Claims for Patent: 6,011,068

Summary for Patent: 6,011,068

Title:	Calcium receptor-active molecules
Abstract:	The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca2+ and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
Inventor(s):	Edward F. Nemeth, Bradford C. Van Wagenen, Manuel F. Balandrin, Eric G. DelMar, Scott T. Moe
Assignee:	Brigham and Womens Hospital Inc , Shire NPS Pharmaceuticals Inc
Application Number:	US08/353,784
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,011,068
Patent Claims:	1. A compound having the chemical formula: ##STR15## wherein alk is selected from the group consisting of n-propylene, 2,4-butylene and 1,3-butylene;R1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and R2 and R3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that if R2 is phenyl, then said phenyl R2 has at least one substituent and is not 4-OH-phenyl; or a pharmaceutically acceptable acid addition salt or complex thereof. 2. The compound of claim 1 wherein alk is n-propylene. 3. The compound of claim 2 wherein R1 is methyl. 4. The compound of claim 3 wherein R2 is a substituted phenyl and R3 is an optionally substituted phenyl. 5. A compound having the chemical formula: ##STR16## wherein alk is either n-propylene, 2,4-butylene, or 1,3-butylene; R1 is a lower alkyl of from 1 to 3 carbon atoms;R2 is either naphthyl or a phenyl substituted with 1 to 5 substituents, and R3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents; wherein each of said R2 substituents and each of said R3 substituents are independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that R2 is not 4-OH-phenyl; or a pharmaceutically acceptable acid addition salt or complex thereof. 6. The compound of claim 5, whereinR1 is methyl; and each of said R2 substituents and each of said R3 substituents are independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 7. The compound of claim 6, whereinR2 is either naphthyl or said phenyl having 1 to 5 substituents; and R3 is either naphthyl or said phenyl optionally substituted with 1 to 5 substituents. 8. The compound of claim 7, wherein alk is 2,4-butylene. 9. The compound of claim 7, wherein alk is 1,3-butylene. 10. The compound of any one of claims 8 or 9, wherein R3 is naphthyl. 11. The compound of any one of claims 8 or 9, wherein R3 is said optionally substituted phenyl. 12. The compound of claim 11, wherein R2 is naphthyl. 13. The compound of claim 11, wherein R2 is said substituted phenyl. 14. The compound of claim 13, wherein said R2 substituted phenyl is a meta-substituted phenyl. 15. The compound of claim 14, wherein said R2 metasubstituted phenyl has a meta substituent selected from the group consisting of: halogen, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 16. The compound of claim 15, wherein said R2 meta substituent is methoxy. 17. The compound of claim 15, wherein said R2 meta substituent is trihalomethyl. 18. The compound of claim 15, wherein said R2 meta substituent is lower thioalkyl of 1 to 3 carbon atoms. 19. The compound of claim 16, wherein said R3 optionally substituted phenyl is a substituted phenyl having one or more substituents each independently selected from the group consisting of: halogen, CF3, alkoxy of 1 to 3 carbon atoms, and lower alkyl of 1 to 3 carbon atoms. 20. The compound of claim 19, wherein said R3 substituted phenyl is an ortho-substituted phenyl having either a chloro or fluoro substituent. 21. The compound of any one of claims 5-7, wherein said compound is an R enantiomer having the following chemical structure: ##STR17## or a pharmaceutically acceptable acid addition salt or complex thereof. 22. The compound of claim 11, wherein said compound is an R enantiomer having the following chemical structure: ##STR18## or a pharmaceutically acceptable acid addition salt or complex thereof. 23. The compound of claim 15, wherein said compound is an R enantiomer having the following chemical structure: ##STR19## or a pharmaceutically acceptable acid addition salt or complex thereof. 24. The compound of claim 5, wherein said compound ##STR20## or a pharmaceutically acceptable acid addition salt or complex thereof. 25. compound of claim 5, wherein said compound ##STR21## or a pharmaceutically acceptable acid addition salt or complex thereof. 26. A compound represented by a formula selected from the group consisting of ##STR22## wherein m is independently an integer of 0 to 5 for naphthyl rings and m is independently an integer of 1 to 5 for phenyl rings;x is independently selected from the group consisting of --Br, --C1, --F, --I, --CN, --NO2, --OR, --NR2, --CF3, --SR, --S(O)R, --S(O)2 R, --C(O)R, --OC(O)R, --C(O)OR, --NRC(O)R, C(O)NR2, methyl and isopropyl radicals; provided that the X substituent on the phenyl ring of the Ph-CHR-group is other than hydroxy, 4-OCH3, or 4-CH3 ; and each R is independently either a hydrogen, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C3 -C10 cycloalkyl, --CF3, --CF2 H, --CFH2, --CH2 CF3 or phenyl radical; provided that if said compound has the chemical formula: ##STR23## wherein the naphthyl is either unsubstitued or substituted with a lower alkyl or halogen and only one substituent is present on the phenyl, then said one substituent is not lower alkyl or halogen; or a pharmaceutically acceptable acid addition salt or complex thereof. 27. The compound of claim 26, wherein each R is independently C1 -C3 alkyl. 28. The compound of claim 26, represented by a formula selected from the group consisting of: ##STR24## wherein each m is independently an integer of 1 to 5; each X is independently selected from the group consisting of --C1, --F, --I, --CF3, --OCF3, --OCH2 CF3, --SCH3, methyl, isopropyl and methoxy radicals; andR is a hydrogen, methyl, ethyl or isopropyl radical; or a pharmaceutically acceptable acid addition salt or complex thereof. 29. The compound of claim 28, wherein each m is independently an integer of 1 or 2;X is independently selected from the group consisting of --C1, --F, --CF3, --SCH3, methyl and methoxy radicals, and R is a hydrogen or methyl radical. 30. The compound of claim 29, wherein said compound has the following formula: ##STR25## or a pharmaceutically acceptable acid addition salt or complex thereof. 31. The compound of claim 29, wherein said compound has the following formula: ##STR26## or a pharmaceutically acceptable acid addition salt or complex thereof. 32. The compound of claim 29, wherein said compound has the following formula: ##STR27## or a pharmaceutically acceptable acid addition salt or complex thereof. 33. The compound of claim 29, wherein said compound has the following formula: ##STR28## or a pharmaceutically acceptable acid addition salt or complex thereof. 34. The compound of claim 29, wherein said compound has the following formula: ##STR29## or a pharmaceutically acceptable acid addition salt or complex thereof. 35. The compound of claim 29, wherein said compound has the following formula: ##STR30## or a pharmaceutically acceptable acid addition salt or complex thereof. 36. The compound of claim 26, wherein said compound has a chemical structure selected from the group consisting of: ##STR31## or a pharmaceutically acceptable acid addition salt or complex thereof. 37. A pharmaceutical composition comprising the compound of any one of claims 26-29 and 30-36, and a pharmaceutically acceptable carrier. 38. A compound having the chemical formula: ##STR32## wherein alk is 1,1-ethylidine or methylene; R1 is lower alkyl of from 1 to 3 carbon atoms or lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; andR2 and R3 are independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that R2 is not and unsubstituted phenyl and R3 is not an unsubstituted phenyl; further provided that if alk is methylene then either, R2 and R3 are both substituted phenyls, R3 does not contain a OH substituent, and R3 is not 4-OCH3 -phenyl, or 4-CH3 -phenyl, or R2 is an optionally substituted naphthyl and R3 is a substituted phenyl not containing an OH substituent; and further provided that if one of R2 or R3 is naphthyl or naphthyl substituted with a lower alkyl of 1 to 3 carbons or halogen and the other of R2 or R3 is phenyl, then the phenyl has 1-5 substituents and if one substituent is present, then the one substituent is other than 2-OH, lower alkyl of 1 to 3 carbons or halogen; or a pharmaceutically acceptable acid addition salt or complex thereof. 39. The compound of claim 38, wherein R2 is either naphthyl or a substituted phenyl having 1 to 5 substituents; andR3 is either naphthyl or a substituted phenyl having 1 to 5 substituents. 40. The compound of claim 39, wherein each of said substituents are independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 41. The compound of claim 40, wherein R3 is substituted phenyl. 42. The compound of claim 41, wherein R2 is naphthyl. 43. The compound of claim 41, wherein R2 is substituted phenyl. 44. The compound of claim 43, wherein said R3 substituted phenyl is substituted with one or more substituents each independently selected from the group consisting of: halogen, CF3, alkoxy of 1 to 3 carbon atoms, and lower alkyl of 1 to 3 carbon atoms. 45. The compound of any one of claims 38-44, wherein said compound is an R enantiomer having the chemical formula: ##STR33## or a pharmaceutically acceptable acid addition salt or complex thereof. 46. The compound of claim 45, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the Cytosolic Ca2+ Cell Assay. 47. The compound of any one of claims 38-44, wherein alk is methylene. 48. The compound of any one of claims 38-44, wherein alk is 1,1-ethylidine. 49. A compound selected from the group consisting of: ##STR34## or a pharmaceutically acceptable acid addition salt or complex thereof. 50. The compound of claim 49, wherein said compound is selected from group consisting of: ##STR35## or a pharmaceutically acceptable acid addition salt or complex thereof. 51. The compound of claim 50, wherein said compound is selecced from the group consistirng of; ##STR36## or a pharmaceutically acceptable acid addition salt or complex thereof. 52. The compound of claim 49, wherein said compound is ##STR37## or a pharmaceutically acceptable acid addition salt or complex thereof. 53. The compound of claim 49, wherein said compound is ##STR38## or a pharmaceutically acceptable acid addition salt or complex thereof. 54. The compound of claim 49, wherein said compound is ##STR39## or a pharmaceutically acceptable acid addition salt or complex thereof. 55. The compound of claim 49, wherein said compound is ##STR40## or a pharmaceutically acceptable acid addition salt or complex thereof. 56. The compound of claim 49, wherein said compound is ##STR41## or a pharmaceutically acceptable acid addition salt or complex thereof. 57. The compound of claim 49, wherein said compound is ##STR42## or a pharmaceutically acceptable acid addition salt or complex thereof. 58. The compound of claim 49, wherein said compound is ##STR43## or a pharmaceutically acceptable acid addition salt or complex thereof. 59. The compound of claim 49, wherein said compound is selected from the group consisting of: ##STR44## or a pharmaceutically acceptable acid addition salt or complex thereof. 60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 49-59. 61. The compound of claim 5, whereinR1 is methyl; and each of said R2 substituents and each of said R3 substituents are independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 62. The compound of claim 61, wherein alk is n-propylene. 63. The compound of claim 61, wherein alk is 1,1-ethylidine. 64. The compound of claim 61, wherein alk is 274-butylene. 65. The compound of claim 61, wherein alk is 1,3-butylene. 66. The compound of any one of claims 61-65, wherein R3 is naphthyl. 67. The compound of any one of claims 61-65, wherein R3 is said optionally substituted phenyl. 68. The compound of claim 67, wherein R2 is naphthyl. 69. The compound of claim 67, wherein R2 is said substituted phenyl. 70. The compound of claim 69, wherein said R2 substituted phenyl is a meta-substituted phenyl. 71. The comnpound of claimn 70, wherein said R2 meta-substituted phenyl has a meta substituent selected from the group consisting of: halogen, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 72. The compound of claim 71, wherein said R2 meta substituent is methoxy. 73. The compound of any one of claims 61-65, wherein said compound is an a enantiomer having the following chemical structure: ##STR45## or a pharmaceutically acceptable acid addition salt or complex thereof. 74. The compound of claim 73, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the Cytosolic Ca2+ Cell Assay. 75. The pharmaceutical composition of claim 100, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the Cytosolic Ca2+ Cell assay. 76. The pharmaceutical composition of claim 101, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the cytosolic Ca2+ cell assay. 77. The compound of claim 21, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the Cytosolic Ca2+ Cell Assay. 78. The compound of claim 23, wherein said compound causes an increase in (Ca2+)i with an EC50 less than or equal to 5 μM as determined by measuring (Ca2+)i in bovine parathyroid cells loaded with fura-2 using the Cytosolic Ca2+ Cell Assay. 79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the chemical formula: ##STR46## wherein alk is a straight- or branched-chain alkylene of from 0 to 6 carbon atoms;R1 is a lower alkyl of from 1 to 3 carbon atoms or a lower haloalkyl of from 1 to 3 carbon atoms substituted with from 1 to 7 halogen atoms; and R2 and R3 are each independently selected monocyclic or bicyclic carbocyclic aryl or cycloalkyl groups, having 5- to 7-membered rings optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; provided that if R2 is phenyl, then R2 is substituted with 1 to 5 substituents; further provided that if R3 is cycloalk and alk is --CH2 --, then R2 is not 4 aminophenyl; or a pharmaceutically acceptable acid addition salt or complex thereof. 80. The pharmaceutical composition of claim 79, wherein alk is 1 to 6 carbon atoms;R1 is lower alkyl of from 1 to 3 carbon atoms; and R2 is either naphthyl or a substituted phenyl having 1 to 5 substituents, and R3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents, wherein each R2 and R3 substituent is independently selected from the group consisting of: OCF3, lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 81. The pharmaceutical composition of claim 79, wherein alk is 1 to 6 carbon atoms;R1 is lower alkyl of from 1 to 3 carbon atoms; R2 is either naphthyl or a substituted phenyl having 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms; and R3 is either cyclohexyl, naphthyl, or a phenyl optionally substituted with 1 to 5 substituents each independently selected from the group consisting of: lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, alkylamino, amido, lower alkylamido of 1 to 3 carbon atoms, cyano, hydroxy, acyl of 2 to 4 carbon atoms, lower hydroxyalkyl of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 82. The pharmaceutical composition of claim 81, wherein alk is an alkylene chain 1 to 3 carbon atoms in length which may be substituted with a methyl. 83. The pharmaceutical composition of claim 81, wherein R1 is methyl. 84. The pharmaceutical composition of claim 83, wherein alk is n-propylene. 85. The pharmaceutical composition of claim 83, wherein alk is 1,1-ethylidine. 86. The pharmaceutical composition of claim 83, wherein alk is 2,4-butylene. 87. The pharmaceutical composition of claim 83, wherein alk is 1,3-butylene. 88. The pharmaceutical composition of claim 83, wherein alk is methylene. 89. The pharmaceutical composition of any one of claims 84-88, wherein R3 is naphthyl. 90. The pharmaceutical composition of any one of claims 84 -88, wherein R3 is said optionally substituted phenyl. 91. The pharmaceutical composition of claim 90, wherein R2 is naphthyl. 92. The pharmaceutical composition of claim 90, wherein R2 is said substituted phenyl. 93. The pharmaceutical composition of claim 92, wherein said R2 substituted phenyl is a meta-substituted phenyl. 94. The pharmaceutical composition of claim 93, wherein said R2 meta-substituted phenyl has a meta substituent selected from the group consisting of: halogen, lower haloalkyl of 1 to 3 carbon atoms substituted with 1 to 7 halogen atoms, lower alkoxy of 1 to 3 carbon atoms, and lower thioalkyl of 1 to 3 carbon atoms. 95. The pharmaceutical composition of claim 94, wherein said R2 meta substituent is methoxy. 96. The pharmaceutical composition of claim 94, wherein said R2 meta substituent is trihalomethyl. 97. The pharmaceutical composition of claim 94, wherein said R2 meta substituent is a lower thioalkyl of 1 to 3 carbon atoms. 98. The pharmaceutical composition of claim 94, wherein said R3 optionally substituted phenyl is a substituted phenyl having one or more substituents each independently selected from the group consisting of: halogen, CF3, alkoxy of 1 to 3 carbon atoms, and lower alkyl of 1 to 3 carbon atoms. 99. The pharmaceutical composition of claim 98, wherein said R3 substituted phenyl is an ortho-substituted phenyl having either a chloro or fluoro substituent. 100. The pharmaceutical composition of any one of claims 80 -83, wherein said compound is an R enantiomer having the following chemical structure: ##STR47## or a pharmaceutically acceptable acid addition salt or complex thereof. 101. The pharmaceutical composition of claim 94, wherein said compound is an R enantiomer having the following chemical structure: ##STR48## or a pharmaceutically acceptable acid addition salt or complex thereof. 102. The pharmaceutical composition of claim 95, wherein said compound is an R enantiomer having the following chemical structure: ##STR49## or a pharmaceutically acceptable acid addition salt or complex thereof. 103. The pharmaceutical composition of claim 79, wherein said compound is ##STR50## or a pharmaceutically acceptable acid addition salt or complex thereof.