WO2009055631A1 - Composés calcilytiques - Google Patents

Composés calcilytiques Download PDF

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Publication number
WO2009055631A1
WO2009055631A1 PCT/US2008/081044 US2008081044W WO2009055631A1 WO 2009055631 A1 WO2009055631 A1 WO 2009055631A1 US 2008081044 W US2008081044 W US 2008081044W WO 2009055631 A1 WO2009055631 A1 WO 2009055631A1
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Prior art keywords
compound according
inden
dimethylethyl
dihydro
amino
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Linda N. Casillas
Joshi M. Ramanjulu
Robert W. Marquis, Jr.
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds, processes for their preparation and their use as calcium receptor antagonists.
  • extracellular Ca ⁇ + In mammals, extracellular Ca ⁇ + is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
  • Extracellular Ca ⁇ + 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 ⁇ + concentration.
  • PTH is the principal endocrine factor regulating Ca ⁇ + homeostasis in the blood and extracellular fluids.
  • PTH by acting on bone and kidney cells, increases the level of Ca ⁇ + in the blood. This increase in extracellular Ca ⁇ + then acts as a negative feedback signal, depressing PTH secretion.
  • the reciprocal relationship between extracellular Ca ⁇ + and PTH secretion forms an important mechanism maintaining bodily Ca ⁇ + homeostasis.
  • Extracellular Ca ⁇ + acts directly on parathyroid cells to regulate
  • this protein acts as a receptor for extracellular Ca , detects changes in the ion concentration of extracellular Ca ⁇ + , and initiates a functional cellular response, PTH secretion.
  • Extracellular Ca ⁇ + influences various cell functions, reviewed in Nemeth et al., Cell Calcium 1 1 :319, 1990.
  • extracellular Ca ⁇ + plays a role in parafollicular (C- cells) and parathyroid cells.
  • C- cells parafollicular cells
  • parathyroid cells See Nemeth, Cell Calcium 1 1 :323, 1990.
  • the role of extracellular Ca ⁇ + 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 ⁇ + .
  • Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca ⁇ + 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 ⁇ + 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, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • the present invention relates to calcium receptor antagonists represented by Formula (I), indicated hereinbelow, compositions comprising the present compounds, and their use 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, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • diseases associated with abnormal bone or mineral homeostasis including but not limited to, hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • the present invention further provides a method for antagonizing calcium receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated hereinbelow.
  • the present invention further provides a method for increasing serum parathyroid levels in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I) indicated hereinbelow.
  • the present invention further provides methods for preparing compounds of Formula (I). DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to novel compounds according to Formula (I):
  • R is a heteroaryl moiety selected from the group consisting of thienyl, thiazolyl, benzothiazolyl, benzothienyl, benzimidazolyl, and pyridinyl, optionally substituted, independently, once or twice, by a substituent selected from the group consisting of C 1-2 alkyl, halogen, pyridinyl, pyrazinyl, benzoic acid and propanoic acid; or a pharmaceutically acceptable salt thereof.
  • C 1-2 alkyl refers to a linear, saturated hydrocarbon group containing 1 to 2 carbon atoms. Examples of such groups include methyl and ethyl.
  • halogen refers to F, Cl, Br or I.
  • heteroaryl refers to a 5-10 membered monocyclic or bicyclic aromatic ring system containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
  • monocylic aromatic rings include thienyl, thiazolyl, pyridinyl, and the like.
  • bicyclic aromatic rings include benzothiazolyl, benzothienyl, benzimidazolyl, and the like.
  • R is a heteroaryl moiety selected from the group consisting of thienyl, thiazolyl, benzothiazolyl, benzothienyl, benzimidazolyl and pyridinyl, optionally substituted, independently, once or twice, by a substituent selected from the group consisting of Ci -2 alkyl, halogen, pyridinyl, pyrazinyl, benzoic acid and propanoic acid.
  • R is thienyl.
  • R is 2-thienyl. In another embodiment, R is 3-thienyl.
  • R is thienyl, substituted once by halogen, pyridinyl, benzoic acid or propanoic acid. In another embodiment, R is thienyl, substituted once by halogen.
  • R is thienyl, substituted once by Br. In another embodiment, R is thienyl, substituted once by Cl.
  • R is thienyl, substituted once by pyridinyl. In another embodiment, R is 2-thienylpyridinyl.
  • R is thienyl, substituted once by benzoic acid.
  • R is 3-thienylbenzoic acid.
  • R is thienyl, substituted once by propanoic acid. In another embodiment, R is 3-thienylpropanoic acid.
  • R is thienyl, substituted twice, independently, by halogen.
  • R is thienyl, substituted twice, independently, by Br or Cl.
  • R is 4-bromo-5-chlorothienyl.
  • R is thiazolyl. In another embodiment, R is 1 ,3-thiazol-2-yl.
  • R is 1 ,3-thiazol-5-yl.
  • R is thiazolyl, substituted once or twice, independently, by Ci -2 alkyl or pyrazinyl.
  • R is substituted by methyl and pyrazinyl.
  • R is 4-methyl-2-(2-pyrazinyl)-1 ,3-thiazol-5-yl.
  • R is pyridinyl
  • R is 3-pyridinyl
  • R is 4-pyridinyl
  • R is 2-pyridinyl. in another embodiment, R is benzothiazolyl.
  • R is 1 ,3-benzothiazol-2-yl.
  • R is benzothienyl
  • R is 1-benzothien-2-yl.
  • R is 1-benzothien-3-yl. in another embodiment, R is 1-benzothien-6-yl.
  • R is benzimidazolyl, optionally substituted once by C 1- 2 alkyl.
  • R is methylbenzimidazolyl
  • R is 1-methyl-1 H-benzimidazol-2-yl.
  • Illustrative compounds of the present invention include, but are not limited to:
  • the present compound is:
  • the present compound is 1-(3-bromo-2-thienyl)-2- ⁇ [2- (2,3-dihydro-1/-/-inden-2-yl)-1 ,1-dimethylethyl]amino ⁇ ethanol or a pharmaceutically acceptable salt thereof.
  • the present compound is 1-(3-chloro-2-thienyl)-2- ⁇ [2-(2,3- dihydro-1 /-/-inden-2-yl)-1 ,1-dimethylethyl]amino ⁇ ethanol or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non- pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • the compounds of the present invention 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.
  • crystalline forms of the present compounds may exist as polymorphs, which are included in the present invention.
  • salts of the compounds of Formula (I) are preferably pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic
  • a pharmaceutically acceptable acid addition salt of a compound of Formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
  • a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-to
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • a suitable solvent such as an organic solvent
  • compositions include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of Formula (I).
  • pharmaceutically acceptable metal salts for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium or magnesium salts
  • pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of Formula (I).
  • non-pharmaceutically acceptable salts eg. oxalates
  • oxalates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula (I).
  • the present compounds may be synthesized according to a process comprising the steps of: (a) reducing an alpha-halo ketone according to Formula (II):
  • the present compounds may be synthesized according to a process comprising the steps of: (a) regioselectively modifying a diol according to Formula (IV):
  • halohydrin can be readily cyclized to oxirane 2 under standard conditions such as, but not limited to, potassium carbonate in ethanol.
  • oxirane 2 Treatment of oxirane 2 with a nucleophilic amine such as, but not limited to, [2-(2,3-dihydro-1 H-inden-2-yl)-1 ,1- dimethylethyl]amine in a high boiling solvent such as, but not limited to, ethanol, yields the target amino alcohol 3.
  • a nucleophilic amine such as, but not limited to, [2-(2,3-dihydro-1 H-inden-2-yl)-1 ,1- dimethylethyl]amine in a high boiling solvent such as, but not limited to, ethanol
  • a commercially available aldehyde such as, but not limited to 4-bromo-2-thiophenecarbaldehyde 4 can be treated under standard Wittig conditions to give the alkene 5.
  • the resulting alkene can undergo asymmetric dihydroxylation under conditions common to the art, such as in the presence of AD-mix- ⁇ and tert-butyl alcohol in water to give the diol 6.
  • This diol can be regioselectively modified to give the primary tosylate under conditions common to the art such as tosyl chloride in the presence of pyridine.
  • the resulting mono-tosylate can then be converted under standard Finkelstein conditions such as sodium iodide in acetone to provide the primary iodide 7.
  • Bromothiophene 9 can be elaborated under standard Heck coupling conditions in the presence of a palladium catalyst with a suitable ligand and alkene coupling partner such as, but not limited to, ethyl acrylate to give alkene 10.
  • the alkene can be reduced under conditions common to the art such as NaBH 4 in the presence of a modifier such as, but not limited to, NiCI 2 , to give alkane 11.
  • Ester hydrolysis under standard conditions common to the art such as an aqueous solution of an inorganic base such as lithium hydroxide in an alcohol solvent such as methanol provides the target carboxylic acid 12.
  • bromothiophene 9 can be elaborated under standard Suzuki coupling conditions in the presence of a palladium catalyst with a suitable ligand, an inorganic base, such as potassium carbonate, and a boronic acid coupling partner such as, but not limited to, ⁇ 4-[(ethyloxy)carbonyl]phenyl ⁇ boronic acid to give biaryl 13.
  • a palladium catalyst with a suitable ligand, an inorganic base, such as potassium carbonate
  • a boronic acid coupling partner such as, but not limited to, ⁇ 4-[(ethyloxy)carbonyl]phenyl ⁇ boronic acid to give biaryl 13.
  • Ester hydrolysis under standard conditions common to the art such as an aqueous solution of an inorganic base such as lithium hydroxide in an alcohol solvent such as methanol provides the target carboxylic acid 14.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as 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, preferably, 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 redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • 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 IC50, EC50, 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 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 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered, for example, from 1 to 6 times per day, such as, once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment of a disease includes, but is not limited to, prevention, slowing the progression of 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, central nervous system disorders, 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 and disorders that might be treated also include diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, nephrosis, hypertension, and renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics).
  • SIADH syndrome of inappropriate ADH secretion
  • Gut motility disorders such as diarrhea and spastic colon
  • Gl ulcer diseases such as Gl diseases with excessive calcium absorption (such as sarcoidosis)
  • Autoimmune diseases, organ transplant rejection, squamous cell carcinoma and pancreatitis might also be treated by the present compounds.
  • the present 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.
  • Another aspect of the present invention describes a method of treating a patient comprising administering to the patient an amount of a present compound sufficient to increase the serum PTH level.
  • the method is carried out by administering 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.
  • the present compound is coadministered with an anti-resorptive agent.
  • Suitable anti-resorptive agents for coadministration include, but are not limited to estrogen, 1 ⁇ , 25-(OH) 2 D 3 , I a-(OH)D 3 , calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+- ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.
  • Composition 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 will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, 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, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a 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.
  • 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.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • the biological activity of the compounds of Formula (I) are demonstrated by the following tests:
  • Cells were maintained in T-150 flasks in selection media (DMEM supplemented with 10% fetal bovine serum and 200 ug/mL hygromycin B), under 5% CC>2:95% air at 37 0 C and were grown up to 90% confluency.
  • the medium was decanted and the cell monolayer was washed twice with phosphate-buffered saline (PBS) kept at 37 0 C.
  • PBS phosphate-buffered saline
  • 6 ml. of 0.02% EDTA in PBS was added and incubated for 4 minutes at 37 0 C. Following the incubation, cells were dispersed by gentle agitation. Cells from 2 or 3 flasks were pooled and pelleted (100 x g). The cellular pellet was resuspended in 10-15 ml. of SPF-PCB+ and pelleted again by centrifugation. This washing was done twice.
  • Sulfate- and phosphate-free parathyroid cell buffer contained 20 mM Na-Hepes, pH 7.4, 126 mM NaCI, 5 mM KCI, and 1 mM MgC ⁇ . 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 CaCl2 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
  • the pellet was resuspended in 10 ml. of SPF-PCB+ containing 2.2 uM fluo-3 (Molecular Probes) and incubated at room temperature for 35 minutes. Following the incubation period, the cells were pelleted by centrifugation. The resulting pellet was washed with SPF-PCB+. After this washing, cells were resuspended in SPF-PCB+ at a density of 1-2 x 10 6 cells/ml_.
  • Intracellular calcium (F-F m j n /F max ) x K ⁇ ; where K ⁇
  • 400 nM.
  • 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 ⁇ + elicited by extracellular Ca ⁇ + .
  • the present compounds were considered active at IC50 values of 10 uM or lower. The present examples were all tested. The compounds tested had an IC 50 value in a range from about 0.50 uM to about 10 uM, except for Example 21 , which tested at above 25 uM. (II) Calcium Receptor Binding Assay
  • 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 was obtained by polytron homogenization or glass douncing in buffer (50 mM Tris-HCI pH 7.4, 1 mM EDTA, 3 mM MgC ⁇ ) in the presence of a protease inhibitor cocktail containing 1 uM Leupeptin, 0.04 uM Pepstatin, and 1 mM PMSF. Aliquoted membrane was snap frozen and stored at -8O 0 C. ⁇ H labeled compound was radiolabeled to a radiospecific activity of 44Ci/mmole and was aliquoted and stored in liquid nitrogen for radiochemical stability.
  • a typical reaction mixture contained 2 nM ⁇ H compound ((R,R)-N-4'-Methoxy-t-3- 3'-methyl-1'-ethylphenyl-1-(1-naphthyl)ethylamine), or ⁇ H compound (R)-N-[2-Hydroxy-3- (3-chloro-2-cyanophenoxy)propyl]-1 ,1-dimethyl-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 was performed in 12 x 75 polyethylene tubes in an ice water bath.
  • the present compounds were considered active at IC50 values of 10 uM or lower.
  • the present examples were all tested.
  • the tested compounds had an IC 50 in a range from about 7nM to about 2uM. Examples
  • Nuclear magnetic resonance spectra were recorded at either 300 or 400 MHz using, respectively, a Bruker ARX 300 or Bruker AVANCE 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d6 is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million ( ⁇ ) downfield from the internal standard tetramethylsilane.
  • 5u Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 u, made by Jones Chromatography, Littleton, Colorado.
  • YMC ODS-AQ ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
  • PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada)
  • Celite® is a filter aid composed of acid- washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
  • Example 6 1 -(3-bromo-2-thienyl)-2-f r2-(2.3-dihvdro-1 H-inden-2-yl)-1.1 - dimethvlethvllamino ⁇ ethanol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des nouveaux composés calcilytiques, des compositions pharmaceutiques, des combinaisons pharmaceutiques, des procédés de synthèse et des procédés pour les utiliser.
PCT/US2008/081044 2007-10-25 2008-10-24 Composés calcilytiques Ceased WO2009055631A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039514B2 (en) 2008-06-05 2011-10-18 Asahi Kasei Pharma Corporation Sulfonamide compounds and use thereof
CN107485788A (zh) * 2017-08-09 2017-12-19 李世俊 一种驱动磁刺激仪线圈位置自动调整的磁共振导航装置

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6022894A (en) * 1996-04-09 2000-02-08 Nps Pharmaceuticals, Inc. Method of using calcilytic compounds
US6916956B2 (en) * 2000-08-11 2005-07-12 Japan Tobacco, Inc. Calcium receptor antagonist
US7109238B2 (en) * 2000-01-24 2006-09-19 Smith Kline Beecham Corporation Calcilytic compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6022894A (en) * 1996-04-09 2000-02-08 Nps Pharmaceuticals, Inc. Method of using calcilytic compounds
US7109238B2 (en) * 2000-01-24 2006-09-19 Smith Kline Beecham Corporation Calcilytic compounds
US6916956B2 (en) * 2000-08-11 2005-07-12 Japan Tobacco, Inc. Calcium receptor antagonist

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039514B2 (en) 2008-06-05 2011-10-18 Asahi Kasei Pharma Corporation Sulfonamide compounds and use thereof
CN107485788A (zh) * 2017-08-09 2017-12-19 李世俊 一种驱动磁刺激仪线圈位置自动调整的磁共振导航装置

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