NZ752732B2 - Oxysterols and methods of use thereof - Google Patents
Oxysterols and methods of use thereof Download PDFInfo
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- NZ752732B2 NZ752732B2 NZ752732A NZ75273217A NZ752732B2 NZ 752732 B2 NZ752732 B2 NZ 752732B2 NZ 752732 A NZ752732 A NZ 752732A NZ 75273217 A NZ75273217 A NZ 75273217A NZ 752732 B2 NZ752732 B2 NZ 752732B2
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- acceptable salt
- pharmaceutically acceptable
- halogen
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- 150000001875 compounds Chemical class 0.000 claims abstract 66
- 150000003839 salts Chemical class 0.000 claims abstract 54
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 7
- 229910052736 halogen Inorganic materials 0.000 claims 43
- 150000002367 halogens Chemical group 0.000 claims 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 33
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 32
- 208000035475 disorder Diseases 0.000 claims 31
- 125000001424 substituent group Chemical group 0.000 claims 31
- 229910052739 hydrogen Inorganic materials 0.000 claims 29
- 239000001257 hydrogen Substances 0.000 claims 25
- 210000003169 central nervous system Anatomy 0.000 claims 20
- -1 -OH Chemical group 0.000 claims 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims 14
- 125000003118 aryl group Chemical group 0.000 claims 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 11
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 125000000623 heterocyclic group Chemical group 0.000 claims 10
- 125000004452 carbocyclyl group Chemical group 0.000 claims 9
- 229910052799 carbon Inorganic materials 0.000 claims 9
- 125000004432 carbon atom Chemical group C* 0.000 claims 9
- 229930182558 Sterol Natural products 0.000 claims 8
- 150000002431 hydrogen Chemical group 0.000 claims 8
- 150000003432 sterols Chemical class 0.000 claims 8
- 235000003702 sterols Nutrition 0.000 claims 8
- 230000015572 biosynthetic process Effects 0.000 claims 7
- 238000003786 synthesis reaction Methods 0.000 claims 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 6
- 208000010877 cognitive disease Diseases 0.000 claims 6
- 201000000980 schizophrenia Diseases 0.000 claims 6
- 208000029560 autism spectrum disease Diseases 0.000 claims 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 5
- 208000030814 Eating disease Diseases 0.000 claims 4
- 208000019454 Feeding and Eating disease Diseases 0.000 claims 4
- 206010072219 Mevalonic aciduria Diseases 0.000 claims 4
- 235000014632 disordered eating Nutrition 0.000 claims 4
- 239000003814 drug Substances 0.000 claims 4
- 230000002496 gastric effect Effects 0.000 claims 4
- 125000004475 heteroaralkyl group Chemical group 0.000 claims 4
- 150000002500 ions Chemical class 0.000 claims 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 4
- 206010072221 mevalonate kinase deficiency Diseases 0.000 claims 4
- 201000006417 multiple sclerosis Diseases 0.000 claims 4
- 125000004043 oxo group Chemical group O=* 0.000 claims 4
- 208000019116 sleep disease Diseases 0.000 claims 4
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- 206010003805 Autism Diseases 0.000 claims 3
- 208000020706 Autistic disease Diseases 0.000 claims 3
- 208000016285 Movement disease Diseases 0.000 claims 3
- 201000007410 Smith-Lemli-Opitz syndrome Diseases 0.000 claims 3
- 102100036325 Sterol 26-hydroxylase, mitochondrial Human genes 0.000 claims 3
- 208000001088 cerebrotendinous xanthomatosis Diseases 0.000 claims 3
- 206010009887 colitis Diseases 0.000 claims 3
- 230000006735 deficit Effects 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims 2
- 208000008958 Anti-N-Methyl-D-Aspartate Receptor Encephalitis Diseases 0.000 claims 2
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- 206010064571 Gene mutation Diseases 0.000 claims 2
- 101000968916 Homo sapiens Methylsterol monooxygenase 1 Proteins 0.000 claims 2
- 208000023105 Huntington disease Diseases 0.000 claims 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims 2
- 102100021091 Methylsterol monooxygenase 1 Human genes 0.000 claims 2
- 208000026682 Microcephaly-congenital cataract-psoriasiform dermatitis syndrome Diseases 0.000 claims 2
- 208000019022 Mood disease Diseases 0.000 claims 2
- 208000032580 NMDA receptor encephalitis Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000029726 Neurodevelopmental disease Diseases 0.000 claims 2
- 201000011252 Phenylketonuria Diseases 0.000 claims 2
- 201000004681 Psoriasis Diseases 0.000 claims 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims 2
- 208000028017 Psychotic disease Diseases 0.000 claims 2
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- 208000012826 adjustment disease Diseases 0.000 claims 2
- 208000029188 anti-NMDA receptor encephalitis Diseases 0.000 claims 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 208000001335 desmosterolosis Diseases 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000018459 dissociative disease Diseases 0.000 claims 2
- 206010015037 epilepsy Diseases 0.000 claims 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims 2
- 230000010370 hearing loss Effects 0.000 claims 2
- 231100000888 hearing loss Toxicity 0.000 claims 2
- 208000016354 hearing loss disease Diseases 0.000 claims 2
- 208000013403 hyperactivity Diseases 0.000 claims 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims 2
- 208000030159 metabolic disease Diseases 0.000 claims 2
- 208000022821 personality disease Diseases 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 208000014081 polyp of colon Diseases 0.000 claims 2
- 208000021011 postpartum psychosis Diseases 0.000 claims 2
- 208000011117 substance-related disease Diseases 0.000 claims 2
- 208000011580 syndromic disease Diseases 0.000 claims 2
- 208000016686 tic disease Diseases 0.000 claims 2
- 231100000886 tinnitus Toxicity 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 208000014644 Brain disease Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000032274 Encephalopathy Diseases 0.000 claims 1
- 208000026680 Metabolic Brain disease Diseases 0.000 claims 1
- 206010062190 Metabolic encephalopathy Diseases 0.000 claims 1
- 208000014060 Niemann-Pick disease Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 206010063985 Phytosterolaemia Diseases 0.000 claims 1
- 208000002227 Sitosterolemia Diseases 0.000 claims 1
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 230000036506 anxiety Effects 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 1
- 230000009529 traumatic brain injury Effects 0.000 claims 1
- 230000000472 traumatic effect Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Abstract
Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R4, R5, and R6 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
Claims (58)
1. A compound of Formula (I-59): (I-59), or a pharmaceutically acceptable salt thereof, wherein: R2 is hydrogen, C1-C6 alkyl, carbocyclyl, or heterocyclyl, wherein said C1-C6 alkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of n, cyano, -OH, and C1-C6 alkoxy, and each of said yclyl and heterocyclyl is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; R3 is hydrogen; or R2 and R3, together with the carbon atom to which they are attached, form a 3-8 membered ring optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; each of R4 and R5 is independently hydrogen, n, or –ORC, wherein RC is en or C1-C6 alkyl optionally substituted with 1-5 substituents ndently ed from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy; or R4 and R5, together with the carbon atom to which they are attached, form an oxo group; R6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; when both of are single bonds, then R6 is hydrogen; and when one of is a double bond, R6 is absent.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen or C1-C6 alkyl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
3. The nd of claim 1, or a pharmaceutically able salt f, wherein R2 is C1-C6 alkyl substituted with 1-5 halogen.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is independently substituted C1-C6 alkyl or hydrogen or C1-C6 alkyl substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is unsubstituted C1-C6 alkyl or hydrogen.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen or C1-C6 alkyl substituted with 1-5 halogen.
7. The compound of claim 1, or a pharmaceutically able salt thereof, wherein R2 is hydrogen, carbocyclyl, or heterocyclyl, wherein each of said carbocyclyl and heterocyclyl is independently optionally substituted with 1-5 substituents independently selected from the group ting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
8. The nd of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is independently en or C2-C6 alkyl optionally substituted with 1-5 tuents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is isopropyl, tert-butyl, or hydrogen, wherein each of said isopropyl and tert-butyl is independently substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is C3-C6 alkyl, carbocyclyl, or heterocyclyl, wherein said C3-C6 alkyl is optionally substituted with 1-5 substituents independently selected from the group ting of halogen, cyano, -OH, and C1-C6 alkoxy, and each of said carbocyclyl and heterocyclyl is independently ally substituted with 1-5 substituents independently selected from the group ting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
11. The compound of claim 1, or a pharmaceutically able salt thereof, wherein R2 and R3, together with the carbon atom to which they are attached, form a 3-8 membered ring optionally tuted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
12. The compound of claim 1, or a pharmaceutically able salt thereof, n R2 is isopropyl or tert-butyl, wherein each of said pyl and tert-butyl is independently ally substituted with 1-5 tuents independently ed from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is tert-butyl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
14. The compound of claim 1, or a ceutically acceptable salt thereof, n R2 is methyl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is – OH or halogen.
16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the carbon atom to which they are attached, form an oxo group.
17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen and R5 is halogen.
18. The compound of claim 1, or a pharmaceutically able salt thereof, wherein R4 and R5 are halogen.
19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are hydrogen.
20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 and R3, together with the carbon atom to which they are attached, form a 5-membered ring optionally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 and R3, together with the carbon atom to which they are attached, form a 6-membered ring optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is carbocyclyl or cyclyl, wherein each of said carbocyclyl and heterocyclyl is independently optionally tuted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
23. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein R2 is
24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is isopropyl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
25. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein R2 and R3, er with the carbon atom to which they are attached, form a 3-8 membered carbocyclic or heterocyclic ring ally substituted with 1-2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl.
26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is cyclobutyl optionally substituted with 1-5 tuents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
27. The compound of claim 1, or a ceutically acceptable salt thereof, wherein R2 is tetrahydropyranyl optionally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I-59) is selected from: (a) a compound of Formula (I-A59), (I-B59), or (I-C59): (I-A59), (I-B59), or (I-C59); (b) a nd of Formula (I-B59): (I-B59); (c) a compound of Formula (I-C59): (I-C59); (d) a compound of Formula (I-D59): (I-D59); (e) a nd of Formula (I-E59): (I-E59); (f) a compound of Formula (I-D-i59) or (I-D-ii59): (I-D-i59) or (I-D-ii59); (g) a compound of Formula (I-E-i59) or (I-E-ii59): (I-E-i59) or (I-E- ii59).
29. The nd of claim 1, wherein the compound is: , , , , , , H H HO H , , , , , , , , , , , , H H , HO H , , , H H , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or
30. The compound of claim 1, n the compound is: , , , , , , , , , , , , , , , or .
31. The compound of claim 1, n the compound is a pharmaceutically acceptable salt , , , , , , H H HO H , , , , , , , , , , , , H H , HO H , , , H H , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or
32. The compound of claim 1, n the compound is a pharmaceutically acceptable salt , , , , , , , , , , , , , , , or .
33. A compound of Formula (I-66): (I-66), or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-C6 alkyl optionally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy; R2 is aralkyl, aralkyl, aryl, or heteroaryl, wherein each of said aralkyl, heteroaralkyl, aryl, and heteroaryl is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; R3 is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or aryl, wherein said C1-C6 alkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 , and each of said carbocyclyl, heterocyclyl, aryl, and heteroaryl is ndently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; each of R4 and R5 is independently hydrogen, n, or –ORC, wherein RC is hydrogen or C1-C3 alkyl optionally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy; or R4 and R5, together with the carbon atom to which they are attached, form an oxo group; R6 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; when both of are single bonds, then R6 is hydrogen; and when one of is a double bond, R6 is absent.
34. The nd of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted C1-C6 alkyl.
36. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is aryl, heteroaryl, or aralkyl, wherein each of said aryl, heteroaryl, and aralkyl is independently ally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
37. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl, pyridyl, or benzyl, wherein each of said phenyl, l, and benzyl is independently optionally substituted with 1-5 substituents independently ed from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy.
38. The nd of claim 33, or a pharmaceutically acceptable salt f, wherein R3 is hydrogen or C1-C6 alkyl optionally substituted with 1-5 substituents ndently selected from the group consisting of halogen, cyano, -OH, and C1-C6 alkoxy.
39. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, tituted C1-C6 alkyl, or C1-C6 alkyl substituted with 1-5 halogen.
40. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R4 is –OH or halogen.
41. The nd of claim 33, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the carbon atom to which they are attached, form an oxo group.
42. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen and R5 is halogen.
43. The nd of claim 33, or a ceutically acceptable salt thereof, wherein R4 and R5 are halogen.
44. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are hydrogen.
45. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein each of said aryl, aryl, aralkyl, and heteroaralkyl is independently optionally substituted with 1-5 substituents independently selected from the group ting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; and R3 is hydrogen, unsubstituted C1-C6 alkyl, or C1-C6 alkyl substituted with 1-5 halogen.
46. The nd of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is aryl, heteroaryl, aralkyl, or aralkyl, wherein each of said aryl, heteroaryl, aralkyl, and heteroaralkyl is ndently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; and R3 is hydrogen, –CH3, or –CF3.
47. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted C1-C6 alkyl; R2 is aryl, heteroaryl, aralkyl, or aralkyl, wherein each of said aryl, heteroaryl, aralkyl, and aralkyl is independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-C6 alkyl, and C1-C6 alkoxy; and R3 is hydrogen, –CH3, or –CF3.
48. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I-66) is selected from: (a) a compound of Formula (I-A66), (I-B66), or (I-C66): (I-A66), (I-B66), or (I-C66); or (b) a compound of Formula (I-A66):
49. The compound of claim 33, wherein the compound is: , , , , , , , , , , , OH OH H N H N H H H H HO HO , , , , , , , , , , , , , , , , , , , , , , , , , or .
50. The compound of claim 33, n the compound is: , , , , , , , or .
51. The compound of claim 33, wherein the nd is a pharmaceutically acceptable salt , , , , , , , , , , , OH OH H N H N H H H H HO HO , , , , , , , , , , , , , , , , , , , , , , , , , or .
52. The compound of claim 33, wherein the nd is a pharmaceutically acceptable salt , , , , , , , or .
53. A pharmaceutical composition comprising a compound of any one of claims 1-30 and 33-50, and a pharmaceutically acceptable r.
54. A pharmaceutical composition comprising a pharmaceutically acceptable salt of any one of claims 1-28, 31-48, and 51-52, and a pharmaceutically acceptable carrier.
55. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-52, or a pharmaceutical composition of claim 53-54, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein: (a) the disorder is a gastrointestinal (GI) er, a structural disorder affecting the GI tract, an anal disorder, colon polyps, cancer, or colitis; (b) the disorder is inflammatory bowel disease; (c) the disorder is cancer, es, or a sterol synthesis disorder; (d) the disorder is a metabolic disorder; (e) the disorder is an autoimmune disorder; (f) the disorder is rheumatoid tis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, tive colitis, or plaque psoriasis; or (g) the disorder is Smith-Lemli-Opitz Syndrome (SLOS), desmosterolosis, erolemia, cerebrotendinous matosis (CTX), Mevalonate Kinase Deficiency (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick e, an autism spectrum disorder, or a disorder associated with phenylketonuria.
56. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-52, or a pharmaceutical composition of claim 53-54, in the manufacture of a medicament for preventing a disorder in a subject in need thereof, wherein: (a) the disorder is a gastrointestinal (GI) disorder, a structural disorder affecting the GI tract, an anal disorder, colon polyps, , or colitis; (b) the disorder is inflammatory bowel disease; (c) the disorder is cancer, diabetes, or a sterol synthesis disorder; (d) the disorder is a metabolic disorder; (e) the disorder is an autoimmune disorder; (f) the disorder is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, or plaque psoriasis; or (g) the er is Smith-Lemli-Opitz Syndrome , desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, an autism spectrum disorder, or a disorder associated with phenylketonuria.
57. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-52, or a pharmaceutical composition of claim 53 or 54, in the cture of a medicament for treating a lated condition in a subject in need thereof, wherein: (a) the CNS-related condition is an adjustment disorder, an anxiety disorder, a cognitive disorder, a dissociative disorder, an eating disorder, a mood disorder, schizophrenia or r psychotic disorder, a sleep disorder, a substance-related disorder, a personality disorder, an autism um disorder, a neurodevelopmental disorder, multiple sclerosis, a sterol synthesis disorder, pain, an alopathy secondary to a medical condition, a seizure disorder, stroke, traumatic brain , a movement disorder, vision impairment, hearing loss, or tinnitus; (b) the CNS-related condition is a sterol synthesis disorder; (c) the CNS-related condition is schizophrenia or another tic disorder, a sleep disorder, an autism um disorder, multiple sclerosis, a movement disorder, attention deficit disorder, attention t hyperactivity disorder, a metabolic alopathy, post-partum psychosis, or a syndrome associated with high titers of anti-NMDA receptor antibodies; (d) the CNS-related condition is a cognitive disorder, a sterol synthesis er, or an eating disorder; (e) the CNS-related ion is schizophrenia; (f) the CNS-related condition is an autism um disorder; (g) the CNS-related condition is Huntington’s disease or Parkinson’s disease; (h) the CNS-related condition is a cognitive disorder; (i) the CNS-related condition is Alzheimer’s disease; or (j) the CNS-related condition is anti-NMDA receptor encephalitis.
58. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-52, or a pharmaceutical composition of claim 53 or 54, in the manufacture of a medicament for preventing a CNS-related ion in a subject in need thereof, n: (a) the CNS-related ion is an adjustment disorder, an anxiety er, a cognitive disorder, a dissociative disorder, an eating disorder, a mood disorder, schizophrenia or another psychotic disorder, a sleep disorder, a substance-related disorder, a personality disorder, an autism spectrum disorder, a neurodevelopmental disorder, multiple sclerosis, a sterol sis disorder, pain, an encephalopathy secondary to a medical condition, a seizure disorder, stroke, traumatic brain injury, a nt disorder, vision impairment, hearing loss, or tinnitus; (b) the lated condition is a sterol synthesis disorder; (c) the CNS-related condition is schizophrenia or another tic disorder, a sleep disorder, an autism spectrum disorder, multiple sclerosis, a movement disorder, attention deficit disorder, ion deficit hyperactivity disorder, a metabolic encephalopathy, post-partum psychosis, or a syndrome associated with high titers of anti-NMDA receptor antibodies; (d) the CNS-related condition is a cognitive disorder, a sterol synthesis disorder, or an eating disorder; (e) the CNS-related condition is schizophrenia; (f) the CNS-related condition is an autism spectrum disorder; (g) the CNS-related condition is Huntington’s disease or son’s disease; (h) the CNS-related condition is a cognitive disorder; (i) the CNS-related condition is mer’s disease; or (j) the CNS-related condition is anti-NMDA receptor encephalitis.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662409772P | 2016-10-18 | 2016-10-18 | |
| US201662409761P | 2016-10-18 | 2016-10-18 | |
| US201662409767P | 2016-10-18 | 2016-10-18 | |
| US201662409764P | 2016-10-18 | 2016-10-18 | |
| US201662409774P | 2016-10-18 | 2016-10-18 | |
| PCT/US2017/057277 WO2018075699A1 (en) | 2016-10-18 | 2017-10-18 | Oxysterols and methods of use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ752732A NZ752732A (en) | 2024-08-30 |
| NZ752732B2 true NZ752732B2 (en) | 2024-12-03 |
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