WO2010059552A1 - Prolyl hydroxylase inhibitors - Google Patents

Prolyl hydroxylase inhibitors Download PDF

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Publication number
WO2010059552A1
WO2010059552A1 PCT/US2009/064539 US2009064539W WO2010059552A1 WO 2010059552 A1 WO2010059552 A1 WO 2010059552A1 US 2009064539 W US2009064539 W US 2009064539W WO 2010059552 A1 WO2010059552 A1 WO 2010059552A1
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Prior art keywords
heteroaryl
aryl
alkyl
group
cycloalkyl
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PCT/US2009/064539
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French (fr)
Inventor
Yonghui Wang
Hongyi Yu
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Glaxosmithkline Llc
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Publication of WO2010059552A1 publication Critical patent/WO2010059552A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to certain 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3- ⁇ i]pyrimidme-7- carboxamide derivatives that are inhibitors of HIF prolyl hydroxylases, and thus have use in treating diseases benefiting from the inhibition of this enzyme, anemia being one example.
  • Anemia occurs when there is a decrease or abnormality in red blood cells, which leads to reduced oxygen levels in the blood. Anemia occurs often in cancer patients, particularly those receiving chemotherapy. Anemia is often seen in the elderly population, patients with renal disease, and in a wide variety of conditions associated with chronic disease.
  • Epo erythropoietin
  • HIF hypoxia inducible factor
  • HIF-alpha subunits HIF-I alpha, HIF-2alpha, and HIF- 3 alpha
  • HIF-I alpha, HIF-2alpha, and HIF- 3 alpha are rapidly degraded by proteosome under normoxic conditions upon hydroxy lation of proline residues by prolyl hydroxylases (EGLNl, 2, 3).
  • Proline hydroxylation allows interaction with the von Hippel Lindau (VHL) protein, a component of an E3 ubiquitin ligase. This leads to ubiquitination of HIF-alpha and subsequent degradation.
  • VHL von Hippel Lindau
  • the compounds of this invention provide a means for inhibiting these hydroxylases, increasing Epo production, and thereby treating anemia. Ischemia, stroke, and cytoprotection may also benefit by administering these compounds.
  • this invention relates to a compound of formula (I):
  • R 1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S;
  • R is unsubstituted or substituted aryl, Ci-Ce alkyl-aryl, heteroaryl, or Ci-C ⁇ alkyl- heteroaryl;
  • R 3 and R 4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , -C(O)R 5 , -C(O)OR 5 , -OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -NR 6 R 7 , -CONR 6 R 7 , - N(R 6 )C(O)R 5 , -N(R 6 )C(O)OR 5 , -OC(O)NR 6 R 7 , -N(R 6 )C(O)NR 6 R 7 , -P(O)(OR 5 ) 2 , -SO 2 NR 6 R 7 , - N(R 6 )SO 2 R 5 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl; or R 6 and R 7 taken together with the nitrogen to which they are attached to form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
  • R 1 or R 2 may be substituted with one or more substituents independently selected from the group consisting Of Ci-C 6 alkyl, aryl, heteroaryl, halogen, -OR 5 , -NR 6 R 7 , cyano, nitro, -C(O)R 5 , -C(O)OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -CONR 6 R 7 , - N(R 6 )C(O)R 5 , -N(R 6 )C(O)OR 5 , -OC(O)NR 6 R 7 , -N(R 6 )C(O)NR 6 R 7 , -SO 2 NR 6 R 7 , -N(R 6 )SO 2 R 5 , C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl
  • a compound of formula (I) or a salt or solvate thereof for use in mammalian therapy, e.g. treating amenia.
  • An example of this therapeutic approach is that of a method for treating anemia caused by increasing the production of erythropoietin (Epo) by inhibiting HIF prolyl hydroxylases comprising administering a compound of formula (I) to a patient in need thereof, neat or admixed with a pharmaceutically acceptable excipient, in an amount sufficient to increase production of Epo.
  • a pharmaceutical composition comprising a compound of formula (I) or a salt, solvate, or the like thereof, and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a compound of formula (I) or a salt or solvate thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inhibiting HIF prolyl hydroxylases, such as an anemia, that can be treated by inhibiting HIF prolyl hydroxylases.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • an "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.
  • alkyl refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms "Ci-C 6 alkyl” refers to an alkyl group having at least 1 and up to 6 carbon atoms respectively.
  • Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, «-butyl, ?-butyl, «-pentyl, isopentyl, n- hexyl and branched analogs of the latter normal alkanes.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Conjugated double bonds are included in this definition. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
  • alkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term “C3-C6 cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C3-C6 cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 5 -C O cycloalkenyl refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and at least one or more carbon-carbon double bonds.
  • Cycloalkenyl includes by way of example cyclopentenyl and cyclohexenyl.
  • C 3 -C 6 heterocycloalkyl means a non-aromatic heterocyclic ring containing the specified number of ring atoms being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1,4-dioxane, 1 ,4-dithiane, 1,3- dioxane, 1,3-dioxolane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, 2-imidazoline, imidazolidine, pyrazolidine, pyrazoline, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • Aryl refers to optionally substituted monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Huckel's Rule.
  • aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
  • Heteroaryl means an optionally substituted aromatic monocyclic ring or polycarbocyclic fused ring system wherein at least one ring complies with Huckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom selected from N, O, and/or S.
  • heteroaryl groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8-naphthyridinyl, benzofuranyl, benzothiophenyl, benz
  • the substituents on aryl or heteroaryl can be selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , -C(O)R 5 , -C(O)OR 5 , -OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -NR 6 R 7 , -CONR 6 R 7 , -N(R 6 )C(O)R 5 , -N(R 6 )C(O)OR 5 , -OC(O)NR 6 R 7 , -N(R 6 )C(O)N 6 R 7 , -P(O)(OR 5 ) 2 , - SO 2 NR 6 R 7 , -N(R 6 )SO 2 R 5 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl,
  • event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
  • solvate refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may 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, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • compounds according to Formula (I) may contain an acidic functional group, one acidic enough to form salts.
  • Representative salts include pharmaceutically - acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically- acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2- hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • pharmaceutically - acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts
  • carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium
  • compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically-acceptable inorganic acids amd pharmaceutically-acceptable organic acids.
  • Representative pharmaceutically- acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate ⁇ acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, />-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, gluta
  • R 1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S;
  • R 2 is aryl, C 1 -C 6 alkyl-aryl
  • R 3 and R 4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C 5 -C 6 cycloalkenyl, aryl, and heteroaryl; each R 5 is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl; or R 6 and R 7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur; If any carbon or heteroatom of R 1 or R 2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting Of Ci-C 6 alkyl, aryl, heteroaryl, halogen, -OR 5 , -NR 6 R 7 , cyano, nitro, -C(O)R 5 , -C(O)OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -CONR 6 R 7 , - N(R 6 )C(O)R 5
  • R 1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S;
  • R 2 is aryl, Ci-C 6 alkyl-aryl;
  • R 3 and R 4 are hydrogen each R 5 is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl; or R 6 and R 7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
  • R 1 or R 2 may be substituted with one or more substituents independently selected from the group consisting Of Ci-C 6 alkyl, aryl, heteroaryl, halogen, -OR 5 , -NR 6 R 7 , cyano, nitro, -C(O)R 5 , -C(O)OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -CONR 6 R 7 , - N(R 6 )C(O)R 5 , -N(R 6 )C(O)OR 5 , -OC(O)NR 6 R 7 , -N(R 6 )C(O)NR 6 R 7 , -SO 2 NR 6 R 7 , -N(R 6 )SO 2 R 5 , C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl
  • Processes for preparing the compound of formula (I) are also within the ambit of this invention (see Illustrated Methods of Preparation section).
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers.
  • the compounds claimed below include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures.
  • Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), or claimed below, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also covers the individual isomers of the claimed compounds 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 claimed compounds are included within the scope of the compounds of formula (I) as disclosed herein above or claimed herein below.
  • compositions which includes a compound of formula (I) and salts, solvates and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and salts, solvates, etc, 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 the formula (I), or salts, solvates etc, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • pro-drugs examples include Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
  • Preferred prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.05 mg to 1 g, preferably 0.1 mg to 700 mg, more preferably 0.5 mg to 100 mg 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 compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • 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 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 compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) 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 nonaqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin 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, 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 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, gelatin, 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, gelatin, 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 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 sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I).
  • Syrups can be prepared by dissolving the compound in a suitably flavored 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, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit pharmaceutical compositions 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.
  • 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 composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the pharmaceutical compositions 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.
  • compositions 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.
  • 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 intended recipient, 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 prescribing the medication.
  • an effective amount of a compound of formula (I) for the treatment of anemia will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, etc. may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • 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 general synthetic methods are set out below and then specific compounds of the invention as prepared are given in the examples.
  • Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of 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).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic processes.
  • the following abeviations are used in the following pages:
  • amines such as appropriately substituted aminopyridines, aminopyrimidines and aminothiazoles, are added to isocyanates in an appropriate solvent, such as DCM, DMF or DMSO, by heating or in room temperature to afford methyl 2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3- ⁇ i]pyrimidine-7-carboxylate.
  • an appropriate base such as NaOH
  • the methyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3- ⁇ i]pyrimidme-7- carboxylate are hydro lyzed to the corresponding acids 2.
  • Step 1 4-Hydroxy-6-methylnicotinic acid (20 g, 0.13 mol) in phosphoryl trichloride(65 mL) was refluxed with stirring, which was monitored by TLC . After 6 hours, the substrate was consumed. The reaction mixture was slowly cooled to room temperature and a saturated aqueous solution of sodium hydroxide was added slowly to adjust the pH to 3-4. The solution was extracted with EtOAc(30 mL x 3). The combined organic layers were washed with brine, and dried over anhydrous MgSO 4 . After concentration in vacuo, the crude solid product (18 g, yield 80%) was obtained which was pure enough for further reaction.
  • Step 2 A mixture of 4-chloro-6-methyl-3-pyridinecarboxylic acid (10 g, 58.4mmol) and KMnO 4 (27.7 g, 175.4 mmol) in H 2 O was reflux with stirring for 24 h. The mixture was cooled to temperature and filtrated. EtOH was added to the filtrate and filtrated again. The filtrate was concentrated by vacuo to give the crude product 17 g which was used directly to the next reaction without further purification.
  • Step 3 To a solution of 4-chloro-2,5-pyridinedicarboxylic acid (17 g, 84.5 mmol) in DMF (100 mL), methyl iodide (26.4 g, 186 mmol) and K 2 CO 3 was added and the mixture was stirred at room temperature for 12 h. Water and EtOAc were added and the organic layer was separated. After washing with brine and drying over MgSO 4 , the solvent was removed under vacuum. The residue was purified by chromatography on silica gel eluting with PE and EtOAc (4: 1) to give desired product (320 mg). MS(ES + ) m/z 136 (MH + ).
  • Step 4 dimethyl 4-chloro-2,5-pyridinedicarboxylate (1.7 g, 7.42 mmol) was dissolved in DMF (80 mL), NaN 3 (482 mg, 7.42 mmol) was added with stirring at room temperature. After 12 h, EtOAc (50 mL ) and H 2 O (100 ml) were added, the organic layer was separated and the aqueous phase was extracted with EtOAc (50 mLx3). The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product 1.6 g (91%).
  • Step 5 A mixture of dimethyl 4-azido-2,5-pyridinedicarboxylate (1.6 g, 6.7 mmol) and 10% Pd/C (160 mg) in methanol was stirred at room temperature under hydrogen atmosphere. After 12 hours the Pd/C was removed by celite pad filtration, the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel column to give 1.25 g of the desired product, as a white solid, mp: 183.8-185.3 0 C, yield 89%.
  • reaction mixture was then poured into cold water (30 mL).
  • the reaction mixture was extracted with ethyl acetate (25 ml, 3x). Combined organic layers were concentrated and the residue was dissolved with DMSO (2mL). DMSO solution was filtered and purified with Gilson preparative HPLC system. The desired product was obtained.
  • reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete.
  • the reaction mixture was then poured into cold water (15 mL).
  • the reaction mixture was extracted with ethyl acetate (25 ml, 3x). Combined organic layers were concentrated and the residue was dissolved with DMSO (2 mL), filtered and purified with a Gilson preparative HPLC system. The desired product was obtained.
  • erythropoietin is a HIF-2 ⁇ target gene in Hep3B and Kelly cells" FASEB J., 2004, 18, 1462-1464.
  • His-MBP-EGLN3 (6HisMBPAttBlEGLN3(l-239)) was expressed in E. CoIi and purified from an amylase affinity column. Biotin-VBC [6HisSumoCysVHL(2-213),
  • Cy5-labelled HIF2 ⁇ CODD, and a biotin-labeled VBC complex were used to determine EGLN3 inhibition.
  • EGLN3 hydroxylation of the Cy5CODD substrate results in its recognition by the biotin-VBC.
  • Addition of a Europium/streptavidin (Eu/SA) chelate results in proximity of Eu to Cy5 in the product, allowing for detection by energy transfer.
  • a ratio of Cy5 to Eu emission (LANCE Ratio) is the ultimate readout, as this normalized parameter has significantly less variance than the Cy5 emission alone.
  • the IC 5 O for exemplified compounds in the EGLN3 assay ranged from approximately 1 - 100 nanomolar. This range represents the data accumulated as of the time of the filing of this initial application. Later testing may show variations in IC 5 O data due to variations in reagents, conditions and variations in the method(s) used from those given herein above. So this range is to be viewed as illustrative, and not a absolute set of numbers.
  • Hep3B cells obtained from the American Type Culture Collection (ATCC) are seeded at 2xlO ⁇ 4 cells/well in Dulbecco's Modified Eagle Medium (DMEM) + 10% FBS in 96-well plates. Cells are incubated at 37degC/5% CO2/90% humidity (standard cell culture incubation conditions). After overnight adherence, medium is removed and replaced with DMEM without serum containing test compound or DMSO negative control. Following 48 hours incubation, cell culture medium is collected and assayed by ELISA to quantitate Epo protein. The EC 50 for exemplar compounds in the Hep3B ELISA assay ranged from approximately

Abstract

The invention described herein relates to certain 2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidme-7-carboxamide derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.

Description

Prolyl Hydroxylase Inhibitors
FIELD OF THE INVENTION
This invention relates to certain 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7- carboxamide derivatives that are inhibitors of HIF prolyl hydroxylases, and thus have use in treating diseases benefiting from the inhibition of this enzyme, anemia being one example.
BACKGROUND OF THE INVENTION
Anemia occurs when there is a decrease or abnormality in red blood cells, which leads to reduced oxygen levels in the blood. Anemia occurs often in cancer patients, particularly those receiving chemotherapy. Anemia is often seen in the elderly population, patients with renal disease, and in a wide variety of conditions associated with chronic disease.
Frequently, the cause of anemia is reduced erythropoietin (Epo) production resulting in prevention of erythropoiesis (maturation of red blood cells). Epo production can be increased by inhibition of prolyl hydroxylases that regulate hypoxia inducible factor (HIF).
One strategy to increase erythropoietin (Epo) production is to stabilize and thus increase the transcriptional activity of the HIF. HIF-alpha subunits (HIF-I alpha, HIF-2alpha, and HIF- 3 alpha) are rapidly degraded by proteosome under normoxic conditions upon hydroxy lation of proline residues by prolyl hydroxylases (EGLNl, 2, 3). Proline hydroxylation allows interaction with the von Hippel Lindau (VHL) protein, a component of an E3 ubiquitin ligase. This leads to ubiquitination of HIF-alpha and subsequent degradation. Under hypoxic conditions, the inhibitory activity of the prolyl hydroxylases is suppressed, HIF-alpha subunits are therefore stabilized, and HIF -responsive genes, including Epo, are transcribed. Thus, inhibition of prolyl hydroxylases results in increased levels of HIF-alpha and thus increased Epo production. The compounds of this invention provide a means for inhibiting these hydroxylases, increasing Epo production, and thereby treating anemia. Ischemia, stroke, and cytoprotection may also benefit by administering these compounds.
SUMMARY OF THE INVENTION In the first instance, this invention relates to a compound of formula (I):
Figure imgf000002_0001
(I) wherein: R1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S;
R is unsubstituted or substituted aryl, Ci-Ce alkyl-aryl, heteroaryl, or Ci-Cβ alkyl- heteroaryl;
R3 and R4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF3, -C(O)R5, -C(O)OR5, -OR5, -SR5, -S(O)R5, -S(O)2R5, -NR6R7, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -P(O)(OR5)2, -SO2NR6R7, - N(R6)SO2R5, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl, and heteroaryl; each R5 is independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached to form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting Of Ci-C6 alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof.
In a second aspect of the present invention, there is provided a compound of formula (I) or a salt or solvate thereof for use in mammalian therapy, e.g. treating amenia. An example of this therapeutic approach is that of a method for treating anemia caused by increasing the production of erythropoietin (Epo) by inhibiting HIF prolyl hydroxylases comprising administering a compound of formula (I) to a patient in need thereof, neat or admixed with a pharmaceutically acceptable excipient, in an amount sufficient to increase production of Epo. In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt, solvate, or the like thereof, and one or more of pharmaceutically acceptable carriers, diluents and excipients.
In a fourth aspect, there is provided the use of a compound of formula (I) or a salt or solvate thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inhibiting HIF prolyl hydroxylases, such as an anemia, that can be treated by inhibiting HIF prolyl hydroxylases.
DETAILED DESCRIPTION OF THE INVENTION For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. An "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. Furthermore, the term "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.
As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms "Ci-C6 alkyl" refers to an alkyl group having at least 1 and up to 6 carbon atoms respectively. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, «-butyl, ?-butyl, «-pentyl, isopentyl, n- hexyl and branched analogs of the latter normal alkanes.
When the term "alkenyl" (or "alkenylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Conjugated double bonds are included in this definition. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
When the term "alkynyl" (or "alkynylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
When "cycloalkyl" is used it refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term "C3-C6 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C3-C6 cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C5-CO cycloalkenyl" refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and at least one or more carbon-carbon double bonds. "Cycloalkenyl" includes by way of example cyclopentenyl and cyclohexenyl.
Where "C3-C6 heterocycloalkyl" is used, it means a non-aromatic heterocyclic ring containing the specified number of ring atoms being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1,4-dioxane, 1 ,4-dithiane, 1,3- dioxane, 1,3-dioxolane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, 2-imidazoline, imidazolidine, pyrazolidine, pyrazoline, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
"Aryl" refers to optionally substituted monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Huckel's Rule. Examples of aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
"Heteroaryl" means an optionally substituted aromatic monocyclic ring or polycarbocyclic fused ring system wherein at least one ring complies with Huckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom selected from N, O, and/or S. Examples of "heteroaryl" groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8-naphthyridinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.
The substituents on aryl or heteroaryl can be selected from the group consisting of hydrogen, nitro, cyano, halogen, CF3, -C(O)R5, -C(O)OR5, -OR5, -SR5, -S(O)R5, -S(O)2R5, -NR6R7, -CONR6R7, -N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)N6R7, -P(O)(OR5)2, - SO2NR6R7, -N(R6)SO2R5, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl, and heteroaryl;
The term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
Herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
In certain embodiments, compounds according to Formula (I) may contain an acidic functional group, one acidic enough to form salts. Representative salts include pharmaceutically - acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically- acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2- hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically-acceptable inorganic acids amd pharmaceutically-acceptable organic acids. Representative pharmaceutically- acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate^ acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, />-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate),/>- aminobenzenesulfonate,/>-toluenesulfonate (tosylate), and napthalene-2-sulfonate. Compounds of particular interest include those wherein:
R1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S;
R2 is aryl, C1-C6 alkyl-aryl; R3 and R4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF3, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl, and heteroaryl; each R5 is independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur; If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting Of Ci-C6 alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof.
Compounds of further interest are those wherein:
R1 is an unsubstituted or substituted 4 to 6-membered mono-cyclic heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S; R2 is aryl, Ci-C6 alkyl-aryl;
R3 and R4 are hydrogen each R5 is independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting Of Ci-C6 alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof. Specific compounds exemplified herein are further illustrated via the Examples set out below.
3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[(4-chlorophenyl)methyl]-2,4-dioxo- 1,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide 3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[(15)-l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[l -(4-chlorophenyl)- 1 -methylethyl]-2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N- {[4-(methylsulfonyl)phenyl]methyl}-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo-N-{[4-(trifluoromethyl)phenyl]methyl}-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide 3-[5,6-bis(methyloxy)-2-pyridinyl]-N- { 1 -[4-(methylsulfonyl)phenyl]ethyl} -2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
Processes for preparing the compound of formula (I) are also within the ambit of this invention (see Illustrated Methods of Preparation section). The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds claimed below include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), or claimed below, as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the claimed compounds 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 claimed compounds are included within the scope of the compounds of formula (I) as disclosed herein above or claimed herein below.
Where there are different isomeric forms they may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. While it is possible that, for use in therapy, a compound of formula (I), as well as salts, solvates and the like, may be administered as a neat preparation, i.e. no additional carrier, the more usual practice is to present the active ingredient confected with a carrier or diluent. Accordingly, the invention further provides pharmaceutical compositions, which includes a compound of formula (I) and salts, solvates and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates, etc, 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. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates etc, with one or more pharmaceutically acceptable carriers, diluents or excipients.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Preferred prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.05 mg to 1 g, preferably 0.1 mg to 700 mg, more preferably 0.5 mg to 100 mg 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 compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. 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. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical 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 compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) with the carrier(s) or excipient(s).
Pharmaceutical 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 nonaqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin 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.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders 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 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, gelatin, 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. The powder mixture can be granulated by 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 sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I). Syrups can be prepared by dissolving the compound in a suitably flavored 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, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
Where appropriate, dosage unit pharmaceutical compositions 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.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions 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.
It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions 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.
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 intended recipient, 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 prescribing the medication. However, an effective amount of a compound of formula (I) for the treatment of anemia will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, etc., may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
Chemical Background:
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 general synthetic methods are set out below and then specific compounds of the invention as prepared are given in the examples. Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of 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). 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 formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific 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 affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. EHeI, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic processes. The following abeviations are used in the following pages:
Figure imgf000012_0001
Figure imgf000013_0002
Illustrated Methods of Preparation
Schemes Included in the present invention is a process according to Scheme 1 for the synthesis of the compounds:
Scheme 1
Figure imgf000013_0001
(I)
Conditions: a) (i) triphosgene, DMAP, DCM, -77 0C; NH2-R1, rt; DMF, 50 0C; (ii) 2N NaOH,
DMF, rt; b) R2NH2, HATU, DIEA, DMF, rt. Dimethyl 4-amino-2,5-pyridinedicarboxylate or appropriately substituted dimethyl 4- amino-2,5-pyridinedicarboxylates 1 are reacted with triphosgene in the presence of base such as DMAP in DCM to give isocyanates. A variety of amines, such as appropriately substituted aminopyridines, aminopyrimidines and aminothiazoles, are added to isocyanates in an appropriate solvent, such as DCM, DMF or DMSO, by heating or in room temperature to afford methyl 2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidine-7-carboxylate. Upon addition of an appropriate base, such as NaOH, the methyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7- carboxylate are hydro lyzed to the corresponding acids 2. Amide formation of the acids 2 with a variety of amines or anilines, such as appropriately substituted benzylamines, in the presence of a coupling reagent, such as HATU, EDC, and base, such as DIEA, in an appropriate solvent like DMF or DCM/DMF at rt produces the desired compounds of formula (I).
Examples
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.
Example 1
Figure imgf000014_0001
3- [5,6-bis(methyloxy)-2-pyridinyl] -N- [(4-chlorophenyl)methyl] -2,4-dioxo-l ,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Ia) dimethyl 4-amino-2,5-pyridinedicarboxylate (Scheme 2)
Scheme 2
Figure imgf000014_0002
Figure imgf000014_0003
Conditions: a) POCl3, reflux, 6h; b) KMnO4, H2O, reflux, 24h; c) K2CO3, DMF, CH3I5Tt, 12h; d) NaN3, DMF, rt, 12h; e) 10% Pd/C, H2, methanol
Step 1: 4-Hydroxy-6-methylnicotinic acid (20 g, 0.13 mol) in phosphoryl trichloride(65 mL) was refluxed with stirring, which was monitored by TLC . After 6 hours, the substrate was consumed. The reaction mixture was slowly cooled to room temperature and a saturated aqueous solution of sodium hydroxide was added slowly to adjust the pH to 3-4. The solution was extracted with EtOAc(30 mL x 3). The combined organic layers were washed with brine, and dried over anhydrous MgSO4. After concentration in vacuo, the crude solid product (18 g, yield 80%) was obtained which was pure enough for further reaction.
Step 2: A mixture of 4-chloro-6-methyl-3-pyridinecarboxylic acid (10 g, 58.4mmol) and KMnO4 (27.7 g, 175.4 mmol) in H2O was reflux with stirring for 24 h. The mixture was cooled to temperature and filtrated. EtOH was added to the filtrate and filtrated again. The filtrate was concentrated by vacuo to give the crude product 17 g which was used directly to the next reaction without further purification.
Step 3: To a solution of 4-chloro-2,5-pyridinedicarboxylic acid (17 g, 84.5 mmol) in DMF (100 mL), methyl iodide (26.4 g, 186 mmol) and K2CO3 was added and the mixture was stirred at room temperature for 12 h. Water and EtOAc were added and the organic layer was separated. After washing with brine and drying over MgSO4, the solvent was removed under vacuum. The residue was purified by chromatography on silica gel eluting with PE and EtOAc (4: 1) to give desired product (320 mg). MS(ES+) m/z 136 (MH+).
Step 4: dimethyl 4-chloro-2,5-pyridinedicarboxylate (1.7 g, 7.42 mmol) was dissolved in DMF (80 mL), NaN3 (482 mg, 7.42 mmol) was added with stirring at room temperature. After 12 h, EtOAc (50 mL ) and H2O (100 ml) were added, the organic layer was separated and the aqueous phase was extracted with EtOAc (50 mLx3). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product 1.6 g (91%).
Step 5: A mixture of dimethyl 4-azido-2,5-pyridinedicarboxylate (1.6 g, 6.7 mmol) and 10% Pd/C (160 mg) in methanol was stirred at room temperature under hydrogen atmosphere. After 12 hours the Pd/C was removed by celite pad filtration, the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel column to give 1.25 g of the desired product, as a white solid, mp: 183.8-185.3 0C, yield 89%. MS(ES+) m/z 211 (MH+); 1H NMR (300 MHz, CDCl3): δ 8.96 (s,lH), 7.43 (s, IH), 3.99(s, 3H), 3.93(s, 3H).
Ib) 3- [5,6-Bis(methyloxy)-2-pyridinyl] -2,4-dioxo-l ,2,3,4-tetrahydropyrido [4,3-</| pyrimidine- 7-carboxylic acid Into a 100 mL round-bottomed flask were added dimethyl 4-amino-2,5- pyridinedicarboxylate (Ia, 105 mg, 0.5mmol), and DMAP (367 mg, 3 mmol) in DCM (30 mL). The resulting reaction mixture was cooled to -77 0C. Triphosgene (49 mg, 0.167 mmol) was added slowly into the mixture. The reaction mixture was stirred at -77 0C for one hour. 5,6- Bis(methyloxy)-2-pyridinamine (77 mg, 0.5 mmol) in DCM solution was added slowly into reaction mixture. The reaction mixture was stirred overnight. Then the reaction mixture was concentrated and dissolved into DMF (1.5 mL). The reaction mixture was stirred at 50 0C for 15 minutes. 2N NaOH solution (2.5 mL) was added and the resulted reaction mixture was stirred for 30 minutes. LCMS showed that reaction was completed. The reaction mixture was acidified with 6N HCl to pH 2. The solution was precipitated and filtered. Solid was collected and dried. Product was used for next step without further purification. Reaction was scaled up to 1.5 gram. Yield: 106 mg, 55 %
1 c) 3- [5,6-bis(methyloxy)-2-pyridinyl] -N- [(4-chlorophenyl)methyl] -2,4-dioxo-l ,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Into a 25 mL round-bottomed flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7-carboxylic acid (Ib, 87 mg, 0.25 mmol), l-(4- chlorophenyl)methanamine (36 mg, 0.25 mmol), and TEA (38 mg, 0.38 mmol) in N,N- dimethylformamide (DMF) (3 mL), and HATU (125 mg, 0.33 mmol) was added slowly into the solution. Reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was then poured into cold water (30 mL). The reaction mixture was extracted with ethyl acetate (25 ml, 3x). Combined organic layers were concentrated and the residue was dissolved with DMSO (2mL). DMSO solution was filtered and purified with Gilson preparative HPLC system. The desired product was obtained. Yield: 14 mg, 12 %; MS(ES+) m/z 468 (MH+); IH NMR (400 MHz, MeOD) δ ppm 3.91 (d, J=1.52 Hz, 6 H) 4.60 (s, 2 H) 6.98 (d, J=7.83 Hz, 1 H) 7.30 - 7.43 (m, 2 H) 7.35 (d, J=5.56 Hz, 3 H) 7.88 (s, 1 H) 9.14 (s, 1 H).
Example 2
Figure imgf000016_0001
3-[5,6-bis(methyloxy)-2-pyridinyl]-Λ'-[l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Into a 10 mL round-bottomed flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7-carboxyric acid (Ib, 35 mg, 0.1 mmol), l-(4- chlorophenyl)ethanamine (16 mg, 0.1 mmol), and TEA (31 mg, 0.3 mmol) in N,N- Dimethylformamide (DMF) (2 mL). HATU (50 mg, 0.13 mmol) was added slowly into the solution. This reaction mixture was then stirred at room temperature for three hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with DMSO,filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 14.5 mg, 30 %; MS(ES+) m/z 482 (MH+); IH NMR (400 MHz, OMSO-d6) δ ppm 1.53 (d, J=7.07 Hz, 3 H) 3.80 (s, 3 H) 3.86 (s, 3 H) 5.15 (m, IH) 7.06 (d, J=8.08 Hz, 1 H) 7.36 - 7.44 (m, 2 H) 7.44 - 7.52 (m, 3 H) 7.77 (s, 1 H) 9.02 (s, 1 H) 9.38 (s, 1 H).
Example 3
Figure imgf000017_0001
3-[5,6-bis(methyloxy)-2-pyridinyl]-Λf-[(15)-l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Into a 20 mL pear flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo- 1,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxylic acid (Ib, 69 mg, 0.2 mmol), (I1S)-I -(4- chlorophenyl)ethanamine (31 mg, 0.2 mmol), and DIEA (31 mg, 0.3 mmol) in N,N- dimethylformamide (DMF) (2.7 mL). 5-Chloro-l,4-dimethyl-3,4-dihydro-2H-pyrrolium (26.5 mg, 0.200 mmol) was added slowly into the solution. Reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 25 mg, 26 %; MS(ES+) m/z 482 (MH+); IH NMR (400 MHz, DMSO-^6) δ ppm 1.53 (d, J=6.82 Hz, 3 H) 3.80 (s, 3 H) 3.86 (s, 3 H) 5.16 (d, J=7.58 Hz, 1 H) 7.06 (d, J=8.08 Hz, 1 H) 7.34 - 7.43 (m, 2 H) 7.43 - 7.51 (m, 3 H) 7.78 (s, 1 H) 9.02 (s, 1 H) 9.39 (d, J=8.59 Hz, 1 H) 12.17 (s, 1 H).
Example 4
Figure imgf000018_0001
3-[5,6-bis(methyloxy)-2-pyridinyl]-Λ'-[l-(4-chlorophenyl)-l-methylethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Into a 25 mL vial were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxylic acid (Ib, 69 mg, 0.2 mmol),), and DIEA (0.105 mL, 0.6 mmol), 5-chloro-l,4-dimethyl-3,4-dihydro-2H-pyrrolium (26.5 mg, 0.2 mmol) in N,N- dimethylformamide (DMF) (3 mL). Then [l-(4-chlorophenyl)-l-methylethyl] amine (34 mg, 0.2 mmol) was added slowly into the solution. The reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 12 mg, 12%; MS(ES+) m/z 496 (MH+); IH NMR (400 MHz, OMSO-d6) δ ppm 1.72 (s, 6 H) 3.81 (s, 3 H) 3.86 (s, 3 H) 7.06 (d, J=8.08 Hz, 1 H) 7.33 - 7.45 (m, 3 H) 7.48 (d, J=8.34 Hz, 1 H) 7.70 (s, 1 H) 8.83 (s, 1 H) 9.04 (s, 1 H) 12.19 (s, 1 H).
Example 5
Figure imgf000018_0002
S-IS^-bisCmethyloxyJ-l-pyridinyll-Λ^-J^^methylsulfonyOphenyllmethylJ-l^-dioxo-l,!^^- tetrahydropyrido [4,3-</| pyrimidine-7-carboxamide
Into a 25 mL round-bottomed flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7-carboxylic acid (Ib, 69 mg, 0.2 mmol),), DIEA (0.105 mL, 0.6 mmol), and 5-chloro-l,4-dimethyl-3,4-dihydro-2H-pyrrolium (26.5 mg, 0.2 mmol) in N,N-Dimethylformamide (DMF) (3 mL), and then l-[4-(methylsulfonyl)phenyl]methanamine (37 mg, 0.2 mmol) was added slowly into the solution. The reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 15 mg, 15 %; MS(ES+) m/z 512 (MH+); IH NMR (400 MHz, DMSO-^6) δ ppm 3.19 (s, 3 H) 3.81 (s, 3 H) 3.86 (s, 3 H) 4.60 (d, J=6.57 Hz, 2 H) 7.06 (d, J=8.08 Hz, 1 H) 7.48 (d, J=8.34 Hz, 1 H) 7.59 (d, J=8.59 Hz, 2 H) 7.82 (s, 1 H) 7.89 (d, J=8.34 Hz, 2 H) 9.02 (s, 1 H) 9.76 (s, 1 H) 12.19 (s, I H).
Example 6
Figure imgf000019_0001
3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo-Λ'-{[4-(trifluoromethyl)phenyl]methyl}-l,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide Into a 25 mL round-bottomed flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7-carboxylic acid (Ib, 69 mg, 0.2 mmol), DIEA (0.105 mL, 0.6 mmol) and l-[4-(trifluoromethyl)phenyl]methanamine (35 mg, 0.2 mmol) in N,N- Dimethylformamide (DMF) (3 mL), and then HATU (76 mg, 0.2 mmol) was added slowly into the solution. The reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was then poured into cold water (15 mL). The reaction mixture was extracted with ethyl acetate (25 ml, 3x). Combined organic layers were concentrated and the residue was dissolved with DMSO (2 mL), filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 25 mg, 25 %; MS(ES+) m/z 502 (MH+); IH NMR (400 MHz, DMSO-^6) δ ppm 3.80 (s, 3 H) 3.86 (s, 3 H) 4.58 (d, J=6.06 Hz, 2 H) 7.07 (d, 1 H) 7.48 (d, J=8.34 Hz, 1 H) 7.55-7.69 (m, 3H) 7.71 (s, 1 H) 7.82 (s, 1 H) 9.02 (s, 1 H) 9.74 (s, I H) 12.19 (s, I H).
Example 7
Figure imgf000019_0002
3-[5,6-bis(methyloxy)-2-pyridinyl]-Λ'-{l-[4-(methylsulfonyl)phenyl]ethyl}-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3-rf] pyrimidine-7-carboxamide
Into a 25 mL round-bottomed flask were added 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidme-7-carboxyric acid (Ib, 172 mg, 0.5 mmol), TEA (0.105 mL, 0.75 mmol) and l-[4-(methylsulfonyl)phenyl]ethanamine (100 mg, 0.5 mmol) in N,N- dimethylformamide (DMF) (3 mL). The reaction mixture was cooled to 0 0C. HATU (209 mg, 0.55 mmol) was added slowly into the solution. The reaction mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was then poured into cold water (25 mL) and stirred. Solid was collected and dissolved with DMSO (2 mL). filtered and purified with a Gilson preparative HPLC system. The desired product was obtained. Yield: 121 mg, 46 %; MS(ES+) m/z 526 (MH+); IH NMR (400 MHz, DMSO-^6) δ ppm
1.57 (d, J=7.07 Hz, 3 H) 3.20 (s, 3 H) 3.80 (s, 3 H) 3.86 (s, 3 H) 5.25 (d, J=7.58 Hz, 1 H) 7.10 (s, 1
H) 7.06 (d, J=8.08 Hz, 1 H) 7.48 (d, J=8.34 Hz, 1 H) 7.71 (d, J=8.59 Hz, 2 H) 7.77 (s, 1 H) 7.89 (d,
J=8.34 Hz, 2 H) 9.03 (s, 1 H) 9.54 (d, J=8.08 Hz, 1 H) 12.17 (s, 1 H).
Biological Background:
The following references set out information about the target enzymes, HIF prolyl hydroxylases, and methods and materials for measuring inhibition of same by small molecules.
M. Hirsila, P. Koivunen, V. Gύnzler, K. I. Kivirikko, and J. Myllyharju "Characterization of the Human Prolyl 4-Hydroxylases That Modify the Hypoxia-inducible Factor" J. Biol. Chem.,
2003, 278, 30772-30780.
C. Willam, L. G. Nicholls, P. J. Ratcliffe, C. W. Pugh, P. H. Maxwell "The prolyl hydroxylase enzymes that act as oxygen sensors regulating destruction of hypoxia-inducible factor α" Advan. Enzyme Regul, 2004, 44, 75-92 M. S. Wiesener, J. S. Jurgensen, C. Rosenberger, C. K. Scholze, J. H. Hδrstrup, C.
Warnecke, S. Mandriota, I. Bechmann, U. A. Frei, C. W. Pugh, P. J. Ratcliffe, S. Bachmann, P. H.
Maxwell, and K. -U. Eckardt "Widespread hypoxia-inducible expression of HIF-2,<v in distinct cell populations of different organs" FASEB J., 2003, 17, 271-273.
S. J. Klaus, C. J. Molineaux, T. B. Neff, V. Guenzler-Pukall, I. Lansetmo Parobok, T. W. Seeley, R. C. Stephenson "Use of hypoxia-inducible factor α (HIF α) stabilizers for enhancing erythropoiesis" PCT Int. Appl. (2004), WO 2004108121 Al
C. Warnecke, Z. Zaborowska, J. Kurreck, V. A. Erdmann, U. Frei, M. Wiesener, and K.-U.
Eckardt "Differentiating the functional role of hypoxia-inducible factor (HIF)- 1 α and HIF-2α
(EPAS-I) by the use of RNA interference: erythropoietin is a HIF-2α target gene in Hep3B and Kelly cells" FASEB J., 2004, 18, 1462-1464.
For the expression ofEGLN3 see:
R. K. Bruick and S. L. McKnight "A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF" Science, 2001, 294, 1337-1340. For the expression ofHIF2a-CODD see: a) P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. von Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P, J. Ratcliffe "Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2- Regulated Prolyl Hydroxylation" Science, 2001, 292, 468-472. b) M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin Jr. "HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing" Science, 2001, 292, 464-468.
For the expression of VHL, elongin b and elongin c see:
A. Pause, S. Lee, R. A. Worrell, D. Y. T. Chen, W. H. Burgess, W. M. Linehan, R. D. Klausner "The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins" Proc. Natl. Acad. ScL USA, 1997, 94, 2156-2161.
Biological Assay(s) EGLN3 Assay Materials:
His-MBP-EGLN3 (6HisMBPAttBlEGLN3(l-239)) was expressed in E. CoIi and purified from an amylase affinity column. Biotin-VBC [6HisSumoCysVHL(2-213),
6HisSumoElonginB(l-l 18), and 6HisSumoElonginC(l-l 12)] and His-GBl-HIF2α-CODD
(6HisGBltevHIF2A(467-572)) were expressed from .E1. CoIi.
Method:
Cy5-labelled HIF2α CODD, and a biotin-labeled VBC complex were used to determine EGLN3 inhibition. EGLN3 hydroxylation of the Cy5CODD substrate results in its recognition by the biotin-VBC. Addition of a Europium/streptavidin (Eu/SA) chelate results in proximity of Eu to Cy5 in the product, allowing for detection by energy transfer. A ratio of Cy5 to Eu emission (LANCE Ratio) is the ultimate readout, as this normalized parameter has significantly less variance than the Cy5 emission alone. Then 5OnL of inhibitors in DMSO (or DMSO controls) were stamped into a 384-well low volume Corning NBS plate, followed by addition of 2.5 μL of enzyme [50 mL buffer (50 mM HEPES/50 mM KCl) + 1 mL of a 10 mg/mL BSA in buffer + 6.25 μL of a lOmg/mL FeCl2 solution in water + 100 μL of a 200 mM solution of ascorbic acid in water + 15.63 μL EGLN3] or control [50 mL buffer + 1 mL of a 10 mg/mL BSA in buffer + 6.25 μL of a lOmg/mL FeCl2 solution in water + 100 μL of a 200 mM solution of ascorbic acid in water]. Following a 3 minutes incubation, 2.5 μL of substrate [5OmL Buffer + 68.6 μL biotin-VBC + 70.4 μL Eu (at 710 μg/mL stock) + 91.6 μL Cy5CODD + 50 μL of a 20 mM solution of 2-oxoglutaric acid in water + 0.3mM CHAPS] was added and incubated for 30 minutes. The plate was loaded into a PerkinElmer Viewlux for imaging. For dose response experiments, normalized data were fit by ABASE/XC50 using the equation y = a + (b-a)/(l+(10Λx/10Λc)Λd), where a is the minimum % activity, b is the maximum % activity, c is the pIC5o, and d is the Hill slope.
The IC5O for exemplified compounds in the EGLN3 assay ranged from approximately 1 - 100 nanomolar. This range represents the data accumulated as of the time of the filing of this initial application. Later testing may show variations in IC5O data due to variations in reagents, conditions and variations in the method(s) used from those given herein above. So this range is to be viewed as illustrative, and not a absolute set of numbers.
Measure Epo protein produced by Hep3B cell line using ELISA method.
Hep3B cells obtained from the American Type Culture Collection (ATCC) are seeded at 2xlOΛ4 cells/well in Dulbecco's Modified Eagle Medium (DMEM) + 10% FBS in 96-well plates. Cells are incubated at 37degC/5% CO2/90% humidity (standard cell culture incubation conditions). After overnight adherence, medium is removed and replaced with DMEM without serum containing test compound or DMSO negative control. Following 48 hours incubation, cell culture medium is collected and assayed by ELISA to quantitate Epo protein. The EC50 for exemplar compounds in the Hep3B ELISA assay ranged from approximately
1 - 20 micromolar using the reagents and under the conditions outlined herein above. This range represents the data accumulated as of the time of the filing of this initial application. Later testing may show variations in EC5O data due to variations in reagents, conditions and variations in the method(s) used from those given herein above. So this range is to be viewed as illustrative, and not a absolute set of numbers.
These compound are believed to be useful in therapy as defined above and to not have unacceptable or untoward effects when used in compliance with a permited therapeutic regime.
The foregoing examples and assay have been set forth to illustrate the invention, not limit it. What is reserved to the inventors is to be determined by reference to the claims.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000023_0001
wherein: R1 is an unsubstituted or substituted 4 to 8-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S;
R2 is unsubstituted or substituted aryl, Ci-Ci0 alkyl-aryl, heteroaryl, or Ci-Ci0 alkyl- heteroaryl; R3 and R4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF3, -C(O)R5, -C(O)OR5, -OR5, -SR5, -S(O)R5, -S(O)2R5, -NR6R7, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -P(O)(OR5)2, -SO2NR6R7, - N(R6)SO2R5, Ci-Cio alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl, and heteroaryl; each R5 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-
Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached to form a 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1 wherein: R1 is an unsubstituted or substituted 4 to 8-membered mono-cyclic heteroaryl or a 9- to 11- membered bicyclic heteroaryl ring containing one or more hetero atoms selected from the group consisting of N, O and S; R2 is aryl, Ci-Ci0 alkyl-aryl;
R3 and R4 are indepedently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF3, CrCio alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl, and heteroaryl; each R5 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-
Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached form a 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof.
3. A compound according to claim 2 wherein: R1 is an unsubstituted or substituted 4 to 8-membered mono-cyclic heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S;
R2 is aryl, Ci-Ci0 alkyl-aryl;
R3 and R4 are hydrogen each R5 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3- Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl;
R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 heterocycloalkyl, aryl, and heteroaryl; or R6 and R7 taken together with the nitrogen to which they are attached form a 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur; If any carbon or heteroatom of R1 or R2 is substituted, it may be substituted with one or more substituents independently selected from the group consisting Of Ci-C6 alkyl, aryl, heteroaryl, halogen, -OR5, -NR6R7, cyano, nitro, -C(O)R5, -C(O)OR5, -SR5, -S(O)R5, -S(O)2R5, -CONR6R7, - N(R6)C(O)R5, -N(R6)C(O)OR5, -OC(O)NR6R7, -N(R6)C(O)NR6R7, -SO2NR6R7, -N(R6)SO2R5, C2- Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl and heteroaryl, wherein R5, R6, and R7 are the same as defined above; or a pharmaceutically acceptable salt or solvate thereof.
4. A compound according to claim 1 which is: 3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[(4-chlorophenyl)methyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[(15)-l-(4-chlorophenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide 3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[l -(4-chlorophenyl)- 1 -methylethyl]-2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N- {[4-(methylsulfonyl)phenyl]methyl}-2,4-dioxo- 1,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo-N-{[4-(trifluoromethyl)phenyl]methyl}- 1,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
3-[5,6-bis(methyloxy)-2-pyridinyl]-N- { 1 -[4-(methylsulfonyl)phenyl]ethyl} -2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[4,3-<i]pyrimidme-7-carboxamide
5. A method for treating anemia in a mammal, which method comprises administering an effective amount of a compound of formula (I) or a salt thereof according to claim 1 to a mammal suffering from anemia which can be treated by inhibiting HIF prolyl hydroxylases.
6. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof according to claim 1 and one or more of pharmaceutically acceptable carriers, diluents and excipients.
PCT/US2009/064539 2008-11-18 2009-11-16 Prolyl hydroxylase inhibitors WO2010059552A1 (en)

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