Agents for preventing and treating disorders involving modulation of the RyR receptors
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-281/02
A61K-031/554
출원번호
UP-0212413
(2005-08-25)
등록번호
US-7704990
(2010-05-20)
발명자
/ 주소
Landry, Donald W.
Deng, Shixian
Cheng, Zhen Zhuang
출원인 / 주소
The Trustees of Columbia University in the City of New York
대리인 / 주소
Wilmer Cutler Pickering Hale and Dorr LLP
인용정보
피인용 횟수 :
1인용 특허 :
131
초록▼
The present invention provides novel compounds of Formula I and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compo
The present invention provides novel compounds of Formula I and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells. Such disorders and diseases include, by way of example only, cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. Cardiac disorder and diseases include, but are not limited to, irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; sudden cardiac death; exercise-induced sudden cardiac death; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include and exercise-induced irregular heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and exercise-induced variants thereof. Skeletal muscular disorder and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence. Cognitive disorders and diseases include, but are not limited to, Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
대표청구항▼
What is claimed is: 1. A method for the synthesis of compounds of the formula wherein R is NH-2-Py, comprising: reacting a compound of formula S26 with a compound of formula RSO2Cl, wherein R is defined as above, to form a reaction mixture; and purifying the reaction mixture to yield a comp
What is claimed is: 1. A method for the synthesis of compounds of the formula wherein R is NH-2-Py, comprising: reacting a compound of formula S26 with a compound of formula RSO2Cl, wherein R is defined as above, to form a reaction mixture; and purifying the reaction mixture to yield a compound of the formula wherein R is defined as above. 2. The method of claim 1, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 3. The method of claim 1, wherein the reaction mixture further comprises a base catalyst. 4. The method of claim 2, further comprising washing the reaction mixture with basic solution. 5. A method for the synthesis of compounds of the formula wherein R is selected from the group consisting of Ph- and 4-N3-2-OH—C6H5, comprising: reacting a compound of formula S26, with a compound of formula RCOX, wherein R is defined as above and X is selected from the group consisting of Cl and NHS, to yield a reaction mixture; and purifying the reaction mixture to yield a compound of formula wherein R is as defined above. 6. The method of claim 5, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 7. The method of claim 5, further comprising adding a base catalyst to the reaction mixture. 8. The method of claim 6, further comprising washing the reaction mixture using basic solution. 9. The method of claim 6, further comprising washing the reaction mixture using acidic solution. 10. A method for the synthesis of compounds of the formula wherein X is S, comprising: reacting a compound of formula S26, with a compound of the formula C6H4—NCX, wherein X is as defined above, to yield a reaction mixture; and purifying the reaction mixture to yield a compound of formula wherein X is as defined above. 11. The method of claim 10, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 12. The method of claim 11, wherein the solvent is a base catalyst. 13. The method of claim 12, further comprising adding additional organic solvent to the reaction mixture following the reaction. 14. The method of claim 11, further comprising washing the reaction mixture using basic solution. 15. The method of claim 11, further comprising washing the reaction mixture using acidic solution. 16. A method for the synthesis of isomers of compounds of the formula comprising: reacting a compound of formula S26, with phenyl methoxyphosphonyl chloride (Ph(MeO)P(O)Cl) to form a reaction mixture; and purifying and separating the product into the isomers. 17. The method of claim 16, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 18. The method of claim 17, further comprising washing the reaction mixture using basic solution. 19. A method for the synthesis of compounds of the formula wherein X is selected from the group consisting of CH2—CH2 and comprising: reacting a compound of formula S26, with a compound of formula ClOC—X—COCl wherein X is defined as above, to form a reaction mixture; and purifying the reaction mixture to yield a compound of formula wherein X is defined as above. 20. The method of claim 19, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 21. The method of claim 19, further comprising adding a base catalyst to the reaction mixture. 22. The method of claim 20, further comprising washing the reaction mixture using basic solution. 23. The method of claim 20, further comprising washing the reaction mixture using acidic solution. 24. A method for the synthesis of S38, comprising: reacting a compound of formula with sodium hydroxide; and purifying S38. 25. The method of claim 24, wherein the reacting takes place in a first solvent and the purifying comprises: removing the first solvent to form a residue; dissolving the residue in water to form an aqueous solution; washing the aqueous solution with an organic solvent; acidifying the aqueous solution; extracting S38 from the aqueous solution using an organic solvent to form an extract; and removing the organic solvent from the extract. 26. The method of claim 25, wherein the first solvent is an organic solvent. 27. A method for the synthesis of S44, comprising: treating a compound of formula S36, with thionyl chloride to form S36-Cl; reacting S36-Cl with cystamine to form a reaction mixture; and purifying the reaction mixture to yield S44. 28. The method of claim 27, wherein cystamine is mono-protected and further comprising removing the protecting group before purifying the reaction mixture. 29. The method of claim 27, wherein the treating takes place in a solvent, wherein the solvent is an organic solvent. 30. The method of claim 27, further comprising adding a base catalyst to the reaction mixture. 31. A method for the synthesis of compounds of the formula wherein X is NHEt, comprising: treating a compound of formula S36, with thionyl chloride to obtain S36-Cl; reacting S36-Cl with a compound of the formula HX, wherein X is defined as above; and purifying the product to yield a compound of the formula wherein X is defined as above. 32. The method of claim 31, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 33. A method for the synthesis of compounds of the formula wherein R is selected from the group consisting of NO2— and HO—, comprising: reacting a compound of formula S36, with thionyl chloride to obtain S36-Cl; reacting S36-Cl with cystamine to form S36-cystamine; and reacting the S36-cystamine with an NHS activated ester of an azido compound in a solvent to yield a compound of the formula wherein R is defined as above. 34. A method for the synthesis of compounds of the formula wherein X is selected from the group consisting of NHEt, NHPh, NH2, and NHCH2-pyridine, comprising: reacting a compound of formula S77, with thionyl chloride to obtain S77-Cl; reacting S77-Cl with a compound of the formula HX, wherein X is defined as above; and purifying the residue to yield a compound of the formula wherein X is defined as above. 35. The method of claim 34, wherein reacting takes place in a solvent, wherein the solvent is an organic solvent. 36. A method for the synthesis of S84, comprising: reacting a compound of formula S68, with benzyl bromide to form a reaction mixture; and purifying the reaction mixture to yield S84. 37. The method of claim 36, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 38. The method of claim 36, further comprising adding a base catalyst to the reaction mixture. 39. A method for the synthesis of S86, comprising: reacting a compound of formula S85, with BBr3 to form a reaction mixture; quenching the reaction mixture to form a product; and purifying the product to yield S86. 40. The method of claim 39, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 41. The method of claim 39, wherein quenching the reaction mixture comprises adding methanol. 42. A method for the synthesis of S87, comprising: reacting a compound of formula S86, with trifluoromethylsulfonyl anhydride to form a reaction mixture; and purifying the reaction mixture to yield S87. 43. The method of claim 42, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 44. The method of claim 42, further comprising adding a base catalyst to the reaction mixture. 45. The method of claim 42, wherein purifying the reaction mixture comprises: quenching the reaction mixture with water to form an aqueous layer; extracting the aqueous layer using an organic solvent to form an organic layer; drying and concentrating the organic layer to form a residue; and purifying the residue to yield S87. 46. A method for the synthesis of compounds of the formula S88, comprising: reacting a compound of formula S87, with tris(dibenzylideneacetone)dipalladium(O), 2-(di-tert-butylphosphino)-biphenyl, morpholine, and K2PO3 to form a reaction mixture; and purifying the reaction mixture to yield S88. 47. The method of claim 46, wherein purifying the reaction mixture comprises: washing the reaction mixture using water to form an aqueous layer; extracting the aqueous layer using an organic solvent to form an organic layer; drying and concentrating the organic layer to form a residue; and purifying the residue to yield S88. 48. A method for the synthesis of S89, comprising: reacting a compound of formula S87, with benzenethiol and a catalyst to form a reaction mixture; and purifying the reaction mixture to yield S89. 49. The method of claim 48, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 50. The method of claim 48, wherein the catalyst is i-Pr2NEt. 51. The method of claim 48, wherein purifying the reaction mixture comprises: washing the reaction mixture; and drying and concentrating the reaction mixture to yield S89. 52. The method of claim 51, wherein washing the reaction mixture comprises using a basic solution and water to wash the reaction mixture. 53. A method for the synthesis of S89, comprising: refluxing a compound of formula S87, with benzenethiol in an organic solvent and i-Pr2Net/Pd2(dba)3/xantphos catalyst to form a product; and purifying the product to yield S89. 54. A method for the synthesis of S90, comprising: reacting a compound of formula S87, with a base, phenylboronic acid, and a catalyst to form a reaction mixture; and purifying the reaction mixture to yield S90. 55. The method of claim 54, wherein the base is K2PO3. 56. The method of claim 54, wherein the catalyst is Pd(Ph3P)4. 57. The method of claim 54, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 58. The method of claim 57, further comprising washing the reaction mixture using water. 59. A method for the synthesis of S92, comprising: reacting a compound of formula S87, with zinc cyanide and a catalyst to form a reaction mixture; and purifying the reaction mixture to yield S92. 60. The method of claim 59, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 61. The method of claim 59, wherein the catalyst is Pd(Ph3P)4. 62. The method of claim 59, wherein purifying the reaction mixture comprises: washing the reaction mixture using water to form an aqueous layer; extracting the aqueous layer using an organic solvent to form an organic extract; washing the organic extract; drying the organic extract; and concentrating the organic extract to yield S92. 63. A method for the synthesis of S94, comprising: reacting a compound of formula S86, with acetic anhydride to form a reaction mixture; and purifying the reaction mixture to yield S94. 64. The method of claim 63, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 65. The method of claim 63, further comprising adding a base catalyst to the reaction mixture. 66. The method of claim 64, wherein purifying the reaction mixture comprises: washing the reaction mixture using water; drying the reaction mixture; removing the solvent from the reaction mixture to yield a residue; and purifying the residue to yield S94. 67. A method for the synthesis of S95, comprising: reacting a compound of formula S94, with anhydrous AlCl3 to form a reaction mixture; and purifying the reaction mixture to yield S95. 68. The method of claim 67, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 69. The method of claim 68, wherein purifying the reaction mixture comprises: extracting the reaction mixture using water to form an organic layer; concentrating the organic layer to form a residue; and purifying the residue to yield S95. 70. A method for the synthesis of S96, comprising: reacting a compound of formula S86, with Nal and Chloramine-T to form a reaction mixture; quenching the reaction mixture; and purifying the reaction mixture to yield S96. 71. The method of claim 70, wherein the reaction takes place in a solvent, wherein the solvent is an organic solvent. 72. The method of claim 70, wherein quenching the reaction mixture comprises adding Na2S2O3 solution to the reaction mixture. 73. A method for the synthesis of S98, comprising: hydrogenating a compound of formula S97, to yield S98. 74. The method of claim 73, wherein hydrogenating comprises: reacting S97 with H2 and Pd/C in an organic solvent to form a reaction mixture; filtering the reaction mixture; concentrating the reaction mixture to yield a residue; and purifying the residue to yield S98. 75. A method for the synthesis of compounds of the formula wherein R is selected from the group consisting of CH2═CH—, Me—, and p-Me—C6H4—, comprising: reacting a compound of formula S26 with a compound of formula RSO2Cl, wherein R is defined as above, to form a reaction mixture; and purifying the reaction mixture to yield a compound of the formula wherein R is defined as above. 76. The method of claim 75, wherein the reaction takes place in a solvent, wherein the solvent is an organic solvent. 77. The method of claim 75, wherein the reaction mixture further comprises a base catalyst. 78. The method of claim 76, further comprising washing the reaction mixture with basic solution. 79. A method for the synthesis of compounds of the formula wherein NR1R2 is selected from the group consisting of and NBu2, comprising: reacting a compound of formula S3, with a compound of formula HNR1R2, wherein HNR1R2 is defined as above, to form a reaction mixture; and purifying the reaction mixture to yield a compound of the formula wherein NR1R2 is defined as above. 80. The method of claim 79, wherein the reaction takes place in a solvent. 81. The method of claim 80, wherein the solvent is an organic solvent. 82. A method for the synthesis of compounds of the formula wherein X is O, comprising: reacting a compound of formula S26, with a compound of the formula C6H4—NCX, wherein X is as defined above, to yield a reaction mixture; and purifying the reaction mixture to yield a compound of formula wherein X is as defined above. 83. The method of claim 82, wherein the reacting takes place in a solvent wherein the solvent is an organic solvent. 84. The method of claim 83, wherein the solvent is a base catalyst. 85. The method of claim 84, further comprising adding organic solvent to the reaction mixture following the reaction. 86. The method of claim 83, further comprising washing the reaction mixture using basic solution. 87. The method of claim 83, further comprising washing the reaction mixture using acidic solution. 88. A method for the synthesis of compounds of the formula wherein n is 1 and R is CH2═CH or wherein n is 2 and R is comprising: treating an intermediate compound of formula wherein R is defined as above, with hydrogen peroxide to form a reaction mixture; drying the reaction mixture to form a residue; and purifying the residue to yield a compound of formula wherein R is defined as above. 89. The method of claim 88, wherein the reaction takes place in a solvent, wherein the solvent is an organic solvent. 90. The method of claim 89, wherein purifying the residue comprises comprising dissolving the residue in an organic solvent to form a mixture, washing the mixture using basic solution, drying the mixture, and removing the organic solvent from the mixture. 91. A method for the synthesis of S57, comprising: reacting a compound of formula S26, with methyl chlorooxoacetate to form a reaction mixture; and purifying the product to yield S57. 92. The method of claim 91, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 93. The method of claim 91, further comprising adding a base catalyst to the reaction mixture. 94. The method of claim 91, further comprising washing the reaction mixture using basic solution prior to purifying the product. 95. The method of claim 92, further comprising washing the reaction mixture using acidic solution prior to purifying the product. 96. A method for the synthesis of S36, comprising: reacting a compound of formula S57, in a first solvent with sodium hydroxide to form a reaction mixture; removing the first solvent to form a residue; and purifying the residue to yield S36. 97. The method of claim 96, wherein the first solvent is an organic solvent. 98. A method for the synthesis of compounds of the formula wherein X is —OCH3, comprising: treating a compound of formula S36, with thionyl chloride to obtain S36-Cl; reacting S36-Cl with a compound of the formula HX, wherein X is defined as above; and purifying the product to yield a compound of the formula wherein X is defined as above. 99. The method of claim 98, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 100. A method for the synthesis of S37, comprising: reacting a compound of formula S26, in a solvent with 4-nitrophenyl chloroformate to form a reaction mixture; washing the reaction mixture using water; removing the solvents from the reaction mixture to form a residue; and purifying the residue to yield S37. 101. The method of claim 100, wherein the solvent is an organic solvent. 102. The method of claim 100, further comprising adding a base catalyst to the reaction mixture. 103. A method for the synthesis of compounds of the formula wherein NR1R2 selected from the group consisting of comprising: reacting a compound of formula with HNR1R2, wherein NR1R2 is defined as above, in a solvent to form a reaction mixture; removing the solvent from the reaction mixture to form a residue; and purifying the residue to yield a compound of formula wherein NR1R2 is defined as above. 104. The method of claim 103, wherein the solvent is an organic solvent. 105. A method for the synthesis of S76, comprising: reacting a compound of formula S68, with methyl chlorooxoacetate to form a reaction mixture; and purifying the reaction mixture to yield S76. 106. The method of claim 105, wherein the reaction takes place in a solvent, wherein the solvent is an organic solvent. 107. The method of claim 105, further comprising adding a base catalyst to the reaction mixture. 108. The method of claim 106, further comprising washing the reaction mixture using basic solution and then removing the solvent. 109. The method of claim 106, further comprising washing the reaction mixture using acidic solution and then removing the solvent. 110. A method for the synthesis of S77, comprising: reacting a compound of formula S76, in a first solvent with sodium hydroxide; removing the first solvent to form a residue; and purifying the residue to yield S77. 111. The method of claim 110, wherein purifying the residue comprises: dissolving the residue in water to form an aqueous solution; washing the aqueous solution with an organic solvent; acidifying the aqueous solution; extracting S77 from the aqueous solution using an organic solvent to form an extract; and removing the organic solvent from the extract. 112. The method of claim 110, wherein the first solvent is an organic solvent. 113. A method for the synthesis of S82, comprising: reacting a compound of formula S68, with CH2CHSO2Cl to form an intermediate product of the formula reacting the intermediate compound with to form a final reaction mixture; and purifying the reaction mixture to yield S82. 114. The method of claim 113, wherein the either or both reacting steps take place in a solvent, wherein the solvent is an organic solvent. 115. A method for the synthesis of S83, comprising: reacting a compound of formula S68, with RCOCl, wherein R is to yield a reaction mixture; and purifying the reaction mixture to yield S83. 116. The method of claim 115, wherein the reacting takes place in a solvent, wherein the solvent is an organic solvent. 117. The method of claim 115, further comprising adding a base catalyst to the reaction mixture. 118. The method of claim 116, further comprising washing the reaction mixture using basic solution. 119. A method for the synthesis of S85, comprising: reacting a compound of formula S26, with Boc2O in an organic solvent to form a protected product in a reaction mixture; washing the reaction mixture using a saturated sodium bicarbonate solution to form an aqueous layer; extracting the aqueous layer using an organic solvent to form organic layers; and drying and concentrating the organic layers to yield S85. 120. The method of claim 119, further comprising adding a base catalyst to the reaction mixture.
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