Agents for preventing and treating disorders involving modulation of the RyR receptors
View Patent ↗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.
1. A compound of formula:
wherein,
n is 0, 1, or 2;
R is located at one or more of positions 6, 7, 8 or 9 on the benzothiazepine ring;
each R is independently selected from the group consisting of H, halogen, —OH, —NH 2 , —NO 2 , —CN, —N 3 , —SO 3 H, acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 1 is selected from the group consisting of H, oxo, alkyl, cycloalkyl, and heterocyclyl; wherein each alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 2 is selected from the group consisting of —C═O(R 5 ), —C═S(R 6 ), —SO 2 R 7 , —POR 8 R 9 , alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 3 is selected from the group consisting of H, CO 2 Y, C(═O)HNY, acyl, alkyl, cycloalkyl, and heterocyclyl; wherein each acyl, alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; and wherein Y is selected from the group consisting of alkyl, aryl, cycloalkyl, and heterocyclyl;
R 4 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, and heterocyclyl; wherein each alkyl, alkenyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 5 is selected from the group consisting of —NHR 16 , NHNHR 16 , NHOH, —OR 15 , CONH 2 NHR 16 , CO 2 R 15 , CONHR 16 , CH 2 X, acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, wherein each acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 6 is selected from the group consisting of —OR 15 , NHNHR 16 , NHOH, —NHR 16 , CH 2 X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 7 is selected from the group consisting of —OR 15 , —NHR 16 , NHNHR 16 , NHOH, CH 2 X, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 8 and R 9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
X is selected from the group consisting of halogen, CN, CO 2 R 15 , CONHR 16 , —NHR 16 , —OR 15 , —SO 2 R 7 , and —POR 8 R 9 ; and
R 15 and R 16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkenyl, alkoxyl, alkyl, alkylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and hydroxyl; or salts thereof;
provided that when each R is H and n is 0, then R 2 is not Me, Et, —C(═O)NH 2 , —C(═O)NHPh, —C(═S)NH-nButyl, —C(═O)NHC(═O)CH 2 Cl, —C(═O)CH═CH 2 , —S(═O) 2 Me, —S(═O) 2 Et, —C(═O)OC(CH 3 ) 3 , 9-β-D-ribofuranosyl-9H-purin-6-yl or —C(═O)Ph;
further provided that when R is H and n is 1 or 2, then R 2 is not S(═O) 2 Me, —S(═O) 2 Et or C(═O)OC(CH 3 ) 3 ;
further provided that when R is Me, Cl, CN or F at the 6 position of the benzothiazepine ring, or Br at position 7 of the benzothiazepine ring, then R 2 is not Me, —C(═O)Ph, —S(═O) 2 Me, or —S(═O) 2 Et;
further provided that when n is 0, and R is H, or OH or C 1 -C 3 alkoxyl at the 7 position of the benzothiazepine ring, then R 2 is not —C(═O)CH═CH 2 , C(═O)CH 2 Br or (CH 2 ) 3 -4-benzylpiperidine;
further provided that when R is H, n is 0 or 2; R 1 is H or oxo; R 3 is H or Me and R 4 is H then R 2 is not C═ONHPh, C═ONHCOCH 2 Cl, C═ONH 2 , C═ONH(n-Bu), C═S(NHPh), C═S(NHCOCH 2 Cl), C═S(NH 2 ), or C═SNH(n-Bu);
further provided that when R is methoxy at positions 3 and 4 of the benzene ring, R 3 and R 4 are each H and n is 0 or 2, then R 1 is not methyl, —CH 2 Ph or 3,4-dimethoxybenzyl;
further provided that when R is H, R 2 is —C(═O)—C 6 H 4 —Cl or 2,2′,3,3′-tetrahydro-4(5H)-1,4 benzothiazepine, R 3 and R 4 are either H or CH 3 but not both CH 3 , then R 1 is not oxo;
further provided that when R 1 , R 3 and R 4 are each H, R is H or CH 3 at position 9 of the benzothiazepine ring and n is 0, then R 2 is not methyl, benzotriazol-1-ylmethyl, ethyl, pentyl, alkyl which is substituted by an aryl, —C(═O)CH═CH 2 or C(═O)CH 2 Br or CH 2 CH 2 C(═O)Ph; and
further provided that when R, R 3 and R 4 are each H, R 1 is oxo and n is 0, then R 2 is not phenyl, —CH 2 -Ph, —(CH 2 ) 3 -mopholin-4-yl or —(CH 2 ) 3 -(4-methylpiperazine).
2. The compound of claim 1 , wherein the compound is S4
3. The compound of claim 1 , wherein the compound is S5
4. The compound of claim 1 , wherein the compound is S7
5. The compound of claim 1 , wherein the compound is S9
6. The compound of claim 1 , wherein the compound is S11
7. The compound of claim 1 , wherein the compound is S12
8. The compound of claim 1 , wherein the compound is S13
9. The compound of claim 1 , wherein the compound is S14
10. The compound of claim 1 , wherein the compound is S20
11. The compound of claim 1 , wherein the compound is S37
12. The compound of claim 1 , wherein the compound is S38
13. The compound of claim 1 , wherein the compound is S46
14. The compound of claim 1 , wherein the compound is S49
15. The compound of claim 1 , wherein the compound is S50
16. The compound of claim 1 , wherein the compound is S51
17. The compound of claim 1 , wherein the compound is S52
18. The compound of claim 1 , wherein the compound is S53
19. The compound of claim 1 , wherein the compound is S54
20. The compound of claim 1 , wherein the compound is S58
21. The compound of claim 1 , wherein the compound is S67
22. The compound of claim 1 , wherein the compound is S73
23. The compound of claim 1 , wherein the compound is S74
24. The compound of claim 1 , wherein the compound is S84
25. The compound of claim 1 , wherein the compound is S85
26. The compound of claim 1 , wherein the compound is S86
27. The compound of claim 1 , wherein the compound is S88
28. The compound of claim 1 , wherein the compound is S89
29. The compound of claim 1 , wherein the compound is S90
30. The compound of claim 1 , wherein the compound is S91
31. The compound of claim 1 , wherein the compound is S92
32. The compound of claim 1 , wherein the compound is S93
33. The compound of claim 1 , wherein the compound is S95
34. The compound of claim 1 , wherein the compound is S96
35. The compound of claim 1 , wherein the compound is S97
36. The compound of claim 1 , wherein the compound is S98
37. The compound of claim 1 , wherein the compound is S99
38. The compound of claim 1 , wherein the compound is S100
39. The compound of claim 1 , wherein R 1 , R 3 and R 4 are each H, and the compound has the structure:
40. The compound of claim 39 , wherein the compound has the structure:
41. The compound of claim 39 , wherein the compound has the structure:
42. The compound of claim 39 , wherein the compound has the structure:
43. The compound of claim 39 , wherein R is independently selected from the group consisting of H, halogen, —OH, alkyl, alkoxyl, haloalkyl and haloalkoxyl.
44. The compound of claim 39 wherein R 2 is —C═O(R 5 ), and the compound has the structure:
45. The compound of claim 44 , wherein R 5 is alkenyl or aryl, wherein said alkenyl or aryl may be substituted with one or more radicals independently selected from the group consisting of halogen, CN, N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl.
46. The compound of claim 44 , wherein the compound has the structure:
47. The compound of claim 44 , wherein R 5 is —OR 15 , and the compound has the following structure:
48. The compound of claim 44 , wherein R 5 is CO 2 R 15 , and the compound has the following structure:
49. The compound of claim 48 wherein R 15 is H, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl.
50. The compound of claim 48 wherein n is 0.
51. The compound of claim 48 , wherein n is 1 or 2.
52. The compound of claim 48 , wherein the compound has the structure:
53. The compound of claim 52 wherein R is OR′ wherein R′ is alkyl.
54. The compound of claim 52 wherein R is H, OH or OCH 3 .
55. The compound of claim 44 , wherein R 5 is —NHR 16 , NHOH, OR 15 , —C(═O)NHR 16 , —CH 2 X, aryl or heterocyclyl, wherein each aryl or heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl.
56. The compound of claim 46 , wherein R 5 is NHR 16 , and the compound has the following structure:
57. The compound of claim 56 , wherein R 16 is H, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl and alkenyl.
58. The compound of claim 46 , which is a pharmaceutically acceptable salt of the compound
59. The compound of claim 58 , wherein the salt is a hydrochloride salt.
60. The compound of claim 44 , wherein R 5 is —C(═O)NHR 16 , and the compound has the following structure:
61. The compound of claim 60 , wherein R 16 is H, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl and alkenyl.
62. The compound of claim 60 , wherein the compound has the structure:
63. The compound of claim 39 , wherein R 2 is alkyl, which may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetetero-)cyclyl.
64. The compound of claim 63 , wherein the compound has the structure:
65. The compound of claim 64 , wherein R is other than hydrogen.
66. The compound of claim 65 , wherein R is methoxy.
67. The compound of claim 39 , wherein R 2 is SO 2 R 7 , and the compound has the following structure:
68. The compound of claim 67 wherein R 7 is alkyl, aryl, or NHR 16 , wherein each alkyl, and aryl may be substituted with one or more radicals independently selected from the group consisting of halogen, CN, N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl.
69. The compound of claim 39 , wherein R 2 is POR 8 R 9 , and the compound has the structure:
70. The compound of claim 39 , wherein R 2 is —C═S(R 6 ), and the compound has the structure:
71. The compound of claim 1 , wherein at least one of R, R 1 , R 2 , R 3 , and R 4 includes at least one radioactive label.
72. The compound of claim 1 , wherein R 1 , R 3 and R 4 are each H, R is H or CH 3 at position 9 of the benzothiazepine ring and n is 0, provided that R 2 is not methyl, benzotriazol-1-ylmethyl, ethyl, pentyl, alkyl which is substituted by an aryl or by an acyl, —C(═O)CH═CH 2 or C(═O)CH 2 Br.
73. The compound of claim 1 , wherein R, R 3 and R 4 are each H, R 1 is oxo and n is 0, provided that R 2 is not aryl or alkyl substituted by aryl or heterocyclyl.
74. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
75. The pharmaceutical composition of claim 74 , wherein the compound is selected from the group consisting of
76. The pharmaceutical composition of claim 74 , wherein the composition is presented in a form selected from the group consisting of capsules, granules, powders, solutions, suspensions, and tablets.
77. The pharmaceutical composition of claim 74 , wherein the composition is administered by a method selected from the group consisting of oral, sublingual, buccal, parenteral, intravenous, transdermal, inhalation, intranasal, vaginal, intramuscular, and rectal modes of administration.
78. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 to effectuate the treatment, wherein the disorder or disease is selected from the group consisting of cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome;
wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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;
wherein the skeletal muscular disorders and diseases are selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence; and
wherein the cognitive disorders and diseases are selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
79. The method of claim 78 , wherein the compound is selected from the group consisting of
80. The method of claim 78 , wherein the compound is administered to the subject to treat cardiac disorders and diseases selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure.
81. The method of claim 80 , wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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.
82. The method of claim 78 , wherein the compound is administered to the subject to treat skeletal muscular disorders and diseases selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence.
83. The method of claim 78 , wherein the compound is administered to the subject to treat cognitive disorders and diseases selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
84. The method of claim 78 , wherein the compound modulates calcium-ion channels in cells of the subject.
85. The method of claim 78 , wherein the subject is an in vitro or in vivo system.
86. The method of claim 78 , wherein the subject is a human.
87. A compound of formula:
wherein,
n is 0, 1, or 2;
R is located at one or more of positions 6, 7, 8 or 9 on the benzothiazepine ring;
each R is independently selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —N 3 , —SO 3 H, acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-)arylthio, and (hetero-)arylamino may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 1 is selected from the group consisting of H, oxo, alkyl, cycloalkyl, and heterocyclyl; wherein each alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 2 is selected from the group consisting of —C═O(R 5 ), —C═S(R 6 ), —SO 2 R 7 , —POR 8 R 9 , alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 3 is selected from the group consisting of H, CO 2 Y, C(═O)NHY, acyl, alkyl, cycloalkyl, and heterocyclyl; wherein each acyl, alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl; and wherein Y is selected from the group consisting of alkyl, aryl, cycloalkyl, and heterocyclyl;
R 4 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, and heterocyclyl; wherein each alkyl, alkenyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 5 is selected from the group consisting of —NHR 16 , NHNHR 16 , NHOH, —OR 15 , CONH 2 NHR 16 , CO 2 R 15 , CONHR 16 , CH 2 X, acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, wherein each acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 6 is selected from the group consisting of —OR 15 , NHNHR 16 , NHOH, —NHR 16 , CH 2 X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 7 is selected from the group consisting of —OR 15 , —NHR 16 , NHNHR 16 , NHOH, CH 2 X, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl wherein each alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 8 and R 9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
X is selected from the group consisting of halogen, CN, CO 2 R 15 , CONHR 16 , —NHR 16 , —OR 15 , —SO 2 R 7 , and —POR 8 R 9 ; and
R 15 and R 16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkenyl, alkoxyl, alkyl, alkylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and hydroxyl; and salts thereof;
provided that when R is Me, Cl, CN or F at the 6 position of the benzothiazepine ring, or Br at position 7 of the benzothiazepine ring, then R 2 is not Me, —C(═O)Ph, —S(═O) 2 Me, or —S(═O) 2 Et; and
further provided that when n is 0, and R is OH or C 1 -C 3 alkoxyl at the 7 position of the benzothiazepine ring, then R 2 is not —C(═O)CH═CH 2 , C(═O)CH 2 Br or (CH 2 ) 3 -4-benzylpiperidine;
further provided that when R is methoxy at positions 3 and 4 of the benzene ring, R 3 and R 4 are each H and n is 0 or 2, then R 1 is not methyl, —CH 2 Ph or 3,4-dimethoxybenzyl;
further provided that when R is CH 3 at position 9 of the benzothiazepine ring, R 1 , R 3 and R 4 are each H and n is 0, then R 2 is not methyl, ethyl, pentyl, —C(═O)CH═CH 2 , —C(═O)CH 7 Br—, CH 2 CH 2 C(═O)Ph, alkyl which is substituted by an aryl, or benzotriazol-1-ylmethyl.
88. A pharmaceutical composition comprising a compound according to claim 87 and a pharmaceutically acceptable carrier.
89. The pharmaceutical composition of claim 88 , wherein the composition is presented in a form selected from the group consisting of capsules, granules, powders, solutions, suspensions, and tablets.
90. The pharmaceutical composition of claim 88 , wherein the composition is administered by a method selected from the group consisting of oral, sublingual, buccal, parenteral, intravenous, transdermal, inhalation, intranasal, vaginal, intramuscular, and rectal modes of administration.
91. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 87 to effectuate the treatment, wherein the disorder or disease is selected from the group consisting of cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome;
wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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;
wherein the skeletal muscular disorders and diseases are selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence; and
wherein the cognitive disorders and diseases are selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
92. The method of claim 91 , wherein the compound is administered to the subject to treat cardiac disorders and diseases selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure.
93. The method of claim 92 , wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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.
94. The method of claim 91 , wherein the compound is administered to the subject to treat skeletal muscular disorders and diseases selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence.
95. The method of claim 91 , wherein the compound is administered to the subject to treat cognitive disorders and diseases selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
96. The method of claim 91 , wherein the subject is an in vitro or in vivo system.
97. The method of claim 91 , wherein the subject is a human.
98. A compound of formula:
wherein,
n is 0, 1, or 2;
R is located at one or more of positions 6, 7, 8 or 9 on the benzothiazepine ring;
each R is independently selected from the group consisting of H, halogen, —OH, —NH 2 , —NO 2 , —CN, —N 3 , —SO 3 H, acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino, wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 1 is selected from the group consisting of H, oxo, alkyl, cycloalkyl, and heterocyclyl; wherein each alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 2 is selected from the group consisting of —C═O(R 5 ), —C═S(R 6 ), —SO 2 R 7 , —POR 8 R 9 , methyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl; wherein each aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 3 is selected from the group consisting of H, CO 2 Y, C(═O)NHY, acyl, alkyl, cycloalkyl, and heterocyclyl; wherein each acyl, alkyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl; and wherein Y is selected from the group consisting of alkyl, aryl, cycloalkyl, and heterocyclyl;
R 4 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, and heterocyclyl; wherein each alkyl, alkenyl, cycloalkyl, and heterocyclyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , —SH, nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 5 is selected from the group consisting of NHNHR 16 , NHOH, —OR 15 , CONH 2 NHR 16 , CO 2 R 15 , CONHR 16 , CH 2 X, acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, wherein each acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 6 is selected from the group consisting of —OR 15 , NHNHR 16 , NHOH, —CH 2 X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
R 7 is selected from the group consisting of —OR 15 , —NHR 16 , NHNHR 16 , NHOH, CH 2 X, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl wherein each alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-) cyclyl;
R 8 and R 9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkyl, alkoxyl, alkylamino, alkenyl, aryl, (hetero-)cycloalkyl, and (hetero-)cyclyl;
X is selected from the group consisting of halogen, CN, CO 2 R 15 , CONHR 16 , —NHR 16 , —OR 15 , —SO 2 R 7 , and —POR 8 R 9 ; and
R 15 and R 16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein each acyl, alkenyl, alkoxyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with one or more radicals independently selected from the group consisting of halogen, —CN, —N 3 , nitro, oxo, acyl, alkenyl, alkoxyl, alkyl, alkylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and hydroxyl; and salts thereof;
provided that when each R is H and n is 0, then R 2 is not Me, —C(═O)CH═CH 2 , —S(═O) 2 Me, —S(═O) 2 Et, —C(═O)OC(CH 3 ) 3 , 9-β-D-ribofuranosyl-9H-purin-6-yl or —C(═O)Ph;
further provided that when each R is H and n is 1 or 2, then R 2 is not S(═O) 2 Me, —S(═O) 2 Et or C(═O)OC(CH 3 ) 3 ;
further provided that when R is Me, Cl, CN or F at the 6 position of the benzothiazepine ring, or Br at position 7 of the benzothiazepine ring, then R 2 is not Me, —C(═O)Ph, —S(═O) 2 Me, or —S(═O) 2 Et; and
further provided that when n is 0, and R is H, or OH or C 1 -C 3 alkoxyl at the 7 position of the benzothiazepine ring, then R 2 is not —C(═O)CH═CH 2 or C(═O)CH 2 Br;
further provided that when R is methoxy at positions 3 and 4 of the benzene ring, R 3 and R 4 are each H and n is 0 or 2, then R 1 is not methyl, —CH 2 Ph or 3,4-dimethoxybenzyl;
further provided that when R is H, R 2 is —C(═O)—C 6 H 4 —Cl or 2,2′,3, 3′-tetrahydro-4(5H)-1,4 benzothiazepine, R 3 and R 4 are either H or CH 3 but not both CH 3 , then R 1 is not oxo;
further provided that when R 1 , R 3 and R 4 are each H, and R is H or CH 3 at position 9 of the benzothiazepine ring and n is 0 and then R 2 is not methyl, —C(═O)CH═CH 2 or —C(═O)CH 2 Br; and
further provided that when R, R 1 and R 4 are each H, R 1 is oxo and n is 0, then R 2 is not phenyl.
99. The compound of claim 1 , wherein R, R 3 and R 4 are each H, R 1 is oxo and n is 0, provided that R 2 is not aryl.
100. A pharmaceutical composition comprising a compound according to claim 98 and a pharmaceutically acceptable carrier.
101. The pharmaceutical composition of claim 100 , wherein the composition is presented in a form selected from the group consisting of capsules, granules, powders, solutions, suspensions, and tablets.
102. The pharmaceutical composition of claim 100 , wherein the composition is administered by a method selected from the group consisting of oral, sublingual, buccal, parenteral, intravenous, transdermal, inhalation, intranasal, vaginal, intramuscular, and rectal modes of administration.
103. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 98 to effectuate the treatment, wherein the disorder or disease is selected from the group consisting of cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome;
wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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;
wherein the skeletal muscular disorders and diseases are selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence; and
wherein the cognitive disorders and diseases are selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
104. The method of claim 103 , wherein the compound is administered to the subject to treat cardiac disorders and diseases selected from the group consisting of irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure.
105. The method of claim 104 , wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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.
106. The method of claim 103 , wherein the compound is administered to the subject to treat skeletal muscular disorders and diseases selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence.
107. The method of claim 103 , wherein the compound is administered to the subject to treat cognitive disorders and diseases selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
108. The method of claim 103 , wherein the subject is an in vitro or in vivo system.
109. The method of claim 103 , wherein the subject is a human.
110. A compound selected from the group consisting of
and salts thereof.
111. A pharmaceutical composition comprising a compound according to claim 110 and a pharmaceutically acceptable carrier.
112. The pharmaceutical composition of claim 111 , wherein the composition is presented in a form selected from the group consisting of capsules, granules, powders, solutions, suspensions, and tablets.
113. The pharmaceutical composition of claim 111 , wherein the composition is administered by a method selected from the group consisting of oral, sublingual, buccal, parenteral, intravenous, transdermal, inhalation, intranasal, vaginal, intramuscular, and rectal modes of administration.
114. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 110 to effectuate the treatment, wherein the disorder or disease is selected from the group consisting of
cardiac disorders and diseases selected from the group consisting of
congestive heart failure, chronic obstructive pulmonary disease, high blood pressure, irregular heartbeat disorders and diseases, exercise-induced irregular heartbeat disorders and diseases, wherein the irregular heartbeat disorders and diseases and exercise-induced irregular heartbeat disorders and diseases are selected from the group consisting of 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 disorders and diseases selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence;
cognitive disorders and diseases selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss;
malignant hyperthermia;
diabetes; and
sudden infant death syndrome.
115. The method of claim 114 , wherein the subject is an in vitro or in vivo system.
116. The method of claim 114 , wherein the subject is a human.