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WO2009039323A1 - Inhibiteurs de la prolyl hydroxylase - Google Patents

Inhibiteurs de la prolyl hydroxylase Download PDF

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Publication number
WO2009039323A1
WO2009039323A1 PCT/US2008/076919 US2008076919W WO2009039323A1 WO 2009039323 A1 WO2009039323 A1 WO 2009039323A1 US 2008076919 W US2008076919 W US 2008076919W WO 2009039323 A1 WO2009039323 A1 WO 2009039323A1
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Prior art keywords
alkyl
cycloalkyl
aryl
heterocycloalkyl
heteroaryl
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PCT/US2008/076919
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English (en)
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Deping Chai
Duke M. Fitch
Rosanna Tedesco
Michael N. Zimmerman
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Smithkline Beecham Corporation
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Publication of WO2009039323A1 publication Critical patent/WO2009039323A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to certain bicyclic heteroaromatic N-substituted glycine derivatives that are inhibitors of HIF prolyl hydroxylases, and thus have use in treating diseases benefiting from the inhibition of these enzymes, 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 hydrogen, -NR 3 R 4 , Ci.Cioalkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -C 8 cycloalkyl, Ci.Cioalkyl-Cs-Cgcycloalkyl, C 5 -C 8 cycloalkenyl, Ci_Ci O alkyl-C 5 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkyl, Ci_Ci O alkyl-C 3 -C 8 heterocycloalkyl, aryl, Ci_Ci O alkyl-aryl, heteroaryl or Ci_Ci 0 alkyl-heteroaryl;
  • R 2 is -NR 6 R 7 or -OR 8 ;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 10 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, , C 1 -C 10 alkyl- C 3 -C 8 heterocycloalkyl, aryl, Ci.Cioalkyl-aryl, heteroaryl, d.Qoalkyl-heteroaryl, -CO(CrC 4 alkyl), -CO(C 3 -C 6 cycloalkyl), -CO(C 3 -C 6 heterocycloalkyl), -CO(aryl), -CO(heteroaryl), and -SO 2 (C 1 -C 4 alkyl); or R 3 and R 4 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
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 _C lo alkenyl, C 2 _C lo alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 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;
  • R 8 is H, a cation, or C ⁇ C ⁇ alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; X, Y, and Z are part of a 5-membered aromatic heterocycle and are independently CR 9 or
  • each R 9 is independently selected from the group consisting of hydrogen, nitro, cyano, halogen, -C(O)R 5 , -C(O)OR 5 , -OR 5 , -SR 5 , -S(O)R 5 , -S(O) 2 R 5 , -NR 3 R 4 , -CONR 3 R 4 , -N(R 3 )C(O)R 5 , -N(R 3 )C(O)OR 5 , -OC(O)NR 3 R 4 , -N(R 3 )C(O)NR 3 R 4 , -P(O)(OR 5 ) 2 , -SO 2 NR 3 R 4 , -N(R 3 )SO 2 R 5 , C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 3 -C 6 cycloalky
  • a compound of formula (I) or a salt 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 effectively production of Epo.
  • a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a compound of formula (I) or a salt 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 4 alkyl” and “Ci_Ci 0 alkyl” refers to an alkyl group having at least 1 and up to 4 or 10 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, n- butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, and branched analogs of the latter 5 normal alkanes.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon double bonds. 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 5 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 “C 3 _Cg cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary “C 3 -C 8 cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cs-Cgcycloalkenyl refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds.
  • Cycloalkenyl includes by way of example cyclopentenyl and cyclohexenyl.
  • C3-C8 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, 1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, 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 H ⁇ ckel'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 H ⁇ ckel'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, benzofuranyl, benzothiophenyl, indolyl, and indazolyl.
  • 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, calcium, magnesium
  • 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
  • X is nitrogen and Y and Z are CR 9 , or Z is nitrogen and Y and Z are CR 9 ;
  • R 1 is hydrogen, Q.Qoalkyl, C 2 _C 10 alkenyl, C 2 _C 10 alkynyl, C 3 -C 8 cycloalkyl, Q.Qoalkyl-
  • R 2 is -NR 6 R 7 or -OR 8 ;
  • R 5 is independently selected from the group consisting of hydrogen, Ci_Ci O alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, -CO(Ci-C 4 alkyl), -CO(aryl), -CO(heteroaryl), -SO 2 (Ci-C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -Ci 4 aryl, heteroaryl, and aryl-Ci_Cio alkyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, Ci-Ci 0 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl, -CO(Ci-C 4 alkyl), and C 3 -C 8 cycloalkyl-Ci-Cio alkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring; R 8 is H, a cation, or Ci_Cioalkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R 9 is independently selected from the group consisting of hydrogen, -NR 3 R 4 , Ci-Ci 0 alkyl, C 3 -C 6 cycloalkyl, C
  • X is nitrogen and Y and Z are CR 9 , or Z is nitrogen and Y and Z are CR 9 ;
  • R 1 is hydrogen, Ci_Ci O alkyl, aryl, C 3 -C 8 cycloalkyl, Ci_Ci 0 alkyl-C 3 -C 8 cycloalkyl, or Ci.Cioalkylaryl;
  • R 2 is -NR 6 R 7 or -OR 8 ;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, Ci -C 6 alkyl, C 3 -C 6 cycloalkyl, C r C 6 alkyl-C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, , Q-C 6 alkyl- C 3 -C 6 heterocycloalkyl, aryl, Ci_C 6 alkyl-aryl, heteroaryl, Ci_C 6 alkyl-heteroaryl, -CO(Ci-C 4 alkyl), -CO(C 3 -C 6 cycloalkyl), -CO(C 3 -C 6 heterocycloalkyl), -CO(aryl), -CO(heteroaryl), -CONR 6 R 7 , and -SO 2 (Ci-C 4 alkyl); or R 3 and R 4 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring optionally containing one other heteroatom
  • R 5 is independently selected from the group consisting of hydrogen, Ci_Ci O alkyl, -CO(Ci- C 4 alkyl), -CO(aryl), -CO(heteroaryl), C 3 -C 8 cycloalkyl, Ci_Ci O alkyl-C 3 -C 8 cycloalky, C 3 -C 8 heterocycloalkyl, C 6 -Ci 4 aryl, heteroaryl, and aryl-Ci_Ci 0 alkyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, Ci-Ci 0 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl, -CO(Ci-C 4 alkyl), and C 3 -C 8 cycloalkyl-Ci-Cio alkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached form
  • X is nitrogen and Y and Z are CR 9 , or Z is nitrogen and Y and Z are CR 9 ;
  • R 1 is hydrogen, Ci_Ci O alkyl, C 3 -C 8 cycloalkyl, Ci_Ci 0 alkyl-C 3 -C 8 cycloalkyl, or Ci_Ci O alkylaryl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C r C 6 alkyl-C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, , Q-C 6 alkyl- C 3 -C 6 heterocycloalkyl, aryl, Ci_C 6 alkyl-aryl, heteroaryl, Ci_C 6 alkyl-heteroaryl, -CO(Ci-C 4 alkyl), -CO(C 3 -C 6 cycloalkyl), -CO(C 3 -C 6 heterocycloalkyl), -CO(aryl), -CO(heteroary
  • R 2 is -OR 8 ;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, Q-Cio alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl, -CO(Ci-C 4 alkyl), and C 3 -C 8 cycloalkyl-Ci-Cio alkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached form a 5- or 6-membered saturated ring;
  • R 8 is H or a cation; and each R 9 is independently selected from the group consisting of hydrogen, -NR 6 R 7 , Ci-Ci 0 alkyl, C 3 -C 6 cycloalkyl, C r Cio alkyl-C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C r Ci 0 alkyl-C 3 -C 6 heterocycloalkyl, aryl, Ci-Ci 0 alkylaryl, and heteroaryl.
  • R 1 , X, Y and Z are the same as for those groups in formula (I) and R' is a ester- forming group, with glycine sodium salt or glycine and an appropriate base, such as 1,8- diazabicyclo[5.4.0]undec-7-ene, sodium ethoxide or sodium hydride, in an appropriate solvent, such as ethanol or 1,4-dioxane, under either conventional thermal conditions or by microwave irradiation, to form a compound of formula (I) where R 2 is -OH.
  • 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.
  • 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.
  • 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.
  • 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, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 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 rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • 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.
  • 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.
  • 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 (1) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. Definitions:
  • 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).
  • N-r(7-hvdroxy-5-oxo-4,5-dihvdropyrazolori,5-alpyrimidin-6-yl)carbonyllglvcine A mixture of lH-pyrazol-5-amine (0.20 g, 2.40 mmol), triethyl methanetricarboxylate (0.51 mL, 2.40 mmol), glycine (0.27 g, 3.60 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.80 mmol) in ethanol (5.0 mL) was heated to 180 0 C for 20 minutes in a Biotage Initiator microwave synthesizer.
  • erythropoietin is a HIF-2 ⁇ target gene in Hep3B and Kelly cells" FASEB J., 2004, 18, 1462-1464.
  • EGLN3 Assay Materials His-MBP-EGLN3 (6HisMBPAttB 1EGLN3( 1-239)) 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-HIF2 ⁇ -CODD (6HisGBltevHIF2A(467-572)) were expressed from E. CoIi. Method: 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 50 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
  • the EC 5 O 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 EC 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.

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Abstract

L'invention concerne certains dérivés hétéroaromatiques bicycliques de la glycine N-substituée de formule (I) servant d'antagonistes à des HIF prolyl hydroxylases. Ces dérivés servent à traiter des maladies pouvant être traitées par inhibition de telles enzymes, comme l'anémie par exemple.
PCT/US2008/076919 2007-09-19 2008-09-19 Inhibiteurs de la prolyl hydroxylase WO2009039323A1 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8217043B2 (en) 2008-08-20 2012-07-10 Fibrogen, Inc. Compounds and methods for their use
WO2012106472A1 (fr) 2011-02-02 2012-08-09 Fibrogen, Inc. Dérivés de naphthyridine en tant qu'inhibiteurs d'un facteur inductible par l'hypoxie
WO2012110789A1 (fr) 2011-02-15 2012-08-23 Isis Innovation Limited Procédé d'analyse de l'activité de l'ogfod1
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
US8324405B2 (en) 2008-02-05 2012-12-04 Fibrogen, Inc. Chromene derivatives and use thereof as HIF hydroxylase activity inhibitors
WO2013014449A1 (fr) 2011-07-28 2013-01-31 Isis Innovation Limited Dosage pour l'activité histidinyle hydroxylase
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US8927591B2 (en) 2008-11-14 2015-01-06 Fibrogen, Inc. Thiochromene derivatives as HIF hydroxylase inhibitors
US8952160B2 (en) 2008-01-11 2015-02-10 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US9145366B2 (en) 2011-06-06 2015-09-29 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10065928B2 (en) 2014-09-02 2018-09-04 Sunshine Lake Pharma Co., Ltd. Quinolinone compound and use thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US10738056B2 (en) 2017-09-15 2020-08-11 Aduro Biotech Inc. Pyrazolopyrimidinone compounds and uses thereof
WO2021210586A1 (fr) * 2020-04-14 2021-10-21 日産化学株式会社 Composé hétérocyclique condensé
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
US20070213335A1 (en) * 2006-03-07 2007-09-13 Fitch Duke M Prolyl Hydroxylase Inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
US20070213335A1 (en) * 2006-03-07 2007-09-13 Fitch Duke M Prolyl Hydroxylase Inhibitors

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US8512972B2 (en) 2006-03-07 2013-08-20 Akebia Therapeutics, Inc. Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8323671B2 (en) 2006-06-26 2012-12-04 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US11426393B2 (en) 2006-06-26 2022-08-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US10729681B2 (en) 2006-06-26 2020-08-04 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
USRE47437E1 (en) 2006-06-26 2019-06-18 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8722895B2 (en) 2006-06-26 2014-05-13 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and method of use
US9598370B2 (en) 2006-06-26 2017-03-21 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8343952B2 (en) 2006-06-26 2013-01-01 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US11883386B2 (en) 2006-06-26 2024-01-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8940773B2 (en) 2006-06-26 2015-01-27 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8598210B2 (en) 2006-06-26 2013-12-03 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US9387200B2 (en) 2008-01-11 2016-07-12 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US8952160B2 (en) 2008-01-11 2015-02-10 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US8324405B2 (en) 2008-02-05 2012-12-04 Fibrogen, Inc. Chromene derivatives and use thereof as HIF hydroxylase activity inhibitors
US8217043B2 (en) 2008-08-20 2012-07-10 Fibrogen, Inc. Compounds and methods for their use
US8927591B2 (en) 2008-11-14 2015-01-06 Fibrogen, Inc. Thiochromene derivatives as HIF hydroxylase inhibitors
US9149476B2 (en) 2008-11-14 2015-10-06 Fibrogen, Inc. Thiochromene derivatives as HIF hydroxylase inhibitors
US9540326B2 (en) 2009-11-06 2017-01-10 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US8778412B2 (en) 2009-11-06 2014-07-15 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US9045495B2 (en) 2009-11-06 2015-06-02 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US10562854B2 (en) 2009-11-06 2020-02-18 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US8536181B2 (en) 2009-11-06 2013-09-17 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US9278930B2 (en) 2009-11-06 2016-03-08 Aerpio Therapeutics, Inc. Methods for increasing the stabilization of hypoxia inducible factor-α
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
US8999971B2 (en) 2009-11-06 2015-04-07 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US8883774B2 (en) 2009-11-06 2014-11-11 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
WO2012106472A1 (fr) 2011-02-02 2012-08-09 Fibrogen, Inc. Dérivés de naphthyridine en tant qu'inhibiteurs d'un facteur inductible par l'hypoxie
WO2012110789A1 (fr) 2011-02-15 2012-08-23 Isis Innovation Limited Procédé d'analyse de l'activité de l'ogfod1
US9776969B2 (en) 2011-06-06 2017-10-03 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US10738010B2 (en) 2011-06-06 2020-08-11 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US9145366B2 (en) 2011-06-06 2015-09-29 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US11267785B2 (en) 2011-06-06 2022-03-08 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
WO2013014449A1 (fr) 2011-07-28 2013-01-31 Isis Innovation Limited Dosage pour l'activité histidinyle hydroxylase
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US10149842B2 (en) 2013-11-15 2018-12-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10596158B2 (en) 2013-11-15 2020-03-24 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10065928B2 (en) 2014-09-02 2018-09-04 Sunshine Lake Pharma Co., Ltd. Quinolinone compound and use thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US10738056B2 (en) 2017-09-15 2020-08-11 Aduro Biotech Inc. Pyrazolopyrimidinone compounds and uses thereof
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US12269802B2 (en) 2018-05-09 2025-04-08 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino] acetic acid
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
WO2021210586A1 (fr) * 2020-04-14 2021-10-21 日産化学株式会社 Composé hétérocyclique condensé
JP7611900B2 (ja) 2020-04-14 2025-01-10 日産化学株式会社 縮合複素環化合物

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