WO2010039911A1 - Composés calcilytique - Google Patents

Composés calcilytique Download PDF

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Publication number
WO2010039911A1
WO2010039911A1 PCT/US2009/059157 US2009059157W WO2010039911A1 WO 2010039911 A1 WO2010039911 A1 WO 2010039911A1 US 2009059157 W US2009059157 W US 2009059157W WO 2010039911 A1 WO2010039911 A1 WO 2010039911A1
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Prior art keywords
benzenesulfonamide
methyl
piperazinyl
phenyloxy
ethyl
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PCT/US2009/059157
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English (en)
Inventor
Jae U. Jeong
Robert W. Marquis, Jr.
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Glaxosmithkline Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on 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
    • C07D333/02—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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 parathyroid hormone
  • 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 PTH secretion.
  • this protein acts as a receptor for extracellular Ca , detects changes in the ion concentration of extracellular Ca2 + , and initiates a functional cellular response, PTH secretion.
  • Extracellular Ca2 + influences various cell functions, reviewed in Nemeth et al., Cell Calcium 1 1 :319, 1990.
  • extracellular Ca2 + 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 Ca2 + on bone osteoclasts has also been studied. See Zaidi, Bioscience
  • Calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca2 + .
  • 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.
  • 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).
  • the present invention relates to novel compounds according to formula (I):
  • X 1 is N or CH, when s is 1 ; or O, when s is 0;
  • X 2 is N or CH
  • R 1 is H, C 1-4 alkyl, -(CH ⁇ p OC ⁇ alkyl or -C(O)OCi- 4 alkyl; m is 0 or 1 ; n is 0 or 1 ;
  • R 2 is aryl, optionally substituted, independently, one to three times, by halogen, C- ⁇ alkyl,
  • Y is CH or N; Z is CH 2 Or O; q is 0 or 1 ; and R 4 is Ci_ 4 alkyl, phenyl or pyridinyl, wherein the phenyl moiety is optionally substituted, one to three times, independently, by C 1-4 alkoxy, halogen or C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.
  • C 1-4 alkyl refers to a linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert butyl.
  • C 1-4 alkoxy refers to an C 1-4 alkyl-O- group wherein Ci -4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, or butoxy.
  • aryl refers to a C6 monocyclic or C5-12bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl, and the like.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • monocyclic aromatic rings include thienyl, furanyl, pyridinyl, and the like.
  • fused aromatic rings include benzodioxolyl, dihydrobenzodioxinyl, benzofuranyl, dihydrobenzofuranyl, and the like.
  • halogen or “halo” refers to fluoro, chloro, bromo or iodo.
  • Xi is N or CH, when s is 1 ; or O, when s is 0;
  • X 1 is N and s is 1. In another embodiment, X 1 is CH and n is 1.
  • X 1 is O and s is 0.
  • X 2 is N or CH.
  • X 2 is N.
  • X 2 is CH.
  • R 1 is H, C 1-4 alkyl, -(CH 2 ) p OC 1-4 alkyl or -C(O)OC 1-4 alkyl.
  • R 1 is H.
  • R 1 is C 1-4 alkyl.
  • R 1 is methyl
  • R 1 is -(CH 2 ) p OC 1-4 alkyl, wherein p is 2. In another embodiment, R 1 is -(CH 2 ) p Omethyl.
  • R 1 is -C(O)OC 1-4 alkyl.
  • R 1 is -C(O)Ot-butyl.
  • m is 0 or 1.
  • n is 1. In another embodiment, m is 0.
  • n is 0 or 1. In one embodiment, n is 1.
  • n 0.
  • both m and n are 0.
  • both m and n are 1.
  • R 2 represents aryl, optionally substituted, independently, one to three times, by halogen, Ci -4 alkyl, CN, OH, CF 3 , OCF 3 , phenyl, phenyloxy, or furanyl; or R 2 is heteroaryl, optionally substituted, once or twice, independently, by halogen or Ci- 4 alkyl.
  • R 2 represents heteroaryl, optionally substituted once or twice, independently, by halogen or
  • R 2 represents benzodioxolyl.
  • R 2 represents benzodioxolyl substituted by fluoro.
  • R 2 represents difluorobenzodioxolyl.
  • R 2 represents 1 ,3-benzodioxol-5-yl. In another embodiment, R 2 represents 2,2-difluoro-1 ,3-benzodioxol-5-yl.
  • R 2 represents dihydrobenzodioxinyl.
  • R 2 represents 2,3-dihydro-1 ,4-benzodioxin-6-yl.
  • R 2 represents thienyl
  • R 2 represents chlorothienyl. In another embodiment, R 2 represents 5-chlorothienyl.
  • R 2 represents 5-chloro-2-thienyl.
  • R 2 represents methylthienyl
  • R 2 represents 5-methyl-2-thienyl.
  • R 2 represents furanyl. In another embodiment, R 2 represents 2-furanyl.
  • R 2 represents benzofuranyl
  • R 2 represents 1-benzofuran-2-yl.
  • R 2 represents dihydrobenzofuranyl.
  • R 2 represents 2,3-dihydro-1-benzofuran-5-yl. In another embodiment, R 2 represents pyridinyl.
  • R 2 represents 2-pyridinyl
  • R 2 represents 3-pyridinyl.
  • R 2 represents 4-pyridinyl
  • R 2 is aryl, optionally substituted, independently, one to three times, by halogen, Ci -4 alkyl, CN, CF 3 , OCF 3 , phenyl or phenyloxy.
  • R 2 is naphthyl. In one embodiment, R 2 is phenyl.
  • R 2 is phenyl
  • R 2 is cyanophenyl
  • R 2 is 3-cyanophenyl or 4-cyanophenyl. In another embodiment, R 2 is phenyl, substituted once by halogen.
  • R 2 is phenyl, substituted once by fluoro, chloro or bromo.
  • R 2 is 2- bromophenyl, 3-bromophenyl or 4-bromophenyl.
  • R 2 is 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl.
  • R 2 is 2-fluorophenyl or 4-fluorophenyl. In another embodiment, R 2 is phenyl, substituted twice, independently, by halogen.
  • R 2 is phenyl substituted by chloro and fluoro.
  • R 2 is 4-chloro-2-fluorophenyl.
  • R 2 is 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, or 3,4-dichlorophenyl. In another embodiment, R 2 is 2,3-difluorophenyl or 3,4-difluorophenyl.
  • R 2 is trifluoromethylphenyl.
  • R 2 is 2-trifluoromethylphenyl or 4-trifluoromethylphenyl.
  • R 2 is trifluoromethoxyphenyl.
  • R 2 is 2-trifluoromethoxyphenyl. In another embodiment, R 2 is phenyl substituted by fluoro end trifluoromethyl.
  • R 2 is 2-fluoro-4-trifluoromethylphenyl.
  • R 2 is phenyl substituted by
  • R 2 is methylphenyl
  • R 2 is 2-methylphenyl or 4-methylphenyl. In another embodiment, R 2 is phenyl substituted by
  • R 2 is methoxyphenyl
  • R 2 is 2-methoxyphenyl or 4-methyloxyphenyl.
  • R 2 is phenyl substituted by fluoro and methoxy.
  • R 2 is 2-fluoro-4-methoxyphenyl or 2-fluoro-5- methoxyphenyl.
  • R 2 is phenyl substituted by fluoro and hydroxy.
  • R 2 is 2-fluoro-5-hydroxyphenyl.
  • R 2 is phenyl substituted by phenyl.
  • R 2 is 2-biphenylyl, 3-biphenylyl or 4-biphenylyl. In another embodiment, R 2 is phenyl substituted with phenyloxy.
  • R 2 is 4-phenyloxyphenyl. In another embodiment, R 2 is furanylphenyl. In another embodiment, R 2 is 2-furanylphenyl.
  • R 3 is:
  • Y is CH or N; Z is CH 2 or O; q is 0 or 1 ;
  • R 4 is Ci -4 alkyl, phenyl or pyridinyl, wherein the phenyl moiety is optionally substituted, one to three times, independently, by C 1-4 alkoxy, halogen or C 1-4 alkyl.
  • Y is N. In another embodiment, Y is CH.
  • Z is CH 2 . In another embodiment, Z is O.
  • the -Z-(CH 2 ) q -R 4 substitutent is at the 4-position of the aryl ring in R 3 . In another embodiment, the -Z-(CH 2 ) q -R 4 substitutent is at the 3-position of the aryl ring in R 3 .
  • q is O. In another embodiment, q is 1. In one embodiment, R 4 is In another embodiment, R 4 is isopropyl.
  • R 4 is butyl. In another embodiment, R 4 is pyridinyl. In another embodiment, R 4 is 2-pyridinyl or 3-pyridinyl.
  • R 4 is phenyl, optionally substituted, one to three times, by a substituent selected from Ci -4 alkoxy, halogen and Ci -4 alkyl. In another embodiment, R 4 is phenyl.
  • R 4 is phenyl substituted by Ci -4 alkoxy. In another embodiment, R 4 is methoxyphenyl. In another embodiment, R 4 is 2-methoxyphenyl. In another embodiment R 4 is phenyl, substituted by Ci -4 alkyl. In another embodiment R 4 is methylphenyl. In another embodiment, R 4 is 2-methylphenyl. In another embodiment, R 4 is phenyl substituted by halogen. In another embodiment, R 4 is fluorophenyl.
  • R 4 is 4-fluorophenyl. In another embodiment, R 4 is chlorophenyl. In another embodiment, R 4 is 2-chlorophenyl or 4-chlorophenyl.
  • Illustrative compounds of the present invention include, but are not limited to:
  • 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.
  • 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 present compounds may have one or more asymmetric carbon atom and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • 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:
  • R 5 represents aryl, optionally substituted, independently, one to three times, by a substituent selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, OH, CF 3 , OCF 3 , phenyl, phenyloxy, and furanyl
  • R 6 represents heteroaryl, optionally substituted once or twice by halogen or d ⁇ alkyl.
  • Novel intermediates of the present invention include compounds according to
  • Scheme 1 depicts the general preparation of piperazinyl-sulfonamide analogs.
  • aryl aldehydes R 5 CHO such as, but not limited to, methylenedioxy benzaldehyde (piperonal) 1 , are condensed with piperazine 2 in the presence of TMSCI and a lewis acid, such as ZnI 2 , under standard Strecker synthesis conditions.
  • the isolated aryl acetonitrile product 3 is then reduced to the corresponding amine utilizing a hydride reducing agent, such as DIBAL(H), in toluene.
  • DIBAL(H) a hydride reducing agent
  • the amine intermediate 4 is then treated with a sulfonyl chloride reagent R 6 SO 2 CI such as, but not limited to, 4-phenoxy- benzenesulfonyl chloride under standard conditions in the presence or absence of a base such as, but not limited to, triethyl amine to generate the desired compound 5.
  • a sulfonyl chloride reagent R 6 SO 2 CI such as, but not limited to, 4-phenoxy- benzenesulfonyl chloride under standard conditions in the presence or absence of a base such as, but not limited to, triethyl amine to generate the desired compound 5.
  • R 5 represents and optionally substituted aryl moiety and R 6 represents an optionally substituted aryl or an optionally substituted heteroaryl moiety.
  • a coupling reaction of the commercially available 2-amino ketone 6d (W NH 2 ) with a sulfonyl chloride R 6 SO 2 CI, yields sulfonamide 7.
  • the 2-amino ketone 6d can be prepared from the ketone 6a from bromination using Br 2 followed by displacement with NaN 3 and reduction under Pd/C and H 2 .
  • Reduction of the ketone 7 using NaBH 4 provides the corresponding alcohol 8, which can be prepared from the commercially available 2- amino alcohol 9 by sulfonylation with sulfonyl chloride R 6 SO 2 CI.
  • Replacement of the hydroxyl group by MsCI using Et 3 N as base followed by replacement with the corresponding cyclic 2° amine such as, but not limited to, piperazine gives the pyrazine sulfonamide 10, (Scheme 2).
  • W is selected from the group consisting of H, Br, N 3 and NH 2 .
  • the commercially available olefin such as 2-chlorostyrene 11 is oxidized to the optically pure (R)-diol 12 (e.e. >98%) using an oxidizing agent such as AD-mix- ⁇ followed by Sharpless' method to prepare the epoxide 13.
  • the epoxide 13 is converted to the phthalimide 14.
  • Treatment of 14 with hydrazine in ethanol followed by sulfonylation with sulfonyl chloride R 6 SO 2 CI yields the sulfonamide 15.
  • the aziridine 16 is generated by treating 15 with methanesulfonyl chloride and triethylamine in dichloromethane followed by the treatment with 4-methylpiperazine in the presence of a lewis acid such as lithium bis(trifluoromethanesulfonyl)imide to provide the optically pure (R)-piperazine 17.
  • a lewis acid such as lithium bis(trifluoromethanesulfonyl)imide
  • the opposite enantiomeric pure (S)-diol is also prepared using AD-mix- ⁇ and following the same procedure shown above to get the final optically pure (S)- piperazine.
  • Scheme 4 depicts the general preparation of the carbon linker sulfonamide analogs.
  • Commercially available 1 ,3-benzodioxol-5-ylacetonitrile (18) is alkylated with commercially available ketone 19 using NaOEt in an ethanolic solution at 70 0 C.
  • the isolated unsaturated nitrile product 20 is then reduced to the saturated nitrile 21 using typical hydrogenation conditions and then further reduced to the amine 22 with a borane dimethyl sulfide complex at elevated temperatures.
  • the amine intermediate 22 is treated with a sulfonyl chloride reagent under standard conditions in the presence or absence of a base such as, but not limited to, triethyl amine to generate the desired compound 23.
  • 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 EC5O' 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.
  • 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(l).
  • 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 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 , Ia-(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. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • 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.
  • 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.
  • Calcilytic activity was measured by determining the IC50 of the test compound for blocking increases of intracellular Ca 2+ elicited by extracellular Ca 2+ in HEK 293 4.0-7 cells stably expressing the human calcium receptor.
  • HEK 293 4.0-7 cells were constructed as described by Rogers et al., J. Bone Miner. Res. 10 Suppl. 1 :S483, 1995 (hereby incorporated by reference to the extent required to conduct the present assay).
  • Intracellular Ca 2+ increases were elicited by increasing extracellular Ca ⁇ + from 1 to 1.75 mM.
  • Intracellular Ca ⁇ + was measured using fluo-3, a fluorescent calcium indicator.
  • 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.
  • SPF-PCB was supplemented with 1 mg/mL of D-glucose and 1 mM CaCl2 and then split into two fractions.
  • bovine serum albumin BSA; fraction V, ICN
  • 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.
  • 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 106 cells/mL.
  • 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 tested active at IC50 values of lower than 30 uM.
  • the present examples were all tested except for Examples 25, 65, 68 and 75.
  • the compounds tested had an IC50 in a range from about 0.1 uM to about 25 uM.
  • 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 MgCl2) 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. 3 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 3 H compound ((R,R)-N-4'-Methoxy-t-3- 3'-methyl-1'-ethylphenyl-1-(1-naphthyl)ethylamine), or 3 H compound (R)-N-[2-Hydroxy-3- (3-chloro-2-cyanophenoxy)propyl]-1 ,1-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 binding reaction was terminated by rapid filtration onto 1% PEI pretreated GF/C filters using a Brandel Harvestor. Filters were placed in scintillation fluid and radioactivity assessed by liquid scintillation counting.
  • the present compounds tested active at IC50 values of 1 OuM or lower. The present examples were all tested except for Examples 24-25, 44-47, 50, 68 and 75. The tested compounds had an IC50 in a range from about 1 nM to about 1 OuM. 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-d ⁇ is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million ( ⁇ ) downfield from the internal standard tetramethylsilane.
  • ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 ⁇ Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 ⁇ , 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 1 is intended to be illustrative only and not limiting in any way:
  • the reaction vessel was fitted with a condenser under dry nitrogen and the resulting solution was stirred at reflux for 4 h and then at RT overnight. Gradual formation of a precipitate was observed while heating.
  • the reaction mixture was concentrated and brought up again in EtOAc and DCM. A moderate amount of solid was isolated by filtration, and the filtrate was purified by FCC (Biotage 65, 50 - 100% EtOAc/Hex/0.5% TEA) to give a tan solid: N3314-17-A2 (10.18 g, 59%).
  • the solid (possibly the HI salt) was treated with EtOAc and 5% NaHCO3 to generate the free base as a tan solid (N3341-30-A2, 0.6 g).
  • the intermediate phenyl bromide compound was prepared following the general procedures of Example 1 except substituting 4-bromobenzenesulfonyl chloride for 4- phenoxybenzenesulfonyl chloride.
  • LCMS (M+1 ) 482/484.
  • N-[2-(1 ,3-benzodioxol-5-yl)-2-oxoethyl]-4-(phenyloxy)benzenesulfonamide (5.1 g, 12.40 mmol) was added to Methanol (100 ml). The solid did not completely dissolve even with heating and sonication. The suspension was cooled to O 0 C and then NaBH 4 (0.563 g, 14.88 mmol) was added slowly. After 1.5 h, there was no starting material present by TLC. The solution was then concentrated H 2 O (100 ml.) was added.
  • Example 26 The title compound was prepared by demethylation of Example 26. ⁇ /-[2-(2-Fluoro- 5-(methyloxy)phenyl)-2-(4-methyl-1-piperazinyl)ethyl]-4-(phenyloxy) benzenesulfonamide (58.5 mg, ) was dissolved in dichlorometane (3.0 ml.) and cooled to -40 0 C. To the mixture was added boron tribromide as a solution in dichloromethne (0.703 ml_, 0.703 mmol). After 2 h, the cooled mixture was quenched with aq. sat'd. NaHCOs then extracted with dichloromethane (2 x 30 ml_).

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Abstract

L'invention porte sur de nouveaux composés calcilytiques, sur de nouvelles compositions pharmaceutiques, sur de nouveaux procédés de synthèse et sur des procédés pour les utiliser.
PCT/US2009/059157 2008-10-01 2009-10-01 Composés calcilytique WO2010039911A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372233A (zh) * 2020-03-09 2021-09-10 中国农业大学 氯丙那林半抗原和人工抗原及其制备方法与应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080125424A1 (en) * 2006-07-10 2008-05-29 Pierre Deprez Derivatives of urea and related diamines, methods for their manufacture, and uses therefor
US20080221101A1 (en) * 2006-10-26 2008-09-11 Amgen Inc. Calcium receptor modulating agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080125424A1 (en) * 2006-07-10 2008-05-29 Pierre Deprez Derivatives of urea and related diamines, methods for their manufacture, and uses therefor
US20080221101A1 (en) * 2006-10-26 2008-09-11 Amgen Inc. Calcium receptor modulating agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARRINGTON ET AL.: "Calcium Sensing Receptor Activators: Calcimimetics", CURRENT MEDICINAL CHEMISTRY, vol. 14, 2007, pages 3027 - 3034 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372233A (zh) * 2020-03-09 2021-09-10 中国农业大学 氯丙那林半抗原和人工抗原及其制备方法与应用

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