WO2010103429A1 - Dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique utiles en tant qu'antagonistes des récepteurs du calcium - Google Patents

Dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique utiles en tant qu'antagonistes des récepteurs du calcium Download PDF

Info

Publication number
WO2010103429A1
WO2010103429A1 PCT/IB2010/050911 IB2010050911W WO2010103429A1 WO 2010103429 A1 WO2010103429 A1 WO 2010103429A1 IB 2010050911 W IB2010050911 W IB 2010050911W WO 2010103429 A1 WO2010103429 A1 WO 2010103429A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
dimethyl
methylsulfanyl
phenyl
carboxylic acid
Prior art date
Application number
PCT/IB2010/050911
Other languages
English (en)
Inventor
Paul Stuart Humphries
David Anthony Price
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2010103429A1 publication Critical patent/WO2010103429A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • extracellular Ca 2+ In mammals, extracellular Ca 2+ is under rigid homeostatic control with the serum calcium concentration strictly maintained at a concentration of approximately 1.1 to 1.3 mM in a healthy mammal.
  • the extracellular Ca 2+ homeostasis depends on integrated regulation of Ca 2+ fluxes with respect to the intestine, kidneys and bone.
  • the extracellular Ca 2+ regulates various processes such as blood coagulation, nerve and muscle excitability, and normal bone homeostasis.
  • the Ca 2+ serum concentration decreases by 50% tetania occurs, and when the Ca 2+ serum concentration increases by 50% consciousness is clouded, in both instances a potentially life threatening circumstance.
  • the extracellular calcium-sensing receptor is a hormone-like receptor, more particularly a plasma membrane-bound G protein-coupled receptor (GPCR) that belongs to family 3 of the GPCR superfamily.
  • GPCR plasma membrane-bound G protein-coupled receptor
  • Family 3 of the GPCR superfamily includes metabotropic glutamate receptors (mGluRs), ⁇ -aminobutyric acid B-type receptors (GABA B Rs) as well as putative pheromone and taste receptors.
  • the CaSR has a large extracellular domain exhibiting "Venus flytrap" topology, a seven-transmembrane domain and a relatively large cytoplasmic domain.
  • Human CaSR consists of 1078 amino acids and shares 93% amino acid homology with bovine CaSR.
  • the CaSR senses and is activated by changes in extracellular Ca 2+ levels.
  • the presence of CaSR on certain specialized cells enables those Ca 2+ -sensing cells to respond to changes in extracellular Ca 2+ concentration.
  • Examples of Ca 2+ -sensing cells include the parathyroid-secreting cells of the parathyroid gland, the calcitonin-secreting C cells of the thyroid gland and certain cells in the kidney.
  • the CaSR has been found in a wide variety of other tissues including intestine, bone, bone marrow, brain, skin, pancreas, lung and heart.
  • the CaSR on the surface of parathyroid chief cells is the primary entity that regulates secretion of PTH from parathyroid cells. Activation of the CaSR on parathyroid chief cells by extracellular Ca 2+ suppresses PTH production and secretion, inhibits parathyroid cellular proliferation and likely inhibits PTH gene expression.
  • the CaSR on the surface of the calcitonin-secreting C cells of the thyroid gland mediate the stimulatory action of high extracellular Ca 2+ concentration on calcitonin secretion, thereby increasing the circulating level of the Ca 2+ -lowehng hormone calcitonin.
  • the CaSR is also present in the kidney, along much of the nephrons and at the basolateral surface in the cortical thick ascending limb.
  • Phenylalkylamine calcimimetic compounds include (R)-N-(I - (3-methoxyphenyl)ethyl)-3-phenylpropan-1 -amine hydrochloride (NPS-467); (R)-3-(2-chlorophenyl)-N-(1 -(3-methoxyphenyl)ethyl)propan-1 -amine hydrochloride (NPS R-568, tecalcet hydrochloride) and (R)-(-)-N-(1 - (naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1 -amine hydrochloride (NPS-1493, cinacalcet hydrochloride).
  • Cinacalcet hydrochloride and uses thereof are disclosed in U.S. Patent Nos. 6,011 ,068; 6,031003; 6,211 ,244 and 6,313,146. Cinacalcet hydrochloride is marketed as Sensipar® and Minpara® in the U.S. and Europe, respectively, and is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for hypercalcemia in patients with parathyroid carcinoma.
  • Calcilytics or calcium receptor antagonists
  • Calcium receptor antagonists 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 CaSR.
  • Target diseases or disorders for calcium receptor antagonists 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.
  • novel calcium receptor antagonists of this invention are useful in the treatment of diseases associated with abnormal bone or mineral homeostasis.
  • these calcium receptor antagonists are useful in the treatment of hypoparathyroidism, osteoporosis, osteopenia, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy.
  • the present invention is directed towards calcium receptor antagonist compounds, pharmaceutical compositions comprising the calcium receptor antagonist compounds and methods of treatment employing the calcium receptor antagonist compounds.
  • the present invention is directed to calcium receptor antagonist derivatives of structural formula I
  • R 1 is methylsulfanyl-phenyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl, wherein said methylsulfanyl-phenyl is optionally substituted on phenyl with a methyl or fluoro and said cyclohexyl is optionally substituted with two fluoro; or a pharmaceutically acceptable salt thereof.
  • FIG. 1 is a chart depicting plasma PTH levels from the time of intravenous injection to 480 minutes following intravenous injection of 1 mg/kg of the compound of Example 1 , in normal rats.
  • the present invention provides novel 1 ,1-(dimethyl-ethylamino)-2- hydroxy-propoxy]-ethyl ⁇ -3-methyl-biphenyl-4-carboxylic acid derivatives and pharmaceutically acceptable salts thereof of structural formula I
  • the pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chlohde, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formula I.
  • the compounds of the present invention may be administered as prodrugs.
  • prodrugs certain derivatives of compounds of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • Some examples of such prodrugs include:
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and the diastereoisomers converted to the corresponding pure diastereomers by means well known to a skilled person.
  • the chiral compounds of the invention may be obtained in diastereomehcally-enhched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Mixtures of diastereoisomers may be separated by conventional techniques known to those skilled in the art.
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds of formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e.
  • substitutions with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • a preferred embodiment of the present invention are compounds of Formula I as described above wherein R 1 is methylsulfanyl-phenyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl, wherein said methylsulfanyl- phenyl is optionally substituted on phenyl with a methyl or fluoro and said cyclohexyl is optionally substituted with two fluoro; or a pharmaceutically acceptable salt thereof.
  • Another preferred embodiment of the present invention is a compound of Formula I, wherein R 1 is methylsulfanyl-phenyl, 3-fluoro-4-methylsulfanyl- phenyl, 3-methyl-4-methylsulfanyl-phenyl, cyclohexyl, difluorocyclohexyl, cycloheptyl or bicyclo[2.2.1]hept-2-yl; or a pharmaceutically acceptable salt thereof.
  • Another preferred embodiment of the present invention is a compound of Formula I, wherein R 1 is 3-methylsulfanyl-phenyl or 4- methylsulfanyl-phenyl; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula I as described in any of the preceding embodiments hereinabove and a pharmaceutically acceptable carrier, adjuvant or diluent.
  • Another embodiment of the present invention is a method of treating a disease or disorder characterized by abnormal bone or mineral homeostasis which comprises the administration to a patient in need of treatment thereof a therapeutically effective amount of a compound according to Formula I as described in any of the preceding embodiments hereinabove.
  • a preferred embodiment of the present invention is the method according to the preceding embodiment wherein the disease or disorder characterized by abnormal bone or mineral homeostasis is selected from the group consisting of osteoporosis, osteopenia, periodontal disease, Paget's disease, bone fracture, osteoarthritis, rheumatoid arthritis, and humoral hypercalcemia of malignancy.
  • the disease or disorder characterized by abnormal bone or mineral homeostasis is osteoporosis.
  • reaction scheme depicts methods of synthesis for compounds of formula I.
  • the variable R 1 is as previously defined for a compound of the formula I unless otherwise stated.
  • the Reaction Scheme herein described is intended to provide a general description of the methodology employed in the preparation of many of the Examples given. However, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further than the general procedures described herein. In particular, it is noted that the compounds prepared according to the Scheme may be modified further to provide new Examples within the scope of this invention.
  • the reagents and intermediates used in the following examples are either commercially available or can be prepared according to standard literature procedures by those skilled in the art of organic synthesis.
  • Reaction Scheme I depicts the synthesis of compounds of formula I.
  • Treatment of an appropriately substituted oxirane derivative of formula IV with an appropriate amine of formula III, in an appropriate solvent, such as toluene, thfluoroethanol or acetonitrile, within a temperature range of approximately room temperature to 150 0 C for a period of approximately 30 minutes to 24 hours provides the corresponding ester compound of formula II.
  • the group C(O)OR in compounds of formula IV and Il represents an appropriate ester moiety wherein R is preferably a lower alkyl group such as methyl or ethyl.
  • Preferred conditions for reacting the oxirane compound of formula IV with the amine of formula III to provide compounds of formula Il include carrying out the reaction in toluene at room temperature in the presence of lithium perchlorate for 12 to 24 hours followed by an extractive workup.
  • the oxirane compound of formula IV can be reacted with the amine of formula III in an appropriate solvent such as acetonitrile or thfluoroethanol under microwave irradiation to provide the compound of formula II.
  • hydroxy groups in intermediates useful for preparing compounds of Formula I may be protected by conventional protecting groups known to those skilled in the art, as required.
  • intermediates containing a hydroxy group may be protected as the corresponding benzyloxy ether and subsequently deprotected by hydrogenation to provide the free hydroxy derivative.
  • Suitable protecting groups and methods for their removal are illustrated in Protective Groups in Organic Synthesis, 3 rd Ed., Theodora W. Greene, and Peter G. M. Wuts (John Wiley & Sons, 1999).
  • the term "patient in need of treatment thereof means humans and other animals who have or are at risk of having a disease or disorder characterized by abnormal bone or mineral homeostasis.
  • the "patient in need of treatment thereof may have or be at risk of having a disease or disorder characterized by abnormal bone or mineral homeostasis selected from the group consisting of osteoporosis, osteopenia, periodontal disease, Paget's disease, bone fracture, osteoarthritis, rheumatoid arthritis, and humoral hypercalcemia of malignancy.
  • a preferred patient is a female, and particularly a postmenopausal female human.
  • the term “treating”, “treat” or “treatment” as used herein includes preventative (e.g., prophylactic), palliative, adjuvant and curative treatment.
  • the treatment of osteoporosis means that a patient having osteoporosis or at risk of having osteoporosis can be treated according to the methods described herein.
  • a resulting reduction in the incidence of the disease state being preventively treated is the measurable outcome of the preventative treatment.
  • the present invention provides methods of treating osteopenia and osteoporosis by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
  • Osteopenia is a thinning of the bones, but less than is seen with osteoporosis and is the stage before true osteoporosis.
  • the World Health Organization has developed diagnostic categories based on bone mass density (BMD) to indicate if a person has normal bones, has osteopenia or has osteoporosis. Normal bone density is within one standard deviation (+1 or -1 ) of the young adult mean bone density.
  • Osteopenia (low bone mass) is defined as bone density of 1 to 2.5 standard deviations below the young adult mean (-1 to -2.5), and osteoporosis is defined as a bone density that is 2.5 standard deviations or more below the young adult mean (>-2.5).
  • Bone fractures can be a fracture to any bone in the body, and hip fracture being of particular concern. Hip fracture has a significant impact on medical resources and patient morbidity and mortality. Few patients admitted with a hip fracture are considered for prophylactic measures aimed at the reduction of further fracture risk. Currently, 10-13% of patients will later sustain a second hip fracture. Of patients who suffered a second hip fracture, fewer patients maintained their ability to walk independently after the second fracture than did so after the first (53 and 91 % respectively, PO.0005). Pearse E.O. et al., Injury, 2003, 34(7), 518-521.
  • Second hip fracture has a significant further impact on patients' mobility and social independence. It is therefore desirable to have new methods for the treatment of bone fractures including hip fracture.
  • the compounds of Formula I can be administered together with additional agents which are useful for treating a disease or disorder characterized by abnormal bone or mineral homeostasis.
  • additional agents include calcium receptor antagonists other than those of Formula I, selective estrogen receptor modulators (SERMs), bisphosphonates, parathyroid hormone (PTH) and fragments and analogues thereof, estrogens, calcitonins, synthetic steroids, synthetic isoflavones, vitamin D analogues, vitamin K analogues, strontium salts, cathepsin K inhibitors, ⁇ v ⁇ 3 integrin (vitronectin) antagonists, prostaglandin (PGE2) receptor agonists and receptor activator of nuclear factor KB ligand (RANKL) inhibitors.
  • SERMs selective estrogen receptor modulators
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • synthetic steroids synthetic isoflavones
  • vitamin D analogues vitamin K analogues
  • Additional calcium receptor antagonists that can be used together with compounds of Formula I in the methods and compositions of this invention include those described in PCT International Publication Nos. WO 93/04373; WO 94/18959; WO 95/11211 ; WO 97/37967; WO 98/44925; WO 98/45255; WO 99/51241 ; WO 99/51569; WO 00/45816; WO 02/14259; WO 02/38106; WO 2004/041755; and WO 2005/030746; Nemeth, E. F.; Journal of Molecular Endocrinology (2002) 29, 15-21 ; Kessler, A. et al.; ChemBioChem (2004) 5, 1131 ; Steddon, SJ.
  • SERMs that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, lasofoxifene (Fablyn®), raloxifene (Evista®), arzoxifene, ospemifene, Chiesi's CHF-4227 and Prostrakan's PSK-3471.
  • Bisphosphonates that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, tiludronate (Skelid®), clondronate (Bonefos®), etidronate (Didronel®), alendronate (Fosamax®), risedronate (Actonel®), ibandronate (Boniva®), zoledronate (Zometa®), minodronate (Onobis®), neridronate and pamidronate.
  • PTH is an 84 amino acid polypeptide produced by the parathyroid gland that controls serum calcium levels through its action on various cells.
  • PTH-related proteins PTH-related proteins
  • Parathyroid hormone (PTH) and fragments and analogues thereof that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, the full length PTH (such as PTH 1 - 84, Preos®/Preotact®, Unigene's 768974, Bone Medical's BN-003), the 1-31 (such as Zelos Therapeutics' Ostabolin-C), 1-34 (such as tehparatide, Forteo®, or Ipsen's BIM-44058) or 1 -38 fragments.
  • PTH Parathyroid hormone
  • the full length PTH such as PTH 1 - 84, Preos®/Preotact®, Unigene's 768974, Bone Medical's BN-003
  • the 1-31 such as Zelos Therapeutics' Ostabolin-C
  • 1-34 such as tehparatide, Forteo®, or Ipsen's BIM-44058
  • Estrogens that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, estradiol, conjugated equine estrogens (Wyeth's Premarin®) or other estrogens.
  • Calcitonin is a 32 amino-acid peptide hormone produced by the thyroid gland which inhibits osteoclast activity by binding to calcitonin receptors on the surface of those cells.
  • Calcitonins that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, human calcitonin or salmon or eel calcitonins.
  • the calcitonins may be used as injectable or intranasal formulations such as Miacalcin®, Miacalcic®, Calcitonia®, Fortical® or Elcitonin® or as oral formulations such as Novartis' SMC-021 , Bone Medical's BN-002 (Capsitonin®) or Nobex's NCT-025 (Oratonin®).
  • Synthetic steroids that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, mixed estrogen and progesterone agonists such as tibolone which is marketed as Livial®.
  • Synthetic isoflavones are chemically synthesized derivatives of plant isoflavones, such as phytoestrogens extracted from soy products.
  • a synthetic isoflavone that can be used together with compounds of Formula I in the methods and compositions of this invention includes, but is not limited to, ipraflavone which is marketed by Takeda as Iprosten® and Osten®.
  • Vitamin D analogues are compounds that act by binding to the nuclear vitamin D receptor in osteoblasts.
  • Vitamin D analogues that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, Chugai's ED-71 and Deltanoid's 2MD.
  • Cathepsin K inhibitors that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, Novartis's AAE-
  • An ⁇ v ⁇ 3 integrin (vitronectin) antagonist that can be used together with compounds of Formula I in the methods and compositions of this invention includes, but is not limited to, Merck's MRL-123.
  • Prostaglandin E2 (PGE2) receptor agonists that can be used together with compounds of Formula I in the methods and compositions of this invention include, but are not limited to, PGE2 subtype 2 (EP2) receptor agonists, such as (3- ⁇ [4-Tert-butyl-benzyl)-(pyhdine-3-sulfonyl)-amino]- methyl ⁇ -phenoxy)-acetic acid, or a pharmaceutically acceptable salt thereof or PGE2 subtype 4 (EP4) receptor agonists, such as ONO-4819.
  • a receptor activator of nuclear factor KB ligand (RANKL) inhibitor that can be used together with compounds of Formula I in the methods and compositions of this invention includes, but is not limited to, Amgen's RANKL antibody AMG-162.
  • Specific combinations of particular interest include compounds of Formula I and lasofoxifene or compounds of Formula I and (3- ⁇ [4-Tert-butyl- benzyl)-(pyhdine-3-sulfonyl)-amino]-methyl ⁇ -phenoxy)-acetic acid, or a pharmaceutically acceptable salt thereof.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products.
  • the compounds may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying.
  • Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the total daily dosage of the compound of formula l/salt/solvate (active ingredient) will, generally, be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.
  • the total daily dose may be administered in single or divided doses.
  • the present invention also encompasses sustained release compositions.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension; for parenteral injection as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream; or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • the dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray- dried dispersion, such as those described by Takeuchi, H., et al. in "Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent depostion method and disintegrants" J. Pharm. Pharmacol., 39, 769-773 (1987).
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1 % and 100% (w/w) active ingredient.
  • a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.
  • additional agents include selective estrogen receptor modulators (SERMs), bisphosphonates, parathyroid hormone (PTH) and fragments and analogues thereof, estrogens, calcitonins, synthetic steroids, synthetic isoflavones, vitamin D analogues, vitamin K analogues, strontium salts, cathepsin K inhibitors, ⁇ v ⁇ 3 integrin (vitronectin) antagonists, prostaglandin (PGE2) receptor agonists and receptor activator of nuclear factor KB ligand (RANKL) inhibitors, such as those described hereinabove.
  • SERMs selective estrogen receptor modulators
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • RTKL nuclear factor KB ligand
  • Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
  • Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue- penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed below.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • a composition of the present invention can be administered by a variety of methods known in the art. The route and/or mode of administration vary depending upon the desired results.
  • the active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydhdes, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, (1978). Pharmaceutical compositions are preferably manufactured under GMP conditions.
  • compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1 ,3-butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • PTH secretion can be measured using techniques known in the art (see, e.g., U.S. 6,031 ,003, hereby incorporated by reference). For example, PTH secretion can be measured by first suspending cells in parathyroid cell buffer containing 0.5 mM CaCI 2 and 0.1 % bovine serum albumin. Incubations can be performed in plastic tubes (Falcon 2058) containing 0.3 ml_ of the cell suspension with or without small volumes of CaCI 2 and/or organic polycations. After incubation at 37 0 C, typically 30 minutes, the tubes can then be placed on ice and the cells pelleted at 2 0 C.
  • parathyroid cell buffer containing 0.5 mM CaCI 2 and 0.1 % bovine serum albumin.
  • Incubations can be performed in plastic tubes (Falcon 2058) containing 0.3 ml_ of the cell suspension with or without small volumes of CaCI 2 and/or organic polycations. After incubation at 37 0 C, typically 30 minutes, the
  • Samples of the supernatant should then be brought to pH 4.5 with acetic acid and, if needed, stored at - 70 0 C.
  • the amount of PTH in bovine cell supernatants can be determined by a homologous radioimmunoassay using GW-1 antibody or its equivalent at a final dilution of 1/45,000.
  • 1251-PTH 65-84; INCSTAR, Stillwater, Minn.
  • Counting of samples and data reduction can be performed on a Packard Cobra 5005 gamma counter.
  • Formula I include the FLIPR Assay for Evaluating the Potency and Selectivity of Test Compounds; Assay for Evaluating the Effects of Test Compounds on Endogenous PTH Secretion; Evaluation of Effects of Test Compounds on PTH Secretion In Vivo; Effect of Calcium Receptor Antagonist Compound of Formula I on Body Weight, Body Composition and Bone Density in the Aged Intact and Ovahectomized Female Rat; and Fracture Healing Assays as described below.
  • FLIPR Assay for Evaluating the Potency and Selectivity of Test Compounds Human kidney cell (HEK 293) expressing the calcium receptor (CasR) are used to detect antagonists of the receptor using Fluoromethc imaging plate reader (FLIPR, Molecular Devices, Sunnyvale CA). Receptor activation by extracellular calcium results in the release of calcium from intracellular stores into the cytosol.
  • a fluorescent indicator (Fluo-4) is internalized by the cells from growth media and interacts with calcium released into the cytosol to provide a means of quantifying intracellular Ca 2+ levels and receptor agonism/antagonism. Fluorescence intensity is detected by the FLIPR CCD camera and traced as a function of time. Potential antagonists are identified by their ability to decrease this fluorescent response.
  • test compound for example the compound of Example 1
  • IC 5 O values are based on the ability of the cells to inhibit the Ca 2+ induced increase in intracellular Ca 2+ .
  • Fluorescence signal is read 42 seconds after the stimulation of the CasR by the addition of 1.7 mM Ca 2+ .
  • Test compounds are given to the animals by various routes of administration including subcutaneous injection, or intraveneous injection. Serum or plasma PTH concentrations are examined before and after dosing at various times using a commercially available rat intact PTH ELISA kit (Immutopics, Inc. San Clemente, CA. Cat.#60-2500).
  • test compositions comprising compounds of Formula I in aged intact or ovariectomized (OVX) female rat model.
  • the compound of Formula I can be administered as a pharmaceutically acceptable salt or prodrug thereof.
  • Sprague-Dawley female rats are sham-operated or OVX at 18 months of age, while a group of rats is necropsied at day 0 to serve as baseline controls.
  • the rats are treated with either vehicle or test compound of Formula I, or a combination of test compound of Formula I and other active agent test compound for 59 days.
  • the vehicle or test compound of Formula I is administered either orally, by oral gavage, or by subcutaneous injection (s. ⁇ ), with the test compound being administered at a therapeutically effective dose.
  • mice All rats are given s.c. injection of 10 mg/kg of calcein (Sigma, St. Louis, MO) for fluorescent bone label 2 and 12 days before necropsy. On the day of necropsy, all rats under ketamine/xylazine anesthesia are weighed and undergoe dual-energy X-ray absorptiometry (DXA, QDR-4500/W, Hologic Inc., Waltham, MA) equipped with Rat Whole Body Scan software for lean and fat body mass determination. The rats are necropsied, then autopsied and blood is obtained by cardiac puncture.
  • DXA dual-energy X-ray absorptiometry
  • pQCT peripheral quantitative computerized tomography
  • volumetric total, trabecular and cortical bone mineral content and density are determined.
  • Peripheral Quantitative Computerized Tomography (pQCT) Analysis Excised femurs are scanned by a pQCT X-ray machine (Stratec XCT Research M, Norland Medical Systems, Fort Atkinson, Wl.) with software version 5.40.
  • a 1 millimeter (mm) thick cross section of the femur metaphysis is taken at 5.0 mm (proximal femoral metaphysis, a primary cancellous bone site) and 13 mm (femoral shafts, a cortical bone site) proximal from the distal end with a voxel size of 0.10 mm.
  • Cortical bone is defined and analyzed using contour mode 2 and cortical mode 4.
  • An outer threshold setting of 340 mg/cm 3 is used to distinguish the cortical shell from soft tissue and an inner threshold of 529 mg/cm 3 to distinguish cortical bone along the endocortical surface.
  • Trabecular bone is determined using peel mode 4 with a threshold of 655 mg/cm 3 to distinguish (sub)cortical from cancellous bone.
  • An additional concentric peel of 1 % of the defined cancellous bone is used to ensure that (sub)cortical bone was eliminated from the analysis.
  • Volumetric content, density, and area are determined for both trabecular and cortical bone (Jamsa T. et al., Bone 23:155-161 , 1998; Ke, H.Z. et al., Journal of Bone and Mineral Research, 16:765-773, 2001 ).
  • Group IV OVX + Test Compound of Formula I (in Vehicle)
  • Group V OVX + Test Compound of Formula I and Additional Active Agent
  • Fracture Healing Assays Assay For Effects On Fracture healing After Systemic Administration Fracture Technique: Sprague-Dawley rats at 3 months of age are anesthetized with Ketamine. A 1 cm incision is made on the anteromedial aspect of the proximal part of the right tibia or femur. The following describes the tibial surgical technique. The incision is carried through to the bone, and a 1 mm hole is drilled 4 mm proximal to the distal aspect of the tibial tuberosity 2 mm medial to the anterior ridge.
  • Intramedullary nailing is performed with a 0.8 mm stainless steel tube (maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the same conditions as the bones). No reaming of the medullary canal is performed. A standardized closed fracture is produced 2 mm above the tibiofibular junction by three-point bending using specially designed adjustable forceps with blunt jaws. To minimize soft tissue damage, care is taken not to displace the fracture. The skin is closed with monofilament nylon sutures. The operation is performed under sterile conditions. Radiographs of all fractures are taken immediately after nailing, and rats with fractures outside the specified diaphyseal area or with displaced nails are excluded.
  • the remaining animals are divided randomly into the following groups with 10 - 12 animals per each subgroup per time point for testing the fracture healing.
  • 10 - 12 rats from each group are anesthetized with Ketamine and sacrificed by exsanguination. Both tibiofibular bones are removed by dissection and all soft tissue is stripped.
  • Bones from 5 - 6 rats for each group are stored in 70% ethanol for histological analysis, and bones from another 5 - 6 rats for each group are stored in a buffered Ringer's solution (+4 0 C, pH 7.4) for radiographs and biomechanical testing which is performed.
  • Sirius red stained sections are used to demonstrate the characteristics of the callus structure and to differentiate between woven bone and lamellar bone at the fracture site. The following measurements are performed: (1 ) fracture gap - measured as the shortest distance between the cortical bone ends in the fracture, (2) callus length and callus diameter, (3) total bone volume area of callus, (4) bony tissue per tissue area inside the callus area, (5) fibrous tissue in the callus, and (6) cartilage area in the callus.
  • Biomechanical Analysis The methods for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats. Calcif Tissue lnt 45:292-297, 1989). Briefly, radiographs of all fractures are taken prior to the biomechanical test. The mechanical properties of the healing fractures are analyzed by a destructive three- or four-point bending procedure. Maximum load, stiffness, energy at maximum load, deflection at maximum load, and maximum stress are determined.
  • a calcium receptor antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of osteoporosis.
  • a calcium receptor antagonist particularly a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from: selective estrogen receptor modulators (SERMs), bisphosphonates, parathyroid hormone (PTH) and fragments and analogues thereof, estrogens, calcitonins, synthetic steroids, synthetic isoflavones, vitamin D analogues, vitamin K analogues, strontium salts, cathepsin K inhibitors, ⁇ v ⁇ 3 integrin (vitronectin) antagonists, prostaglandin (PGE2) receptor agonists and receptor activator of nuclear factor KB ligand (RANKL) inhibitors as described hereinabove.
  • SERMs selective estrogen receptor modulators
  • PTH parathyroid hormone
  • PTH parathyroid hormone
  • synthetic steroids synthetic isoflavones
  • vitamin D analogues vitamin K analogues
  • strontium salts cathepsin
  • TLC thin layer chromatography
  • Rf is the distance traveled by a compound divided by the distance travelled by the solvent front on a TLC plate.
  • HPLC high performance liquid chromatography.
  • (+)-DIP-ChlorideTM is 1 IpC 2 BCI (derived from (-)- ⁇ - pinene), DIP-Chloride is a trademark of Sigma-Aldrich Corporation, 50.0 g) was dissolved in dry THF (200 ml_) under argon and cooled to -25 0 C. Bromoacetophenone (20.7 g) was then added and the resulting reaction mixture stirred at ⁇ -25 0 C for 5 hours. Solvent was removed under reduced pressure and the residue redissolved in diethyl ether (500 ml_). Diethanolamine (24 g) was then added and the reaction mixture stirred at ambient temperature overnight.
  • reaction mixture was degassed for -10 min and then heated at reflux for 3h. The mixture was cooled to room temperature and stirred 60 h then was concentrated in vacuo. Water and EtOAc were added to the mixture and the mixture was extracted three times with EtOAc. The organic layer was washed with water, brine, dried and concentrated to give the crude product which was purified by flash chromatography (EtOAc/heptane gradient) to afford the desired product as a yellow viscous liquid ( 7.66 g, 68%).
  • EtOH (20 mL) was added to KOH (1.47 g) and stirred until the KOH dissolved.
  • a solution of 2-Methyl-benzenethiol (3.11 g) in EtOH (20 mL) was then added and the resulting solution was stirred 40 min at room temperature.
  • Methyl iodide (1.6 mL) was added via syringe and a white precipitate formed immediately. The mixture was stirred at room temp 3h. The white solid was filtered off and washed with EtOH. The filtrate was concentrated in vacuo to give a white gummy solid, which was dissolved in EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc.
  • Bromine (9.9 ml_) was added dropwise to a solution of 2- fluorothioanisole (27.5 g) in CH 2 CI 2 (190 ml_) at 0 0 C.
  • the resulting solution was stirred at room temperature overnight.
  • Half-saturated sodium thiosulfate was added to quench the reaction and the reaction mixture was stirred vigorously for 10 min.
  • the layers were separated and the aqueous layer was washed three more times with CH 2 CI 2 . .
  • the combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to afford the desired product as a light yellow oil (41 g, 9:1 mix of product to starting material).
  • the crude material was carried forward without further purification.
  • Methylmagnesium bromide (100 ml_, 3.0 M in Et 2 O) was added dropwise to cyclohexyl-acetic acid methyl ester (16.4 ml_, 100 mmol) in THF (200 ml_) at 0 ° C and the mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was cooled to 0 0 C, quenched with sat. aq. NH 4 CI (200 ml_), diluted with water, and extracted with EtOAc (3x 400 ml_). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo to provide the desired product as a clear oil (15.8 g, 101 %).
  • N-(2-Bicyclo[2.2.1]hept- 2-yl-1 ,1-dimethyl-ethyl)-2-chloro-acetamide (12 g) was prepared from 1 - Bicyclo[2.2.1]hept-2-yl-2-methyl-propan-2-ol (Preparation 22, 7.6 g).
  • the following table provides FLIPR IC50 data for the specified Examples. The IC 50s are reported as micromolar concentration with n being the number of times the particular compound was assayed.

Abstract

La présente invention porte sur de nouveaux dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique et sur leurs sels pharmaceutiquement acceptables de formule structurale I, dans laquelle la variable R1 est telle que décrite dans l'invention. L'invention porte également sur des compositions pharmaceutiques comprenant les composés de formule (I) ainsi que sur des méthodes de traitement faisant appel à des composés de formule (I) pour traiter une maladie ou un trouble caractérisé par une anomalie de l'homéostase osseuse ou minérale tel que l'hypoparathyroïdisme, l'ostéoporose, l'ostéopénie, la paradontopathie, la maladie osseuse de Paget, les fractures osseuses, l'ostéoarthrite, l'arthrite rhumatoïde et l'hypercalcémie humorale maligne.
PCT/IB2010/050911 2009-03-10 2010-03-03 Dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique utiles en tant qu'antagonistes des récepteurs du calcium WO2010103429A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15887009P 2009-03-10 2009-03-10
US61/158,870 2009-03-10

Publications (1)

Publication Number Publication Date
WO2010103429A1 true WO2010103429A1 (fr) 2010-09-16

Family

ID=42062608

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/050911 WO2010103429A1 (fr) 2009-03-10 2010-03-03 Dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique utiles en tant qu'antagonistes des récepteurs du calcium

Country Status (1)

Country Link
WO (1) WO2010103429A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106029662A (zh) * 2013-12-20 2016-10-12 默沙东公司 新型三环钙敏感受体拮抗剂
CN110357850A (zh) * 2018-03-26 2019-10-22 广东东阳光药业有限公司 一种含硫杂环化合物的制备方法

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993004373A1 (fr) 1991-08-23 1993-03-04 Nps Pharmaceuticals, Inc. Molecules agissant sur les recepteurs de calcium
WO1994018959A1 (fr) 1993-02-23 1994-09-01 Brigham And Women's Hospital, Inc. Molecules actives sur les recepteurs du calcium
WO1995011211A1 (fr) 1993-10-22 1995-04-27 Ihara Chemical Industry Co., Ltd. Derive de propane-2,2-bis(4-hydroxyphenyle-3,5-disubstitute), procede pour produire ce compose et procede pour produire du pyrogallol a partir de ce compose
WO1997037967A1 (fr) 1996-04-09 1997-10-16 Nps Pharmaceuticals, Inc. Composes calcilytiques
WO1998044925A1 (fr) 1997-04-04 1998-10-15 Smithkline Beecham Corporation Composes calcilytiques
WO1998045255A1 (fr) 1997-04-08 1998-10-15 Smithkline Beecham Corporation Composes calcilytiques
WO1999051241A1 (fr) 1998-04-08 1999-10-14 Smithkline Beecham Corporation Composes calcilytiques et leur utilisation
WO1999051569A1 (fr) 1998-04-08 1999-10-14 Smithkline Beecham Corporation Composes calcilytiques
US6011068A (en) 1991-08-23 2000-01-04 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
WO2000045816A1 (fr) 1999-02-02 2000-08-10 Smithkline Beecham Corporation Composes calcilytiques
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
WO2002014259A1 (fr) 2000-08-11 2002-02-21 Japan Tobacco Inc. Antagonistes du recepteur de calcium
WO2002038106A2 (fr) 2000-10-25 2002-05-16 Smithkline Beecham Corporation Composes calcilytiques
WO2002059102A2 (fr) 2001-01-26 2002-08-01 Aventis Pharma S.A. Derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et utilisation
WO2004041755A2 (fr) 2002-11-04 2004-05-21 Nps Pharmaceuticals, Inc. Composes de quinazolinone utilises comme calcilytiques
WO2005030746A1 (fr) 2003-09-24 2005-04-07 Glaxo Group Limited Composes calcilytiques
EP1619180A1 (fr) * 2003-04-23 2006-01-25 Japan Tobacco Inc. ANTAGONISTE DE CaSR

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6011068A (en) 1991-08-23 2000-01-04 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
WO1993004373A1 (fr) 1991-08-23 1993-03-04 Nps Pharmaceuticals, Inc. Molecules agissant sur les recepteurs de calcium
WO1994018959A1 (fr) 1993-02-23 1994-09-01 Brigham And Women's Hospital, Inc. Molecules actives sur les recepteurs du calcium
WO1995011211A1 (fr) 1993-10-22 1995-04-27 Ihara Chemical Industry Co., Ltd. Derive de propane-2,2-bis(4-hydroxyphenyle-3,5-disubstitute), procede pour produire ce compose et procede pour produire du pyrogallol a partir de ce compose
US6211244B1 (en) 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
WO1997037967A1 (fr) 1996-04-09 1997-10-16 Nps Pharmaceuticals, Inc. Composes calcilytiques
WO1998044925A1 (fr) 1997-04-04 1998-10-15 Smithkline Beecham Corporation Composes calcilytiques
WO1998045255A1 (fr) 1997-04-08 1998-10-15 Smithkline Beecham Corporation Composes calcilytiques
WO1999051241A1 (fr) 1998-04-08 1999-10-14 Smithkline Beecham Corporation Composes calcilytiques et leur utilisation
WO1999051569A1 (fr) 1998-04-08 1999-10-14 Smithkline Beecham Corporation Composes calcilytiques
WO2000045816A1 (fr) 1999-02-02 2000-08-10 Smithkline Beecham Corporation Composes calcilytiques
WO2002014259A1 (fr) 2000-08-11 2002-02-21 Japan Tobacco Inc. Antagonistes du recepteur de calcium
WO2002038106A2 (fr) 2000-10-25 2002-05-16 Smithkline Beecham Corporation Composes calcilytiques
WO2002059102A2 (fr) 2001-01-26 2002-08-01 Aventis Pharma S.A. Derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et utilisation
WO2004041755A2 (fr) 2002-11-04 2004-05-21 Nps Pharmaceuticals, Inc. Composes de quinazolinone utilises comme calcilytiques
EP1619180A1 (fr) * 2003-04-23 2006-01-25 Japan Tobacco Inc. ANTAGONISTE DE CaSR
WO2005030746A1 (fr) 2003-09-24 2005-04-07 Glaxo Group Limited Composes calcilytiques

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Sustained and Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
BAK; ANDREASSEN: "The Effects of Aging on Fracture Healing in Rats", CALCIF TISSUE INT, vol. 45, 1989, pages 292 - 297
E L ELIEL: "Stereochemistry of Organic Compounds", 1994, WILEY
H BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
JAMSA T. ET AL., BONE, vol. 23, 1998, pages 155 - 161
KE, H.Z. ET AL., JOURNAL OF BONE AND MINERAL RESEARCH, vol. 16, 2001, pages 765 - 773
KESSLER, A. ET AL., CHEMBIOCHEM, vol. 5, 2004, pages 1131
MOSEKILDE; BAK: "The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description", BONE, vol. 14, 1993, pages 19 - 27
NEMETH, E.F., JOUMAL OF MOLECULAR ENDOCRINOLOGY, vol. 29, 2002, pages 15 - 21
NEMETH, E.F., JOURNAL OF MOLECULAR ENDOCRINOLOGY, vol. 29, 2002, pages 15 - 21
PEARSE E.O. ET AL., INIURV, vol. 34, no. 7, 2003, pages 518 - 521
SHCHERBAKOVA, I. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 1557 - 1560
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
STEDDON, S.J. ET AL., LANCET, vol. 365, 2005, pages 2237 - 2239
T HIGUCHI; W STELLA: "Pro-drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14
TAKEUCHI, H. ET AL.: "Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent depostion method and disintegrants", J. PHARM. PHARMACOL., vol. 39, 1987, pages 769 - 773
THEODORA W. GREENE; PETER G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106029662A (zh) * 2013-12-20 2016-10-12 默沙东公司 新型三环钙敏感受体拮抗剂
CN110357850A (zh) * 2018-03-26 2019-10-22 广东东阳光药业有限公司 一种含硫杂环化合物的制备方法

Similar Documents

Publication Publication Date Title
US7829572B2 (en) Pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as calcium receptor antagonists
CA2976634C (fr) Derives d'acide nonanoique tetrahydronaphthyridinyle fluores et leurs utilisations
EP0724561B1 (fr) Arylalkylamines agissant sur les recepteurs du calcium
EP2511273B1 (fr) Inhibiteurs de la réplication virale, leur procédé de préparation et leurs utilisations thérapeutiques
Kiefer et al. Design and synthesis of cyclic sulfonamides and sulfamates as new calcium sensing receptor agonists
EP2968330B1 (fr) Composés et procédés pour l'induction de la chondrogenèse
WO2019240938A1 (fr) Agonistes du récepteur de l'hormone thyroïdienne et utilisations associées
AU2011269067B2 (en) 6,7-Dihydro-5H-benzo[7]annulene derivatives, process for preparation thereof, pharmaceutical preparations comprising them, and the use thereof for production of medicaments
PL192670B1 (pl) Agoniści prostaglandyny, ich zastosowanie i środek farmaceutyczny
US7109203B2 (en) Sulfonamide derivatives
Chegaev et al. Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents
CZ301729B6 (cs) Nesteroidní ligandy estrogenového receptoru
SK11822003A3 (sk) N-fenpropylcyklopentylom substituované glutaramidové deriváty ako NEP inhibítory pre FSAD
UA69372C2 (en) Pharmaceutical compositions useful for treatment of bone disorders with decreasing mass of bone tissue (variants) and pharmaceutical kit for treatment (variants)
JP2015500814A (ja) ６，７−ジヒドロ−５ｈ−ベンゾ［７］アヌレン誘導体、その製造方法、それを含む医薬製品および医薬の製造のためのその使用
US10251868B2 (en) Benzothiazolone compound
TW200821276A (en) Substituted acetylenic compounds useful for the treatment of diseases
US11339124B2 (en) 3-(benzylamino)-4-(cyclohexylamino)-n-(2-(piperazin-1-yl)ethyl)benzenesulfonamide derivatives and related ferrostatin-1 analogues as cell death inhibitors for treating e.g. stroke
EP4103572A1 (fr) Préparation d'un antagoniste p2x3
WO2010103429A1 (fr) Dérivés de l'acide 1,1-(diméthyl-éthylamino)-2-hydroxy-propoxy]-éthyl}-3-méthyl-biphényl-4-carboxylique utiles en tant qu'antagonistes des récepteurs du calcium
SG178835A1 (en) Co-crystals of tramadol and coxibs
US9499488B2 (en) Vitamin D receptor agonists and uses thereof
CN101862317A (zh) 用于治疗纤维肌痛和其它疾病的普加巴林衍生物
JP2023531097A (ja) テトラヒドロイソキノリン類誘導体の塩、その製造方法及びその医薬学的応用
Kress Synthesis of Novel Small Molecule PPARδ Agonists for Controlling Mesenchymal Stem Cell Osteogenesis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10708815

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10708815

Country of ref document: EP

Kind code of ref document: A1