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WO2006042007A2 - Utilisation de composes de chromenone comme calcilytiques - Google Patents

Utilisation de composes de chromenone comme calcilytiques Download PDF

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Publication number
WO2006042007A2
WO2006042007A2 PCT/US2005/035974 US2005035974W WO2006042007A2 WO 2006042007 A2 WO2006042007 A2 WO 2006042007A2 US 2005035974 W US2005035974 W US 2005035974W WO 2006042007 A2 WO2006042007 A2 WO 2006042007A2
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lower alkyl
compound
disease
compounds
administered
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WO2006042007A3 (fr
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Robert W. Marquis
Irina Shcherbakova
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Shire NPS Pharmaceuticals Inc
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NPS Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to chromenone compounds able to inhibit calcium receptor activity, pharmaceutical compositions containing these compounds, and methods for preparing the compounds and compositions.
  • the present invention also relates to the uses of such compounds and compositions, particularly their use in administering to patients to achieve a therapeutic effect.
  • extracellular Ca 2+ is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
  • Extracellular Ca 2+ inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
  • Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca 2+ concentration.
  • PTH is the principal endocrine factor regulating Ca 2+ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca 2+ in the blood. This increase in extracellular Ca 2+ then acts as a negative feedback signal, depressing PTH secretion.
  • the reciprocal relationship between extracellular Ca 2+ and PTH secretion forms an important mechanism maintaining bodily Ca 2+ homeostasis.
  • Extracellular Ca 2+ acts directly on parathyroid cells to regulate PTH secretion.
  • the existence of a parathyroid cell surface protein which detects changes in extracellular Ca 2+ has been confirmed. See Brown et al., Nature 366:574, 1993.
  • this protein the calcium receptor, acts as a receptor for extracellular Ca 2+ , detects changes in the ion concentration of extracellular Ca 2+ , and initiates a functional cellular response, PTH secretion.
  • Extracellular Ca 2+ influences various cell functions, reviewed in Nemeth et al., Cell Calcium 11 :319, 1990.
  • extracellular Ca 2+ plays a role in parafollicular (C-cells) and parathyroid cells.
  • C-cells parafollicular
  • parathyroid cells See Nemeth, Cell Calcium 11 :323, 1990.
  • the role of extracellular Ca 2+ on bone osteoclasts has also been studied. See Zaidi, Bioscience Reports 10:493, 1990.
  • Calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca 2+ .
  • Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca 2+ receptors.
  • Such calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca 2+ receptors.
  • Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral " homeostasis.
  • Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
  • calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, joint replacement, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • Chromenone compounds are disclosed herein which are useful as calcium receptor antagonists in the treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, joint replacement, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • the compounds are represented by Formula (I) hereinbelow.
  • a method for antagonizing calcium receptors in an animal, including humans, is also disclosed. The method comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated hereinbelow.
  • a method for increasing serum parathyroid levels in an animal, including humans, is additionally disclosed.
  • the method comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated herein below.
  • Chromenone compounds are disclosed herein which are useful as calcilytic compounds or calcilytics.
  • Calcilytics and “calcilytic compounds” refer to compounds able to inhibit calcium receptor activity.
  • the ability of a compound to "inhibit calcium receptor activity” means that the compound causes a decrease in one or more calcium receptor activities evoked by extracellular Ca 2+ .
  • the use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient are described below. More specifically, the ability of calcilytic compounds to increase PTH secretion is demonstrated, thereby confirming that the parathyroid gland calcium receptor is a target site for these compounds. Also described below are techniques which can be used to obtain additional calcilytic compounds. [0014] Examples of the featured calcilytic compounds are provided by the chemical formula depicted in Structure I and the accompanying description.
  • R 1 and R 2 are independently one of: H, halogen, CN, CF 3 , lower alkyl, cycloalk, or aryl; or R 1 and R 2 are together -(CHa) n - and n is 5, 4, or 3; or R 1 and R 2 are together an aromatic ring;
  • R 3 is an aryl group, which may have 0 to 4 substituents in the aryl ring and each substituent is at least one of: halogen, CN, CF 3 , OCF 3 , lower alkyl, N(lower alkyl) 2 , lower alkoxy, OH, OC(O)-lower alkyl, OC(O)-lower alkylamino, or OC(O)-lower alkyl-N(lower alkyl) 2 ;
  • R 4 is one of H, lower alkyl, and a group of the formula -(CH 2 ) n -R 5 wherein n is 0, 1 , or 2, and R 5 is an aryl group which may have 0 to 3 substituents on the aryl ring and each substituent is at least one of: halogen, CN, CF 3 , OCF 3 , lower alkyl, lower alkoxy, NH-lower alkyl, NH-alkylaryl, N(lower alkyl) 2 , OH, OC(O)-lower alk, OC(O)-lower alkylamino, and OC(O)- lower alkyl-N(lower alk) 2 ; or pharmaceutically acceptable salts, hydrates, tautomers, solvates or complexes thereof.
  • alkyl refers to an optionally substituted hydrocarbon group joined by single carbon-carbon bonds and having 1-20 carbon atoms joined together.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
  • Substituents on optionally substituted alkyl may be one of: aryl, CO 2 R, CO 2 NHR, OH, OR, CO, NH 2 , halo, CF 3 , OCF 3 or NO 2 , wherein R represents H, C 1-4 alkyl, C 3 . 6 cycloalkyl, C 2 . 5 alkenyl, C 2 . 5 alkynyl, heterocycloalkyl, or aryl.
  • Additional substituents may be at least one of: F, Cl, Br, I, N, S or O. In one embodiment, no more than three substituents are present. In another embodiment, the alkyl has 1-12 carbon atoms and is unsubstituted. The alkyl group may be linear. [0016] As used herein "cycloalkyl" refers to optionally substituted 3-7 membered carbocyclic rings wherein any substituents may be at least one of, F, Cl, Br, I, N(R 1 Zt) 2 , SR 4 or OR 4 , unless otherwise indicated.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl, and biaryl groups, all of which may be optionally substituted. Phenyl and naphthyl are particularly useful aryl.
  • suitable substituents include at least one of: halogen, C 1-4 alkyl, OCF 3j CF 3j OMe, CN, OSO 2 R or NO 2j wherein R represents C 1-4 alkyl or C 3 . 6 cycloalkyl.
  • heteroaryl refers to an aryl ring containing 1 , 2 or 3 heteroatoms such as N, S, or O.
  • alkenyl refers to an optionally substituted hydrocarbon group containing at least one carbon-carbon double bond and containing up to 5 carbon atoms joined together.
  • the alkenyl hydrocarbon chain may be straight, branched or cyclic.
  • the substituents are at least one of: halogen, C 1-4 alkyl, OCF 3j
  • alkynyl refers to an optionally substituted hydrocarbon group containing at least one carbon-carbon triple bond between the carbon atoms and containing up to 5 carbon atoms joined together.
  • the alkynyl hydrocarbon group may be straight-chained, branched or cyclic.
  • the substituents are at least one of: halogen, C 1-4 alkyl, OCF 3 , CF 3 , OMe, CN, OSO 2 R or NO 2 , wherein R represents C 1-4 alkyl or C 3-6 cycloalkyl.
  • the chromenone compound may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention. [0022]
  • One compound corresponding with Formula (I) is:
  • Example 1 provides a method for preparing this compound.
  • Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Hydrochloride is a particularly useful pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • the compounds of Formula (I) above may be prepared using standard techniques. An overall strategy for preparing preferred compounds described herein can be carried out as described in this section. The examples, which follow, illustrate the synthesis of specific compounds. Using the protocols described herein as a model, one of ordinary skill in the art can readily produce other compounds of the present invention.
  • chromenones disclosed herein may be synthesized in the general manner outlined below in Scheme 1 with the starting compound, 2'-hydroxychalcone, identified as compound (1 ) and the final compound identified as compound (7).
  • 1-(2- Hydroxyphenyl)-4-phenyl-butanone (3) is prepared from 2'-hydroxychalcone (1) following literature procedures (Henke, B. R.; Adkison, K.K.; Blanchard, S. G.; Leesnitzer, L. M.; Mook, R.A.; Plunket, K.D.; Ray, J.A.; Roberson, C; Unwalla, R.; Willson, T.M. Biorg. and Med. Chem. Lett. 1999, 9, 3329).
  • the calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • Oral administration is suitable for systemic administration.
  • the compounds can be formulated into conventional oral dosage forms. Examples of suitable oral dosage forms include capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions.
  • the compounds may be formulated in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissoived or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be achieved by transmucosal or transdermal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC 50 , EC 50 , the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is typically administered in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from about 0.01 to about 500 mg/kg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the dosage unit for oral administration may also be about 0.1 to about 50 mg/kg.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from about 0.01 mg to about 100 mg/kg, of a compound of Formula (I).
  • a topical formulation contains suitably about 0.01 to about 5.0% of a compound of Formula (I). While a single does is convenient, multiples doses, such as 2 to 6 times per day may be utilized.
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • Diseases and disorders which might be treated or prevented, based upon the affected cells include bone and mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, such as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome; diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics); gut motility disorders such as diarrhea and spastic colon; Gl ulcer diseases; Gl diseases with excessive calcium absorption
  • the chromenone compounds are used to increase serum parathyroid hormone ("PTH") levels.
  • PTH serum parathyroid hormone
  • Increasing serum PTH levels can be helpful in treating diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy and osteoporosis.
  • the chromenone compounds can be co-administered with an anti- resorptive agent.
  • agents include, but are not limited estrogen, 1 , 25 (OH) 2 vitamin D3, calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.
  • the compounds disclosed herein can be utilized in a method of treating a patient to increase the patient's serum PTH level. The method is carried out by administering to the patient an amount of the compound effective to cause an increase in duration and/or quantity of serum PTH level sufficient to have a therapeutic effect.
  • the compound administered to a patient causes an increase in serum PTH having a duration of up to one hour, about one to about twenty-four hours, about one to about twelve hours, about one to about six hours, about one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours.
  • the compound administered to a patient causes an increase in serum PTH having a duration of more than about twenty four hours provided that it is co-administered with an anti resorptive agent.
  • the compound administered to a patient causes an increase in serum PTH of up to two fold, two to five fold, five to ten fold, and at least 10 fold, greater than peak serum PTH in the patient.
  • the peak serum level is measured with respect to a patient not undergoing treatment.
  • compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally, can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation generally comprises a suspension or solution of the compound or salt in a liquid carrier.
  • suitable liquid carriers include ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any routine encapsulation is suitable.
  • the aforementioned carriers used in preparing tablets may be utilized to form a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered.
  • suitable materials for forming a soft gelatin capsule shell include aqueous gums, celluloses, silicates and oils.
  • Typical parenteral compositions comprise a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • composition is conveniently provided in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • Calcilytic activity was measured by determining the IC 50 of the test compound, 2-(2-hydroxyphenyl)-3-(2-phenylethyl)-4H-chromen-4-one, for blocking increases of intracellular Ca 2+ elicited by extracellular Ca 2+ in HEK 293 4.0-7 cells stably expressing the human calcium receptor.
  • HEK 293 4.0-7 cells were constructed as described by Rogers et al., J. Bone Miner. Res. 10 Suppl. 1 :S483, 1995 (hereby incorporated by reference herein).
  • Intracellular Ca 2+ increases were elicited by increasing extracellular Ca 2+ from 1 to 1.75 mM.
  • Intracellular Ca 2+ was measured using fluo-3, a fluorescent calcium indicator.
  • Sulfate- and phosphate-free parathyroid cell buffer contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCI, 5 mM KCI, and 1 mM MgCI 2 .
  • SPF-PCB was made up and stored at 4 0 C. On the day of use, SPF-PCB was supplemented with 1 mg/mL of D-glucose and 1 mM CaCI 2 and then split into two fractions. To one fraction, bovine serum albumin (BSA; fraction V, ICN) was added at 5 mg/mL (SPF-PCB+). This buffer was used for washing, loading and maintaining the cells. The BSA-free fraction was used for diluting the cells in the cuvette for measurements of fluorescence.
  • BSA bovine serum albumin
  • test compound or vehicle as a control
  • Calcilytic compounds were detected by their ability to block, in a concentration-dependent manner, increases in the concentration of intracellular Ca 2+ elicited by extracellular
  • Compounds having an IC 50 value in the Calcium Receptor Inhibitor which are greater than 50 uM were considered to be inactive. Note that it is desirable for compounds to have lower IC 50 values in the Calcium Receptor Inhibitor Assay. For example, it is desirable for the compounds to have an IC 50 of 1OuM or lower, an IC 50 of 1uM, and an IC 50 of 0.1 uM or lower.
  • HEK 293 4.0-7 cells stably transfected with the Human Parathyroid Calcium Receptor (“HuPCaR”) were scaled up in T180 tissue culture flasks.
  • Plasma membrane is obtained by polytron homogenization or glass douncing in buffer (5OmM Tris-HCI pH 7.4, 1 mM EDTA, 3mM MgCI 2 ) in the presence of a protease inhibitor cocktail containing 1 uM Leupeptin, 0.04 uM Pepstatin, and 1 mM PMSF.
  • a typical reaction mixture contains 2 nM 3 H compound ((R,R)-N-4'- Methoxy-t-3-3'-methyl-1'-ethylphenyl-1-(1-naphthyl)ethylamine), or 3 H compound (R)-N-[2-Hydroxy-3-(3-chloro-2-cyanophenoxy)propyl]-1 , 1 -dimethy!-2-(4- methoxyphenyl)ethylamine 4-10 ug membrane in homogenization buffer containing 0.1 % gelatin and 10% EtOH in a reaction volume of 0.5 mL. Incubation is performed in 12 x 75 polyethylene tubes in an ice water bath.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des composés calcilytiques ainsi que des procédés de préparation de ces composés. De plus, l'invention concerne des procédés d'utilisation de ces composés calcilytiques.
PCT/US2005/035974 2004-10-06 2005-10-06 Utilisation de composes de chromenone comme calcilytiques Ceased WO2006042007A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9861606B2 (en) 2012-09-28 2018-01-09 King's College London Therapeutic for treating inflammatory lung disorders

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEVAI ET AL.: 'Synthesis of 3-Benzylflavones and 3-benzyl-4-thioflavones' JOURNAL OF CHEMICAL RESEARCH (S) no. 11, November 1992, pages 380 - 381 *
LIGHT ET AL.: 'Aroylations of Beta-Diketones, etc.' JOURNAL OF ORGANIC CHEMISTRY vol. 25, April 1960, pages 538 - 546 *
WEBER ET AL.: 'Synthesis and in vitro Studies of Pyrone Derivatives as Scavengers of Active Oxygen Species' ARZNEIM-FORSCH/DRUG RESEARCH vol. 51, no. II, February 2001, 884, page 877 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9861606B2 (en) 2012-09-28 2018-01-09 King's College London Therapeutic for treating inflammatory lung disorders

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