexanes/CH 2 C1 2 ) to yield the title compund in (92% yield).
  • the title compound was synthesized from 2- ⁇ [4-(2-furyl)pyrimidin-2-yl]thio ⁇ - ⁇ fiV-dimethylethanamine (500 mg, 2 mmol) and 2-(4-bromophenylthio)-JV,iV- dimethylethanamine (624 mg, 2.4 mmol) using the method described for compound (1), and the product was obtained in 72% yield (617 mg).
  • the title compound (215 mg, 0.5 mmol) was dissolved in a small amount of methanol (1 mL). Then a solution of HCl in diethyl ether (3 mL, IM) was added dropwise at 0 0 C and the mixture was stirred for 30 min. Diethyl ether (20 mL) was added, the precipitated solid was filtered and dried under vacuum to obtain the corresponding hydrochloride salt for the title compound.
  • Daudi cells were either left untreated or treated with IFN in the presence or absence of compounds for 15 mins. Nuclear extracts from these cells were prepared, mixed with a 32 P-labeled palindromic
  • IFN-responsive element 32 PpIRE

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Abstract

La présente invention porte sur des composés de pyrimidine substitués de Formule I et sur leur utilisation en tant que ligands pour les IFNAR. L'invention porte en outre sur des procédés de traitement ou de prévention de maladies ou de troubles qui bénéficient de la modulation des IFNAR par l'administration d'une quantité efficace vis-à-vis des IFNAR desdits composés de Formule (I) à un sujet en ayant besoin.
PCT/CA2009/000325 2008-03-14 2009-03-16 Composés de pyrimidine substitués et leurs utilisations en tant que médiateurs d'ifnar Ceased WO2009111893A1 (fr)

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US61/036,550 2008-03-14

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BELLO A. ET AL.: "De Novo Design ofNonpeptidic Compounds Targeting the Interactions between Interferon-a and its Cognate Cell Surface Receptor", J. MEDICINAL CHEMISTRY, vol. 51, no. 9, pages 2734 - 2743 *
KUMARAN J. ET AL.: "A Structural Basis for Interferon-a-receptor Interactions", THE FASEB JOURNAL, vol. 21, no. 12, pages 3288 - 3296 *

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