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WO2010059549A1 - Inhibiteurs de la prolyl hydroxylase - Google Patents

Inhibiteurs de la prolyl hydroxylase Download PDF

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Publication number
WO2010059549A1
WO2010059549A1 PCT/US2009/064534 US2009064534W WO2010059549A1 WO 2010059549 A1 WO2010059549 A1 WO 2010059549A1 US 2009064534 W US2009064534 W US 2009064534W WO 2010059549 A1 WO2010059549 A1 WO 2010059549A1
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Prior art keywords
methyloxy
dioxo
bis
tetrahydro
methyl
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Inventor
Mark James Schulz
Yonghui Wang
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Publication of WO2010059549A1 publication Critical patent/WO2010059549A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to certain 2,4-dioxo-l,2,3,4-tetrahydro-7-quinazolinecarboxamide 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 be treated 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 2 is unsubstituted or substituted aryl, Ci-C 6 alkyl-aryl, heteroaryl, or Ci-C 6 alkyl- heteroaryl;
  • R 3 , R 4 and R 5 each independently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , -C(O)R 6 , -C(O)OR 6 , -OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -NR 7 R 8 , -CONR 7 R 8 , - N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)N 7 R 8 , -P(O)(OR 6 ) 2 , -SO 2 NR 7 R 8 , - N(R 7 )SO 2 R 6 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -Q heterocycloalkyl, aryl, and heteroaryl; or R 7 and R 8 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 6 , -NR 7 R 8 , cyano, nitro, -C(O)R 6 , -C(O)OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -CONR 7 R 8 , - N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)NR 7 R 8 , -SO 2 NR 7 R 8 , -N(R 7 )SO 2 R 6 , C 2 - Cio alkenyl, C 2 -Ci 0 alkynyl, C 3 -C 8 cycloal
  • 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. 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 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 six carbon atoms.
  • 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 at least 1 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.
  • 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 6 , -C(O)OR 6 , -OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -NR 7 R 8 , -CONR 7 R 8 , -N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)N 7 R 8 , -P(O)(OR 6 ) 2 , - SO 2 NR 7 R 8 , -N(R 7 )SO 2 R 6 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl,
  • 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
  • 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 , R 4 and R 5 each independently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , -C(O)R 6 , -C(O)OR 6 , -OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -NR 7 R 8 , -CONR 7 R 8 , - N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)N 7 R 8 , -P(O)(OR 6 ) 2 , -SO 2 NR 7 R 8 , - N(R 7 )SO 2 R 6 , C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl, and heteroaryl; or R 7 and R 8 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;
  • R 1 or R 2 may be substituted with one or more substituents independently selected from the group consisting Of C 1 -C 6 alkyl, aryl, heteroaryl, halogen, -OR 6 , -NR 7 R 8 , cyano, nitro, -C(O)R 6 , -C(O)OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -CONR 7 R 8 , - N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)NR 7 R 8 , -SO 2 NR 7 R 8 , -N(R 7 )SO 2 R 6 , C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloal
  • 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, C 1 -C 6 alkyl-aryl
  • R 3 , R 4 and R 5 each independently selected from the group consisting of hydrogen, nitro, cyano, halogen, CF 3 , -C(O)R 6 , -C(O)OR 6 , -OR 6 , -SR 6 , -S(O)R 6 , -S(O) 2 R 6 , -NR 7 R 8 , -CONR 7 R 8 , - N(R 7 )C(O)R 6 , -N(R 7 )C(O)OR 6 , -OC(O)NR 7 R 8 , -N(R 7 )C(O)N 7 R 8 , -P(O)(OR 6 ) 2 , -SO 2 NR 7 R 8 , -
  • R 7 N(R 7 )SO 2 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 heterocycloalkyl, C 5 -C 6 cycloalkenyl, aryl, and heteroaryl; each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl, C 4 -C 6 heterocycloalkyl, aryl, and heteroaryl; R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 heterocycloalkyl, aryl, and heteroaryl; or R 7 and R 8 taken together with the nitrogen to which they are attached form a 5- or 6- membered saturated ring optionally containing one other heteroatom which
  • 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, 0.5 mg to 1 g, or 1 mg to 700 mg, or further, 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 non- aqueous 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.
  • 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.
  • 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.
  • 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).
  • Dimethyl 2-amino-l,4-benzenedicarboxylate or appropriately substituted dimethyl 2- amino- 1 ,4-benzenedicarboxylates 1 react with with triphosgene in the presence of a base such as DIEA to give isocyanates.
  • a base such as DIEA
  • 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 cyclized methyl 2,4-dioxo- l,2,3,4-tetrahydro-7-quinazolinecarboxylates.
  • the methyl 2,4-dioxo-l,2,3,4-tetrahydro-7-quinazolinecarboxylates are hydrolyzed 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 DMC, 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).
  • 3-Amino-4-[(methyloxy)carbonyl]benzoic acid or appropriately substituted 3-amino-4- [(methyloxy)carbonyl]benzoic acids 4 react with amines 3, such as appropriately substituted benzylamines, in the presence of a coupling reagent, such as HATU, and base, such as DIEA, in an appropriate solvent like DMF at rt to give the amides 5.
  • amines 3 such as appropriately substituted benzylamines
  • a coupling reagent such as HATU
  • base such as DIEA
  • 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 the desired compounds of formula (I).
  • a variety of amines or anilines such as appropriately substituted aminopyridines, aminopyrimidines and aminothiazoles, are added to isothiocyanates 6 in an appropriate solvent, such as DMF or DMSO, by heating or in room temperature to afford cyclized 4-oxo-2-thioxoquinazolinecarboxylates Upon addition of an appropriate base, such as NaOH, the 4-oxo-2-thioxoquinazolinecarboxylates are hydrolyzed to the corresponding acids 7.
  • an appropriate solvent such as DMF or DMSO
  • Step 1 4-Methyl benzoic acid (50 g, 368 mmole) was dissolved in cone, sulfuric acid (500 ml) and cone, nitric acid (200 ml) was added slowly at 18-20 0 C over a period of 3 h. After addition, the reaction mixture was then allowed to come to room temperature and stirred for 2 h. During this period, the dark viscous reaction mixture turned yellow in color with some amount of yellow solid precipitation. TLC revealed the disappearance of starting material. The reaction mixture was poured over crushed ice water (1 kg) and stirred for 30 minutes.
  • Step 2 A solution of 4-methyl-3,5-dinitrobenzoic acid (70 g, 307 mmole) in methanol (750 ml) was warmed to 60 0 C and a 30% solution of sodium hydrogen sulfide (133 ml, 539 mmole) was added slowly over a period of 30 minutes. The reaction mixture was refluxed for 3 h. The reaction mixture was evaporated to dryness and the resulting residue was treated with water (500 ml). The mixture was acidified to pH 3 using dil. HCl.
  • Step 3 To a suspension of 3-amino-4-methyl-5-nitrobenzoic acid (50 g, 254 mmole) in a mixture of cone, hydrochloric acid (350 ml) and water (350 ml) was added at between 0-5 0 C a solution of sodium nitrite (18.6 g, 270 mmole) in water (30 ml) over a period of 15 to 20 minutes. After stirring at 0-5 0 C for another 30 minutes, the reaction mixture was then slowly added to a cold cuprous bromide (73.21 g, 516 mmole) solution in cone, hydrochloric acid (220 ml) with stirring.
  • Step 4 To a solution Of KMnO 4 (176.85 g, 1.12 mole) in water (2650 ml) was added at ambient temperature 3-bromo-4-methyl-5-nitrobenzoic acid (97 g, 373 mmole) and the mixture was then heated to reflux. After every 3 h, additional lots Of KMnO 4 (58.95g, 373 mmole; 117.9g, 746 mmole; 58.95g, 373 mmole) were added and thereafter refluxing continued for a further 5 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to approximately 400 ml on a rotavap.
  • Step 5 To a suspension of 2-bromo-6-nitroterephthalic acid (80 g, 276 mmole) in methanol (2000 ml) was added, at ambient temperature, cone, sulfuric acid (25 ml) and the mixture was refluxed for 1O h. The reaction mixture was filtered and concentrated on a rota-vap. The resulting residue was dissolved in ethyl acetate (800 ml) and washed with water (2 x 50 ml). The organic layer was dried over Na 2 SO 4 and evaporated under vacuum to yield 70 g of 2-bromo-6- nitro-terephthalic acid 4-methyl ester as colorless solid (83%).
  • Step 6 To a solution of 2-bromo-6-nitro-terephthalic acid 4-methyl ester (25 g, 82 mmole) in methanol (50 ml) maintained between 0-5 0 C was added an ethereal solution of diazomethane (340 ml) [prepared from 50% aq. KOH (156 ml) and N-nitroso methylurea (34 g, 330mmole)] over a period of 30 minutes. The reaction mixture was stirred between 0-5 0 C for 1 h and then allowed to come to room temperature. Excess diazomethane was quenched by adding acetic acid.
  • Step 7 To a solution of dimethyl 2-bromo-5-nitroterephthalate (12 g; 38 mmole) in toluene (50ml) maintained at ambient temperature were added cesium carbonate (36 g; 110 mmole), tetrakis(triphenylphosphine)palladium (4.32 g; 3.8 mmole) and trimethylboroxine (5.28 ml; 38 mmole) sequentially under an inert atmosphere (nitrogen). The mixture was heated to 100- 110 0 C for 8 h. Another lot of trimethylboroxine (5.28 ml; 38 mmole) was added and the mixture was heated at 100-110 0 C for another 8 h.
  • cesium carbonate 36 g; 110 mmole
  • tetrakis(triphenylphosphine)palladium 4.32 g; 3.8 mmole
  • trimethylboroxine 5.28 ml; 38 mmole
  • Step 8 Mixture of dimethyl 2-methyl-6-nitroterephthalate (5.7 g; 22.4 mmoles), 5% Pd/C (0.7 g) in methanol (228 ml) was hydrogenated under a hydrogen pressure of 40 psi for 2 h in a Parr hydrogenator. The mixture was filtered under nitrogen and filtrate was concentrated to give 4.2 g (84%) of dimethyl 2-amino-6-methylterephthalate as yellow solid.
  • Step 2 To an ice-cold cone, nitric acid (500 ml) was added slowly under stirring over a period of 20 minutes 2-methoxy- 1 ,4-dimethylbenzene (45 g, 330 mmole). To this cold reaction mixture, sodium nitrite (67.5g, 990 mmole) was added slowly in lots over a period of 1 h while maintaining the temperature below 2°C. The reaction mixture was stirred at between 0-5 0 C for 5 h. The reaction mass was poured over ice-cold water (2000 ml) and the precipitated solid was filtered, washed with cold water (200 ml) and dried.
  • Step 3 A mixture of 2-methoxy-5-nitro-l,4-dimethylbenzene (28 g, 153 mmole) and KMnO 4 (79 g; 500 mmole) in water (1500 ml) was reflux for 5 h under stirring. After the disappearance of KMn ⁇ 4 color, TLC showed the presence of starting material. Additional KMn ⁇ 4 (79 g; 500 mmole) was added and refluxing continued for 5 h. TLC showed the presence of starting material, another lot of KMn ⁇ 4 (50.5 g; 320 mmole) was added and refluxing continued for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to approx. 300ml on a rotavap.
  • Step 4 To a solution of 2-methoxy-5-nitroterephthalic acid (15 g, 61 mmole) in methanol (200 ml), an ethereal solution of diazomethane (1000 ml) [prepared from 50% aq. KOH (100 ml) and N-nitroso methylurea (60 g, 580 mmole)] was added maintaining the temperature at between 0-5 0 C over a period of 30 minutes. The reaction mixture was stirred at between 0-5 0 C for 1 h and then allowed to come to room temperature. Excess of diazomethane was quenched with acetic acid.
  • Step 5 A mixture of dimethyl 2-methoxy-5-nitroterephthalate (15.5 g; 57 mmoles), 5% Pd/C (1 g) in methanol (160 ml) was hydrogenated under hydrogen pressure of 50 psi for 1 h in a Parr hydrogenator. This mixture was filtered under nitrogen and the filtrate was concentrated to get 13.5 g (99%) of dimethyl 2-amino-5-methoxyterephthalate as yellow solid.
  • Step 1 4-Methyl benzoic acid (50 g, 368 mmole) was dissolved in cone, sulfuric acid (500 ml) and cone, nitric acid (200 ml) was added slowly at 18-20 0 C over a period of 3 h. After addition, the reaction mixture was then allowed to come to room temperature and stirred for 2 h. During this period, the dark viscous reaction mixture turned yellow in color with some amount of yellow solid precipitation. TLC revealed disappearance of starting material. The reaction mixture was poured over crushed ice water (1 kg) and stirred for 30 minutes.
  • Step 2 A solution of 4-methyl-3,5-dinitrobenzoic acid (70 g, 307 mmole) in methanol (750 ml) was warmed to 60 0 C and a 30% solution of sodium hydrogen sulfide (133 ml, 539 mmole) was added slowly over a period of 30 minutes. The reaction mixture was refluxed for 3 h. It was evaporated to dryness and resulting residue was treated with water (500 ml). The mixture was acidified to pH 3 using dil. HCl.
  • Step 3 To a suspension of 3-amino-4-methyl-5-nitrobenzoic acid (25 g, 127 mmole) in a mixture of cone, hydrochloric acid (100 ml) and water (100 ml), a solution of sodium nitrite (9.3 g, 135 mmole) in water (25 ml) was added at between 0-5 0 C over a period of 15 to 20 minutes. After stirring at 0-5 0 C for another 30 minutes, the reaction mixture was slowly added to cold cuprous chloride (27.8 g, 280 mmole) solution in cone, hydrochloric acid (60 ml) with stirring. The reaction mixture was allowed to come to room temperature and stirred for 1 h.
  • KMnO 4 (31.6 g; 200 mmole) in water (475 ml) was refluxed for 4 h under stirring. After the disappearance of KMnO 4 color, TLC showed the presence of starting material. Additional KMnO 4 (15.8 g; 100 mmole) was added and refluxing continued for 4 h. When TLC revealed the disappearance of starting material, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to ca. 150 ml on a rotavap. The concentrated aqueous mixture was cooled to 0-5 0 C and acidified to pH 2 with cone. HCl.
  • Step 5 To a suspension of 2-chloro-6-nitroterephthalic acid (12 g, 48 mmole) in methanol (300 ml) was added cone, sulfuric acid (7.5 ml) at ambient temperature and the mixture was refluxed for 18 h. The reaction mixture was concentrated on a rotavap and the resulting residue was dissolved in ethyl acetate (25 ml) and washed with water (2 x 20 ml). The organic phase was dried over anhydrous Na 2 SO 4 and evaporated under vacuum to yield 1O g of 2-chloro-6-nitro- terephthalic acid 4-methyl ester as colorless solid (80%).
  • Step 6 To a solution of 2-chloro-6-nitro-terephthalic acid 4-methyl ester (1Og, 38 mmole) in methanol (200 ml), an ethereal solution of diazomethane (100 ml) [prepared from 50% aq. KOH (56 ml) and N-nitroso methylurea (14 g, 135 mmole)] was added at between 0-5 0 C over a period of 30 minutes. The reaction mixture was stirred between 0-5 0 C for 1 h and then allowed to come to ambient temperature. Excess of diazomethane was quenched by adding acetic acid.
  • Step 7 To a solution of dimethyl 2-chloro-6-nitroterephthalate (9.5 g, 35 mmole) in toluene (400 ml), iron (2Og, 357 mmole) was added at ambient temperature and mixture was heated to reflux. Under reflux condition, acetic acid (33 ml) was added slowly over a period of 1 h and refluxing continued for 2 h. Another lot of acetic acid (33 ml) was added over a period of 1 h and refluxing continued for 2 h. As TLC revealed presence of the starting material, another lot of acetic acid (33 ml) was added over a period of 1 h and refluxing continued for 2 h.
  • Step 1 A mixture of 2-bromo-p-xylene (18.5 g, 100 mmole) and KMnO 4 (15.8 g; 100 mmole) in water (225 ml) was refluxed for 2 h under stirring. After the disappearance of KMnO 4 - color, TLC showed the presence of starting material. Additional KMnO 4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, another lot Of KMnO 4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, however, the reaction was worked up. The mixture was cooled to RT and filtered.
  • the filtrate was extracted with ethyl acetate (2 X 25 ml). The ethyl acetate layer was dried and evaporated to recover 6.15 g (33%) of the starting material.
  • the aqueous filtrate was concentrated to half volume on a rotavap. The concentrated aqueous mixture was cooled to 0-5 0 C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water and dried to yield 11.39 g (47%) of 2-bromo terephthalic acid as a colorless solid.
  • Step 2 2-Bromo terephthalic acid (13.8 g, 56.3 mmole) was slowly added under stirring to cone. H 2 SO 4 (78 ml) at 0-5 0 C over 5 minutes. To the resulting mixture was added 1: 1 mixture of cone. H 2 SO 4 and cone. HNO3 (15 ml) dropwise over 20 min. at 0-5 0 C. The mixture was then heated to 100 0 C for 2 h. After cooling and stirring for 18 h at ambient temperature, mixture was poured into 100 g of ice-water. The resulting colorless solid was filtered and dried. The solid was recrystallized from ethanol to give 10.5 g (64%) of 2-bromo-5-nitroterephthalic acid.
  • Step 3 To a suspension of 2-bromo-5-nitroterephthalic acid (10.5 g; 36.2 mmole) in methanol (200 ml) was added dropwise cone H 2 SO 4 (5 ml) at rt. The mixture was refluxed for 18 h. TLC showed the disappearance of starting material and formation of non-polar product along with small amount of monoester.
  • Step 4 A mixture of dimethyl 2-bromo-5-nitroterephthalate (8.5 g; 26.7 mmole), PEG 400 (1.92 g) and KF (5.35 g, 92.1mmole) in DMSO (250 ml) was heated at 90 0 C for 8 h. 1 H-NMR of the reaction mass showed disappearance of starting material along with the formation of a phenolic impurity. The reaction mixture was quenched with water (500 ml) and the mass was extracted with ethyl acetate (3 x 100 ml).
  • Step 1 To a suspension of 2-amino terephthalic acid (10 g, 55 mmole) in cone, hydrochloric acid (14.3 ml) and water (28.6 ml) a solution of sodium nitrite (3.8 g, 55 mmole) in water (18 ml) was added between 0-5 0 C over a period of 15 to 20 minutes. After stirring at 0-5 0 C for another 30 minutes, the reaction mixture was slowly added to cold cuprous chloride (12 g, 122 mmole) solution in cone, hydrochloric acid (60 ml) under stirring. The reaction mixture was then allowed to come to RT and stirred for 3 h.
  • Step 2 2-Chloro terephthalic acid (8 g, 40 mmole) was dissolved in cone, sulfuric acid (33 ml) under ice-cooling. To the cold reaction mixture, 1 :1 mixture of cone, nitric acid (3.6 ml) and cone, sulfuric acid (3.6 ml) was added slowly between 0-5 0 C over a period of 15 minutes. After addition reaction mixture was heated at 100 0 C for 2 h after which TLC revealed disappearance of starting material. Mixture was then cooled to rt and quenched with cold water (250 ml). Precipitated solid was filtered and washed with cold water (25 ml) and dried under vacuum to get 6 g of product (61%). 1 H NMR in CD 3 OD- ⁇ 4 ⁇ ppm : 7.93 (IH, s Ar-H) 8.34 (IH, s, Ar-H).
  • Step 3 Mixture of 2-chloro-5-nitroterephthalic acid (10 g, 41 mmole) and stannous chloride dihydrate (27.5 g, 132 mmole) in ethyl acetate (375 ml) was stirred overnight at ambient temperature. TLC indicated disappearance of starting material. Mixture was diluted with ethyl acetate (200 ml) and washed with saturated aq. sodium chloride solution (75 ml). Ethyl acetate layer was evaporated and resulting residue was treated with 5% aq. sodium bicarbonate solution till the pH was ⁇ 7. The semi-solid reaction mass was then stirred with ethyl acetate (500 ml) and filtered.
  • Step 1 4-Methyl benzoic acid (50 g, 368 mmole) was dissolved in cone, sulfuric acid (500 ml) and cone, nitric acid (200 ml) was added slowly 18-20 0 C over a period of 3 h. After addition, the reaction mixture was then allowed to come to room temperature and stirred for 2 h. During this period, the dark viscous reaction mixture turned yellow in color with some amount of yellow solid precipitated. TLC revealed disappearance of starting material. The reaction mixture was poured over crushed ice water (1 kg) and stirred for 30 minutes.
  • Step 2 A solution of 4-methyl-3,5-dinitrobenzoic acid (70 g, 307 mmole) in methanol (750 ml) was warmed to 60 0 C and a 30% solution of sodium hydrogen sulfide (133 ml, 539 mmole) was added slowly over a period of 30 minutes. The reaction mixture was refluxed for 3 h. The reaction mixture was evaporated to dryness and resulting residue was treated with water (500 ml). The mixture was acidified to pH 3 using dil. HCl.
  • Step 3 A mixture of cone, sulfuric acid (367.5 ml) and water (117.6 ml) was heated to 90-100 0 C and 3-amino-4-methyl-5-nitrobenzoic acid (29.4 g, 149 mmole) was added in small portion over a period of 30 minutes. The reaction mixture was then cooled to 0-5 0 C and a solution of sodium nitrite (20.7 g, 300 mmole) in water (117.6 ml) was added over a period of 60 minutes. After addition, reaction mixture was stirred at 0-5 0 C for another 30 minutes.
  • Step 4 At 0-5 0 C, to a solution of 3-hydroxy-4-methyl-5-nitrobenzoic acid (28 g, 141 mmole) in methanol (280 ml), thionyl chloride (15.5ml, 212 mmole) was added dropwise over a period of 30 minutes. After the addition, the reaction mixture was brought to room temperature and then refluxed for 4 h. The reaction mixture was concentrated under vacuum. The resulting solid residue was dissolved in ethyl acetate (500 ml) and washed with sodium bicarbonate solution. Ethyl acetate extract was dried over Na 2 SO 4 and concentrated under vacuum to yield 30 g of methyl 3-hydroxy-4-methyl-5-nitrobenzoate as colorless solid (quantitative). The crude product was used as such for the next step without characterization.
  • Step 5 To a mixture of methyl 3-hydroxy-4-methyl-5-nitrobenzoate (3O g, 141 mmole), and K 2 CO 3 (38.9 g; 282 mmole) in acetone (300 ml) under inert atmosphere (nitrogen) was added methyl iodide (22.2 g, 156 mmole) at ambient temperature. The mixture was stirred overnight at the same temperature. The reaction mixture was filtered and acetone was removed on a rotavap. The resulting residue was dissolved in ethyl acetate (500 ml) and washed with dil. HCl.
  • Step 6 To a solution of methyl 3-methoxy-4-methyl-5-nitrobenzoate (30 g, 132 mmole) in methanol (200 ml) was added at room temperature IM NaOH solution (158 ml, 158 mmole) and stirred overnight. The reaction mixture was concentrated on a rotavap and the resulting mixture was cooled to 5-10 0 C and acidified with dil HCl to pH 2. Precipitated solid was filtered, washed with water and partly dried under vacuum. Partially dried colorless 3-methoxy-4-methyl-5- nitrobenzoic acid, weighing 30 g was used as such for the next step.
  • 1 H NMR in DMSO-d 6 ⁇ ppm 2.32 (3H, s, CH3) 3.95 (3H, s, OCH3) 7.69 (IH, s, ArH) 7.93 (IH, s, ArH).
  • Step 7 To a solution Of KMnO 4 (44.56 g, 282 mmole) in water (675 ml) was added at room temperature 3-methoxy-4-methyl-5-nitrobenzoic acid (30 g, 141 mmole) and the mixture was heated to reflux. After 2 h and 4h of refluxing another lot of KMnO4 44.56g (282 mmole) and 22.28 g (141mmole) were added respectively. After complete consumption of starting material, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to ca. 200ml on a rotavap. The concentrated aqueous mixture was cooled to 0-5 0 C and acidified to pH 2 with cone. HCl.
  • Step 8 To a solution of 2-methoxy-6-nitroterephthalic acid (5 g, 21 mmole) in methanol (280 ml) maintained at 0-5 0 C was added dropwise thionyl chloride (2.4ml, 32 mmole) over a period of 5 minutes. The mixture was slowly brought to ambient temperature and was then refluxed for 4 h. The reaction mixture was concentrated under vacuum. The resulting solid residue was dissolved in ethyl acetate (150 ml) and washed with saturated Na 2 CO 3 solution. Ethyl acetate extract was dried over Na 2 SO 4 and evaporated to yield 5 g of 2-methoxy-6-nitro-terephthalic acid 4-methyl ester as colorless solid (93%).
  • Step 9 To a solution of 2-methoxy-6-nitro-terephthalic acid 4-methyl ester (7g, 27 mmole) in methanol (100 ml) was added between 0-5 0 C an ethereal solution of diazomethane (100 ml) [prepared from 50% aq. KOH (45 ml) and N-nitroso methylurea (11.3 g, 108 mmole)] over a period of 30 minutes.
  • Step 10 To a solution of dimethyl 2-methoxy-6-nitroterephthalate (9.45 g, 35 mmole) in toluene (400 ml) was added at room temperature iron (2Og, 357 mmole) and the mixture was heated to reflux. Under reflux condition, acetic acid (33 ml) was added slowly over a period of 1 h and refluxing continued for 2 h. Two more lots of acetic acid (33 ml each) were added after a gap of 2 h for complete conversion. The reaction mass was cooled to room temperature and filtered through celite.
  • Step 1 To a tetrahydrofuran solution (2 mL) of dimethyl 2-chloro-5-nitro-l,4- benzenedicarboxylate (547 mg, 2 mmol) in a 5 mL microwave tube, was added dimethylamine (90mg, 2.0 mmol) to give a yellow solution. The reaction was heated via Biotage Microwave reactor at 85°C for 15 minutes and checked by LCMS. The reaction mixture was concentrated, diluted with ethyl acetate (75 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title product (564 mg, 100 %) which was used without purification.
  • Reaction mixture was stirred at rt for 1 hour. 5,6-bis(methyloxy)-2-pyridinamine (77 mg, 0.5 mmol) was added into reaction mixture. Reaction mixture was stirred at rt for one hour. Reaction was concentrated and residue was dissolved with DMF (2 mL). 2N NaOH (0.5 mL) solution was added into reaction solution. The reaction mixture was then heated at 50 0 C for one hour. The reaction mixture was poured into ice water and a precipitate formed. The solid was filtered off and collected. The solid was dissolved with 1.5 mL of DMSO. purified with a Gilson HPLC system (20-50% gradient in 8.5 minutes).
  • erythropoietin is a HIF-2 ⁇ target gene in Hep3B and Kelly cells" FASEB J., 2004, 18, 1462-1464.
  • HIF2a-CODD Modify HIF" Science, 2001, 294, 1337-1340.
  • HIF2a-CODD see: a) P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. von Kriegsheim, H. F. Hebeminister, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P, J. Ratcliffe "Targeting of HIF- ⁇ to the von Hippel-Lindau Ubiquitylation Complex by O 2 - Regulated Prolyl Hydroxylation" Science, 2001, 292, 468-472.
  • 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-HIF2 ⁇ -CODD (6HisGBltevHIF2A(467-572)) were expressed from .E 1 . 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.
  • Hep3B cells obtained from the American Type Culture Collection 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.
  • DMEM Dulbecco's Modified Eagle Medium
  • 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 porte sur certains dérivés de la 2,4-dioxo-l,2,3,4-tétrahydro-7-quinazolinecarboxamide de formule (I), qui sont des antagonistes de prolyl hydroxylases HIF et qui sont utiles pour traiter des maladies bénéficiant de l'inhibition de cette enzyme, l'anémie en étant un exemple.
PCT/US2009/064534 2008-11-18 2009-11-16 Inhibiteurs de la prolyl hydroxylase Ceased WO2010059549A1 (fr)

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WO2012110789A1 (fr) 2011-02-15 2012-08-23 Isis Innovation Limited Procédé d'analyse de l'activité de l'ogfod1
WO2013014449A1 (fr) 2011-07-28 2013-01-31 Isis Innovation Limited Dosage pour l'activité histidinyle hydroxylase
CN114573467A (zh) * 2022-03-21 2022-06-03 北京印刷学院 2，4-二甲基-3-氨基苯甲酸的绿色合成工艺
CN116143768A (zh) * 2022-12-25 2023-05-23 浙江工业大学 含硫代喹唑啉酮环的苯并噁嗪酮类化合物及其制备方法和应用
CN118515568A (zh) * 2024-07-19 2024-08-20 天津深蓝工程技术有限公司 一种3-氯-2-甲基苯胺制备方法

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WO2005085227A1 (fr) * 2004-03-02 2005-09-15 Smithkline Beecham Corporation Inhibiteurs de l'activite de la proteine kinase b (akt)
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WO2012110789A1 (fr) 2011-02-15 2012-08-23 Isis Innovation Limited Procédé d'analyse de l'activité de l'ogfod1
WO2013014449A1 (fr) 2011-07-28 2013-01-31 Isis Innovation Limited Dosage pour l'activité histidinyle hydroxylase
CN114573467A (zh) * 2022-03-21 2022-06-03 北京印刷学院 2，4-二甲基-3-氨基苯甲酸的绿色合成工艺
CN114573467B (zh) * 2022-03-21 2023-11-21 北京印刷学院 2，4-二甲基-3-氨基苯甲酸的合成工艺
CN116143768A (zh) * 2022-12-25 2023-05-23 浙江工业大学 含硫代喹唑啉酮环的苯并噁嗪酮类化合物及其制备方法和应用
CN118515568A (zh) * 2024-07-19 2024-08-20 天津深蓝工程技术有限公司 一种3-氯-2-甲基苯胺制备方法

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